Prior behavioral and fMRI studies demonstrate face processing deficits in pediatric bipolar disorder (BD;
McClure et al., 2005;
Rich et al., 2006). Specifically, compared to healthy subjects, BD youth: 1) view neutral faces as more threatening; and 2) have increased left amygdala activity when rating their fear of, or the hostility on, neutral faces (
Rich et al., 2006). To expand on these findings, we compared functional connectivity (
Friston et al., 1997) between the left amygdala and other brain regions in BD youth versus healthy controls when processing facial expressions. Functional connectivity provides a measure of the temporal correlation of activity between different brain regions. We found that BD youth have significantly less functional connectivity between the left amygdala and a network involving a region bordering the right posterior cingulate/precuneus, and another region bordering the right fusiform gyrus (FG)/parahippocampal gyrus (PHG).
Our results indicate that BD youth display impaired signal communication in neural networks critical to processing faces and emotional stimuli. Both the FG and posterior cingulate are associated with the visual processing of facial expressions. Specifically, the FG is specialized in processing face identity and, to a lesser extent, face expression (
Haxby et al., 2000;
Kanwisher et al., 1997), while the posterior cingulate responds to threatening stimuli that are of immediate social importance (
Critchley et al., 2000). Further, the PHG has been implicated in emotional and cognitive learning, specifically associating stimuli with affective meaning (
Fanselow & LeDoux, 1999;
Yaniv et al., 2000). Face emotion classification is thought to reflect, in part, the amygdala-FG-posterior cingulate network (
Haxby et al., 2002), while the amygdala receives input from the PHG (
Shi & Cassell, 1999). Thus, disruption of these circuits may explain partly the face emotion misperception seen in BD youth.
The previously documented amygdala hyperactivity in BD youth (
Rich et al., 2006) may reflect the end result of deficient signal transmission from a network involving the FG, posterior cingulate, or PHG to the amygdala. The amygdala regulates the attribution of emotional significance to threatening faces (
Calder et al., 2001). Thus, if the amygdala fails to receive from the FG, posterior cingulate, or PHG information regarding face expression or stimulus affective meaning, BD youth may aberrantly perceive neutral faces as threatening. Conversely, information is transmitted from the amygdala to regions of the temporal association cortex (
LeDoux, 2000). Impaired connectivity in BD youth may mean that such information is transmitted incompletely to regions such as the FG or posterior cingulate, possibly resulting in face emotion misperceptions.
In addition to elucidating possible neural correlates of face misperception in pediatric BD, our results may help to explain the social deficits seen in these youth (
Geller et al., 2000;
Lewinsohn et al., 2003). The coordinated function of the amygdala-FG-posterior cingulate circuit mediates not only face emotion processing, as already noted, but also a diverse set of social functions, including interpretation of social signals and regulation of emotional and behavioral responses to these signals (
Amaral et al., 1992;
Critchley et al., 2000;
Haxby et al., 2002). Further, the PHG is thought to be the ‘gateway’ for cortical sensory input to the amygdala before this information is sent to neural regions responsible for regulating behavior (
Kolb, 1990). Thus, disruption of these circuits, as tentatively documented here, is likely to impair social signal processing and emotional and behavioral regulation, which in turn is likely to result in the social deficits that characterize BD youth.
The involvement of the posterior cingulate, precuneus, and PHG also indicate that memory may be a factor in the face misperception and social deficits seen in BD youth. Memory impairments are thought to be a trait marker of adult and pediatric BD (
Martinez-Aran et al., 2000;
Pavuluri et al., 2006b), and prior research finds diminished recall of face expressions by BD youth (
Dickstein et al., in press). The posterior cingulate (
Maddock et al., 2003) and precuneus (
Cavanna & Trimble, 2006) play primary roles in retrieving prior experiences and regulating the impact of emotional salience on memory, and the amygdale–PHG circuit has been implicated in the formation of aversive emotional memories (
Fanselow & LeDoux, 1999;
Yaniv et al., 2000). Impaired connectivity between the amygdala and the posterior cingulate, FG, and PHG may lead to inadequate recall of prior social encounters which would otherwise serve to shape BD youth’s face processing and social function.
This study broadens our understanding of the pathophysiology of pediatric BD. Our results expand upon prior research which has documented in BD youth volumetric deficits and functional aberrations in the FG (
Frazier et al., 2005a;
Pavuluri et al., 2006a), posterior cingulate (
Chang et al., 2004;
Kaur et al., 2005), and amygdala (
Blumberg et al., 2003;
Blumberg et al., 2005;
Chang et al., 2005;
Chen et al., 2004;
Delbello et al., 2004;
Dickstein et al., 2005a;
Rich et al., 2006). Thus, neuroimaging research is consistent in implicating volumetric, functional, and now connectivity impairments of the amygdala, FG, and posterior cingulate in the pathophysiology of pediatric BD.
Although memory deficits are thought to be trait markers of BD, as noted above, there is heterogeneity in studies investigating potential neural correlates. We are not aware of functional nor structural studies reporting perturbations in the precuneus or PHG in pediatric BD. In BD adults, memory tasks have evoked both heightened (
Deckersbach et al., 2006) and diminished (
Malhi et al., 2007) PHG activation, as well as hypoactivation of the precuneus (
Malhi et al., 2007). If discussion of the neural correlates of memory is expanded to include the hippocampal formation, results of structural studies are inconsistent in both BD youth (
Blumberg et al., 2003;
Chang et al., 2005;
Chen et al., 2004;
Dickstein et al., 2005a;
Frazier et al., 2005b) and adults (
Altshuler et al., 2000;
Hauser et al., 2000;
Strakowski et al., 1999;
Strasser et al., 2005;
Yucel et al., 2007). Hippocampal hyperactivation has been reported in BD adults during a memory task involving word lists (
Deckersbach et al., 2006), but it is unclear how this relates to a visual task such as face perception. Further, there are no reports of hippocampal functional perturbations in pediatric BD. Clearly, additional research is required to better understand the role of the precuneus and PHG, or even more generally the hippocampal formation, in BD.
A primary limitation of our study is the clinical diversity of our BD sample, though this is typical of that seen in other samples of BD youth (
Birmaher et al., 2006). While there were high rates of comorbidity in our BD patients, the fact that BD youth without comorbid ADHD, ODD, or anxiety had significantly lower connectivity than controls indicates that the deficit may reflect BD itself rather than the presence of a co-occurring disorder.
Medication status is an additional potential confound. Since most BD patients were medicated, we were unable to fully determine the extent to which our results were associated with BD or, instead, with medication effects. However, there was no relationship between number of medications and connectivity, and lower connectivity in BD youth did not seem to be due to the presence of a particular class of medication. The results of all post hoc analyses should be interpreted with caution because they are subject to Type I error due to multiple comparisons and Type II error due to small sample sizes.
Finally, it is important to note that an alternate explanation for our results is differences in measurement error between the groups, which would impact the estimated regression coefficient magnitude via attenuation bias (
van Belle & Fisher, 1996). Further, it is possible that a hypothesis- driven study may fail to confirm the preliminary results presented here.
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