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324 REVERSIBLE DISORDERS OF BRAIN DEVELOPMENTwith BD, as activation did not increase with age as it did in controls (Blumberg,Martin, et al., 2003). The second, our study, found increased DLPFC activationin bipolar offspring with BD when viewing negatively valenced stimuli or performinga visuospatial working memory task (K. Chang et al., 2004). We alsodetected subcortical limbic overactivation in these participants, primarily insular.We were not able to determine whether prefrontal overactivation was in regulatoryresponse to subcortical/limbic overactivation. Nonetheless, it is clear that PFCis involved in BD, likely with overactivity in response to stress/affect in early stagesof the disorder, progressively decreasing toward underactivation after sustainedperiods of continued mood episodes (K. Chang et al., 2004). The role of both PFCand amygdala are summarized in figure 14-2.Again, one could presume that these patterns of prefrontal and limbic overactivationmay be present before onset of first manic episode. Indeed, preliminarydata on our prodromal offspring indicate that they have similar patterns ofprefrontal-subcortical overactivation to affective stimuli (Chang et al., unpublisheddata). However, these participants need to be compared to other participants withsimilar disorders (ADHD, depression) before the specificity of these findings canbe determined. Regardless, it is possible that decreased amygdalar gray matter,amygdalar hypersensitivity, and prefrontal overactivation could serve as componentsof a set of markers used to determine risk for BD development. Genes thatDLPFCpCingACCCaudate/putamenThalamusCerebellarvermisAmygdalaInf frontalHypthInsulaFigure 14-2 Corticolimbic model of mood regulation in bipolar disorder. Abnormallyelevated activation of subcortical structures such as amygdala and insula require greateractivation of prefrontal areas such as DLPFC and ACC to modulate subcortical signalsand regulate emotion and mood. Neurodegeneration of prefrontal areas may lead to decreasedability to modulate subcortical signals, leading to mood episodes, rapid cycling,and treatment resistance (K. Chang et al., 2004). DLPFC = dorsolateral prefrontal cortex,pCing = posterior cingulate, ACC = anterior cingulate cortex, Hypth = hypothalamus, Inffrontal = inferior frontal cortex; areas in gray indicate other areas that likely have a modulatoryrole by communicating with both cortical and subcortical structures.