Resilience as a translational endpoint in the treatment of PTSD

Abstract

Resilience is a neurobiological entity that shapes an individual's response to trauma. Resilience has been implicated as the principal mediator in the development of mental illness following exposure to trauma. Although animal models have traditionally defined resilience as molecular and behavioral changes in stress responsive circuits following trauma, this concept needs to be further clarified for both research and clinical use. Here, we analyze the construct of resilience from a translational perspective and review optimal measurement methods and models. We also seek to distinguish between resilience, stress vulnerability, and posttraumatic growth. We propose that resilience can be quantified as a multifactorial determinant of physiological parameters, epigenetic modulators, and neurobiological candidate markers. This multifactorial definition can determine PTSD risk before and after trauma exposure. From this perspective, we propose the use of an 'R Factor' analogous to Spearman's g factor for intelligence to denote these multifactorial determinants. In addition, we also propose a novel concept called 'resilience reserve', analogous to Stern's cognitive reserve, to summarize the sum total of physiological processes that protect and compensate for the effect of trauma. We propose the development and application of challenge tasks to measure 'resilience reserve' and guide the assessment and monitoring of 'R Factor' as a biomarker for PTSD.

Figure 1

The Venn diagram models how resilience relates to stress vulnerability and post-traumatic growth. We hypothesize that both post-traumatic growth and stress vulnerability are subsets of resilience. Both stress vulnerability and resilience share common mechanisms that predispose individuals to develop PTSD upon exposure to stress. However, stress vulnerability only quantifies risk for developing PTSD, whereas resilience encompasses the effects of developing PTSD from exposure to stress, both positive and negative. Post-traumatic growth includes only positive changes occurring in an individual after an adverse event. Our proposed consensus definition of resilience is a multifactorial construct that is determined from biological mechanisms and physiological parameters that mediate maintenance of an optimal functional trajectory after a traumatic event. This definition differs from both post-traumatic growth and stress vulnerability in that they are not multi-factorial constructs. In addition, resilience encompasses adaptive behavioral and neurobiological responses to trauma, which are specific to the construct. Examining the relationship between these constructs requires longitudinal studies that collect our proposed precision predictive panel markers prior to and following trauma exposure. We elucidate further on this in table 2 and in the latter part of the article under ‘Future Directions in Resilience Research’.

Figure 2

In this figure we provide a visual representation of components that help derive the R factor. Preclinical animal models of resilience support the use of a resilience challenge task that can be used to measure resilience. In humans, key environmental parameters that influence resilience include, but are not limited to, prenatal stress, childhood trauma, childhood neglect/abuse, nutrition, and psychosocial variables such as family and community support, poverty, and community violence. Key biological (intrinsic) parameters that influence resilience include genotype, gene expression serum markers, structure and function of the brain (neuroimaging), epigenetics, cognitive appraisal skills, psychophysiological and autonomic response, gut microbiome, and gut biology. R factor would provide an objective assessment of resilience as a multifactorial determinant using our proposed precision predictive panel. We hypothesize R factor as a measurable endpoint to assess ‘resilience reserve’ analogous to Stern’s cognitive reserve. Assessing resilience in a quantified manner as a multifactorial determinant will help develop new treatment targets and strategies.