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Original Investigation
March 21, 2018

Neural Markers of Resilience in Adolescent Females at Familial Risk for Major Depressive Disorder

Author Affiliations
  • 1Department of Psychology, Stanford University, Stanford, California
  • 2Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California
  • 3Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 4Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge
JAMA Psychiatry. Published online March 21, 2018. doi:10.1001/jamapsychiatry.2017.4516
Key Points

Question  What are neural markers of resilience in adolescent females at risk for depression?

Findings  In this longitudinal study of 65 adolescent females, we examined functional connectivity in limbic, salience, and executive control networks. High-risk adolescent females who were resilient to depression had greater connectivity between regions in limbic and executive control networks than did high-risk adolescent females who developed depression and low-risk control adolescents; further, the strength of this connectivity was correlated with positive life events in the group of resilient adolescent females.

Meaning  Our findings highlight functional neuroimaging biomarkers of resilience to adolescent depression that may be candidate targets for the prevention and treatment of depression.


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.