Schizophrenia

Schizophrenia is associated with deficits in multiple cognitive functions. Thus, cognitive activation paradigms can be used to elucidate deficits in patients with schizophrenia as they undergo functional neuroimaging. The most consistent brain area implicated in the functional neuroimaging of schizophrenia is the dorsolateral prefrontal cortex. Working memory tasks (such as the N-back test) have consistently demonstrated reduced activation on PET and fMRI in the dorsolateral prefrontal cortex of patients with schizophrenia compared with healthy controls.28,29 Reduced dorsolateral prefrontal cortex activation has also been found in tests of mental flexibility and set shifting, most notably the Wisconsin Card Sort Test (which typically activates the dorsolateral prefrontal cortex in healthy individuals).7,29

Other studies have discovered abnormalities in prefrontal activation during procedural learning tasks and tasks of skill automatization.7,30 However, Callicott7 has cited some studies in which dorsolateral prefrontal cortex activation is actually increased. In addition to investigating dysfunction in specific brain regions, aberrant functional connectivity between regions has been investigated using fMRI. Such studies have shown reduced coupling between medial temporal and prefrontal regions in schizophrenic patients.31 Other neuroimaging studies have probed the underpinnings of positive symptoms in schizophrenia. Studies of patients actively experiencing auditory hallucinations have had variable results, including reduced temporal lobe activation,32 a decrease in the response of the primary auditory cortex to external auditory stimuli,10 and an activation of primary auditory cortex during subjective reporting of auditory hallucinations.33

As mentioned above, PET studies have the particular advantage of characterizing neuroreceptors through the use of radioligands. This technique has been thoroughly applied to the study of dopamine receptor binding in schizophrenia. PET and SPECT studies in schizophrenia generally fall into 1 of 2 categories: clinical studies, in which neurotransmitter binding is examined between schizophrenic patients and healthy controls; and occupancy studies that probe the action of neuroleptics in terms of their receptor binding.34 Such studies have suggested overactivity or increased density of striatal D2 dopamine receptors and underactivity or decreased density of cortical D1 receptors.35 Recent research has also implicated aberrant glutamatergic transmission in N-methyl d-aspartate receptors in the pathogenesis of the disease.35,36

There is also an increasing amount of literature involving the use of DT-MRI in schizophrenic patients. Such studies have suggested abnormalities in white matter tracts that connect prefrontal and temporal areas, including the uncinate fasciculus, the cingulum bundle, and the arcuate fasciculus.37 Although some authors have argued that there are inconsistent findings in such studies,38 many believe that with the proper methodological refinements, DT-MRI can be a useful tool in understanding the pathophysiology of schizophrenia.

Finally, Callicott7 and others have suggested a role for functional neuroimaging in psychiatric genetic studies. By using functional imaging, an intermediate phenotype can be identified in individuals who are genetically similar to patients with schizophrenia. In this way, if abnormalities detected during the functional neuroimaging of patients with schizophrenia are also found in their healthy relatives, that functional abnormality can be inferred to be heritable. For example, Callicott and colleagues39 found that cognitively normal siblings of patients with schizophrenia showed exaggerated activation of the right dorsolateral prefrontal cortex during a working memory task. Although the siblings appeared cognitively intact, they showed an activation pattern that was different from that of healthy controls and similar to that of patients with schizophrenia. It is hoped that such intermediate phenotypes can pave the way for the continued discovery of susceptibility genes for schizophrenia.

CONCLUSIONS

Structural neuroimaging is sometimes indicated to rule out an occult medical or neurological disorder in patients who present with psychiatric symptoms. Although formal guidelines have yet to be established, many investigators agree that acute alterations in mental status, the presence of focal neurological signs, and a history of significant head trauma or epilepsy are all indications for neuroimaging. When imaging is warranted, MRI is the preferred modality unless it is contraindicated. Although abnormalities on structural imaging have been associated with many psychiatric diseases, these changes are both too subtle and too variable to be used as reliable diagnostic tools. PET, SPECT, fMRI, and other techniques have been invaluable research tools to identify regional brain abnormalities in psychiatric disease. In the future, these technologies may also guide clinical diagnosis of psychiatric conditions and the choice of appropriate treatment.

 

Drugs Mentioned in this Article
Fluoxetine (Prozac, Sarafem)
Lithium (Eskalith, Lithane, Lithobid)
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