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.

Keywords: Biological Markers; Cognitive Neuroscience; Emotion; Posttraumatic Stress Disorder.

FIGURE 1.

Generalization Results Across Groups for Ratings of Perceived Risk of Shock in a Study of Neural Substrates of Overgeneralized Conditioned Fear^{a a} Perceived risk of shock (0=no risk, 1=some risk, 2=high risk) was assessed during conditioned danger cues (CS+), generalization stimuli (GS₃, GS₂, GS₁), and conditioned safety cues (ring-shaped [oCS−] or V-shaped [vCS−]), forming a continuum of similarity between CS+ and CS−. Generalized conditioned fear was evidenced by the main effects of stimulus type in each group (all p values <0.0001), reflecting downward gradients of perceived risk as stimuli differentiated from CS+. Dotted lines indicate hypothetical linear decreases in responding from CS+ to oCS− with which to visualize the deviation of gradients from linearity in each group. Such deviations reflect a significantly stronger linear component in the generalization gradient of posttraumatic stress disorder (PTSD) subjects relative to trauma control subjects (p=0.01) and of subthreshold PTSD subjects relative to trauma control subjects (p=0.04), indicating more gradual, linear declines indicative of overgeneralization in PTSD. To identify the point on the continuum of similarity at which perceived risk ceased to generalize for each group, planned comparisons contrasting oCS− against CS+ and GS₃, GS₂, and GS₁ were computed. Red data points signify stimulus types eliciting increased risk ratings relative to oCS− after applying Hochberg’s adjustment for multiple tests (23). In trauma control subjects, perceived risk was elevated from oCS− to CS+ (p<0.0001) and GS₃ (p<0.0001), but not GS₂ (p=0.06) or GS₁ (p=0.91). By contrast, in PTSD and subthreshold PTSD subjects, perceived risk was elevated from oCS− to CS+ (all p values <0.0001), GS₃ (all p values <0.0001), GS₂ (all p values <0.0001), and GS₁ (all p values ≤0.016). Thus, while trauma control subjects generalized perceived risk only to one degree of differentiation from CS+ (i.e., GS₃), those with PTSD and subthreshold PTSD generalized to three degrees of differentiation (i.e., GS₃–GS₁). Ellipses around the rightmost data points highlight response slopes from CS+ to GS₃ that are more gradual and linear in PTSD and subthreshold PTSD but more steep than linear in trauma control subjects.

FIGURE 2.

Group Differences in Positive Neural Gradients of Generalization in a Study of Neural Substrates of Overgeneralized Conditioned Fear^{a a} Brain activations reflect functional regions of interest responding more strongly to a conditioned danger cue (CS+) compared with a V-shaped conditioned safety cue (vCS−) (orange activations) for which the shape of positive generalization gradients depended on group status. Dotted lines indicate hypothetical linear decreases in responding from CS+ to a ring-shaped conditioned safety cue (oCS−) with which to visualize the deviation of gradients from linearity in each group. Subjects with posttraumatic stress disorder (PTSD) (relative to trauma control subjects) displayed markedly less deviation from linearity (i.e., fewer quadratic declines) in all functional regions of interest, indicating a tendency toward less steep generalization gradients (or stronger generalization) in veterans with PTSD. This assertion was further tested with planned comparisons contrasting levels of reactivity to oCS− compared with CS+ and the three classes of generalization stimuli (GS₃, GS₂, and GS₁) to identify the point on the continuum of similarity at which activations in functional regions of interest cease to generalize for each group. Red data points signify stimulus types eliciting brain responses stronger than oCS− after applying Hochberg’s adjustment for multiple comparisons at the group level for each functional region of interest. As stipulated by the Hochberg procedure (23), specific criterion p values were a function of p values generated by each set of comparisons and ranged from p≤0.0125 to p≤0.05. L=left; R=right; dmPFC=dorsomedial prefrontal cortex; BA=Brodmann’s area. Coordinates are based on the left-posterior-inferior (LPI) system.

FIGURE 3.

Group Differences in Negative Neural Gradients of Generalization in a Study of Neural Substrates of Overgeneralized Conditioned Fear^{a a} Brain activations reflect functional regions of interest responding more strongly to a V-shaped conditioned safety cue (vCS−) compared with a conditioned danger cue (CS+) (blue activations) for which the shape of negative generalization gradients depended on group status. Dotted lines indicate hypothetical linear decreases in responding from a ring-shaped conditioned safety cue (oCS−) to CS+ with which to visualize the deviation of gradients from linearity in each group. To identify the point on the continuum of similarity at which safety-related brain responses come online in each group, planned comparisons contrasted responses to CS+ versus oCS−, GS₁, GS₂, and GS₃. Red data points signify stimulus types eliciting brain responses stronger than CS+ after applying Hochberg’s adjustment for multiple comparisons at the group level for each functional region of interest. As stipulated by the Hochberg procedure (23), specific criterion p values were a function of p values generated by each set of comparisons and ranged from p≤0.0125 to p≤0.05. L=left; R=right; vmPFC=ventromedial prefrontal cortex. Coordinates are based on the left-posterior-inferior (LPI) system.

FIGURE 4.

Scatterplots Displaying Significant Bivariate Relations Across All Subjects (N=61) Between Total Scores on the Clinician-Administered PTSD Scale (CAPS) and the Steepness of Positive and Negative Neural Gradients of Generalization in a Study of Neural Substrates of Overgeneralized Conditioned Fear^{a a} Bivariate relation between CAPS scores and the steepness of both positive neural gradients of generalization in the right anterior insula and negative neural gradients of generalization in the left ventral hippocampus/amygdala. The y-axis shows a measure of gradient steepness reflecting the degree to which generalization gradients deviated from linearity. Larger linear deviation scores reflect more shallow downward slopes from the conditioned danger cue (CS+) to the conditioned safety cue (CS−) in the case of positive gradients and more shallow upward slopes from CS+ to CS− in the case of negative gradients. Of note, linear deviation was reverse scored for negative gradients such that larger scores consistently indicated greater generalization whether the generalization gradient was negative or positive. As shown, increasing levels of generalization at both these neural loci are associated with increasing levels of PTSD symptom severity as measured by the CAPS.