Neural Substrates of Overgeneralized Conditioned Fear in PTSD

Abstract

Objective: Heightened generalization of fear from an aversively reinforced conditioned stimulus (CS+, a conditioned danger cue) to resembling stimuli is widely accepted as a pathogenic marker of posttraumatic stress disorder (PTSD). Indeed, a distress response to benign stimuli that "resemble" aspects of the trauma is a central feature of the disorder. To date, the link between overgeneralization of conditioned fear and PTSD derives largely from clinical observations, with limited empirical work on the subject. This represents the first effort to examine behavioral and brain indices of generalized conditioned fear in PTSD using systematic methods developed in animals known as generalization gradients: the gradual decline in conditioned responding as the presented stimulus gradually differentiates from CS+.Method: Gradients of conditioned fear generalization were assessed using functional MRI and behavioral measures in U.S. combat veterans who served in Iraq or Afghanistan and had PTSD (N=26), subthreshold PTSD (N=19), or no PTSD (referred to as trauma control subjects) (N=17). Presented stimuli included rings of graded size, with extreme sizes serving as CS+ (paired with shock) and as a nonreinforced conditioned stimulus (CS-, a conditioned safety cue), and with intermediate sizes forming a continuum of similarity between CS+ and CS-. Generalization gradients were assessed as response slopes from CS+, through intermediate ring sizes, to CS-, with less steep slopes indicative of stronger generalization.Results: Relative to trauma control subjects, PTSD patients showed stronger conditioned generalization, as evidenced by less steep generalization gradients in both behavioral risk ratings and brain responses in the left and right anterior insula, left ventral hippocampus, dorsolateral and dorsomedial prefrontal cortex, and caudate nucleus. Severity of PTSD symptoms across the three study groups was positively correlated with levels of generalization at two such loci: the right anterior insula and left ventral hippocampus. Conclusions:The results point to evidence of brain-based markers of overgeneralized fear conditioning related to PTSD. These findings provide further understanding of a central yet understudied symptom of trauma-related psychopathology. Am J Psychiatry 2017; 174:125-134; doi: 10.1176/appi.ajp.2016 Generalization of conditioned fear is a basic, cross-species, associative-learning process whereby fear acquired to a conditioned stimulus (CS+), paired with an aversive unconditioned stimulus, transfers to safe stimuli resembling the CS+ (1). Heightened levels of generalized conditioned fear have been adopted as a core feature of trauma-related psychopathology (2), and DSM-5 criteria for posttraumatic stress disorder (PTSD) include heightened distress to situations "resembling" aspects of the trauma. The pathogenic contribution of conditioned generalization to PTSD follows from the undue proliferation of trauma cues in an individual's posttrauma environment that then increases and/or sustains PTSD sympt...

Generalization of fear in post‐traumatic stress disorder

“…Lissek and van Meurs () reported stronger generalization in a small group of 13 PTSD patients with mixed trauma histories compared with healthy controls. This finding is in line with a study in U.S. combat veterans: they expected a higher risk of threat toward stimuli not only in response to the conditioned danger cue but also to stimuli with perceptual similarity to the CS+ (Kaczkurkin et al, ). Overgeneralization in these patients was also linked to altered brain responses in areas such as the anterior insula, the ventral hippocampus, the dorsolateral and dorsomedial prefrontal cortex, and the caudate nucleus (Kaczkurkin et al, ; Morey et al, ).…”

“…Their findings support an overgeneralization of fear in different mental disorders. This holds true for anxiety disorders such as social anxiety disorder (Lenaert, Boddez, Vervliet, Schruers, & Hermans, ), panic disorder (Lissek et al, ), generalized anxiety disorder (Lissek et al, ), and obsessive‐compulsive disorder (Kaczkurkin & Lissek, ), as well as for PTSD after combat exposure (Kaczkurkin et al, ; Morey et al, ). The present study reveals that overgeneralization can also be observed in PTSD related to repeated physical and or sexual childhood abuse.…”

Brain circuit dysfunction in post-traumatic stress disorder: from mouse to man

“…Given that vmPFC-mediated inhibition of the amygdala is thought to be necessary for fear extinction 31 , these changes could offer a mechanistic basis for the decrements in extinction retention observed in PTSD subjects. There is also some evidence to support the idea that patients with PTSD might exhibit an increased capacity for fear conditioning itself 44 or a greater propensity for increased fear generalization 45–47 ; however, there have been no longitudinal studies of these traits in patients at risk of developing PTSD, making it unclear whether these characteristics are a cause or an effect of developing PTSD.…”

Behavioral pattern separation and its link to the neural mechanisms of fear generalization

“…It can however become maladaptive when an individual fearfully responds to environmental cues that actually convey safety. This is called overgeneralization, and it has been suggested to represent a phenotypic marker of anxiety disorders and post-traumatic stress disorder (PTSD) (Lissek 2012; Kaczkurkin et al , 2016). If overgeneralization of fear occurs in many day-to-day situations, it can severely impact on daily functioning (Dymond et al , 2014; Dunsmoor and Paz, 2015).…”