A number of non-causal psychological mechanisms have been implicated in the development and maintenance of schizophrenia. Cognitive biases that have been identified in those with a diagnosis or those at risk, especially when under stress or in confusing situations, include excessive attention to potential threats, jumping to conclusions, making external attributions, impaired reasoning about social situations and mental states, difficulty distinguishing inner speech from speech from an external source, and difficulties with early visual processing and maintaining concentration. Some cognitive features may reflect global neurocognitive deficits in memory, attention, problem-solving, executive function or social cognition, while others may be related to particular issues and experiences. Despite a common appearance of "blunted affect", recent findings indicate that many individuals diagnosed with schizophrenia are highly emotionally responsive, particularly to stressful or negative stimuli, and that such sensitivity may cause vulnerability to symptoms or to the disorder. Some evidence suggests that the content of delusional beliefs and psychotic experiences can reflect emotional causes of the disorder, and that how a person interprets such experiences can influence symptomatology. The use of "safety behaviors" to avoid imagined threats may contribute to the chronicity of delusions. Further evidence for the role of psychological mechanisms comes from the effects of therapies on symptoms of schizophrenia.
Studies using neuropsychological tests and brain imaging technologies such as fMRI and PET to examine functional differences in brain activity have shown that differences seem to most commonly occur in the frontal lobes, hippocampus and temporal lobes. These differences have been linked to the neurocognitive deficits often associated with schizophrenia.
Particular focus has been placed upon the function of dopamine in the mesolimbic pathway of the brain. This focus largely resulted from the accidental finding that a drug group which blocks dopamine function, known as the phenothiazines, could reduce psychotic symptoms. It is also supported by the fact that amphetamines, which triggers the release of dopamine may exacerbate the psychotic symptoms in schizophrenia. An influential theory, known as the Dopamine hypothesis of schizophrenia, proposed that excess activation of D2 receptors was the cause of (the positive symptoms of) schizophrenia. Although postulated for about 20 years based on the D2 blockade effect common to all antipsychotics, it was not until the mid-1990s that PET and SPET imaging studies provided supporting evidence. This theory is now thought to be overly simplistic as a complete explanation, partly because newer antipsychotic medication (called atypical antipsychotic medication) can be equally effective as older medication (called typical antipsychotic medication), but also affects serotonin function and may have slightly less of a dopamine blocking effect.
Interest has also focused on the neurotransmitter glutamate and the reduced function of the NMDA glutamate receptor in schizophrenia. This has largely been suggested by abnormally low levels of glutamate receptors found in postmortem brains of people previously diagnosed with schizophrenia and the discovery that the glutamate blocking drugs such as phencyclidine and ketamine can mimic the symptoms and cognitive problems associated with the condition. The fact that reduced glutamate function is linked to poor performance on tests requiring frontal lobe and hippocampal function and that glutamate can affect dopamine function, all of which have been implicated in schizophrenia, have suggested an important mediating (and possibly causal) role of glutamate pathways in schizophrenia. Positive symptoms fail however to respond to glutamatergic medication.
There have also been findings of differences in the size and structure of certain brain areas in schizophrenia. A 2006 metaanlaysis of MRI studies found that whole brain and hippocampal volume are reduced and that ventricular volume is increased in patients with a first psychotic episode relative to healthy controls. The average volumetric changes in these studies are however close to the limit of detection by MRI methods, so it remains to be determined whether schizophrenia is a neurodegenerative process that begins at about the time of symptom onset, or whether it is better characterised as a neurodevelopmental process that produces abnormal brain volumes at an early age. In first episode psychosis typical antipsychotics like haloperidol were associated with significant reductions in gray matter volume, whereas atypical antipsychotics like olanzapine were not. Studies in non-human primates found gray and white matter reductions for both typical and atypical antipsychotics.
A 2009 meta-analysis of diffusion tensor imaging studies identified two consistent locations of fractional anisotropy reduction in schizophrenia. One region, in the left frontal lobe, is traversed by white matter tracts interconnecting the frontal lobe, thalamus and cingulate gyrus; the second region in the temporal lobe, is traversed by white matter tracts interconnecting the frontal lobe, insula, hippocampus–amygdala, temporal and occipital lobe. The authors suggest that two networks of white matter tracts may be affected in schizophrenia, with the potential for "disconnection" of the gray matter regions which they link. During fMRI studies, greater connectivity in the brain's default network and task-positive network has been observed in schizophrenic patients, and may reflect excessive orientation of attention to introspection and to extrospection, respectively. The greater anti-correlation between the two networks suggests excessive rivalry between the networks.
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