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Causes

The causes of schizophrenia are unknown, and a number of models have been put forward to explain the link between altered brain function and schizophrenia. The prevailing model of schizophrenia is that of a neurodevelopmental disorder, and the underlying changes that occur before symptoms become evident are seen as arising from the interaction between genes and the environment. Extensive studies support this model. Maternal infections, malnutrition and complications during pregnancy and childbirth are known risk factors for the development of schizophrenia, which usually emerges between the ages of 18 and 25, a period that overlaps with certain stages of neurodevelopment. Gene-environment interactions lead to deficits in the neural circuitry that affect sensory and cognitive functions.

The common dopamine and glutamate models proposed are not mutually exclusive; each is seen to have a role in the neurobiology of schizophrenia. The most common model put forward was the dopamine hypothesis of schizophrenia, which attributes psychosis to the mind's faulty interpretation of the misfiring of dopaminergic neurons. This has been directly related to the symptoms of delusions and hallucinations. Abnormal dopamine signaling has been implicated in schizophrenia based on the usefulness of medications that affect the dopamine receptor and the observation that dopamine levels are increased during acute psychosis. A decrease in D receptors in the dorsolateral prefrontal cortex may also be responsible for deficits in working memory.

The glutamate hypothesis of schizophrenia links alterations between glutamatergic neurotransmission and the neural oscillations that affect connections between the thalamus and the cortex. Studies have shown that a reduced expression of a glutamate receptor – NMDA receptor, and glutamate blocking drugs such as phencyclidine and ketamine can mimic the symptoms and cognitive problems associated with schizophrenia. Post-mortem studies consistently find that a subset of these neurons fail to express GAD67 (GAD1), in addition to abnormalities in brain morphometry. The subsets of interneurons that are abnormal in schizophrenia are responsible for the synchronizing of neural ensembles needed during working memory tasks. These give the neural oscillations produced as gamma waves that have a frequency of between 30 and 80 hertz. Both working memory tasks and gamma waves are impaired in schizophrenia, which may reflect abnormal interneuron functionality. An important process that may be disrupted in neurodevelopment is astrogenesis – the formation of astrocytes. Astrocytes are crucial in contributing to the formation and maintenance of neural circuits and it is believed that disruption in this role can result in a number of neurodevelopmental disorders including schizophrenia. Evidence suggests that reduced numbers of astrocytes in deeper cortical layers are assocociated with a diminished expression of EAAT2, a glutamate transporter in astrocytes; supporting the glutamate hypothesis.

Deficits in executive functions, such as planning, inhibition, and working memory, are pervasive in schizophrenia. Although these functions are separable, their dysfunction in schizophrenia may reflect an underlying deficit in the ability to represent goal related information in working memory, and to use this to direct cognition and behavior. These impairments have been linked to a number of neuroimaging and neuropathological abnormalities. For example, functional neuroimaging studies report evidence of reduced neural processing efficiency, whereby the dorsolateral prefrontal cortex is activated to a greater degree to achieve a certain level of performance relative to controls on working memory tasks. These abnormalities may be linked to the consistent post-mortem finding of reduced neuropil, evidenced by increased pyramidal cell density and reduced dendritic spine density. These cellular and functional abnormalities may also be reflected in structural neuroimaging studies that find reduced grey matter volume in association with deficits in working memory tasks.

Positive symptoms have been linked to cortical thinning in the superior temporal gyrus. The severity of negative symptoms has been linked to reduced thickness in the left medial orbitofrontal cortex. Anhedonia, traditionally defined as a reduced capacity to experience pleasure, is frequently reported in schizophrenia. However, a large body of evidence suggests that hedonic responses are intact in schizophrenia, and that what is reported to be anhedonia is a reflection of dysfunction in other processes related to reward. Overall, a failure of reward prediction is thought to lead to impairment in the generation of cognition and behavior required to obtain rewards, despite normal hedonic responses.

Another theory links abnormal brain lateralization to the development of being left-handed which is significantly more common in those with schizophrenia. This abnormal development of hemispheric asymmetry is noted in schizophrenia. Studies have concluded that the link is a true and verifiable effect that may reflect a genetic link between lateralization and schizophrenia.

Bayesian models of brain functioning have been used to link abnormalities in cellular functioning to symptoms. Both hallucinations and delusions have been suggested to reflect improper encoding of prior expectations, thereby causing expectation to excessively influence sensory perception and the formation of beliefs. In approved models of circuits that mediate predictive coding, reduced NMDA receptor activation, could in theory result in the positive symptoms of delusions and hallucinations.