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A neural model of vulnerability and resilience to stress-related disorders linked to differential susceptibility


Expert opinion remains divided concerning the impact of putative risk factors on vulnerability to depression and other stress-related disorders. A large body of literature has investigated gene by environment interactions, particularly between the serotonin transporter polymorphism (5-HTTLPR) and negative environments, on the risk for depression. However, fewer studies have simultaneously investigated the outcomes in both negative and positive environments, which could explain some of the inconclusive findings. This is embodied by the concept of differential susceptibility, i.e., the idea that certain common gene polymorphisms, prenatal factors, and traits make some individuals not only disproportionately more susceptible and responsive to negative, vulnerability-promoting environments, but also more sensitive and responsive to positive, resilience-enhancing environmental conditions. Although this concept from the field of developmental psychology is well accepted and supported by behavioral findings, it is striking that its implementation in neuropsychiatric research is limited and that underlying neural mechanisms are virtually unknown. Based on neuroimaging studies that examined how factors mediating differential susceptibility affect brain function, we posit that environmental sensitivity manifests in increased salience network activity, increased salience and default mode network connectivity, and increased salience and central executive network connectivity. These changes in network function may bring about automatic exogenous attention for positive and negative stimuli and flexible attentional set-shifting. We conclude with a call to action; unraveling the neural mechanisms through which differential susceptibility factors mediate vulnerability and resilience may lead us to personalized preventive interventions.

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Fig. 1: Schematic presentation of a neural model for environmental sensitivity, derived from findings related to the 5-HTTLPR and SPS.


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We thank research assistant Madeleine Ghazarian for helping with the literature search. This work was supported by the Dutch Research Council through the ERANID Grant “STANDUP” awarded to JH. The Dutch Research Council had no role in the creation of this manuscript.

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Homberg, J.R., Jagiellowicz, J. A neural model of vulnerability and resilience to stress-related disorders linked to differential susceptibility. Mol Psychiatry (2021).

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