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Original Investigation | Meta-analysis

Developmental Meta-analyses of the Functional Neural Correlates of Bipolar Disorder

Ezra Wegbreit, PhD1; Grace K. Cushman, BS1; Megan E. Puzia, BA1; Alexandra B. Weissman, BA1; Kerri L. Kim, PhD1; Angela R. Laird, PhD2; Daniel P. Dickstein, MD1
[+] Author Affiliations
1Pediatric Mood, Imaging, and Neurodevelopment Program, Department of Psychiatry and Human Behavior, Brown University Alpert Medical School, and Bradley Hospital, East Providence, Rhode Island
2Department of Physics, Florida International University, Miami
JAMA Psychiatry. 2014;71(8):926-935. doi:10.1001/jamapsychiatry.2014.660.
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Importance  Bipolar disorder (BD) is a debilitating mental illness associated with high costs to diagnosed individuals and society. Within the past 2 decades, increasing numbers of children and adolescents have been diagnosed as having BD. While functional magnetic resonance imaging (fMRI) studies have begun to investigate the neural mechanisms underlying BD, few have directly compared differences in youths with BD and adults with BD (hereafter BD-youths and BD-adults, respectively).

Objective  To test the hypothesis that BD-youths (<18 years old) would show greater convergence of amygdala hyperactivation and prefrontal cortical hypoactivation vs BD-adults.

Data Sources  PubMed and PsycINFO databases were searched on July 17, 2013, for original, task-related coordinate-based fMRI articles.

Study Selection  In total, 21 pediatric studies, 73 adult studies, and 2 studies containing distinct pediatric and adult groups within the same study met inclusion criteria for our ALE analyses.

Data Extraction and Synthesis  Coordinates of significant between-group differences were extracted from each published study. Recent improvements in GingerALE software were used to perform direct comparisons of pediatric and adult fMRI findings. We conducted activation likelihood estimation (ALE) meta-analyses directly comparing the voxelwise convergence of fMRI findings in BD-youths vs BD-adults, both relative to healthy control (HC) participants.

Results  Analyses of emotional face recognition fMRI studies showed significantly greater convergence of amygdala hyperactivation among BD-youths than BD-adults. More broadly, analyses of fMRI studies using emotional stimuli showed significantly greater convergence of hyperactivation among BD-youths than BD-adults in the inferior frontal gyrus and precuneus. In contrast, analyses of fMRI studies using nonemotional cognitive tasks and analyses aggregating emotional and nonemotional tasks showed significantly greater convergence of hypoactivation among BD-youths than BD-adults in the anterior cingulate cortex.

Conclusions and Relevance  Our data suggest that amygdala, prefrontal, and visual system hyperactivation is important in the emotional dysfunction present in BD-youths, as well as that anterior cingulate cortex hypoactivation is relevant to the cognitive deficits in BD-youths. Future studies are required to determine if the developmental fMRI differences between BD-youths and BD-adults identified by our ALE meta-analyses are useful as brain-based diagnostic or treatment markers of BD, including either longitudinal neuroimaging studies of BD-youths as they become adults or cross-sectional imaging studies directly comparing BD-youths with BD-adults.

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Figure 1.
Flow Diagram of the Literature Search

BD indicates bipolar disorder; DTI, diffusion-tensor imaging; EEG/MEG, electroencephalography/magnetoencephalography; fMRI, functional magnetic resonance imaging; HC, healthy control; MRS, magnetic resonance spectroscopy; NIRS, near-infrared spectroscopy; PET/SPECT, positron emission tomography/single-photon emission computed tomography; and VBM, voxel-based morphometry.

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Figure 2.
Results From Developmental Contrasts of Pairwise Activation Likelihood Estimation Analyses

A, Greater convergence of hyperactivation in youths with bipolar disorder (BD-youths) than adults with bipolar disorder (BD-adults) in the emotional face perception tasks contrast (x = 28, y = −6, z = −10; right amygdala cluster size, 512 mm3). B, Greater convergence of hyperactivation in BD-youths than BD-adults in the emotional tasks contrast (x = −34, y = 16, z = −8; left inferior frontal gyrus cluster size, 392 mm3). C, Greater convergence of hyperactivation in BD-youths than BD-adults in the emotional tasks contrast (x = −31, y = 18, z = −9; left precuneus cluster size, 344 mm3). D, Greater convergence of hypoactivation in BD-youths than BD-adults in the nonemotional tasks contrast (x = 9, y = 36, z = 7; right pregenual anterior cingulate cortex cluster size, 728 mm3). E, Greater convergence of hypoactivation in BD-youths than BD-adults in the contrast that included data from all tasks (x = 8, y = 40, z = 12; right pregenual anterior cingulate cortex cluster size, 664 mm3). The right side of all coronal and axial images corresponds to the right side of the brain. All images are thresholded at P < .05, whole-brain corrected.

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