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Early-Onset Bipolar Disorder 323Role of Prefrontal Cortex in Bipolar DisorderThe human prefrontal cortex (PFC) is responsible for many higher functions, includingregulation of mood/emotion and attention (Goethals, Audenaert, Van deWiele, & Dierckx, 2004; Ramnani & Owen, 2004). Several analyses of cerebrallobes and subregions in BD suggest abnormalities of the PFC. These abnormalitiesinclude decreased neuronal and glial density in the dorsolateral PFC (DLPFC;Rajkowska, Halaris, & Selemon, 2001), decreased subgenual prefrontal gray matter(Drevets et al., 1997) and glial cells (Ongur, Drevets, & Price, 1998), and decreasedprefrontal gray matter volumes bilaterally (Lopez-Larson, DelBello, Zimmerman,Schwiers, & Strakowski, 2002). Given this convergence of positive histopathologicaland morphometric findings, it is likely that prefrontal gray matter volumeis abnormal in adults with BD, but it is less clear whether these abnormalities arepresent before the onset of mania.We recently detected a trend toward decreased cortical gray matter volume inbipolar offspring with BD (K. Chang, Karchemskiy, Barnea-Goraly, Simeonova,et al., 2005). In this analysis, we found no statistically significant differencesbetween bipolar participants and controls in ventricular to brain ratio (VBR) ornumber of participants with significant WMH. Due to these findings, we do notfeel that variables such as VBR or WMH are good candidates for further study asbiological markers of BD, as they may become relevant only after onset of BD.PFC gray matter volume may be a slightly better marker, as we did detect a trendfor overall decreased gray matter in patients with BD compared to controls (p =.09; K. Chang, Karchemskiy, Barnea-Goraly, Simeonova, et al., 2005). This decreasein cortical gray matter (4.3%) was not as robust as the 9.4–16.8 % reportedin adult samples with BD (Lim, Rosenbloom, Faustman, Sullivan, & Pfefferbaum,1999; Lopez-Larson et al., 2002). Thus we feel in most cases PFC gray mattervolume may begin to decrease more sharply only after years of bipolar illness(Gallelli et al., 2005). However, we did not account for genetic variation withinour bipolar group. For example, it is possible that those with the val66met alleleof the BDNF gene may have relatively decreased prefrontal gray matter volumescompared to those without this allele (see below).Although prefrontal morphometric abnormalities may not be easily detectedbefore the onset of BD, prefrontal function might be significantly different premorbidly.Functional imaging studies have supported PFC functional abnormalitiesin BD. Yurgulen-Todd et al. (2000) found adults with BD to have decreasedDLPFC activation when viewing fearful faces. Importantly, during this taskincreased amygdalar activation also was found in patients with BD. Decreasedactivation in adults with BD was found in medial prefrontal cortex during a continuousperformance task (Strakowski, Adler, Holland, Mills, & DelBello, 2004)and in ventral PFC independent of mood state during a color-word Stroop task(Blumberg, Leung, et al., 2003). There have been only two fMRI studies publishedin pediatric BD. The first found abnormalities in ventral PFC activation in adolescents