The functional MRI group of CBDB consists of multidisciplinary specialists with expertise in neurology, psychiatry, physics, biology and MRI techniques. This group pursues a variety of research agendas involving study of brain function and metabolism in normal healthy controls and patients with neuropsychiatric disorders. The lion's share of the effort of this group over the last year has continued to be in studies of cognitive activation during neuropsychiatric tasks and imaging of brain metabolites [N acetyl aspartate (NAA), choline and creatine] using magnetic resonance spectroscopic imaging (MRSI) in normal individuals, patients with schizophrenia and their unaffected siblings, animal models of schizophrenia, and in patients with Parkinson's disease. Several interesting findings have emerged from these studies: 1) In an experiment investigating prefrontal cortex (PFC) function in schizophrenia using functional magnetic resonance imaging (fMRI), a group of patients with schizophrenia who performed relatively well on a parametric version of the n-back working memory (WM) task showed three fundamental deviations from the """"""""healthy""""""""pattern of PFC fMRI activation to varying WM load. The first characteristic was a greater magnitude of PFC fMRI activation in spite of slightly impaired WM performance (i.e., physiological inefficiency). The second was that the significant correlations between behavioral WM performance and fMRI activation was in opposite directions in the two groups. Third, the magnitude of the abnormal PFC fMRI response was predicted by an assay of n-acetyl aspartate concentrations (NAA) in dorsal PFC, a measure of neuronal pathology obtained using proton magnetic resonance spectroscopy. Patients had significantly lower dorsal PFC NAA than controls and dorsal PFC NAA inversely predicted the fMRI response in dorsal PFC (areas 9-10/46) to varying WM load; supporting the assumption that abnormal PFC responses arose from abnormal PFC neurons. While PFC neuronal pathology appears to explain in part limited WM capacity, these data further suggest that there may be greater functional impairment in dorsal than ventral PFC in schizophrenia.2) Prefrontal efficiency appears to be a general characteristic within healthy subjects as well. We hypothesized that Catechol-O-methyltransferanse (COMT) genotype [COMT is an enzyme in the catabolic pathway of dopamine and has a functional polymorphism (Val158Met)] would have a measurable impact on PFC efficiency during working memory challenge. Preliminary results from an ongoing fMRI study suggest that COMT genotypes predict the prefrontal cortical BOLD response to a working memory task with val/val individuals least efficient followed by val/met and met/met. These data emphasize the importance of optimal dopamine tone in prefrontal cortex for modulating working memory performance. The presence of the met allele confers greater prefrontal cortical efficiency. 3) In a double-blinded placebo controlled study, the effect of dextroamphetamine on performance and prefrontal cortical activation was heterogeneous across the group. It improved performance only in those subjects who had relatively low working memory capacity at baseline, whereas in subjects that had relatively high working memory capacity at baseline it worsened performance. In subjects whose performance deteriorated, signal change was relatively greater than in subjects who had an improvement in performance. These data shed light on the manner in which monoaminergic tone, working memory, and prefrontal function interact and, moreover, demonstrate that even in normal subjects the behavioral and neurophysiologic effects of dextroamphetamine are not homogeneous. These heterogeneic effects of dextroamphetamine may be explained by genetic variations that interact with the effects of dextroamphetamine. Further studies are in progress to explore this hypothesis. 4) In addition to the classic motor symptoms, patients with Parkinson's disease also suffer from cognitive deficits including decreased working memory capacity. In the absence of any significant difference in performance of a working memory task, patients with Parkinson's disease show a greater extent of activation in the cortical regions subserving working memory (particularly in the dorsolateral prefrontal cortex and parietal regions) during the off-state than during the on-state. These results suggest that the hypodopaminergic state of Parkinson's disease is associated with decreased efficiency of the cortical regions subserving working memory. Further, they demonstrate the neuromodulatory effects of dopamine in improving the efficiency of these cortical regions. 5) Preliminary analysis from an ongoing study revealed that both patients with schizophrenia and their siblings differed from normal control subjects in the functional lateralization of the sensorimotor cortex. Patients and their siblings had significantly reduced motor cortex laterality than normal subjects. A larger database is being collected to evaluate if this phenomenon represents an intermediate phenotype associated with schizophrenia. 5) In patients with schizophrenia, NAA measures in dorsolateral prefrontal cortex selectively predicted striatal displacement of 11C raclopride after amphetamine infusions and a higher D-2 binding potential in the basal ganglia (as measured by I123IBZM SPECT). In contrast, NAA measures in other cortical regions and in healthy subjects did not show any correlation. These results support the hypothesis that in schizophrenia neuronal pathology of dorsolateral prefrontal cortex is directly related to abnormal subcortical dopamine function.6) Measures of NAA in DLPFC strongly correlated with activation of the distributed working memory network, including dorsolateral prefrontal, temporal, and inferior parietal cortices during working memory tasks in two independent groups of patients with schizophrenia. In contrast, NAA in other cortical regions or in comparison subjects did not show these relationships. These findings directly implicate a population of DLPFC neurons as selectively accounting for the activity of the distributed working memory cortical network in schizophrenia and compliment other evidence that DLPFC connectivity is fundamental to the pathophysiology of the disorder. 7) A regionally specific negative correlation was found between prefrontal NAA measures and negative symptom ratings. No significant correlations were found for any other regional NAA measure and negative symptoms or for any regional NAA measure and positive symptoms. Lower prefrontal NAA -- and by inference greater neuronal pathology -- predicted more severe negative symptoms in these patients. These data represent the first direct demonstration of a relationship between an intraneuronal measure of DLPFC integrity and negative symptoms in vivo and represent further evidence for the involvement of DLPFC in negative symptoms associated with schizophrenia.8) Results from a study performed to assess whether antipsychotics modify brain NAA measures of patients with schizophrenia suggest that antipsychotic drugs increase NAA measures selectively in the dorsolateral prefrontal cortex. These results suggest that antipsychotics modify the function of cortical neurons in a region specific manner. Studies in the upcoming years will continue in the realm of brain studies of cognitive activation during neuropsychiatric tasks with pharmacological manipulations, and mapping brain function and metabolism in family members who are at risk for neuropsychiatric illnesses such as schizophrenia, Parkinson's disease, etc. It is conceivable that a genetic risk marker, possibly of use in linkage studies, could be identified.
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