Regional brain changes in bipolar I depression: a functional magnetic resonance imaging study

The lifetime prevalence for bipolar disorder is 2% in the United States (1) and patients spend the majority of their time in episodes of depression, not mania (2–5). As bipolar depression is associated with high levels of morbidity and mortality across the life span, efforts aimed at identifying the biological mechanisms that contribute to the diathesis for this phase of the illness are imperative. Functional neuroimaging studies of patients with unipolar depressive disorder have begun to reveal the dysregulated neuroanatomic circuits associated with this syndrome (6–21). Similar studies in patients with bipolar depression are more limited. To our knowledge, five studies have been performed using functional magnetic resonance imaging (fMRI) in patients with bipolar disorder during the depressed phase (22–26). Only three of these fMRI studies used affective paradigms known to activate limbic structures, although the paradigms differed across studies. In one study, patients observed emotional expressions; bipolar depressed patients demonstrated increased subcortical (left amygdala, caudate, putamen, thalamus, right globus pallidus) and prefrontal responses to both positive (happy) and negative (fearful) expressions compared to the control group (22). In another study involving the cognitive generation of affect, distinct patterns of regional activation were found with bipolar depressed patients generating predominantly right-sided subcortical activation (basal ganglia, thalamus, hypothalamus, and amygdala) (26). A third study used a paradigm to assess implicit versus explicit facial emotion recognition and found that bipolar depressed subjects tended to over activate fronto-striato-thalamic regions in response to fearful faces (24). Functional neuroimaging studies in normal subjects using neuropsychological paradigms that involve the processing of emotional facial expression have reported specificity for activation of orbitolateral prefrontal cortex and amygdala in normal subjects (27–32). Several fMRI studies of bipolar subjects during the manic state, including work from our group, have demonstrated either attenuation of orbitofrontal cortex (OFC) function and/or heightened amygdala activation compared to controls (22, 24, 33, 34). The presence of an attenuated OFC response and a heightened amygdala response in mania suggests an alteration in a prefrontal-amygdala circuit. The OFC has been purported to play a role in the integration of emotional information and the regulation of intensity of emotional response (35, 36). Dysfunction in this area could provide a mechanism for understanding a failure to appropriately modulate other brain regions and perhaps result in a range of intensity of mood shifts in people with bipolar disorder. The current study used fMRI and a facial affect processing task to assess orbitofrontal cortical and amygdala reactivity in subjects with bipolar depression. While the few studies reviewed above that used affective paradigms suggest that amygdala activity might increase during bipolar depression, we hypothesized that orbitofrontal activity would be heightened and amygdala activity reduced in subjects with bipolar depression compared to a normal control group. Given our data regarding mania, and assuming depression represents a mood state that might involve the same brain regions but with an alternate activation, we hypothesized that we would see an activation pattern opposite to what we had observed in mania.