Brain function in schizophrenia
It is clear that schizophrenia is characterised by subtle but important changes in brain structure. However, psychotic symptoms and the cognitive deficits associated with schizophrenia reflect abnormal functioning of the brain. Therefore there is a great deal of interest in studying what is happening in the brain of a person with schizophrenia. Modern imaging techniques such as Positron Emission Tomography (PET), Single Photon Emission Computed Tomography (SPECT), functional Magnetic Resonance Imaging (fMRI), and Magnetic Resonance Spectroscopy (MRS) allow us to study the mechanism of action of antipsychotic drugs, and to identify those regions of the brain that may be functionally abnormal.
Neurochemistry of Schizophrenia
Imaging Neurotransmitter Receptor Function
Communication within the brain occurs via chemical messengers called neurotransmitters such as serotonin (5-HT) and dopamine. There is now abundant evidence that there is a widespread imbalance in brain chemistry in schizophrenia.
Early theories of neurochemical dysfunction focussed on the dopamine system. There were two reasons for this: firstly, it was realised that some people who used amphetamines developed a form of temporary psychosis that bore similarities to positive symptoms of schizophrenia. Amphetamines are known to act on the dopamine system. Secondly, drugs such as chlorpromazine that are widely used to treat people with schizophrenia were also known to affect dopamine transmission. Therefore the dopamine hypothesis developed that schizophrenia was a disorder of dopamine activity.
However, it has become clear that the neurochemistry of schizophrenia is more complex that that. PET and SPECT allow us to investigate neurotransmitter function and to study how antipsychotic drugs work. By injecting subjects with small amounts of a radioactive substance that acts on a specific neurochemical system (e.g. dopamine), it is possible to quantify numbers of neurotransmitter receptors, and to study where an antipsychotic drug is acting.
PET and SPECT studies have shown us that although most antipsychotic drugs do target dopamine receptors, modern atypical antipsychotic drugs such as clozapine and risperidone, that may be more effective in improving negative symptoms and cognitive function, also have pronounced effects on 5-HT transmission.
Magnetic Resonance Spectroscopy in Schizophrenia
Magnetic Resonance Spectroscopy (MRS) is an in vivo imaging technique that is used to study the levels of chemicals in the brain (see Kegeles et al. 1998 for an introduction to MRS and a review of findings in schizophrenia). MRS studies have consistently found lower levels of a chemical called N-Acetyl htmartate (NAA) in brain regions important in schizophrenia such as the hippocampus and the prefrontal cortex. NAA is believed to be a marker of neuronal integrity, so reduced levels indicate loss, or abnormal function of neurons. Other consistent findings are of abnormal levels of chemicals present in cell membranes such as phospholipids, and compounds such as Adenosine Triphosphate (ATP) that are measures of cellular metabolism and activity. Although limited in terms of separating similar compounds, there is also some tentative evidence from MRS of changes in levels of metabolites of the neurotransmitter glutamate.
Imaging Brain Activity in Schizophrenia
Imaging Cognitive Function
People with schizophrenia demonstrate impairments on tests of a variety of cognitive functions, including working memory, planning and set shifting (need ref). Techniques such as Positron Emission Tomography (PET) and functional Magnetic Resonance Imaging (fMRI) allow us to "look inside" the brain to study what regions are active (the functional neuroanatomy) while subjects are performing a task.
In a landmark study, Ingvar & Frandsen (1972) used PET to study regional cerebral blood flow (rCBF) in people with schizophrenia. They showed that blood flow was lower in frontal regions in these people compared to controls, a finding that has become known as hypofrontality. Studies have moved on from resting-state to look at brain activity while doing a task, and have shown that people with schizophrenia often show reduced activation in frontal regions during tasks known to normally activate them.
Imaging Drug Effects
A recent study has shown that modern drugs may be able to "reactivate" some parts of the brain. Honey et al (2000) used fMRI to study people with schizophrenia during a working memory task. At the time of the first scan, all the patients were taking conventional antipsychotic drugs. They showed reduced activity in frontal regions during the task, compared to controls. Some of the patients were then switched to the atypical drug risperidone. After six weeks all subjects were scanned again. At the second scan, those patients who had been switched to risperidone showed a marked increase in activity in frontal regions.
Imaging Psychotic Symptoms
There is a great deal of interest in understanding what is happening in the brain when people are experiencing a psychotic episode. There is evidence that brain function is different when people are actively psychotic, compared to when their symptoms have remitted. For example, Spence et al (1998) found that when psychotic, people showed hypofrontality, however this disappeared when rescanned when their symptoms had improved.
Other studies have looked at brain activity in people experiencing particular types of symptoms such as auditory hallucinations. These studies have consistently shown that people with a history of auditory hallucinations have abnormal activity of frontal and temporal lobe regions of the brain involved in speech and language. Based on these findings, it has been proposed that auditory hallucinations may arise when a person's brain is unable to "keep track" of their own thoughts, such that they do not recognize what they hear in their head as their own thoughts, but instead perceive them as coming from others.
Schizophrenia as a disorder of functional dysconnectivity
Any brain function requires the activation of structures that may be located far apart. Therefore, in studying brain function it is important to recognize that abnormal activity in one region may not be due to an abnormality in that structure, but may be due to abnormal activity of an upstream or downstream structure. People are beginning to study how activity in one region affects activity in another - functional connectivity. There is already evidence of changes in functional connectivity between frontal and temporal lobe regions in schizophrenia.
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