Using oxygen-15 water positron emission tomography to measure regional cerebral blood flow (rCBF), a marker of local neuronal activity, we have found that normal subjects performing tasks involving working memory use a cortical network that includes dorsolateral prefrontal cortex, the inferior parietal lobule, and inferior temporo-occipital cortex. In further explorations of tasks related to prefrontal cortex, we have shown 1) with a maze task that the acquisition, but not the retrieval of spatial data involves the frontal cortex, particularly on the right and 2) with word generation tasks that semantic and phonologic cues activate similar brain regions including anterior cingulate, left frontal cortex, thalamus and cerebellum, but that some subtle differences exist between them that are consistent with the lesion literature. Studies of normal monozygotic and dizygotic twins aimed at determining the degree of heritability of cognitively-related regional brain function had suggested that while there are more similarities between twins than between age and sex-matched unrelated individuals, the degree of genetic influence may not be large. This is confirmed with multivariate canonical correlation analysis. We have also found that several different pathophysiological mechanisms underly cognitive changes that occur in normal aging. In regions where physiological activity is normally suppressed when young subjects perform the tasks older subjects activate more, and, moreover, the more they activate (or fail to suppress), the worse they perform on the tasks. In other areas, where physiological activity is normally increased in young people performing the tasks, older subjects activate less; and the less they activate these regions, the more impaired their performance. We have also carried out several experiments aimed at exploring the working memory system in normals under conditions that have relevance for the cognitive symptoms of schizophrenia. First, in a dual-task paradigm that may tap into patients' limited working memory capacity, a fundamental characteristic of prefrontal cortex appeared to be attenuated activation in the face of supramaximal demands for stimulus processing. A second physiological response to dual tasks that demand rapid attentional shifts and multiple stimulus response mappings involved large increases in neocerebellar activation, perhaps reflecting a time-sharing function for this structure. Second, in a set of experiments aimed exploring the effects of increasing working memory load, Increasing the """"""""working"""""""" (i.e. number of manipulations on remembered material) and the """"""""memory"""""""" (i.e. the amount of material) within working memory produced markedly different patterns of activation within the frontal lobes. Increasing the amount of remembered material produced graded physiological responses primarily in areas that play a primary role in preparing a response within the motor domain, including verbal responses.
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