Baseline and follow-up activity and functional connectivity in reward neural circuitries in offspring at risk for bipolar disorder

Abstract

Bipolar disorder (BD) is a serious psychiatric illness with demonstrated abnormalities in reward processing circuitry. Examining this circuitry in youth at familial risk for BD may provide further insight into the underlying mechanisms of BD development. In this study, we compared offspring of bipolar parents (OBP, n = 32), offspring of comparison parents with non-BD psychopathology (OCP, n = 36), and offspring of healthy parents (OHP, n = 39) during a functional magnetic resonance imaging reward processing task. Elastic net regression analyses identified 26 activity, functional connectivity (FC), and demographic variables that explained 34.24% of the variance in group (λ = 0.224). ANOVA and post-hoc analyses revealed that OBP had significantly lower right ventral striatum-left caudal anterior cingulate FC to loss (OBP versus OCP: p = 0.028, OBP versus OHP: p = 0.015) and greater right pars orbitalis-left (OBP versus OCP: p = 0.003, OBP versus OHP: p = 0.036) and -right (OBP versus OCP: p = 0.001, OBP versus OHP: p = 0.038) orbitofrontal cortex FC to reward versus OCP and OHP, respectively. These findings were not affected by non-BD psychopathology, psychotropic medication use, or symptomatology. There were no changes in, or relationships between, neuroimaging or symptom measures at follow-up (mean(SD) = 2.70(1.22) year inter-scan interval) in a subset of youth with follow-up data (OBP, n = 14; OCP, n = 8; OHP, n = 19). These findings suggest that lower right ventral striatum-left caudal anterior cingulate FC to loss and greater right pars orbitalis-orbitofrontal cortex FC to reward may be trait-level neural markers that may reflect risk for BD in at-risk youth. These findings comprise important steps toward identifying neural markers of BD risk, which may enhance early identification and guide interventions for youth at familial risk for BD.

Fig. 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 = 0.224) corresponds to the λ which corresponds to the selected model with 26 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. OBP offspring of bipolar parents, OCP offspring of comparison parents, OHP offspring of healthy parents

Fig. 2

Group differences in neuroimaging measures. Tukey HSD-corrected group comparisons in significant non-zero predictor neuroimaging measures. a OBP had significantly lower bilateral VS–left caudal ACC functional connectivity when processing loss compared with OCP (p = 0.025) and OHP (p = 0.049). b OBP had significantly greater bilateral pars orbitalis–left OFC functional connectivity to reward (p = 0.001), bilateral pars orbitalis–right OFC functional connectivity to reward (p < 0.001), and bilateral pars triangularis–right OFC functional connectivity to loss (p = 0.033) compared with OCP. OCP had significantly lower bilateral pars orbitalis–right OFC functional connectivity to reward compared with OHP (p = 0.046). *Significant at p = 0.05. OBP offspring of bipolar parents, OCP offspring of comparison parents, OHP offspring of healthy parents, VS ventral striatum, ACC anterior cingulate cortex, FC functional connectivity, vlPFC ventrolateral prefrontal cortex, OFC orbitofrontal cortex, SES socioeconomic status

Fig. 3

Group differences in neuroimaging measures: left- versus right-sided seed regions. a Tukey HSD-corrected group comparisons in significant non-zero predictor neuroimaging measures with left-sided seeds. OBP had significantly greater left pars orbitalis—left (p = 0.002) and right (p = 0.002) OFC functional connectivity to reward compared with OCP. OCP had significantly lower left pars orbitalis–left OFC functional connectivity to reward compared with OHP (p = 0.045). b Tukey HSD-corrected group comparisons in significant non-zero predictor neuroimaging measures with right-sided seeds. OBP had significantly lower right VS–left caudal ACC functional connectivity to loss compared with OCP (p = 0.028) and OHP (p = 0.015). OBP had significantly greater right pars orbitalis—left and right OFC functional connectivity compared with OCP (p = 0.003, 0.001) and OHP (p = 0.036, 0.038), respectively. *Significant at p = 0.05. OBP offspring of bipolar parents, OCP offspring of comparison parents, OHP offspring of healthy parents, VS ventral striatum, ACC anterior cingulate cortex, OFC orbitofrontal cortex

Fig. 4

Group differences in symptom measures. Tukey HSD-corrected group comparisons in symptom measures. Compared with OCP, OBP had significantly greater scores on CALS-P (p = 0.024). Compared with OHP, OBP had significantly greater scores on SCARED-P (p = 0.002), CALS-P (p < 0.001), MFQ-P (p = 0.003), KDRS (p = 0.004), and KMRS (p = 0.004), and OCP had significantly greater scores on SCARED-P (p = 0.002). *Significant at p = 0.05. OBP offspring of bipolar parents, OCP offspring of comparison parents, OHP offspring of healthy parents, SCARED-P Parent-Reported Screen for Child Anxiety Related Disorders, CALS-P Parent-Reported Children’s Affective Lability Scale, MFQ Parent-Reported Mood and Feelings Questionnaire, KDRS Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children Depression Rating Scale, KMRS Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children Mania Rating Scale