The Butterfly Effect of Trauma Contextualization: How neurobiological variation in context encoding impacts susceptibility to post-traumatic stress disorder

Abstract

People differ remarkably in their response to traumatic events: some develop post-traumatic stress disorder (PTSD), while others are resilient and adapt successfully. PTSD is a debilitating condition that –among other things- is characterized by re-experiencing trauma. Since traumatic events are common and usually unavoidable, the key to PTSD prevention may be hidden in i) understanding who might be at risk, so that risky situations may be avoided as much as possible; and in case this is not possible, ii) modulating the neurobiological systems that give rise to between-individual variation in the processing of traumatic experiences. In this thesis we focused on inter-individual variation in time-dependent learning and memory processes after stress, to get more insight into (part of) the variety of post-trauma responses, and hence the potential susceptibility to PTSD. We integrated methodological approaches from experimental psychology and translational neuroscience to optimally answer our research questions. Multiple study designs, participant species (i.e. humans and rodents), and analysis strategies were combined throughout the chapters of this interdisciplinary thesis: including multiple meta-analyses, a human RCT, a prospective animal study, classical hypothesis testing, and machine learning approaches. We found that: 1) PTSD patients and animal models of PTSD show abnormalities in learning and memory of neutral information, and the extinction of fear; 2) an endogenous stress response of healthy individuals modulates the contextualization of neutral -not emotional- information in a time-dependent manner; 3) personality traits, life adversity, and state characteristics shape the dynamic effects of the stress-response phases on memory contextualization (the actual interplay between these factors depends on the emotional significance of the to-be-contextualized material); 4) the ability to contextualize neutral information under non-stressful conditions protects against PTSD-like behavior in rats. Together, the research described in this thesis illustrates that the ability to form context-dependent memories after stress arises from a complex system with nonlinear interactions between the emotional significance of an event, time-dependent dynamics of the stress response, and between-individual variations in personality traits, experienced life adversity, and state mood and arousal. This is not surprising as brain functioning and cognition arise from complex interactions across many levels (from neuronal to social networks). We found that the complex (neurobiological) system underlying the ability to contextualize memories impacts susceptibility to PTSD-like behavior in rats, potentially by modulating the encoding of (neutral) contextual information in traumatic memories. This provides evidence for the hypothesis that context-processing is central to PTSD pathology. This pre-trauma risk factor may be part of a broader cognitive vulnerability that also contributes to the cross-species impairment in neutral learning and memory, and fear extinction observed in PTSD. We reflect on our methodological choices and translate our findings into clinical perspectives and directions for future research.