An inability to inhibit learned fear under conditions of safety can underlie several PTSD symptoms, most notably re-experiencing(3
). Our group has previously shown fear inhibition deficits in response to safety cues in both civilian(16
) and combat PTSD patients(15
). In the present study, we expanded this investigation of fear inhibition in PTSD using a fear-potentiated startle extinction paradigm employed in our prior investigations(30
). The primary findings of the current study are: (a) both PTSD+ participants and traumatized PTSD− individuals displayed robust fear-potentiated startle to the CS+ and significant discrimination between the CS+ and CS− during Acquisition, (b) the PTSD+ group showed increased fear-potentiated startle to both the CS+ and CS− compared to the PTSD− group during late Acquisition, (c) individuals with higher re-experiencing and hyper-arousal symptoms, as measured by the PSS, showed greater levels of fear to the CS+ and CS−, during Acquisition, compared to those with lower re-experiencing and hyper-arousal symptoms, (d) the PTSD+ group showed increased fear-potentiated startle to the previously reinforced CS+ compared to the PTSD− group during early and middle Extinction, (e) individuals with higher re-experiencing symptoms showed increased fear-potentiated startle to the previously reinforced CS+ compared to the low re-experiencing group during Extinction, (f) elevated fear-potentiated startle responses to the CS− (safety) during Acquisition predicted greater fear-potentiated startle to the previously reinforced CS+ during Extinction, and (g) within the PTSD+ group, those who were poor inhibitors to the CS− demonstrated delayed extinction of fear. This final finding suggests that there may be two separate subgroups within the PTSD cohort, one with a primary phenotype of enhanced fear expression, and a second with impaired inhibition of fear and delayed extinction.
Using fear-potentiated startle, we have shown alterations in fear processing in both combat-related PTSD(15
) and civilian PTSD(16
). In our previous studies using a conditional discrimination paradigm, we have consistently found that PTSD is associated with impaired inhibition of fear(15
), and a lack of CS+/CS− discrimination when more ambiguous cues are used(16
). The present study used a simple discrimination task that reduces the level of ambiguity involved in learning. The result of this simplified task were heightened fear expression to the CS+, which was more than two-fold greater in the PTSD subjects compared to the traumatized controls during late Acquisition. This exaggerated fear expression was also observed in early and mid Extinction, so that fear potentiation to the CS+ continued to be high in the PTSD group after the CS+ was no longer reinforced. Although the sample in the present study was not medication free, the use of psychotropic medication was low and equally distributed across groups; therefore, medication effects did not account for the observed group differences.
Although most fear conditioning studies in PTSD, including our own, have found deficits in safety cue processing, i.e. diagnostic group differences were greater in responses to CS− than group differences to the CS+(16
), neuroimaging data showing amygdala hyper-activation in response to fear-related cues in PTSD would support the finding of heightened fear expression(34
). In order to selectively account for responses to danger and safety cues, we then selected PTSD individuals who were also high responders to the CS− during late Acquisition, when CS− potentiation should be low. These individuals, who appeared to be poor inhibitors of fear when learning the safety cue, were also impaired in Extinction. In addition, they did not show decreased startle potentiation to the CS+ in the extinction phase. Given that extinction is thought to be a new inhibitory learning, rather than erasure of the original fear memory(36
), similar neural mechanisms may be involved in safety signal processing and extinction of responses to danger signals.
It is important to note that heightened fear expression resulted in an impairment at the onset of extinction, in that PTSD subjects exhibited significantly more fear during early and mid Extinction relative to controls; however, it did not eliminate extinction all together there were no group differences in late Extinction. Therefore, given enough trials, exaggerated fear may be overcome. On the other hand, PTSD participants who showed a deficit in safety cue processing did not show extinction even after 6 blocks. Therefore, it is possible the heightened fear expression accounts for deficits in extinction rate, while impaired fear inhibition accounts for an inability to extinguish danger cues. The observed elevation in fear-potentiated startle to the previously reinforced CS+ during the early and middle stages of the fear extinction session has clinical implications for the treatment of PTSD. Fear extinction is an analog of clinical interventions such as prolonged exposure therapy(4
) that rely on the repeated presentation of trauma-related stimuli (CSs) under conditions of safety (ie., devoid of noxious consequences). Recent translational work has suggested that d-cycloserine, or other novel cognitive enhancers, may facilitate exposure-based psychotherapy and reduce the number of exposure sessions required to reduce fear(37
). The present results suggest the use of this paradigm as a model for the pre-clinical assessment of novel extinction facilitators as treatment options for PTSD especially for those participants in which re-experiencing symptoms produce the greatest degree of impairment.
Notably, the current study sample consisted predominantly of African-American participants, which may potentially reduce generalizability to other populations. To our knowledge, there have been no reports of ethnic/racial differences in the acquisition and extinction of fear-potentiated startle. We have, however, reported differences in baseline startle levels between European-Americans and African-Americans(41
). In most of our previous studies (which included Caucasian and African-American participants) individuals who displayed low baseline startle responses consistently showed a robust increase in startle upon introduction of the conditioning paradigm.
An intriguing question raised is the degree to which the PTSD+ and PTSD− participants would recall extinction learning when tested after an elapsed period of time. Prior research has shown that extinction recall is impaired in PTSD(17
). The sensitivity in detecting extinction recall deficits using paradigms such as this remains unclear given that there are currently conflicting results. For example, we have previously observed spontaneous recovery in psychiatrically healthy volunteers using the same paradigm as that which was administered in the current study(30
) whereas other groups (e.g., Milad et al., 2009) have not reported this effect; however, the latter group employed skin conductance and not fear-potentiated startle. Extinction recall studies are currently underway in the urban traumatized population described herein.
These results suggest that extinction deficits may be due to two independent mechanisms: high fear load may account for exaggerated fear at the onset of extinction, while low fear inhibition may account for deficits in fully extinguishing fear responses. In relation to PTSD symptoms, these two mechanisms may be related to differential symptom presentation, so that higher fear load may be associated with re-experiencing, while lower fear inhibition may be associated with hyper-arousal(16
). Furthermore, it is possible that these two mechanisms have different, albeit interconnected, neural underpinnings. High fear load, and re-experiencing may be associated with hyperactivity in the amygdala(42
), while impaired fear inhibition, both during fear conditioning and extinction, may reflect altered prefrontal control of the amygdala(43
). Although the re-experiencing symptoms appear to be most strongly related to fear load, the high correlation between symptom sub-clusters and total PTSD symptoms makes it difficult to parse out the unique contribution of re-experiencing vs. overall symptom severity.
The current findings suggest that PTSD participants experience a greater “fear load” following the acquisition of conditioned fear and that this elevated level of fear may persist after acquisition. The observed increase in fear-potentiated startle to the CS+ following acquisition and during extinction is consistent with previous neurobiological data showing amygdalar hyperactivity and prefrontal cortical hypoactivity in PTSD. In addition, elevated fear levels in PTSD participants are most pronounced during early stages of extinction suggesting that enhancement of extinction learning (e.g., via pharmacological interventions such as d-cycloserine) may prove beneficial in treating PTSD. The extinction paradigm employed here, which demonstrates robust effect sizes supporting smaller study designs, may serve as an effective psychophysiological tool for assessing pre-clinical candidate drug efficacy as well as an objective measure of clinical outcome in PTSD treatment groups using extinction-based exposure therapies.