Impaired fear inhibition is a biomarker of PTSD but not depression.

BACKGROUND: A central problem in posttraumatic stress disorder (PTSD) is a reduced capacity to suppress fear under safe conditions. Previously, we have shown that combat-related PTSD patients have impaired inhibition of fear-potentiated startle (FPS). Given the high comorbidity between PTSD and depression, our goal was to see whether this impairment is specific to PTSD, or a non-specific symptom associated with both disorders. METHODS: Fear-potentiated startle was assessed in 106 trauma-exposed individuals divided into four groups: (a) No diagnosis control, (b) PTSD only, (c) major depression (MDD) only, and (d) comorbid PTSD and MDD. We used a novel conditional discrimination procedure, in which one set of shapes (the danger signal) was paired with aversive airblasts to the throat, and different shapes (the safety signal) were presented without airblasts. The paradigm also included fear inhibition transfer test. RESULTS: Subjects with comorbid MDD and PTSD had higher FPS to the safety signal and to the transfer test compared to controls and MDD only subjects. In contrast to the control and MDD groups, the PTSD and comorbid PTSD and MDD groups did not show fear inhibition to safety cues. CONCLUSIONS: These results suggest that impaired fear inhibition may be a specific biomarker of PTSD symptoms.

Fear potentiation is associated with hypothalamic-pituitary-adrenal axis function in PTSD.

A central problem in posttraumatic stress disorder (PTSD) is the inability to suppress fear under safe conditions. We have previously shown that PTSD patients cannot inhibit conditioned fear. Another relevant finding in PTSD is the hypersensitivity of the hypothalamic-pituitary-adrenal (HPA) axis feedback. Given their common neurobiological pathways, alterations in HPA function in PTSD may be associated with impaired fear inhibition. The present study examined the relationship between HPA axis function and fear-potentiated startle and inhibition of conditioned fear in trauma-exposed individuals. We used a conditional discrimination procedure (AX+/BX-), in which one set of shapes (AX+) was paired with aversive airblasts to the throat (danger signal), and the same X shape with a different shape (BX-) were presented without airblasts (safety signal). The paradigm also included a transfer of fear inhibition test (AB). In addition to fear-potentiated startle, blood was drawn for neuroendocrine analysis and the dexamethasone suppression test (DEX) was performed; cortisol and ACTH were assessed at baseline and post-DEX. Ninety highly traumatized individuals recruited from Grady Hospital in Atlanta, GA participated in the study. The sample was divided into those who met DSM-IV criteria for PTSD (n=29) and Non-PTSD controls (n=61) using the PTSD symptom scale (PSS). Both groups showed significant reduction in cortisol and ACTH levels after DEX. Subjects with PTSD had higher fear-potentiated startle to the safety signal, BX- (F(1,88)=4.44, p<0.05) and fear inhibition trials, AB (F(1,88)=5.20, p<0.05), both indicative of less fear inhibition in the presence of B, compared to control subjects. In addition, fear-potentiated startle to AX+, BX-, and AB was positively correlated with baseline and post-DEX ACTH in PTSD subjects. These results suggest that impaired fear inhibition and associated alterations in HPA feedback may reflect amygdala hyperactivity in subjects with PTSD.

Childhood abuse is associated with increased startle reactivity in adulthood.

BACKGROUND: Understanding the neurobiological correlates of childhood maltreatment is critical to delineating stress-related psychopathology. The acoustic startle response (ASR) is a subcortical reflex modulated by neural systems implicated in posttraumatic stress disorder (PTSD). The ASR is conserved across species and is increased in rodent models of developmental stress. METHODS: We measured ASR to a 40 ms noise probe as well as fear-potentiated startle using electromyographic recordings of the eyeblink in a primarily African American sample (N=60) from a highly traumatized civilian population. We assessed self-reported history of abuse with the Childhood Trauma Questionnaire and current symptoms with the PTSD Symptom Scale and the Beck Depression Inventory. RESULTS: We found that subjects reporting a history of high levels of physical or sexual abuse had increased startle on all trial types relative to those with low abuse (P<.01). This effect remained significant after co-varying for the subjects' age and sex, as well as PTSD and depression symptoms. Perceived childhood sexual abuse was the greatest predictor of increased startle response. Notably, emotional abuse in childhood did not affect baseline startle, and all groups demonstrated equivalent levels of fear-potentiated startle. CONCLUSIONS: The long-lasting effects of early life trauma result in increased risk for adult psychopathology. These new data demonstrate that a self-report history of child abuse is related to altered baseline startle response that is not accounted for by PTSD or depression symptoms. Increased startle may be a biomarker of stress responsiveness that can be a persevering consequence of early trauma exposure during childhood.

Delayed extinction attenuates conditioned fear renewal and spontaneous recovery in humans.

This study investigated whether the retention interval after an aversive learning experience influences the return of fear after extinction training. After fear conditioning, participants underwent extinction training either 5 min or 1 day later and in either the same room (same context) or a different room (context shift). The next day, conditioned fear was tested in the original room. When extinction took place immediately, fear renewal was robust and prolonged for context-shift participants, and spontaneous recovery was observed in the same-context participants. Delayed extinction, by contrast, yielded a brief form of fear renewal that reextinguished within the testing session for context-shift participants, and there was no spontaneous recovery in the same-context participants. The authors conclude that the passage of time allows for memory consolidation processes to promote the formation of distinct yet flexible emotional memory traces that confer an ability to recall extinction, even in an alternate context, and minimize the return of fear. Furthermore, immediate extinction can yield spontaneous recovery and prolong fear renewal. These findings have potential implications for ameliorating fear relapse in anxiety disorders.

Effects of stress and sex on acquisition and consolidation of human fear conditioning.

We examined the relationship between stress hormone (cortisol) release and acquisition and consolidation of conditioned fear learning in healthy adults. Participants underwent acquisition of differential fear conditioning, and consolidation was assessed in a 24-h delayed extinction test. The acquisition phase was immediately followed by an 11-min psychosocial stress period (arithmetic test combined with a public speech). Salivary cortisol was sampled at various time points before and after acquisition and retention of fear conditioning. Results showed two effects of endogenous cortisol. Post-acquisition cortisol correlated with fear acquisition in male but not female participants. In addition, post-acquisition cortisol correlated with consolidation of fear but only in those participants with high cortisol levels. We conclude that in the short term, a robust and sexually dimorphic relationship exists between fear learning and stress hormone levels. For those participants whose fear learning is accompanied by high stress hormone levels, a long-term relationship exists between cortisol release and memory consolidation. These short-term and long-term effects may relate to the differential involvement of mineralocorticoid and glucocorticoid receptor subtypes, respectively. The findings have implications for understanding the role of stress, sex, and hormones in different stages of fear learning and memory.