Journal of Anxiety Disorders 28 (2014) 358–362

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Journal of Anxiety Disorders

Changes in trauma-potentiated startle with treatment of posttraumatic stress disorder in combat Veterans夽 E. Jenna Robison-Andrew a,∗ , Elizabeth R. Duval b,c , C. Beau Nelson b,c , Aileen Echiverri-Cohen b , Nicholas Giardino b,c , Andrew Defever b , Seth D. Norrholm d , Tanja Jovanovic d , Barbara O. Rothbaum d , Israel Liberzon b,c , Sheila A.M. Rauch b,c a

Minneapolis VA Medical Center, United States PTSD Clinical Team, VA Ann Arbor Healthcare System, United States c Department of Psychiatry, University of Michigan Medical School, United States d Department of Psychiatry, Emory University, United States b

a r t i c l e

i n f o

Article history: Received 14 November 2013 Received in revised form 27 March 2014 Accepted 2 April 2014 Available online 15 April 2014 Keywords: PTSD Treatment Exposure therapy CBT Veteran Combat Trauma

a b s t r a c t Emotional Processing Theory proposes that habituation to trauma-related stimuli is an essential component of PTSD treatment. However, the mechanisms underlying treatment-related habituation are not well understood. We examined one psychophysiological measure that holds potential for elucidating the biological processes involved in treatment response: trauma-potentiated startle response. Seventeen OEF/OIF combat Veterans participated in the study and completed three assessments using a trauma-potentiated startle paradigm over PTSD treatment. Results revealed different patterns of traumapotentiated startle across treatment for responders and nonresponders, but no differences in within task habituation. Responders showed an increase followed by a decrease in trauma-potentiated startle, whereas nonresponders showed a relatively flat response profile. Results suggested that PTSD patients who engage with emotional content as demonstrated by greater startle reactivity may be more likely to respond to PTSD treatment. Furthermore, trauma-potentiated startle shows promise as an objective measure of psychophysiological responses involved in PTSD recovery. © 2014 Elsevier Ltd. All rights reserved.

Clinical practice guidelines for posttraumatic stress disorder (PTSD) strongly support prolonged exposure (PE) therapy as a first-line treatment (IOM, 2007; VA/DOD, 2010). Several PTSD treatment meta-analyses support the efficacy of exposure-based psychotherapy for producing clinically meaningful reductions in PTSD symptoms and improvement in mental health (Bradley, Greene, Russ, Dutra, & Westen, 2005; Sherman, 1998; Steenkamp & Litz, 2013). Exposure-based psychotherapy for PTSD has also been shown to improve patients’ interpersonal and emotion regulation skills (Cloitre, Koenen, Cohen, & Han, 2002), as well as to reduce comorbid guilt, anger, depression, and anxiety (Cahill, Rauch, Hembree, & Foa, 2003; Foa et al., 2005; Rauch et al., 2009; Sherman, 1998) Furthermore, patients who received PE have

夽 Dr. Rauch’s work and the study were supported by a CDA-2 Award from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Clinical Sciences Research and Development. ∗ Corresponding author at: Minneapolis VA Medical Center, 1 Veterans Drive, Minneapolis, MN 55417, United States. Tel.: +1 612 467 1463. E-mail address: [email protected] (E.J. Robison-Andrew). http://dx.doi.org/10.1016/j.janxdis.2014.04.002 0887-6185/© 2014 Elsevier Ltd. All rights reserved.

demonstrated improved social functioning and reduced negative health perceptions (Rauch et al., 2009). Biological changes have also been demonstrated in patients with PTSD who participated in exposure-based psychotherapy (Gerardi, Cukor, Difede, Rizzo, & Rothbaum, 2010). As such, exposure-based psychotherapy for PTSD appears to result in meaningful changes across multiple symptom and biological domains. Whereas Emotional Processing Theory (Foa & Kozak, 1986) proposes that PE engages patients in exposure processes that promote habituation to trauma-related stimuli, and potentially extinction of fear conditioned responses (Norrholm & Jovanovic, 2010), the mechanisms involved in this process are not well understood. Few studies have examined whether PE actually achieves the predicted extinction and habituation processes (Jaycox, Foa, & Morral, 1998; Van Minnen & Hagenaars, 2002). Even fewer studies have examined whether the magnitude of change in these processes is related to treatment response (Rauch, Foa, Furr, & Filip, 2004). To date, studies of habituation/extinction processes in PE have focused on patients’ ratings of their subjective distress (Subjective Units of Distress; SUDS). However, psychophysiological measures can provide

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additional, and more objective, insight into habituation/extinction processes and related underlying biological changes not easily assessed via self-report indices. The acoustic startle response is manifested in the reflexive contraction of skeletal, facial, and neck muscles in humans and animals (Koch, 1999; Lang, Bradley, & Cuthbert, 1990). Acoustic startle of the orbicularis oculi muscles that results in reflexive eyelid closure has been extensively studied using auditory probes, (e.g., 108 dB white noise; see Norrholm et al., 2011). The acoustic startle response is well-suited for studying the acquisition and extinction of fear due to its direct links to the amygdala (Davis, Walker, Miles, & Grillon, 2010; Walker, Toufexis, & Davis, 2003) and sympathetic nervous system, which helps prepare an organism for fight or flight (Koch, 1999). Furthermore, patient report of exaggerated startle response is considered a hallmark symptom of PTSD (APA, 2013) thought to exemplify the hyperarousal experienced by and observed among patients. Researchers have offered different explanations for exaggerated startle in PTSD (Pole, 2007), and it remains unclear whether it represents a premorbid vulnerability or reflects a development or psychopathological process resulting from exposure to one or more traumatic events. Fear-potentiated startle (FPS) paradigms examine relative increases in the startle reflex during exposure to a cue associated with an aversive stimulus (e.g., shock), as compared with startle responses elicited to neutral cues. Previous studies of FPS in PTSD patients have shown increased startle to anxiety-provoking aspects of the experimental context (Grillon & Morgan, 1999; Grillon, Morgan, Davis, & Southwick, 1998; Grillon et al., 2009; Morgan, Grillon, Southwick, Davis, & Charney, 1995) as well as a heightened response during fear expression (i.e., “fear load” during the acquisition and extinction of fear-potentiated startle in the presence of reinforced conditioned stimuli (Norrholm et al., 2011, 2013)). However, research on PTSD patients’ startle responses to cues that are specifically related to their traumas is limited. To better understand psychophysiological responses to trauma memories and related stimuli in this population, it may be informative to examine startle responses in the presence of trauma-relevant cues. Whereas the trauma cues may not represent the exact nature of the specific trauma experienced by the individual, it is plausible that general combat-related stimuli could elicit substantial anxiety and arousal among patients whose traumas are combat-related (Maren, Phan, & Liberzon, 2013). Furthermore, understanding how startle responses among patients with PTSD change over the course of PTSD treatment is not well understood. Recent research suggests that exaggerated startle in patients with PTSD can be modified with treatment. One study found that female assault survivors with PTSD who responded to Cognitive Processing Therapy (CPT) showed a significant reduction in their acoustic startle response at post-treatment compared to treatment nonresponders (Griffin, Resick, & Galovski, 2012). Despite these encouraging results, replication with larger samples is necessary to confirm the reliability of this effect. In the present study, we investigated whether PTSD treatment would promote reduced hyperarousal associated with sympathetic nervous system arousal, as evidenced by attenuation in trauma-relevant, cue-potentiated, acoustic startle responses among combat Veterans. To this end, we compared acoustic startle responses in the context of trauma-relevant cues among PTSD treatment responders versus nonresponders in Veterans from Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF, respectively). Responders were defined as Veterans who evidenced a 50% reduction on the Clinician-Administered PTSD Scale scores, (CAPS; Blake, Weathers, Nagy, & Kaloupek, 1995) from pre to post-treatment, while nonresponders had less than 50% symptom reduction. This conservative measure of treatment response was used in order to increase the likelihood to detect

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differences between the groups. The present study was part of a broader study that examined the efficacy of PE compared to a control treatment (Present Centered Therapy; PCT) for OEF/OIF Veterans with PTSD. We expected treatment responders to show larger reductions in acoustic startle potentiated by trauma-related stimuli, across the course of the treatment, compared to treatment nonresponders. 1. Methods 1.1. Participants Thirty-six OEF/OIF Veterans with PTSD of at least three months duration were recruited from an outpatient PTSD clinic within the VA Ann Arbor Healthcare System (VAAAHS). A standard intake evaluation using the Mini International Neuropsychiatric Interview (MINI; Sheehan et al., 1998) and the CAPS was used to determine diagnostic eligibility for the study. PTSD clinic providers with specialty mental health training at the Master’s degree level or higher completed all assessments. Individuals were excluded from participating if they had: (1) elevated risk of self-harm requiring immediate, focused intervention; (2) unmanaged psychosis or bipolar disorder; (3) alcohol or substance dependence in the past 3 months; (4) employment requiring night-shifts; (5) changes to psychoactive medications in the past 4 weeks; or (6) medications that may alter HPA axis indices. Eligible Veterans who consented to participate were randomly assigned to receive up to twelve, 80min sessions of PE or PCT. The protocol was approved by the VA Ann Arbor Healthcare System Human Subjects Committee. Among 36 Veterans who were eligible for the study, 26 completed treatment. To be included in the final analysis, participants had to have complete data for all three assessments (i.e., pre, mid, post). Among the 26 participants who completed the treatment, four did not complete all three assessments and five had startle data from one or more of the assessments that could not be scored. The final sample consisted of 17 participants (16 male) with an age range of 24–45 years (M = 32.82, SD = 7). Seven (41%) were married, two (12%) remarried, four (23.5%) divorced and four (23.5%) never married. One (6%) identified as Asian, 5 (28%) as black, and 11 (64%) as white. Eight participants received PE, and 9 received PCT. 1.2. Procedure Participants completed major assessments at pre-, mid-, and post-treatment. Assessments lasted approximately 3 h and consisted of an interview, symptom-based questionnaires, psychophysiological assessment, and salivary cortisol collection (Rauch, King, Rothbaum, Smith, & Liberzon, 2011). The startle paradigm was presented as part of a longer psychophysiological assessment protocol. EMG was used to index the startle eyeblink reflex using two 5-mm Ag/AgCl electrodes filled with electrolyte gel placed on the right orbicularis oculi muscle. Electrode placement was consistent with published startle guidelines (Blumenthal et al., 2005); one was placed 1 cm below the pupil, another was placed 1 cm below the lateral canthus, and the ground was placed over the mastoid process. Participants were seated approximately 36 in front of a 19 LCD computer monitor where they viewed study stimuli. The visual and auditory features of the sequences were presented on the computer screen via SuperLab 4.0 for Windows (Cedrus Corp., San Pedro, CA). Startle eyeblink responses were acquired using the EMG 100c module of the BIOPAC MP150 psychophysiological recording system (Biopac Systems, Inc., Camino Goleta, CA) with Acqknowledge data collection software version 4.2.0 for Windows (1995–2011). Startle eyeblink data were sampled at 1000 kHz, amplified by a

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gain of 5000, filtered (10–500 Hz band pass) and rectified (time constant = 30 ms) on-line. The bioamplification system was interfaced with the laboratory computer using the National Instruments A/D and digital I/O card. Participants were instructed to focus their attention on the computer monitor during startle portion of the study. They were presented with two blocks of visual stimuli, each consisting of three 2-min visual sequences taken from a Virtual Iraq/Afghanistan environment that has been used to treat PTSD (Roy et al., 2010). Two sequences were presented from the perspective of a soldier in either the gun turret (Humvee Turret) or inside the cabin (Humvee Convoy) of a Humvee as their convoy is confronted with improvised explosive devices (IEDs) and ambushes. The third sequence was from the perspective of a soldier on foot patrol through a village marketplace replete with explosions and terrorists firing rocket-propelled grenades (City). The virtual trauma-relevant sequences were separated by inter-trial intervals showing a blank blue screen for 30 s (termed “Blue Square”). A total of 42 startle eliciting probe presentations of a 40 ms, 108 dB(A) white noise stimuli with instantaneous rise time (0–1 ms) were presented across the two blocks (Blocks 1 and 2) at each assessment. The startle probes were presented as follows: first, the session began with 2 startle probes during a Blue Square. Next, the first block of visual stimuli presented a total of 20 startle-eliciting probes (i.e., 5 probes during the Humvee Turret sequence; 5 probes during the Humvee Convoy sequence; 4 probes during the City sequence; and 2 probes during each of three Blue Squares for 6 total probes during Blue Square). The block was then repeated. In both blocks, startle probes were presented randomly throughout the video, with 9–22 s between probes as in previous work (e.g., Norrholm et al., 2013). 1.3. Data scoring Startle eyeblink EMG was scored in accordance with the startle guidelines (Blumenthal et al., 2005). Startle response was defined as the peak rectified EMG value within a window of 20–150 ms following the onset of the startle stimulus. Startle magnitudes were calculated by averaging peak startle response, including trials with a value of zero, during trauma-relevant sequences and blue squares separately. Startle magnitudes elicited during the blue squares provided a baseline level of responding. A t-test revealed overall larger startle response magnitude during Trauma, compared to Blue Square stimuli (p < .001). Finally, we calculated trauma-potentiated startle by subtracting startle response during the blue square from startle response during the trauma-relevant stimuli; the difference score represented the amplification in startle due to threat stimuli. All calculations were computed across both blocks of the task at each assessment. Trials with responses outside the scoring window, spontaneous blinks, or significant noise in the EMG signal were considered invalid responses and were excluded from all subsequent analyses. Participants who did not complete all three assessments or who had missing data on at least 50% of the trials for any of the three assessments (pre, mid, post) were also excluded from analyses. 1.4. Data analysis To examine the differences in the treatment effects on traumapotentiated startle between responders and nonresponders, we conducted a 2 (group: responder, nonresponder) by 3 (assessment; pre-, mid-, or post-treatment) repeated measures ANOVA on trauma potentiated startle response. Polynomial trends were also examined to further investigate the nature of trauma potentiated startle response patterns over time. To examine habituation of startle responses within each assessment period, we conducted

Trauma Potenated Startle

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50 45 40 35 30 25 20 15 10 5 0

Non-Responder Responder

Pre

Mid

Post

Fig. 1. Trauma-potentiated startle magnitude as a function of treatment assessment timepoint and responder status (difference in startle during trauma stimulus–blue square; N = 17).

a 2 (group: responder, nonresponder) by 2 (stimulus: Blue Square, Trauma) by 3 (assessment: pre-, mid-, or post-treatment) repeated measures ANOVA on habituation scores, calculated as startle magnitude during Block 1 minus Block 2. An alpha level of .05 was used for all statistical comparisons. For each analysis we used Greenhouse–Geisser correction (Blumenthal et al., 2005). 2. Results Responders (N = 8, 7 male) and nonresponders (N = 9, all male) did not differ based on total CAPS score pre-treatment (responder M = 73, SD = 17, nonresponder M = 78, SD = 11), t(15) < 1, p > .40; BDI score pre-treatment (responder M = 23.4, SD = 11, nonresponder M = 25, SD = 8), t(15) < 1, p > .70; or age (responder M = 32.5, SD = 8, nonresponder M = 33, SD= 8), t(15) < 1, p > .80. As intended, following treatment, CAPS scores differed significantly between groups (responder M = 19.3, SD = 10, nonresponder M = 63.5, SD = 15), t(15) = 7.93, p < .001). To investigate trauma-potentiated startle over the course of treatment, we conducted a repeated measures ANOVA with assessment (pre, mid, and post) as a within-subjects factor and responder status (responder, nonresponder) as a between-subjects factor. Results revealed no significant main or interaction effects; however, the polynomial trend analysis revealed a significant quadratic interaction between responder status and assessment time, F(1, 15) = 4.59, p < .05. Results suggested that treatment responders showed a differential pattern of startle response over the course of treatment compared to nonresponders1 . While responders exhibited an increase in trauma potentiated startle at mid-assessment followed by a subsequent reduction in trauma potentiated startle (inverted U-shape), nonresponders exhibited a relatively flat profile in trauma potentiated startle over time (see Fig. 1). This may suggest that responders engaged with the stimuli during the treatment phase more than the nonresponders. Next, we examined whether startle response habituation within the assessment (Block 1–Block 2) differed across conditions by conducting a repeated measures ANOVA with assessment (pre, mid, and post) and stimulus (Blue Square, Trauma) as withinsubjects factors and responder status (responder, nonresponder) as a between group factor. Results did not reveal any significant main or interaction effects (all ps > .05), confirming that habituation to the startle probe throughout the task did not differ between responders and nonresponders, and was not affected by stimulus type or assessment time.

1 Analyses were repeated with removal of the one female participant and the pattern remained unchanged.

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3. Discussion The purpose of this study was to investigate changes in traumapotentiated startle responses over the course of treatment for PTSD. Overall, trauma-potentiated startle responses showed a different pattern over across treatment among responders compared to nonresponders. Specifically, results suggested that patients who responded to PTSD treatment exhibited an increase in traumapotentiated startle at the mid-treatment assessment followed by a subsequent decrease at the post treatment assessment. This quadratic response pattern in startle potentiation among treatment responders may suggest that patients who respond to treatment are able to engage with the emotional content of their trauma memory as indexed by increased trauma potentiated startle at the midpoint of treatment compared to when they first initiate treatment. Furthermore, a patient’s treatment engagement, as demonstrated by elevated fear responding, may be a critical element in successful PTSD treatment. In comparison, treatment nonresponders demonstrated a more consistent pattern of trauma-potentiated startle over time, suggesting that they may not have fully engaged with trauma relevant stimuli, or may have used more avoidance-based coping during simulated combat scenes. While the sample size is small and replication is needed, this differential pattern suggests a potential mechanism of response to exposure therapy that is consistent with Emotional Processing Theory. Specifically, our results support the assertion that patients may need to allow themselves to connect with the emotional content of their trauma memory (such as fear, sadness, etc.) and experience heightened psychophysiological responding during treatment in order to have the largest reductions in PTSD symptoms. Considering the role of the amygdala in modulating startle responses (Davis, 1992), engagement of the amygdala during exposure therapy may be vital for successful habituation/extinction, which can be indexed using startle eyeblink paradigms. Future research is needed to elucidate such supposition. This is consistent with recent findings of enhanced fear extinction after amygdala activation (Monfils, Cowansage, Klann, & LeDoux, 2009) and consistent with Emotional Processing Theory that suggests fear activation is necessary for therapeutic response. Contrary to expectations, treatment responders did not show greater habituation to trauma-relevant stimuli than nonresponders. Moreover, neither treatment responders nor nonresponders showed habituation to the trauma-relevant stimuli across assessment blocks. It is possible that patients showed no evidence of within-assessment startle response habituation because two blocks were insufficient to assess habituation. However, previous studies using the same startle probe have shown that PTSD patients may have more difficulty with habituation compared to controls, who showed a significant reduction of startle response after only 7 trials (Jovanovic, Norrholm, Sakoman-Jambrosic, Esterjaher, & Kozaric-Kovacic, 2009). In the present study, the trauma stimuli would contribute to the lack of habituation; it is possible that presenting several blocks of trauma stimuli would allow for habituation to occur. Replication and extension to larger samples may help to clarify. It is possible that we obtained null results because our study paradigm evoked an emotion other than fear, such as anger. OEF/OIF Veterans with PTSD (Rothbaum et al., in press). Therefore, evidence suggests that our paradigm has effectively potentiated the startle reflex. The present study included several strengths. First, participants were OEF/OIF/OND Veterans presenting to the VA for treatment. The fact that these Veterans were seeking treatment independent of study participation reduces the likelihood of demand effects that could influence the results. Second, our definition of treatment response included participants in both PE and PCT groups. Although

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we were primarily interested in the effects of PE treatment on startle response, inclusion of treatment responders among PCT recipients enabled us to examine overall impact of effective treatment on startle response. Third, our study included assessments at multiple time points, which enabled us to examine treatment response over time. However, our study also included some limitations. First, the small sample size could have contributed to the lack of significant effects detected in the current study. In the absence of a notreatment control condition, we are unable to distinguish whether startle responses to the stimuli were potentiated beyond what would be expected in a healthy sample. In addition, the absence of a neutral visual stimulus in the startle task matched to the trauma stimulus on complexity and other stimulus variables prevents us from concluding that startle potentiation was due solely to the trauma content as opposed to more complex stimuli during trauma scenes vs. blue squares. Moreover, the paradigm used was not optimized for startle eyeblink elicitation, as there were various sounds throughout the video that could have interfered with responding to the startle stimulus. This could have resulted in faster habituation to the startle stimulus and possibly blunted trauma-potentiated startle responses. Future studies should attempt to replicate this study using a paradigm optimized for startle data collection, a healthy control group, a larger sample, and a neutral visual stimulus during the startle task. The present study is the first to examine the impact of PTSD treatment on trauma-potentiated startle responses using traumarelevant virtual scenarios. Identifying the mechanisms through which exposure therapy acts on PTSD symptoms has the potential to improve our understanding of the development and pathophysiology of PTSD. Investigation of mechanisms involved in exposure therapy may also inform development of more efficient and targeted treatment techniques and clarify patient prognosis. Furthermore, better understanding of how exposure therapy works to reduce symptoms may implicate novel pre-morbid biological risk factors for PTSD. A recent review (Pitman et al., 2012) suggested that, whereas researchers have made great progress in uncovering the biological underpinnings of PTSD, we have yet to develop effective translational models that clarify the links between biology and treatment. In sum, research on mechanisms involved in successful PTSD treatment is needed to improve understanding of biology, psychology, and treatment for PTSD. References APA. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing. Blake, D. D., Weathers, F. W., Nagy, L. M., & Kaloupek, D. G. (1995). The development of a Clinician-Administered PTSD Scale. Journal of Traumatic Stress, 8(1), 75–90. Blumenthal, T. D., Cuthbert, B. N., Filion, D. L., Hackley, S., Lipp, O. V., & Van Boxtel, A. (2005). Committee report: guidelines for human startle eyeblink electromyographic studies. Psychophysiology, 42, 1–15. Bradley, R., Greene, J., Russ, E., Dutra, L., & Westen, D. (2005). A multidimensional meta-analysis of psychotherapy for PTSD. American Journal of Psychiatry, 162(2), 214–227. Cahill, S. P., Rauch, S. A., Hembree, E. A., & Foa, E. B. (2003). Effect of cognitivebehavioral treatments for PTSD on anger. Journal of Cognitive Psychotherapy, 17(2), 113–131. Cloitre, M., Koenen, K. C., Cohen, L. R., & Han, H. (2002). Skills training in affective and interpersonal regulation followed by exposure: a phase-based treatment for PTSD related to childhood abuse. Journal of Consulting and Clinical Psychology, 70(5), 1067–1074. Davis, M. (1992). The role of the amygdala in conditioned fear. In: J. P. Aggleton (Ed.), The amygdala: neurobiological aspects of emotion, memory, and mental dysfunction (pp. 255–306). New York, NY, USA: Wiley-Liss. Davis, M., Walker, D. L., Miles, L., & Grillon, C. (2010). Phasic vs sustained fear in rats and humans: role of the extended amygdala in fear vs anxiety. Neuropsychopharmacology, 35, 105–135. Foa, E. B., Hembree, E. A., Cahill, S. P., Rauch, S. A. M., Riggs, D. S., Feeny, N. C., & Yadin, E. (2005). Randomized trial of prolonged exposure for posttraumatic stress disorder with and without cognitive restructuring: outcome at academic and community clinics. Journal of Consulting and Clinical Psychology, 73(5), 953–964.

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Changes in trauma-potentiated startle with treatment of posttraumatic stress disorder in combat Veterans.

Emotional Processing Theory proposes that habituation to trauma-related stimuli is an essential component of PTSD treatment. However, the mechanisms u...
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