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and
McDonald (1964), and Stewart, Keay, and Smith
(1968/69) all used more detail in recording limb ano-
malies but their population samples (4412, 5964,
and 2500, respectively) were too small to give a re-
liable population frequency.
Birch-Jensen (1949), by searching through all the
Danish hospital records, found 625 patients with
'absence' deformities of the upper extremities who
Received 7 December 1973.
were living in Denmark and had been born before
1 January 1947.
He defined 'absence' deformities
as 'those due to absence or atrophy of larger or
smaller portions of the skeleton of the extremity'.
After classification, he related them to the popula-
tion of Denmark published in the Danish Year
Book of Statistics (1946) thus establishing the fre-
quency of the separate deformities.
However, this
cannot have given the true incidence at birth since it
excluded both
perinatal and
later
deaths.
His
study did not include any other congenital de-
formities of the limbs.
None of these surveys had
follow-up studies to establish whether other de-
fects became evident with growth.
Genetic factors have been described for several of
the
structural limb anomalies,
particularly
syn-
dactyly, polydactyly, and brachydactyly (Temtamy
and McKusick,
1969; Woolf and Woolf,
1970;
David, 1972), and there have been innumerable re-
ports of individual families with limb anomalies.
However, most congenital limb
defects
seen in
clinical practice are sporadic, whether occurring in
221
li.


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Journal of Medical Genetics (1975).
12, 44.
Giemsa banding of chromosome qh+ and linkage
analysis
PATRICIA N. HOWARD,* GAYLE R. STODDARD,* MICHAEL W. GODDARD,
and J. RODMAN SEELY
From the Department of Pediatrics and Clinical Research Center, Oklahoma Children's Memorial Hospital, University
of Oklahoma Health Sciences Center, PO Box 26901, Oklahoma City, Oklahoma 73190, USA
Summary.
A four-generation transmission of a lqh+ chromosome was ascer-
tained by routine chromosome analysis of a mildly dysmorphic and retarded 6j-
year-old female.
Concordance between synophrys and the lqh+ marker was the
only consistent phenotypic relationship.
The variant chromosome did not appear
uncoiled, and Giemsa centromeric staining (C-bands) revealed an increased width
of the heterochromatin commensurate with the increased length of the long arm.
Giemsa banding ofthe entire chromosome (G-bands) revealed two heterochromatin
bands, identical in appearance, in the centromeric region with the remainder of the
chromosome showing normal banding.
The distribution of Duffy blood groups
in the pedigree was consistent with the locus being on chromosome No. 1.
Variant No. 1 chromosomes with an increase in
the length of the long arm are reported fairly fre-
quently.
Data from the New Haven newborn sur-
vey (Lubs and Ruddle, 1971) show this variant to
occur in about one of every 400 Caucasian births.
This type ofvariant has been reported in both abnor-
mal and normal individuals (Cooper and Hernits,
1963; Yunis and Gorlin, 1963; Donahue et al, 1968;
Ying and Ives, 1968).
Further characterization of these chromosomes is
now possible by means ofthe fluorescent and Giemsa
banding techniques (reviewed by Pearson, 1972).
Lobitz, McCaw, and Hecht (1972) have reported a
three-generation pedigree segregating for a
1q +
variant showing an increased number of bands in
the centromeric region of the long arm.
Holzer,
Rosenkranz, and Glatzl (1972) have described a
family with a segregating lqh + chromosome and


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noted that four individuals have the variant in a
homozygous state.
Osztovics et al (1973) and Kim
(1973) also reported lqh + chromosomes.
We have investigated a four-generation pedigree
segregating for a similar variant chromosome No. 1.
We have shown this chromosome to have an in-
Received 4 June 1974.
* Present address: Institute of Genetics, University of Southern
Mississippi, Hattiesburg, Mississippi, USA.
44
creased length due to an increase in the hetero-
chromatic region and have studied the linkage ofthis
marker with three traits.
Methods and materials
Slides were made from cultures of human lympho-
cytes and centromeric banding (C-bands) and individual
banding pattems (G-bands) were produced as previ-
ously described (Howard, Stoddard, and Seely, 1973).
Determination of the Duffy and Rhesus blood group
phenotypes was done by standard techniques.
Case report
The proposita, a part American Indian female, was
referred at 6+ years of age because of poor school per-
formance and dysmorphic features. Phenotype included
a prominent synophrys, mild hypertelorism, epicanthal
folds, uptumed nose with a wide philtrum, a high nar-
row palate, and a small, downtumed mouth.
Other
features included generalized hypertrichosis, brachy-
dactyly with broad great toes, clinodactyly of the little
fingers, and abnormal dermatoglyphics.
Radiographic
evaluation revealed anomalies of the lumbar spine and
malrotation of the right kidney.
Psychometrics showed
a dull normal intellectual function.
The phenotype of the proposita's father was normal;
her mother had significant dysmorphic features which


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Journal of Medical Genetics (1975).
12, 83.
Haemoglobin Lepore Boston and elliptocytosis in a
family of Indonesian-German ancestry
L. N. WENT, W. W. de JONG,* and S. E. BOS
Departmenzt of Human Genetics, Faculty of Medicine and Elisabeth Hospital, Leiden, The Netherlands
Summary.
A family is presented in which Hb Lepore Boston was found in six
individuals over three generations.
The gene must have had its origin either in Java
(Indonesia) or in what is now the Federal Republic ofGermany.
The haemoglobin
was characterized by amino-acid analysis of the six tryptic peptides that have a dif-
ferent composition in the
/- and the 3-chain.
The ratio of glycine to alanine in
position 136 ofthe fetal haemoglobin, which was somewhat raised in the Hb Lepore
carriers, averaged 31:69.
In addition an elliptocytosis gene was found, which was inherited independently
from Hb Lepore; the simultaneous presence of elliptocytosis in three family mem-
bers did not seem to aggravate the mild anaemia caused by Hb Lepore.
The Lepore haemoglobins are interesting from a
molecular-, clinical-, and population-genetical point
of view.
Structurally they are characterized by the
presence of globin chains which are fusion products
of 8- and ,8-chains.
These 83/-chains seem to be the
result of unequal crossing-over between the closely
linked
3- and /3-genes
(Baglioni,
1962).
Three
different types of Hb Lepore are known, which
differ in the position of the crossing-over.
The
regions of 3/3 fusion in Hb Lepore Hollandia, Hb
Lepore
Baltimore, and Hb Lepore Boston
are
located between residues 22 and 50, 50 and 86, and
87 and 116, respectively.
Hb Lepore Hollandia is
rather common among the Papuans of New Guinea
(Barnabas and Muller, 1962).
Hb Lepore Balti-
more has
been
characterized
once
in
a North
American negro (Ostertag and Smith, 1969).
Hb
Lepore Boston is rather wide spread in middle- and
eastern-Mediterranean populations (Fessas, Stama-
toyannoupoulos,
and
Karaklis,
1962;
Quattrin,
1967; Duma et al, 1968) and is also present in


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Jamaican negroes (Ahern et al, 1972). Definite bio-
chemical characterization of the 3/-chain of Hb
Lepore Boston has only been performed in some
individuals of Italian ancestry (Baglioni, 1965; Labie,
Schroeder,
and
Huisman,
1966;
Baglioni
and
Ventruto, 1968), in three Jamaican negro families
(de
Jong,
1969;
Ahern
et
al,
1972),
in two
Macedonians (L. F. Bernini, personal communi-
cation), and in a case from Greece (Baglioni and
Ventruto, 1968).
We now report the finding and
characterization of Hb Lepore Boston in a Dutch
family of Indonesian and German ancestry.
This
family possessed in addition a gene for hereditary
elliptocytosis, which provided the opportunity to
study
the
interaction between Hb Lepore and
elliptocytosis.
Methods
Haematological data were obtained using standard
methods.
Starch gel electrophoresis of haemolysates
was carried out in Tris-EDTA-borate buffer, pH 8-9
(Smithies,
1965).
Fetal haemoglobin was
estimated
using the alkali-denaturation procedure of Singer, Cher-
noff, and Singer (1951).
Quantitation of Hb Lepore and
Hb A2 was done on DEAE-cellulose columns according
to the method of Bernini (1969).
The methods for the
structural characterization of Hb Lepore were the same
as described previously (de Jong, Bemini, and Khan,
1971) and comprised the isolation of pure Hb Lepore,
conversion to globin, separation of a- and Spl-chains,
aminoethylation and tryptic digestion, peptide mapping,
and amino-acid analyses of tryptic peptides.
The proportions of the two types of y-chains, Ay and
Gy were determined in the fetal haemoglobin present in
83
Received 9 April 1974.
* Present
address:
Department
of Biochemistry,
Faculty
of
Science, Nijmegen, The Netherlands.


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Thorax (1963), 18, 29!
Neuropathological findings in patients
dying after open-heart surgery
J.
B. BRIERLEY
From
the Departmetnt of Neuropathology, Institute of Psychiatry, London
Although cerebral damage has been regarded as
the cause of death in some patients dying after
open operations on the heart, this conclusion rests
almost entirely on clinical evidence such as an
impaired level of consciousness after the opera-
tion, abnormalities of muscle tone and reflexes,
visual and extrapyramidal disorders or epilepsy.
Accounts of cerebral pathology in fatal cases
are limited to that of Bjork and Hultquist (1960)
and a group of papers describing the cerebral
emboli due to the anti-foam agent employed in the
oxygenator
(Yates,
Cassie,
Dark,
Jack,
and
Riddell,
1959;
Smith,
1960;
Lindberg,
Lucas,
Sheagren, and Malm, 1961 ; Thomassen, Howbert,
Winn, and Thompson, 1961).
In the 11 patients reported by Bjork and Hult-
quist, death was attributed to cerebral damage in
eight, all children. As yet there appears to have
been no detailed pathological study of the brains
of adults dying from presumed cerebral damage.
Here we present the neuropathological findings
in the first 11 of a series of patients who died from
six and a half hours to 11 days after open cardiac
surgery. The brains, received from six cardiac sur-
gery units, were from patients 10 to 51 years of
age, and all but one were subjected to some degree
of hypothermia.
The cases are divided into two groups: Group I,
two cases in which cardio-pulmonary bypass was
not employed and in which there was deliberate
circulatory arrest under mild hypothermia; and
Group II, nine cases in which cardio-pulmonary
bypass was effected by a pump oxygenator. Mild
to moderate hypothermia was employed in eight,
being produced by a heat exchanger in seven and
by surface cooling in one. There was no deliberate
arrest of the circulation by interruption
of the
perfusion.
MATERIAL AND METHODS
Unless previously dissected, the brains were cut into


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coronal slices after removal of the brain stem and
cerebellum.
Blocks were taken from
the temporal
lobes (to include basal ganglia), frontal and occipital
lobes, midbrain, pons, medulla, and cerebellum and
embedded in nitrocellulose. Sections were stained with
haematoxylin
and
eosin,
haematoxvlin
and
Van
Gieson's
counterstain,
the method
of
Nissl
(using
cresyl
violet),
with
Mallory's phosphotungstic
acid
haematoxylin,
with Heidenhain's haematoxylin. and
by the periodic acid Schiff technique.
Frozen sections were stained with Oil Red 0.
SUMMARIES OF CASES IN GROUP
I
THE principal cerebral structures referred to in the
text are indicated in Diagrams
1 and 2.
CASE
1 (MaudsleY No. 1339)
A boy aged 16 years
had
congenital
pulmonary
stenosis
without
septal
defect.
Operation
Cooling
was
obtained
by
the
veno-
venous technique of Ross (1954) from 36° to 31'C. in
27 minutes. The heart was arrested for 4 min. 20 sec.
and the valve was incised. Rewarming to 33.2°C. took
12 minutes. The heart re-started
satisfactorily and
the blood pressure was normal.
Post-operative course
There were signs of extreme
cerebral irritation on leaving the theatre, and so intra-
venous
urea and
sucrose were
given,
but without
effect. Athetoid movements were noted and five left-
sided fits occurred within an hour. Tracheostomy and
assisted
respiration
became
necessary
and
surface
cooling to 32°C. was carried out. On the first post-
operative day the patient was unconscious. A right
frontal burr hole excluded a subdural haematoma.
On the third post-operative day an anuric regime was
begun
and
was
successful.
On
the
seventh
post-
operative day athetoid movements of the right arm
and leg were noted and there was gradual deteriora-
tion to death on the tenth post-operative day.
Necropsy
Some antemortem thrombus was
seen
in the inferior vena cava and portal vein; there was
also altered blood in the small and large intestines.
Macroscopic
examination
of
the
brain
showed
slight convolutional flattening and considerable con-


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gestion both most marked over the occipital lobes. A
thin
film of subarachnoid blood covered the right
occipital lobe. There were no internal herniae and the
basal vessels were normal.
The right hemisphere was slightly expanded and its
ventricles small. A recent haemorrhage (1-0 cm. dia-
meter) was noted
in the white
matter of the
left
291


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Thorax (1964), 19, 515.
Familial interstitial pulmonary fibrosis
E.
W. HUGHES
From Tehidy Hospital, Camborne, Cornwall
In
1944 Hamman
and
Rich
first
described
a
disease that caused an acute diffuse
interstitial
fibrosis of the lungs, and which resulted in the
death of four patients within six months of the
onset of symptoms. Since then countless further
cases have been reported in the literature, and our
knowledge of the subject has advanced.
It is recognized that the interstitial fibrotic pro-
cess may be localized as well as diffuse; that more
often than not the disease follows a more pro-
tracted course than it did in the cases first de-
scribed; that natural remissions may sometimes
occur; and that corticosteroid therapy is some-
times effective in 'suppressing' the disease process
and delaying its progress.
Little,
however,
has
been
learned
about
its
causation. It is known that interstitial pulmonary
fibrosis, may be the consequence of a variety of
pulmonary diseases, such as sarcoidosis or chronic
pulmonary tuberculosis, or that it may occur as
a manifestation of various systemic diseases such
as scleroderma. But in the vast majority the aetio-
logy remains obscure, and we are
left with a
heterogeneous group of cases which many authors
are wont to class together under the general head-
ing of Hamman-Rich syndrome.
This may be
inadvisable when
it is
still not known whether
the acute, subacute, and chronic types represent
varying
reactions
to
one,
or more
than
one,
aetiological agent, and on this account Scadding
(1960)
recommends the use of descriptive terms.
One of the most remarkable features at the pre-
sent time is the absence in the English literature
of any examples of the familial type of the disease
which has been recorded by several authors in
America and on the Continent. Here
I record
three such cases of diffuse interstitial pulmonary
fibrosis from one family who have been under
my care for the past three years and who also
manifest the acute, subacute, and chronic forms
of the disease.


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CASE REPORTS
CASE 1
J. S., a woman aged 30.
Single. Occupation:
housekeeper.
This young lady had a normal chest radiograph in
January 1959 and was in good health until January
1961, when breathlessness on exertion was first experi-
enced. It became progressively more severe, and when
admitted
to another hospital
at
the end
of May
she was acutely ill and had a slight productive cough.
On
examination
there
was
central
cyanosis,
and
crepitations were audible at the bases of both lungs.
Clubbing
was
not
present.
The
temperature
was
raised, reaching on occasions 105° F., and there was a
sinus tachycardia of 140/minute. Hb 68%
W.B.C.
9,000
per
c.mm.;
polymorphs
460
;
lymphocytes
38%; monocytes 16%; E.S.R. 131 mm. in one hour.
The
chest
radiograph
showed
generalized
fine
mottling throughout both lungs and dilatation of the
pulmonary
artery. The
fever was
uninfluenced
by
broad-spectrum
chemotherapy, but
settled by
lysis
when the antibiotics were withdrawn during the third
week. In the meantime the breathlessness had become
so severe that speech was barely possible, and, in
the middle of June, she was transferred to Tehidy
Hospital for further investigation.
The chest signs were as before except for an in-
crease in the rate of respiration from 20 to 40 excur-
sions per minute.
The heart sounds were normal
and there was no evidence of heart failure. The blood
pressure was
120/70 mm. Hg; Hb 54% ;
R.B.C.
2,550,000 per c.mm.; W.B.C. 5,200 per c.mm.; poly-
morphs 62%; lymphocytes
31 %;
monocytes
1 %;
myelocytes 2%; metamylocytes 4%; E.S.R. 77 mm.
in one hour; blood group A Rhesus negative-, serum
albumin 4 g./100 ml.; serum globulin 2-8 g./100 ml.;
alpha
1
globulin 0 3 g./100 ml.; alpha 2 globulin
0 5
g./100 ml.; beta globulin 0 3 g./100 ml.; gamma
globulin
1-3 g./100 ml.; R.A. (latex) test negative;
L.E. (latex) test negative; Mantoux 1/100 O.T. nega-
tive.
The
chest
radiograph
showed
extension
of
mottling with areas of confluence in the left middle
and right lower zones (Fig.
1). All other measures
having
failed,


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failed,
adrenocorticotrophic
hormone
(A.C.T.H.) was given on an empirical basis, and from
that time her condition slowly but steadily improved.
Within four days the pulse rate fell from 120 to 90
per minute, the dyspnoea became noticeably less, and
the chest radiograph showed considerable clearing of
the scattered mottling. A week later dyspnoea was
only mild, the weight had increased by 6 lb., crepita-
tions were no longer audible, and radiologically the
picture was one of continuing resolution. One month
after admission
she
was
well enough
for
a lung
515


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Thorax (1964), 19, 530
Tracheal atresia associated with
cor biloculare
A. W. McCRACKEN, NEIL FLANAGAN, AND
PAUL FLANAGAN
From the Royal Air Force Institute of Pathology and Tropical Medicine, Halton, Bucks
Atresia of the trachea is an extreme rarity (Willis,
1962), and cor biloculare
is a very uncommon
cardiac anomaly. These two abnormalities were
found together in the case described, a combina-
tion which, we believe, has not been previously
reported.
CASE REPORT
The infant was the second child of healthy parents.
There was no history of congenital abnormalities in
the family. The mother's pregnancy had been normal
up to the thirty-second week, when uterine enlarge-
ment was found to be equivalent to that of a 36-week
pregnancy. Radiographic examination showed a single
foetus. A
diagnosis
of moderate
hydramnios
was
made. The mother's blood group was B Rhesus posi-
tive. She did not contract any infectious disease or
take any drugs during her pregnancy.
Labour began spontaneously at 39 weeks. There
was a precipitate vertex delivery of a female infant
weighing 6 lb. 9 oz. On delivery the infant gave a
few gasps and showed obvious respiratory difficulty.
Tracheal intubation was unsuccessful. Tracheostomy
was attempted but was abandoned when no trachea
was found. Thirty minutes after delivery no heart
beat could be detected.
NECROPSY
There was marked cyanosis and complete
tracheal atresia from immediately below the cricoid
cartilage. A thin fibrous tissue condensation imme-
diately
anterior
to
the
oesophagus
suggested
the
usual
course of the
trachea. The two main
stem
bronchi were normal and joined each other smoothly
in the mid-line, 3 cm. below the larynx (Fig.
1). A
direct fistula, 1 mm. in diameter, from the oesophagus
entered the bronchi at this point. The oesophagus was
otherwise normal.
The route of the circulation
is shown in Fig.
2.
The heart was
sited normally in the mediastinum.
Blood entered the atrium from four sources-the pul-
monary veins, the superior and inferior venae cavae,


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and the coronary sinus, which also drained a patent
vein of Marshall. Blood passed through a single atrio-
ventricular valve
into
an enlarged
single
ventricle
with a wall 2 mm. thick. There was a normal pul-
monary valve and proximal pulmonary artery. Dis-
tally,
the
pulmonary
artery
divided
into
three
branches; the right and left pulmonary arteries, and
FIG. 1.
Diagram of the tracheal atresia. L, larynx; Tr,
tracheal remnant;
F,
tracheo-oesophageal fistula;
Br,
bronchi; 0, oesophagus; S, stomach.
cm.
FIG. 2.
Diagram of the heart showing the abnormal route
of the circulation. SVC, IVC, superior and inferior venae
cavae; VM, vein of Marshall; PV, pulmonary veins; At,
single atrium; V, single ventricle; PA, pulmonary artery;
R, rudimentary chamber; DA, ductus arteriosus; Ao,
aorta; LPA, left pulmonary artery; DAo, &scending aorta.
530


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Thorax (1965), 20, 528.
Oesophageal obstruction following
hyperemesis gravidarum
R. ABBEY SMITH AND C.
S. NELSON
From the Thoracic Surgical Unit, King Edward VII Chest Hospital, Hertford Hill, near Warwick
Although
since
1921
(Vinson,
1921)
severe
obstruction of the oesophagus has been known
to follow vomiting in pregnancy, little is known
about the subject, and the significance of a history
of vomiting
in pregnancy
is not always
recog-
nized. We record five patients with severe oeso-
phageal
obstruction
thought
to
be
caused
by
hyperemesis gravidarum. The poor outlook for
spontaneous and complete cure of the oesophageal
obstruction is apparent.
It
is
generally
believed
that
post-pregnancy
oesophageal obstruction is associated with a hiatus
hernia and is due to oesophagitis from vomiting
or reflux of gastric
juice, producing
a fibrous
stricture
in the oesophagus
(Allison, Johnstone,
and Royce, 1943
; Rennie, Land, and Park, 1949;
and Cranmer, 1955). In one of our patients a hiatus
hernia could
not be demonstrated
on repeated
examination. A number of points regarding the
cause of the obstruction will be discussed.
Dutton and Bland (1953) observed nine patients
in a maternity unit between 1950 and 1952. Each
of these nine patients had a sliding hiatus hernia.
One patient suffered transient dysphagia; another
developed
severe dysphagia within three months
of delivery. This patient vomited excessively from
the twentieth week of pregnancy. The oesophageal
stricture, which was the cause of the obstruction,
was subsequently resected. These authors suggest
the need for a large-scale investigation to ascertain
the
role of
hiatus
hernia
in
the
vomiting
of
pregnancy; they state that a patient with a hiatus
hernia may be symptom-free.
Marchand (1955) examined 250 women within
one week
of
delivery;
180 (70%)
experienced
heartburn during pregnancy, sufficiently severe in
93
to require a regular antidote. Of these, only
three had
symptoms
before
pregnancy.
Of
14
patients examined radiologically, none was found
to
have
a
hiatus


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a
hiatus
hernia
and
no
patient
with
dysphagia
was
recorded.
These
figures
suggest
that reflux occurs in pregnancy where no hiatus
hernia
exists. The
apparent
anomalies
between
Marchand's
findings
and
those
of Dutton
and
Bland are presumably explained by the higher inci-
dence of abnormal pregnancy in the latter's patients.
It seems certain that dysphagia is more likely to
occur after pregnancy complicated by hyperemesis
gravidarum, and is more commonly encountered
therefore in a maternity unit treating complicated
pregnancy. The
presence
of
a
gastro-duodenal
(Ryle) tube in the oesophagus and stomach may
be
important
in
the
genesis
of
oesophageal
stricture.
The
subject
has
been
discussed
by
Douglas (1956). He regarded the Ryle tube as a
factor of secondary importance to the excessive
vomiting; he stated that 'the combination of these
three factors,
regurgitation,
the gastro-duodenal
tube, and debilitation, may result in a stricture
being formed'.
Hussain
(1964) described
a 22-
year-old primigravida suffering from hyperemesis
gravidarum who complained
of dysphagia one
week after the removal of a Ryle tube which had
been
passed
to
treat
excessive
vomiting.
A
stricture of the oesophagus developed and was
resected eight months later; a hiatus hernia was
present.
Intubation of the oesophagus cannot seriously
be considered as a cause in our patients, nor is
there evidence that relaxation of the controlling
mechanism at the cardia, due to anaesthesia or
the
ingestion
of
irritant
anaesthetic
agents
(suggested by Hara (1949) as a possible cause),
was a factor of any importance in the production
of the oesophageal obstruction.
To avoid repetition in the case histories of our
patients a number of features common to each
must be mentioned. It was ascertained from the
parents of each of these patients that none of the
patients
ever
suffered from
feeding
difficulties,
excessive
vomiting,
or
difficulty
in
swallowing
during infancy. The importance of this will be
discussed later. Each suffered from hyperemesis


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with excessive vomiting during her pregnancy and
was
told, when the dysphagia
began,
that the
condition was of functional origin. Indeed, in two
patients
psychiatric
treatment
was
given.
No
patient complained of dysphagia whilst carrying
the
baby. Fear of exacerbating symptoms was
given
as
the
reason
for
four
of
the
patients
528


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Thorax (1966), 21, 193.
Pedunculated haemangiopericytoma attached to the
thoracic aorta
W. K. BLENKINSOPP AND
J. T. HOBBS
From
the Department of Pathology and the Surgical Unit, St. Mary's Hospital, London W.2
In
1942 Murray and Stout reported on
tissue
culture of the
'epithelioid'
cells of the glomus
tumour and suggested that they were the pericytes
of Zimmermann. In the same year these authors
(Stout and Murray, 1942) published the first d>-
scription
of another tumour of the same
cells
which they named 'haemangiopericytoma'. Since
then more than 300 examples of this tumour have
been reported, at least 90% of them in America.
This paper describes an unusual presentation of
haemangiopericytoma and remarks on the rarity
of reported cases in this country.
CASE REPORT
In
1959
a
woman
of
63
noticed
a
'scratching'
sensation in her chest, but a chest radiograph at the
Hampstead
Chest
Clinic
showed
no
abnormality.
Five years later she had acute bronchitis; this quickly
cleared up with a course of tetracycline, but a chest
radiograph at this time showed a mass in the para-
aortic region. Subsequent radiographic examinations
showed that the mass was increasing in size, and in
January 1965 the patient was referred to the thoracic
surgical unit at St. Mary's Hospital with a tentative
diagnosis of aortic aneurysm.
The patient gave a history of winter cough with
sputum for six years; she had noticed that left chest
discomfort was brought on by coughing and deep
inspiration, and sometimes it was relieved by choline
theophyllinate. Her weight was increasing. Examina-
tion showed a fit, slightly overweight, elderly woman
with no cardiovascular abnormalities except a blood
pressure of 150/100 mm. Hg; the pulse was regular
at 73/minute. The chest was emphysematous, and
there were scattered rhonchi in both lung fields. The
abdomen was obese, but no viscus or abnormal mass
was palpable.
INVESTIGATIONS Haemoglobin 99%, packedcellvolume
45%, white
cell count 7,000/c.mm.;
sedimentation


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rate 16 mm./hr.; plasma electrolytes normal, plasma
urea 30 mg./100 ml., serum calcium 10 mg./100 ml.;
Wassermann reaction and Harris test both negative;
blood
group 0
rhesus-positive;
electrocardiogram
normal. The forced vital capacity was 1,130 ml., and
the ratio of forced expiratory volume in one second
to the forced vital capacity was 63-5%. Chest radio-
graphs (Fig. 1) revealed a large rounded mass in the
left
paravertebral
gutter,
and
chest
tomography
showed normal thoracic vertebrae with the main mass
posterior
to the aortic plane but extending
to the
aortic arch; an arch aortogram via the left axillary
artery showed a normal lumen and no filling of the
mass.
A diagnosis of aortic aneurysm was thus not con-
firmed by angiography, and a provisional diagnosis
of neurofibroma was doubted because there was no
extension towards the intervertebral foramina and no
widening of the rib spaces locally; the possibility of
an
enteric
cyst was
considered.
Because
the mass
had been rapidly increasing in size a surgical explora-
tion was decided upon, and on 9 March 1965 the left
chest was
opened
through
the
seventh
intercostal
space. There was no pleural effusion and the pleura
and left lung appeared normal, but when the lung
was
displaced
forwards
a
tense,
fleshy,
mobile
tumour, about 8 cm. long, was seen in the para-
vertebral gutter, attached by a pedicle to the antero-
lateral aspect of the descending aorta at the level of
T8; there was no local infiltration. The mass was
easily removed when a cleavage plane was formed in
the outermost layers of the adventitia of the aorta,
and
the
left
thoracotomy
was
then
closed.
The
patient's recovery was uneventful,' and three months
later she was symptom-free.
HISTOLOGY
The specimen was a firm, encapsulated
mass, measuring 8-5 by 5-0 by 4-5 cm., including at
one end a pedicle
1-5 cm. long and 3 cm. in dia-
meter. The cut surface
of the tumour was
fleshy,
and the base of the pedicle was composed of loose
connective tissue. Histologically the tumour consisted
of
very
numerous


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numerous
capillaries
separated
by
fairly
regular rounded cells (Figs 2 and 3). Reticulin staining
showed the
cells
to be lying outside the capillary
sheaths, and most of the cells were surrounded by
reticulin
fibres;
the
reticulin was not arranged
in
alveoli. Scattered among the tumour cells there were
193


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Dopaminergic medication normalizes aberrant cognitive control circuit signalling in Parkinson’s disease


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Dopaminergic medication normalizes 
aberrant cognitive control circuit signalling in 
Parkinson’s disease
Weidong Cai,1,2 Christina B. Young,3 Rui Yuan,1 Byeongwook Lee,1 Sephira Ryman,3 
Jeehyun Kim,3 Laurice Yang,3 Victor W. Henderson,2,3,4 Kathleen L. Poston2,3,5 
and Vinod Menon1,2,3
Dopaminergic medication is widely used to alleviate motor symptoms of Parkinson’s disease, but these medications 
also impact cognition with significant variability across patients. It is hypothesized that dopaminergic medication 
impacts cognition and working memory in Parkinson’s disease by modulating frontoparietal-basal ganglia cognitive 
control circuits, but little is known about the underlying causal signalling mechanisms and their relation to individual 
differences in response to dopaminergic medication. Here we use a novel state-space computational model with ul-
tra-fast (490 ms resolution) functional MRI to investigate dynamic causal signalling in frontoparietal-basal ganglia 
circuits associated with working memory in 44 Parkinson’s disease patients ON and OFF dopaminergic medication, 
as well as matched 36 healthy controls.
Our analysis revealed aberrant causal signalling in frontoparietal-basal ganglia circuits in Parkinson’s disease pa-
tients OFF medication. Importantly, aberrant signalling was normalized by dopaminergic medication and a novel 
quantitative distance measure predicted individual differences in cognitive change associated with medication in 
Parkinson’s disease patients. These findings were specific to causal signalling measures, as no such effects were de-
tected with conventional non-causal connectivity measures. Our analysis also identified a specific frontoparietal cau-
sal signalling pathway from right middle frontal gyrus to right posterior parietal cortex that is impaired in Parkinson’s 
disease. Unlike in healthy controls, the strength of causal interactions in this pathway did not increase with working


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memory load and the strength of load-dependent causal weights was not related to individual differences in working 
memory task performance in Parkinson’s disease patients OFF medication. However, dopaminergic medication in 
Parkinson’s disease patients reinstated the relation with working memory performance.
Our findings provide new insights into aberrant causal brain circuit dynamics during working memory and identify 
mechanisms by which dopaminergic medication normalizes cognitive control circuits.
1
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
2
Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
3
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
4
Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA 94305, USA
5
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA
Correspondence to: Weidong Cai, PhD  
1070 Arastradero Rd., Palo Alto, CA 94304, USA  
E-mail: wdcai@stanford.edu
Correspondence may also be addressed to: Vinod Menon, PhD  
E-mail: menon@stanford.edu
Received July 30, 2021. Revised December 03, 2021. Accepted December 10, 2021. Advance access publication August 19, 2022
© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: 
journals.permissions@oup.com
https://doi.org/10.1093/brain/awac007
BRAIN 2022: 145; 4042–4055 | 4042


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Recurrent chest infections, ciliary abnormalities and partial complement deficiency in Jordanian family


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Thorax 1981; 36: 502-7
Recurrent chest infections, ciliary abnormalities and
partial complement deficiency in a Jordanian family
ID STARKE, B CORRIN, PJ SELBY, ADB WEBSTER, M TURNER-WARWICK
From the Cardiothoracic Institute andBrompton Hospital and St Thomas's Hospital Medical School,
London, and the Clinical Research Centre, Harrow, Middlesex
ABSTRACT
Four girls born to second cousin parents developed chronic chest infection and bronchi-
ectasis in infancy. Three were studied in detail: they all had the same HLA haplotype, all showed
random orientation of cilia or compound cilia in the respiratory tract, and all had low levels of the
Cl and C2 components of the complement system. Although the cause of the respiratory disease in
this family remains unclear, it is suggested that the low Cl levels may have contributed to the
disease in two of the children while the low C2 levels were artefacts and the ciliary abnormalities
were secondary to chronic chest infection.
We have recently encountered a Jordanian family in
which four children born to second cousin parents
suffered from recurrent chest infections and bronchi-
ectasis. An inherited abnormality was suspected and,
because primary defects in host defence often have a
genetic
basis, 1-3
we
have
investigated
defence
mechanisms against infection as fully as possible in
this family.
Case histories
CASE
1
This girl (As J, aged 10 years) had had a productive
cough and catarrh since infancy. At 8 years she had
been admitted to a sanatorium with suspected, but
unconfirmed, pulmonary tuberculosis. At 9 years she
had undergone a left pneumonectomy. On examina-
tion she was a small,
thin child with scattered
crackles and wheezes over the right hemithorax. Her
chest radiograph showed absence of the left lung,
right
middle
lobe
collapse
and
bronchial
wall
thickening at the right base. The maxillary sinuses
were opaque and the frontal sinuses were absent.
CASE 2
This girl (Kh J, aged 9 years) had been short of
Address for reprint requests: Dr ID Starke, MRC Leukaemia


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Unit, Royal Postgraduate Medical School, Hammersmith
Hospital, Ducane Road, London W12 OHS.
breath and had had a productive cough
since
infancy. On examination she had finger clubbing and
central cyanosis. There was dullness to percussion
and widespread crackles were heard over the left
hemithorax. The chest radiograph showed a con-
i
'.
II'
Fig 1
Chest radiograph ofpatient 2. There is contraction
ofthe left lung with widespread cavityformation, together
with some consolidation in the right lower zone.
502
ja
4


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Thorax 1984;39:561-567
Editorial
The third nervous system in the lung:
physiology and clinical perspectives
The
autonomic
nervous
system
controls many
aspects of pulmonary function' and, until recently, it
was thought that this was achieved entirely by means
of classical cholinergic and adrenergic mechanisms.
This view has recently been challenged by the
demonstration of a third nervous system in the air-
ways (fig). Although the identities of the neuro-
transmitters in this newly recognised nervous system
are not certain, there is increasing evidence that they
are peptides. This third nervous system is of particu-
lar interest as it is the predominant inhibitory nerv-
ous pathway to human airway smooth muscle and
this raises the possibility that a functional defect in
this nervous system might underlie bronchial hyper-
reactivity in asthma. The recognition that a third
component of the autonomic nervous system regu-
lates airway smooth muscle tone and other aspects
of lung physiology has stimulated great interest,
since it may provide new insights into diseases such
as asthma and chronic obstructive lung disease, and
may also lead to novel therapeutic approaches.
A third component of the autonomic nervous system
The existence of a nervous system in the gastrointes-
tinal
tract
which
is
neither
adrenergic
nor
cholinergic has been established for many years.
Non-adrenergic, non-cholinergic (NANC) nerves
control gut motility and secretions and have been
demonstrated in vertebrates from fish to man.23
Indeed, the presence of NANC nerves in primitive
vertebrates
indicates
that
this
nervous
system
developed early in evolution. The third nervous sys-
tem has also been demonstrated in the urogenital
tract,
the
eye, and
the
cardiovascular
system.3
Because the airways develop embroyologically from
the foregut it is not surprising to find that NANC
nerves are also present in the lung.
NANC nerves in the airways
Inhibitory nerves which relax toad lungs and which
Address for reprint requests: Dr Peter J Barnes, Department of


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Medicine (Respiratory
Division), Royal Postgraduate Medical
School, Hammersmith Hospital, London W12 OHS.
are
neither
adrenergic
nor
cholinergic
were
described by Campbell in 1971.4 Since then NANC
nerves which relax airway smooth muscle have been
found in several species, including man.55 In these
studies airway strips are mounted in an organ bath
and stimulated by an electrical current that selec-
tively activates nerves. In guinea pig tracheal strips
electrical field stimulation produces an initial con-
traction that is blocked by the anticholinergic drug
atropine and therefore due to acetylcholine release
from cholinergic nerves. The initial contraction is
followed by a relaxation, which
is only partially
inhibited by ,3 adrenergic blockers.56 Thus, although
a
component
of
the
inhibitory
response
is
adrenergic,
there
is
a component
that
is non-
adrenergic. The nerve toxin tetrodotoxin abolishes
these responses to field stimulation and proves that
they are mediated by nerves (which must be post-
ganglionic), and not due to a direct effect on smooth
muscle. Thus guinea pig trachea appears to have
excitatory cholinergic nerves and inhibitory nerves
which are both adrenergic and non-adrenergic. In
similar studies on human airway smooth muscle a
cholinergic contractile component is also demon-
strable, but the inhibitory response is unaffected by
adrenergic blockade.78 This indicates, rather surpris-
ingly, that there is no functional sympathetic inner-
vation of human airway smooth muscle and that
inhibitory nerves are non-adrenergic. The absence
of sympathetic nerves in human airway smooth
muscle is supported by histological studies showing
an absence of adrenergic nerve terminals within
smooth muscle,79 by studies showing a lack of effect
of cocaine (a neuronal uptake inhibitor) on norad-
renaline dose-response curves,'0 and by the lack of
effect of tyramine (which directly releases norad-
renaline from nerve terminals) on airway function in
man." There are, of course, adrenergic receptors in


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airway smooth muscle,'2 and these are presumably
regulated by circulating adrenaline.'3 NANC nerves
appear to be the only neural inhibitory pathway in
human airway smooth muscle from the trachea to
the smallest bronchi,7 and for this reason there is
particular interest in their physiological role and
regulation.
NANC nerves have also been demonstrated in
561


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Thorax 1986;41:386-395
Cerebral blood flow during cardiopulmonary bypass
in man: effect of arterial filtration
LEIFHENRIKSEN, ERIKHJELMS
From the Departments ofNeurology and Thoracic Surgery, State University Hospital, Copenhagen, Denmark
ABSTRACT Cerebral blood flow was recorded in 39 patients undergoing cardiac surgery by intra-
arterial injection of xenon 133. There were three subgroups of patients: 10 patients had a 20 micron
arterial filter (Johnson) and 11 a 40 micron filter (Pall), and 18 had no arterial filtration. All patients
had a 40 micron (Pall) filter in the coronary suction line. Significant changes in cerebral blood flow
occurred during extracorporeal circulation (p < 0.0001). For all patients cerebral blood flow in-
creased from a resting prebypass level of 30 to 46 and 57 ml/100 g a minute during initial and stable
hypothermic extracorporeal circulation respectively. Both measurements were obtained at 26°C and
the recordings were made on average 12 and 55 minutes after the extracorporeal circulation was
started. During rewarming cerebral blood flow increased to 64, 53, 41, and 36 ml/g a minute at 310,
330, 350, and 37°C respectively, and when measured four and 16 minutes on average after bypass it
was 44 and 41 ml/100 g a minute. This general brain hyperperfusion was noticed in all patients with
a high enough mean blood pressure to produce hyperaemia. Interposing 20 and 40 micron arterial
filters reduced cerebral blood flow but did not prevent this hyperaemia. The cerebral autoregulation,
which maintains a constant cerebral blood flow within wide limits of perfusion pressures, was not
affected by arterial filtration. The lower limit of blood pressure at which a further reduction in blood
pressure was followed by a reduction in cerebral blood flow was around 60mmHg in all three
groups.
Currently postoperative mortality is of little use as a
measure of the quality of cardiac surgery, as mortality
rates are generally low, despite strikingly different


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perfusion techniques. A new index of the quality of
surgery is emerging, based on psychometric analysis
of the extent to which complex mental functioning is
preserved in the early postoperative period, combined
with more quantitative methods, such as analysis of
spinal
fluid
intracellular
markers1- 3
and
mea-
surements of cerebral blood flow during and after car-
diac surgery.4-8
In our earlier studies of cerebral blood flow during
cardiac surgery we found a consistent hyperperfusion
of the brain during cardiopulmonary bypass6 -8 and a
diffusely reduced regional cerebral blood flow after
surgery,5 the most reasonable explanation being a
Address for reprint requests: Dr Leif Henriksen, Department of
Neurology, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen,
Denmark.
Accepted 13 November 1985
diffuse
microvascular
blockage
of microembolic
origin.
Filtration of the blood returned from the coronary
suction line has become widely accepted, but the
beneficial effect of arterial line filters is still ques-
tioned. The introduction of refined techniques for de-
tecting microemboli present in the arterial line and in
the carotid arteries have suggested that the incidence
of potentially hazardous microemboli during con-
ventional cardiopulmonary bypass is much greater
than previously realised. Since the size of micro-
emboli that would be safe cannot be defined, it seems
reasonable to reduce the quantity as much as possible.
The present study was designed
to determine
whether arterial filtration could prevent the abnormal
brain hyperperfusion usually noted in our patients
during bypass.
Methods
The results and their interpretation are based on a
study of 39 unselected adult patients undergoing open
386


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Thorax 1992;47:1044-1049
Endothelin, vasopressin, and substance P like
immunoreactivity in cultured and intact
epithelium from rabbit trachea
R E Rennick, A Loesch, G Burnstock
Abstract
Background
The
control
of airways
reactivity is essential to our understand-
ing of disease processes such as asthma.
Many studies have examined the neural
control of the airways, but more recently
there has been evidence to show that the
epithelium
lining
the
airways
may
influence airways reactivity.
Methods
Rabbit tracheal epithelial cells
were dispersed with enzymes, grown in
primary culture and fixed. Tissue from
intact tracheas was also sampled and
fixed. Localisation of the vasoactive sub-
stances endothelin-1, arginine-vasopres-
sin, and substance P was investigated by
immunolabelling techniques.
Results
Scattered immunolabelling to
endothelin-1, arginine-vasopressin, and
substance P was found throughout the
cultures (with
< 20% of cells staining
positively
to
each
antibody).
At
the
ultrastructural
level
this
immuno-
reactivity was found in the cytoplasmic
matrix. In addition, immunoreactivity of
intact tissue to endothelin-1, arginine-
vasopressin,
and
substance
P
was
examined and positively staining cells
were found to be scattered through the
epithelium.
Conclusions
The
presence
of
these
vasoactive substances within the epithe-
lium lining the airways supports the view
that
epithelial
cells may
provide
an
additional mechanism in the control of
airways reactivity.
(Thorax 1992;47:1044-1049)
Department of
Anatomy and
Developmental
Biology and Centre
for Neuroscience,
University College
London, London
WC1E 6BT
R E Rennick
A Loesch
G Burnstock
Reprint requests to:
Professor Burnstock
Received 4 December 1991
Returned to authors
22 January 1992
Revised version received
8 June 1992
Accepted 18 June 1992
Hyperreactivity of the airways is a characteris-
tic feature of asthma. In such patients damage
or loss of the airways epithelium is a common
finding.' The epithelium lining the airways was
originally
considered
merely
as
a


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as
a
barrier
preventing passage of dust, microorganisms,
and other airborne particles into the underlying
tissue. More recently, however,
it has been
shown that removal of the airways epithelium
leads
to increased responses of the smooth
muscle of the airways to various contractile
stimuli.2 This phenomenon occurs in the air-
ways of a number of different species, including
dog, guinea pig, rabbit, and man.8 Studies by
Flavahan and Vanhoutte9 showed that there
was increased sensitivity of the airways
to
histamine, acetylcholine, and 5-hydroxytryp-
tamine (5-HT) after removal of the epithelium.
They suggested that this might indicate that an
epithelium derived relaxing factor, analogous
to the endothelium derived relaxing factor
released from vascular endothelial cells,'" is
active in the airways. Orehek et al examined the
influence on airways reactivity ofdrugs inhibit-
ing prostaglandin synthesis and their results
suggested
that
release
of products
of the
cyclooxygenase pathway may be responsible
for airways relaxation."
Since the early 1970s it has been known that
there are amine precursor uptake and decar-
boxylation (APUD) cells present in the airways
epithelium."2 These cells are found throughout
the airways in innervated groups, known as
neuroepithelial bodies, but in the trachea they
occur only as
single
cells.'3
Studies using
microspectrofluorometry have shown that these
cells contain amines such as 5-HT.'4'5 It is
possible that other vasoactive substances that
may influence airways reactivity are present
within the airways epithelium. In this study,
tracheal epithelial cells were isolated and cul-
tured and the presence, in both isolated cells
and
intact
tissue,
of endothelin- 1
(ET- 1),
arginine-vasopressin (AVP), and substance P
(SP) examined at the light and electron micro-
scopic levels.
Methods
CELL CULTURE
Male New Zealand White rabbits aged 4-6
months were injected with a lethal dose of
Sagatal (RMB Animal Health, Dagenham,
UK) and exsanguinated. Tracheal epithelial


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cells were isolated by enzymatic treatment.'6
Briefly, the trachea was removed under sterile
conditions and placed in Hanks' Balanced Salt
Solution (HBSS; Gibco/Life Technologies,
Paisley, UK) supplemented with penicillin
(2 x 10' units/l; Glaxo Laboratories, Green-
ford), cleaned of adherent muscle and connec-
tive tissue, then clamped at one end and filled
with a solution of 0- 1% protease (Sigma, Poole,
UK) in HBSS. The other end was clamped so
that the tissue formed a sealed tube, and the
tissue was then incubated overnight at 4°C.
The following morning the tissue was un-
clamped, the lumen washed thoroughly with
HBSS, and the resulting suspension centri-
fuged at 100 g for 5 minutes. The resulting
pellet was resuspended in HBSS and spun as
above. The cells were resuspended in Ham's
F12 media (Gibco) supplemented with 5%
1044


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Thorax 1995;50:484-486
Gene therapy for respiratory diseases: potential applications
and difficulties
The use of genetic materials for treatment is a relatively
simple concept which, if successful, could revolutionise
the management of both inherited and acquired disease.
The aim is to modify production of a specific protein either
through upregulation by introducing the DNA of interest,
or downregulation through the use of antisense oligo-
nucleotides. Such modification could be for long term
correction of an inherited genetic defect such as cystic
fibrosis or ot,-antitrypsin deficiency, on the one hand, or
an acquired defect such
as
cancer on the other. Al-
ternatively, short term modification of protein production
could be used to alter inflammation in conditions such as
asthma and oxidant-mediated lung injury. Although the
concepts are simple, the technology is complex and poorly
understood, and it will be some time before gene therapy
is routinely available in clinical practice. This editorial
outlines the technology of gene transfer and reviews pro-
gress towards therapy for the three lung conditions with
approved gene therapy protocols, namely cystic fibrosis,
ocl-antitrypsin deficiency, and lung cancer.
Gene transfer techniques
Gene transfer requires two principal components
- the
cDNA of interest linked to an appropriate promoter, and
a gene transfer agent to facilitate entry into the cell. Most
current studies use "ubiquitous" promoters such as SV40,
CMV and RSV which are derived from eukaryotic viruses
and, in theory,
are active in any nucleated cell. Lung
specific promoters such as SP-C (surfactant protein C) and
CC 10 (Clara cell) are also being investigated.' There has,
to date, been relatively little work done to define the relative
advantages of the different promoters. It is likely, however,
that cell specificity will prove to be valuable as it will limit
gene expression to a desired cell population and may also
be easier to control.
The two main approaches being investigated with regard


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to gene transfer agents are the use ofviruses and liposomes.
Each has certain advantages and problems and future
systems may combine the best features of both.
Retroviruses
can produce efficient gene transfer, in-
cluding the integration of the DNA into the host genome.
These viruses are well suited to ex vivo transfection of cells
which are removed from the body and then replaced in
a modified form
as, for example, for hepatocytes and
production of ac-antitrypsin considered below. They are,
however, unsuitable for topical lung delivery since they only
transfect dividing cells and not the terminally differentiated
airway epithelium. Furthermore, in vivo use may carry the
risks of germ line transfection and the induction of other
unwanted changes by virtue of their random integration
into the host genome.
Adenoviruses have the advantage of being trophic for
the respiratory epithelium and should, in theory, produce
relatively efficient gene transfer to the airways. However,
two principal concerns about their use centre around safety
and efficacy on repeated administration. Portions of the
virus's own genome are deleted, partly to provide space
for the gene of interest to be inserted and partly to produce
a replication incompetent virus. The principal problem
relates to the viral coat proteins which are immunogenic
and which result in the production ofinflammation through
cytotoxic T lymphocytes
or neutralising antibodies
re-
ducing
the
efficiency
and
duration
of repeated
ap-
plications.2 A second theoretical risk is recombination with
a wild type virus which might restore the ability to replicate
and cause infection. Increasingly extensive deletions of the
viral genome are therefore being investigated to reduce
immunogenicity and replication potential.3
Liposomes are lipid vesicles which form spontaneously
when certain lipid preparations are mixed in polar so-
lutions. Cationic liposomes form complexes with DNA
(which has a net negative charge) and have been used


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for some years for in vitro gene transfer. Liposomes are
relatively inefficient at gene transfer compared with viral
vectors but have some major advantages. They have low
toxicity and are unlikely to provoke inflammation or to
initiate an immune reaction on repeated administration.
Liposomes
have
complex
physicochemical
properties
which are only poorly understood and which probably
underlie their variable performance in gene transfer ex-
periments.4
Administration of gene transfer systems
Nebulisation is likely to be the most acceptable delivery
system for routine repeated application to the lower airways
in man. It has the advantages of widespread deposition
which can, to a limited extent, be controlled by varying
droplet size. Contact time may also be enhanced by pro-
longed nebulisation, important in the light of mucociliary
clearance within the airways. A theoretical disadvantage is
the considerable mechanical stress applied to the liquid
during the process of nebulisation. This might damage the
gene transfer agent and, in particular, might alter the
structure of a liposome-DNA complex. The presence of
mucus and airway surface liquid further complicates pre-
dictions of whether efficient delivery can be achieved,
particularly since purulent secretions contain DNases. The
mucus layer may impair access to the cell surface, whilst
the aqueous layer may dilute and alter the composition of
any topically applied liquid. A recent report of pulmonary
epithelial gene transfer following intravenous injection of
a liposome-reporter gene complex is tantalising5 and, if
repeatable, suggests the possibility of other gene transfer
strategies. One potential disadvantage is widespread gene
transfer to other organs, but organ or cell specific promoters
or targeted gene transfer may help to overcome this dif-
ficulty.
Gene therapy for cystic fibrosis
Gene therapy for cystic fibrosis has become a possibility
since the isolation of the gene in 1989.6 The protein coded
for by this gene, cystic fibrosis transmembrane conductance


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regulator (CFTR), functions as a cAMP-regulated chloride
channel on the mucosal surface of the airway epithelium.7
Initial studies demonstrated that CFTR gene transfer into
cystic fibrosis cells in vitro could correct this chloride
defect.89 Using both adenovirus'0 and liposome" mediated
gene transfer it was subsequently demonstrated that the
CFTR gene could be expressed in the airways of normal
mice in vivo. Instillation of the CFTR gene into the lungs
was followed by appearance of mRNA at day
1, with
expression sustained for up to four weeks. Transgenic
cystic
fibrosis
mice
have
also
been
used
to
assess
CFTR gene transfer in vivo. Thus, both instillation'2 and
4.84


key: title
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Sleep-related breathing disorders 1Series Obstructive sleep apnoea: definitions, epidemiology, and natural history


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Sleep-related breathing disorders 1Series editor: PM A Calverley
Obstructive sleep apnoea: definitions,
epidemiology, and natural history
J R Stradling
Definitions, epidemiology, and the natural his-
tory of obstructive sleep apnoea (OSA) are
usefully considered together. This is because
OSA is not a condition that one either has or
does not have, but it exists in a continuum
between complete normality through to gross,
all night, obstructive sleep apnoea. Thus, the
prevalence of the condition depends critically
upon definitions and where one draws the ar-
bitrary line between normality and abnormality.
A further complication is that, particularly in
the mid range of severity, there is considerable
night to night variation.' As with systemic hy-
pertension, it is probably not very useful to try
to define a threshold for normality, but rather
to accept that a continuum exists and quote
prevalences for various levels of "sleep apnoea
activity". This should allow correlations with
symptoms and secondary consequences to be
drawn, and an attempt made to calculate risk!
benefit ratios for various treatments at these
different "sleep apnoea activity" levels - again,
similar to the approach in systemic hyper-
tension. This, or course, supposes that we
know exactly how to measure "sleep apnoea
activity" (as well as its main consequences,
sleep fragmentation) but, as we discuss later,
we do not.
believed to be the primary (and only) path-
ological event.3 An early definition of the
sleep apnoea syndrome required the counting
of these apnoeas, and >5/hour of >10 second
apnoeas was an early popular example.3 The
choice of >5/hour and of >10 second duration
was almost entirely arbitrary, but some defin-
itions were needed in the early days to facilitate
research in this area. The recognition of hypo-
pnoeas as arousing events4 required the ad-
dition of some definition of these events too.
Definitions of hypopnoeas are less universal
than those for apnoea. Sometimes a 50% re-
duction in ribcage and abdominal excursion


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for 10 seconds is required, the 10 second re-
quirement may or may not be abandoned if a
dip of >3% or >4% in Sao2 accompanies it,
and the calculation of the preceding baseline
varies between laboratories as well. These rigid
definitions have now largely outlived their clin-
ical usefulness5 because of the recognition of
sleep disturbance from upper airways nar-
rowing,
even
without hypopnoea
or hyp-
oxaemia - a point to which we will return.
This might imply that the real requirement is
to measure short arousals from the EEG but,
despite
attempts
to
define
arbitrarily such
arousals,6 there is no useful recognised stand-
Aetiology
At sleep onset all skeletal muscle loses tone.
This is probably necessary to sleep comfortably.
The pharyngeal muscles that dilate and main-
tain patency in the upper airway share in this
general loss of muscle tone so that even in
totally normal, non-snoring, individuals there
is narrowing of the upper airway2 with an in-
crease in airways resistance (fig 1). This nar-
rowing
at
sleep
onset
varies
considerably
between individuals and, when occurring be-
yond a certain degree, thepharyngeal walls come
close enough together (with or without the
uvula within the lumen) to generate snoring.
Further narrowing allows complete collapse,
hence the term "sleep apnoea". Although the
degree of narrowing is a continuous variable,
the onset of snoring and of complete collapse
are clearly two "steps" in the process which
have been seized on as easily defined and meas-
ured consequences. So dramatic is the point
of onset of apnoeas that initially these were
N
I
E
0Q
'U
CO
U,1
U)a.a.
20 F-
16 e
12 H
8
4
Awake
Non-REM
sleep
Figure 1
Changes in upper airways resistance with the
onset of non-REM sleep in six normal, non-snoring,
subjects. Note the considerable interindividual variability.
Redrawn from Wwgand et al.'
24 r
Osler Chest Unit,
The Churchill
Hospital,
Headington, Oxford
OX3 7LJ, UK
J R Stradling
n
n%
Thorax 1995;50:683-689
683
v


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The Journal of Clinical Investigation   
R E V I E W
1
Introduction
Over 200 viruses are known to cause disease in humans, yet cur-
rently approved antiviral drugs are available to treat only about 
10 of these viral infections. The past decade has underscored the 
global threat posed by emerging viruses. Spillovers from animals 
to humans have resulted in several Ebola virus disease (EVD) out-
breaks, the Middle East respiratory syndrome (MERS) outbreak, 
and possibly the current coronavirus disease 2019 (COVID-19) 
pandemic. Global warming, increased urbanization, and air trav-
el have contributed to the spread of vector-borne viruses endem-
ic to various parts of the world, including dengue virus (DENV), 
estimated to infect 400 million people in over 128 countries, and 
Zika virus (ZIKV), the causative agent of a 2015 outbreak. More-
over, political instability in various parts of the world continues to 
pose risks to our military forces and civilians from potential spread 
of biothreat agents, such as poxviruses — whose natural spread 
caused the ongoing monkeypox virus (MPXV) outbreak — and 
Venezuelan equine encephalitis virus (VEEV) (1, 2). There is thus 
a huge unmet need for the development of effective therapeutics 
for the treatment of existing and newly emerging viral infections.
Most approved antivirals target viral enzymes, particularly 
proteases and polymerases (Figure 1). Such direct-acting antivi-
rals (DAAs) have shown tremendous utility for the treatment of 
hepatitis C virus (HCV) and human immunodeficiency virus type 
1 (HIV-1) infections, and more recently COVID-19. However, 
this approach to drug development has several major limitations. 
First, the spectrum of coverage provided is typically narrow, rang-
ing from a single viral genotype to a few related viruses at best. 
Moreover, this approach is not scalable to address the large unmet 
need. It takes, on average, an 8- to 12-year timeline (3) and an aver-
age cost of over $2 billion to develop a new drug. Thus, targeting


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viruses individually is expensive and slow. While timely, effective 
efforts were noted during the COVID-19 outbreak, the rapid rollout 
of nirmatrelvir, for example, was enabled by accelerated derivat-
ization of an existing series of SARS-CoV-1 main protease (Mpro) 
inhibitors. No such DAAs are, however, currently available for the 
majority of viral families. The inability to predict the next emerg-
ing viral infection is another limitation, hampering adequate global 
health protection and national security preparedness. Lastly, when 
used individually, treatment with conventional DAAs often results 
in rapid emergence of drug resistance, complicating monotherapy 
regimens for HIV, HCV, and influenza A virus (IAV). In the case of 
SARS-CoV-2, escape mutations conferring high-level resistance 
to remdesivir and nirmatrelvir have already been selected in vitro 
and identified in circulating strains (4, 5). While combining drugs 
that target distinct viral functions can overcome viral resistance, as 
exemplified by HIV and HCV treatment, developing such “cock-
tail” regimens for multiple acute infections is not feasible.
An alternative solution is the development of broad-spectrum 
antiviral drugs. One advantage of this approach is reduced time 
and cost associated with the early stages of drug development per 
approved indication. It can also diminish the clinical risks in more 
advanced stages of development. The off-label use of approved 
antivirals against new viral indications can provide further eco-
nomic incentives, as these drugs were already rigorously tested for 
toxicity, pharmacokinetics, pharmacodynamics, dosing, etc. These 
advantages have been recently demonstrated by the repurposing of 
remdesivir and molnupiravir — originally developed to treat EVD 
and VEEV, respectively — for the treatment of COVID-19 (6, 7). 
Importantly, this approach can facilitate readiness for future out-
breaks of newly emerging pathogens. Broad-spectrum antivirals


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could also be used to treat rare viral infections for which no drug is 
available. Lastly, a broad-spectrum antiviral could be administered 
There is a large global unmet need for the development of countermeasures to combat hundreds of viruses known to cause 
human disease and for the establishment of a therapeutic portfolio for future pandemic preparedness. Most approved 
antiviral therapeutics target proteins encoded by a single virus, providing a narrow spectrum of coverage. This, combined 
with the slow pace and high cost of drug development, limits the scalability of this direct-acting antiviral (DAA) approach. 
Here, we summarize progress and challenges in the development of broad-spectrum antivirals that target either viral 
elements (proteins, genome structures, and lipid envelopes) or cellular proviral factors co-opted by multiple viruses 
via newly discovered compounds or repurposing of approved drugs. These strategies offer new means for developing 
therapeutics against both existing and emerging viral threats that complement DAAs.
Preparing for the next viral threat with broad-spectrum 
antivirals
Marwah Karim,1 Chieh-Wen Lo,1 and Shirit Einav1,2,3
1Division of Infectious Diseases and Geographic Medicine, Department of Medicine, and 2Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA. 
3Chan Zuckerberg Biohub San Francisco, San Francisco, California, USA.
Authorship note: MK and CWL contributed equally to this work.
Conflict of interest: The authors have declared that no conflict of interest exists.
Copyright: © 2023, Karim et al. This is an open access article published under the 
terms of the Creative Commons Attribution 4.0 International License.
Reference information: J Clin Invest. 2023;133(11):e170236.  
https://doi.org/10.1172/JCI170236.


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Gene therapy ameliorates spontaneous seizures associated with cortical neuron loss in a Cln2 mouse model


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The Journal of Clinical Investigation   
R E S E A R C H  A R T I C L E
1
Introduction
The neuronal ceroid lipofuscinoses (NCLs) are a group of neuro-
degenerative lysosomal storage disorders affecting children and 
young adults (1). Classic late infantile NCL, or CLN2 disease, is 
one of the most common forms of NCL and caused by a deficiency 
of tripeptidyl peptidase 1 (TPP1) (2–4). Patients with CLN2 disease 
develop signs typically between 2 and 4 years of age including sei-
zures and ataxia, often accompanied by speech delay (5, 6). These 
are followed by progressive psychomotor deterioration, and, if 
untreated, these children die during their teenage years (7). A dis-
ease-modifying enzyme replacement therapy (ERT) for CLN2 dis-
ease is now available and appears to slow disease progression (8, 
9). However, ERT requires invasive biweekly infusions and is not 
curative. Therefore, a need remains to develop less invasive and 
more effective therapies for CLN2 disease.
Progress toward this goal has been hampered by a fundamen-
tal lack of knowledge of how TPP1 deficiency affects the central 
nervous system (CNS). Therapy-resistant epilepsy is a major clin-
ical feature in children with CLN2 disease and causes significant 
morbidity (5–7). Cln2 mice often die suddenly, and the timing 
appears to be coincident with seizure-like behavior. However, 
their epileptic seizure phenotype and how this relates to survival 
have yet to be explored. The histopathological outcome measures 
used in NCL preclinical studies typically include storage material 
accumulation, glial activation, and neuron loss (10, 11). The onset 
and progression of these phenotypes have been characterized in 
detail in mouse models of multiple other forms of NCL. These 
studies have revealed temporal and regional differences between 
the NCLs, information that is important for the targeting of ther-
apies (12–19). Similar neuropathological phenotypes are evident in 
Cln2-knockout mice at the end stage and have been used to judge


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efficacy at disease end stage in preclinical studies (20–22). Howev-
er, the onset, the regional and cellular specificity of these pheno-
types, and how they progress over time have yet to be determined.
We have addressed both of these knowledge gaps in a poten-
tially new knockin mouse (Cln2R207X) that models the most com-
mon human disease-causing mutation in the CLN2 gene (23). We 
report a robust and potentially novel spontaneous seizure pheno-
type that is associated with a loss of cortical neurons, including 
interneurons, and significantly contributes to morbidity. Our data 
also reveal a range of pronounced differences in the staging of 
CLN2 disease neuropathology compared with other forms of NCL. 
Having described these clinically relevant readouts, we then used 
Although a disease-modifying therapy for classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) exists, poor 
understanding of cellular pathophysiology has hampered the development of more effective and persistent therapies. Here, 
we investigated the nature and progression of neurological and underlying neuropathological changes in Cln2R207X mice, 
which carry one of the most common pathogenic mutations in human patients but are yet to be fully characterized. Long-
term electroencephalography recordings revealed progressive epileptiform abnormalities, including spontaneous seizures, 
providing a robust, quantifiable, and clinically relevant phenotype. These seizures were accompanied by the loss of multiple 
cortical neuron populations, including those stained for interneuron markers. Further histological analysis revealed early 
localized microglial activation months before neuron loss started in the thalamocortical system and spinal cord, which was 
accompanied by astrogliosis. This pathology was more pronounced and occurred in the cortex before the thalamus or spinal 
cord and differed markedly from the staging seen in mouse models of other forms of neuronal ceroid lipofuscinosis. Neonatal


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administration of adeno-associated virus serotype 9–mediated gene therapy ameliorated the seizure and gait phenotypes 
and prolonged the life span of Cln2R207X mice, attenuating most pathological changes. Our findings highlight the importance of 
clinically relevant outcome measures for judging preclinical efficacy of therapeutic interventions for CLN2 disease.
Gene therapy ameliorates spontaneous seizures 
associated with cortical neuron loss in a Cln2R207X 
mouse model
Keigo Takahashi,1 Elizabeth M. Eultgen,1 Sophie H. Wang,1 Nicholas R. Rensing,2 Hemanth R. Nelvagal,1 Joshua T. Dearborn,3 
Olivier Danos,4 Nicholas Buss,4 Mark S. Sands,3,5 Michael Wong,2 and Jonathan D. Cooper1,2,5
1Department of Pediatrics, 2Department of Neurology, and 3Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA. 4REGENXBIO Inc., Rockville, Maryland, USA. 
5Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.
Conflict of interest: JDC has received research support from BioMarin Pharmaceutical 
Inc., Abeona Therapeutics Inc., REGENXBIO Inc., and Neurogene and is a consultant 
for JCR Pharmaceuticals. OD and NB were paid employees of REGENXBIO Inc. at the 
time of the study.
Copyright: © 2023, Takahashi et al. This is an open access article published under the 
terms of the Creative Commons Attribution 4.0 International License.
Submitted: October 5, 2022; Accepted: April 25, 2023; Published: June 15, 2023.
Reference information: J Clin Invest. 2023;133(12):e165908. 
https://doi.org/10.1172/JCI165908.


key: title
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Cerebral infarction due carotid occlusion and carbon monoxide Pathophysiological and neuropathological investigations


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Journal of Neurology, Neurosurgery, and Psychiatry 1983;46:756-767
Cerebral infarction due to carotid occlusion and
carbon monoxide exposure: I. Pathophysiological and
neuropathological investigations
RUDOLF LAAS, JORG IGLOFFSTEIN, SOLVEIGH MEYERHOFF
From the Department ofNeuropathology, EppendorfHospitals, University ofHamburg, Hamburg, Federal
Republic of Germany
SUMMARY
Ligation of one common carotid artery and exposure to carbon monoxide has proved
to be a reliable method of producing unilateral cerebral infarcts in the rat, allowing controlled
experiments in any given sample size. Pathophysiological measurements in awake and narcotised
rats has shown that, in contrast to hypoxic hypoxia, the carbon monoxide-induced functional
anaemia (3000 ppm in room air) did not stimulate chemoreceptors, thus causing a severe sys-
temic hypotension owing to peripheral vascular dilatation. This hypotension is likely to represent
the main pathogenetic factor in this model. An inhibition of ferro-enzymes by carbon monoxide
did not seem to be involved. The only cause of death was shown to be diffuse ipsilateral brain
oedema with or without extra-vasation of serum proteins. The EEG, the systemic arterial pres-
sure, rotational behaviour, and carotidal stump pressure proved to be reliable predictors of
outcome.
Small animal models are valuable in the investiga-
tion of brain infarction by providing a sample size
sufficient for statistical analysis. Those models pro-
ducing unilateral infarcts are further advantageous
in that the contralateral hemisphere is available for
comparison in morphological and biochemical inves-
tigations. Moreover, unilateral infarcts allow the
study
of
brain
damage
by way
of
lateralised
neurological signs.
The mongolian gerbil is useful for the develop-
ment of unilateral brain infarcts after ligation of one
common carotid artery owing to functional insuffi-
ciency of the circle of Willis.' However, this animal
is not large enough for easy invasive monitoring of


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its effects. This objection does not hold for the
Levine model in which unilateral brain infarcts are
produced in the rat by ligation of one common
carotid artery and subsequent exposure to hypoxic
hypoxia.2
However,
the
hypoxia
induces
a
sympatho-adrenal
stimulation
so that substantial
oxygen deficiency is required for cerebral infarcts to
result, and this demands close monitoring of the
Address for reprint requests: Rudolf Laas, MD, Department of
Neuropathology, Eppendorf Hospitals, University of Hamburg,
Martinistrasse 52, 2000 Hamburg 20, Fed Rep Germany.
Received 6 August 1982 and in revised form 18 January 1983.
Accepted 4 March 1983
individual animal.34 This difficulty can only be over-
come by controlling hypoxaemia and arterial blood
pressure by means of continuous anaesthesia and
artificial respiration.5 We therefore attempted to
avoid stimulation of the chemoreceptors by using a
functional anaemia induced by carbon monoxide.
This procedure proved to be reliable and amenable
to controlled experiments.
Material and methods
Male albino rats (Chbb:THOM strain) had free access to
standard rat chow and tap water.
Series I
After anaesthesia with diethyl-ether one common carotid
artery was ligated and transsected. Twenty-four hours later
the animals were exposed to carbon monoxide (3000 ppm
in room air) for 90 minutes while held in a plastic box with
a volume of 3001, allowing the exposure of eight animals at
a time. The gas mixture was stirred by a fan. The concent-
ration of carbon monoxide was continuously monitored
inside the plastic container and in its immediate vicinity by
an infrared spectrometer (URAS I, Hartmann & Braun,
FRG) to assure a continuous exposure of the animals and
to protect laboratory personnel against accidental leaks. At
the 48th hour after exposure the rats were anaesthetised
with diethyl-ether and perfused via the ascending aorta
with formalin after briefly washing out the vasculature with
saline.
756


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Journal of Neurology, Neurosurgery, and Psychiatry 1983;46:774-779
Cerebral infarction due to carotid occlusion and
carbon monoxide exposure
III. Influence of neck vein occlusion
RUDOLF LAAS, JORG IGLOFFSTEIN
From the Department ofNeuropathology, Eppendorf Hospitals, University ofHamburg, Hamburg,
Federal Republic of Germany
SUMMARY
Unilateral cerebral infarcts were produced in the rat by ligation of one common
carotid artery and a subsequent exposure to carbon monoxide. In animals which had undergone
an additional ligation of the external jugular veins leading to a moderate increase of the cephalic
venous pressure the outcome of the procedure was ameliorated significantly. Venous pressure
elevation was thought to reduce the venous vascular resistance effectively by preventing the
leptomeningeal veins from collapsing. Collapse of the leptomeningeal veins probably occurred
during the severe carbon monoxide-induced hypotension causing a steep increase of cerebral
vascular resistance.
There is evidence that the threshold value of cere-
bral
perfusion
pressure
below
which
cerebral
infarcts occur is conspicuously clear-cut.' 2 We pre-
sume that this in part can be attributed to the col-
lapse of leptomeningeal veins, which is known to
increase flow resistance. Since a collapsed vessel can
be distended by adding a flow resistance to its outlet
we
tested the hypothesis that the incidence of
hypotension-induced brain lesions could be reduced
by elevating the cephalic venous flow resistance. We
used a modified Levine procedure which has been
described in detail.3
Material and methods
The experiments were perfonned with unstarved male
albino rats of the Chbb:THOM strain.
Series I
In 88 of 175 animals (body weight: 300-400 g) both
external jugular veins were ligated at the time of unilateral
common carotid artery ligation. Twenty-four hours later
the carbon monoxide exposure (3000 ppm in room air, 90
minutes duration) was performed.
Address for reprint requests: Rudolf Laas, MD, Department of


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Neuropathology, Eppendorf Hospitals, University of Hamburg,
Martinistrasse 52, 2000 Hamburg 20, Fed Rep Germany.
Received 6 August 1982 and in revised form 18 January 1983
Accepted 4 March 1983
Series II
Pathophysiological investigations.
Fifteen animals (body
weight: 300-400 g) were anaesthetised with ketamine (125
mg/kg body weight). The arterial blood pressure was
measured distally and proximally to the common carotid
artery ligation via PVC-catheters. The cephalic venous
pressure was measured by means of silastic catheters which
were inserted into one of the greater branches of one
external jugular vein. Thereafter, both external jugular
veins were occluded for two minutes by means of gentle
compression. This manoeuvre was repeated seven times
with intervals of 4 minutes. In the individual animal the
mean arterial and venous pressures were computed from
about 50 values each for the occlusion and nonocclusion
episodes. In nine of the animals seven additional episodes
of bilateral venous occlusion were performed during an
exposure to carbon monoxide. For technical reasons the
carbon monoxide exposure was by an intraperitoneal injec-
tion of technical carbon monoxide per 100 g body weight
according to Fodor et al.4 The carboxyhaemoglobin (CO-
Hb) concentration was determined discontinuously (for
details see ref 3). In order to achieve steady state condi-
tions occlusion of the jugular veins was not started before
20 minutes after carbon monoxide injection. The exposure
was terminated by removing the gas from the abdominal
cavity through a small incision made into the abdominal
wall.
Results
Series I
Lethality. Thirteen of 87 control animals and three
of 88 experimental animals died within 48 hours
774


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Journal of Neurology, Neurosurgery, and Psychiatry 1983 ;46:809-8 17
Behaviour disturbances during recovery from herpes
simplex encephalitis
RICHARD GREENWOOD,* ASHOK BHALLA,* ALAN GORDON,t JEREMY ROBERTS*
From The National Hospitals for Nervous Diseases, London, * and the Department ofNeurophysiology,
Southend Hospital, t Southend, UK
SUMMARY
Bizarre behaviour disturbances in four patients occurring during incomplete recovery
from herpes simplex encephalitis are described. Some aspects of their behaviour were similar to
that originally described by Kluver and Bucy in monkeys following bilateral temporal lobectomy.
Previous reports of behavioural disturbances in man after herpes simplex encephalitis are
reviewed and attention drawn to the aggressive and disruptive behaviour that is often seen. With
the reduced mortality in herpes simplex encephalitis in recent years it is possible that behaviour
disturbances such as those described here will be seen more frequently.
Herpes simplex virus, type 1, is probably the com-
monest
cause
of
acute
sporadic
necrotising
encephalitis in temperate climates. Its clinical and
pathological features are now well recognised' as is
the tendency for the necrotic lesions to localise in
the inferior and medial parts of the temporal lobes
and the orbito-frontal cortex. Recently this has been
demonstrated during
life by CT scanning.2 This
localisation may be related to the route of entry of
the virus into the brain, either via the olfactory
tracts3 or via fibres from the trigeminal ganglion
supplying the basal meninges of the middle and
anterior fossae,4 and results in the characteristic
focal neurological features seen at presentation.
Olfactory, gustatory and auditory hallucinations,
speech
and
memory
disturbances,
and
bizarre
behaviour abnormalities leading to psychiatric con-
sultation are all well documented.
Documented
neurological
deficits
in
survivors
also accord with known limbic and temporal lobe
mechanisms. A residual amnesic syndrome, origi-


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nally described by Rose and Symonds,5 and subse-
quently reported by others, 16-8 is now well recog-
nised. Behavioural disorders following herpes sim-
plex encephalitis are less well documented. Oxbury
and Maccallum9 give some details of ten survivors,
two
of whom
exhibited behaviour disturbances
reminiscent of the Kluver-Bucy syndrome. A much
more detailed account of the cognitive, behavioural
Address for reprint requests: Dr R Greenwood, Hurstwood Park
Neurological Centre, Haywards Heath, W. Sussex, RHI117 7SJ, UK.
Received 17 March 1983
Accepted 16 April 1983
and emotional deficits in ten survivors of a necrotis-
ing limbic encephalitis, probably due to herpes sim-
plex, is given by Hierons, Janota and Corsellis.'0
Kluver-Bucy features were seen in some patients
and this, they point out, emphasises the focal nature
of the encephalitis,
as does the amnesic deficit.
Other authors have described single cases in the
same light" 12 or as examples of the Kluver-Bucy
syndrome in man.'3-'8
Although mortality in herpes simplex encephalitis
has probably been reduced in recent years,'9 the
incidence of deficit in survivors is still high; such
deficits will thus be seen more frequently in the
future. This aspect of the illness has received little
attention in the past, apart from the literature cited
above.
In
their monograph
on herpes simplex
encephalitis Illis and Gostling,' for instance, devote
only two paragraphs to the neurological sequelae.
Behaviour disturbances following herpes simplex
encephalitis are probably more common than
is
generally recognised. We have recently observed
bizarre behaviour disturbances in four patients dur-
ing
incomplete
recovery
from
herpes
simplex
encephalitis and report them here.
Case reports
Case I
On 18 January 1980 JBR, a 23-year-old interna-
tional sportsman and electronics undergraduate, com-
plained of a "funny smell". The following day he became
pyrexial and developed a sore throat and headache. On 22
January 1980, following a grand mal seizure, he was admit-


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ted to the local hospital. He was alert and febrile and his
neck was stiff. CSF examination revealed a protein of 0-56
809


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Journal of Neurology, Neurosurgery, and Psychiatry 1983;46:824-826
Sex hormones, sexual activity and plasma
anticonvulsant levels in male epileptics
BK TOONE, M WHEELER, M NANJEE, P FENWICK, R GRANT
From the David Lewis Centre for Epilepsy, Alderley Edge, and the Department of Chemical Pathology, St
Thomas's Hospital, London UK
SUMMARY
Testosterone, LH, FSH, PRL, and sex hormone binding globulin (SHBG) were meas-
ured in 72 male epileptic patients on chronic anticonvulsant drug regimes. Sexual activity was
estimated and plasma anticonvulsants measured. Total testosterone (TT), LH, FSH, PRL, and
SHBG
were
increased;
free
testosterone
(FT)
was
decreased.
Sexual
activity appeared
diminished particularly in relation to reduced FT.
Disturbances
in male
sex hormones have been
recently reported in male epileptic patients on anti-
convulsant drugs. Christiansen et all were the first to
observe diminished excretion of androsterone and
dehydroepiandosterone compared with normal con-
trols. The same group2 studied endocrine change
after three months of treatment with either pheny-
toin or carbamazepine. They confirmed the reduced
excretion of androgens, but noted an increase in the
serum concentration of testosterone in patients on
phenytoin. An
increase
in
TT
has
now
been
reported by two further groups in association with
raised SHBG34. LH and FSH were also increased
Finally Dana-Haeri et a15 have observed reduced
levels of FT.
There have been numerous reports of disturbed
sexual activity and orientation in epilepsy. Libido
may be increased or decreased; sexual orientation
may be disturbed, particularly in association with
temporal lobe epilepsy.6 However, there has been
little attempt to explore the relationship between
sexual activity and sex hormone function. In order
to do this we have investigated the residential popu-
lation at the David Lewis Centre for Epilepsy. This
paper reports changes in sex hormone patterns,
relates these to sexual activity and dosage of anti-
convulsant drugs.
Patients


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Patients
All male patients at the David Lewis Centre who were
between the ages of 17 and 60 years and who were on
anticonvulsant medication were considered. Twelve who
Address for reprint requests: Dr BK Toone, Maudsley Hospital,
Denmark Hill, London SE5 8A2, UK.
Received 9 October 1982 and in revised form 24 February 1983.
Accepted 7 May 1983
were receiving medication known to interfere with endoc-
rine function were omitted, as were two patients with evi-
dence of primary endocrine disorders. Seventy-two patients
(mean age 34-5 years) finally entered the study. Only six
patients were on a single anticonvulsant drug regime.
Forty-eight patients were prescribed phenytoin (mean
plasma level 9-1 mg/I), 19 phenobarbitone (1 1-2 mg/I),
41
carbamazepine
(4.4
mg/l),
32
sodium
valproate
(25-3
mg/l),
24
primidone
(2-4
mg/l)
and
six
ethosuximide. Each patient received an average of 2-3
anticonvulsant
drugs.
Fifteen
patients
also
received
some
form
of
benzodiazepine,
principally
as
night
sedation. A diagnosis of primary generalised epilepsy
was
made
in
eight
cases,
secondary
generalised
epilepsy in 19, temporal lobe epilepsy in 32, and some
other form
of focal epilepsy
in
12. Ten experienced
partial seizures with simple symptomatology, 37 partial
seizures with complex symptomatology, 44 secondary
generalised
seizures,
19
generalised
tonic-clonic
seizures, and five akinetic seizures. The average age of
onset was 5-2 years and the duration of epilepsy 29*0
years.
Controls
Hormonal data was compared with a control group com-
prising 82 male volunteers from the staff of St Thomas's
Hospital (mean age 38-8 years).
Method
The interview
The interview was conducted by a consultant psychiatrist
(BKT or PF) and lasted approximately 30 minutes. The
first part of the interview was unstructured: the subject was
encouraged to describe his sexual interests, attitudes and
experiences. The meanings of certain technical terms were
explained. Complete confidentiality was assured. The sub-


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ject was then questioned systemnatically about certain
aspects of bodily function, sexual interest, and activity.
These were selected to reflect the influence of androgens
on sexual behaviour. The level of sexual interest was partly
824


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Journal of Neurology, Neurosurgery, and Psychiatry 1983;46:837-843
The orbicularis oculi response after hemispheral
damage
A BERARDELLI, N ACCORNERO, G CRUCCU, F FABIANO, V GUERRISI,
M MANFREDI
From the Laboratorio di Neurofisiologia, V Clinica Neurologica and Servizio di Neuroradiologia,
Dipartimento di Scienze Neurologiche, Universit& di Roma "La Sapienza", Italy
SUMMARY The corneal and blink reflexes were evaluated in 20 normal subjects and in 30 patients
with motor deficits secondary to unilateral hemispheral lesions of vascular origin. In the normal
population there were no differences between subjects below and subjects above 50 years of age.
In the patients the reflex evoked by electrical stimulation of the cornea of the clinically affected
side was depressed in 24 out of 30 cases. The depression mainly affected the afferent branch of
the circuit, which triggers both homolateral and contralateral orbicularis oculi discharge (afferent
abnormality). In three cases the depression was exerted concomitantly on the efferent branch
(afferent and efferent abnormality) and only in one case was it limited to the efferent branch
(efferent abnormality). The late R2 component of the blink reflex was depressed in 15 out of 30
patients. The early Rl component was slightly facilitated on the affected side. The changes of the
comeal reflex and of the R2 component of blink reflex were similar, but the blink reflex had a
greater safety factor.
The patients with an abnormal corneal reflex had more extensive damage than had the patients
with normal corneal response, as shown by computer tomography, but the site of the lesion was
comparable in the two groups. Conduction through the brain stem circuits mediating the
orbicularis oculi
response
is normally under pyramidal facilitatory influences while facial
motoneurons are subjected to pyramidal inhibition. After pyramidal damage the transmission of
impulses in the brain stem was slowed down, ultimately to a degree that abolished the reflex.


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Removal of pyramidal inhibition on facial motoneurons is probably the basis of the slight facilita-
tion of the Rl component of the blink reflex.
Several authors'-4 have observed a depression of
the corneal reflex evoked from the eye contralateral
to an hemispheral lesion, but Magladery and Teas-
dalL,' using electromyographic recordings, reported
that the latency of the reflex was only slightly
increased
after
a
unilateral
hemispheral
lesion.
More recently Ongerboer de Visser6 observed that
the electromyographic response was reduced
in
most of the patients with unilateral cerebral lesions.
The blink reflex evoked by electrical stimulation
of the supraorbital nerve also has been investigated.
Address for reprint requests: Prof. Mario Manfredi, V Clinica
Neurologica, Universiti di Roma, Viale dell'UniversitA, 30 00185
- Roma.
Received 12 November 1982 and in revised form 12 March 1983
Accepted 16 April 1983
837
Both direct and consensual R2 components elicited
from the paretic side are depressed according to
Messina and Quattrone,7 Kimura" and Fisher et al,9
while Dehen et all' found that R2 was depressed on
the affected side and facilitated on the normal one,
whether evoked from the normal or the paretic side.
The homolateral'R1 component was augmented on
the paretic side according to Messina and Quat-
trone7 while was unaffected
in
the population
studied by Kimura.8 Fisher et al9 reported that the
Rl was delayed during the early phase after a
stroke.
In the present study we compared the behaviour
of the orbicularis oculi response (comeal reflex and
blink reflex to supraorbital nerve stimulation) in a
group of patients with unilateral hemispheral lesions
and in normal controls. The comeal reflex has been
elicited by mechanical stimuli and by electrical


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Journal ofNeurology, Neurosurgery, and Psychiatry 1983;46: 943-952
CT scan correlates of gesture recognition
JOSE M FERRO, ISABEL P MARTINS, GABRIELA MARIANO, A CASTRO CALDAS
From the Neurobehavioral Unit, Centro de Estudos Egas Moniz, Department ofNeurology, Hospital de Santa
Maria, Lisboa, Portugal
SUMMARY The ability to recognise gestures was studied in 65 left-hemispheric stroke patients
whose lesions were located by CT scan. In the acute stage (first month) frontal lobe and basal
ganglia were frequently involved in patients showing inability to recognise gestures. In the later
(third
to fourth month) and chronic stages
( >6 months) parietal lobe involvement was
important; lesions causing gesture recognition impairment were larger, had more extensive and
frequent parietal involvement and produced less temporal lobe damage than those causing aural
comprehension defects. These findings are discussed in the light of recent models of cerebral
localisation of complex functions.
Several studies have demonstrated that some apha-
sics do not recognise gestures.1-5 This disturbance
correlates
with
comprehension
impairment,'24
alexia34 and constructional apraxia.4 Gesture recog-
nition impairment in aphasics has been attributed to
asymbolia,l to an impairment of "semantic under-
standing",2 to damage to a "symbolic unit" that rela-
tes gestures to the corresponding objects4 following
"plausability"
rules,5
or due
to
loss
of visuo-
kinesthetic motor engrams of gestures.4
None of these previous studies addressed the
question of the anatomical localisation of the lesions
that cause impairment of gesture identification. In a
previous work, we found that this disturbance of
gesture recognition was more common and severe in
global, transcortical and Wemicke's aphasics, inde-
pendent of the severity of auditory comprehension
impairment.4 This could reflect the major role of
posterior
left
hemispheric
areas
for
gesture
identification. The strong correlation found with.
constructional apraxia could indicate a more exten-


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sive involvement of the parietal lobe in aphasic
patients displaying defective gesture recognition.
These suggestions were investigated in the present
study.
Method
The study was of 65 adult right-handed patients, 41 males
Address for reprint requests: Jose M Ferro MD, Neurobehavioral
Unit, Centro de Estudos Egas Moniz, Hospital de Santa Maria,
1600 Lisboa, Portugal.
Received 3 December 1982 and in revised form 3 May 1983.
Accepted 14 May 1983
and 24 females (mean age 56-4 ± 11.6 years) who had
suffered a single ischaemic cerebrovascular accident of the
left hemisphere. Patients with intracerebral haematomas,
cerebral infarct associated with subarachnoid haemorrhage
and those in whom CT scan showed multiple or bilateral
lesions, or diffuse white matter hypodensity suggestive of
arteriosclerotic
subcortical
encephalopathy6
were
not
included in this series. Thirty-two patients were tested
during the 1st month after stroke (acute patients), 37
during the 3rd-4th months after stroke (recent patients)
and 44 in the six or more months after stroke (chronic
patients). Thirty-three patients were observed in more
than one period (acute, recent and chronic stages, 18
patients; acute and recent, eight patients; recent and
chronic, six patients; acute and chronic, one patient).
All patients had a comprehensive neuropsychological
evaluation including testing for aphasia, alexia, agraphia,
apraxia and constructional ability. Diagnosis of aphasia
was carried out by means of a standardised battery.'7 Two
tests of auditory comprehension deserve a brief description
as their scores were compared with Gesture Recognition
Test score. On the test of object identification by name,
patients were requested to point to objects (two sets of
eight) named by the examiner, while on the test of oral
understanding they had to follow four one-step and four
two-steps oral.commands. Each correct response is scored
one point in both tests. Normal controls made no errors on
these tasks. Classification by aphasia types was based on


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taxonomic criteria according to the scores obtained in the
tests of speech fluency, naming, understanding of oral
commands and repetition of words.4
The ability to recognise gestures was assessed by means
of the Gesture Recognition Test (GRT).4 This
is a
multiple-choice test that requires the patient to point to 12
objects or drawings corresponding to gestures played by
the examiner. This test is divided in two parts, preceded by
two training items. The training items (spoon, comb) are
placed in front of the patient. The examiner pantomimes
943


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Journal of Neurology, Neurosurgery, and Psychiatry 1983;46: 953-955
Short report
Old photographs: postencephalitic Parkinsonism in
two small boys
J PURDON MARTIN
From the National Hospital for Nervous Diseases, Queen Square, London, UK
SUMMARY My interest in posture and its central nervous control dates from my early days in
neurology. That was also the time of the epidemic of encephalitis lethargica. A few years ago I
came upon some old photographs dating from this period and among them were several of two
small boys suffering from the after-effects of encephalitis with severe disorders of postural
control. Each of these boys, if placed on an ordinary chair would let his body fall forward and
would "roll" off the chair and lie motionless on the floor. In more recent years it has been shown
experimentally that similar symptoms in monkeys are associated with bilateral lesions of the
globus pallidus; in post-encephalitic patients of long standing degenerative changes are present in
the pallida, but it now seems likely that deficiency of the neuro-transmitter, dopamine, may bear
as much responsibility for their symptoms as anatomical lesions. Neurology was slow to appreci-
ate the contribution of the basal ganglia to postural activity.
In my early days in neurology the subject of posture
and its central nervous control was very much in the
air. Holmes,' in his Croonian lectures of 1922, gave
the classic description of "The clinical symptoms of
cerebellar
diseases
and
their
interpretation.";
Walshe,23 on his appointment to the honorary staff
of the National Hospital, had been given six months
leave of absence to go and study with Sherrington
and after his return was applying Sherringtonian
physiology
to
the
hemiplegics and paraplegics;
Magnus and de Kleijn had described various post-
ural reflexes (in the cat) from 1912 onwards, and
Magnus's great "Korperstellung", in which they
were all brought together, appeared in 1924 and was
accorded an eight page review by Walshe4 in Brain.


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In such an atmosphere one could hardly fail to
develop a lasting interest in the subject.
A few years ago among some old papers I came
upon some photographs dating from this period.
They were all concerned with posture, and among
them were
several showing the
after-effects of
encephalitic lethargica and, in particular, these pic-
tures (fig 1) of two small boys who had been in the
hospital
at the same time suffering from post-
encephalitic Parkinsonism with severe postural dis-
turbances. They had been taken by the late Dr WG
Wylie, who was at that time RMO at the National
Hospital, and afterwards physician to the Hospital
Accepted 25 February 1983
for Sick Children and to Maida Vale Hospital.
Encephalitis lethargica was still prevalent and its
numerous and very varied after-effects were becom-
ing known. In the children the usual sequelae were
behaviour
disorders
and
disturbances
of
sleep
rhythm, and the Parkinsonian state was not com-
mon, and to have two very similar cases in the hospi-
tal at the same time was a matter of considerable
interest. Unfortunately, the notes of these boys have
been lost; what I remember best about them is that
each of them, when placed on an ordinary chair,
would let his body gradually sink forward and would
"roll" off the chair. The first reaction of the nursing
staff was to keep the boys in bed when a medical
visit was expected, and so the physician, and even
the house-physician on
his round, might easily
remain in ignorance of this peculiar phenomenon.
At that time we had no armchairs for the patients to
lie back in, let alone the modern harness to hold the
incapable ones in position.
It is evident from the photographs that the smaller
boy (fig 1) was much more rigid than the other one,
and in spite of his rigidity his body sinks down as he
stands. I do not know the intervals between the
photographs-the clinical cinematograph was still
about twenty-five years away-and so it is not poss-
ible to say exactly how quickly this occurred, but


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from the evidence of other cases, it seems likely that
it would be no more than a few minutes. The sharp-
ness of the pictures shows that there was no tremor.
953


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Journal ofNeurology, Neurosurgery, and Psychiatry 1984;47: 56-60
The olfactory bulbs in Alzheimer's disease
MARGARET M ESIRI, GORDON K WILCOCK
From the Departments ofNeuropathology and Geriatric Medicine, The Radcliffe Infirmary, Oxford, UK
SUMMARY The olfactory bulbs have been examined in patients with Alzheimer's disease and
compared with those in elderly undemented and younger undemented control patients. In
Alzheimer's disease neurofibrillary tangles were found in the anterior olfactory nucleus but not
elsewhere in the olfactory bulb. Cell loss in the anterior olfactory nucleus was also found in
Alzheimer's disease. It is clear that the olfactory sensory pathway is pathologically affected in
Alzheimer's disease and would merit further study.
Alzheimer's disease is characterised pathologically
by
the
development
of
numerous
argyophilic
plaques and neurofibrillary tangles within the brain.
Regions of the brain that are particularly severely
affected in this disease include important parts of
the olfactory system such as the uncus' and the
cortico-medial part of the amygdaloid nucleus.2 We
therefore decided to examine more peripheral parts
of the olfactory sensory pathway. The olfactory
bulbs and anterior olfactory nuclei have not to our
knowledge been studied previously in Alzheimer's
disease. Neurofibrillary tangles have been described
in
the
olfactory
bulbs of several
cases of the
Parkinsonism-dementia complex of Guam but not in
Alzheimer's disease.3 We report here our observa-
tions
on
these
structures
in
patients
with
Alzheimer's disease and in undemented young and
elderly control patients.
Materials and methods
Pairs of olfactory bulbs from six patients with Alzheimer's
disease,
five
undemented
elderly
(>60
yrs)
control
patients, and five younger (<60 yrs) control patients (see
table), were removed from the necropsy brains after
fixation in 10% neutral formalin, and embedded in paraffin
wax. Patients included in the group with Alzheimer's dis-
ease had been prospectively assessed for dementia during


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life and had the diagnosis confirmed neuropathologically
by demonstrating the presence of numerous neurofibrillary
tangles and argyrophilic plaques in frontal and temporal
lobe neocortex. The elderly control patients had also been
assessed prospectively and the absence of intellectual
impairment confirmed. The methods employed are dis-
Address
for
reprint
requests:
Dr M
Esiri,
Department
of
Neuropathology,
The
Radcliffe
Infirmary,
Woodstock
Road,
Oxford, OX2 6HE, UK.
Received 25 May 1983. Accepted 5 July 1983
cussed in detail elsewhere.4 Examination of their brains at
necropsy had shown that neurofibrillary
tangles were
absent or were present in very small numbers in the
hippocampus and parahippocampal gyrus only. The young
undemented patients had died of acute subarachnoid and
intracerebral haemorrhage associated with the presence of
a ruptured berry aneurysm on a major cerebral artery.
Serial 10 ,u horizontal sections of the olfactory bulb were
cut and the first and every following 30th section stained
using Cross' modification of the Palmgren stain5 to demon-
strate neurofibrillary tangles. A 20 IL section immediately
adjacent to each of these was stained with cresyl fast violet.
Quantitative studies were made at a magnification of 320
on the anterior olfactory nuclei using a semi-automatic
image analyser (Graphic Information Systems). Within the
bulb the arrangement of the cells of the anterior olfactory
nuclei precluded cell counting in random fields. In each
case, therefore, the three fields which were judged by vis-
ual inspection to have the greatest cell density within the
anterior olfactory nuclei were graded (on a scale of 0-3)
according to the number of neurofibrillary tangles present
(0 = absence of tangle formation; 1= minimal; 2 = mod-
erate; 3 = severe). The two highest grades in each case
were recorded for analysis. Cresyl fast violet-stained sec-
tions were used to perform neuron cell counts on the
anterior olfactory nuclei
at 320 magnification using a


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Weibel graticule and a point counting technique on five
fields where cell density was judged by visual inspection to
be highest. The three highest counts for each case were
then used for the analysis. Cells were only counted if they
were large (>20 .) and the nucleus contained a prominent
nucleolus.
Results
The several layers of the olfactory bulb were readily
distinguishable in all three groups of patients studied
though some distortion or irregularity of the cell
layers was common in all groups. As described by
Crosby et al,6 the neurons of the anterior olfactory
nuclei were visible lying deep within the olfactory
56


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Journal of Neurology, Neurosurgery, and Psychiatry 1984;47: 365-371
Common carotid artery stump pressure in the gerbil
stroke model
RUDOLF LAAS
From the Department ofNeuropathology, Eppendorf Hospitals, University ofHamburg, Fed Rep Germany
SUMMARY
In 106 slightly anaesthetised adult mongolian gerbils one common carotid artery
(CCA) was ligated and the blood pressure in the distal and in the proximal stump was monitored
for 8 minutes. The mean distal CCA stump pressure of the 39 nonsurvivors was 15 (±6) mm Hg,
that of the 25 survivors with retinocerebral infarcts was 25 (±+6) mm Hg, and that of the 42 intact
survivors was 31 (±+7) mm Hg. The corresponding mean arterial blood pressures (MABP), as
measured in the proximal CCA stump, were 81 (+12) mm Hg, 84 (+13) mm Hg, and 87 (+11)
mm Hg, respectively. There were no differences between the samples concerning sex, body
weight, rectal temperature, arterial blood gases, arterial pH, and haematocrit. Measurements in a
second series of 10 awake gerbils showed that the mean values of MABP, heart rate, and
respiratory rate of the nonsurvivors were less than those of the survivors during 90 minutes after
CCA ligation. It is inferred that in the mongolian gerbil the lower threshold of the arterial blood
pressure for the development of brain infarcts ranges within 22 and 25 mm Hg, that is, within the
values found in monkeys and cats. The longlasting depression of respiration and circulation in the
nonsurvivors is considered to be related to the phenomenon of diaschisis.
As revealed by measurements in cats' and monk-
eys23 the threshold value of the arterial blood pres-
sure for the development of brain infarcts appears to
be consistent and clear-cut. From experiments on
rats we gained some evidence that this in part may
be due to collapse of the leptomeningeal veins which
is considered to induce a steep increase of cerebro-
vascular resistance.4 In order further to substantiate
this hypothesis, we determined the arterial blood
pressure threshold value in rodents.


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We chose the mongolian gerbil as the experimen-
tal animal, since this small rodent is inexpensive and
offers some experimental advantages. Depending on
the size of the posterior communicating artery and
its contribution to the anterior circulation, the ger-
bils exhibit a greater or lesser susceptibility to brain
infarction
after ligation of one common carotid
artery.56 From this we inferred that in the mon-
Address for reprint requests: Rudolf Laas, MD, Department of
Neuropathology, Eppendorf Hospitals, University of Hamburg,
Martinistrasse 52, 2000 Hamburg 20, Fed Rep Germany.
Received 7 July 1983 and in revised forn
6 October
1983.
Accepted 28 October 1983
golian gerbil the threshold value in question could
be determined simply by measuring the arterial
blood pressure distal to the common carotid artery
(CCA) ligation and by relating this value to vital
and/or histological outcome. Thus, the known risk of
artificial reduction of systemic arterial blood pres-
sure was avoided.3
In order to minimise stress, which is likely to
worsen outcome, the measuring period was limited
to a few minutes. We then attempted to gain insight
into the course of systemic circulation and respira-
tion in a second series.
Material and methods
Series I
One hundred and six adult mongolian gerbils (53 males, 53
females) had free access to standard chow and tap water.
The animals were anaesthetised with diethylether. The
left common carotid artery (CCA) was ligated after mid-
line incision of the neck. Catheters were inserted into the
distal and proximal stump and connected
to pressure
transducers (P50, Statham, USA). The average duration of
the procedure was 10 minutes. Modest anticoagulation was
effected by the injection of heparin, so that no uncontroll-
365


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Journal of Neurology, Neurosurgery, and Psychiatry 1984;47: 377-385
Pure psychic akinesia with bilateral lesions of basal
ganglia
DOMINIQUE LAPLANE, MICHEL BAULAC, DANIEL WIDLOCHER, BRUNO DUBOIS
H6pital de la Salpetriere, Paris, France
SUMMARY Three
patients
showed
dramatic
psychic
akinesia
after
recovery
from
toxic
encephalopathy. They had no or only mild motor disorders. The spontaneous psychic akinesia
was reversible when the patient was stimulated, as if there was a loss of self psychic activation.
Intellectual capacities were normal. Two patients had stereotyped behaviours resembling com-
pulsions. In all patients CT cans showed bilateral lesions in the basal ganglia, mainly within the
globus pallidus.
Mental disorders occur very frequently
in basal
ganglia
diseases,
such
as
Wilson's,
Parkinson's,
Hallervorden-Spatz
diseases, Huntington
chorea,
and progressive supranuclear palsy ... The clinical
picture
of these
mental
disorders however,
are
extremely varied; they consist of psychiatric disor-
ders, personality changes and often various degrees
of intellectual deterioration, but this last feature can
be absent. In spite of this diversity a peculiar clinical
picture characterisation by slowing down of thought
processes, inertia and memory disorders has been
identified in several degenerative diseases, and has
been
described
under
the
term
of
'subcortical
dementia".' 2 Degenerative lesions are generally not
limited to the basal ganglia, so eventual role in men-
tal processes cannot be established. Contrarily, in
the motor control field, there is much anatomical,
physiological and clinical evidence (the two latter
largely from the study of Parkinson's disease), lead-
ing to the conclusion that basal ganglia should be
regarded as organs of motor control, as recently
emphazised by Marsden.3
We have recently drawn attention to a psychic
picture,4 5 possibly the consequence of bilateral sub-
cortical
lesions
in
the
basal
ganglia, which was
characterised by pure psychic akinesia without per-
manent
dementia,
and
by


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and
by
pseudo-obsessional
activities. We now report three similiar cases, which,
in combination with some clinical and anatomical
data in the literature, may furnish some support to
Address for reprint requests: Dr D Laplane, H6pital de la Salpet-
riere, 47 Boulevard de
l-Hopital, 75651 Paris Cedex 13, France
Received 23 June 1983 and in revised form 10 October 1983
Accepted 14 October 1983
the hypothesis of a role played by the basal ganglia
in mental processes.
Case reports
Case 1: In 1968, Mr V, a 41-year-old healthy man was
stung on the left arm by a wasp. He immediately sustained
a convulsive coma for 24 hours, then adopted intensive
choreic
movements
(which
were
alleviated
by
thio-
properazine),
and
impairment
of
gait.
These
extra-
pyramidal symptoms diminished
over
several
months.
Then, and during the twelve following years he appeared
to be a mild dement, He was evaluated by us in 1980, and
was at this time not receiving drugs. All his activities were
dramatically reduced. He spent many days doing nothing,
without initiative or motivation, but without getting bored.
The patient described this state as "a blank in my mind".
His affect was disturbed. When talking about family prob-
lems, sad or pleasant, he had an appropriate behaviour and
gave signs of normal interest, but this attitude did not last
and he became rapidly indifferent again. His fantasy life
was poor, but dreaming was preserved. But when stimu-
lated by external events, or more specially by another per-
son he could perform quite correct complex tasks (for
example,
playing
bridge).
This
fact was
dramatically
demonstrated by neuropsychological tests which showed
intellectual capacities within the normal range (table).
Two years after the encephalopathy, he began to show
stereotyped activities. The most frequent consisted in men-
tal counting, for example, up to twelve or a multiple of
twelve, but sometimes it was a more complex calculation.
Such mental activities sometimes were accompanied by


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gestures, such as a finger pacing of the counts. To switch on
and off a light for one hour or more was another of his
most
common
compulsions.
When
asked
about
this
behaviour he answered that he had to count. .. that he
could not stop it ... as that it was stronger than him ....
Once he was found on his knees pushing a stone with the
hands; he gave the explanation that he must push the
377


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Journal of Neurology, Neurosurgery, and Psychiatry 1984;47:485-491
Cholinergic system and constructional praxis: a
further study of physostigmine in Alzheimer' s disease
OSAMU MURAMOTO,* MORIHIRO SUGISHITA,t KAZUYA ANDOt
From the Department ofNeurology, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, *
Department ofNeurology, Institute ofBrain Research, University of Tokyo, t and National Centre for
Nervous, Mental and Muscular Disorders, Tokyo, t Japan
SUMMARY Subcutaneous or intravenous administration of physostigmine improved the copying
of geometric figures in three out of six patients with presumed Alzheimer's disease who showed a
remarkable constructional disturbance. This improvement reached its maximum 30 to 60 minutes
after the physostigmine administration. These results not only provide further evidence support-
ing the hypothesis that central cholinergic potentiation ameliorates some of the impairments of
Alzheimer's disease, but implicate a possible important role of the cholinergic system in the
integration of constructional praxis.
Since the first reports of beneficial effects of physos-
tigmine on the cognitive functions of patients with
Alzheimer's disease appeared in 1979,'-3 several
trials have confirmed that memory disturbance in
some patients could be ameliorated by the use of
centrally active anticholinesterases. Some of these
trials produced substantial improvement,45 which
was considered to be consistent with the hypothesis
of selective loss of central cholinergic neurons in
Alzheimer's disease.67
The effect of physostigmine on constructional dis-
ability in Alzheimer's disease, which we first noted
in a single case in 1979,3 has not yet been confirmed.
Since our first report, we have examined five addi-
tional patients with Alzheimer's disease of mild to
moderate
severity who could undergo repeated
psychometric tests for drug evaluation under rela-
tively constant conditions. Of the total sample of six
patients, three showed an improvement in construc-


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tional ability when given physostigmine, as assessed
by copying of geometric figures. In this report we
describe
further
observations on
the
effect
of
physostigmine
on
constructional
disability
in
Alzheimer's disease.
Supported by Grant No. 80-09 and 81-03 from National Centre for
Nervous, Mental and Muscular Disorders (NCNMMD) of the
Ministry of Health and Welfare of Japan.
Address for reprint requests: Dr Osamu Muramoto, Department of
Neurology, Institute of Clinical Medicine, University of Tsukuba,
Ibaraki 305, Japan.
Received 23 June 1983 and in revised form 28 October 1983.
Accepted 2 December 1983
Patients and methods
A description of six patients who participated in this study
and the overall results appear in table 1. The patients were
selected from sixteen patients clinically diagnosed as hav-
ing presenile dementia of the Alzheimer type whom we
have followed for the past four years. The criteria for selec-
tion were as follows: (1) remarkable constructional distur-
bance, (2) mild to moderate dementia and (3) willingness
to undergo repeated psychometric tests under relatively
constant conditions. Clinical diagnosis of Alzheimeres dis-
ease was based on published research criteria.8 Other
treatable and non-treatable causes of dementia were ruled
out by extensive physical, neurological, neuroradiological
and laboratory examinations. All patients scored four or
less on the ischaemic score of Hachinski et al.9 Clinical
features of these six patients was quite similar. They had
mild to moderate degree of amnesia and disorientation.
Most of them had difficulty in writing but their ability to
read was relatively well preserved. Patients 1, 3 and 4 also
showed dressing apraxia. Patient 3 had a moderate degree
of amnestic aphasia. Although no patient showed obvious
pyramidal or extrapyramidal signs, patients
1, 3 and 4
showed occasional jerky movements of the limbs and
trunk, probably myoclonus. All patients showed diffuse
brain atrophy of mild to moderate severity on the CT scan.


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The EEG was abnormal with theta-dominant slowing, but
without paroxysmal discharges
in
all patients.
It was
difficult to estimate objectively the rapidity of the progress
of dementia in these patients because most of them were in
the early stage of the disease. However, at least at the time
of this study, it was our impression that the disease prog-
ressed relatively rapidly. This was especially true in the
case of patients 1, 2, 3 and 6, whose constructional distur-
bance deteriorated so rapidly that within half a year they
could no longer do the same tasks as they did in the present
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Journal of Neurology, Neurosurgery, and Psychiatry 1984;47:799-804
Looking with a paralysed eye: adaptive plasticity of
the vestibulo-ocular reflex
BRUNO ESTANOL,* GUILLERMO LOPEZ-RIOSt
From the Departments ofNeurology* and Neuro-otology, t Hospital General, Centro Medico Nacional,
Instituto Mexicano Del Seguro Social, Mexico City, Mexico
SUMMARY When a patient with a peripheral monocular paresis is forced to look with the paretic
eye, head movements induce the sensation of an unstable visual world. The patient behaves as if
he had acute bilateral labyrinthine lesions. These symptoms are due to the lack of compensatory
ocular movement and the patients complain that the visual objects move in the direction opposite
to the head. The patients develop ataxia, nausea, vomiting and past pointing. The symptoms,
however, are transient and consistently disappear after approximately 48 hours. The central
adaptation to looking and seeing with the paralysed eye is associated with a plastic change of the
VOR. This plastic adaptation is probably induced by the large retinal slip produced by the lack of
compensatory movement of the eye and can be studied in the normally mobile eye in the dark.
The psychophysical adaptation is probably generated by an efferent copy or corollary discharge
of the vestibular system to the visual system that cancels the retinal error.
When a patient with a monocular paresis is forced to
use his paretic eye by patching his normally mobile
eye, head movements induce the sensation of an
unstable visual world. The subject develops ataxia,
nausea and vomiting. He develops hypermetria in
the finger to nose test with consistent over-shooting.
If he lies still without moving the head, the sensation
that the visual surroundings are moving decreases.
The patient behaves as if he had acute bilateral
labyrinthine lesions. Nevertheless, the symptoms
consistently disappear after the sound eye is persis-
tently covered for 24 to 48 hours. The patient is able
to walk again without ataxia. The nausea and vomit-


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ing and the overshooting vanish. The patient states
that the oscillopsia is greatly diminished. Since the
eye is paralysed there has occurred a central com-
pensation in subjects with a normal central nervous
system. How does this compensation come about?
Two
types
of
adaptation
may
explain
these
phenomenon. A plastic change in the motor output
of the vestibular system or the neurons of the
oculomotor nuclei or a psycho-physical adaptation
Address for reprint requests: Dr Bruno Estahiol,
Division de
Medicina, Hospital General, Centro Medico Nacional, Instituto
Mexicano Del Seguro Social, Cuauhtemoc 330, Mexico 7, D.F.,
Mexico City Code: 06720.
Received 20 September 1983 and in revised form 4 February 1984.
Accepted 18 February 1984
to the increased retinal slip.
We postulated that the plastic adaptation of the
vestibulo-ocular reflex (VOR) in turn, may be an
increase in the gain of the reflex that attempts to
compensate the large retinal error or a decrease in
the gain in the reflex in order to diminish the mis-
match in the brain between visual and vestibular
impulses. An adaptive plasticity in the vestibulo-
ocular responses to a change in the visual retinal
error has been well demonstrated in the monkey and
normal human subjects.36 Thus, an increase in reti-
nal error by wearing 2 x magnifying lenses, has been
shown to induce a high gain of the VOR. We
decided to investigate the behaviour of the gain of
the VOR in the normally mobile eye in darkness in
patients with monocular paralysis in order to eluci-
date
the central mechanisms operating when
a
patient with a paretic eye is forced to look with the
abnormal eye, the sound eye being covered. This
model is ideal to study changes in gain of the VOR
in human subjects because the normally mobile eye
receives a normal efferent outflow of impulses from
the vestibular and the ocular-motor systems.
Patients and methods
Patient 1
A
28-year-old
female,
with
a
history
of
migraine,
developed a week prior to her admission, severe pain in the
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Journal of Neurology, Neurosurgery, and Psychiatry 1984;47:1002-1008
EMG patterns in abnormal involuntary movements
induced by neuroleptics
N BATHIEN, RM KOUTLIDIS, P RONDOT
From the Service de Neurologie, Hopital Saint-Anne, Cochin-Port-Royal, and the Laboratoire de Physiologie,
Faculte de Medicine, Saint-Antoine, Paris France
SUMMARY Electromyographic (EMG) activity of abnormal involuntary movements and their
modifications after Piribedil, a dopaminergic agonist, were analysed in patients presenting with
tremor or tardive dyskinesia induced by treatment with neuroleptics. Quantitative analysis of
EMG bursts and of their phase relationships with bursts of antagonist muscles revealed differ-
ences between tremor and tardive dyskinesia; three separate EMG types of the latter were found.
In tremor, EMG activity was coordinated between agonists and antagonists. Length and fre-
quency of bursts are characteristic. In tardive dyskinesia, phase histograms of antagonist muscle
bursts showed an absence of reciprocal organisation of EMG activity. This activity was made up
of either rhythmical bursts (type I and II according to the frequency) or irregular discharges (type
III). Piribedil decreased tremor but facilitated EMG activity in tardive dyskinesia. These results
give an objective measurement or classification of tremor and tardive dyskinesia induced by
neuroleptics.
Neuroleptics have been known to produce abnor-
malities of movement ever since their introduction
into
psychiatric
therapy
in
1952. Tremor
and
choreoathetotic movements induced by neuroleptics
were first described by Delay et al.' Dyskinesia sec-
ondary to long-term neuroleptic treatment was then
reported by Sigwald et a12 and was subsequently
called tardive dyskinesia.3 From a pharmacological
point of view the mechanisms of these two motor
disorders are different. Tremor is caused by block-
ade of dopaminergic receptors4 whereas the gener-
ally accepted explanation for tardive dyskinesia is
that
of functional
overactivity
of dopaminergic
receptors
due


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due
to
hyper-sensitivity
induced
by
"chemical denervation".58
As regards tardive dyskinesia several discrepan-
cies exist between the animal model and clinical
experience in man. For example, in rats, behavioural
supersensitivity to apomorphine after discontinua-
tion of one year of neuroleptic treatment was pres-
Address for reprint requests: Dr N Bathien, Lab. Physiologie, Fac.
Med. Saint-Antoine, 27, rue Chaligny, 75571 Paris Cedex 12,
France.
Received 2 August 1983 and in revised form 19 December 1983.
Accepted 4 February 1984
ent after one month, but had returned to normal
after 3 months.9 "° In man, however, tardive dys-
kinesia may persist long after discontinuation of
neuroleptic
treatment."
Further,
typical
tremor
activity in the upper limbs has been recorded in
patients with tardive dyskinesia activity localised in
the face or the lower limbs.'2 13 In the light of these
data we thought it appropriate to test the applicabil-
ity of the supposed pharmacological mechanisms to
the actual human model. In this work, EMG pat-
terns of neuroleptic-induced tremor and tardive
dyskinesia
were
first
established.
Piribedil,
a
dopaminergic agonist, was then injected and subse-
quent modifications of these patterns were used to
measure the response of the dopaminergic system.
Patients and methods
Twenty-four patients were included in the study, 16 with
tardive dyskinesia and eight with Parkinsonism induced by
neuroleptic treatment. Details of the clinical features are
given in table
1. The neurophysiological examinations
were carried out when the condition of each patient was
stable. Recordings were performed with the patient in sit-
ting position while at rest. The patient was seated in an
arm-chair, the upper limb semi-flexed, the forearm sup-
ported. The leg was extended with the knee slightly flexed.
Muscle activity was recorded from a pair of antagonist
1002


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Journal ofNeurology, Neurosurgery, and Psychiatry 1984;47: 1016-1019
Transient inaccuracy in reaching caused by a posterior
parietal lobe lesion
JOSE M FERRO
From the Neurobehavioral Unit, Centro de Estudos Egas Moniz, Department ofNeurology, Hospital de Santa
Maria, Lisbon, Portugal
SUMMARY A transient disturbance of manual reaching in both hemispaces associated with a small
contralateral posterior perietal lobe (area 7) lesion is described. This defect was increased when
the patient tried to reach without viewing of the affected arm. Inacurate reaching is a distinct
syndrome from visuomotor or optic ataxia, and is interpreted as a failure in guiding the arm
towards specific sites of the space.
Inaccurate reaching and manual ataxia are consis-
tent findings after posterior parietal lesions in the
monkey.'-' This defect is confined to the limbs con-
tralateral to the lesion. In humans unimanual reach-
ing defects affecting both visual fields are very rare
and unilateral posterior parietal lesions usually pro-
duce visuomotor ataxia of one or both hands in the
contralateral half-field.'-'
Tzavaras and Masure,'"
Levine,
Kauffman and
Mohr,'3
Perenin
et
al14
described patients who were mostly impaired when
they tried to reach with the contralesional arm into
both half-fields. Misreaching was interpreted by
Levine et al'4 as due to a loss of posterior parietal
neurons subserving a supramodal function of integ-
ration of visual and upper extremity sensory and
motor information.
We report a patient who had a similar but trans-
ient disorder of reaching caused by a small ischaemic
left posterior parietal lesion.
Case report
A
73-year-old
right-handed
woman
came
to
the
emergency room of our hospital complaining of speech
disturbance, incoordination of her right hand and of bump-
ing obstacles with her right limbs. These symptoms had
suddenly appeared four hours before. Blood pressure was
110-80 mmHg and general physical examination was nega-
tive. Neurological examination disclosed fluent speech with


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abundant circumlocutions and some verbal paraphasias.
Understanding
of
oral commands
and naming were
Address
for
reprint
requests:
Jost
M.
Ferro,
M.D.,
Neurobehavioral Unit, Centro de Estudos Egas Moniz, Hospital de
Santa Maria, 1600 Lisboa, Portugal.
Received 25 October 1983, and in revised form 7 March 1984.
Accepted 10 March 1984.
impaired but repetition was normal. There was a right
homonymous hemianopia, flattened right naso-labial fold,
an old left peripheral facial palsy and a questionable right
extensor plantar response. Limb strength, tonus and deep
tendon reflexes were symmetrical. Manual reaching was
disturbed with the right hand in both hemispaces and to a
minor degree with the left hand in the right hemispace.
(We use the term hemispace in the sense defined by Heil-
man and Valenstein:"I the space to one side of the midline
of the body).
Routine blood counts and serum chemistry examinations
were normal except for an abnormal response on a glucose
loading test.
Formal neuropsychological evaluations were carried out
on the 3rd, 7th and 10th days of illness. On the 3rd day
after onset language disturbance assessed with a standar-
dised aphasia battery'6 was very mild: spontaneous speech
was fluent and anomic, confrontation naming was moder-
ately impaired (10 out of 16 objects). Aural comprehen-
sion and word and sentence repetition were normal. The
patient showed very severe alexia, agraphia and contruc-
tional disability: she could neither read or copy (with either
hand) letters and her own name, nor copy (with either
hand) simple drawings. Her performance on the Benton
Fogel Test of three-dimensional constructional praxis was
very poor: she scored 4/29 and presented "closing-in"
phenomenon. She showed no bucco-facial or limb apraxia,
but she was somewhat clumsy when manipulating objects
with the right hand. She still presented a right homonym-
ous hemianopia and right threat reflex was absent. Visual
fixation, spontaneous conjugate eye movements, slow and


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saccadic pursuit were normal. Optokinetic nystamus was
diminished to the right. Right hand strength and sensation
were normal. However, even with free eye and head
movements, when she attempted
to reach
for
visual
targets, (for example, trying to grasp the examiner's index
finger with her index finger and thumb) her right hand
performance was impaired in both hemi-spaces, while the
left hand performance
was
accurate. When
free eye
1016


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Journal ofNeurology, Neurosurgery, and Psychiatry 1984;47:1075-1080
Behavioural manifestations of third ventricular
colloid cysts
JEFFREY M LOBOSKY,* JOHN C VANGILDER,* ANTONIO R DAMASIOt
From the Department ofSurgery (Division of Neurosurgery*), and Department ofNeurology (Divisioni of
Behavioural Neurologyt), The University of Iowa College of Medicine, Iowa City, Iowa, USA
SUMMARY Three patients with third ventricular colloid cysts manifested disturbances of memory,
emotion and personality in the absence of hydrocephalus. All three patients demonstrated
significant improvement following removal of the tumours. The symptoms and signs associated
with these neoplasms may be attributed to compression or vascular compromise of the diencepha-
lon with disorder of major limbic system structures. Tumour removal should be undertaken in
patients with symptoms even in the absence of hydrocephalus, and ventricular shunting may be
inadequate as a sole therapeutic measure.
Colloid cysts of the third ventricle are uncommon,
comprising less than 1% of intracranial neoplasms.
Initially described by Wallmann'
in
1858,
they
remained no more than a pathologic curiosity until
Dandy's2 first successful operative removal of this
tumour in 1921. These midline masses are benign
and
lend
themselves
to complete removal
with
minimal morbidity and mortality utilising micro-
scopic surgical techniques.
Colloid tumours afflict males and females with
equal frequency. They have been reported between
the age extremes of 2 months and 79 years but most
become symptomatic between the third and fifth
decades of life. The cysts range in size from 0-3 to 9
cm but the majority are found to be between 1 and 3
cm
in diameter.
Sjovall3
initially postulated the
paraphysis as the site of origin of these tumours but
this
theory
was
later
challenged
by
Kappers.4
Shuangshoti5 subsequently suggested that the cysts
arise from infolding of the neuroepithelium which
lines the ventricular cavities thus accounting for


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their occurrence in areas other than the anterior
third ventricle. Most neuropathologists concur with
this latter theory of pathogenesis.
The symptomatology of colloid cysts is protean
and the classical history of positional headache with
intermittent apoplectic episodes is rare. Nonethe-
Address for reprint requests: Jeffrey M Lobosky, MD, Division of
Neurosurgery, The University of Iowa Hospitals and Clinics, Iowa
City, Iowa 52242, USA.
Received 31 January 1984
Accepted 10 March 1984
less, headache is the most consistent complaint and
is usually related to accompanying hydrocephalus.
Venous distention secondary to compression of the
deep cerebral veins or their tributaries has also been
postulated as a contributing cause of the cephal-
gia.67
Less attention has been focused upon the abnor-
mal behavioural manifestations of this disorder and
early authors-5I
considered the neuropsychological
disturbances to be a reflection of ventricular dilata-
tion. Others' "12-'4 have noted a similarity between
the mental decline in patients with colloid cysts and
in those with normal pressure hydrocephalus. Thus,
a
causative
relationship
between
the
two
has
become
accepted. The
alternative
possibility
of
diencephalic dysfunction from the tumour has been
largely ignored.
Yenerman,'4
in his review of 54 patients with
neuroepithelial cysts, agreed that hydrocephalus was
the most likely cause for the frequently observed
dementia. He and others6"
14 added, however, that
pressure effects from the tumour on diencephalic
structures might play a significant aetiologic role. In
this report we describe three patients with colloid
cysts of the third ventricle whose findings may help
elucidate the role of diencephalic dysfunction in the
generation of abnormal behavioUral symptoms.
Case reports
Case 1
In June, 1980. a 64-year-old housewife was investigated
for a 3 year history of progressive gait difficulty and uri-
1075


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Journal of Neurology, Neurosurgery, and Psychiatry 1985;48:145-149
Cerebellar degeneration in dominantly inherited
spastic paraplegia
CL SCHOLTZ, M SWASH
From the Departments ofNeuropathology and Neurology, The London Hospital and The London Hospital
Medical College, London, UK
SUMMARY The clinical features of five affected members in three generations of a family with
dominantly inherited Strumpell's spastic paraplegia are described, together with the pathological
findings in two cases. The late presentation and slow progression of the disease encompass
features of the types I and II of other authors illustrating the heterogeneous expression of the
disorder. Cerebellar involvement was evident clinically and pathologically.
Hereditary spastic paraplegia is a disorder character-
ised by slowly increasing spasticity and weakness of
the lower limbs.' Since Seeligmuller s original study2
and the reports of Strumpell34 and Lorrain5 approx-
imately 200 families with the disorder have been
described.6" Pathologically
it is characterised by
degeneration of the corticospinal tracts and, to a
lesser extent, of the posterior columns.' 67 It may
present as a pure form, "Strumpell-Lorrain Dis-
ease" ,
in which degeneration of the corticospi-
nal
tracts occurs below
the decussation
of the
pyramids,7 or as a complicated form in which there is
extension of the disease process into other neuronal
systems.8 In the latter, optic nerve involvement and
retinal
degeneration
have
been
described
and
extrapyramidal features, distal atrophy of the upper
limbs, and dementia may also occur.9 Mild cerebel-
lar ataxia may occur in the arms in some cases, but
ataxia of gait is uncommon.'0 Hereditary spastic
paraplegia is of adult onset and progression is slow;
longevity is usually unimpaired.
Two forms of pure dominantly inherited spastic
paraplegia have been recognised.78 In the Type 1
form, spasticity of the lower limbs is more marked
than weakness. In this group of patients there is usu-
ally a history of delay in developmental milestones,


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particularly in walking, and the disorder usually pre-
sents before the age of 35 years. Progression is slow
and disability variable. In the Type 2 form muscle
weakness, distal sensory loss and urinary urgency or
even incontinence may be evident. This form usually
Address for reprint requests: Dr M Swash, The London Hospital,
Whitechapel, London El 1BB, UK.
Received 3 April 1984 and in revised form 19 July 1984.
Accepted 21 July 1984
presents after the age of 35 years but progresses
more rapidly resulting in more disability than in the
Type 1 form. Families affected by a similar disorder,
but inherited as an autosomal recessive trait have
also been reported, but this mode of inheritance is
uncommon.8 " Many of these latter families show
other features,
in addition to corticospinal
tract
involvement.8
In
this
report we
describe
the
clinical
and
pathological features of. a late-onset, dominantly
inherited form of the disease in which ataxia accom-
panied severe spastic paraplegia.
Clinical features
The family tree is illustrated in fig 1.
Generation II (six members; one affected)
I.1. female, I1.2. female, I1.3. female. Died in infancy
cause unknown.
II.4. female. Died aged 83 yr. She was bedridden for many
years before her death. Postmortem examination carried
out 40 years ago at another hospital showed degeneration
of the
lateral columns and spinocerebellar
tracts. No
further details are known'
11.5. female. Died in childhood.
11.6. male. Died aged 36 yr of pulmonary tuberculosis.
Generation III (six members; two affected)
111.1. female. Died aged 60 yr of pneumonia and renal
disease.
111.2. female. Presented aged 50 yr with gradually progres-
sive spastic paraplegia. She required a wheelchair by the
age of about 70 years. No cerebellar ataxia was observed in
the arms. Eye movements and vision were normal. She
died at the age of 84 years. Postmortem examination was
performed.
111.3. female. Died aged 5 yr of meningitis.
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Journal of Neurology, Neurosurgery, and Psychiatry 1985;48:256-262
Ultrastructure of cerebral arteries following
experimental subarachnoid haemorrhage
JD PICKARD,* DI GRAHAM,t ELIZABETH MATEAR,t P MACPHERSON,t
A TAMURA, W FITCH§
From the Departments ofNeurosurgery, * Neuropathology, t Neuroradiologyt and Neuroanaesthesia§
Institute ofNeurological Sciences, Southern General Hospital, Glasgow, Scotland, UK
SUMMARY Scanning and transmission electron microscopy have been used to examine the ultra-
structure of cerebral arteries taken from dogs up to nine days following the injection of autolog-
ous blood into the suprachiasmatic cistern and using meticulous perfusion-fixation technique. No
ultrastructural changes in the cerebral arteries were noted either at sites of radiologically demon-
strated arterial constriction or elsewhere. The only abnormality noted was the presence of some
leucocytes and macrophages in the subarachnoid space surrounding the arteries. These results are
discussed in relation to changes in cerebrovascular reactivity that occur at this stage following
subarachnoid haemorrhage.
Post-mortem studies in man have revealed that
where death occurs at least three weeks after sub-
arachnoid haemorrhage, there may be subendothel-
ial infiltration with lymphocytes and macrophages
followed by fibrosis localised to the segment of
artery shown previously to be in spasm by angiogra-
phy.'-3 Where death occurs earlier there may be
some inflammatory changes within the adventitia
and possibly some necrosis within the tunica media.
Controversy has arisen over whether or not such
structural changes are reproducible in laboratory
animals. Three types of experimental subarachnoid
haemorrhage have been used: the cisternal injection
of autologous blood; the rupture of an intracranial
artery and the application of high concentrations of
spasmogenic agents directly onto a cerebral artery.
Within days, at least in the subhuman primate and
the dog, the changes described included swelling and


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separation of endothelial cells from the internal elas-
tic lamina and degeneration of some smooth muscle
cells. However, more recent work using the techni-
que of cisternal injection of autologous blood has
failed to replicate these findings in the cat, dog and
baboon
(see
discussion
for
references).
This
Address for reprint requests: Mr JD Pickard, Wessex Neurological
Centre, Southampton General Hospital, Shirley, Southampton
S09 4XY, UK.
Dr A Tamura: present address, Dept of Neurosurgery, Teiko Uni-
versity Hospital, 2-11-1 Kaga Itaboshi-Ku, Tokyo, Japan.
Received 30 May 1984 and in revised form 31 July 1984.
Accepted 6 August 1984
method, however, is known to induce changes in the
responsiveness of the cerebral circulation to hyper-
capnia and drug induced hypotension, when studied
one week later both in the baboon and dog and is
associated with abnormal CSF prostanoid levels.46
The aim of our study was to determine whether
such "physiological" changes are associated with
ultrastructural changes in the cerebral arteries. A
possible explanation for the contradictory results in
the literature might be poor fixation and hence we
paid particular attention to the technique of perfu-
sion fixation in order to correlate the scanning and
transmission electron microscopic appearances with
the angiographic findings.
Material and methods
General preparation
Twenty-three adult mongrel dogs of either sex were used
weighing between nine and 25 kg. There were three
categories of dogs, namely three controls, seven acute and
thirteen chronic preparations. The animals were starved
overnight and on the day of the experiment anaesthesia
was induced with intravenous sodium thiopentone (10-30
mg/kg iv). The animals were intubated and allowed to
breathe spontaneously on a mixture of 70% nitrous oxide
and 30% oxygen. Under sterile conditions a femoral artery
was exposed and a headhunting catheter inserted. Using an
image intensifier this was guided into a common carotid
artery and angiography performed by injecting 5 ml of


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Journal of Neurology, Neurosurgery, and Psychiatry 1985;48:297-301
Occasional review
The limbic system and the localisation of herpes
simplex encephalitis
ANTONIO R DAMASIO,* GARY W VAN HOESEN*t
From the Departments ofNeurology* and Anatomyt, University ofIowa College of Medicine, Iowa City,
Iowa, USA
SUMMARY The selective destruction of temporal and frontal lobe structures by herpes simplex
encephalitis has been explained as a consequence of the proximity of those regions to the point of
entry of the virus in the encephalon, through olfactory pathways or meningeal branches of the
trigeminal nerves. An alternative hypothesis is presented: that the encephalitis is due to a special
affinity of the herpes simplex Type 1 virus for the limbic cortices, that is, that distinctive
neuroanatomical, neurochemical and neuroimmunological properties of those cortices permit the
virus to manifest its destructive behaviour, regardless of the route of entry to the CNS, possibly
during altered immunological states. The study of the neurochemical and neuroimmunological
properties of the limbic cortices may be a useful approach to the enigma of why and when herpes
simplex Type 1 causes encephalitis.
Despite some advances in antiviral therapy, herpes
simplex encephalitis is still a devastating and often
fatal disease.' Patients who survive do so with major
defects of memory and affect, often incompatible
with personal and social rehabilitation. The agent of
the encephalitis, the herpes simplex virus Type 1,
resides latent, possibly for many years, in the trigem-
inal ganglia of its victims.2 4 But the reason why the
virus abandons its dormant state to invade and des-
troy the central nervous system remains a mystery.
It is also not known why the virus selectively dam-
ages some neural structures of the temporal and
frontal lobes and spares most other cortices, gray
matter nuclear masses and related white matter.
Considering that infection with herpes simplex virus
Type 1 is highly prevalent in humans, it is important


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to discover (a) why the virus turns from relatively
benign tenant to malignant invader, (b) the route
Address for reprint requests: Antonio R Damasio, MD PhD,
Department of Neurology. University of Iowa Hospitals & Clinics,
Iowa City, IA 52242, USA.
Received 8 June 1984 and in revised form 6 September 1984.
Accepted 18 September 1984
This work was supported by NINCDS Grant P01 NS 19632-01.
taken to invade the central nervous system, and (c)
the reasons why a specific set of neural structures is
consistently chosen as target. In this article we
address the latter two issues.
The first explanation proposed for the unique
localisation of herpes simplex encephalitis invoked
intranasal inoculation and spread along the olfactory
pathways into the nearby temporal and frontal cor-
tices.5 More recently, Davis and Johnson advanced
another explanation.6 They postulated that from its
latent site in the trigeminal ganglia, the virus would
travel through the tentorial branches of the trigemi-
nal nerve in the direction of the dura mater. Because
the tentorial nerves supply the dura mater in both
the middle and anterior fossae, in and about the
areas that the mesial and polar temporal lobes and
the inferior surface of the frontal lobes directly over-
lie,' the virus would then travel in cell to cell contact
across the meninges and into the subjacent cortices.
Both explanations are plausible but they do not
acknowledge (a) that the structures damaged by
herpes simplex encephalitis are part of an anatomi-
cal and functional neural unit, the limbic system; (b)
that the boundaries of that anatomical system are
respected, often faithfully, by the destructive pro-
cess; (c) that if the location of damage would be due
297


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Cholinergic correlates of cognitive impairment in Parkinson' disease: comparisons with Alzheimer' disease


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Journal of Neurology, Neurosurgery, and Psychiatry 1985;48:413-421
Cholinergic correlates of cognitive impairment in
Parkinson' s disease: comparisons with Alzheimer' s
disease
ELAINE K PERRY,* MICHAEL CURTIS,t DAVID J DICK,t JOHN M CANDY,§
JOHN R ATACK,* CLIVE A BLOXHAM,* GARRY BLESSED,II ANDREW FAIRBAIRN,**
BERNARD E TOMLINSON,* ROBERT H PERRY§
From the Department ofNeuropathology, Newcastle General Hospital; * Department ofPathology, Royal
Victoria Infirmary; t Regional Neurological Centre, Newcastle General Hospital; t MRC Neuroendocrinology
Unit, Newcastle General Hospital; § Psychogeriatric Unit, Newcastle General Hospitall and St Nicholas
Hospital, Newcastle Upon Tyne,** UK
SUMMARY Dementia in Parkinson's disease has previously been attributed to the presence in the
cerebral cortex of Alzheimer-type neuropathological abnormalities. New evidence suggests,
however, that dementia in this disease usually occurs in the absence of substantial Alzheimer-
type changes in the cortex and may be related to abnormalities in the cortical cholinergic system.
Thus, in Parkinsonian patients with dementia there were extensive reductions of choline acetyl-
transferase and less extensive reductions of acetylcholinesterase in all four cortical lobes. Choline
acetyltransferase reductions in temporal neocortex correlated with the degree of mental impair-
ment assessed by a test of memory and information but not with the extent of plaque or tangle
formation. In Parkinson's but not Alzheimer's disease the decrease in neocortical (particularly
temporal) choline acetyltransferase correlated with the number of neurons in the nucleus of
Meynert suggesting that primary degeneration of these cholinergic neurons may be related,
directly or indirectly, to declining cognitive function in Parkinson's disease.
Evidence of an involvement of the transmitter,
acetylcholine, in memory' 2 has stimulated investiga-
tion of the cholinergic system in disorders of the
human brain affecting memory and other cognitive


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functions. An abnormality of the cholinergic system
in Alzheimer-type dementia is now well established
and correlations between the severity of the disease
(assessed either neuropathologicallly or clinically)
and reductions in the cortical cholinergic enzyme,
choline
acetyltransferase
(CAT),
have
been
reported.34 Dementia or cognitive impairment also
occurs in a significant number of patients with Par-
kinson's disease (for review, see reference 5) and
several reports have attributed the dementia to the
presence of Alzheimer-type cortical neuropathology
in these cases.67
Address for reprint requests: Dr EK Perry, Dept of Neuropathol-
ogy
Research,
Newcastle
General
Hospital,
Westgate
Rd,
Newcastle upon Tyne, NE4 6BE, UK.
Received 14 February 1984 and in revised form 3 October 1984.
Accepted 10 October 1984.
The condition of the cortical cholinergic system in
Parkinson's disease is unclear since some groups
have reported, in cases not assessed for mental func-
tion, normal CAT
activities8 9
whereas another
group has reported CAT reductions correlating with
the degree of dementia assessed retrospectively.'0
With
respect
to the condition
of the principal
cholinergic nucleus innervating the neocortex-the
nucleus of Meynert-there is evidence that loss of
neurons occurs in both Parkinson's and Alzheimers
disease." 12 Whether this neuronal degeneration in
both diseases is closely associated with the cortical
cholinergic abnormalities (assessed biochemically) is
unclear although this issue is relevant to the ques-
tion
of whether
subcortical
cholinergic
abnor-
malities represent primary or secondary features of
the disease processes.
The present investigation was undertaken primar-
ily to examine the relationship between, on the one
hand, cognitive impairment or dementia in Parkin-
son's disease and, on the other hand, the presence
of
cortical
cholinergic
abnormalities,
cortical
413


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Journal of Neurology, Neurosurgery, and Psychiatry 1985;48:977-981
The influence of physostigmine on visual-vestibular
interaction in hereditary ataxias
CC TIJSSEN,t LJ ENDTZ,* C GOORt
From the Departments ofNeurology* and Neurophysiology, t Municipal Hospital Leyenburg, The Hague,
The Netherlands
SUMMARY Visual suppression of caloric nystagmus was studied in five patients with hereditary
ataxia before and after administration of physostigmine. All patients had an initial abnormal
ocular fixation index that improved after physostigmine was given. The data indicate that there is
a partly reversible disturbance of visual-vestibular interaction in patients with hereditary ataxia,
caused by an impairment of a central cholinergic mechanism.
The
hereditary
ataxias
constitute
a number
of
degenerative cerebellar diseases having ataxia as
their common feature. The pathophysiological basis
underlying
this group of disorders
is unknown.
Hereditary factors play an important role in their
aetiology but sporadic cases also occur.' Recent
studies have indicated a possible biochemical deficit.
Primary or secondary abnormalities of pyruvate
metabolism have been identified in up to 50% of
unselected series of patients with hereditary atax-
ias,23 and in patients with Friedreich's ataxia a low-
ered activity of pyruvate oxidation caused by a
defect at the level of the third component of the
pyruvate
dehydrogenase
complex,
that
is
the
lipoamide
dehydrogenase,
has
been
demons-
trated.4-6 This disturbance of the pyruvate metabol-
ism
leads
to
impaired
production
of
acetyl-
coenzyme A and subsequently to impaired synthesis
of the
neurotransmitter
acetylcholine.26
Acetyl-
choline
synthesis
seems
exquisitely
sensitive
to
impaired pyruvate oxidation.3 Clinical studies have
suggested that low doses of physostigmine, a cen-
trally active cholinesterase inhibitor, improve signs
of ataxia
in patients with hereditary ataxias.79
Objective criteria to evaluate the influence of this
drug are however lacking.
A
number
of
ocular
abnormalities
occur


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occur
in
hereditary ataxias including nystagmus (especially
gaze-evoked, rebound and downbeat nystagmus),
impaired smooth pursuit, saccadic dysmetria and
Present address and address for reprint requests: Dr CC Tijssen,
Department of Neurology, St. Elisabeth Hospital, P.O. Box 90151,
5000 LC Tilburg, The Netherlands.
Received 6 July 1984 and in revised form 6 November 1984.
Accepted 12 January 1985
defective visual suppression of vestibular nystag-
MUS.'0-'2 The
ability
to suppress the vestibulo-
ocular reflex (VOR) by fixation is a valuable indica-
tion of cerebellar pathology.'2-5 There is evidence
that
the
vestibulo-cerebellum,
especially
the
flocculus,
is
an
important
site
for
this
visual-
vestibular
interaction
that
facilitates
adaptive
changes in the VOR.'6-2'
In this study we investigated the influence of the
drug physostigmine on the visual suppression of
caloric-induced vestibular nystagmus in five patients
with hereditary ataxia.
Material and methods
Five patients with hereditary ataxia were studied, whose
relevant data are summarised in the table. The patients
used no drugs at the time of investigation. Each subject
was
examined
with
electro-nystagmography
(ENG)
equipment using a time constant of 5 seconds and a filter of
15 Hz (3 dB). Horizontal eye movements were recorded
with surface electrodes placed near the inner and outer
canthus of both eyes. A voluntary eye movement over 200
was used for calibration of the angular velocity of the slow
phase of the nystagmus. Caloric stimulation was applied by
irrigating both ears with 50 ml of water at 30°C during 20
seconds with eyes closed. If no good response was obtained
water at 15°C was also applied. With this procedure a max-
imum slow phase eye velocity occurs at about 45 seconds
after the onset of irrigation and maintains for about 30
seconds.25 The visual suppression test was carried out dur-
ing this maximum intensity of caloric nystagmus at 55 sec-
onds after the onset of irrigation. The patients were asked


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to open their eyes and fix their gaze upon a red spot light at
a distance of 11/2 metre for 15 seconds. Nystagmus fre-
quency, amplitude and slow phase velocity, which was
averaged over 10 wave forms, were measured before and
after eye opening. The maximum response during visual
977


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A study of the relationship between neurological function and vitamin E concentrations in patients with cystic fibrosis


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Journal ofNeurology, Neurosurgery, and Psychiatry 1985;48: 1097-1102
A study of the relationship between neurological
function and serum vitamin E concentrations in
patients with cystic fibrosis
HJ WILLISON,* DPR MULLER,t S MATTHEWS,t S JONES,t A KRISS, RJ STEAD,*
ME HODSON,* AE HARDINGt
From Brompton Hospital and the Cardiothoracic Institute, * the Institute ofChild Health, t and the Institute of
Neurology,t London, UK
SUMMARY A patient with cystic fibrosis and undetectable serum vitamin E concentrations is
described who developed a progressive spinocerebellar syndrome and pigmentary retinopathy
with abnormal somatosensory and visual evoked potentials (SSEPs and VEPs). In order to assess
the relationship between neurological function and serum vitamin E concentrations in cystic
fibrosis, 29 unselected patients who had no neurological symptoms were examined neurologi-
cally. Ten were randomly selected for neurophysiological assessment by recording SSEPs and
VEPs. Electroretinograms (ERGs) were also performed in five cases. The findings were corre-
lated with serum vitamin E concentrations which were unknown to the neurological investigators
prior to completion of the study. Only one patient had definite reflex and sensory abnormalities,
and the remaining 28 were clinically normal. The ERG was abnormal in two cases, one of whom
had abnormal VEPs. SSEPs were normal in all 10 cases. Twenty six patients had serum vitamin E
concentrations below the normal range. In two of the three patients who had definite neurological
or electrophysiological abnormalities serum vitamin E concentrations were below the median
value for the whole group.
Severe vitamin E deficiency as a consequence of pro-
longed fat malabsorption is now a well established
cause of a progressive neurological disorder com-
prising ataxia, areflexia, and proprioceptive loss.
This syndrome is particularly prevalent in children
with abetalipoproteinaemia and chronic liver dis-
ease.' It has also been reported after extensive ileal


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resection23 and in a few cases of cystic fibrosis.4-6
Pathological
studies in man78 and experimental
animals9 have shown that vitamin E deficiency pro-
duces a dying-back neuropathy in sensory neurons
which affects the centrally directed fibres in the
posterior columns more severely than the peripheral
axons. Mild degenerative changes also occur in the
spinocerebellar tracts.7
Reduced serum concentrations of vitamin E are
common in patients with cystic fibrosis, but it is not
Address for reprint requests: Dr DPR Muller, Department of Child
Health, Institute of Child Health, 30 Guilford Street, London
WC1N IEM.
Received 11 January 1985 and in revised form 26 March 1985.
Accepted 5 April 1985
clear how often these are of clinical or pathological
significance. This paper describes a patient with
undetectable serum vitamin E concentrations who
developed a spinocerebellar syndrome and a pig-
mentary retinopathy. The results of a study correlat-
ing
vitamin
E
status
with
clinical
and
neurophysiological observations in 29 neurologi-
cally asymptomatic cases of cystic fibrosis are also
reported.
Case report
A 22-year-old woman with cystic fibrosis presented with
meconium ileus in infancy. She had steatorrhoea and
recurrent chest infections throughout childhood, and a
number of episodes of jaundice before the age of five.
Hepatomegaly was first noted when she was 12, and on
investigation it appeared that her liver disease resulted
from chronic active hepatitis. At the age of 14 yr she com-
plained of night blindness and was found to have a pigmen-
tary retinopathy. This was attributed to a documented
severe deficiency of vitamin A but her symptoms progres-
sed despite replacement therapy. Serum vitamin A con-
centrations increased but remained below the normal
1097


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conduction velocity in the human spinal cord: slowed conduction in multiple sclerosis and radiation myelopathy


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Journal ofNeurology, Neurosurgery, and Psychiatry 1985;48: 1135-1139
Motor conduction velocity in the human spinal cord:
slowed conduction in multiple sclerosis and radiation
myelopathy
SJ SNOOKS, M SWASH
From St Mark's Hospital, and The London Hospital, London, UK
SUMMARY Transcutaneous electrical stimulation of the central nervous system was used to meas-
ure motor conduction velocity in the human spinal cord in 21 subjects aged 22 to 75 years (mean
55 years), none of whom had neurological disease. The motor conduction velocity between the
sixth cervical (C6) and first lumbar (L1) vertebral levels was 67-4
+ 9-1 m/s. This probably
represents conduction velocity in the corticospinal tracts. In these subjects the motor conduction
velocity in the cauda equina, between the first lumbar (Li) and fourth lumbar (L4) vertebral
levels, was 57 9 + 10*3 m /s. In four of five patients with multiple sclerosis, all with corticospinal
signs in the legs, motor conduction velocity between C6 and Li was slowed (41-8 + 16-8 m /s), but
cauda equina conduction was normal (55.8
+ 7-8 m/s). Similar slowing of spinal cord motor
conduction was found in a patient with radiation myelopathy. This method should provide a
relevant, simple clinical test in patients with spinal cord disease.
The scope of electrophysiological investigation of
the central nervous system is limited and, in particu-
lar, there is no method available for assessment of
the motor system in the spinal cord. We have
devised a method for measurement of the motor
conduction velocity in the human spinal cord by
adapting the technique of transcutaneous electrical
stimulation of the CNS devised by Merton and Mor-
ton.' 2 This method promises to be of considerable
practical value in clinical practice. It also enables
motor conduction
to be
assessed
in the cauda
equina. In this report we present our results in nor-
mal subjects and show that motor conduction veloc-
ity in the spinal cord is slowed in some patients with
demyelinating diseases.
Methods


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Methods
We stimulated the spinal cord and cauda equina at C6, Li
and L4 vertebral levels respectively using a device consist-
ing of two
1 cm diameter saline-soaked pad electrodes
mounted 5 cm apart. We have not found it possible, so far,
to stimulate reliably the motor roots of the cauda equina at
Address for reprint requests: Dr M Swash, The London Hospital,
London El lBB, UK.
Received 14 August 1984 and in revised form 19 November 1984.
Accepted 23 November 1984
a lower vertebral level than L4. The subject lay in the left
lateral position and an earth electrode was applied to the
right upper thigh. The stimulating electrodes, mounted on
a holder, were pressed firmly against the skin overlying the
spine at the appropriate level, in the midline, with the
cathode caudally. Single shocks of 800-1500 volts, decay-
ing with a time constant of 50 uts, were used.2 The stimulus
triggered
the
oscilloscope
of a Medelec MS6 EMG
apparatus through the delay line. Muscle contraction was
observed in response to the stimulus in the paravertebral
and abdominal muscles and in the muscles of the buttocks
and legs. This was perceived as a jolt, but was not painful.
We recorded the muscle response from the pelvic floor
muscles, innervated by the S3-4 myotomes3 using intra-
anal surface electodes or, as in cases 4 and 6 (table), from
tibialis anterior (L4-5 myotomes). Selection of a lower
limb muscle, for example tibialis anterior, excludes the sac-
ral component of the spinal cord from the measurement,
but does allow lateralisation of the response. The intra-
anal recording electrode consisted of a modified telephone
jack placed in the anal canal adjacent to the external anal
sphincter muscle2 or a pair of electrodes mounted on the
tip of a rubber finger stall held digitally in the anal canal
against the puborectalis bar.4 The latter technique gave the
better result (fig 1).
The latencies from transcutaneous stimulation at C6, Li
and L4 vertebral levels, with a constant recording site,


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were used to determine latencies between C6 and Li, rep-
resenting the length of the spinal cord from C6 to the conus
medullaris, and between Li and L4, representing the ros-
tral portion of the motor roots in the cauda equina. After
1135


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Journal ofNeurology, Neurosurgery, and Psychiatry 1985;48: 1277-1283
Dopamine agonists suppress visual-cortical reflex
myoclonus
JA OBESO, J ARTIEDA, T TUNON,* MR LUQUIN, JM MARTINEZ LAGE
From the Movement Disorders Unit, Department ofNeurology, Clinica Universitaria, University ofNavarra,
Pamplona, Spain.
SUMMARY Two patients with a diagnosis of olivo-ponto-cerebellar atrophy developed cortical
reflex myoclonus to visual (flash) and somaesthetic stimuli. Oral treatment with levodopa-
carbidopa (1000/100 mg) or subcutaneous administration of apomorphine (1 mg) abolished the
visually-triggered myoclonus, without modifiying reflex myoclonus to electrical or tactile stimula-
tion. Intravenous administration of lisuride (0-1 mg) produced a marked reduction in both types
of reflex myoclonus. These results indicate a selective inhibitory effect of dopamine agonist drugs
on visual reflex myoclonus of cortical origin.
In recent years the pharmacological basis of myo-
clonus has been focused on a disorder of cerebral
serotoninergic mechanisms. This followed the dis-
covery by Lhermitte
et al,' 2
later confirmed by
others,36
that
oral
treatment
with
5-hydroxytryptophan (5-HTP) plus carbidopa pro-
duced a reduction in post-anoxic action myoclonus,
and
the
findings
of
low
CSF
levels
of
5-hydroxyindolacetic acid in similar patients who
responded
to
treatment
with
5-HTP
or
clonazepam.78 However, a deficit of serotonin may
not be important in other myoclonic disorders9 10 in
which other neurotransmitters may be involved. The
anti-myoclonic effect of clonazepam, valproic acid
or primidone might be due at least partially, to
enchancement of cerebral gamma aminobutyric acid
(GABA) activity." A protective effect of apomor-
phine against visually induced myoclonus has been
demonstrated in the baboon.'2 Quesney et al'3 found
that in patients with generalised epilepsy, apomor-
phine produced transient inhibition of spike and
wave EEG activity induced by photic stimulation,
suggesting a dopamine influence on certain types of
myoclonus.


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Cortical reflex myoclonus results from abnormal
*Present address: Neuropathology section, Hospital de Navarra,
Pamplona.
Address for reprint requests: Dr JA Obeso, Neurologia, Clinica
Universitaria, Apartado 192, Pamplona, Spain.
Received 23 January 1985 and in revised form 9 May 1985.
Accepted 17 May 1985
motor cortex activity triggered by sensory input.'4 '5
Electrophysiological characteristics of cortical myo-
clonus are the presence of enhanced cortical evoked
potentials, EEG activity time-locked to the muscle
jerks and brief EMG discharges.4 12 Clinical and
electrophysiological studies indicate the existence of
separate mechanisms underlying different types of
cortical myoclonus in man.'6 Such pathophysiologi-
cal discrimination may also indicate different phar-
macological characteristics. For example, cortical
reflex myoclonus
to somaesthetic
stimulation
is
highly responsive to serotonin agonists, but is not
improved by dopaminergic drugs.'7 We now report a
selective effect of levodopa-carbidopa and apomor-
phine on cortical reflex myoclonus induced by photic
stimulation
in
two
patients
with
olivo-ponto-
cerebellar-atrophy. These two cases were included
in a previous report on the pathophysiology of corti-
cal myoclonus.'6
Method
Electrophysiological technique
A Medelec MS 6 machine
was
used
for
electrophysiological
investigations.
Somatosensory evoked potentials (SEPs) to digital nerve
stimulation were recorded from a scalp electrode placed on
the hand area (7 cm lateral and 2 cm posterior to the
vertex) with the reference electrode on Fz (10-20 EEG
international system). Visual evoked potentials (VEPs) to
flash stimulation recorded from the scalp over the occipital
cortex also were recorded. For reasons explained previ-
ously,'8 we have designated the major cortical potential
peaks by their polarity and sequence (Ni, P1, N2, etc).
The electromyographic (EMG) reflex responses elicited by
electrical or flash stimulation were recorded simultane-
1277


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Effect of ammonia intoxication cerebral blood flow, its autoregulation and responsiveness carbon dioxide and papaverine


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Journal of Neurology, Neurosurgery, and Psychiatry 1986;49:302-309
Effect of ammonia intoxication on cerebral blood
flow, its autoregulation and responsiveness to carbon
dioxide and papaverine
ADAM CHODOBSKI,* JOANNA SZMYDYNGER-CHODOBSKA,t
KRYSTYNA SKOLASINSKA*
From the Microcirculation Research Unit,* and Department of Physiology,t Institute of Physiological
Sciences, School of Medicine, Warsaw, Poland
SUMMARY Cerebral blood flow (CBF) was measured in anaesthetised cats with 133Xe clearance
method under normal conditions and with hyperammonaemia. Elevation of blood ammonia con-
centration by an intravenous infusion of ammonium acetate caused an increase in CBF and a
parallel decrease in cerebrovascular resistance (CVR). These parameters reached, however, plateau
at an arterial blood ammonia level exceeding 500 Mmol/l. Cerebrovascular reactivity to CO2 dimin-
ished following elevation of blood ammonia concentration and at arterial blood ammonia level
exceeding 500 umol/l it was virtually abolished. In contrast, hyperammonaemia influenced neither
cerebrovascular responsiveness to papaverine nor autoregulatory properties of the cerebral circu-
lation. It is concluded, therefore, that hyperammonaemia exerts some dilatatory effect on cerebral
vessels and severely impairs chemical regulation of CBF but does not elicit cerebral vasomotor
paralysis.
A pathogenic role of ammonia in hepatic encepha-
lopathy and coma had already been recognised at the
end of the last century.' However, the mechanisms by
which hyperammonaemia affects the central nervous
system are not clear. Especially, the effect ofammonia
on regulation of the cerebral blood flow (CBF) still
remains to be elucidated.
In
1976
Chandler
and
Kindt2
demonstrated
significant elevation of intracranial pressure (ICP) in
patients suffering from hepatic encephalopathy of
different aetiologies. An increase in ICP by 200-300%
of control values has also been found in rhesus mon-
keys during hyperammonaemia
elicited by intra-


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venous infusion of ammonium acetate.3 Altenau and
Kindt4 using the same experimental model have
found that ammonia intoxication causes an increase
in CBF and impairs cerebrovascular reactivity to CO2
and autoregulatory properties of cerebral circulation.
Basing on these results, these authors have postulated
that ammonia intoxication brings about the cerebral
vasomotor paralysis leading to an increase in intra-
Address for reprint requests: Adam Chodobski, Microcirculation
Research
Unit,
Institute
of Physiological
Sciences,
School
of
Medicine, Krakowskie Przedmieicie 26/28, 00-927 Warsaw, Poland.
Received 23 November 1984 and in revised form 9 July 1985.
Accepted 13 July 1985
cranial blood volume, which in turn would produce an
elevation of ICP.
The present study was undertaken to evaluate the
effect of elevation of blood ammonia concentration
on CBF and its responsiveness to CO2. Furthermore,
cerebrovascular reactivity to papaverine, the agent
known to affect cerebral vessels in a manner different
from carbon dioxide, as well as autoregulatory prop-
erties of cerebral circulation were examined under
normal conditions and with hyperammonaemia in
order to elucidate whether an elevation of blood
ammonia concentration may result in the vasomotor
paralysis of the cerebral vessels.
Materials and methods
The experiments were carried out on 82 cats of either sex
weighing between 2 4 and 3 8 kg. Anaesthesia was induced
with
pentobarbital
sodium (Nembutal-Abbott)
injected
intraperitoneally in a dose of 20 mg/kg and maintained with
intravenous alpha-chloralose (60 mg/kg). A tracheostomy
was performed and catheters inserted into the left femoral
artery and vein for measurement of mean arterial blood
pressure (MABP), collection of arterial blood samples and
intravenous administration of drugs and solutions. In the
experiments, in which autoregulation of CBF was examined
the right femoral artery was additionally cannulated for
withdrawal of blood to produce controlled hypotension. The
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Journal of Neurology, Neurosurgery, and Psychiatry 1986;49:702-705
Short report
The effect on plasma prolactin levels of interictal
epileptiform EEG activity
MICHAEL J AMINOFF,* ROGER P SIMON,* ECKEHART WIEDEMANNt
From the Departments ofNeurology* and Medicine,t School ofMedicine, University of California, San
Francisco, California
SUMMARY
Because of the known effects of seizures on plasma prolactin, the plasma prolactin levels
were measured before and after generalised interictal epileptiform activity was provoked in the EEG
in five epileptic patients. The findings were compared with those obtained in five normal subjects
and three epileptic patients who were also exposed to flicker stimulation, but who did not develop
a photoconvulsive EEG response. There was no significant difference in baseline prolactin values,
and levels did not change with photic stimulation or in response to the presence of generalised
epileptiform activity in the EEG.
A marked increase in plasma prolactin level is known
to occur in many patients shortly after a tonic-clonic
seizure' -5 and may sometimes occur also following
partial seizures.`
However, the effect on plasma
prolactin of interictal epileptiform EEG activity is un-
known. Epileptiform EEG discharges (that is, abnor-
mal paroxysmal activity consisting of spike, polyspike
or sharp wave discharges with or without associated
slow waves) may occur without obvious clinical ac-
companiments in many patients with epilepsy. Never-
theless such EEG discharges may be accompanied by
an increase in reaction time, or by complete failure to
respond to a stimulus.8 Indeed, some authors con-
sider that generalised spike-wave activity is always ac-
companied by impaired performance.9 The likelihood
of discerning some impairment of cerebral function
during the occurrence of epileptiform activity de-
pends upon the testing technique used. In particular,
simple motor tasks are relatively little affected by gen-
eralised spike-wave EEG activity, whereas choice re-


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action time, signal detection, and short-term memory
tasks are more sensitive.8
Address for reprint requests: Dr Michael J Aminoff, Room 794-M,
Department of Neurology, University of California, School of
Medicine, San Francisco, California 94143, USA.
Received 30 July 1985.
Accepted 10 October 1985
We have examined the effect of interictal epi-
leptiform EEG activity on plasma prolactin levels be-
cause any change in prolactin levels under these
circumstances might provide further support for the
belief that interictal generalised epileptiform EEG
discharges are of functional significance. At the same
time, it would detract from the possible importance of
measuring plasma prolactin levels when attempting to
determine in epileptic patients whether clinical at-
tacks of uncertain nature represent seizures. Finally,
any increase in prolactin level with subclinical gener-
alised interictal epileptiform EEG discharges might
provide further insight to the basis of the prolactin
response accompanying seizures.
Methods
Spontaneous interictal epileptiform EEG activity occurs un-
predictably, and this would preclude the taking of blood
samples for baseline purposes before the occurrence of such
activity. Accordingly we had to use some means of pro-
voking a generalised epileptiform discharge in the EEG, and
this was achieved by photic stimulation. The subject lay on
a couch in a quiet, darkened room while a 16-channel EEG
was recorded for one hour. A Grass intermittent photic
stimulator was then used to cause rhythmic flash stimulation
while the EEG was recorded bipolarly from a wide region of
the scalp including the parietal and occipital areas. Flash
stimuli were delivered at 1, 3, 6, 9, 12, 15, 18 and 21 Hz. At
each flash rate the EEG was recorded with the subject's eyes
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This Week in The Journal
Retinal Pigmented Epithelium
“Nibbles” Away Outer Segment
Tips
Ankita Umapathy, Gil Torten, Antonio
E. Paniagua, Julie Chung, Madeline
Tomlinson, et al.
(see pages 2653–2664)
The retinal pigmented epithelium (RPE)
serves a remarkable support role in the
retina, nourishing and maintaining pho-
toreceptor cells in ways that are crucial
for vision. This includes “nibbling” away
at the tips of the outer segment (OS) of
rods and cones. Photoreceptors are made
up of stacks of membranous discs that
contain photoreceptive proteins. As these
discs are added at the base of the OS,
the tip must be removed and recycled
to make way. Deficits in this membrane
ingestion and degradation by the RPE
can lead to retinal degradation and blind-
ness. Scientists have long marveled at this
process, but little is known about how it
occurs, although some proteins required
for the activity have been identified. Now,
Umapathy et al. investigate using high-
speed 3D live-cell imaging in mice to vis-
ualize the spatiotemporal details of the
phagocytic event. The researchers created
a culture of primary RPE cells together
with OSs and then transiently transfected
RPEs with F-tractin-RFP to label actin
filaments. Peak coordinated ingestion
occurred over 30–45 min but could be
observed for up to 90 min. Actin fila-
ments extended apical membranes from
RPE cells, which enveloped the tip of an
OS and engulfed the separated cellular
matter, suggesting a scission event medi-
ated by dynamic actin filaments. The
specific events suggested a process called
trogocytosis. Inhibition of actin poly-
merization prolonged but did not pre-
vent the scission process. The authors
then honed in on which proteins played a
part in the scission events—specifically the
Bin-Amphiphysin-Rev domain-contain-
ing proteins formin-binding protein
17 (FBP17) and amphiphysin-1 (AMPH1),
which sense and bind to curved mem-
branes and can induce further curvature.
Live imaging revealed that fluorescently la-
beled FBP17 and AMPH1 were associated


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with membrane “cups” of RPE cells con-
taining OS tips, albeit in slightly different
localization patterns. The study finds once
and for all that, rather than the OS pas-
sively shedding its distal discs for phagocy-
tosis, RPE cells actively trogocytose, or
nibble away, the tips.
Abstract Sequential Monitoring
Occurs in the Prefrontal Cortex
Nadira Yusif Rodriguez, Theresa H.
McKim, Debaleena Basu, Aarit Ahuja,
and Theresa M. Desrochers
(see pages 2741–2755)
Imagine walking into a kitchen stocked
with ingredients, tools, and appliances—
but to make a successful meal, you’ll need
a recipe. The cognitive processes needed
to keep track of such sequential, abstract
instructions requires an active process
called sequence monitoring. The neural
underpinnings of such abstract monitor-
ing remain mostly unknown, but brain-
imaging studies in humans indicate that it
includes activity in the left or bilateral ros-
trolateral prefrontal cortex (RLPFC), and
studies in nonhuman primates suggest
that the dorsolateral PFC (DLPFC) medi-
ates abstract thought and sequential in-
formation. This week, Yusif Rodriguez
et al. explore the possibility in monkeys
that area 46 of the DLPFC, an area an-
alogous to human RLPFC, monitors
abstract visual sequential information.
The authors conducted functional mag-
netic resonance imaging in three awake
adult male rhesus macaque monkeys
that fixated on a central spot while
viewing fractal images in four-item
visual sequences. No responses were
required, and monkeys received con-
tinuous liquid reward as long as they
maintained fixation.
Visual
stimuli
were presented in blocks that either
followed or deviated from sequential
rules. The imaging data suggested that
both the right and left sides of area 46
of DLPFC monitors abstract visual
sequence structure. Interestingly, the
right and left sides seemed to track the
abstract information with differing dy-
namics, with onset-based activity on the
right and ramping dynamics during
the presentation on the left. Importantly,


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the data show that similar brain areas in
humans and nonhuman primates mediate
abstract sequence monitoring, although
in humans the activity is more consistent
bilaterally. The work brings us a step
closer to deciphering the neural sub-
strates of abstract sequential cognitive
processes.
ThisWeekinTheJournalwaswrittenbyStephaniSutherland
https://doi.org/10.1523/JNEUROSCI.twij.43.15.2023
Inset, fluorescently labeled f-actin (red) of a phagocytic cup
engulfing the tip of an OS labeled with antibody (green);
the larger image is a 3D rendering of the interaction.
2630 • The Journal of Neuroscience, April 12, 2023 • 43(15):2630


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Hindbrain Adenosine 5-Triphosphate (ATP)-Purinergic Signaling Triggers LH Surge and Ovulation via Activation of AVPV Kisspeptin Neurons in Rats


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Systems/Circuits
Hindbrain Adenosine 5-Triphosphate (ATP)-Purinergic
Signaling Triggers LH Surge and Ovulation via Activation of
AVPV Kisspeptin Neurons in Rats
Naoko Inoue,p Safiullah Hazim,p Hitomi Tsuchida, Yuri Dohi, Ren Ishigaki, Ai Takahashi, Yuki Otsuka,
Koki Yamada, Yoshihisa Uenoyama, and Hiroko Tsukamura
Laboratory of Animal Reproduction, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan
Ovulation disorders are a serious problem for humans and livestock. In female rodents, kisspeptin neurons in the anteroven-
tral periventricular nucleus (AVPV) are responsible for generating a luteinizing hormone (LH) surge and consequent ovula-
tion. Here, we report that adenosine 5-triphosphate (ATP), a purinergic receptor ligand, is a possible neurotransmitter that
stimulates AVPV kisspeptin neurons to induce an LH surge and consequent ovulation in rodents. Administration of an ATP
receptor antagonist (PPADS) into the AVPV blocked the LH surge in ovariectomized (OVX) rats treated with a proestrous
level of estrogen (OVX 1 high E2) and significantly reduced the ovulation rate in proestrous ovary-intact rats. AVPV ATP
administration induced a surge-like LH increase in OVX 1 high E2 rats in the morning. Importantly, AVPV ATP administra-
tion could not induce the LH increase in Kiss1 KO rats. Furthermore, ATP significantly increased intracellular Ca21 levels in
immortalized kisspeptin neuronal cell line, and coadministration of PPADS blocked the ATP-induced Ca21 increase.
Histologic analysis revealed that the proestrous level of estrogen significantly increased the number of P2X2 receptor (an
ATP receptor)-immunopositive AVPV kisspeptin neurons visualized by tdTomato in Kiss1-tdTomato rats. The proestrous
level of estrogen significantly increased varicosity-like vesicular nucleotide transporter (a purinergic marker)-immunopositive
fibers projecting to the vicinity of AVPV kisspeptin neurons. Furthermore, we found that some hindbrain vesicular nucleotide


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transporter-positive neurons projected to the AVPV and expressed estrogen receptor a, and the neurons were activated by
the high E2 treatment. These results suggest that hindbrain ATP-purinergic signaling triggers ovulation via activation of
AVPV kisspeptin neurons.
Key words: estrogen-positive feedback; GnRH/LH surge; kisspeptin neuron
Significance Statement
Ovulation disorders, which cause infertility and low pregnancy rates, are a serious problem for humans and livestock. The
present study provides evidence that adenosine 5-triphosphate, acting as a neurotransmitter in the brain, stimulates kisspep-
tin neurons in the anteroventral periventricular nucleus, known as the gonadotropin-releasing hormone surge generator, via
purinergic receptors to induce the gonadotropin-releasing hormone/luteinizing hormone surge and ovulation in rats. In addi-
tion, histologic analyses indicate that adenosine 5-triphosphate is likely to be originated from the purinergic neurons in the
A1 and A2 of the hindbrain. These findings may contribute to new therapeutic controls for hypothalamic ovulation disorders
in humans and livestock.
Received July 26, 2022; revised Dec. 15, 2022; accepted Feb. 8, 2023.
Author contributions: N.I. and H. Tsukamura designed research; N.I., S.H., H. Tsuchida, Y.D., R.I., A.T., and K.Y.
performed research; N.I., S.H., Y.D., R.I., A.T., Y.O., K.Y., and Y.U. contributed unpublished reagents/analytic tools; N.I.,
S.H., H. Tsukamura, Y.D., R.I., A.T., Y.O., K.Y., Y.U., and H. Tsukamura analyzed data; N.I., S.H., Y.U., and H. Tsukamura
wrote the paper.
This work was supported in part Japan Society for the Promotion of Science a Grant-in-Aid for a Research
Fellow KAKENHI Grants 19H03103 to N.I., 20H03127 to Y.U., and 18H03973 and 21H05031 to H. Tsukamura;
the Naito Foundation to N.I.; and Nagoya University Interdisciplinary Frontier Fellowship supported by Nagoya
University and JST, the establishment of university fellowships towards the creation of science technology


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innovation, Grant JPMJFS2120 to S.H. The RIA was performed at the Nagoya University Radioisotope Research
Center. We thank the National Hormone and Peptide Program for the rat LH assay kit; and Dr. Jeremy Allen
(Edanz Group; https://en-author-services.edanz.com) and Dr. Nicola Skoulding for editing a draft of this
manuscript.
*N.I. and S.H. contributed equally to this work as co-first authors.
The authors declare no competing financial interests.
Correspondence should be addressed to Naoko Inoue at ninoue@agr.nagoya-u.ac.jp.
https://doi.org/10.1523/JNEUROSCI.1496-22.2023
Copyright © 2023 Inoue, Hazim et al.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0
International license, which permits unrestricted use, distribution and reproduction in any medium provided
that the original work is properly attributed.
2140 • The Journal of Neuroscience, March 22, 2023 • 43(12):2140–2152


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Macrophages Promote Repair of Inner Hair Cell Ribbon Synapses following Noise-Induced Cochlear Synaptopathy


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Development/Plasticity/Repair
Macrophages Promote Repair of Inner Hair Cell Ribbon
Synapses following Noise-Induced Cochlear Synaptopathy
Vijayprakash Manickam,1 Dinesh Y. Gawande,1 Andrew R. Stothert,1 Anna C. Clayman,2 Lyudmila Batalkina,1
Mark E. Warchol,2 Kevin K. Ohlemiller,2 and Tejbeer Kaur1
1Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, Nebraska 68178, and 2Department of Otolaryngology,
School of Medicine, Washington University, St. Louis, Missouri 63110
Resident cochlear macrophages rapidly migrate into the inner hair cell synaptic region and directly contact the damaged synaptic con-
nections after noise-induced synaptopathy. Eventually, such damaged synapses are spontaneously repaired, but the precise role of mac-
rophages in synaptic degeneration and repair remains unknown. To address this, cochlear macrophages were eliminated using colony
stimulating factor 1 receptor (CSF1R) inhibitor, PLX5622. Sustained treatment with PLX5622 in CX3CR1GFP/1 mice of both sexes led
to robust elimination of resident macrophages (;94%) without significant adverse effects on peripheral leukocytes, cochlear function,
and structure. At 1 day (d) post noise exposure of 93 or 90dB SPL for 2 hours, the degree of hearing loss and synapse loss were
comparable in the presence and absence of macrophages. At 30d after exposure, damaged synapses appeared repaired in the presence
of macrophages. However, in the absence of macrophages, such synaptic repair was significantly reduced. Remarkably, on cessation of
PLX5622 treatment, macrophages repopulated the cochlea, leading to enhanced synaptic repair. Elevated auditory brainstem response
thresholds and reduced auditory brainstem response Peak 1 amplitudes showed limited recovery in the absence of macrophages but
recovered similarly with resident and repopulated macrophages. Cochlear neuron loss was augmented in the absence of macrophages


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but showed preservation with resident and repopulated macrophages after noise exposure. While the central auditory effects of
PLX5622 treatment and microglia depletion remain to be investigated, these data demonstrate that macrophages do not affect synap-
tic degeneration but are necessary and sufficient to restore cochlear synapses and function after noise-induced synaptopathy.
Key words: cochlea; inner hair cells; macrophages; noise-induced hearing loss; PLX5622; ribbon synapses
Significance Statement
The synaptic connections between cochlear inner hair cells and spiral ganglion neurons can be lost because of noise over expo-
sure or biological aging. This loss may represent the most common causes of sensorineural hearing loss also known as hidden
hearing loss. Synaptic loss results in degradation of auditory information, leading to difficulty in listening in noisy environ-
ments and other auditory perceptual disorders. We demonstrate that resident macrophages of the cochlea are necessary and
sufficient to restore synapses and function following synaptopathic noise exposure. Our work reveals a novel role for innate-
immune cells, such as macrophages in synaptic repair, that could be harnessed to regenerate lost ribbon synapses in noise- or
age-linked cochlear synaptopathy, hidden hearing loss, and associated perceptual anomalies.
Introduction
Sensorineural hearing loss reflects damage to the sensory recep-
tors (i.e., hair cells and/or spiral ganglion neurons [SGNs]) or to
the ribbon synapses between inner hair cells (IHCs) and SGNs.
Noise trauma is the most common preventable cause of hearing
loss. It has been suggested that at least 10 million adults (6%) in
the United States under age 70, and perhaps as many as 40 mil-
lion adults (24%), have features of hearing loss from exposure to
loud noise; and 12% or more of the world population is at risk
for noise-induced loss of hearing (Le et al., 2017; Sliwinska-
Kowalska and Zaborowski, 2017; GBD 2019 Hearing Loss


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Collaborators, 2021; World Health Organization, 2021).
Research in rodents and primate models and in humans has
shown that IHC ribbon synapses are vulnerable to rapid and
Received June 26, 2022; revised Feb. 7, 2023; accepted Feb. 10, 2023.
Author contributions: V.M., D.Y.G., A.R.S., and T.K. designed research; V.M., D.Y.G., A.R.S., A.C.C., L.B., and
T.K. performed research; V.M., D.Y.G., A.R.S., A.C.C., and T.K. analyzed data; V.M., M.E.W., K.K.O., and T.K.
wrote the first draft of the paper; V.M., M.E.W., K.K.O., and T.K. edited the paper.
This work was supported by National Institute on Deafness and Other Communication Disorders Grants R03
DC015320 and R01 DC019918, Nebraska State Funds, and Bellucci Translational Hearing Research Funds to
T.K. This work was also supported by the Translational Hearing Center at Creighton University, Boys Town
National Research Hospital, and University of Nebraska Medical Center with CoBRE Award GM139762 from the
National Institute of General Medical Science, a component of the National Institutes of Health. This
investigation is solely the responsibility of the authors and does not necessarily represent the official views of
any supporting institution. We thank Sharon Kujawa (Massachusetts Eye and Ear) and the Translational
Hearing Research Group, Creighton University, Omaha, Nebraska for constructive criticism that tremendously
improved the manuscript.
The authors declare no competing financial interests.
Correspondence should be addressed to Tejbeer Kaur at TejbeerKaur@creighton.edu.
https://doi.org/10.1523/JNEUROSCI.1273-22.2023
Copyright © 2023 the authors
The Journal of Neuroscience, March 22, 2023 • 43(12):2075–2089 • 2075


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The Basolateral Amygdala Sends a Mixed (GABAergic and Glutamatergic) Projection to the Mediodorsal Thalamic Nucleus


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Systems/Circuits
The Basolateral Amygdala Sends a Mixed (GABAergic and
Glutamatergic) Projection to the Mediodorsal Thalamic
Nucleus
Nowrin Ahmed and Denis Paré
Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, New Jersey 07102
The medial prefrontal cortex receives converging inputs from the mediodorsal thalamic nucleus (MD) and basolateral amyg-
dala (BLA). Although many studies reported that the BLA also projects to MD, there is conflicting evidence regarding this
projection, with some data suggesting that it originates from GABAergic or glutamatergic neurons. Therefore, the present
study aimed to determine the neurotransmitter used by MD-projecting BLA cells in male and female rats. We first examined
whether BLA cells retrogradely labeled by Fast Blue infusions in MD are immunopositive for multiple established markers of
BLA interneurons. A minority of MD-projecting BLA cells expressed somatostatin (;22%) or calretinin (;11%) but not
other interneuronal markers, suggesting that BLA neurons projecting to MD not only include glutamatergic cells, but also
long-range GABAergic neurons. Second, we examined the responses of MD cells to optogenetic activation of BLA axons using
whole-cell recordings in vitro. Consistent with our immunohistochemical findings, among responsive MD cells, light stimuli
typically elicited isolated EPSPs (73%) or IPSPs (27%) as well as coincident EPSPs and IPSPs (11%). Indicating that these
IPSPs were monosynaptic, light-evoked EPSPs and IPSPs had the same latency and the IPSPs persisted in the presence of
ionotropic glutamate receptor antagonists. Overall, our results indicate that the BLA sends a mixed, glutamatergic-GABAergic
projection to MD, which likely influences coordination of activity between BLA, MD, and medial prefrontal cortex. An impor-
tant challenge for future studies will be to examine the connections formed by MD-projecting glutamatergic and GABAergic
BLA cells with each other and other populations of BLA cells.


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Key words: amygdala; basolateral; mediodorsal; optogenetics; prefrontal; thalamus
Significance Statement
The mediodorsal thalamic nucleus (MD) and basolateral amygdala (BLA) send convergent projections to the medial prefron-
tal cortex. Although many studies reported that the BLA also projects to MD, there is conflicting evidence as to whether this
projection is glutamatergic or GABAergic. By combining tract tracing, immunohistochemistry, optogenetics, and patch clamp
recordings in vitro, we found that BLA neurons projecting to MD not only include glutamatergic cells, but also long-range
GABAergic neurons. Differential recruitment of these two contingents of cells likely influences coordination of activity
between the BLA, MD, and medial prefrontal cortex.
Introduction
Although the basolateral complex of the amygdala (BLA) is often
likened to the cerebral cortex (Carlsen and Heimer, 1988), some
of its features are inconsistent with this analogy. Reminiscent of
cortex, the BLA contains a similar complement of cell types, includ-
ing a majority of spiny glutamatergic projection cells and a hetero-
geneous group of aspiny inhibitory interneurons (McDonald, 1992;
Smith and Paré, 1994; Mascagni and McDonald, 2007; Spampanato
et al., 2011; Capogna, 2014; Vereczki et al., 2021). Also, as in cortex
where inter-related areas tend to project to the same striatal territo-
ries (Alexander et al., 1986), the BLA innervates cortical areas that
target the same regions of the striatum as it does (Groenewegen et
al., 1990; McDonald, 1991).
However, the analogy breaks down when considering BLA’s
thalamic connections. Unlike the generally reciprocal connec-
tions between the dorsal thalamus and cortex (Jones, 2007), most
dorsal thalamic nuclei projecting to the BLA receive little or no
return afferents. Indeed, the BLA receives heavy inputs from
parts of the ventroposterior and medial geniculate nuclei as well
Received Oct. 11, 2022; revised Dec. 13, 2022; accepted Dec. 20, 2022.


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Author contributions: N.A. and D.P. designed research; N.A. performed research; N.A. and D.P. analyzed
data; N.A. and D.P. edited the paper; D.P. wrote the first draft of the paper; D.P. wrote the paper.
This work was supported by the National Institutes of Health National Institute of Mental Health Grant R01
MH-107239 (to D.P.). N.A. was supported by the Behavioral and Neural Sciences Graduate Program of Rutgers
University.
The authors declare no competing financial interests.
Correspondence should be addressed to Denis Paré at pare@rutgers.edu.
https://doi.org/10.1523/JNEUROSCI.1924-22.2022
Copyright © 2023 the authors
2104 • The Journal of Neuroscience, March 22, 2023 • 43(12):2104–2115


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Systems/Circuits
Sensory and Choice Responses in MT Distinct from Motion
Encoding
Aaron J. Levi,1p
Yuan Zhao,2p
Il Memming Park,2 and Alexander C. Huk1,3
1Center for Perceptual Systems, Departments of Neuroscience and Psychology, The University of Texas at Austin, Austin, Texas 78705,
2Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, New York 11794, and 3Fuster Laboratory, University of
California Los Angeles, Los Angeles CA 90095
The macaque middle temporal (MT) area is well known for its visual motion selectivity and relevance to motion perception,
but the possibility of it also reflecting higher-level cognitive functions has largely been ignored. We tested for effects of task
performance distinct from sensory encoding by manipulating subjects’ temporal evidence-weighting strategy during a direc-
tion discrimination task while performing electrophysiological recordings from groups of MT neurons in rhesus macaques
(one male, one female). This revealed multiple components of MT responses that were, surprisingly, not interpretable as behaviorally
relevant modulations of motion encoding, or as bottom-up consequences of the readout of motion direction from MT. The time-vary-
ing motion-driven responses of MT were strongly affected by our strategic manipulation—but with time courses opposite the subjects’
temporal weighting strategies. Furthermore, large choice-correlated signals were represented in population activity distinct from its
motion responses, with multiple phases that lagged psychophysical readout and even continued after the stimulus (but which preceded
motor responses). In summary, a novel experimental manipulation of strategy allowed us to control the time course of readout to
challenge the correlation between sensory responses and choices, and population-level analyses of simultaneously recorded ensembles
allowed us to identify strong signals that were so distinct from direction encoding that conventional, single-neuron-centric analyses


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could not have revealed or properly characterized them. Together, these approaches revealed multiple cognitive contributions to MT
responses that are task related but not functionally relevant to encoding or decoding of motion for psychophysical direction discrimi-
nation, providing a new perspective on the assumed status of MT as a simple sensory area.
Key words: choice-related activity; decision-making; population decoding; temporal weighting; visual motion
Significance Statement
This study extends understanding of the middle temporal (MT) area beyond its representation of visual motion. Combining
multineuron recordings, population-level analyses, and controlled manipulation of task strategy, we exposed signals that
depended on changes in temporal weighting strategy, but did not manifest as feedforward effects on behavior. This was dem-
onstrated by (1) an inverse relationship between temporal dynamics of behavioral readout and sensory encoding, (2) a
choice-correlated signal that always lagged the stimulus time points most correlated with decisions, and (3) a distinct choice-
correlated signal after the stimulus. These findings invite re-evaluation of MT for functions outside of its established sensory
role and highlight the power of experimenter-controlled changes in temporal strategy, coupled with recording and analysis
approaches that transcend the single-neuron perspective.
Introduction
Primate middle temporal (MT) area plays a critical role in the
perception of visual motion. A long line of study has established
that MT’s encoding of motion direction is quantitatively consist-
ent with perceptual sensitivity, that noise in its responses is cor-
related with behavioral variability, and that causal perturbations
of its activity affect motion perception in lawful and substantial
ways (Newsome and Paré, 1988; Britten et al., 1992; Salzman et
al., 1992; Britten et al., 1996). Owing to this powerfully integrated
set of findings, many models and experiments have been able to


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assume that MT is the key place that the brain looks to for infor-
mation about visual motion. However, these successes do not
Received Feb. 6, 2022; revised Jan. 16, 2023; accepted Jan. 19, 2023.
Author contributions: A.J.L. and A.C.H. designed research; A.J.L. performed research; A.J.L., Y.Z., and I.M.P.
analyzed data; A.J.L. and A.C.H. wrote the paper.
I.M.P and A.C.H. were supported by National Science Fondation Grant IIS-1734910. A.J.L. was supported by
National Institutes of Health/National Eye Institute Grant R01-EY-017366. We thank A. Laudano for animal
support, C. Badillo for technical support, as well as J. Yates and L. Katz for helpful advice and discussion.
*A.J.L. and Y.Z. contributed equally to this work.
The authors declare no competing financial interests.
Correspondence should be addressed to Aaron J. Levi at alevi813@gmail.com or Alexander C. Huk at
alexhuk@ucla.edu.
https://doi.org/10.1523/JNEUROSCI.0267-22.2023
Copyright © 2023 Levi, Zhao et al.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0
International license, which permits unrestricted use, distribution and reproduction in any medium provided
that the original work is properly attributed.
2090 • The Journal of Neuroscience, March 22, 2023 • 43(12):2090–2103


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The Human Centromedial Amygdala Contributes to Negative Prediction Error Signaling during Appetitive and Aversive Pavlovian Gustatory Learning


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Behavioral/Cognitive
The Human Centromedial Amygdala Contributes to
Negative Prediction Error Signaling during Appetitive and
Aversive Pavlovian Gustatory Learning
Emilia Kolada,1 Krzysztof Bielski,1 Mateusz Wilk,1 Krystyna Rymarczyk,2 Piotr Bogorodzki,3 Paweł Kazulo,3
Bartosz Kossowski,4 Marek Wypych,4 Artur Marchewka,4 Leszek Kaczmarek,5
Ewelina Knapska,1
and
Iwona Szatkowska1
1Neurobiology of Emotions Laboratory, Centre of Excellence for Neural Plasticity and Brain Disorders (BrainCity), Nencki Institute of Experimental
Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland, 2Behavioral Neuroscience Laboratory, Department of Biological Psychology, SWPS
University, 03-815 Warsaw, Poland, 3Institute of Radioelectronics and Multimedia Technology, Warsaw University of Technology, 00-665 Warsaw,
Poland, 4Laboratory of Brain Imaging, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland, and
5Laboratory of Neurobiology, Centre of Excellence for Neural Plasticity and Brain Disorders (BrainCity), Nencki Institute of Experimental Biology,
Polish Academy of Sciences, Warsaw, 02-093, Poland
Prediction error (PE) is the mismatch between a prior expectation and reality, and it lies at the core of associative
learning about aversive and appetitive stimuli. Human studies on fear learning have linked the amygdala to aversive
PEs. In contrast, the relationship between the amygdala and PE in appetitive settings and stimuli, unlike those that
induce fear, has received less research attention. Animal studies show that the amygdala is a functionally heterogene-
ous structure. Nevertheless, the role of the amygdala nuclei in PE signaling remains unknown in humans. To clarify
the role of two subdivisions of the human amygdala, the centromedial amygdala (CMA) and basolateral amygdala
(BLA), in appetitive and aversive PE signaling, we used gustatory pavlovian learning involving eating-related natural-


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istic outcomes. Thirty-eight right-handed individuals (19 females) participated in the study. We found that surprise
with neutral feedback when a reward is expected triggers activity within the left and right CMA. When an aversive
outcome is expected, surprise with neutral feedback triggers activity only within the left CMA. Notably, the BLA was
not activated by those conditions. Thus, the CMA engages in negative PE signaling during appetitive and aversive gus-
tatory pavlovian learning, whereas the BLA is not critical for this process. In addition, PE-related activity within the
left CMA during aversive learning is negatively correlated with neuroticism and positively correlated with extraver-
sion. The findings indicate the importance of the CMA in gustatory learning when the value of outcomes changes and
have implications for understanding psychological conditions that manifest perturbed processing of negative PEs.
Key words: centromedial amygdala; extraversion; gustatory learning; neuroticism; pavlovian learning; prediction error
Significance Statement
A discrepancy between a prediction and an actual outcome (PE) plays a crucial role in learning. Learning improves when an
outcome is more significant than expected (positive PE) and worsens when it is smaller than expected (negative PE). We
found that the negative PE during appetitive and aversive taste learning is associated with increased activity of the CMA,
which suggests that the CMA controls taste learning. Our findings may have implications for understanding psychological
states associated with deficient learning from negative PEs, such as obesity and addictive behaviors.
Received May 13, 2022; revised Mar. 6, 2023; accepted Mar. 13, 2023.
Author contributions: E. Kolada, A.M., L.K., E. Knapska, and I.S. designed research; E. Kolada, K.B., K.R., B.K., and I.S.
performed research; E. Kolada, K.B., M. Wilk, P.B., P.K., and M. Wypych analyzed data; E. Kolada, E. Knapska, and
I.S. wrote the paper.


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This work was supported by National Science Center (Poland) Grant 2014/15/B/HS6/03658) to I.S. and BrainCity
Center of Excellence for Neural Plasticity and Brain Disorders Grant MAB 2 to E. Kolada, K.B., L.K., and E. Knapska.
K. Bielski’s present address: Institute of Psychology, Jagiellonian University, 30-060 Cracow, Poland.
The authors declare no competing financial interests.
Correspondence should be addressed to Emilia Kolada at e.kolada@nencki.edu.pl or Iwona Szatkowska at
i.szatkowska@nencki.edu.pl.
https://doi.org/10.1523/JNEUROSCI.0926-22.2023
Copyright © 2023 Kolada et al.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0
International license, which permits unrestricted use, distribution and reproduction in any medium provided
that the original work is properly attributed.
3176 • The Journal of Neuroscience, April 26, 2023 • 43(17):3176–3185


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Concurrent- and After-Effects of Medial Temporal Lobe Stimulation on Directed Information Flow to and from Prefrontal and Parietal Cortices during Memory Formation


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Behavioral/Cognitive
Concurrent- and After-Effects of Medial Temporal Lobe
Stimulation on Directed Information Flow to and from
Prefrontal and Parietal Cortices during Memory Formation
Anup Das1 and Vinod Menon1,2,3
1Department of Psychiatry & Behavioral Sciences, 2Department of Neurology & Neurological Sciences, and 3Stanford Neurosciences Institute,
Stanford University School of Medicine, Stanford, California 94305
Electrical stimulation of the medial temporal lobe (MTL) has the potential to uncover causal circuit mechanisms underlying
memory function. However, little is known about how MTL stimulation alters information flow with frontoparietal cortical
regions implicated in episodic memory. We used intracranial EEG recordings from humans (14 participants, 10 females) to
investigate how MTL stimulation alters directed information flow between MTL and PFC and between MTL and posterior pa-
rietal cortex (PPC). Participants performed a verbal episodic memory task during which they were presented with words and
asked to recall them after a delay of ;20 s; 50 Hz stimulation was applied to MTL electrodes on selected trials during mem-
ory encoding. Directed information flow was examined using phase transfer entropy. Behaviorally, we observed that MTL
stimulation reduced memory recall. MTL stimulation decreased top-down PFCﬁMTL directed information flow during
both memory encoding and subsequent memory recall, revealing aftereffects more than 20 s after end of stimulation.
Stimulation suppressed top-down PFCﬁMTL influences to a greater extent than PPCﬁMTL. Finally, MTLﬁPFC informa-
tion flow on stimulation trials was significantly lower for successful, compared with unsuccessful, memory recall; in con-
trast, MTLﬁventral PPC information flow was higher for successful, compared with unsuccessful, memory recall.
Together, these results demonstrate that the effects of MTL stimulation are behaviorally, regionally, and directionally spe-


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cific, that MTL stimulation selectively impairs directional signaling with PFC, and that causal MTL-ventral PPC circuits
support successful memory recall. Findings provide new insights into dynamic casual circuits underling episodic memory
and their modulation by MTL stimulation.
Key words: causal circuits in episodic memory; deep brain stimulation; directed information flow; human intracranial
EEG; medial temporal lobe; prefrontal and parietal cortices
Significance Statement
The medial temporal lobe (MTL) and its interactions with prefrontal and parietal cortices (PFC and PPC) play a critical role in
human memory. Dysfunctional MTL-PFC and MTL-PPC circuits are prominent in psychiatric and neurologic disorders, includ-
ing Alzheimer’s disease and schizophrenia. Brain stimulation has emerged as a potential mechanism for enhancing memory and
cognitive functions, but the underlying neurophysiological mechanisms and dynamic causal circuitry underlying bottom-up and
top-down signaling involving the MTL are unknown. Here, we use intracranial EEG recordings to investigate the effects of MTL
stimulation on causal signaling in key episodic memory circuits linking the MTL with PFC and PPC. Our findings have implica-
tions for translational applications aimed at realizing the promise of brain stimulation-based treatment of memory disorders.
Introduction
The medial temporal lobe (MTL) and its interactions with pre-
frontal cortex (PFC) play a foundational role in human memory
(Vogt and Pandya, 1987; Wagner et al., 2005; Curtis, 2006;
Husain and Nachev, 2007; Cabeza et al., 2008; Eichenbaum,
2017; Rolls, 2018, 2019; Rutishauser et al., 2021; Amer and
Davachi, 2022). Dysfunctional MTL-PFC circuits are prominent
in psychiatric and neurologic disorders, including Alzheimer’s
disease and schizophrenia (Meyer-Lindenberg et al., 2005;
Dickerson and Eichenbaum, 2010; Uhlhaas and Singer, 2012).
Received Sep. 10, 2022; revised Mar. 6, 2023; accepted Mar. 13, 2023.


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Author contributions: A.D. and V.M. designed research; A.D. and V.M. performed research; A.D. analyzed
data; A.D. wrote the first draft of the paper; A.D. and V.M. edited the paper; A.D. and V.M. wrote the paper.
This work was supported by National Institutes of Health Grants NS086085 and EB022907. We thank Dr.
Yuan Zhang for assistance with statistical analysis.
The authors declare no competing financial interests.
Correspondence should be addressed to Anup Das at a1das@stanford.edu or Vinod Menon at
menon@stanford.edu.
https://doi.org/10.1523/JNEUROSCI.1728-22.2023
Copyright © 2023 the authors
The Journal of Neuroscience, April 26, 2023 • 43(17):3159–3175 • 3159


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Systems/Circuits
Subgenual and Hippocampal Pathways in Amygdala Are Set
to Balance Affect and Context Processing
Mary Kate P. Joyce,1,2
Jingyi Wang,1 and
Helen Barbas1,2,3
1Neural Systems Laboratory, Department of Health Sciences, Boston University, Boston, Massachusetts 022152, 2Graduate Program in
Neuroscience, Boston University and School of Medicine, Boston, Massachusetts 02118, and 3Department of Anatomy and Neurobiology, Boston
University School of Medicine, Boston, Massachusetts 02118
The amygdala, hippocampus, and subgenual cortex area 25 (A25) are engaged in complex cognitive-emotional processes. Yet
pathway interactions from hippocampus and A25 with postsynaptic sites in amygdala remain largely unknown. In rhesus
monkeys of both sexes, we studied with neural tracers how pathways from A25 and hippocampus interface with excitatory
and inhibitory microcircuits in amygdala at multiple scales. We found that both hippocampus and A25 innervate distinct as
well as overlapping sites of the basolateral (BL) amygdalar nucleus. Unique hippocampal pathways heavily innervated the
intrinsic paralaminar basolateral nucleus, which is associated with plasticity. In contrast, orbital A25 preferentially innervated
another intrinsic network, the intercalated masses, an inhibitory reticulum that gates amygdalar autonomic output and inhib-
its fear-related behaviors. Finally, using high-resolution confocal and electron microscopy (EM), we found that among inhibi-
tory postsynaptic targets in BL, both hippocampal and A25 pathways preferentially formed synapses with calretinin (CR)
neurons, which are known for disinhibition and may enhance excitatory drive in the amygdala. Among other inhibitory post-
synaptic sites, A25 pathways innervated the powerful parvalbumin (PV) neurons which may flexibly regulate the gain of neu-
ronal assemblies in the BL that affect the internal state. In contrast, hippocampal pathways innervated calbindin (CB)


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inhibitory neurons, which modulate specific excitatory inputs for processing context and learning correct associations.
Common and unique patterns of innervation in amygdala by hippocampus and A25 have implications for how complex cog-
nitive and emotional processes may be selectively disrupted in psychiatric disorders.
Key words: emotional regulation; fear conditioning; inhibitory neurons; neural circuits; nonhuman primate; ventrome-
dial prefrontal cortex
Significance Statement
The hippocampus, subgenual A25, and amygdala are associated with learning, memory, and emotions. We found that A25 is
poised to affect diverse amygdalar processes, from emotional expression to fear learning by innervating the basal complex
and the intrinsic intercalated masses. Hippocampal pathways uniquely interacted with another intrinsic amygdalar nucleus
which is associated with plasticity, suggesting flexible processing of signals in context for learning. In the basolateral (BL)
amygdala, which has a role in fear learning, both hippocampal and A25 interacted preferentially with disinhibitory neurons,
suggesting a boost in excitation. The two pathways diverged in innervating other classes of inhibitory neurons, suggesting cir-
cuit specificities that could become perturbed in psychiatric diseases.
Introduction
The amygdala, hippocampus, and subgenual cingulate area
25 (A25) of the medial prefrontal cortex (mPFC) are essen-
tial for processes associated with emotion, memory, and in-
ternal states, and disruption of these nodes can precipitate
psychiatric disturbances in humans (for review, see Hiser
and Koenigs, 2018; Gray et al., 2020; Kaul et al., 2021).
Understanding the organization of these circuits in nonhu-
man primates remains an urgent goal, as novel and safe
therapies for mood disorders have proven difficult to trans-
late from rodent models, although remarkable strides have
been made (Roberts, 2020).
Received Nov. 5, 2022; revised Mar. 2, 2023; accepted Mar. 13, 2023.


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Author contributions: M.K.P.J., J.W., and H.B. designed research; M.K.P.J. and J.W. performed research;
M.K.P.J., J.W., and H.B. analyzed data; M.K.P.J. wrote the first draft of the paper; M.K.P.J., J.W., and H.B.
edited the paper; M.K.P.J., J.W., and H.B. wrote the paper.
This work was supported by National Institutes of Health Grants R01MH057414 and R01MH117785 (to H.B.).
We thank Jess Holz, MFA for electron microscopy and technical assistance.
The authors declare no competing financial interests.
Correspondence should be addressed to Helen Barbas at barbas@bu.edu.
https://doi.org/10.1523/JNEUROSCI.2066-22.2023
Copyright © 2023 the authors
The Journal of Neuroscience, April 26, 2023 • 43(17):3061–3080 • 3061


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Pharmacological Inactivation of the Bed Nucleus of the Stria Terminalis Increases Affiliative Social Behavior in Rhesus Macaques


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Behavioral/Cognitive
Pharmacological Inactivation of the Bed Nucleus of the Stria
Terminalis Increases Affiliative Social Behavior in Rhesus
Macaques
Jessica T. Jacobs,1,2
Rafael S. Maior,2,3 Hannah F. Waguespack,1,2 Carolina Campos-Rodriguez,2
Patrick A. Forcelli,1,2,4p and Ludise Malkova1,2p
1Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC, 20057, 2Department of Pharmacology & Physiology, Georgetown
University, Washington, DC, 20057, 3Laboratory of Neurosciences, Metabolism and Behavior, Department of Physiological Sciences, Institute of
Biology, University of Brasilia, 70910-900, Brasilia, Brazil, and 4Department of Neuroscience, Georgetown University, Washington, DC 20057
The bed nucleus of the stria terminalis (BNST) has been implicated in a variety of social behaviors, including aggression,
maternal care, mating behavior, and social interaction. Limited evidence from rodent studies suggests that activation of the
BNST results in a decrease in social interaction between unfamiliar animals. The role of the BNST in social interaction in pri-
mates remains wholly unexamined. Nonhuman primates provide a valuable model for studying social behavior because of
both their rich social repertoire and neural substrates of behavior with high translational relevance to humans. To test the
hypothesis that the primate BNST is a critical modulator of social behavior, we performed intracerebral microinfusions of the
GABAA agonist muscimol to transiently inactivate the BNST in male macaque monkeys. We measured changes in social inter-
action with a familiar same-sex conspecific. Inactivation of the BNST resulted in significant increase in total social contact.
This effect was associated with an increase in passive contact and a significant decrease in locomotion. Other nonsocial
behaviors (sitting passively alone, self-directed behaviors, and manipulation) were not impacted by BNST inactivation. As


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part of the “extended amygdala,” the BNST is highly interconnected with the basolateral (BLA) and central (CeA) nuclei of
the amygdala, both of which also play critical roles in regulating social interaction. The precise pattern of behavioral changes
we observed following inactivation of the BNST partially overlaps with our prior reports in the BLA and CeA. Together, these
data demonstrate that the BNST is part of a network regulating social behavior in primates.
Key words: amygdala; BNST; macaque; muscimol; primate
Significance Statement
The bed nucleus of the stria terminalis (BNST) has a well-established role in anxiety behaviors, but its role in social behavior
is poorly understood. No prior studies have evaluated the impact of BNST manipulations on social behavior in primates. We
found that transient pharmacological inactivation of the BNST increased social behavior in pairs of macaque monkeys. These
data suggest the BNST contributes to the brain networks regulating sociability.
Introduction
The bed nucleus of the stria terminalis (BNST) is a subcortical
structure located in the ventral forebrain. It has been described
as a component of the “extended amygdala” because of its ana-
tomic and functional similarities to the amygdaloid complex
(Alheid and Heimer, 1988; Alheid et al., 1998; Fox et al., 2015).
The BNST is densely and reciprocally interconnected with key
limbic structures, including the amygdala and the hypothalamus
(Silverman et al., 1981; Weller and Smith, 1982; Dong et al.,
2001a; Dong and Swanson, 2004; deCampo and Fudge, 2013;
Kim et al., 2013; Torrisi et al., 2015; Fudge et al., 2017; Huang et
al., 2021) and has been implicated in a range of behavioral func-
tions, including the stress response, extended-duration fear states
(i.e., anxiety), and social behavior (Walker et al., 2003; Lebow
and Chen, 2016; Lischinsky and Lin, 2020; Flanigan and Kash,
2022).
The BNST, and its contributions to social behavior, has been
most extensively studied in rodent models. In both rats and


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Received Nov. 9, 2022; revised Feb. 6, 2023; accepted Feb. 27, 2023.
Author contributions: J.T.J., P.A.F., and L.M. designed research; J.T.J., R.S.M., H.F.W., C.C.-R., P.A.F., and
L.M. performed research; J.T.J., P.A.F., and L.M. analyzed data; J.T.J. wrote the first draft of the paper; J.T.J.,
R.S.M., H.F.W., C.C.-R., P.A.F., and L.M. edited the paper.
This work was supported by the National Institute of Mental Health R01MH120638 to L.M. and P.A.F. RSM
was the recipient of a researcher fellowship from the Brazilian National Council for Scientific and
Technological Development (CNPq; 308291/2020-4).
*P.A.F. and L.M. contributed equally to this work.
The authors declare no competing financial interests.
Correspondence should be addressed to Ludise Malkova at malkoval@georgetown.edu or Patrick A. Forcelli
at paf22@georgetown.edu.
https://doi.org/10.1523/JNEUROSCI.2090-22.2023
Copyright © 2023 the authors
The Journal of Neuroscience, May 3, 2023 • 43(18):3331–3338 • 3331


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Behavioral/Cognitive
Beta Oscillations in Monkey Striatum Encode Reward
Prediction Error Signals
Ruggero Basanisi,1 Kevin Marche,1,2 Etienne Combrisson,1
Paul Apicella,1  and
Andrea Brovelli1 
1Institut de Neurosciences de la Timone, Aix Marseille Université, Unité Mixte de Recherche 7289 Centre National de la Recherche Scientifique,
Marseille 13005, France and 2Wellcome Center for Integrative Neuroimaging, Department of Experimental Psychology, University of Oxford,
Oxford OX3 9DU, United Kingdom
Reward prediction error (RPE) signals are crucial for reinforcement learning and decision-making as they quantify the mis-
match between predicted and obtained rewards. RPE signals are encoded in the neural activity of multiple brain areas, such
as midbrain dopaminergic neurons, prefrontal cortex, and striatum. However, it remains unclear how these signals are
expressed through anatomically and functionally distinct subregions of the striatum. In the current study, we examined to
which extent RPE signals are represented across different striatal regions. To do so, we recorded local field potentials (LFPs)
in sensorimotor, associative, and limbic striatal territories of two male rhesus monkeys performing a free-choice probabilistic
learning task. The trial-by-trial evolution of RPE during task performance was estimated using a reinforcement learning
model fitted on monkeys’ choice behavior. Overall, we found that changes in beta band oscillations (15–35 Hz), after the out-
come of the animal’s choice, are consistent with RPE encoding. Moreover, we provide evidence that the signals related to
RPE are more strongly represented in the ventral (limbic) than dorsal (sensorimotor and associative) part of the striatum. To
conclude, our results suggest a relationship between striatal beta oscillations and the evaluation of outcomes based on RPE
signals and highlight a major contribution of the ventral striatum to the updating of learning processes.
Key words: learning; LFP; mutual information; rewards; striatum


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Significance Statement
Reward prediction error (RPE) signals are crucial for reinforcement learning and decision-making as they quantify the mismatch
between predicted and obtained rewards. Current models suggest that RPE signals are encoded in the neural activity of multiple
brain areas, including the midbrain dopaminergic neurons, prefrontal cortex and striatum. However, it remains elusive whether
RPEs recruit anatomically and functionally distinct subregions of the striatum. Our study provides evidence that RPE-related modu-
lations in local field potential (LFP) power are dominant in the striatum. In particular, they are stronger in the rostro-ventral rather
than the caudo-dorsal striatum. Our findings contribute to a better understanding of the role of striatal territories in reward-based
learning and may be relevant for neuropsychiatric and neurologic diseases that affect striatal circuits.
Introduction
The striatum is the major component of the basal ganglia, and it
plays a key role in reward-guided learning under the influence of
ascending dopaminergic projections from the ventral midbrain.
Indeed, dopaminergic neurons are known to encode the differ-
ence between received and expected rewards, the so-called reward
prediction error (RPE; Schultz, 2007, 2016a,b; Fujiyama et al.,
2015), which is crucial for updating action values in reinforce-
ment learning models (Sutton and Barto, 1998). Previous neuro-
physiological studies on primates’ and rodents’ striatum have
shown that subsets of output neurons (Roesch et al., 2009; Oyama
et al., 2010; Asaad and Eskandar, 2011) and putative interneurons
(Apicella et al., 2009; Stalnaker et al., 2012) may carry RPE signals
to promote reward-guided learning. Functional neuroimaging
studies in humans have also highlighted the role of the striatum
in encoding RPEs (O’Doherty, 2004, 2007; Bray and O’Doherty,
2007; Brovelli et al., 2008; Valentin and O’Doherty, 2009; Park et
Received May 19, 2022; revised Feb. 22, 2023; accepted Mar. 17, 2023.


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Author contributions: K.M. and P.A. designed research; K.M. and P.A. performed research; R.B., K.M., E.C.,
P.A., and A.B. contributed unpublished reagents/analytic tools; R.B. and A.B. analyzed data; R.B. and A.B.
wrote the first draft of the paper; R.B., K.M., E.C., P.A., and A.B. edited the paper; R.B., K.M., P.A., and A.B.
wrote the paper.
R.B., E.C., and A.B. were supported by the Agence National de la Recherche Grant ANR-18-CE28-0016. R.B.
was supported by a PhD Scholarship awarded by the Neuroschool. E.C. was supported by the European
Union’s Horizon 2020 Framework Program for Research and Innovation under the Specific Grant Agreement
No. 945539 (Human Brain Project SGA3). P.A. and K.M. were supported by the Agence Nationale de la
Recherche Grant ANR-11-BSV4-006. Support for K.M. was partially provided by Association Française du
Syndrome de Gilles de la Tourette. The Center de Calcul Intensif of the Aix-Marseille University is
acknowledged for granting access to its high-performance computing resources. We thank L. Renaud for
assistance with monkey surgery and Dr. M. Esclapez for help with histology.
pR.B. and K.M. contributed equally to this work.
ppP.A. and A.B. are co-senior authors.
The authors declare no competing financial interests.
Correspondence should be addressed to Andrea Brovelli at andrea.brovelli@univ-amu.fr or Ruggero
Basanisi at ruggero.basanisi@gmail.com.
https://doi.org/10.1523/JNEUROSCI.0952-22.2023
Copyright © 2023 the authors
The Journal of Neuroscience, May 3, 2023 • 43(18):3339–3352 • 3339


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Report
ASO targeting RBM3 temperature-controlled poison
exon splicing prevents neurodegeneration in vivo
Marco Preußner1,*,†
, Heather L Smith2,3,†, Daniel Hughes2,‡
, Min Zhang1,‡,
Ann-Kathrin Emmerichs1, Silvia Scalzitti1, Diego Peretti2, Dean Swinden2,3, Alexander Neumann1,4,
Tom Haltenhof1,4, Giovanna R Mallucci2,3,**
& Florian Heyd1,***
Abstract
Neurodegenerative diseases are increasingly prevalent in the aging
population, yet no disease-modifying treatments are currently
available. Increasing the expression of the cold-shock protein
RBM3 through therapeutic hypothermia is remarkably neuropro-
tective. However, systemic cooling poses a health risk, strongly
limiting its clinical application. Selective upregulation of RBM3 at
normothermia thus holds immense therapeutic potential. Here we
identify a poison exon within the RBM3 gene that is solely respon-
sible for its cold-induced expression. Genetic removal or antisense
oligonucleotide (ASO)-mediated manipulation of this exon yields
high RBM3 levels independent of cooling. Notably, a single admin-
istration of ASO to exclude the poison exon, using FDA-approved
chemistry, results in long-lasting increased RBM3 expression in
mouse brains. In prion-diseased mice, this treatment leads to
remarkable neuroprotection, with prevention of neuronal loss and
spongiosis despite high levels of disease-associated prion protein.
Our promising results in mice support the possibility that RBM3-
inducing ASOs might also deliver neuroprotection in humans in
conditions ranging from acute brain injury to Alzheimer’s disease.
Keywords alternative splicing coupled to nonsense-mediated decay;
hypothermia; neurodegenerative diseases; neuroprotection; RBM3
Subject Categories Genetics, Gene Therapy & Genetic Disease; Molecular
Biology of Disease; Neuroscience
DOI 10.15252/emmm.202217157 | Received 9 November 2022 |
Revised 16 February 2023 | Accepted 18 February 2023 | Published online 22
March 2023
EMBO Mol Med (2023) 15: e17157
Introduction


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The expression of glycine-rich RNA-binding proteins upon cooling,
such as CIRBP (Cold-induced RNA-binding protein) and RBM3
(RNA-binding motif-3), was originally described in the 1990s (Danno
et al, 1997; Nishiyama et al, 1997). However, despite evolutionary
conservation (Ciuzan et al, 2015) and extreme temperature sensitiv-
ity of this phenomenon (Jackson et al, 2015; Los et al, 2022), the
mechanistic basis for cold-induced RBM3 expression has remained
enigmatic. Our recent identification of temperature-regulated alter-
native splicing coupled to nonsense-mediated decay (NMD) provides
a global mechanism for the control of temperature-dependent gene
expression (Neumann et al, 2020). The NMD pathway recognizes
mRNA isoforms containing premature termination codons (PTCs)
and targets these mRNAs for degradation, thus allowing splicing-
controlled
regulation
of
gene
expression
(Lykke-Andersen
&
Jensen, 2015). NMD-inducing poison isoforms are frequently found
in RNA-binding proteins (Neumann et al, 2020) and exclusion of a
poison exon upon cooling in CIRBP provides an explanation for
cold-induced expression (Haltenhof et al, 2020). While CIRBP has
diverse functions ranging from circadian sleep homeostasis to
inflammation and cancer (Morf et al, 2012; Qiang et al, 2013; Lujan
et al, 2018; Hoekstra et al, 2019), the closely related RBM3 protein is
strongly associated with the neuroprotective effect of hypothermia.
This has been observed in scenarios ranging from in vitro protection
from forced apoptosis of neuronal cell lines and brain slices (Chip
et al, 2011) to profound neuroprotective effects in vivo, where RBM3
induction by cooling or over-expression restores memory, prevents
synapse and neuronal loss, and extends survival in preclinical
mouse models of prion and Alzheimer’s disease (Peretti et al, 2015,
2021). More recently, RBM3 has been shown to stimulate neurogen-
esis in rodent brain after hypoxic–ischemic brain injury (Zhu
et al, 2019) and to protect against neurotoxin effects in neuronal cell


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lines (Yang et al, 2019). Therapeutic hypothermia is used in some
1 Institut f€ur Chemie und Biochemie, RNA Biochemie, Freie Universit€at Berlin, Berlin, Germany
2
UK Dementia Research Institute and Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
3
Altos Labs, Cambridge Institute of Science, Cambridge, UK
4 Omiqa Bioinformatics, Berlin, Germany
*Corresponding author. Tel: +49 30 838 70703; E-mail: mpreussner@zedat.fu-berlin.de
**Corresponding author. Tel: +44 7766 924461; E-mail: gmallucci@altoslabs.com
***Corresponding author. Tel: +49 30 838 62938; E-mail: florian.heyd@fu-berlin.de
†These authors contributed equally to this work
‡These authors contributed equally to this work
 2023 The Authors. Published under the terms of the CC BY 4.0 license.
EMBO Molecular Medicine
15: e17157 | 2023
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Article
Brain p3-Alcb peptide restores neuronal viability
impaired by Alzheimer’s amyloid b-peptide
Saori Hata1,2,†, Haruka Saito1,3,†, Takeharu Kakiuchi4, Dai Fukumoto4, Shigeyuki Yamamoto4
,
Kensaku Kasuga5
, Ayano Kimura1, Koichi Moteki1,3, Ruriko Abe3, Shungo Adachi6, Shoich Kinoshita1,3,
Kumiko Yoshizawa-Kumagaye7, Hideki Nishio7, Takashi Saito8,9
, Takaomi C Saido8
,
Tohru Yamamoto10
, Masaki Nishimura11, Hidenori Taru1,3, Yuriko Sobu1,3, Hiroyuki Ohba4
,
Shingo Nishiyama4, Norihiro Harada4
, Takeshi Ikeuchi5
, Hideo Tsukada4
, Yasuomi Ouchi12,* &
Toshiharu Suzuki1,3,**
Abstract
We propose a new therapeutic strategy for Alzheimer’s disease
(AD). Brain peptide p3-Alcb37 is generated from the neuronal pro-
tein alcadein b through cleavage of c-secretase, similar to the gen-
eration of amyloid b (Ab) derived from Ab-protein precursor/APP.
Neurotoxicity by Ab oligomers (Abo) is the prime cause prior to the
loss of brain function in AD. We found that p3-Alcb37 and its
shorter peptide p3-Alcb9-19 enhanced the mitochondrial activity
of neurons and protected neurons against Abo-induced toxicity.
This is due to the suppression of the Abo-mediated excessive Ca2+
influx into neurons by p3-Alcb. Successful transfer of p3-Alcb9-19
into the brain following peripheral administration improved the
mitochondrial viability in the brain of AD mice model, in which the
mitochondrial activity is attenuated by increasing the neurotoxic
human Ab42 burden, as revealed through brain PET imaging to
monitor mitochondrial function. Because mitochondrial dysfunc-
tion is common in the brain of AD patients alongside increased Ab
and reduced p3-Alcb37 levels, the administration of p3-Alcb9-19
may be a promising treatment for restoring, protecting, and pro-
moting brain functions in patients with AD.
Keywords AD therapy; alcadein; Alzheimer’s disease (AD); mitochondria; PET
imaging
Subject Category Neuroscience
DOI 10.15252/emmm.202217052 | Received 16 October 2022 | Revised 14


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March 2023 | Accepted 14 March 2023 | Published online 30 March 2023
EMBO Mol Med (2023) 15: e17052
Introduction
Alzheimer’s disease (AD) is an incurable neurodegenerative disor-
der that causes progressive dementia in aged subjects. More than 50
million people live with dementia worldwide and AD accounts for
60–80% of these cases (World Alzheimer’s Report, 2018). The gen-
eration and accumulation of neurotoxic amyloid b (Ab) protein, a
pathogenic hallmark in the AD brain, are believed to be the primary
cause of neurodegeneration, resulting in cognitive deficits and mem-
ory loss (McLean et al, 1999; Hardy & Selkoe, 2002). In neurons, Ab
is generated from Ab-protein precursor (APP), a single membrane-
spanning protein, via intramembrane proteolysis of c-secretase after
the
shedding
of
the
APP
extracellular/luminal
region
by
b-
secretase/BACE1 (De Strooper et al, 1998; Vassar et al, 1999; Thina-
karan & Koo, 2008).
Alcadeins (Alcs)/calsyntenins (Clstns) are a family of type I trans-
membrane proteins expressed in neurons. This family includes alca-
dein a (Alca/Clstn1), b (Alcb/Clstn3), and c (Alcc/Clstn2), which
are
encoded
by
separate
genes
(Hintsch
et
al,
2002;
Araki
et al, 2003). Alca/Clstn1 is a cargo receptor of kinesin-1 (Konecna
1
Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
2
Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan
3
Advanced Prevention and Research Laboratory for Dementia, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
4
Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Japan
5
Molecular Genetics, Niigata University Brain Research Institute, Nigata, Japan
6
Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan
7
Peptide Institute, Inc., Ibaraki, Japan
8


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8
Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science Institute, Wako, Japan
9
Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
10
Department of Molecular Neurobiology, Factory of Medicine, Kagawa University, Takamatsu, Japan
11
Molecular Neuroscience Research Center, Shiga University of Medical Science, Shiga, Japan
12
Department of Biofunctional Imaging, Preeminent Medical Education & Research Center, Hamamatsu University School of Medicine, Hamamatsu, Japan
*Corresponding author. Tel: +81 53 435 2466; E-mail: ouchi@hama-med.ac.jp
**Corresponding author. Tel: +81 11 706 3250; E-mail: tsuzuki@pharm.hokudai.ac.jp
†These authors contributed equally to this work
 2023 The Authors. Published under the terms of the CC BY 4.0 license.
EMBO Molecular Medicine
15: e17052 | 2023
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Effect of a False Inertial Cue in the Velocity-Storage Circuit on Head Posture and Inertia Perception


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Systems/Circuits
Effect of a False Inertial Cue in the Velocity-Storage Circuit
on Head Posture and Inertia Perception
Jeong-Yoon Choi,1,2 Yu Jin Koo,1 Jung-Mi Song,1 Hyo-Jung Kim,3 and Ji-Soo Kim1,2
1Dizziness Center, Clinical Neuroscience Center, and Department of Neurology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi
13620 South Korea, 2Department of Neurology, Seoul National University College of Medicine, Seoul 03080, South Korea, and 3Research
Administration Team, Seoul National University Bundang Hospital, Seongnam, Gyeonggi 13620 South Korea
The velocity-storage circuit participates in the vestibulopostural reflex, but its role in the postural reflex requires further elu-
cidation. The velocity-storage circuit differentiates gravitoinertial information into gravitational and inertial cues using rota-
tional cues. This implies that a false rotational cue can cause an erroneous estimation of gravity and inertial cues. We
hypothesized the velocity-storage circuit is a common gateway for all vestibular reflex pathways and tested that hypothesis by
measuring the postural and perceptual responses from a false inertial cue estimated in the velocity-storage circuit. Twenty
healthy human participants (40.5 6 8.2 years old, 6 men) underwent two different sessions of earth-vertical axis rotations at
120°/s for 60 s. During each session, the participants were rotated clockwise and then counterclockwise with two different
starting head positions (head-down and head-up). During the first (control) session, the participants kept a steady head posi-
tion at the end of rotation. During the second (test) session, the participants changed their head position at the end of rota-
tion, from head-down to head-up or vice versa. The head position and inertial motion perception at the end of rotation were
aligned with the inertia direction anticipated by the velocity-storage model. The participants showed a significant correlation


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between postural and perceptual responses. The velocity-storage circuit appears to be a shared neural integrator for the vesti-
bulopostural reflex and vestibular perception. Because the postural responses depended on the inertial direction, the postural
instability in vestibular disorders may be the consequence of the vestibulopostural reflex responding to centrally estimated
false vestibular cues.
Key words: perception; posture; velocity-storage; vestibular system
Significance Statement
The velocity-storage circuit appears to participate in the vestibulopostural reflex, which stabilizes the head and body position
in space. However, it is still unclear whether the velocity-storage circuit for the postural reflex is in common with that
involved in eye movement and perception. We evaluated the postural and perceptual responses to a false inertial cue esti-
mated by the velocity-storage circuit. The postural and perceptual responses were consistent with the inertia direction pre-
dicted in the velocity-storage model and were correlated closely with each other. These results show that the velocity-storage
circuit is a shared neural integrator for vestibular-driven responses and suggest that the vestibulopostural response to a false
vestibular cue is the pathomechanism of postural instability clinically observed in vestibular disorders.
Introduction
To maintain head and body stability, humans must update and
adjust their head and body positions in a given reference frame,
such as head and body positions in space or the position of the
head on the body (Suzuki and Cohen, 1964; Goldberg and Cullen,
2011). Although multisensorial inputs, such as vestibular, visual,
proprioceptive, and efference copy cues, are involved in this func-
tion, vestibular cues play a primary role in stabilizing head and
body positions in space through the vestibulocollic reflex (VCR)
and vestibulospinal reflex (VSR; Angelaki and Cullen, 2008; Cullen,
2011). This function also operates while standing upright through


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the righting reflex, a kind of VCR and VSR, which activates the
neck and spine extensors to counteract the gravity force (Molina-
Negro et al., 1980; Dichgans and Diener, 1989).
Despite the common vestibular inputs, the vestibulopostural
reflex shows a response distinct from that resulting from the
Received June 10, 2022; revised Dec. 16, 2022; accepted Jan. 8, 2023.
Author contributions: J.-Y.C. and J.-M.S. designed research; Y.-J.K., J.-M.S., and H.-J.K. performed research;
J-Y.C., Y.-J.K., J.-M.S., and H.-J.K. contributed unpublished reagents/analytic tools; J.-Y.C., Y.-J.K., H.-J.K., and
J.-S.K. analyzed data; and J.-Y.C. and J.-S.K. wrote the paper.
This study was supported by the Basic Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of Science and ICT (2020R1A2C4002281).
The authors declare no competing financial interests.
Correspondence should be addressed to Jeong-Yoon Choi at saideiju@gmail.com.
https://doi.org/10.1523/JNEUROSCI.1148-22.2023
Copyright © 2023 the authors
1530 • The Journal of Neuroscience, March 1, 2023 • 43(9):1530–1539


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Behavioral/Cognitive
Nutrient-Sensitive Reinforcement Learning in Monkeys
Fei-Yang Huang (黃飛揚)1,2 and
Fabian Grabenhorst1,2
1Department of Experimental Psychology, University of Oxford, Oxford OX1 3TA, United Kingdom and 2Department of Physiology, Development
and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom
In reinforcement learning (RL), animals choose by assigning values to options and learn by updating these values from
reward outcomes. This framework has been instrumental in identifying fundamental learning variables and their neuronal
implementations. However, canonical RL models do not explain how reward values are constructed from biologically critical
intrinsic reward components, such as nutrients. From an ecological perspective, animals should adapt their foraging choices
in dynamic environments to acquire nutrients that are essential for survival. Here, to advance the biological and ecological
validity of RL models, we investigated how (male) monkeys adapt their choices to obtain preferred nutrient rewards under
varying reward probabilities. We found that the nutrient composition of rewards strongly influenced learning and choices.
Preferences of the animals for specific nutrients (sugar, fat) affected how they adapted to changing reward probabilities; the
history of recent rewards influenced choices of the monkeys more strongly if these rewards contained the their preferred
nutrients (nutrient-specific reward history). The monkeys also chose preferred nutrients even when they were associated with
lower reward probability. A nutrient-sensitive RL model captured these processes; it updated the values of individual sugar
and fat components of expected rewards based on experience and integrated them into subjective values that explained the
choices of the monkeys. Nutrient-specific reward prediction errors guided this value-updating process. Our results identify
nutrients as important reward components that guide learning and choice by influencing the subjective value of choice


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options. Extending RL models with nutrient-value functions may enhance their biological validity and uncover nutrient-spe-
cific learning and decision variables.
Key words: food; learning; nutrients; preference; reward; reward prediction error
Significance Statement
RL is an influential framework that formalizes how animals learn from experienced rewards. Although reward is a founda-
tional concept in RL theory, canonical RL models cannot explain how learning depends on specific reward properties, such as
nutrients. Intuitively, learning should be sensitive to the nutrient components of the reward to benefit health and survival.
Here, we show that the nutrient (fat, sugar) composition of rewards affects how the monkeys choose and learn in an RL paradigm
and that key learning variables including reward history and reward prediction error should be modified with nutrient-specific
components to account for the choice behavior observed in the monkeys. By incorporating biologically critical nutrient rewards
into the RL framework, our findings help advance the ecological validity of RL models.
Introduction
According to reinforcement learning (RL) theory, animals
choose by assigning values to options and learn by updating
these values from experienced rewards (Sutton and Barto, 1998).
This framework has been instrumental in identifying learning
and decision variables that explain animal behavior, including
object values and action values, which guide choices, and reward
prediction errors, which update values from experienced out-
comes. Physical implementations of these concepts have been
discovered in neurons of the primate dopamine system, striatum,
amygdala, and frontal cortex (Schultz et al., 1997; Samejima et
al., 2005; Lau and Glimcher, 2008; So and Stuphorn, 2010; Lee et
al., 2012; Seo et al., 2012; Tsutsui et al., 2016; Costa et al., 2019;
Grabenhorst et al., 2019a). One important factor that limits the
biological validity of canonical RL models is that they do not


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explain how learning and choice depend on the composition of
experienced rewards. Nutrients, for example, are biologically
critical intrinsic components of food rewards that engage
dedicated sensory and physiological mechanisms and are
essential for survival (Carreiro et al., 2016; Rolls, 2020;
Simpson and Raubenheimer, 2020). Thus, investigating how
Received Apr. 16, 2022; revised Nov. 27, 2022; accepted Dec. 19, 2022.
Author contributions: F.-Y.H. and F.G. designed research; F.-Y.H. and F.G. performed research; F.-Y.H. and
F.G. analyzed data; F.-Y.H. and F.G. wrote the paper.
This work was supported by Wellcome Trust Grants 206207/Z/17/Z and 206207/Z/17/A to F.G. F.-Y.H. was
supported by a fellowship from the Taiwan Ministry of Education. We thank Wolfram Schultz and group for
support and discussions, Putu Khorisantono for discussions, Christina Thompson and Aled David for animal
care, Polly Taylor for anesthesia, and Henri Bertrand for veterinary care.
The authors declare no competing financial interests.
Correspondence should be addressed to Fabian Grabenhorst at fabian.grabenhorst@psy.ox.ac.uk.
https://doi.org/10.1523/JNEUROSCI.0752-22.2022
Copyright © 2023 the authors
1714 • The Journal of Neuroscience, March 8, 2023 • 43(10):1714–1730


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Neurons in Primate Area MSTd Signal Eye Movement Direction Inferred from Dynamic Perspective Cues in Optic Flow


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Systems/Circuits
Neurons in Primate Area MSTd Signal Eye Movement
Direction Inferred from Dynamic Perspective Cues in Optic
Flow
Grace F. DiRisio,1,4
Yongsoo Ra,1,2 Yinghui Qiu,1,3 Akiyuki Anzai,1 and
Gregory C. DeAngelis1
1Department of Brain and Cognitive Sciences, Center for Visual Science, University of Rochester, Rochester, New York 14627, 2Department of
Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, 3College of Veterinary Medicine, Cornell University, Ithaca, New York 14853-
6401, and 4Department of Neurobiology, University of Chicago, Chicago, Illinois 60637
Smooth eye movements are common during natural viewing; we frequently rotate our eyes to track moving objects or to
maintain fixation on an object during self-movement. Reliable information about smooth eye movements is crucial to various
neural computations, such as estimating heading from optic flow or judging depth from motion parallax. While it is well
established that extraretinal signals (e.g., efference copies of motor commands) carry critical information about eye velocity,
the rotational optic flow field produced by eye rotations also carries valuable information. Although previous work has shown
that dynamic perspective cues in optic flow can be used in computations that require estimates of eye velocity, it has
remained unclear where and how the brain processes these visual cues and how they are integrated with extraretinal signals
regarding eye rotation. We examined how neurons in the dorsal region of the medial superior temporal area (MSTd) of two
male rhesus monkeys represent the direction of smooth pursuit eye movements based on both visual cues (dynamic perspec-
tive) and extraretinal signals. We find that most MSTd neurons have matched preferences for the direction of eye rotation
based on visual and extraretinal signals. Moreover, neural responses to combinations of these signals are well predicted by a


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weighted linear summation model. These findings demonstrate a neural substrate for representing the velocity of smooth eye
movements based on rotational optic flow and establish area MSTd as a key node for integrating visual and extraretinal sig-
nals into a more generalized representation of smooth eye movements.
Key words: eye movements; motion processing; optic flow; smooth pursuit; visual cortex
Significance Statement
We frequently rotate our eyes to smoothly track objects of interest during self-motion. Information about eye velocity is cru-
cial for a variety of computations performed by the brain, including depth perception and heading perception. Traditionally,
information about eye rotation has been thought to arise mainly from extraretinal signals, such as efference copies of motor
commands. Previous work shows that eye velocity can also be inferred from rotational optic flow that accompanies smooth
eye movements, but the neural origins of these visual signals about eye rotation have remained unknown. We demonstrate
that macaque neurons signal the direction of smooth eye rotation based on visual signals, and that they integrate both visual
and extraretinal signals regarding eye rotation in a congruent fashion.
Introduction
During natural viewing, we rotate and reorient our body, head,
and eyes to focus on relevant objects and collect information
about the visual scene. When the eyes rotate smoothly to track a
target of interest, there are associated motor signals (i.e., effer-
ence copies of motor commands), and there are also visual con-
sequences in the form of global optic flow. Traditionally, these
visual consequences have been considered undesirable, thus
requiring compensation by extraretinal signals such as efference
copies of motor commands (von Holst and Mittelstaedt, 1950;
Wallach, 1987; Royden et al., 1992; Bradley et al., 1996; Ben
Hamed et al., 2003). However, theoretical work has emphasized
Received Oct. 5, 2022; revised Jan. 18, 2023; accepted Jan. 24, 2023.


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Author contributions: A.A. and G.C.D. designed research; G.F.D., Y.R., and Y.Q. performed research; A.A.
contributed unpublished reagents/analytic tools; G.F.D., Y.R., Y.Q., and G.C.D. analyzed data; G.F.D. and G.C.D.
wrote the paper.
This work was supported by National Eye Institute (NEI) Grant R01-EY-013644 and by Core Grant EY-
001319 from the NEI. We thank Johnny Wen and Amanda Yung for assistance with the programming of
visual stimuli. We also thank Dina Graf and Emily Murphy for assistance with animal training and care. In
addition, we thank Marjena Popovic for assistance with data collection for one animal.
The authors declare no competing financial interests.
Correspondence should be addressed to Gregory C. DeAngelis at gdeangelis@ur.rochester.edu.
https://doi.org/10.1523/JNEUROSCI.1885-22.2023
Copyright © 2023 the authors
1888 • The Journal of Neuroscience, March 15, 2023 • 43(11):1888–1904


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Systems/Circuits
Vestibular Contributions to Primate Neck Postural Muscle
Activity during Natural Motion
Robyn L. Mildren and
Kathleen E. Cullen
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland 21205
To maintain stable posture of the head and body during our everyday activities, the brain integrates information across mul-
tiple sensory systems. Here, we examined how the primate vestibular system, independently and in combination with visual
sensory input, contributes to the sensorimotor control of head posture across the range of dynamic motion experienced dur-
ing daily life. We recorded activity of single motor units in the splenius capitis and sternocleidomastoid muscles in rhesus
monkeys during yaw rotations spanning the physiological range of self-motion (up to 20Hz) in darkness. Splenius capitis motor
unit responses continued to increase with frequency up to 16Hz in normal animals, and were strikingly absent following bilateral
peripheral vestibular loss. To determine whether visual information modulated these vestibular-driven neck muscle responses, we
experimentally controlled the correspondence between visual and vestibular cues of self-motion. Surprisingly, visual information
did not influence motor unit responses in normal animals, nor did it substitute for absent vestibular feedback following bilateral
peripheral vestibular loss. A comparison of muscle activity evoked by broadband versus sinusoidal head motion further revealed
that low-frequency responses were attenuated when low- and high-frequency self-motion were experienced concurrently. Finally,
we found that vestibular-evoked responses were enhanced by increased autonomic arousal, quantified via pupil size. Together, our
findings directly establish the vestibular system’s contribution to the sensorimotor control of head posture across the dynamic
motion range experienced during everyday activities, as well as how vestibular, visual, and autonomic inputs are integrated for pos-
tural control.


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Key words: motor unit; natural motion; neck muscle; postural control; vestibular; vestibulocollic
Significance Statement
Our sensory systems enable us to maintain control of our posture and balance as we move through the world. Notably, the
vestibular system senses motion of the head and sends motor commands, via vestibulospinal pathways, to axial and limb
muscles to stabilize posture. By recording the activity of single motor units, here we show, for the first time, that the vestibu-
lar system contributes to the sensorimotor control of head posture across the dynamic motion range experienced during
everyday activities. Our results further establish how vestibular, autonomic, and visual inputs are integrated for postural con-
trol. This information is essential for understanding both the mechanisms underlying the control of posture and balance, and
the impact of the loss of sensory function.
Introduction
The ability to maintain posture and balance during our everyday
activities requires the integration of multiple sensory and motor
signals. In this context, the vestibular organs provide essential in-
formation about motion of the head in space, which is rapidly
transmitted via central vestibular pathways to drive compensatory
vestibulospinal reflexes that help stabilize head and body posture
(Roy and Cullen, 2001; Cullen and Roy, 2004; Brooks and Cullen,
2013). To date, however, the vestibular system’s contributions to
the control of posture during natural motion experienced in daily
life, both independently and in combination with other sensory
cues, are not well understood.
In this context, the pathways responsible for stabilizing the
head relative to space constitute an excellent model to under-
stand the vestibular system’s contribution to postural control.
First, the central brainstem and cerebellar vestibular circuits that
mediate compensatory neck muscle responses have been well
characterized in primates (Roy and Cullen, 2001; Cullen and
Roy, 2004; Brooks and Cullen, 2013; Zobeiri and Cullen, 2022).


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Second, relative to the complex biomechanics of the appendicu-
lar system, the biomechanics of head-on-body motion in the yaw
plane are relatively simple because the majority of movement
Received Sep. 26, 2022; revised Jan. 10, 2023; accepted Feb. 13, 2023.
Author contributions: R.L.M. and K.E.C. designed research; R.L.M. performed research; R.L.M. analyzed
data; R.L.M. wrote the first draft of the paper; R.L.M. and K.E.C. edited the paper; R.L.M. and K.E.C. wrote the
paper.
We thank Olivia Leavitt for assistance with the modeling; oMid Zobeiri and Dale Roberts for technical
assistance; and Oliver Stanley, Dr. Patrick Forbes, and Dr. Silvia Muceli for critical feedback on the manuscript.
The authors declare no competing financial interests.
Correspondence should be addressed to Kathleen E. Cullen at kathleen.cullen@jhu.edu.
https://doi.org/10.1523/JNEUROSCI.1831-22.2023
Copyright © 2023 the authors
2326 • The Journal of Neuroscience, March 29, 2023 • 43(13):2326–2337


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Shared Neural Activity But Distinct Neural Dynamics for Cognitive Control in Monkey Prefrontal and Parietal Cortex


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Behavioral/Cognitive
Shared Neural Activity But Distinct Neural Dynamics for
Cognitive Control in Monkey Prefrontal and Parietal Cortex
Rachael K. Blackman,1,2,3 David A. Crowe,2,4 Adele L. DeNicola,1,2 Sofia Sakellaridi,1,2
Jacob A. Westerberg,5
Anh M. Huynh,4 Angus W. MacDonald,6 Scott R. Sponheim,7,8 and Matthew V. Chafee1,2
1Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, 2Brain Sciences Center, VA Medical Center, Minneapolis,
Minnesota 55417, 3Medical Scientist Training Program (MD/PhD), University of Minnesota, Minneapolis, Minnesota 55455, 4Department of
Biology, Augsburg University, Minneapolis, Minnesota 55454, 5Neuroscience Program, St. Olaf College, Northfield, Minnesota 55057, 6Department
of Psychology, University of Minnesota, Minneapolis, Minnesota 55455, 7Minneapolis VA Health Care System, Minneapolis, Minnesota 55417, and
8Department of Psychiatry and Behavioral Sciences, University of Minnesota, Minneapolis, Minnesota 55454
To better understand how prefrontal networks mediate forms of cognitive control disrupted in schizophrenia, we translated a vari-
ant of the AX continuous performance task that measures specific deficits in the human disease to 2 male monkeys and recorded
neurons in PFC and parietal cortex during task performance. In the task, contextual information instructed by cue stimuli deter-
mines the response required to a subsequent probe stimulus. We found parietal neurons encoding the behavioral context instructed
by cues that exhibited nearly identical activity to their prefrontal counterparts (Blackman et al., 2016). This neural population
switched their preference for stimuli over the course of the trial depending on whether the stimuli signaled the need to engage cog-
nitive control to override a prepotent response. Cues evoked visual responses that appeared in parietal neurons first, whereas popu-
lation activity encoding contextual information instructed by cues was stronger and more persistent in PFC. Increasing cognitive


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control demand biased the representation of contextual information toward the PFC and augmented the temporal correlation of
task-defined information encoded by neurons in the two areas. Oscillatory dynamics in local field potentials differed between corti-
cal areas and carried as much information about task conditions as spike rates. We found that, at the single-neuron level, patterns
of activity evoked by the task were nearly identical between the two cortical areas. Nonetheless, distinct population dynamics in
PFC and parietal cortex were evident. suggesting differential contributions to cognitive control.
Key words: AX-CPT; cognitive control; monkey; parietal; prefrontal; schizophrenia
Significance Statement
We recorded neural activity in PFC and parietal cortex of monkeys performing a task that measures cognitive control deficits
in schizophrenia. This allowed us to characterize computations performed by neurons in the two areas to support forms of
cognitive control disrupted in the disease. Subpopulations of neurons in the two areas exhibited parallel modulations in firing
rate; and as a result, all patterns of task-evoked activity were distributed between PFC and parietal cortex. This included the
presence in both cortical areas of neurons reflecting proactive and reactive cognitive control dissociated from stimuli or
responses in the task. However, differences in the timing, strength, synchrony, and correlation of information encoded by
neural activity were evident, indicating differential contributions to cognitive control.
Received Aug. 28, 2022; revised Jan. 15, 2023; accepted Feb. 15, 2023.
Author contributions: R.K.B., D.A.C., A.L.D., S.S., A.W.M., S.R.S., and M.V.C. designed research;
R.K.B., D.A.C., A.L.D., S.S., and M.V.C. performed research; R.K.B., D.A.C., A.L.D., J.A.W., A.M.H., and M.V.C.
analyzed data; R.K.B., D.A.C., A.L.D., S.S., J.A.W., A.M.H., A.W.M., S.R.S., and M.V.C. edited the paper;
R.K.B., D.A.C., and M.V.C. wrote the paper.


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This work was supported by National Institutes of Health R01MH077779, R01MH107491, and
P50MH119569; the Department of Veterans Affairs; the American Brain Sciences Chair; the Wilfred Wetzel
Graduate Fellowship; and National Institute of General Medical Sciences T32 GM008244 and T32 HD007151.
This work was performed while R.K.B. was employed at the University of Minnesota. The opinions expressed
in this article are the author’s own and do not reflect the views of the National Institutes of Health, the
Department of Health and Human Services, or the U.S. Government. This material is the result of work
supported with resources and the use of facilities at the Minneapolis VA Health Care System. The contents do
not represent the views of the U.S. Department of Veterans Affairs, the National Institutes of Health, the
Department of Health and Human Services, or the U.S. Government. We thank C. Dean Evans for technical
assistance during surgeries and neural recordings as well as exemplary animal care; Dale Boeff for assistance
with computer programming as well as design and construction of neurophysiological recording equipment;
and A.D. Reddish for insightful suggestions regarding the decoding analyses.
R. K. Blackman’s present address: National Institute of Mental Health, National Institutes of Health,
Bethesda, MD 20892.
A. L. DeNicola’s present address: Department of Neurology, University of Minnesota, Minneapolis, MN 55455.
S. Sakellaridi’s present address: Bioengineering Department, University of California Riverside, Riverside, CA 92521.
J. A. Westerberg’s present address: Department of Vision and Cognition, Netherlands Institute for
Neuroscience, Royal Netherlands Academy of Arts and Sciences, 1105 BA, Amsterdam, The Netherlands.
The authors declare no competing financial interests.
Correspondence should be addressed to Matthew V. Chafee at chafe001@umn.edu.
https://doi.org/10.1523/JNEUROSCI.1641-22.2023
Copyright © 2023 the authors
The Journal of Neuroscience, April 12, 2023 • 43(15):2767–2781 • 2767


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Behavioral/Cognitive
Monkey Dorsolateral Prefrontal Cortex Represents Abstract
Visual Sequences during a No-Report Task
Nadira Yusif Rodriguez,1,2 Theresa H. McKim,1 Debaleena Basu,1 Aarit Ahuja,1,2 and
Theresa M. Desrochers1,2,3
1Department of Neuroscience, Brown University, Providence, RI 02912, 2Robert J. and Nancy D. Carney Institute for Brain Science, Brown
University, Providence, RI 02912, and 3Department of Psychiatry and Human Behavior, Brown University, Providence, RI 02912
Monitoring sequential information is an essential component of our daily lives. Many of these sequences are
abstract, in that they do not depend on the individual stimuli, but do depend on an ordered set of rules (e.g., chop
then stir when cooking). Despite the ubiquity and utility of abstract sequential monitoring, little is known about its
neural mechanisms. Human rostrolateral prefrontal cortex (RLPFC) exhibits specific increases in neural activity (i.e.,
“ramping”) during abstract sequences. Monkey dorsolateral prefrontal cortex (DLPFC) has been shown to represent
sequential information in motor (not abstract) sequence tasks, and contains a subregion, area 46, with homologous
functional connectivity to human RLPFC. To test the prediction that area 46 may represent abstract sequence infor-
mation, and do so with parallel dynamics to those found in humans, we conducted functional magnetic resonance
imaging (fMRI) in three male monkeys. When monkeys performed no-report abstract sequence viewing, we found
that left and right area 46 responded to abstract sequential changes. Interestingly, responses to rule and number
changes overlapped in right area 46 and left area 46 exhibited responses to abstract sequence rules with changes in
ramping activation, similar to that observed in humans. Together, these results indicate that monkey DLPFC moni-
tors abstract visual sequential information, potentially with a preference for different dynamics in the two hemi-


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spheres. More generally, these results show that abstract sequences are represented in functionally homologous
regions across monkeys and humans.
Key words: abstract sequence; fMRI; nonhuman primate; prefrontal cortex; ramping activation
Significance Statement
Daily, we complete sequences that are “abstract” because they depend on an ordered set of rules (e.g., chop then stir when
cooking) rather than the identity of individual items. Little is known about how the brain tracks, or monitors, this abstract se-
quential information. Based on previous human work showing abstract sequence related dynamics in an analogous area, we
tested whether monkey dorsolateral prefrontal cortex (DLPFC), specifically area 46, represents abstract sequential informa-
tion using awake monkey functional magnetic resonance imaging (fMRI). We found that area 46 responded to abstract
sequence changes, with a preference for more general responses on the right and dynamics similar to humans on the left.
These results suggest that abstract sequences are represented in functionally homologous regions across monkeys and
humans.
Received Nov. 1, 2022; revised Feb. 22, 2023; accepted Feb. 24, 2023.
Author contributions: N.Y.R. and T.M.D. designed research; N.Y.R., T.H.M., D.B., A.A., and T.M.D. performed
research; N.Y.R., T.H.M., D.B., A.A., and T.M.D. contributed unpublished reagents/analytic tools; N.Y.R. and
T.M.D. analyzed data; N.Y.R. and T.M.D. wrote the first draft of the paper; N.Y.R., T.H.M., D.B., A.A., and
T.M.D. edited the paper; N.Y.R. and T.M.D. wrote the paper.
This study was supported by the National Science Foundation (NSF) Established Program to Stimulate Competitive
Research (EPSCoR) Neural Basis of Attention Grant 1632738 (N.Y.R. and T.M.D.), the National Institute of General
Medical Sciences (NIGMS)-National Institutes of Health (NIH) Initiative to Maximize Student Development Grant IMSD
R25GM083270 (N.Y.R.), the NIH-NIGMS Grant COBRE P20GM103645 (T.M.D), NIH National Institutes of Mental Health


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(NIMH) R21MH125010 (T.M.D.), NSF Faculty Early Career Development (CAREER) Program Award 2143656 (T.M.D.), and
the Carney Institute for Brain Science Innovation Award (T.M.D.). Part of this research was conducted using
computational resources and services at the Center for Computation and Visualization, Brown University (NIH Grant
S10OD025181). We thank Matthew Maestri for his assistance with animal training and data collection. We thank Dr.
Michael Worden, Lynn Fanella, Fabienne McEleney, and Brown University’s MRI Facilities staff for their support and
guidance throughout this project. We also thank Dr. David Sheinberg, Dr. David Badre, Dr. Amitai Shenhav, Dr. Katherine
Conen, and Dr. Diana Burk for their continued support throughout this project and preparation of this publication as well
as members of both the Sheinberg and the Desrochers Labs for many helpful discussions and contributions.
T. H. McKim’s present address: Department of Child and Adolescent Psychiatry, Psychosomatics and
Psychotherapy, University Hospital Würzburg, Würzburg, Germany, 97080.
The authors declare no competing financial interests.
Correspondence should be addressed to Theresa M. Desrochers at theresa_desrochers@brown.edu.
https://doi.org/10.1523/JNEUROSCI.2058-22.2023
Copyright © 2023 the authors
The Journal of Neuroscience, April 12, 2023 • 43(15):2741–2755 • 2741


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Spatiotemporal Live-Cell Analysis of Photoreceptor Outer Segment Membrane Ingestion by the Retinal Pigment Epithelium Reveals Actin-Regulated Scission


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Cellular/Molecular
Spatiotemporal Live-Cell Analysis of Photoreceptor Outer
Segment Membrane Ingestion by the Retinal Pigment
Epithelium Reveals Actin-Regulated Scission
Ankita Umapathy, Gil Torten, Antonio E. Paniagua, Julie Chung, Madeline Tomlinson, Caleb Lim, and
David S. Williams
Department of Ophthalmology and Stein Eye Institute, and Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles,
California 90095
The photoreceptor outer segment (OS) is the phototransductive organelle in the vertebrate retina. OS tips are regularly
ingested and degraded by the adjacent retinal pigment epithelium (RPE), offsetting the addition of new disk membrane at
the base of the OS. This catabolic role of the RPE is essential for photoreceptor health, with defects in ingestion or degrada-
tion underlying different forms of retinal degeneration and blindness. Although proteins required for OS tip ingestion have
been identified, spatiotemporal analysis of the ingestion process in live RPE cells is lacking; hence, the literature reflects no
common understanding of the cellular mechanisms that affect ingestion. We imaged live RPE cells from mice (both sexes) to
elucidate the ingestion events in real time. Our imaging revealed roles for f-actin dynamics and specific dynamic localizations
of two BAR (Bin-Amphiphysin-Rvs) proteins, FBP17 and AMPH1-BAR, in shaping the RPE apical membrane as it surrounds
the OS tip. Completion of ingestion was observed to occur by scission of the OS tip from the remainder of the OS, with a
transient concentration of f-actin forming around the site of imminent scission. Actin dynamics were also required for regu-
lating the size of the ingested OS tip, and the time course of the overall ingestion process. The size of the ingested tip is con-
sistent with the term “phagocytosis.” However, phagocytosis usually refers to engulfment of an entire particle or cell, whereas


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our observations of OS tip scission indicate a process that is more specifically described as “trogocytosis,” in which one cell
“nibbles” another cell.
Key words: actin dynamics; BAR proteins; live-cell imaging; phagocytosis; RPE; trogocytosis
Significance Statement
The ingestion of the photoreceptor outer segment (OS) tips by the retinal pigment epithelium (RPE) is a dynamic cellular pro-
cess that has fascinated scientists for 60years. Yet its molecular mechanisms had not been addressed in living cells. We devel-
oped a live-cell imaging approach to investigate OS tip ingestion, and focused on the dynamic participation of actin filaments
and membrane-shaping BAR proteins. We observed scission of OS tips for the first time, and were able to monitor local
changes in protein concentration preceding, during, and following scission. Our approach revealed that actin filaments were
concentrated at the site of OS scission and were required for regulating the size of the ingested OS tip and the time course of
the ingestion process.
Introduction
The retinal pigment epithelium (RPE) is an extraordinary epithe-
lium. It performs several specialized functions that are crucial to
the maintenance of vision (Strauss, 2005; Lakkaraju et al., 2020).
In one such function, it takes care of the catabolic phase of pho-
toreceptor outer segment (OS) renewal. OSs are composed of
tightly packed membranous disks, which contain the phototrans-
ductive proteins. The distal tip, amounting to ;10% of each OS
in mammals, is phagocytosed by the RPE each day (Young, 1967;
Young and Bok, 1969). Given that each RPE cell interfaces with
numerous photoreceptors, .200 in the central mouse retina
(Volland et al., 2015), it must ingest and degrade large amounts
Received Sep. 9, 2022; revised Jan. 16, 2023; accepted Jan. 18, 2023.
Author contributions: A.U., G.T., and D.S.W. designed research; A.U., G.T., A.E.P., J.C., M.T., and C.L.
performed research; A.U., G.T., J.C., M.T., C.L., D.S.W., and A.P. analyzed data; A.U. and D.S.W. wrote the
paper.


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paper.
The study was supported by NIH NEI grants R01EY027442, R01EY033035, R21EY031109, T32EY007026, and
P30EY00333, and a program project grant from the Foundation Fighting Blindness. We thank Barry Burgess
for technical support, Fei Yu for assistance with statistical analysis, and Michael Schell for generously
providing the F-Tractin constructs.
The authors declare no competing financial interests.
Correspondence should be addressed to David S. Williams at dswilliams@ucla.edu.
https://doi.org/10.1523/JNEUROSCI.1726-22.2023
Copyright © 2023 the authors
The Journal of Neuroscience, April 12, 2023 • 43(15):2653–2664 • 2653


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Systems/Circuits
Sound Improves Neuronal Encoding of Visual Stimuli in
Mouse Primary Visual Cortex
Aaron M. Williams,1,2,3
Christopher F. Angeloni,1,4 and
Maria N. Geffen1,2,3
1Department of Otorhinolaryngology, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, 2Department of Neuroscience, University of
Pennsylvania, Philadelphia, Pennsylvania, 19104, 3Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, and
4Department of Psychology, University of Pennsylvania, Philadelphia, Pennsylvania 19104
In everyday life, we integrate visual and auditory information in routine tasks such as navigation and communication.
While concurrent sound can improve visual perception, the neuronal correlates of audiovisual integration are not
fully understood. Specifically, it remains unclear whether neuronal firing patters in the primary visual cortex (V1) of
awake animals demonstrate similar sound-induced improvement in visual discriminability. Furthermore, presentation
of sound is associated with movement in the subjects, but little is understood about whether and how sound-associ-
ated movement affects audiovisual integration in V1. Here, we investigated how sound and movement interact to
modulate V1 visual responses in awake, head-fixed mice and whether this interaction improves neuronal encoding of
the visual stimulus. We presented visual drifting gratings with and without simultaneous auditory white noise to
awake mice while recording mouse movement and V1 neuronal activity. Sound modulated activity of 80% of light-
responsive neurons, with 95% of neurons increasing activity when the auditory stimulus was present. A generalized
linear model (GLM) revealed that sound and movement had distinct and complementary effects of the neuronal visual
responses. Furthermore, decoding of the visual stimulus from the neuronal activity was improved with sound, an
effect that persisted even when controlling for movement. These results demonstrate that sound and movement modu-


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late visual responses in complementary ways, improving neuronal representation of the visual stimulus. This study
clarifies the role of movement as a potential confound in neuronal audiovisual responses and expands our knowledge
of how multimodal processing is mediated at a neuronal level in the awake brain.
Key words: auditory cortex; electrophysiology; multimodal; visual cortex; visual processing
Significance Statement
Sound and movement are both known to modulate visual responses in the primary visual cortex; however, sound-
induced movement has largely remained unaccounted for as a potential confound in audiovisual studies in awake
animals. Here, authors found that sound and movement both modulate visual responses in an important visual
brain area, the primary visual cortex, in distinct, yet complementary ways. Furthermore, sound improved encoding
of the visual stimulus even when accounting for movement. This study reconciles contrasting theories on the mech-
anism underlying audiovisual integration and asserts the primary visual cortex as a key brain region participating
in tripartite sensory interactions.
Introduction
Our brains use incoming sensory information to generate a
continuous perceptual experience across sensory modal-
ities. The neuronal systems underlying sensory perception
of different modalities interact in a way that often improves
perception of the complementary modality (Gingras et al.,
2009; Gleiss and Kayser, 2012; Bigelow and Poremba, 2016;
Hammond-Kenny et al., 2017; Meijer et al., 2018; Stein et
al., 2020). In the audiovisual realm, it is often easiest to
understand what someone is saying in a crowded room by
additionally relying on visual cues such as lip movement
and facial expression (Maddox et al., 2015; Tye-Murray et
Received Dec. 2, 2021; revised Feb. 14, 2023; accepted Feb. 23, 2023.
Author contributions: A.M.W. and M.N.G. designed research; A.M.W., C.F.A., and M.N.G. performed


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research; A.M.W. and C.F.A. contributed unpublished reagents/analytic tools; A.M.W. and C.F.A. analyzed data;
A.M.W. and M.N.G. wrote the first draft of the paper; A.M.W., C.F.A., and M.N.G. edited the paper; A.M.W.
and M.N.G. wrote the paper.
This work was supported by National Institute of Health National Institute on Deafness and Other
Communication Disorders Grants 5T32DC016903 (to A.M.W. and C.F.A.), F31DC016524 (to C.F.A.), and
R01DC015527, R01DC014479, and R01NS113241 (to M.N.G.). We thank Gabrielle Samulewicz for assistance
with experiments and members of the Geffen laboratory for helpful discussions, as well as Dr. Jay Gottfried
and Dr. Yale Cohen at the University of Pennsylvania.
The authors declare no competing financial interests.
Correspondence should be addressed to Maria N. Geffen at mgeffen@pennmedicine.upenn.edu.
https://doi.org/10.1523/JNEUROSCI.2444-21.2023
Copyright © 2023 the authors
The Journal of Neuroscience, April 19, 2023 • 43(16):2885–2906 • 2885


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Systems/Circuits
Face-Selective Patches in Marmosets Are Involved in
Dynamic and Static Facial Expression Processing
Audrey Dureux,1 Alessandro Zanini,1 and
Stefan Everling1,2
1Centre for Functional and Metabolic Mapping, Robarts Research Institute, University of Western Ontario, London, Ontario N6A 5K8, Canada and
2Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario N6A 5K8, Canada
The correct identification of facial expressions is critical for understanding the intention of others during social communica-
tion in the daily life of all primates. Here we used ultra-high-field fMRI at 9.4 T to investigate the neural network activated
by facial expressions in awake New World common marmosets from both male and female sex, and to determine the effect
of facial motions on this network. We further explored how the face-patch network is involved in the processing of facial
expressions. Our results show that dynamic and static facial expressions activate face patches in temporal and frontal areas
(O, PV, PD, MD, AD, and PL) as well as in the amygdala, with stronger responses for negative faces, also associated with an
increase of the respiration rates of the monkey. Processing of dynamic facial expressions involves an extended network
recruiting additional regions not known to be part of the face-processing network, suggesting that face motions may facilitate
the recognition of facial expressions. We report for the first time in New World marmosets that the perception and identifi-
cation of changeable facial expressions, vital for social communication, recruit face-selective brain patches also involved in
face detection processing and are associated with an increase of arousal.
Key words: awake marmosets; faces; facial expressions; fMRI; respiration rate; social communication
Significance Statement
Recent research in humans and nonhuman primates has highlighted the importance to correctly recognize and process facial


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expressions to understand others’ emotions in social interactions. The current study focuses on the fMRI responses of emo-
tional facial expressions in the common marmoset (Callithrix jacchus), a New World primate species sharing several similar-
ities of social behavior with humans. Our results reveal that temporal and frontal face patches are involved in both basic face
detection and facial expression processing. The specific recruitment of these patches for negative faces associated with an
increase of the arousal level show that marmosets process facial expressions of their congener, vital for social communication.
Introduction
Social cognition requires the ability to perceive, process, and rec-
ognize the emotional expressions of conspecifics (Ferretti and
Papaleo, 2019). This ability is crucial not only for humans but
also many other social species (Parr et al., 1998; Tate et al., 2006;
Albuquerque et al., 2016), allowing them to communicate inten-
tions and to better adapt to environmental challenges (Russell,
1997). Facial expressions are particularly necessary during social
interactions, constituting a powerful route of rapid nonverbal
communication in all primates (Darwin, 2004).
Functional magnetic resonance imaging (fMRI) studies have
identified the neural networks underlying faces and facial
expression processing in humans and nonhuman primates.
In humans, faces elicit activity in a cortical and subcortical
network that includes the fusiform gyrus, amygdala, and fron-
totemporal areas in anterior and posterior regions of the supe-
rior temporal sulcus (STS) and in the inferotemporal cortex as
well as the orbitofrontal cortex (Kanwisher et al., 1997; Puce et al.,
1998; Haxby et al., 2000; Fusar-Poli et al., 2009). Distinct pat-
terns of activation have also been associated with the process-
ing of facial expressions. Overall, the processing of emotional
faces is associated with increased activation in most occipito-
temporal face-selective regions, prefrontal and orbitofrontal


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areas as well as subcortical areas including the amygdala and
cerebellum (Kanwisher et al., 1997; Puce et al., 1998; Haxby et
al., 2000; Blair, 2003; Murphy et al., 2003; Posamentier and
Abdi, 2003; Strauss et al., 2005; Hennenlotter and Schroeder,
2006; Vuilleumier and Pourtois, 2007; Fusar-Poli et al., 2009;
Received Aug. 2, 2022; revised Mar. 9, 2023; accepted Mar. 25, 2023.
Author contributions: A.D. and S.E. designed research; A.D. and A.Z. performed research; A.D. analyzed
data; A.D. wrote the paper.
Support was provided for this research by the Canadian Institutes of Health Research (Grant FRN 148365),
the Canada First Research Excellence Fund to BrainsCAN, and a Discovery grant by the Natural Sciences and
Engineering Research Council of Canada to S.E. We thank Cheryl Vander Tuin, Whitney Froese, Hannah
Pettypiece, and Miranda Bellyou for animal preparation and care; and Dr. Alex Li for scanning assistance.
The authors declare no competing financial interests.
Correspondence should be addressed to Audrey Dureux at audrey.dureux@gmail.com.
https://doi.org/10.1523/JNEUROSCI.1484-22.2023
Copyright © 2023 the authors
The Journal of Neuroscience, May 10, 2023 • 43(19):3477–3494 • 3477


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Behavioral/Cognitive
Intrinsic Neural Timescales in the Temporal Lobe Support
an Auditory Processing Hierarchy
Riccardo Cusinato,1,2p Sigurd L. Alnes,1,2p Ellen van Maren,2 Ida Boccalaro,2 Debora Ledergerber,3
Antoine Adamantidis,2 Lukas L. Imbach,3 Kaspar Schindler,2 Maxime O. Baud,2 and Athina Tzovara1,2,4
1Institute of Computer Science, University of Bern, Bern 3012, Switzerland, 2Center for Experimental Neurology, Sleep Wake Epilepsy Center,
NeuroTec, Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern 3010, Switzerland, 3Swiss Epilepsy Center,
Klinik Lengg, Zurich 8008, Switzerland, and 4Helen Wills Neuroscience Institute, University of California–Berkeley, Berkeley 94720, California
During rest, intrinsic neural dynamics manifest at multiple timescales, which progressively increase along visual and somato-
sensory hierarchies. Theoretically, intrinsic timescales are thought to facilitate processing of external stimuli at multiple
stages. However, direct links between timescales at rest and sensory processing, as well as translation to the auditory system
are lacking. Here, we measured intracranial EEG in 11 human patients with epilepsy (4 women), while listening to pure
tones. We show that, in the auditory network, intrinsic neural timescales progressively increase, while the spectral exponent
flattens, from temporal to entorhinal cortex, hippocampus, and amygdala. Within the neocortex, intrinsic timescales exhibit
spatial gradients that follow the temporal lobe anatomy. Crucially, intrinsic timescales at baseline can explain the latency of
auditory responses: as intrinsic timescales increase, so do the single-electrode response onset and peak latencies. Our results
suggest that the human auditory network exhibits a repertoire of intrinsic neural dynamics, which manifest in cortical gra-
dients with millimeter resolution and may provide a variety of temporal windows to support auditory processing.


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Key words: amygdala; aperiodic activity; auditory processing; hippocampus; intracranial EEG; timescales
Significance Statement
Endogenous neural dynamics are often characterized by their intrinsic timescales. These are thought to facilitate processing
of external stimuli. However, a direct link between intrinsic timing at rest and sensory processing is missing. Here, with intra-
cranial EEG, we show that intrinsic timescales progressively increase from temporal to entorhinal cortex, hippocampus, and
amygdala. Intrinsic timescales at baseline can explain the variability in the timing of intracranial EEG responses to sounds:
cortical electrodes with fast timescales also show fast- and short-lasting responses to auditory stimuli, which progressively
increase in the hippocampus and amygdala. Our results suggest that a hierarchy of neural dynamics in the temporal lobe
manifests across cortical and limbic structures and can explain the temporal richness of auditory responses.
Introduction
The human brain gives rise to rich neural dynamics, which
play a fundamental role in processing sensory information.
Intrinsic dynamics of the brain operate at multiple time-
scales (Hasson et al., 2008; Honey et al., 2012; Murray et al.,
2014; Raut et al., 2020) through oscillatory (Frauscher et al.,
2018; Mahjoory et al., 2020; Vezoli et al., 2021) and non-
oscillatory (Gao et al., 2020) processes. In the visual and
somatosensory systems, intrinsic timescales manifest at
rest, in ongoing neural activity: primary areas exhibit short
timescales that may facilitate a quick reaction to incoming
stimuli (Murray et al., 2014; Siegle et al., 2021). These pro-
gressively increase while advancing through the cortical hi-
erarchy, supporting integration of information (Murray et
al., 2014; Chaudhuri et al., 2015). Whether a similar hierar-
chy of intrinsic dynamics exists in the auditory system, and
in particular within the temporal lobe, a hub for auditory
processing, remains underexplored.


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Received Oct. 25, 2022; revised Feb. 21, 2023; accepted Mar. 2, 2023.
Author contributions: R.C. analyzed data; R.C. and A.T. wrote the first draft of the paper; R.C., S.L.A.,
E.v.M., I.B., D.L., A.A., L.L.I., K.S., M.O.B., and A.T. edited the paper; R.C., S.L.A., E.v.M., I.B., D.L., A.A., L.L.I.,
K.S., M.O.B., and A.T. wrote the paper; S.L.A., I.B., A.A., and A.T. designed research; S.L.A., E.v.M., D.L., L.L.I.,
K.S., and M.O.B. performed research.
This work was supported by Inselspital University Hospital Bern; the Interfaculty Research Cooperation
“Decoding Sleep: From Neurons to Health & Mind” of the University of Bern to A.A., I.B., A.T., and S.L.A.;
Swiss National Science Foundation to A.A. and 320030_188737 to A.T.; European Research Council CoG-
725850 to A.A.; the Synapsis Foundation to A.A.; the University of Bern to A.A.; and Fondation Pierre Mercier
pour la science to A.T. We thank Prof. Johannes Sarnthein for support with recordings and feedback on the
manuscript.
*R.C. and S.L.A. contributed equally to this work.
M.O.B. holds shares with Epios SA, a medical device company based in Geneva. The remaining authors
declare no competing financial interests.
Correspondence should be addressed to Athina Tzovara at athina.tz@gmail.com.
https://doi.org/10.1523/JNEUROSCI.1941-22.2023
Copyright © 2023 the authors
3696 • The Journal of Neuroscience, May 17, 2023 • 43(20):3696–3707


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From Prediction to Action: Dissociable Roles of Ventral Tegmental Area and Substantia Nigra Dopamine Neurons in Instrumental Reinforcement


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Behavioral/Cognitive
From Prediction to Action: Dissociable Roles of Ventral
Tegmental Area and Substantia Nigra Dopamine Neurons in
Instrumental Reinforcement
Kurt M. Fraser,1 Heather J. Pribut,1 Patricia H. Janak,1,2,3 and
Ronald Keiflin4,5
1Department of Psychological & Brain Sciences, Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, Maryland 21218, 2The
Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, 3Kavli
Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, 4Department of Psychological & Brain
Sciences, University of California, Santa Barbara, Santa Barbara, California 93106, and 5Neuroscience Research Institute, University of California
Santa Barbara, Santa Barbara, California, 93106
Reward seeking requires the coordination of motor programs to achieve goals. Midbrain dopamine neurons are critical for
reinforcement, and their activation is sufficient for learning about cues, actions, and outcomes. Here we examine in detail
the mechanisms underlying the ability of ventral tegmental area (VTA) and substantia nigra (SNc) dopamine neurons to sup-
port instrumental learning. By exploiting numerous behavioral tasks in combination with time-limited optogenetic manipula-
tions in male and female rats, we reveal that VTA and SNc dopamine neurons generate reinforcement through separable
psychological processes. VTA dopamine neurons imbue actions and their associated cues with motivational value that allows
flexible and persistent pursuit, whereas SNc dopamine neurons support time-limited, precise, action-specific learning that is
nonscalable and inflexible. This architecture is reminiscent of actor–critic reinforcement learning models with VTA and SNc
instructing the critic and actor, respectively. Our findings indicate that heterogeneous dopamine systems support unique


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forms of instrumental learning that ultimately result in disparate reward-seeking strategies.
Key words: dopamine; ICSS; motivation; operant conditioning; reinforcement; reward
Significance Statement
Dopamine neurons in the midbrain are essential for learning, motivation, and movement. Here we describe in detail the abil-
ity of VTA and SNc dopamine neurons to generate instrumental reinforcement, a process where an agent learns about actions
they can emit to earn reward. While rats will avidly work and learn to respond for activation of VTA and SNc dopamine neu-
rons, we find that only VTA dopamine neurons imbue actions and their associated cues with motivational value that spur con-
tinued pursuit of reward. Our data support a hypothesis that VTA and SNc dopamine neurons engage distinct psychological
processes that have consequences for our understanding of these neurons in health and disease.
Introduction
Midbrain dopamine (DA) neurons encode reward prediction
errors, a fundamental parameter in reinforcement learning
(Schultz et al., 1997; Waelti et al., 2001; Glimcher, 2011), and their
activation promotes learning about events leading to reward
(Steinberg et al., 2013; Ilango et al., 2014; Ramayya et al., 2014;
Chang et al., 2016; Stauffer et al., 2016; Keiflin et al., 2019).
Although early studies reported relatively broad and homogene-
ous responses to unexpected rewards across midbrain dopamine
cell groups—including the ventral tegmental area (VTA) and the
substantia nigra (SNc)—(Mirenowicz and Schultz, 1996; Schultz,
1998; Bayer and Glimcher, 2005), more recent studies have dem-
onstrated considerable heterogeneity in the response pattern of
different dopamine subsystems, particularly in relation to nonre-
ward variables (Matsumoto and Hikosaka, 2009; Barter et al.,
2015; Lerner et al., 2015; Howe and Dombeck, 2016; Menegas et
al., 2018; de Jong et al., 2019; Engelhard et al., 2019; Yuan et al.,
2019). For instance, dopamine neurons in the medial VTA sig-


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nal cue-related and outcome-related information, whereas do-
pamine neurons located in the lateral VTA and SNc appear to
encode motor parameters in reward-guided tasks (Howe and
Dombeck, 2016; Engelhard et al., 2019). Moreover, these different
Received Jan. 3, 2023; revised Apr. 6, 2023; accepted Apr. 14, 2023.
Author contributions: K.M.F., P.H.J., and R.K. designed research; K.M.F., H.J.P., and R.K. performed
research; K.M.F., H.J.P., and R.K. analyzed data; K.M.F., P.H.J., and R.K. wrote the paper.
This research was supported by Department of Health and Human Services | National Institutes of Health |
National Institute on Drug Abuse Grant R01-DA-035943.
The authors declare no competing financial interests.
Correspondence should be addressed to Ronald Keiflin at rkeiflin@ucsb.edu or Patricia H. Janak
atpatricia.janak@jhu.edu.
https://doi.org/10.1523/JNEUROSCI.0028-23.2023
Copyright © 2023 the authors
The Journal of Neuroscience, May 24, 2023 • 43(21):3895–3908 • 3895


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Rapid Input-Output Transformation between Local Field Potential and Spiking Activity during Sensation but not Action in the Superior Colliculus


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Systems/Circuits
Rapid Input-Output Transformation between Local Field
Potential and Spiking Activity during Sensation but not
Action in the Superior Colliculus
Clara Bourrelly,1,4 Corentin Massot,1,2,4 and
Neeraj J. Gandhi1,3,4
1Departments of Bioengineering, 2Neurobiology, 3Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, and 4Center for Neural
Basis of Cognition, University of Pittsburgh, Pittsburgh, Pennsylvania 15213
Sensorimotor transformation is the sequential process of registering a sensory signal in the environment and then responding
with the relevant movement at an appropriate time. For visually guided eye movements, neural signatures in the form of
spiking activity of neurons have been extensively studied along the dorsoventral axis of the superior colliculus (SC). In con-
trast, the local field potential (LFP), which represents the putative input to a region, remains largely unexplored in the SC.
We therefore compared amplitude levels and onset times of both spike bursts and LFP modulations recorded simultaneously
with a laminar probe along the dorsoventral axis of SC in 3 male monkeys performing the visually guided delayed saccade
task. Both signals displayed a gradual transition from sensory activity in the superficial layers to a predominantly motor
response in the deeper layers, although the transition from principally sensory to mostly motor response occurred ;500 lm
deeper for the LFP. For the sensory response, LFP modulation preceded spike burst onset by ,5 ms in the superficial and in-
termediate layers and only when data were analyzed on a trial-by-trial basis. The motor burst in the spiking activity led LFP
modulation by .25 ms in the deeper layers. The results reveal a fast and efficient input-output transformation between LFP
modulation and spike burst in the visually responsive layers activity during sensation but not during action. The spiking pat-


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tern observed during the movement phase is likely dominated by intracollicular processing that is not captured in the LFP.
Key words: frontal eye field; local field potential; oculomotor; saccade; superior colliculus
Significance Statement
What is the sequence of events between local field potential (LFP) modulation and spiking activity during sensorimotor trans-
formation? A trial-by-trial analysis reveals that the LFP activity leads the spike burst in the superficial and intermediate layers
of the superior colliculus during visual processing, while both trial-by-trial and the average analyses show that the spike burst
leads the LFP modulation during movement generation. These results suggest an almost instantaneous LFP input, spike burst
output transformation in the visually responsive layers of the superior colliculus when registering the stimulus. In contrast,
substantial intracollicular processing likely results in a saccade-related spike burst that leads LFP modulation.
Introduction
The orientation of gaze toward an object located in the visual
field results from successions of neural processing that converts
sensory information into movement generation. Located in the
midbrain, the superior colliculus (SC) is an essential structure
involved in this sensorimotor transformation (Sparks, 1986;
Krauzlis, 2005; Gandhi and Katnani, 2011; Basso and May, 2017;
Sajad et al., 2020; Cooper and McPeek, 2021). Studies using sin-
gle-channel and multichannel electrodes have shown that the SC
is functionally organized across its dorsoventral axis, such that
its neurons modulate their activities in response to either stimu-
lus appearance (superficial layers), saccade generation (deeper
layers), or both (intermediate layers) (Mohler and Wurtz, 1976;
Ikeda et al., 2015; Massot et al., 2019). The spikes emitted by neu-
rons, identified after high-pass filtering and thresholding of the
neural signal, are not the only signature of neural processing.
The local field potential (LFP) present in the lower-frequency


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spectrum is also informative. Whereas the spikes are the output
of neurons, the nature of the LFP is still debated and largely
Received Dec. 20, 2022; revised Apr. 19, 2023; accepted Apr. 21, 2023.
Author contributions: C.B., C.M., and N.J.G. designed research; C.B. and C.M. performed research; C.B.
analyzed data; C.B. wrote the first draft of the paper; C.B., C.M., and N.J.G. edited the paper; C.B. and N.J.G.
wrote the paper.
N.J.G. was supported by National Institutes of Health Grants R01 EY024831, R01 EY022854, and R21
EY030667. The work was also supported by National Institutes of Health Core Grant P30 EY08098 to the
Department of Ophthalmology. We thank the Division of Laboratory Animal Resources for veterinarian care
and surgical assistance.
The authors declare no competing financial interests.
Correspondence should be addressed to Neeraj J. Gandhi at neg8@pitt.edu or Clara Bourrelly at clb240@
pitt.edu.
https://doi.org/10.1523/JNEUROSCI.2318-22.2023
Copyright © 2023 the authors
The Journal of Neuroscience, May 31, 2023 • 43(22):4047–4061 • 4047


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Fast-Spiking Interneurons of the Premotor Cortex Contribute to Initiation and Execution of Spontaneous Actions


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Systems/Circuits
Fast-Spiking Interneurons of the Premotor Cortex Contribute
to Initiation and Execution of Spontaneous Actions
Nadia Giordano,1,2
Claudia Alia,1 Lorenzo Fruzzetti,1,3,4 Maria Pasquini,3,4 Giulia Palla,1,2 Alberto Mazzoni,3,4
Silvestro Micera,3,4,5 Leonardo Fogassi,6 Luca Bonini,6 and
Matteo Caleo7,1
1Neuroscience Institute, National Research Council (CNR), Pisa 56124, Italy, 2Scuola Normale Superiore, Pisa 56127, Italy, 3The BioRobotics
Institute, Scuola Superiore Sant’Anna, Pontedera 56025, Italy, 4Department of Excellence in Robotics & IA, Scuola Superiore Sant’Anna, Pisa 56127,
Italy, 5Centre for Neuroprosthetics and Institute of Bioengineering, Bertarelli Foundation Chair in Translational NeuroEngineering Laboratory,
École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland, 6Department of Medicine and Surgery, University of Parma, Parma
43125, Italy, and 7Department of Biomedical Sciences, University of Padua, Padua 35121, Italy
Planning and execution of voluntary movement depend on the contribution of distinct classes of neurons in primary motor
and premotor areas. However, timing and pattern of activation of GABAergic cells during specific motor behaviors remain
only partly understood. Here, we directly compared the response properties of putative pyramidal neurons (PNs) and
GABAergic fast-spiking neurons (FSNs) during spontaneous licking and forelimb movements in male mice. Recordings cen-
tered on the face/mouth motor field of the anterolateral motor cortex (ALM) revealed that FSNs fire longer than PNs and
earlier for licking, but not for forelimb movements. Computational analysis revealed that FSNs carry vastly more information
than PNs about the onset of movement. While PNs differently modulate their discharge during distinct motor acts, most
FSNs respond with a stereotyped increase in firing rate. Accordingly, the informational redundancy was greater among FSNs


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than PNs. Finally, optogenetic silencing of a subset of FSNs reduced spontaneous licking movement. These data suggest that
a global rise of inhibition contributes to the initiation and execution of spontaneous motor actions.
Key words: electrophysiology; fast spiking neurons; licking; premotor cortex; pyramidal neurons; single unit activity
Significance Statement
Our study contributes to clarifying the causal role of fast-spiking neurons (FSNs) in driving initiation and execution of spe-
cific, spontaneous movements. Within the face/mouth motor field of mice premotor cortex, FSNs fire before pyramidal neu-
rons (PNs) with a specific activation pattern: they reach their peak of activity earlier than PNs during the initiation of licking,
but not of forelimb, movements; duration of FSNs activity is also greater and exhibits less selectivity for the movement type,
as compared with that of PNs. Accordingly, FSNs appear to carry more redundant information than PNs. Optogenetic silenc-
ing of FSNs reduced spontaneous licking movement, suggesting that FSNs contribute to the initiation and execution of spe-
cific spontaneous movements, possibly by sculpting response selectivity of nearby PNs.
Introduction
Activity occurring before the initiation of voluntary move-
ments is critical for action planning and execution (Weinrich
and Wise, 1982; Godschalk et al., 1985; Wise and Mauritz,
1985; Churchland et al., 2006; Guo et al., 2014; Murakami et
al., 2014; Li et al., 2016; Gao et al., 2018). Specifically, premo-
tor areas act as a conductor to orchestrate the network activity
of the rest of the motor modules, on a moment-by-moment
basis, and exhibit tuning for specific movements (Georgopoulos
et al., 1982; Godschalk et al., 1985; Hocherman and Wise, 1991;
Riehle and Requin, 1993; Messier and Kalaska, 2000;
Churchland et al., 2006; Churchland and Shenoy, 2007). How do
distinct neuronal classes contribute to this process? The anticipa-
tory activity of pyramidal neurons (PNs) has been previously


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examined (Svoboda and Li, 2018), however little is known on the
Received Apr. 11, 2022; revised Mar. 24, 2023; accepted Mar. 28, 2023.
Author contributions: N.G., C.A., L.B., and M.C. designed research; N.G., C.A., G.P., and M.C. performed research; N.G.,
C.A., L.Fr., M.P., G.P., and A.M. analyzed data; N.G. and C.A. wrote the first draft of the paper; N.G., C.A., L.Fr., A.M.,
S.M., L.Fo., L.B., and M.C. edited the paper; N.G., C.A., L.Fr., L.B., and M.C. wrote the paper.
This project was supported by the H2020 EXCELLENT SCIENCE-European Research Council (ERC) Grant
Agreement 692943 (BrainBIT); Regione Toscana (PERSONA Project, Bando Salute 2018); Fondazione Cassa di
Risparmio di Padova e Rovigo (Foundation Cariparo, Project #52000; to M.C.); and the Ministry of University
(MUR) Grant FARE2020, project n. R20NJ7BBA7 “CIRCEM” (to L.B.). We thank Francesca Biondi (National
Research Council Pisa) for excellent animal care.
This manuscript is dedicated to the memory of Prof. Matteo Caleo (DOD April 12, 2022), who was a model for
enthusiasm and dedication in science and who introduced us (N.G. and C.A.) to the extraordinary world of this story.
*N.G. and C.A. contributed equally to this work.
The authors declare no competing financial interests.
Correspondence should be addressed to Claudia Alia at alia@in.cnr.it.
https://doi.org/10.1523/JNEUROSCI.0750-22.2023
Copyright © 2023 Giordano, Alia et al.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0
International license, which permits unrestricted use, distribution and reproduction in any medium provided
that the original work is properly attributed.
4234 • The Journal of Neuroscience, June 7, 2023 • 43(23):4234–4250


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The Differential Weights of Motivational and Task Performance Measures on Medial and Lateral Frontal Neural Activity


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Behavioral/Cognitive
The Differential Weights of Motivational and Task
Performance Measures on Medial and Lateral Frontal Neural
Activity
Clément Goussi-Denjean,1 Vincent Fontanier,1 Frederic M. Stoll,2 and
Emmanuel Procyk1
1Inserm, Stem Cell and Brain Research Institute U1208, Université Lyon 1, Bron, 69500, France and 2Nash Family Department of Neuroscience and
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029
Behavioral adaptations are triggered by different constraints given by rules, and are informed by outcomes, or motivational
changes. Neural activity in multiple frontal areas is modulated during behavioral adaptations, but the source of these modula-
tions and the nature of the mechanisms involved are unclear. Here we tested how different variables related to changes in
task performance and to behavioral adaptation impact the amplitude of event-related local field potentials (LFPs) in the lat-
eral prefrontal and midcingulate cortex of male rhesus macaques. We found that the behavioral task used induced consis-
tently different types of performance modulation: in relation to task difficulty (imposed by the experimental setup), to
successes and errors, and to the time spent in the task. Difficulty had a significant effect on monkeys’ accuracy and reaction
times. Interestingly, there is also a strong interaction between difficulty and trial success on the reaction times variation.
However, LFP modulations were mostly related to reaction times, touch position, feedback valence and time-in-session, with
little, if any, effect of difficulty. Hence, difficulty modulated performance but not LFP activity. This suggests that, in our ex-
perimental design, execution, regulation, and motivation-related factors are the main factors influencing medial and lateral
frontal activity.
Key words: cingulate cortex; cognitive control; difficulty; electrophysiology; local field potential; monkeys
Significance Statement


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Adapting decisions might be determined by several mechanisms and might be driven by motivational factors and/or factors
inherent to the task at hand. Multiple frontal areas contribute to behavioral adaptations. One current challenge is to under-
stand which information they process contributes to behavioral changes. Diverging views have emerged on whether task
demands, like the decision difficulty, or factors linked to incentives to adapt, are driving frontal activity. Here we show that
task difficulty had a strong effect on performance (accuracy and reaction times) but little effect on LFP recorded in monkey
lateral prefrontal and midcingulate cortex. However, information related to actions, outcome valence, and time-in-session
had major influences. Thus, task difficulty modulated performance but not LFP activity in frontal areas.
Introduction
Animals adapt dynamically to external events and internal stim-
uli to reactively or proactively improve their own state. The
underlying adaptive mechanisms are investigated in experimen-
tal conditions by varying, for instance, the multiplicity of options
to choose from, their order, the complexity of sensory informa-
tion relevant to the task, the temporal scale over which informa-
tion should be integrated for optimal response, or the nature of
rewards associated to options (Chen et al., 2008; Quilodran et al.,
2008; Kawai et al., 2015; Stoll et al., 2016a). In experimental as
well as in natural settings, other factors also influence behavior:
intrinsic motivation, satiety, fatigue, boredom, etc. (Stoll et al.,
2016b). All those factors can be reflected in performance (i.e., the
accuracy or the speed with which task trials are solved) (Procyk
and Goldman-Rakic, 2006; Martinez-Garcia et al., 2015).
Received Jan. 3, 2022; revised Feb. 17, 2023; accepted Feb. 24, 2023.
Author contributions: C.G.-D., V.F., F.M.S., and E.P. analyzed data; C.G.-D. and E.P. wrote the first draft of


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the paper; C.G.-D., V.F., F.M.S., and E.P. edited the paper; C.G.-D. and E.P. wrote the paper; V.F. and F.M.S.
performed research; F.M.S. and E.P. designed research.
This work was supported by Fondation pour la Recherche Médicale, DECCA ANR-10-SVSE4-1441 and
NORAD ANR-19-CE37-0008-01 projects, and was performed within the framework of the LABEX CORTEX (ANR-
11-LABX-0042) of Université de Lyon operated by the French National Research Agency (ANR). E.P. is
employed by the Center National de la Recherche Scientifique. We thank Monkeys H, A, O, and D for their
work.
The authors declare no conflict of interest.
Correspondence should be addressed to Emmanuel Procyk at emmanuel.procyk@inserm.fr.
https://doi.org/10.1523/JNEUROSCI.0007-22.2023
Copyright © 2023 Goussi-Denjean et al.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0
International license, which permits unrestricted use, distribution and reproduction in any medium provided
that the original work is properly attributed.
The Journal of Neuroscience, June 7, 2023 • 43(23):4329–4340 • 4329


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REVIEW
How sex and age affect immune responses, susceptibility to
infections, and response to vaccination
Carmen Gieﬁng-Kro¨ ll, Peter Berger, Gu¨ nter Lepperdinger
and Beatrix Grubeck-Loebenstein
Institute for Biomedical Aging Research of Innsbruck University, Innsbruck,
Austria
Summary
Do men die young and sick, or do women live long and healthy?
By trying to explain the sexual dimorphism in life expectancy,
both biological and environmental aspects are presently being
addressed. Besides age-related changes, both the immune and
the endocrine system exhibit signiﬁcant sex-speciﬁc differences.
This review deals with the aging immune system and its interplay
with sex steroid hormones. Together, they impact on the
etiopathology of many infectious diseases, which are still the
major causes of morbidity and mortality in people at old age.
Among men, susceptibilities toward many infectious diseases
and the corresponding mortality rates are higher. Responses to
various types of vaccination are often higher among women
thereby also mounting stronger humoral responses. Women
appear immune-privileged. The major sex steroid hormones
exhibit opposing effects on cells of both the adaptive and the
innate immune system: estradiol being mainly enhancing, tes-
tosterone by and large suppressive. However, levels of sex
hormones change with age. At menopause transition, dropping
estradiol potentially enhances immunosenescence effects posing
postmenopausal women at additional, yet speciﬁc risks. Conclu-
sively during aging, interventions, which distinctively consider
the changing level of individual hormones, shall provide potent
options in maintaining optimal immune functions.
Key words: hormone replacement; immunosenescence; infec-
tious diseases; menopause; sex differences; vaccination.
Introduction
A paradoxical situation between aging male and female is evident in
particular regarding health status and the corresponding survival rates
(Oksuzyan et al., 2008). Women exhibit signiﬁcantly higher life expec-


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tancies, while frequently experiencing disabilities earlier in life (Van Oyen
et al., 2013). Independent of age, death rates due to cancer, heart
disease, accidents, inﬂuenza, or pneumonia are signiﬁcantly higher in
men (Austad, 2006). Here, major contributors appear to be lifestyle
differences: smoking accounts for ~60% of gender-speciﬁc mortality in
Europe, alcohol abuse for ~30% (McCartney et al., 2011), followed by
risk-taking and seeking and complying with medical therapies (Oksuzyan
et al., 2008). Besides that, major biological determinants of the sexual
dimorphism in longevity are X chromosome diploidy, as well as distinct
differences in immune and hormone responses (Vina et al., 2005;
Austad, 2006; Oksuzyan et al., 2008), the latter both showing consistent
changes with aging.
Women carry two X chromosomes. The X chromosome expresses
several genes implicated in immunological processes, such as Toll-like
receptors, multiple cytokine receptors, genes involved in T-cell and B-cell
activity, and transcriptional and translational regulatory factors (Fish,
2008), while in turn the Y chromosome encodes for a number of
inﬂammatory pathway genes, which are exclusively expressed in men
(Flanagan, 2014). Most alleles on one X chromosome are randomly
silenced during X chromosome inactivation already during embryogen-
esis. Polymorphism of X-linked genes and cellular mosaicism for X-linked
parental alleles may offer additional advantages to women during host
responses, in particular by providing a more adaptive and balanced
cellular machinery during innate immune responses (Spolarics, 2007;
Libert et al., 2010). Here, we therefore reviewed the current consistent
knowledge on aging and sex-dimorphic susceptibility to infectious
diseases and vaccination response in the context of changing levels of
sex steroid hormones.
Sexual dimorphic susceptibility to infectious
diseases
Sex-speciﬁc infection and mortality rates have been documented in
humans (Table 1). This sexual dimorphism commences already during


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intrauterine development, for example, a male fetus experiencing a
chronic inﬂammatory environment primarily being induced by the
maternal immune system in the male placenta via decidual sites yet
also likely due to a higher gestational infection rate of male placenta
[(Goldenberg et al., 2006), reviewed in detail in (Clifton, 2010)]. Later in
life very probably due to socioeconomic behavior, such as higher
pathogen exposure during agricultural or occupational activities, men
are more susceptible to many infections caused by viruses, bacteria,
parasites, and fungi. They are signiﬁcantly more predisposed especially
to environmental and vector-borne diseases such as leptospirosis (3.5- to
4-fold increased incidence), schistosomiasis (1.5-fold), brucellosis, or
rabies (Corbel, 2006; Guerra-Silveira & Abad-Franch, 2013). Albeit at
comparable exposure levels, men exhibit higher incidence rates for
leishmaniasis (2.5- to 3.5-fold increased incidence), pulmonary tubercu-
losis (2- to 3-fold), and hepatitis A (1.4-fold), again surmising the role of
distinct biological differences (Guerra-Silveira & Abad-Franch, 2013).
Similarly, premenopausal women succumb less often to meningococcal
or pneumococcal infections. Testosterone exerts immune suppressive
effects thereby increasing the severity of malaria, leishmaniasis, amebi-
asis, and tuberculosis, while at the same time supporting the clearance
of toxoplasmosis (Bernin & Lotter, 2014; Nhamoyebonde & Leslie, 2014).
Correspondence
Professor Beatrix Grubeck-Loebenstein, Institute for Biomedical Aging Research,
Innsbruck University, Rennweg 10, 6020 Innsbruck, Austria.
Tel.: +43 512 507 50801; fax: +43 512 507 50899;
e-mail: beatrix.grubeck-loebenstein@uibk.ac.at
Accepted for publication 16 December 2014
ª 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use,


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distribution and reproduction in any medium, provided the original work is properly cited.
309
Aging Cell (2015) 14, pp309–321
Doi: 10.1111/acel.12326
Aging
 
Cell


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Allergy. 2023;78:369–388. 
 
 | 369
wileyonlinelibrary.com/journal/all
Received: 20 August 2022 | Revised: 1 November 2022 | Accepted: 22 November 2022
DOI: 10.1111/all.15593  
R E V I E W  A R T I C L E
Recent developments in the immunopathology of COVID- 19
Huan- ping Zhang1
 |   Yuan- li Sun2 |   Yan- fen Wang3 |   Duygu Yazici4 |   Dilek Azkur5
 |   
Ismail Ogulur4 |   Ahmet Kursat Azkur6
 |   Zhao- wei Yang7
 |   Xiao- xue Chen1 |    
Ai- Zhi Zhang8 |   Jia- qian Hu2 |   Guang- Hui Liu2 |   Mübeccel Akdis4
 |    
Cezmi A. Akdis4
 |   Ya- dong Gao2
1Department of Allergology, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, 
Taiyuan, China
2Department of Allergology, Zhongnan Hospital of Wuhan University, Wuhan, China
3Department of Pediatrics, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, 
Taiyuan, China
4Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
5Division of Pediatric Allergy and Immunology, Department of Pediatrics, Faculty of Medicine, University of Kirikkale, Kirikkale, Turkey
6Department of Virology, Faculty of Veterinary Medicine, University of Kirikkale, Kirikkale, Turkey
7Department of Allergy and Clinical Immunology, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated 
Hospital of Guangzhou Medical University, Guangzhou, China
8Intensive Care Unit, The Second Hospital of Shanxi Medical University, Taiyuan, China
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction 
in any medium, provided the original work is properly cited and is not used for commercial purposes.
© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.
Correspondence


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Ya- dong Gao, Department of Allergology, 
Zhongnan Hospital of Wuhan University, 
Donghu Road 169, Wuhan 430071, Hubei, 
China.
Email: gaoyadong@whu.edu.cn
Funding information
Scientific Research Initiative Funds 
of Shanxi Bethune Hospital (Number: 
2020RC004).; Shanxi Medical University
Abstract
There has been an important change in the clinical characteristics and immune pro-
file of Coronavirus disease 2019 (COVID- 19) patients during the pandemic thanks to 
the extensive vaccination programs. Here, we highlight recent studies on COVID- 19, 
from the clinical and immunological characteristics to the protective and risk factors 
for severity and mortality of COVID- 19. The efficacy of the COVID- 19 vaccines and 
potential allergic reactions after administration are also discussed. The occurrence 
of new variants of concerns such as Omicron BA.2, BA.4, and BA.5 and the global 
administration of COVID- 19 vaccines have changed the clinical scenario of COVID- 19. 
Multisystem inflammatory syndrome in children (MIS- C) may cause severe and het-
erogeneous disease but with a lower mortality rate. Perturbations in immunity of T 
cells, B cells, and mast cells, as well as autoantibodies and metabolic reprogramming 
may contribute to the long- term symptoms of COVID- 19. There is conflicting evidence 
about whether atopic diseases, such as allergic asthma and rhinitis, are associated 
with a lower susceptibility and better outcomes of COVID- 19. At the beginning of 
pandemic, the European Academy of Allergy and Clinical Immunology (EAACI) de-
veloped guidelines that provided timely information for the management of allergic 
diseases and preventive measures to reduce transmission in the allergic clinics. The


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C l i n i c a l  r e s e a r c h
Huntington disease: a single-gene 
degenerative disorder of the striatum
Peggy C. Nopoulos, MD
Introduction
 Huntington disease (HD) is an autosomal domi-
nant, neurodegenerative disorder with a primary etiolo-
gy of corticostriatal pathology. HD is caused by a DNA 
trinucleotide (triplet) repeat expansion of equal to or 
greater than 40 CAG repeats within the gene Hunting-
tin (HTT, OMIM 613004). Repeat numbers vary from 
6 to 35 in the general population. When there are less 
than 27 repeats, there is no manifestation of HD, and 
the gene is stable upon transmission. Repeat lengths in 
the range of 27 to 35 also are not associated with devel-
opment of HD; however, there is a possibility of expan-
sion upon transmission, giving rise to the phenomenon 
of genetic anticipation. Expansion upon transmission is 
more likely at longer repeat lengths within this range, 
and is also more likely to happen during male transmis-
sion.1 CAG repeats in the range of 36 to 39 are of incom-
plete penetrance with variable disease manifestation.
Phenomenology
HD is a rare disease with a prevalence of approximately 
10 to 12 individuals per 100 000 of European ancestry.2 
Copyright © 2016 AICH – Servier Research Group.  All rights reserved  
91 
www.dialogues-cns.org
Keywords: Huntington disease; neurodevelopment; striatum   
Author affiliations: Department of Psychiatry, University of Iowa, Iowa 
City, Iowa, USA
Address for correspondence: University of Iowa, Department of Psychia-
try, 200 Hawkins Drive, W278 GH, Iowa City, IA 52242, USA 
(email: peggy-nopoulos@uiowa.edu)
Huntington disease (HD) is an autosomal dominant, 
neurodegenerative disorder with a primary etiology 
of striatal pathology. The Huntingtin gene (HTT) has a 
unique feature of a DNA trinucleotide (triplet) repeat, 
with repeat length ranging from 10 to 35 in the nor-
mal population. Repeat lengths between 36 and 39 
cause HD at reduced penetrance (some will get the dis-
ease, others won’t) and when expanded to 40 or more


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repeats (mHTT), causes HD at full penetrance (every 
person with this length or beyond will definitely de-
velop the disease). The symptoms of HD may be motor, 
cognitive, and psychiatric, and are consistent with the 
pathophysiology of frontostriatal circuitry malfunction. 
Expressed ubiquitously and throughout the entire life 
cycle (development through adulthood), mHTT causes 
initial dysfunction and eventual death of a specific cell 
population within the striatum. Although all areas of 
the brain are eventually affected, the primary pathol-
ogy of the disease is regionally specific. As a single-gene 
disorder, HD has the distinction of having the potential 
of treatment that is aimed directly at the known patho-
genic mechanism by gene silencing, providing hope for 
neuroprotection and ultimately, prevention. 
© 2016, AICH – Servier Research Group 
Dialogues Clin Neurosci. 2016;18:91-98.


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Estrogen and Mitochondria Function in Cardiorenal Metabolic 
Syndrome
Guanghong Jia*,†, Annayya R. Aroor*,†, and James R. Sowers*,†,‡
*Division of Endocrinology, Diabetes, and Metabolism, Diabetes Cardiovascular Center, 
Columbia, Missouri, USA
†Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri, USA
‡Department of Medical Pharmacology and Physiology, Columbia, Missouri, USA
Abstract
The cardiorenal metabolic syndrome (CRS) consists of a constellation of cardiac, renal, and 
metabolic disorders including insulin resistance (IR), obesity, metabolic dyslipidemia, high-blood 
pressure, and evidence of early cardiac and renal disease. Mitochondria dysfunction often occurs 
in the CRS, and this dysfunction is promoted by excess reactive oxygen species, genetic factors, 
IR, aging, and altered mitochondrial biogenesis. Recently, it has been shown that there are 
important sex-related differences in mitochondria function and metabolic, cardiovascular, and 
renal components. Sex differences in the CRS have mainly been attributed to the estrogen’s effects 
that are mainly mediated by estrogen receptor (ER) α, ERβ, and G-protein coupled receptor 30. In 
this review, we discuss the effects of estrogen on the mitochondrial function, insulin metabolic 
signaling, glucose transport, lipid metabolism, and inflammatory responses from liver, pancreatic 
β cells, adipocytes, skeletal muscle, and cardiovascular tissue.
1. INTRODUCTION
The cardiorenal metabolic syndrome (CRS) consists of risk factors that include 
asatherogenic dyslipidemia, elevated blood pressure, high plasma glucose, prothrombotic 
disorder, and proinflammatory state (metabolic syndrome).1 There are a number of 
important bidirectional interactions among heart, kidney, brain, liver, muscle, and fat tissues, 
which cause a constellation of cardiac, renal, and metabolic disorders including insulin 
resistance (IR), obesity, metabolic dyslipidemia, high-blood pressure, and evidence of early


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cardiac and renal disease (Fig. 9.1). Epidemiological studies have shown that 36.1% of adult 
men and 32.4% of women had metabolic syndrome in the USA in 2010. This was a 
considerable increase from 21.8% to 23.7%, respectively, in 2002.2 The total number of 
adults with metabolic syndrome ranges from almost 77 million to almost 86 million in 
America.2 The first formal definition of the metabolic syndrome was proposed by the World 
Health Organization in 1998.3 International Diabetes Federation, American Heart 
Association, National Heart, Lung, and Blood Institute, World Heart Federation, 
© 2014 Elsevier Inc. All rights reserved.
The authors have no conflict of interest associated with this manuscript.
NIH Public Access
Author Manuscript
Prog Mol Biol Transl Sci. Author manuscript; available in PMC 2015 February 05.
Published in final edited form as:
Prog Mol Biol Transl Sci. 2014 ; 127: 229–249. doi:10.1016/B978-0-12-394625-6.00009-X.
NIH-PA Author Manuscript
NIH-PA Author Manuscript
NIH-PA Author Manuscript


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Complement Activation by Adeno-Associated Virus-Neutralizing
Antibody Complexes
Cara West,1,{,{ Joel D. Federspiel,2,{ Kara Rogers,3 Arpana Khatri,1 Sheila Rao-Dayton,4 Mireia Fernandez Ocana,2
Sean Lim,5 Aaron Michael D’Antona,5 Sandra Casinghino,3 and Suryanarayan Somanathan1,*
1Pﬁzer, Inc., Rare Disease Research Unit, Cambridge, Massachusetts, USA; 2Pﬁzer, Inc., Drug Safety Research & Development, Andover, Massachusetts, USA;
3Pﬁzer, Inc., Drug Safety Research & Development, Groton, Connecticut, USA; 4Pﬁzer, Inc., Rare Disease Research Unit, Kit Creek, North Carolina, USA; 5Pﬁzer, Inc.,
Biomedicine Design, Cambridge, Massachusetts, USA.
{Current afﬁliation: Afﬁnia Therapeutics, Waltham, Massachusetts, USA.
{These authors contributed equally to this work.
Treatment of monogenetic disorders using vectors based on adeno-associated virus (AAV) is an area of intense interest.
AAV is non-pathogenic human virus, and preexisting capsid antibodies are prevalent in the population posing a challenge
to the safety and efﬁcacy of AAV-mediated gene therapies. In this study, we investigated the risk of AAV-mediated
complement activation when sera from a cohort of human donors were exposed to AAV9 capsid. Seropositive donor sera
carrying neutralizing antibodies from a previous environmental exposure activated complement when admixed with
AAV9 capsids and complement activation was associated with donors who had higher levels of anti-AAV IgG1
antibodies. These ﬁndings were consistent with mass spectrometry analysis that identiﬁed increased binding of immuno-
globulins and complement factors when AAV9 capsids were admixed with seropositive sera. Finally, complement acti-
vation was abrogated after IgG-depletion using afﬁnity columns or serum pretreatment with an IgG degrading enzyme.
Overall, these results demonstrate an important role of preexisting neutralizing antibodies in activating complement; a risk


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that can be mitigated by using adequate immunosuppression strategies when dosing seropositive patients with vector.
Keywords: AAV, complement activation, neutralizing antibodies
INTRODUCTION
ADENO-ASSOCIATED VIRUS (AAV)-mediated gene therapy
has been approved to treat retinal blindness, neuromus-
cular disorders, and dyslipidemia.1–3 The clinical success
with AAV gene therapy has led to several ongoing late-
stage clinical trials to treat a myriad of rare monogenetic
disorders.4 An impediment to successful AAV gene
transfer is the presence of preexisting antibodies from
wild-type AAV infection in patients.5–8 Antibodies thwart
in vivo gene transfer, and transgene expression has been
ineffectual after vector administration to seropositive non-
human primates (NHPs) and human subjects.9,10 Conse-
quently, exclusion of seropositive patients with preexist-
ing antibodies above a neutralizing level (titer cutoff) has
been implemented in several clinical trials. These mea-
sures have provided beneﬁt by avoiding the complexities
that accompany vector administration to seropositive pa-
tients. Nevertheless, there is interest in extending AAV
gene therapies to additional patients by raising the titer
cutoff.
These proposals have been bolstered by reports of sta-
ble FIX expression in a gene therapy trial that inadver-
tently administered AAV5.FIX vector to seropositive
patients.11 While no adverse events have been reported in
*Correspondence: Dr. Suryanarayan Somanathan, Pﬁzer, Inc., Rare Disease Research Unit, 1 Portland St, Cambridge, MA 02139, USA. E-mail: suryanarayan.somanathan@pﬁzer.com
ª Cara West et al. 2023; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License [CC-BY] (http://
creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
554 j
HUMAN GENE THERAPY, VOLUME 34, NUMBERS 11 and 12
DOI: 10.1089/hum.2023.018
Mary Ann Liebert, Inc.


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string_value:
journal of Medical Genetics (1973).
10, 1.
/
t
I
,)
,
i9/3
/C
Rh Prevention: A Report andVnaysis'of
a National Programme
J. EKLUND and H. R. NEVANLINNA
Finnish Red Cross Blood Transfusion Service, Helsinki 31, Finland
Summary.
A nation-wide Rh prevention programme was started in Finland in
1969.
Before that, a control series of approximately 1000 Rh-negative mothers
giving birth to an Rh-positive child was collected to estimate the number ofmothers
with antibodies at either three, six, or nine months post partum.
During the three-
and-a-half year period altogether 14,980 Rh-negative patients were given 250 ,tg of
anti-D immunoglobulin prepared from Finnish raw material in the Central Labora-
tory of the Dutch Red Cross.
Out of those treated before the end of June 1972,
12,720 (97%,/) were tested four to six months post partum.
Seventeen or 0.13%
had detectable antibodies; in five ofthem the infant was ABO incompatible.
The
number ofprotected mothers with a subsequent Rh-positive infant was 1017; 10
had formed antibodies before the delivery of the second child.
The risk of primary immunization initiated during a single pregnancy was esti-
mated to be 0.35o/.
In addition, there was approximately a 0 60% risk of forming
antibodies by the next Rh-positive pregnancy.
The effect of prevention on the prevalence of haemolytic disease was calculated
and compared with observed figures.
The preventive effect of the administration of
anti-D
immunoglobulin
is
well
documented.
(Combined study from Centres in England and
Baltimore,
1971; WHO
Scientific Group,
1971;
Woodrow
et al, 1971; Clarke, 1972; Clarke and
McConnell,
1972.)
The failure incidence varies
between 0 0 and 0.6% (Schneider,
1971).
The
evidence is mainly derived from comparisons with a
large series of post-delivery control samples.
The
possible boosting effect of an additional Rh-positive
child during the next pregnancy has so far only
been studied in rather limited series (Woodrow,
1970;
Schneider,
1971; Woodrow
et
al,
1971).


key: chroma:document
string_value:
1971).
With a few exceptions (Zipursky and Israels, 1967;
Godel et al, 1968; Buchanan et al, 1969; V. J. Freda
and J. G. Gorman in Journal of Reproductive Medi-
cine, 1971) the reports pay little or no attention to
the group of patients excluded from prevention due
to antibody formation before the delivery.
The purpose of this report is to present the results
of a national Rh prevention programme including
Received 23 November 1972.
more than 12,000 patients followed up four to six
months after delivery and more than 1000 of these
who, after the administration of anti-D immuno-
globulin, gave birth to another Rh-positive child.
The results were analysed in order to compare the
observed with the expected risk of immunization
and to predict the effect of prevention on the inci-
dence of haemolytic disease in the future.
Other
details of possible theoretical and practical impor-
tance are discussed.
Control Series
The control series comprised 1707 Rh-negative
mothers delivered at two large lying-in hospitals in
Helsinki between 1 October 1967 and 31 December
1968.
All those without detectable antibodies at
delivery who gave birth to an Rh-positive child
were asked to give a follow up sample three, six, and
nine months after delivery.
The participation rate
was good at 93, 90, and 85%.
D antibodies were
found in 35 out of 1012 mothers, all but four of the
antibodies being already present at three months.
1


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Nature | www.nature.com | 1
Article
An atlas of substrate specificities for the 
human serine/threonine kinome
Jared L. Johnson1,2,28, Tomer M. Yaron1,2,3,4,5,28, Emily M. Huntsman1,2, Alexander Kerelsky1,2,3, 
Junho Song1,2, Amit Regev1,2, Ting-Yu Lin1,2,6, Katarina Liberatore1,2, Daniel M. Cizin1,2, 
Benjamin M. Cohen1,2, Neil Vasan7,8, Yilun Ma1,2, Konstantin Krismer9,10, 
Jaylissa Torres Robles11,12, Bert van de Kooij10, Anne E. van Vlimmeren10, 
Nicole Andrée-Busch13, Norbert F. Käufer13, Maxim V. Dorovkov14, Alexey G. Ryazanov14, 
Yuichiro Takagi15, Edward R. Kastenhuber1,2, Marcus D. Goncalves1,16, Benjamin D. Hopkins17, 
Olivier Elemento3,4, Dylan J. Taatjes18, Alexandre Maucuer19, Akio Yamashita20, 
Alexei Degterev21, Mohamed Uduman22, Jingyi Lu22, Sean D. Landry22, Bin Zhang22, 
Ian Cossentino22, Rune Linding23, John Blenis1,24,25, Peter V. Hornbeck22, Benjamin E. Turk11 ✉, 
Michael B. Yaffe10,26,27 ✉ & Lewis C. Cantley1,2 ✉
Protein phosphorylation is one of the most widespread post-translational 
modifications in biology1,2. With advances in mass-spectrometry-based 
phosphoproteomics, 90,000 sites of serine and threonine phosphorylation have so  
far been identified, and several thousand have been associated with human diseases  
and biological processes3,4. For the vast majority of phosphorylation events, it is not  
yet known which of the more than 300 protein serine/threonine (Ser/Thr) kinases 
encoded in the human genome are responsible3. Here we used synthetic peptide 
libraries to profile the substrate sequence specificity of 303 Ser/Thr kinases, comprising 
more than 84% of those predicted to be active in humans. Viewed in its entirety, the 
substrate specificity of the kinome was substantially more diverse than expected and 
was driven extensively by negative selectivity. We used our kinome-wide dataset to 
computationally annotate and identify the kinases capable of phosphorylating every 
reported phosphorylation site in the human Ser/Thr phosphoproteome. For the small


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minority of phosphosites for which the putative protein kinases involved have been 
previously reported, our predictions were in excellent agreement. When this approach 
was applied to examine the signalling response of tissues and cell lines to hormones, 
growth factors, targeted inhibitors and environmental or genetic perturbations, it 
revealed unexpected insights into pathway complexity and compensation. Overall, 
these studies reveal the intrinsic substrate specificity of the human Ser/Thr kinome, 
illuminate cellular signalling responses and provide a resource to link phosphorylation 
events to biological pathways.
Phosphorylation of proteins at serine, threonine, tyrosine and histi-
dine residues controls nearly every aspect of eukaryotic cellular func-
tion1,2,5,6. Misregulation of protein kinase signalling commonly results 
in human disease7. Deciphering the cellular roles of any protein kinase 
requires the elucidation of its downstream effector substrates. How-
ever, the majority of kinase–substrate relationships that have been 
published to date involve a relatively small number of well-studied 
protein kinases, while few, if any, substrates have been identified for 
the majority of the approximately 300 human protein Ser/Thr kinases 
within the human kinome8–10. This lack of knowledge of kinase–sub-
strate relationships limits the interpretation of large mass spectrometry 
(MS)-based phosphoproteomic datasets, which to date have collec-
tively reported over 200,000 Ser and Thr phosphorylation sites on 
human proteins3,4,11–13. The specific kinases that are responsible for 
these phosphorylation events have been reported for less than 4% 
of these sites3, substantially limiting the understanding of cellular 
phosphorylation networks.
Well-studied Ser/Thr kinases are generally known to recognize spe-
cific amino acid residues at multiple positions surrounding the site 
of phosphorylation14–17. This short linear motif, which is characteris-


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tic of a given protein kinase, ensures fidelity in signalling pathways 
regulating phosphorylation at a given Ser or Thr residue. Knowledge of 
kinase-recognition motifs can facilitate the discovery of new substrates, 
for example, by scanning phosphoproteomics data for matching 
sequences. However, to date, phosphorylation-site sequence motifs are 
known for only a subset of the human protein Ser/Thr kinome. We have 
previously described combinatorial peptide library screening methods 
that enable the rapid determination of specificity for individual kinases 
https://doi.org/10.1038/s41586-022-05575-3
Received: 1 May 2022
Accepted: 17 November 2022
Published online: xx xx xxxx
Open access
 Check for updates
A list of affiliations appears at the end of the paper.


key: title
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Anti-PD-1 PD-L1 immunotherapy in patients with solid organ transplant, HIV or hepatitis BC infection


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string_value:
Anti-PD-1/PD-L1 immunotherapy in patients with solid organ 
transplant, HIV or hepatitis B/C infection
Martin Tioa,*, Rajat Raia, Ogochukwu M. Ezeokeb, Jennifer L. McQuadec, Lisa Zimmerd, 
Chloe Khooe, John J. Parkf,g, Lavinia Spainh, Samra Turajlich,i, Luke Ardolinoj, Desmond 
Yipk,l, Simone M. Goldingerm, Justine V. Cohenn, Michael Millwardo, Victoria Atkinsonp, 
Alisa Y. Kaneq,r, Paolo A. Asciertos, Claus Garbet, Ralf Gutzmeru, Douglas B. Johnsonv, 
Hira A. Rizvib, Anthony M. Joshuaa,j,w, Matthew D. Hellmannb, Georgina V. Longa,x,y, 
Alexander M. Menziesa,x,y
aMelanoma Institute Australia, Sydney, Australia
bMemorial Sloan Kettering Cancer Center, New York, USA
cMD Anderson Cancer Center, Houston, USA
dUniversity of Duisburg-Essen Hospital, Heidelberg, Germany
ePeter MacCallum Cancer Centre, Melbourne, Australia
fCrown Princess Mary Cancer Centre, Sydney, Australia
gWestmead Hospital, Sydney, Australia
hSkin and Renal Unit, The Royal Marsden NHS Foundation Trust, London, UK
iFrancis Crick Institute, London, UK
*Corresponding author. mtio0565@uni.sydney.edu.au (M. Tio). 
Conflict of interest statement
Chloe Khoo received travel and conference support from Roche. Lisa Zimmer served a consultant for Roche, Bristol-Myers Squibb, 
Merck Sharp & Dohme, Novartis, Sanofi and Pierre Fabre; received honoraria from Roche, Bristol-Myers Squibb, Merck Sharp & 
Dohme, Novartis, Merck KGaA and Pierre Fabre and support for scientific meetings from Bristol-Myers Squibb, Merck Sharp & 
Dohme, Novartis, Amgen and Pierre Fabre. Michael Millward was an advisory board member for Bristol-Myers Squibb, Roche, 
AstraZeneca and Merck Sharp & Dohme. Paolo A. Ascierto served as a consultant for Bristol-Myers Squibb, Roche-Genentech, 
Merck Sharp & Dohme, Novartis, Amgen, Array, Merck Serono, Pierre Fabre, Incyte, NewLink Genetics, Genmab, Medimmune, 
AstraZeneca, Syndax, Sun Pharma, Sanofy, Idera and Ultimovacs and received research funding from Bristol-Myers Squibb, Roche-


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Genentech and Array. Douglas B. Johnson was an advisory board member for Array, Bristol-Myers Squibb, Incyte and Merck and 
received research funding from Bristol-Myers Squibb and Incyte. Victoria Atkinson was an advisory board member for Bristol-Myers 
Squibb, Merck Sharp & Dohme, Pierre Fabre and Novartis and received travel support from Bristol-Myers Squibb and speakers fee 
from Merck Sharp & Dohme, Novartis and Bristol-Myers Squibb. Simone M. Goldinger was an advisory board member and received 
travel grant support from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme and Novartis. Claus Garbe received grant support 
from Bristol-Myers Squibb, Novartis and Roche and personal fees from Amgen, Bristol-Myers Squibb, Novartis, Roche, Merck Sharp 
& Dohme and Philogen. Ralf Gutzmer received lecture fees from Amgen, Boehringer Ingelheim, AstraZeneca, Roche, Bristol-Myers 
Squibb, Novartis, Pierre Fabre, Merck-EMD and Almirall-Hermal; honoraria from Amgen, Leo Pharma, Inctye, Roche, Bristol-Myers 
Squibb, Novartis, Regeneron, 4SC, Pierre Fabre, Merck-EMD and Almirall-Hermal; patient fees from Amgen, Roche, Bristol-Myers 
Squibb, Novartis, Regenerom, 4SC, Philogen and Array; grant support from Novartis, Pfizer and Johnson & Johnson and support for 
scientific meetings from Roche, Bristol-Myers Squibb, Pierre Fabre. Matthew Hellman was a consultant for Bristol-Myers Squibb, 
Merck, Genentech, Roche, Astra-Zeneca, MedImmune, Novartis and Janssen and received research funding from Bristol-Myers 
Squibb. Georgina V. Long was a consultant for Array, Bristol-Myers Squibb, Novartis, Roche, Amgen, Pierre Fabre, Merck Sharp & 
Dohme and Incyte. Alexander M. Menzies was an advisory board member for Merck Sharp & Dohme, Chugai, Novartis and Pierre 
Fabre and received honoraria from Bristol-Myers Squibb and Novartis. All other authors report no conflicts of interest to disclose.
Writing assistance
None.
HHS Public Access
Author manuscript
Eur J Cancer. Author manuscript; available in PMC 2023 May 12.


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Published in final edited form as:
Eur J Cancer. 2018 November ; 104: 137–144. doi:10.1016/j.ejca.2018.09.017.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript


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Safety and Immunogenicity of Ad26-Vectored HIV Vaccine With Mosaic Immunogens and a Novel Mosaic Envelope Protein in HIV-Uninfected Adults


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The Journal of Infectious Diseases                                
M A J O R  A R T I C L E
vided the original work is not altered or transformed in any way, and that the work is properly 
Safety and Immunogenicity of Ad26-Vectored HIV Vaccine 
With Mosaic Immunogens and a Novel Mosaic Envelope 
Protein in HIV-Uninfected Adults: A Phase 1/2a Study
Daniel J. Stieh,1,a Dan H. Barouch,2,3,a Christy Comeaux,1 Michal Sarnecki,4 Kathryn E. Stephenson,2 Stephen R. Walsh,5,6 Sheetal Sawant,7
Jack Heptinstall,7 Georgia D. Tomaras,7 James G. Kublin,8 M. Juliana McElrath,8 Kristen W. Cohen,8 Stephen C. De Rosa,8 Galit Alter,3, Guido Ferrari,7
David Montefiori,7 Philipp Mann,8 Steven Nijs,9 Katleen Callewaert,9 Paul A. Goepfert,10 Srilatha Edupuganti,11 Etienne Karita,12 Michael S. Seaman,2
Lawrence Corey,8 Lindsey R. Baden,6 Maria G. Pau,1 Hanneke Schuitemaker,1 and Frank Tomaka,13 on behalf of the ASCENT/HVTN118/HPX2003 Study Team
1Janssen Vaccines and Prevention Leiden, the Netherlands; 2Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA; 3Ragon Institute of MGH, MIT, and 
Harvard, Cambridge, Massachusetts, USA; 4Janssen Vaccines, Bern, Switzerland; 5Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; 
6Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; 7Department of Surgery, Center for Human Systems Immunology, and Duke Human Vaccine Institute, Duke 
University, Durham, North Carolina, USA; 8Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA; 9Janssen Research and Development, Beerse, 
Belgium; 10Division of Infectious Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA; 11Division of Infectious Diseases, Department of Medicine, 
Emory University School of Medicine, Atlanta, Georgia, USA; 12Rwanda Zambia HIV Research Group, Kigali, Rwanda; and 13Janssen Research and Development, Titusville, New Jersey, USA


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Background. Developing a cross-clade, globally effective HIV vaccine remains crucial for eliminating HIV.
Methods. This placebo-controlled, double-blind, phase 1/2a study enrolled healthy HIV-uninfected adults at low risk for HIV 
infection. They were randomized (1:4:1) to receive 4 doses of an adenovirus 26-based HIV-1 vaccine encoding 2 mosaic Gag and 
Pol, and 2 mosaic Env proteins plus adjuvanted clade C gp140 (referred to here as clade C regimen), bivalent protein regimen (clade 
C regimen plus mosaic gp140), or placebo. Primary end points were safety and antibody responses.
Results. In total 152/155 participants (clade C, n = 26; bivalent protein, n = 103; placebo, n = 26) received ≥1 injection. The 
highest adverse event (AE) severity was grade 3 (local pain/tenderness, 12%, 2%, and 0% of the respective groups; solicited 
systemic AEs, 19%, 15%, 0%). HIV-1 mosaic gp140-binding antibody titers were 79 595 ELISA units (EU)/mL and 137 520 EU/mL 
in the clade C and bivalent protein groups (P < .001) after dose 4 and 16 862 EU/mL and 25 162 EU/mL 6 months later. Antibody 
response breadth against clade C gp140 and clade C/non-clade C gp120 was highest in the bivalent protein group.
Conclusions. Adding mosaic gp140 to the clade C regimen increased and broadened the elicited immune response without 
compromising safety or clade C responses.
Clinical Trials Registration. NCT02935686.
Keywords. Ad26 HIV vaccine; broad immunogenicity; cross-clade; heterologous regimen; mosaic HIV antigen; tetravalent.
Received 05 July 2022; editorial decision 04 November 2022; accepted 07 November 2022; 
published online 9 November 2022
aD. J. S. and D. H. B. contributed equally.
Presented in part: 10th International AIDS Society Conference on HIV Science, 21–24 July 
2019, Mexico City, Mexico.
Correspondence: Daniel J. Stieh, PhD, Janssen Vaccines and Prevention, Archimedesweg 6, 
Leiden 2333, the Netherlands (dstieh@ITS.JNJ.com).
The Journal of Infectious Diseases®
2023;227:939–50


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© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases 
Society of America. 
This is an Open Access article distributed under the terms of the Creative Commons Attribution- 
NonCommercial-NoDerivs 
licence 
(https://creativecommons.org/licenses/by-nc-nd/4.0/), 
which permits non-commercial reproduction and distribution of the work, in any medium, pro-
cited. For commercial re-use, please contact journals.permissions@oup.com
https://doi.org/10.1093/infdis/jiac445
With 38 million people living with human immunodeficien-
cy virus (HIV) worldwide, a safe, globally effective vaccine 
remains essential to curb further HIV transmission [1]. To 
date, 4 preventive HIV vaccine concepts have been tested 
in efficacy studies, only 1 of which demonstrated vaccine ef-
ficacy (31% in the RV144 trial) [2, 3]. The vaccines’ 
immunogens’ inability to elicit a sufficiently broad and 
durable immune response to counter the extensive diversity 
of HIV-1 is likely one of the main reasons for their poor 
efficacy [4].
A multivalent HIV vaccine based on the replication- 
incompetent recombinant adenovirus serotype 26 (Ad26) vec-
tor was developed using a mosaic immunogen approach to 
elicit broader responses against diverse variants of HIV-1 
[5–7]. The in silico-designed mosaic antigens include a maxi-
mum number of potential epitopes from group M variants of 
HIV-1 envelope (Env), group-specific antigen (Gag), and po-
lymerase (Pol) proteins [8]. These Ad26-delivered HIV-1 mo-
saic antigens elicited broad cellular immune responses and 
partially protected against neutralization-resistant simian- 
human immunodeficiency virus SHIVSF162P3 in rhesus mon-
keys [6, 9]. Furthermore, the addition of adjuvanted recombi-
nant glycoprotein (gp)140 to the Ad26-based mosaic vaccine 
substantially improved protection in rhesus monkeys [10]. 
Env-specific binding antibodies were repeatedly identified as 
a correlate of protection for these mosaic vaccines [7, 10, 11].


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Sex Differences in Cognitive Impairment and Alzheimer’s
Disease
Rena Li1,* and Meharvan Singh2
1Center for Hormone Advanced Science and Education (CHASE), Roskamp Institute, Sarasota,
FL 34243
2Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer’s Disease
Research (IAADR), Center FOR HER, University of North Texas, Health Science Center, Fort
Worth, TX 76107
Abstract
Studies have shown differences in specific cognitive ability domains and risk of Alzheimer’s
disease between the men and women at later age. However it is important to know that sex
differences in cognitive function during adulthood may have their basis in both organizational
effects, i.e., occurring as early as during the neuronal development period, as well as in
activational effects, where the influence of the sex steroids influence brain function in adulthood.
Further, the rate of cognitive decline with aging is also different between the sexes. Understanding
the biology of sex differences in cognitive function will not only provide insight into Alzheimer’s
disease prevention, but also is integral to the development of personalized, gender-specific
medicine. This review draws on epidemiological, translational, clinical, and basic science studies
to assess the impact of sex differences in cognitive function from young to old, and examines the
effects of sex hormone treatments on Alzheimer’s disease in men and women.
1. Introduction
The popular quote, “Men are from Mars and women are from Venus”, has been commonly
applied to many different situations including physiology, sociology and pathology; the
gender differences in cognitive functioning are no exception. The differences of learning and
memory between male and female brains are confirmed by both human and animal studies
from early development stages throughout their life spans. In addition, many neurological
diseases exhibit gender biases, such that one sex has a greater prevalence or severity of the


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disease than the other. Neurological diseases in the young and the elderly also demonstrate
gender-specific responses to therapies. However, the question is how much, rather than
whether or not, the biology of sex contributes to normal cognitive function. Accordingly,
such understanding may provide better insight into the factors that contribute to the risk of
© 2014 Elsevier Inc. All rights reserved.
*Corresponding author: Li, Rena (rli@rfdn.org), CHASE, Roskamp Institute, Sarasota, Florida, 34243, 941-752-2949 x 383.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our
customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of
the resulting proof before it is published in its final citable form. Please note that during the production process errors may be
discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
NIH Public Access
Author Manuscript
Front Neuroendocrinol. Author manuscript; available in PMC 2015 August 01.
Published in final edited form as:
Front Neuroendocrinol. 2014 August ; 35(3): 385–403. doi:10.1016/j.yfrne.2014.01.002.
NIH-PA Author Manuscript
NIH-PA Author Manuscript
NIH-PA Author Manuscript


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Annals ofthe Rheumatic Diseases 1990; 49: 262-264
REVIEW ARTICLE
Acquired chondronecrosis
Leon Sokoloff
Abstract
Zonal necrosis of chondrocytes is a character-
istic feature of Kashin-Beck disease. Infer-
ences about chondronecrosis in several spon-
taneous and experimental arthropathies of
other species may be relevant to the cause of
Kashin-Beck disease and conceivably, too,
banal osteoarthritis in man.
Although it is not commonly recognised as a
category of the general disease of joints, selec-
tive necrosis of articular and growth plate
cartilages occurs with a distinct prevalance in
humans and several animal species. In man the
prototype
is Kashin-Beck disease. Chondro-
necrosis in other human disorders occurs in
more complex circumstances. 'Laminar chon-
dritis'
or,
as
it
is now known,
idiopathic
chondrolysis, was
originally described
as a
necrosis of articular cartilage in young children.
Cell death is, however, not the definitive event.1
Necrosis of cartilages is a feature of inherited
adenosine deaminase deficiency. Affected infants
die long before locomotor disabilities are mani-
fest.2 Death of chondrocytes is also the rule in
ochronotic cartilage.
The animal lesions, spontaneous and experi-
mental, have no defined human analogues.
Nevertheless,
they
share
several
important
features with Kashin-Beck disease: they are
acquired and affect growing individuals; damage
or necrosis of articular chondrocytes leads to
osteochondritis
dissecans and
osteoarthritis;
and involvement ofgrowth plate cartilage results
in disproportionate dwarfism and malformation
of the skeleton. These features suggest that at
some early stage in the life of skeletal chondro-
cytes the cells are particularly susceptible to
defined noxious agents or else have special
metabolic requirements.
This article reviews the comparative pathology
of the several disorders and the environmental
factors that may be involved in their cause.
Although chondrocytes are the apparent seat of
the disease process, the possibility that the


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primary disturbance resides in the subchondral
microcirculatory bed, and that the viability of
the cells is compromised as a consequence,
cannot be dismissed out of hand; nor can the
Department of
possibility that primary changes in the pericel-
Pathology, Health
lular matrix embarrass the nutrition of the cells.
Sciences Center,
State University of
New York, Stony Brook,
Kashin-Beck disease
NY 11794-8691, USA
L Sokoloff
This non-inflammatory joint disease is widely
prevalent in parts of northern China and neigh-
bouring Siberia.3 Perhaps two million people
are affected, many of them terribly crippled. In
some communities the prevalence is up to 85%
of the population. All evidence indicates that
Kashin-Beck disease is of environmental origin.
The earliest morphological change is coagulation
necrosis of the deepest zone of the articular and
epiphysial growth plate cartilages of preadoles-
cent children. Detachment of articular cartilage
gives rise to loose bodies later on as well as
deformities of multiple appendicular
joints.
Stunting of growth at times is marked.
Despite intensive studies by Russian, Japan-
ese, and Chinese investigators over the course of
the last century no toxic material has been
identified
as
responsible
for
Kashin-Beck
disease; nor has a specially required nutritional
factor for the cartilages been found. There is no
evidence for an infectious agent. Three types of
thinking are now entertained in different re-
search laboratories: (a) trace metal toxicities,
perhaps
complicating
excessive
phosphate
ingestion; (b) mycotoxicosis arising from grains
contaminated by Fusarium oxysporum; and (c)
deficiency
of
selenium.
The
incidence
of
Kashin-Beck disease in Siberia has declined
as food has been brought in from other areas.
Selenium deficiency may be responsible for the
cardiomyopathy, Keshan disease, that also is
endemic in that part of the world, but its link
with Kashin-Beck disease is at best tenuous.
Osteochondrosis
This term applies to one or more veterinary


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disorders of great economic importance to the
livestock, kennel, and poultry industries. There
are many reports on the subject, few of which
are known to the medical profession.
Like
Kashin-Beck disease, osteochondrosis occurs in
very young animals and has as its principal
target the joint and growth plate cartilages.
Lameness, osteochondritis dissecans, stunted
growth,
and,
ultimately,
osteoarthritis
are
characteristic of cases with advanced disease.
There are variations from species to species, and
we may be dealing with more than one entity.
Focal failure of endochondral ossification and
hence persistence ofnubs of basilar cartilage is a
prominent feature of osteochondrosis in swine
and dogs. This is often associated with necrosis
and horizontal splitting of articular cartilage at
the junction of the hypertrophic and calcified
layers." The necrosis at times is sufficiently
extensive for it to resemble Kashin-Beck disease.
262


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Aetiology of rheumatoid arthritis: an attempt to transmit an infective agent from patients with rheumatoid arthritis to baboons


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Annals of the Rheumatic Diseases, 1983, 42, 443-447
Aetiology of rheumatoid arthritis: an attempt to
transmit an infective agent from patients with
rheumatoid arthritis to baboons
J. M. K. MacKAY,l* A. K. SIM,' J. N. McCORMICK,3 B. P. MARMION,'t
A. P. McCRAW,' J. J. R. DUTHIE,3 AND D. L. GARDNER4
From the 'Department ofBacteriology University ofEdinburgh; 'Inveresk Research International,
Musselburgh; 'the Rheumatic Diseases Unit, Northern General Hospital, Edinburgh; and the 4Institute of
Pathology, the Queen's University of Belfast
SUMMARY
Thirty baboons were injected intravenously and intra-articularly with material from the
joints of 19 patients with active rheumatoid arthritis or with control material. Fifteen of the 30
animals received synovial fluid cells or synovial membrane cells from 3 patients with seronegative
arthritis. Ten animals received pooled cells from a total of 16 cases of seropositive arthritis. Five
animals were given nonrheumatoid cells. No signs of arthritis were recognised in the 27 surviving
animals during 3 years of observation. No significant biochemical, haematological, or serological
changes occurred during this period, and no gross or microscopic evidence of synovial or systemic
disease was found post mortem.
The theory that a bacterial or viral infection
is
aetiologically related to rheumatoid arthritis (RA) is
tenaciously held despite many false leads and the
absence of firm confirmatory evidence.' A variety of
experimental approaches in different disciplines has
produced candidate organisms ranging from bac-
teria-in particular diphtheroids"3-to mycoplasmas4'6
and to viruses.7'-0 There is no conclusive evidence
linking diphtheroids or mycoplasmas to the
dis-
ease.'-4 Similarly, a search for viruses by miscel-
laneous techniques has also been negative,5 though
there
is
serological
evidence
of
a
relationship
between Epstein-Barr virus infection and RA."
Another way to demonstrate an infective aetiology
for RA is to attempt to transmit the disease to


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experimental animals. Warren and his colleagues2-' 6
claim to have transmitted RA to mice, chickens and
rats by the injection of human synovial membrane
extracts, but other workers'7 have failed to reproduce
these findings. Crocker et al.,"8 using complement-
deficient mice, have found that the intraperitoneal
Accepted for publication 24 May 1982.
Correspondence
to
Professor
D.
L.
Gardner,
Department
of
Histopathology,
University Hospital of South Manchester, Nell
Lane, Withington, Manchester M20 8LR.
*Deceased.
tPresent address: Division of Medical Virology, Institute of Medical
and Veterinary Science, Adelaide, South Australia.
injection of homogenates of RA synovial membrane
produces inflammatory swelling of the tails and limbs
of mice and occasional runting. Such changes do not
necessarily
indicate
transmission
of an
infective
agent, and as far as we can determine no confirma-
tory reports of this observation have appeared.
It is recognised that the host range of certain
human viruses is restricted and that negative trans-
mission experiments with common laboratory ani-
mals do not finally exclude the presence of a virus in
human tissues. For example, human hepatitis B and
non-A, non-B viruses grow in chimpanzees but not in
small laboratory
animals.
It
therefore appeared
reasonable to attempt to transmit RA to nonhuman
primates. This paper describes such an attempt by the
inoculation of human synovial cells and cell prepara-
tions into the knee joints of baboons.
Materials and methods
Thirty female, immature and mature, 7*8-19*2 kg
baboons were imported from Africa and held at
Inveresk Research International, Edinburgh. They
were housed in large gang cages and kept under close
observation for 5 months. During this period they
were examined clinically at regular intervals and
underwent biochemical, haematological, serological,
and
radiological
investigations.
All
the
animals
443


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CLINICAL CANCER RESEARCH | REVIEW
T-Cell Receptor Repertoire Sequencing in the Era of
Cancer Immunotherapy
Meredith L. Frank1,2, Kaylene Lu1,2,3, Can Erdogan1,4, Yi Han5, Jian Hu2,3, Tao Wang5,6, John V. Heymach1,2,
Jianjun Zhang1,2,7, and Alexandre Reuben1,2
ABSTRACT
◥
T cells are integral components of the adaptive immune sys-
tem, and their responses are mediated by unique T-cell receptors
(TCR) that recognize speciﬁc antigens from a variety of biological
contexts. As a result, analyzing the T-cell repertoire offers a better
understanding of immune responses and of diseases like cancer.
Next-generation sequencing technologies have greatly enabled
the high-throughput analysis of the TCR repertoire. On the basis
of our extensive experience in the ﬁeld from the past decade,
we provide an overview of TCR sequencing, from the initial
library preparation steps to sequencing and analysis methods and
ﬁnally to functional validation techniques. With regards to data
analysis, we detail important TCR repertoire metrics and present
several computational tools for predicting antigen speciﬁcity.
Finally, we highlight important applications of TCR sequencing
and repertoire analysis to understanding tumor biology and
developing cancer immunotherapies.
Introduction
Our immune system is composed of the innate and adaptive
immune systems; the innate immune system protects against
general threats and conserved pathogenic sequences while the
adaptive immune system targets and retains memory of speciﬁc
pathogens (1). T cells are critical mediators of adaptive immunity,
speciﬁcally driving cellular immunity as opposed to B cells that
govern humoral immunity. Functionally, T cells kill infected cells
or release cytokines to recruit other immune cells after recognizing
foreign antigens presented on infected cells (2). Immature T cells
migrate from hemopoietic tissues to the thymus where they mature
into na€ve T cells that express a unique and functional T-cell
receptor (TCR) that grants them the ability to recognize speciﬁc


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antigens (3). The thymus is also where T cells differentiate from
an initial CD4/CD8 double-positive state into either a CD4þ or
CD8þ lineage. CD4þ T cells execute helper functions while CD8þ
T cells are cytotoxic (4). Na€ve T cells become antigen-experienced
T cells after encountering their cognate antigen presented on major
histocompatibility complex (MHC) molecules through their TCRs.
TCRs are highly diverse heterodimeric surface receptors that
enable T cells to provide protection against a variety of different
pathogens. A functional TCR is comprised of two paired protein
chains, with either alpha (a) and beta (b) chains or gamma (g) and
delta (d) chains (Fig. 1A). The majority of T cells express ab
TCRs that recognize antigens presented on MHC proteins (3).
Only 1%–5% of T cells express gd TCRs, which are not MHC
restricted and participate in innate immune responses. It is un-
clear which exact ligands gd T cells bind (5). For these reasons, ab
TCRs are typically the focus of TCR sequencing and subsequent
clinical applications.
Regardless of type, the chains of a TCR contain an N-terminus
variable region capable of antigen recognition and a C-terminus
constant region. The variable region is assembled from variable (V),
diversity (D), and joining (J) gene segments through an ordered
process called V(D)J recombination, in which one allele of each
gene segment is randomly recombined with other gene segment
alleles to form a functional antigen recognition region (Fig. 1B;
refs. 6, 7). TCRa and g chains are comprised of V and J gene
segments, while TCRb and d chains also include the D gene
segment, offering more diversity in structure. The overall combi-
natorial diversity of the gene segments is accompanied by junctional
diversity, which is driven by the random addition or deletion of
nucleotides at junctions between gene segments. Both combina-
tional and junctional diversity grant T cells a substantial range of
antigen speciﬁcities, potentially accounting for 1015 to 1020 possible


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TCR chains (8). Importantly, immature T cells commit to either an
ab or gd lineage during V(D)J recombination, where the commit-
ment to ab is facilitated by the successful recombination of the
b-chain and commitment to gd is facilitated by successful recom-
bination of both the g and d chain (9).
The variable domains for each of the TCR chains have three
complementarity-determining regions (CDR): CDR1, CDR2, and
CDR3. CDR1 and CDR2, which are encoded by the V gene segment,
primarily facilitate the interaction between the TCR and MHC through
contact with the conserved a-helices of MHC. CDR3 is encoded by
the junction of V and J or D and J gene segments, resulting in high
1Department of Thoracic/Head and Neck Medical Oncology, The University of
Texas MD Anderson Cancer Center, Houston, Texas. 2The University of Texas MD
Anderson Cancer Center UT Health Houston Graduate School of Biomedical
Sciences, Houston, Texas. 3Department of Cancer Biology, The University of
Texas MD Anderson Cancer Center, Houston, Texas. 4Rice University, Houston,
Texas. 5Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of
Public Health, University of Texas Southwestern Medical Center, Dallas, Texas.
6Center for the Genetics of Host Defense, University of Texas Southwestern
Medical Center, Dallas, Texas. 7Department of Genomic Medicine, The University
of Texas MD Anderson Cancer Center, Houston, Texas.
M.L. Frank and K. Lu co-wrote the manuscript.
J. Zhang and A. Reuben co-supervised the preparation of the manuscript.
Corresponding Authors: Alexandre Reuben, The University of Texas MD
Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030.
Phone: (713) 745-3014; E-mail: areuben@mdanderson.org; and Jianjun Zhang,
jzhang20@mdanderson.org
Clin Cancer Res 2023;29:994–1008
doi: 10.1158/1078-0432.CCR-22-2469
This open access article is distributed under the Creative Commons Attribution-
NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.


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CLINICAL MICROBIOLOGY REVIEWS,
0893-8512/99/$04.0010
July 1999, p. 383–393
Vol. 12, No. 3
Copyright © 1999, American Society for Microbiology. All Rights Reserved.
Intranasal Antibody Prophylaxis for Protection
against Viral Disease
RICHARD WELTZIN* AND THOMAS P. MONATH
OraVax, Inc., Cambridge, Massachusetts 02139
INTRODUCTION.......................................................................................................................................................383
ANTIBODY AS A MEDIATOR OF RESPIRATORY TRACT IMMUNITY.......................................................383
Roles of Immunoglobulins G and A in Antiviral Immunity.............................................................................383
Induction of Immunity in Respiratory Tract Lymphoid Tissue.......................................................................385
Active versus Passive Intranasal Immunization To Prevent Human Viral Diseases....................................385
Treatment of Established Infections....................................................................................................................386
PASSIVE NASAL IMMUNIZATION STUDIES WITH ANIMAL MODELS OF VIRAL INFECTION........386
Inﬂuenza Virus........................................................................................................................................................386
Sendai Virus ............................................................................................................................................................386
Respiratory Syncytial Virus...................................................................................................................................387
PASSIVE NASAL IMMUNIZATION STUDIES WITH HUMANS.....................................................................389
Immunoglobulin Treatment...................................................................................................................................389


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Monoclonal Antibody Treatment..........................................................................................................................390
POTENTIAL FOR THERAPEUTIC NASAL ANTIBODY TREATMENT TO REDUCE DISEASE ..............390
CONCLUSIONS .........................................................................................................................................................391


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CLINICAL MICROBIOLOGY REVIEWS,
0893-8512/99/$04.0010
July 1999, p. 405–428
Vol. 12, No. 3
Copyright © 1999, American Society for Microbiology. All Rights Reserved.
Molecular Basis of the Interaction of Salmonella with the
Intestinal Mucosa
K. HERAN DARWIN AND VIRGINIA L. MILLER*
Departments of Pediatrics and Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110
INTRODUCTION.......................................................................................................................................................406
General Background on Salmonellosis................................................................................................................406
General Description of Pathogenesis...................................................................................................................406
ATTACHMENT...........................................................................................................................................................407
Type 1 Fimbriae......................................................................................................................................................410
Long Polar Fimbriae ..............................................................................................................................................411
Plasmid-Encoded Fimbriae ...................................................................................................................................411
Thin Aggregative Fimbriae....................................................................................................................................412
Rck ............................................................................................................................................................................412
Functional Redundancy?........................................................................................................................................412


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MUCOSAL INVASION..............................................................................................................................................412
Apparatus Genes.....................................................................................................................................................413
invH.......................................................................................................................................................................413
invG.......................................................................................................................................................................414
invE .......................................................................................................................................................................414
invA .......................................................................................................................................................................414
invB .......................................................................................................................................................................415
invC .......................................................................................................................................................................415
invI (spaM)...........................................................................................................................................................415
spaP, spaQ, spaR (surface presentation of antigen) .......................................................................................415
spaS .......................................................................................................................................................................415
prgH (phoP-repressed gene)...............................................................................................................................416


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prgI and prgJ........................................................................................................................................................416
prgK.......................................................................................................................................................................416
orgA (oxygen-regulated gene) ............................................................................................................................416
Secreted Proteins and Their Chaperones............................................................................................................416
SPI1-encoded secreted proteins ........................................................................................................................417
(i) invJ (spaN) and spaO ................................................................................................................................417
(ii) sicA (Salmonella invasion chaperone)....................................................................................................417
(iii) sipB/sspB (Salmonella invasion protein or Salmonella secreted protein) .........................................417
(iv) sipC/sspC ...................................................................................................................................................417
(v) sipD/sspD ....................................................................................................................................................418
(vi) sipA/sspA....................................................................................................................................................418
(vii) iacP (invasion-associated acyl carrier protein)..................................................................................418
(viii) sicP ..........................................................................................................................................................418


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(ix) sptP (secreted protein tyrosine phosphatase)......................................................................................418
(x) avrA (avirulence).......................................................................................................................................418
Non-SPI1-encoded proteins dependent on SPI1 for secretion .....................................................................418
(i) sigDE/sopB (Salmonella invasion gene/Salmonella outer protein)........................................................418
(ii) sopE ............................................................................................................................................................419
Regulators................................................................................................................................................................419
invF .......................................................................................................................................................................419
hilA-iagB ...............................................................................................................................................................420
sirA (Salmonella invasion regulator).................................................................................................................420
phoPQ....................................................................................................................................................................420
Operon structure and regulation of SPI1-encoded genes .............................................................................420
DIARRHEA..................................................................................................................................................................420


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CONCLUSIONS .........................................................................................................................................................423
ACKNOWLEDGMENTS ...........................................................................................................................................423


key: title
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Sensorimotor Alterations Induced by Novel Fentanyl Analogs in Mice: Possible Impact on Human Driving Performances


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Current Neuropharmacology
	

	

	





Send Orders for Reprints to reprints@benthamscience.net 
Current Neuropharmacology, 2023, 21, 87-104 
87 
REVIEW ARTICLE 
Sensorimotor Alterations Induced by Novel Fentanyl Analogs in Mice: 
Possible Impact on Human Driving Performances 
Sabrine Bilel1,#, Arianna Giorgetti2,#, Micaela Tirri1, Raffaella Arfè1, Virginia Cristofori3,  
Beatrice Marchetti1, Giorgia Corli1, Lorenzo Caruso4, Giorgio Zauli5, Raffaele Giorgetti6, and
Matteo Marti1,7,*, 
1Department of Translational Medicine, Section of Legal Medicine and LTTA Center, University of Ferrara, 44121 
Ferrara, Italy; 2Department of Medical and Surgical Sciences, Unit of Legal Medicine, University of Bologna, Via 
Irnerio 49, 40126 Bologna, Italy; 3Department of Chemistry and Pharmaceutical Sciences, University of Ferrara, Italy; 
4Department of Environment and Prevention Sciences, University of Ferrara, Ferrara, Italy; 5Research Department, 
King Khaled Eye Specialistic Hospital, Riyadh, Saudi Arabia; 6Department of Excellence of Biomedical Science and 
Public Health, Faculty of Medicine, Polytechnic University of Marche, Ancona, Italy; 7Collaborative Center of the Na-
tional Early Warning System, Department for Anti-Drug Policies, Presidency of the Council of Ministers, Ferrara, Italy 
Abstract: Operating a vehicle is a complex task that requires multiple cognitive functions and psy-
chomotor skills to cooperate. Driving might be impaired by licit or illicit drugs, including novel psy-
choactive substances (NPS) and novel synthetic opioids (NSO), the effects of which are still yet to be 
elucidated in humans. In the present work, a revision of the literature regarding the psychomotor im-
pairing effects of Fentanyl (FENT) and three analogues (Acrylfentanyl, Ocfentanyl and Furanylfenta-
nyl) is presented, as emerged by experimental studies on humans, driving under the influence of a drug


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(DUID) and intoxication cases. An experimental study on a mouse model evaluated the sensorimotor 
alterations induced by FENT and the three fentalogs. Acute systemic administration of the four opi-
oids (0.01-15 mg/kg i.p.) dose-dependently decreased the visual object and placing tests, the acoustic 
and the tactile responses of mice. The preclinical data are in accordance with the data that emerged 
from the revision of the literature regarding experimental data on humans, driving under the influence 
of drugs and intoxication cases, suggesting that novel synthetic opioids might affect the psychomotor 
performances on daily human tasks with a particular focus on driving. 
A R T I C L E  H I S T O R Y 
Received: June 30, 2022 
Revised: July 23, 2022 
Accepted: August 01, 2022 
DOI:  
10.2174/1570159X21666221116160032
Keywords: Acrylfentanyl, Furanylfentanyl, Ocfentanyl, naloxone, sensorimotor alterations, novel psychoactive substances, 
DUID, opioids. 
1. INTRODUCTION
Driving under the influence of drugs (DUID) refers to the
act of operating a vehicle following ingestion, inhalation, 
absorption, or injection of drugs or medications other than 
alcohol, that could interfere with the capacity to drive an 
automobile safely [1]. Driving is a complex task, where the 
driver continuously elaborates and responds to information 
received from the external surroundings, and requires several 
cognitive and psychomotor functions to cooperate [2]. Many 
substances, both licit and illicit, may cause impairment of 
driving performance, affecting the body and the behavior in 
*Address correspondence to this author at the Department of Translational
Medicine, Section of Legal Medicine and LTTA Center, University of Fer-
rara, 44121 Ferrara, Italy; Tel: +39 0532 455781; Fax: +39 0532 455777;
E-mail: matteo.marti@unife.it
#These authors contributed equally to the work and can be all considered
first authors. 
These authors share the seniorship. 
different ways. The most reported effects in cases of DUID


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consist of impairments of psychomotor skills and cognitive 
functions critical to driving, including vigilance, time and 
distance perception and monitoring, visual acuity, cognition, 
judgement and risk-taking behavior, reaction time, divided 
attention, keeping co-ordination and balance [2, 3]. A great 
alarm has been raised recently by the increase of DUID and 
traffic accidents due to the use of drugs. Cannabis was the 
illicit drug most frequently detected in cases of DUID, fol-
lowed by cocaine while amphetamines and illicit opioids 
were less frequently detected. In addition to traditional sub-
stances, novel psychoactive substances (NPS) have also been 
related to DUID cases. Over the period from January 2019 to 
April 2020, 670 toxicology cases involving 46 individual NPS 
were reported to the UNODC. Of these cases, 62% were clas-
sified as DUID [4]. Synthetic cathinones are the most fre-
quently detected NPS in Europe together with synthetic can-
nabinoids. However, the reports regarding the involvement 
1875-6190/23
© 2023  Bentham Science Publishers
This is an Open Access article  published 
under CC BY 4.0  
https://creativecommons.org/licenses/
by/4.0/legalcode


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Selecting the Best Animal Model of Parkinson's Disease for Your Research Purpose: Insight from in vivo PET Imaging Studies


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Current Neuropharmacology
	

	

	





Send Orders for Reprints to reprints@benthamscience.net 
 
Current Neuropharmacology, 2023, 21, 1241-1272 
1241 
REVIEW ARTICLE 
Selecting the Best Animal Model of Parkinson’s Disease for Your Research 
Purpose: Insight from in vivo PET Imaging Studies 
 
Caroline Cristiano Real1,2, Karina Henrique Binda1,2, Majken Borup Thomsen1,2,  
Thea Pinholt Lillethorup1,2, David James Brooks1,3 and Anne Marlene Landau1,2,* 
1Department of Nuclear Medicine and PET Center, Aarhus University Hospital, Aarhus, Denmark; 2Translational Neu-
ropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 3Institute of Translational 
and Clinical Research, University of Newcastle, Upon Tyne, UK 
 
Abstract: Parkinson’s disease (PD) is a debilitating neurodegenerative multisystem disorder lead-
ing to motor and non-motor symptoms in millions of individuals. Despite intense research, there is 
still no cure, and early disease biomarkers are lacking. Animal models of PD have been inspired by 
basic elements of its pathogenesis, such as dopamine dysfunction, alpha-synuclein accumulation, 
neuroinflammation and disruption of protein degradation, and these have been crucial for a deeper 
understanding of the mechanisms of pathology, the identification of biomarkers, and evaluation of 
novel therapies. Imaging biomarkers are non-invasive tools to assess disease progression and re-
sponse to therapies; their discovery and validation have been an active field of translational re-
search. Here, we highlight different considerations of animal models of PD that can be applied to 
future research, in terms of their suitability to answer different research questions. We provide the 
reader with important considerations of the best choice of model to use based on the disease fea-
tures of each model, including issues related to different species. In addition, positron emission to-


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mography studies conducted in PD animal models in the last 5 years are presented. With a variety 
of different species, interventions and genetic information, the choice of the most appropriate model 
to answer research questions can be daunting, especially since no single model recapitulates all as-
pects of this complex disorder. Appropriate animal models in conjunction with in vivo molecular 
imaging tools, if selected properly, can be a powerful combination for the assessment of novel ther-
apies and developing tools for early diagnosis. 
 
A R T I C L E  H I S T O R Y 
 
Received: August 17, 2022 
Revised: September 08, 2022 
Accepted: September 08, 2022 
 
DOI:  
10.2174/1570159X21666230216101659 
 
Keywords: Animal models, Parkinson’s disease, rodent, non-human primate, minipig, alpha-synuclein, positron emission to-
mography, autoradiography.  
1. INTRODUCTION 
 
Parkinson’s disease (PD) is an age-related progressive 
neurodegenerative disorder characterized by neuronal and 
neuritic accumulation of misfolded and aggregated alpha-
synuclein (α-syn) containing inclusions called Lewy bodies 
and Lewy neurites in brain regions targeting the substantia 
nigra pars compacta (SNpc) and also peripheral organs. Loss 
of dopaminergic neurons in the SNpc causes a reduction in 
available dopamine (DA) in the striatum, which affects sig-
nalling to the motor cortex and initiates the most characteris-
tic clinical symptoms of PD, namely limb bradykinesia in 
combination with rigidity and/or rest tremor [1, 2]. The 
spread of α-syn inclusions and neurodegeneration affect not 
 
*Address correspondence to this author at the Translational Neuropsychiatry 
Unit, Department of Clinical Medicine, Aarhus University Hospital, A701 - 
Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark; Tel: +45 
50209259; E-mail: alandau@clin.au.dk  
only the dopaminergic system but also the serotonergic, nor-
adrenergic and cholinergic systems. These are responsible 
for the non-motor features of PD, including sleep, autonomic


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and psychiatric dysfunctions, such as insomnia, rapid eye 
movement (REM), sleep behaviour disorder (RBD), consti-
pation, depression, and hyposmia [2]. The development of 
the non-motor features can occur both prodromally and at a 
later stage of PD. Failure to clear α-syn or its overexpression, 
misfolding, aggregation and propagation is the underlying 
mechanism driving Lewy body disorders; this molecular 
pathogenesis also leads to altered mitochondrial function, 
oxidative stress, and neuroinflammation/glial activation. 
While age is the greatest risk factor for PD, multiple aspects 
have been suggested to play a role in the aetiology of PD, 
including inflammation, gut microbiome composition [3, 4], 
and exposure to environmental factors, including infection, 
pesticides and air pollution [5, 6]. The majority of PD cases 
are idiopathic though 5-40% have a genetic origin depending 
1875-6190/23 $65.00+.00
© 2023 Bentham Science Publishers


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Drug Repurposing and Observational Studies: The Case of Antivirals
for the Treatment of COVID-19
Miguel A. Hernán, MD; and Julia del Amo, MD
Remdesivir and molnupiravir were the only 2 repurposed antivi-
rals that were approved for emergency use during the COVID-19
pandemic. Both drugs received their emergency use authorization
on the basis of a single industry-funded phase 3 trial, which was
launched after evidence of in vitro activity against SARS-CoV-2. In
contrast, for tenofovir disoproxil fumarate (TDF), little in vitro evi-
dence was generated, no randomized trials for early treatment
were done, and the drug was not considered for authorization.
Yet, by the summer of 2020, observational evidence suggested a
substantially lower risk for severe COVID-19 in TDF users
compared with nonusers. The decision-making process for
the launching of randomized trials for these 3 drugs is reviewed.
Observational data in favor of TDF was systematically dismissed,
even though no viable alternative explanations were proposed
for the lower risk for severe COVID-19 among TDF users.
Lessons learned from the TDF example during the ﬁrst 2 years
of the COVID-19 pandemic are described, and the use of
observational clinical data to guide decisions about the launch
of randomized trials during the next public health emergency is
proposed. The goal is that gatekeepers of randomized trials
make better use of the available observational evidence for the
repurposing of drugs without commercial value.
Ann Intern Med. doi:10.7326/M22-3582
Annals.org
For author, article, and disclosure information, see end of text.
This article was published at Annals.org on 28 March 2023.
W
hen seeking to repurpose drugs to treat a new
disease, deciding which compounds graduate to
randomized trials typically relies on preclinical evidence:
In silico mathematical models and in vitro studies in bio-
logical samples are followed by in vivo animal experi-
ments before human trials. What if observational studies


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show that users of a drug have better outcomes after
acquiring the new disease? Should this information inform
the launch of human trials?
We review the decision-making process for 3 drugs
considered for repurposing for COVID-19: remdesivir,
molnupiravir, and tenofovir. Remdesivir and molnupiravir
were the only 2 repurposed antivirals that were approved
for emergency use. Both were studied in randomized tri-
als. Tenofovir, with observational evidence suggesting
favorable COVID-19 outcomes, was not adequately stud-
ied in trials and never received emergency use approval.
Using these case studies, we make proposals to help
make better use of the available observational evidence
during the next public health emergency.
WHY DID REMDESIVIR MAKE IT INTO
RANDOMIZED TRIALS?
Remdesivir, developed by Gilead Sciences and studied
as a potential treatment of Ebola virus infection, received
U.S. Food and Drug Administration emergency use au-
thorization on 1 May 2020 for in-hospital treatment of
COVID-19. At that time, the only randomized trial avail-
able had reported quicker recovery and lower mortality
with remdesivir versus placebo (1). Three additional trials
done in 2020 and 2021 reported no or a modest survival
beneﬁt with remdesivir in hospitalized patients (2–4).
Remdesivir, an intravenous and expensive drug, had
been prioritized for randomized trials by the World
Health Organization Scientiﬁc Advisory Group on the ba-
sis of its broad antiviral spectrum, the available in vitro
and in vivo data available, and the clinical safety data (5).
Yet, many antivirals have broad spectrum, the in vivo evi-
dence was indirect (activity against Middle East respiratory
syndrome–CoV and SARS-CoV), and remdesivir had a
short safety record compared with other antivirals. These
recommendations encouraged randomized trials of remde-
sivir, such as the 4-group Solidarity trial, which studied
remdesivir, lopinavir–ritonavir, hydroxychloroquine, and
interferon (2). The last 3 groups were abandoned because


