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Reviews and Overviews   |    
A Critical Appraisal of Neuroimaging Studies of Bipolar Disorder: Toward a New Conceptualization of Underlying Neural Circuitry and a Road Map for Future Research
Mary L. Phillips, M.D.; Holly A. Swartz, M.D.
Am J Psychiatry 2014;171:829-843. doi:10.1176/appi.ajp.2014.13081008
View Author and Article Information

The authors report no financial relationships with commercial interests.

Dr. Phillips received support from NIMH grants R01MH0076971, U01MH092221, R01MH073953, and R01MH060952. Dr. Swartz received support from NIMH grants R01 MH84831 and R01 MH83647.

From the Department of Psychiatry, University of Pittsburgh, and the Western Psychiatric Institute and Clinic, Pittsburgh.

Address correspondence to Dr. Phillips (phillipsml@upmc.edu).

Received August 01, 2013; Revised October 22, 2013; Revised January 1, 2014; Revised January 17, 2014; Accepted January 17, 2014.


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.

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FIGURE 1. Emotion-Processing and Emotion-Regulation Circuitrya

a Panel A is a schematic diagram highlighting key nodes in emotion-processing and emotion-regulation neural circuitry in healthy individuals; arrows represent key regulatory connections between prefrontal cortical regions and the amygdala. In panel B, key functional abnormalities in individuals with bipolar disorder are highlighted in red (in regions and connections between regions); these include abnormally increased amygdala activity during emotion processing, emotion regulation, and performance of nonemotional tasks; abnormally decreased activity in the ventrolateral prefrontal cortex and orbitofrontal cortex during emotion regulation; and decreased functional connectivity between these prefrontal cortical regions and the 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 the amygdala and hippocampus, and abnormally decreased fractional anisotropy in white matter tracts connecting the ventral prefrontal cortex and anterior temporal regions. These changes are indicated by smaller sizes of ovals representing these regions. ACC=anterior cingulate cortex; dlPFC=dorsolateral prefrontal cortex; mdPFC=mediodorsal prefrontal cortex; OFC=orbitofrontal cortex; vlPFC=ventrolateral prefrontal cortex.

FIGURE 2. Reward-Processing Neural Circuitrya

a Panel A is a schematic diagram highlighting key nodes in reward-processing circuitry in healthy individuals. In panel B, key functional abnormalities in individuals with bipolar disorder are highlighted in red; these include abnormally increased activity in the ventral striatum, ventrolateral prefrontal cortex, and orbitofrontal cortex 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 exhibited 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. ACC=anterior cingulate cortex; mdPFC=mediodorsal prefrontal cortex; OFC=orbitofrontal cortex; vlPFC=ventrolateral prefrontal cortex.

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TABLE 1.Main Themes From Functional Neuroimaging Studies in Bipolar Disordera
Table Footer Note

a See Table S1 in the online data supplement for more detailed information regarding the design and findings of the studies associated with each of these themes.

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TABLE 2.Structural Neuroimaging and Diffusion Imaging Studies in Bipolar Disordera
Table Footer Note

a See Tables S2 and S3 in the online data supplement for more details regarding the design and specific findings of these studies.

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TABLE 3.A Road Map for Future Neuroimaging Research in Bipolar Disorder


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