A critical appraisal of neuroimaging studies of bipolar disorder: toward a new conceptualization of underlying neural circuitry and a road map for future research

Abstract

Objective: In this critical review, the authors appraise neuroimaging findings in bipolar disorder in emotion-processing, emotion-regulation, and reward-processing neural circuitry in order to synthesize the current knowledge of the neural underpinnings of bipolar disorder and provide a neuroimaging research road map for future studies.

Method: The authors examined findings from all major studies in bipolar disorder that used functional MRI, volumetric analysis, diffusion imaging, and resting-state techniques, integrating findings to provide a better understanding of larger-scale neural circuitry abnormalities in bipolar disorder.

Results: Bipolar disorder can be conceptualized, in neural circuitry terms, as parallel dysfunction in prefrontal cortical (especially ventrolateral prefrontal cortical)-hippocampal-amygdala emotion-processing and emotion-regulation circuits bilaterally, together with an "overactive" left-sided ventral striatal-ventrolateral and orbitofrontal cortical reward-processing circuitry, resulting in characteristic behavioral abnormalities associated with bipolar disorder: emotional lability, emotional dysregulation, and heightened reward sensitivity. A potential structural basis for these functional abnormalities is gray matter volume decreases in the prefrontal and temporal cortices, the amygdala, and the hippocampus and fractional anisotropy decreases in white matter tracts connecting prefrontal and subcortical regions.

Conclusions: Neuroimaging studies of bipolar disorder clearly demonstrate abnormalities in neural circuits supporting emotion processing, emotion regulation, and reward processing, although there are several limitations to these studies. Future neuroimaging research in bipolar disorder should include studies adopting dimensional approaches; larger studies examining neurodevelopmental trajectories in youths with bipolar disorder or at risk for bipolar disorder; multimodal neuroimaging studies using integrated systems approaches; and studies using pattern recognition approaches to provide clinically useful individual-level data. Such studies will help identify clinically relevant biomarkers to guide diagnosis and treatment decision making for individuals with bipolar disorder.

Figure 1

A. A schematic diagram highlighting key nodes in emotion processing and emotion regulation and neural circuitries in healthy individuals. dlPFC: dorsloateral prefrontal cortex; vlPFC: ventrolateral prefrontal cortex; mdPFC: mediodorsal prefrontal cortex; ACC: anterior cingulate cortex. Arrows represent key regulatory connections between prefrontal cortical regions and amygdala. B. A schematic diagram highlighting key functional abnormalities in red in regions and connections between regions in individuals with bipolar disorder. These include abnormally increased amygdala activity during emotion processing, emotion regulation and during performance of non-emotional tasks; abnormally decreased activity in vlPFC and OFC during emotion regulation; and decreased functional connectivity between these prefrontal cortical regions and amygdala during emotion regulation. In parallel, there are widespread abnormal decreases in gray matter volume and cortical thickness in prefrontal cortical regions, decreased gray matter volume in amygdala and hippocampus, and abnormally decreased fractional anisotropy in white matter tracts connecting ventral prefrontal cortex and anterior temporal regions. These changes are indicated by decreased sizes of ovals representing these regions.

Figure 2

A. A schematic diagram highlighting key nodes in reward processing neural circuitry in healthy individuals. Abbreviations are as for Figure 1. B. A schematic diagram highlighting key functional abnormalities in red in regions in individuals with bipolar disorder. These include abnormally increased VS, vlPFC and OFC activity during reward processing, especially during reward anticipation. While not yet reported in the literature, it is likely that patterns of aberrant functional connectivity among these regions are shown by individuals with bipolar disorder during reward processing. In parallel, there are widespread decreases in gray matter volume and cortical thickness in prefrontal cortical regions and striatal regions in individuals with bipolar disorder.