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 Pavlovian fear to safe stimuli resembling conditioned-danger cues (CS+) is a widely accepted conditioning correlate of clinical anxiety. Though much of the pathogenic influence of such generalization may lie in the associated avoidance, few studies have assessed maladaptive avoidance decisions associated with Pavlovian generalization. Lab-based assessments of this process, here referred to as aversive Pavlovian-instrumental covariation during generalization (APIC-G), have recently begun. The current study represents a next step in this line of work by conducting the first examination of anxiety-related dimensions of personality that may exacerbate APIC-G. Specifically, we test anxiety sensitivity (AS) and intolerance of uncertainty (IU) as moderators of relations between Pavlovian generalization and maladaptive avoidance decisions in 102 undergraduate students with wide-ranging levels of IU and AS. Results indicate a facilitative effect of AS on this APIC-G process, with AS strengthening relations between Pavlovian generalization and maladaptive generalized avoidance whether operationalizing Pavlovian generalization with psychophysiological (fear-potentiated startle) or behavioral measures. Additionally, IU was found to facilitate APIC-G when indexing Pavlovian generalization with behavioral but not fear-potentiated startle measures. Moderating effects of AS were most pronounced for stimulus classes bearing the highest resemblance to CS+, whereas effects of IU were most pronounced for the stimulus class with the highest level of threat ambiguity. Results implicate AS and IU as risk factors for the maladaptive decisional correlates of Pavlovian generalization and suggest that established associations between these traits and clinical anxiety may derive, in part, from their enhancement of maladaptive APIC-G.

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The Hierarchical Taxonomy of Psychopathology (HiTOP) is an empirical structural model of psychological symptoms formulated to improve the reliability and validity of clinical assessment. Neurobiology can inform assessments of early risk and intervention strategies, and the HiTOP model has greater potential to interface with neurobiological measures than traditional categorical diagnoses given its enhanced reliability. However, one complication is that observed biological correlates of clinical symptoms can reflect various factors, ranging from dispositional risk to consequences of psychopathology. In this paper, we argue that the HiTOP model provides an optimized framework for conducting research on the biological correlates of psychopathology from an ontogenetic perspective that distinguishes among indicators of liability, current symptoms, and consequences of illness. Through this approach, neurobiological research can contribute more effectively to identifying individuals at high dispositional risk, indexing treatment-related gains, and monitoring the consequences of mental illness, consistent with the aims of the HiTOP framework.

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Our capacity to measure diverse aspects of human biology in vivo has developed rapidly in the past decades, but the rate at which these techniques have generated translatable insights into the biology of psychopathological conditions has lagged far behind. This slow progress is partly due to the poor sensitivity, specificity, and replicability of many findings in the literature, which have in turn been attributed to small effect sizes, small sample sizes, and low statistical power. A commonly proposed solution is to rely on large, consortia-sized samples to facilitate discovery of replicable findings. Here, we argue that increasing sample sizes will have limited impact unless a more fundamental issue is addressed: the precision with which target behavioral phenotypes are measured. We discuss key problems and outline several ways forward, largely centered on the use of appropriate statistical models with deep, transdiagnostic assessment of hierarchically organized and homogeneous psychopathology dimensions across the full range of the severity spectrum. We provide worked examples to demonstrate key problems and potential solutions. Arguably, a precision phenotyping approach can enhance the discovery and replicability of associations between biology and behavior, thereby facilitating insights into the pathophysiological mechanisms underlying psychiatric disorders.