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Connectomic markers of disease expression, genetic risk and resilience in bipolar disorder.

ABSTRACT: Bipolar disorder (BD) is characterized by emotional dysregulation and cognitive deficits associated with abnormal connectivity between subcortical-primarily emotional processing regions-and prefrontal regulatory areas. Given the significant contribution of genetic factors to BD, studies in unaffected first-degree relatives can identify neural mechanisms of genetic risk but also resilience, thus paving the way for preventive interventions. Dynamic causal modeling (DCM) and random-effects Bayesian model selection were used to define and assess connectomic phenotypes linked to facial affect processing and working memory in a demographically matched sample of first-degree relatives carefully selected for resilience (n=25), euthymic patients with BD (n=41) and unrelated healthy controls (n=46). During facial affect processing, patients and relatives showed similarly increased frontolimbic connectivity; resilient relatives, however, evidenced additional adaptive hyperconnectivity within the ventral visual stream. During working memory processing, patients displayed widespread hypoconnectivity within the corresponding network. In contrast, working memory network connectivity in resilient relatives was comparable to that of controls. Our results indicate that frontolimbic dysfunction during affect processing could represent a marker of genetic risk to BD, and diffuse hypoconnectivity within the working memory network a marker of disease expression. The association of hyperconnectivity within the affect-processing network with resilience to BD suggests adaptive plasticity that allows for compensatory changes and encourages further investigation of this phenotype in genetic and early intervention studies.

SUBMITTER: Dima D

PROVIDER: S-EPMC5068872 | biostudies-other | 2016 Jan

REPOSITORIES: biostudies-other

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Connectomic markers of disease expression, genetic risk and resilience in bipolar disorder.

Dima D D Roberts R E RE Frangou S S

Translational psychiatry 20160105

Bipolar disorder (BD) is characterized by emotional dysregulation and cognitive deficits associated with abnormal connectivity between subcortical-primarily emotional processing regions-and prefrontal regulatory areas. Given the significant contribution of genetic factors to BD, studies in unaffected first-degree relatives can identify neural mechanisms of genetic risk but also resilience, thus paving the way for preventive interventions. Dynamic causal modeling (DCM) and random-effects Bayesian ...[more]

PMID: 26731443

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Project description:OBJECTIVE:In this study, we performed a candidate genetic risk score (GRS) analysis of early-onset bipolar disorder (BD). METHODS:Treatment of Early Age Mania (TEAM) study enrollment and sample collection took place from 2003 to 2008. Mayo Clinic Bipolar Biobank samples were collected from 2009 to 2013. Genotyping and analyses for the present study took place from 2013 to 2014. The diagnosis of BD was based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. Eight single-nucleotide polymorphisms (SNPs), previously reported in genome-wide association studies to be associated with BD, were chosen for GRS analysis in early-onset bipolar disease. These SNPs map to 3 genes: CACNA1C (calcium channel, voltage-dependent, L type, alpha 1C subunit), ANK3 (ankyrin-3, node of Ranvier [ankyrin G]), and ODZ4 (teneurin transmembrane protein 4 [formerly "odz, odd Oz/10-m homolog 4 {Drosophila}, ODZ4"]). The 8 candidate SNPs were genotyped in patients from the TEAM study (n = 69); adult patients with BD (n = 732), including a subset with early-onset illness (n = 192); and healthy controls (n = 776). GRS analyses were performed to compare early-onset cases with controls. In addition, associations of early-onset BD with individual SNPs and haplotypes were explored. RESULTS:GRS analysis revealed associations of the risk score with early-onset BD (P = .01). Gene-level haplotype analysis comparing TEAM patients with controls suggested association of early-onset BD with a CACNA1C haplotype (global test, P = .01). At the level of individual SNPs, comparison of TEAM cases with healthy controls provided nominally significant evidence for association of SNP rs10848632 in CACNA1C with early-onset BD (P = .017), which did not remain significant after correction for multiple comparisons. CONCLUSIONS:These preliminary analyses suggest that previously identified BD risk loci, especially CACNA1C, have a role in early-onset BD, possibly with stronger effects than for late-onset BD.

Project description:Importance:Adolescence is a neurodevelopmental period during which experience-dependent plasticity in brain circuitry may confer vulnerability to depression as well as resilience to disorder. Little is known, however, about the neural mechanisms that underlie resilience during this critical period of brain development. Objective:To examine neural functional connectivity correlates of resilience in adolescent females at high and low familial risk for depression who did and did not develop the disorder. Design, Setting, and Participants:A longitudinal study was conducted at Stanford University from October 1, 2003, to January 31, 2017. Sixty-five female adolescents participated in the study: 20 at high risk in whom depression did not develop (resilient), 20 at high risk in whom depression developed (converted), and 25 at low risk with no history of psychopathology (control). Main Outcomes and Measures:We compared functional connectivity between resilient and converted, and between resilient and control, adolescent females using voxelwise 2-sided t tests to examine neural markers of resilience to depression as the main outcomes of interest. Specifically, we assessed differences in connectivity of the limbic (amygdala seed), salience (anterior insula seed), and executive control (dorsolateral prefrontal cortex seed) networks, implicated in emotion regulation. We also examined the association between functional connectivity and life events. Results:Of the 65 participants (mean [SD] age, 18.9 [2.5] years), adolescent females in the resilient group had greater connectivity between the amygdala and orbitofrontal cortex (z score?=?0.23; P?<?.001) and between the dorsolateral prefrontal cortex and frontotemporal regions (z score?=?0.24; P?<?.001) than did converted adolescent females. In adolescent females in the resilient group only, strength of amygdala-orbitofrontal cortex connectivity was correlated with positive life events (r18?=?0.48; P?=?.03). Resilient adolescent females had greater connectivity within frontal (z score?=?0.07; P?<?.001) and limbic (z score?=?0.21; P?<?.001) networks than did control individuals. Both high-risk groups had greater salience network connectivity: the converted group had greater intranetwork connectivity than did the resilient (z score?=?0.13; P?<?.001) and control (z score?=?0.10; P?<?.001) groups, and the adolescent females in the resilient group had greater salience network connectivity with the superior frontal gyrus than did the converted (z score?=?0.24; P?<?.001) adolescent females. Conclusions and Relevance:Resilient adolescent females have compensatory functional connectivity patterns in emotion regulatory networks that correlate with positive life events, suggesting that experience-dependent plasticity within these networks may confer resilience to depression. Further studies are warranted concerning connectivity-associated targets for promoting resilience in high-risk individuals.

Dataset Information

Connectomic markers of disease expression, genetic risk and resilience in bipolar disorder.

Publications

Connectomic markers of disease expression, genetic risk and resilience in bipolar disorder.

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