Mri Studies Of Brain Function And Metabolism

National Institute Of Mental Health

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Abstract

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. Over the last year the group has made more strides in the field of "Imaging Genomics", a relatively new paradigm in brain research using clinical genetics and neuroimaging, to explore the basic molecular biology and genetics of human information processing in normal health and as related to major psychiatric illnesses. Interesting findings have emerged from these studies: 1) In a study aimed at exploring the effects of a common single nucleotide polymorphism (SNP) in the targeting region of the human brain-derived neurotrophic factor (BDNF) gene (val66met) on hippocampal function, we found that met carriers exhibited relatively diminished hippocampal activity during both encoding and retrieval and were significantly poorer at recognizing previously encoded items than val homozygotes. Remarkably, the interaction between BDNF val66met genotype and hippocampal engagement during encoding accounted for 25% of the total variation in memory performance. These data implicate a specific genetic mechanism for substantial normal variation in human declarative memory. 2) In another study we explored the effect of a VNTR polymorphism of the dopamine transporter (DAT) gene (SLC6A3) that has been shown to effect the translation of this protein, and amphetamine on motor task-related basal ganglia activity in healthy volunteers. We found that relatively increased dopaminergic availability in 9/10 individuals presumably due to lower DAT availability, and following amphetamine administration irrespective of DAT genotype appears to improve the speed of motor activity. The effect of amphetamine, however, was much more pronounced in the 9/10 individuals than in the 10/10 individuals. These results suggest that allelic variation of the DAT gene appears to contribute to individual variability in the speed of motor response, as well as to the functional response of putamen to amphetamine. The group also performed several studies in patients with schizophrenia to explore the integrity of brain structures underlying cognitive function and affective behavior. 1) In a study aimed at exploring the phenomenon of hypoactivity and hyperactivity of the dorsolateral prefrontal cortex in schizophrenia, the groups were subdivided on the basis of performance on the working memory task into high or low performing subgroups. Results show that while locales of greater prefrontal activation as well as locales of less activation were found in the high-performing patients, only locales of underactivation were found in the low performing patients. These findings suggest that patients with schizophrenia whose performance on the N-back working memory task is similar to that of healthy comparison subjects use greater prefrontal resources but achieve lower accuracy (i.e., inefficiency) and that other patients with schizophrenia fail to sustain the prefrontal network that processes the information, achieving even lower accuracy as a result. These findings add to other evidence that abnormalities of prefrontal cortical function in schizophrenia are not reducible to simply too much or too little activity but, rather, reflect a compromised neural strategy for handling information mediated by the dorsolateral prefrontal cortex. 2) In another study aimed at exploring the integrity of memory-related hippocampal activity during both the encoding and retrieval of novel, visual stimuli in patients with schizophrenia we found that in comparison to normal controls patients with schizophrenia fail to recruit the hippocampal formation and ventral PFC during both the encoding and retrieval of visual stimuli. As engagement of these regions in normal controls is predictive of successful recall, such deficient response patterns may contribute to the significant memory impairments typical in schizophrenia. 3) In a study aimed at exploring the functional integrity of brain structures underlying affective behavior, such as the amygdala and PFC, in patients with schizophrenia we found that both patients and controls exhibited robust activation in the amygdala and ventral PFC during the linguistic evaluation of emotional face expressions. However, between group comparisons revealed relatively decreased left amygdala and bilateral ventral PFC activity in patients with schizophrenia compared to the healthy control subjects. This was found in the absence of a significant difference in accuracy or reaction time on the task. These preliminary data suggest that the emotional and social deficits observed in patients with schizophrenia may be linked to the abnormal cognitive appraisal of emotional stimuli. The group also pursued studies to explore the neurophysiological correlates of altered brain function associated with senescence. In a study aimed at exploring the nature of age-related changes in brain circuits related to cognitive skill learning we found that in the elderly the extent of caudate and prefrontal activation was less, and parietal activation was greater relative to younger subjects. Percent correct and reaction time was primarily positively correlated with caudate and prefrontal activation in young, but mainly with prefrontal and parietal cortices in older participants. Differential activation within a circumscribed neural network combined with equivalent probabilistic learning suggests that some brain regions, such as the parietal cortices, may provide a compensatory mechanism for healthy older adults in the context of deficient prefrontal cortex and caudate nuclei responses. While studies of declarative memory demonstrate that distinct and collateral cortical regions function in a compensatory manner in healthy older adults, results from the current study suggest that during probabilistic learning older adults utilize the same brain regions as young adults albeit to differential degrees to attain equivalent learning and performance. These changes may reflect the reorganization and redistribution that takes place with aging in the functional networks to compensate for the age-related structural and neurochemical changes. Studies are being pursued to explore the effect of aging on other brain systems, and the role of genetics on these changes.