Association of Neuroimaging Measures of Emotion Processing and Regulation Neural Circuitries With Symptoms of Bipolar Disorder in Offspring at Risk for Bipolar Disorder

Abstract

Importance: Bipolar disorder (BD) is difficult to distinguish from other psychiatric disorders. Neuroimaging studies can identify objective markers of BD risk.

Objective: To identify neuroimaging measures in emotion processing and regulation neural circuitries and their associations with symptoms specific to youth at risk for BD.

Design, setting, and participants: This cross-sectional (August 1, 2011, to July 31, 2017) and longitudinal (February 1, 2013, to November 30, 2017) neuroimaging study performed at the University of Pittsburgh Medical Center compared a sample of 31 offspring of parents with BD (OBP) with 28 offspring of comparison parents with non-BD psychopathologies (OCP) and 21 offspring of healthy parents (OHP); OBP, OCP, and OHP were recruited from the Bipolar Offspring Study and the Longitudinal Assessment of Manic Symptoms Study.

Main outcomes and measures: Group differences in activity and functional connectivity during emotional face processing and n-back task performance in amygdala, dorsolateral and ventrolateral prefrontal cortices (PFC), caudal anterior cingulate cortices (cACC), and rostral anterior cingulate cortices (rACC) neuroimaging measures showing between-group differences and symptom severity (anxiety, affective lability, depression, mania). We hypothesized that elevated amygdala activity and/or lower PFC activity and abnormal amygdala to PFC functional connectivity would distinguish OBP from OCP and OHP, and magnitudes of these abnormalities would positively correlate with elevated symptom severity. We explored associations between changes in neuroimaging and symptom measures over follow-up (mean [SD], 2.9 [1.4] years) in a subset of participants (n = 30).

Results: Eighty participants were included (mean [SD] age, 14.2 (2.1) years; 35 female). Twelve neuroimaging measures explained 51% of the variance in the results of neuroimaging measures overall. Of the 12, 9 showed significant main associations of the group; however, after post hoc analyses and Bonferroni corrections, only 7 showed statistically significant associations between groups (corrected P < .05 for all). Of the 7, 2 showed significant relationships with symptoms. Offspring of parents with BD had greater right rACC activity when regulating attention to happy faces vs OCP (mean [SD] difference, 0.744 [0.249]; 95% CI, 0.134-1.354; P = .01), which positively correlated with affective lability severity (ρ = 0.304; uncorrected P = .006). Offspring of parents with BD had greater amygdala to left cACC functional connectivity when regulating attention to fearful faces vs OCP (mean [SD] difference, 0.493 [0.169]; 95% CI, 0.079-0.908; P = .01). Increases in this measure positively correlated with increases in affective lability over follow-up (r = 0.541; P = .003).

Conclusions and relevance: Greater anterior cingulate cortex activity and functional connectivity during emotion regulation tasks may be specific markers of BD risk. These findings highlight potential neural targets to aid earlier identification of and guide new treatment developments for BD.

Figure 1.. Elastic Net Plots Generated in GLMNET

A-B. Plots of variable fit for BD risk group (OBP versus OCP and OHP, A) and general risk group (OBP and OCP versus OHP, B). Each curve corresponds to an independent variable in the full model prior to optimization. Curves indicate the path of each variable coefficient as λ varies. Lambda.min (λ=0.553) corresponds to the λ which corresponds to the selected model with 12 predictor variables. C. Plot of non-zero variable fit after cross validation. Representation of the 10-fold cross validation performed for the elastic net regression that chooses the optimal λ. Lambda.min corresponds to the λ which minimizes mean squared error. Lambda.1se corresponds to the λ that is one standard error from the lambda.min. Abbreviations: Bipolar Disorder (BD); Offspring of Bipolar Parents (OBP); Offspring of Comparison Parents (OCP); Offspring of Healthy Parents (OHP).

Figure 2.. Group Differences in Neuroimaging Measures

Bonferroni-corrected group comparisons in non-zero predictor neuroimaging measures. A. For the dynamic faces task, compared with OHP, OBP had significantly lower left dlPFC activity to angry faces versus shapes (mean(SD) difference=.108(.033), 95%CI=.027-.189, P=.005). B. For the emotional face 2-back task, compared with OCP, OBP had significantly greater left cACC-amygdala FC to fearful (mean(SD) difference=.493(.169), 95%CI=.079-.908, P=.014), happy (mean(SD) difference=.516(.148), 95%CI=.155-.877, P=.002), and neutral (mean(SD) difference=.604(.159), 95%CI=.215-.992, P=.001) versus no faces. C. For the emotional face 2-back task, compared with OCP, OBP had significantly greater right rACC activity to happy versus no faces (mean(SD) difference=.744(.249), 95%CI=.134–1.354, P=.011). D. For the emotional face 0-back task, compared with OHP, OCP had significantly lower left (mean(SD) difference=.802(.241), 95%CI=.212–1.391, P=.004) and right (mean(SD) difference=.691(.236), 95%CI=.113–1.269, P=.014) rACC activity to happy versus neutral faces; compared with OHP, OBP had significantly lower right rACC activity to happy versus neutral faces (mean(SD) difference=.626(.231), 95%CI=.060–1.192, P=.025). Abbreviations: ^a=significant at P=.05; Offspring of Bipolar Parents (OBP); Offspring of Comparison Parents (OCP); Offspring of Healthy Parents (OHP); Dorsolateral Prefrontal Cortex (dlPFC); Caudal Anterior Cingulate Cortex (cACC); Functional Connectivity (FC); Rostral Anterior Cingulate Cortex (rACC).

Figure 3.. Relationships between Symptoms and Neuroimaging Measures

Bonferroni-corrected group comparisons in symptom measures. A. Bonferroni corrections for eight parallel tests revealed two significant findings: CALS-P (F(2,77)=6.464, P=.003(.024, corrected)) and KMRS (F(2,75)=6.223, P=.003(.024, corrected)). Bonferroni-corrected post-hoc t-tests revealed that OBP had greater CALS-P severity than OHP (mean(SD) difference=6.575(1.853), 95%CI=2.04–11.11, P=.002), and greater KMRS severity than OHP (mean(SD) difference=1.722(.529), 95%CI=.43–3.02, P=.005) and OCP (mean(SD) difference=1.238(.473), 95%CI=.08–2.40, P=.032). B. Across all subjects, baseline CALS-P severity positively correlated with emotional face 2-back task right rACC activity to happy faces (ρ=.304, P=.006, uncorrected). C. Follow-up analyses comparing changes in symptom and neuroimaging measures in a subset of thirty subjects. Across all thirty subjects, changes in CALS-P scores were positively correlated with changes in emotional face 2-back task amygdala-left cACC FC to fearful faces (r=.541, P=.003(.042, corrected)). Changes in CALS-P scores, with age, gender, IQ, time between scans, and scanner, significantly predicted changes in emotional face 2-back task amygdala-left cACC FC to fearful faces (R²=.423, F(6,21)=2.569, P=.050). Abbreviations: ^a=significant at P=.05; Offspring of Bipolar Parents (OBP); Offspring of Comparison Parents (OCP); Offspring of Healthy Parents (OHP); Parent-Reported Children’s Affective Lability Sale (CALS-P); Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children Mania Rating Scale (KMRS); Rostral Anterior Cingulate Cortex (rACC); Caudal Anterior Cingulate Cortex (cACC); Functional Connectivity (FC).