On the Road to Translation for PTSD Treatment: Theoretical and Practical Considerations of the Use of Human Models of Conditioned Fear for Drug Development

Abstract

The use of quantitative, laboratory-based measures of threat in humans for proof-of-concept studies and target development for novel drug discovery has grown tremendously in the last 2 decades. In particular, in the field of posttraumatic stress disorder (PTSD), human models of fear conditioning have been critical in shaping our theoretical understanding of fear processes and importantly, validating findings from animal models of the neural substrates and signaling pathways required for these complex processes. Here, we will review the use of laboratorybased measures of fear processes in humans including cued and contextual conditioning, generalization, extinction, reconsolidation, and reinstatement to develop novel drug treatments for PTSD. We will primarily focus on recent advances in using behavioral and physiological measures of fear, discussing their sensitivity as biobehavioral markers of PTSD symptoms, their response to known and novel PTSD treatments, and in the case of d-cycloserine, how well these findings have translated to outcomes in clinical trials. We will highlight some gaps in the literature and needs for future research, discuss benefits and limitations of these outcome measures in designing proof-of-concept trials, and offer practical guidelines on design and interpretation when using these fear models for drug discovery.

Fear learning alterations after traumatic brain injury and their role in development of posttraumatic stress symptoms

“…The relative contribution of TBI versus PTSD to cognitive outcomes can be difficult to disentangle (Bombardier et al., ; Bryant et al., ; Carlson et al., ; Hoge, Goldberg, & Castro, ; Perry et al., ; Stein et al., ; Vasterling et al., ; Wisco et al., ; Yurgil et al., ). We and others have shown that PTSD is associated with increased fear learning and reduced extinction, however there is limited research on whether TBI affects these learning processes (Acheson et al., ; Norrholm et al., ; Risbrough et al., ). Obvious potential confounders would be both trauma exposure and PTSD, as TBI (whether during deployment or prior to deployment) is associated with higher deployment stress and likelihood of meeting PTSD diagnostic criteria.…”

“…Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are "signature injuries" of recent U.S. military conflicts. Prevalence rates for veterans of these conflicts are estimated at 23% for PTSD (Fulton et al, 2015) and 10-23% for TBI (Hoge et al, 2008;O'Neil et al, (Acheson et al, 2015;Briscione, Jovanovic, & Norrholm, 2014;Craske & Mystkowski, 2006;Grillon et al, 2009;Hermans, CRASKE, Mineka, & Lovibond, 2006;Lissek & van Meurs, 2015;Milad et al, 2009;Mineka & Zinbarg, 2006;Norrholm et al, 2011;Risbrough, Glenn, & Baker, 2016;VanElzakker, Dahlgren, Davis, Dubois, & Shin, 2014). Thus, head injuries affecting circuits involved with regulation of learned fear processes may increase risk for developing and maintaining PTSD symptoms (Yeh et al, 2016).…”

“…PTSD is consistently associated with alterations in fear‐learning processes. Contemporary models of PTSD implicate elevated fear‐memory acquisition, poor contextual gating of fear, and impaired learning and retention of fear extinction in the development of exaggerated, enduring fear responses (Acheson et al., ; Briscione, Jovanovic, & Norrholm, ; Craske & Mystkowski, ; Grillon et al., ; Hermans, CRASKE, Mineka, & Lovibond, ; Lissek & van Meurs, ; Milad et al., ; Mineka & Zinbarg, ; Norrholm et al., ; Risbrough, Glenn, & Baker, ; VanElzakker, Dahlgren, Davis, Dubois, & Shin, ). Thus, head injuries affecting circuits involved with regulation of learned fear processes may increase risk for developing and maintaining PTSD symptoms (Yeh et al., ).…”

Extinction after fear memory reactivation fails to eliminate renewal in rats

“…Even with extensive clinical and pharmaceutical treatments, humans often exhibit relapse of pathological fear and anxiety (Borkovec & Costello, 1993; Hermans et al, 2006; Vervliet et al, 2013a, 2013b; Wicking et al, 2016). Fear relapse can be modeled in the laboratory using Pavlovian fear conditioning and extinction (Bouton, 1993, 2002, 2004, 2014; Bouton et al, 2006; Craske et al, 2014; Goode & Maren, 2014; Haaker et al, 2014; Hermans et al, 2006; Kim & Richardson, 2010; Maren & Holmes, 2016; Maren et al, 2013; Vervliet et al, 2013a, 2013b), which may contribute to and interact with fear and anxiety disorders (Careaga et al, 2016; Nees et al, 2015; Ribrough et al, 2016; Smith et al, 2017; Zuj et al 2016). Specifically, Pavlovian fear conditioning consists of pairing a harmless conditioned stimulus (“CS”; e.g., auditory tone) with a noxious unconditioned stimulus (“US”; e.g., footshock) (Konorski, 1948; Pavlov & Anrep, 1927; Rescorla, 1988).…”

Survival circuits in affective disorders

“…Relative to healthy adults, individuals with anxiety disorders/PTSD demonstrate increased fear responses to CS+, greater generalization of fear to stimuli that resemble the CS+, and increased fear responses to conditional safety cues (CS-) during fear acquisition [7][8][9]. During extinction, when CS+ is no longer paired with aversive US, individuals with anxiety disorders show stronger fear responses to CS+ than healthy individuals, resulting in delayed or reduced extinction [8][9][10][11]. Impaired extinction recall, primarily heightened responding to CS+E, has also been demonstrated in anxiety disorders and PTSD [9].…”