Alterations in neural Theory of Mind processing in euthymic patients with bipolar disorder and unaffected relatives.

OBJECTIVES: Behavioral deficits in the Theory of Mind (ToM) have been robustly demonstrated in bipolar disorder. These deficits may represent an intermediate phenotype of the disease. The aim of this study was: (i) to investigate alterations in neural ToM processing in euthymic patients with bipolar disorder, and (ii) to examine whether similar effects are present in unaffected relatives of patients with bipolar disorder suggesting that ToM functional activation may be, in part, due to genetic risk for the disease. METHODS: A total of 24 euthymic patients with bipolar disorder, 21 unaffected first-degree relatives, and 81 healthy controls completed a ToM task while undergoing functional magnetic resonance imaging. RESULTS: We observed reduced bilateral activation of the temporoparietal junction (TPJ) and diminished functional fronto-temporoparietal connectivity in patients compared to controls. Relatives tended towards intermediate temporoparietal activity and functional coupling with medial prefrontal areas. There was also evidence for a potentially compensatory enhanced recruitment of the right middle temporal gyrus and stronger connectivity between this region and the medial prefrontal cortex in relatives. CONCLUSIONS: These findings provide further evidence of altered neural ToM processing in euthymic patients with bipolar disorder. Further, our findings in relatives lend support to the idea that altered ToM processing may act as an intermediate phenotype of the disorder.

Decreased medial prefrontal cortex activation during self-referential processing in bipolar mania.

BACKGROUND: Patients with bipolar disorder in mania exhibit symptoms pointing towards altered self-referential processing, such as decreased self-focus, flight of ideas and high distractibility. In depression, the opposite pattern of symptoms has been connected to increased activation of medial prefrontal cortex (mPFC) during self-referential processing. In this study, we hypothesized that (1) patients with mania will exhibit decreased activation in the mPFC during self-referential processing and (2) will be more alexithymic and that levels of alexithymia will correlate negatively with mPFC activation. METHODS: The neural response to standardized pictures was compared in 14 patients with bipolar I disorder in mania to 14 healthy controls using blood oxygen level dependent contrast magnetic resonance imaging. Participants were asked to indicate with button press during the scanning session for each picture whether the pictures personally related to them or not. Toronto alexithymia scale (TAS) scores were recorded from all participants. RESULTS: In the group analysis, patients with mania exhibited decreased activation in a predefined region of interest in the mPFC during self-referential processing compared to healthy controls. Patients with mania showed significantly higher levels of alexithymia, attributable to difficulties in identifying and describing emotions. Activation in the mPFC correlated negatively with levels of alexithymia. LIMITATIONS: Results presented here should be replicated in a larger group, potentially including unmedicated patients. CONCLUSIONS: The finding of decreased mPFC activation during self-referential processing in mania may reflect decreased self-focus and high distractibility. Support for this view comes from the negative correlation between higher alexithymia scores and decreased mPFC activation. These findings represent an opposite clinical and neuroimaging pattern to findings in depression.

Common and distinct networks for self-referential and social stimulus processing in the human brain.

Self-referential processing is a complex cognitive function, involving a set of implicit and explicit processes, complicating investigation of its distinct neural signature. The present study explores the functional overlap and dissociability of self-referential and social stimulus processing. We combined an established paradigm for explicit self-referential processing with an implicit social stimulus processing paradigm in one fMRI experiment to determine the neural effects of self-relatedness and social processing within one study. Overlapping activations were found in the orbitofrontal cortex and in the intermediate part of the precuneus. Stimuli judged as self-referential specifically activated the posterior cingulate cortex, the ventral medial prefrontal cortex, extending into anterior cingulate cortex and orbitofrontal cortex, the dorsal medial prefrontal cortex, the ventral and dorsal lateral prefrontal cortex, the left inferior temporal gyrus, and occipital cortex. Social processing specifically involved the posterior precuneus and bilateral temporo-parietal junction. Taken together, our data show, not only, first, common networks for both processes in the medial prefrontal and the medial parietal cortex, but also, second, functional differentiations for self-referential processing versus social processing: an anterior-posterior gradient for social processing and self-referential processing within the medial parietal cortex and specific activations for self-referential processing in the medial and lateral prefrontal cortex and for social processing in the temporo-parietal junction.

Perception of social stimuli in mania: an fMRI study.

Patients with mania show alterations of social behaviour. Neuropsychological studies in euthymic bipolar disorder (BD) have revealed deficits in cognitive, but not emotional aspects of social cognition (SC). Here, we studied the neural signature of social stimulus processing in mania. We expected alterations in regions associated with cognitive SC (dorsal-medial prefrontal cortex, dMPFC). Participants comprised 14 manic patients and 14 matched healthy controls who viewed standardized pictures with social and non-social content during functional magnetic resonance imaging (fMRI). Region-of-interest-analyses focused on areas related to SC (dorsal/ventral medial prefrontal cortex; temporo-parietal junction), determined by a quantitative meta-analysis. Between-group comparisons ('social>non-social') revealed reduced BOLD responses in the right dMPFC in manic patients, but no significant group difference in the ventral MPFC. In addition, manic patients showed elevated BOLD activation in the right temporo-parietal junction during perception of social stimuli, which was correlated with increased delusional ideation. Patients with mania show diminished BOLD responses to social stimuli in the right dMPFC, associated with cognitive SC and this may be related to reported deficits in understanding others' mental states. At the same time, manic patients show hyperactivation of the right temporo-parietal junction, likely related to exaggerated attribution of meaning to social stimuli.