Neural Markers in Pediatric Bipolar Disorder and Familial Risk for Bipolar Disorder

Abstract

Objective: Bipolar disorder (BD) is highly heritable. Neuroimaging studies comparing unaffected youth at high familial risk for BD (i.e., those with a first-degree relative with the disorder; termed "high-risk" [HR]) to "low-risk" (LR) youth (i.e., those without a first-degree relative with BD) and to patients with BD may help identify potential brain-based markers associated with risk (i.e., regions where HR+BD≠LR), resilience (HR≠BD+LR), or illness (BD≠HR+LR).

Method: During functional magnetic resonance imaging (fMRI), 99 youths (i.e., adolescents and young adults) aged 9.8 to 24.8 years (36 BD, 22 HR, 41 LR) performed a task probing face emotion labeling, previously shown to be impaired behaviorally in youth with BD and HR youth.

Results: We found three patterns of results. Candidate risk endophenotypes (i.e., where BD and HR shared deficits) included dysfunction in higher-order face processing regions (e.g., middle temporal gyrus, dorsolateral prefrontal cortex). Candidate resilience markers and disorder sequelae (where HR and BD, respectively, show unique alterations relative to the other two groups) included different patterns of neural responses across other regions mediating face processing (e.g., fusiform), executive function (e.g., inferior frontal gyrus), and social cognition (e.g., default network, superior temporal sulcus, temporo-parietal junction).

Conclusion: If replicated in longitudinal studies and with additional populations, neural patterns suggesting risk endophenotypes could be used to identify individuals at risk for BD who may benefit from prevention measures. Moreover, information about risk and resilience markers could be used to develop novel treatments that recruit neural markers of resilience and attenuate neural patterns associated with risk. Clinical trial registration information-Studies of Brain Function and Course of Illness in Pediatric Bipolar Disorder and Child and Adolescent Bipolar Disorder Brain Imaging and Treatment Study; https://ichgcp.net/clinical-trials-registry/NCT00025935" title="See in ClinicalTrials.gov">NCT00025935 and NCT00006177.

Keywords: adolescence; bipolar; brain; endophenotype; risk.

Conflict of interest statement

Disclosure: Drs. Wiggins, Brotman, Adleman, Kim, Chen, Towbin, Pine, Leibenluft, Ms. Wambach, and Mr. Reynolds report no biomedical financial interests or potential conflicts of interest.

Published by Elsevier Inc.

Figures

FIGURE 1

Identifying neural markers associated with risk, resilience, or disorder sequelae. Note: Having all three of these groups (high- and low-risk youths and those with bipolar disorder [BD]) is necessary to disentangle these markers. Brain activation patterns (a) shared by high-risk (HR) and BD (but not low-risk [LR]) youths (HR+BD≠LR) may indicate potential risk endophenotypes; (b) unique to high-risk youths (HR≠BD+LR) may indicate potential resilience markers; (c) and unique to youths with BD (BD≠HR+LR) may indicate potential disorder sequelae.

FIGURE 2

Candidate risk endophenotypes: regions where activation related to face emotion labeling in low-risk (LR) youth differ from those of high-risk (HR) youth and youth with bipolar disorder (BD), across all stimuli (group main effect). Note: Circled clusters correspond to statistical information below brain image; other clusters are significant group differences that do not fit the pattern of a risk endophenotype (i.e., LR≠HR+BP). Axial sections shown in radiological view (left = right) in all figures. Clusters for all figures significant at whole-brain corrected p < .05.

FIGURE 3

Candidate resilience markers: regions where the high-risk (HR) group shows unique neural alterations, relative to the low-risk (LR) and bipolar disorder (BD) groups across all stimuli (group main effect), dependent on face emotion (group × emotion), and dependent on both face emotion and intensity of emotion (group × emotion × intensity). Note: Intensity modeled cubically in the group × emotion × intensity interaction. F and p values on plots reflect post hoc analyses comparing groups for each emotion separately. All p values reflect false discovery rate (FDR) correction. Asterisks on plots indicate that HR cubic response curve significantly differs from those of LR youth and youth with BD in FDR-corrected post hoc comparisons. See Figure 2 for information on brain images.

FIGURE 3

Candidate resilience markers: regions where the high-risk (HR) group shows unique neural alterations, relative to the low-risk (LR) and bipolar disorder (BD) groups across all stimuli (group main effect), dependent on face emotion (group × emotion), and dependent on both face emotion and intensity of emotion (group × emotion × intensity). Note: Intensity modeled cubically in the group × emotion × intensity interaction. F and p values on plots reflect post hoc analyses comparing groups for each emotion separately. All p values reflect false discovery rate (FDR) correction. Asterisks on plots indicate that HR cubic response curve significantly differs from those of LR youth and youth with BD in FDR-corrected post hoc comparisons. See Figure 2 for information on brain images.

FIGURE 4

Candidate disorder sequelae: activation specific to the bipolar disorder (BD) group, relative to the low-risk (LR) and high-risk (HR) group, across all stimuli types (group main effect) and in specific emotions (group × emotion). Note: See Figure 2 for information on brain images.