Presence and acquired origin of reduced recall for fear extinction in PTSD: Results of a twin study

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Abstract

Recall of fear extinction, which is thought to aid in recovery from a psychologically traumatic event, is hypothesized to be deficient in post-traumatic stress disorder (PTSD), but this has not yet been demonstrated in the laboratory, nor has its origin been investigated. To address these two issues, 14 pairs of monozygotic twins discordant for combat exposure, in 7 of which the combat-exposed twin had PTSD, underwent a two-day fear conditioning and extinction procedure. On Day 1, subjects viewed colored light conditioned stimuli, some of which were paired with mild electric shock, followed by extinction of the conditioned responses. On Day 2, recall of Day 1 extinction learning (i.e., extinction retention) was assessed. Skin conductance response (SCR) was the dependent measure. There were no group differences during acquisition or extinction learning. However, a significant PTSD Diagnosis (in the exposed twin) × combat Exposure interaction emerged during extinction recall, with the PTSD combat veterans having larger SCRs than their own co-twins, and than the non-PTSD combat veterans and their co-twins. These results indicate that retention of extinction of conditioned fear is deficient in PTSD. Furthermore, they support the conclusion that this deficit is acquired as a result of combat trauma leading to PTSD, rather than being a predisposing factor to developing PTSD upon the stress of combat.

Introduction

Extinction is the reduction in conditioned responses (CRs) that occurs when the conditioned stimulus (CS) no longer predicts the unconditioned stimulus (US). Post-traumatic stress disorder (PTSD) involves learned fear (Rothbaum and Davis, 2003). Abnormally high psychophysiological conditioned responses to reminders of traumatic events can persist as long as 50 years following its cessation (Orr et al., 1993). These data suggest that a deficit in either extinction learning or retention of that learning may underlie failure to recover from the effects of the traumatic stressor (Rauch et al., 2006, Milad et al., 2006, Davis et al., 2006, Sotres-Bayon et al., 2004, Maren and Quirk, 2004). Consistent with this view, slower extinction of corrugator electromyogram responses were found to represent a pre-trauma risk factor for PTSD-related symptoms following a traumatic event (Guthrie and Bryant, 2006). Although studies have supported impaired extinction learning in PTSD (Blechert et al., 2007, Orr et al., 2000, Peri et al., 2000), no previous studies have reported deficits in extinction retention.

If extinction retention is deficient in PTSD, it could represent either an acquired PTSD sign, e.g., result from the traumatic stress that caused the PTSD and/or the stress of having PTSD, or a pre-existing vulnerability factor for developing PTSD upon traumatic exposure. We have been studying monozygotic twin pairs discordant for combat exposure to address the pre-existing vs. acquired origin of biological abnormalities found in PTSD (Pitman et al., 2006). If an abnormality is genetic or due to environmental influences shared by twins during their rearing, i.e., is a “familial” vulnerability factor, then it should be present in the non-trauma-exposed co-twins of trauma-exposed twins with PTSD. Alternatively, if the abnormality results from the traumatic event, then their combat-unexposed co-twins should not share it.

To test the presence and origin of deficient extinction retention in PTSD, we used a two-day fear conditioning and extinction protocol that has been successfully employed in persons without mental disorders (Milad et al., 2005a, Milad et al., 2006a). On the first day, subjects underwent fear conditioning in one virtual context followed by extinction learning in another virtual context. On the second day, extinction recall was tested in the previous extinction context. The conditioned stimuli (CSs) were colored lights that were presented within both contexts. This protocol differed from other studies that examined conditioning and extinction learning in PTSD (for example, Orr et al., 2000) in two ways: (1) conditioning and extinction learning were conducted in two different virtual contexts, and (2) an extinction retention test was conducted 24 h after extinction learning.

Section snippets

Subjects

Subjects were drawn from a pool of identical twins who had participated in a previous study of physiological responses to loud tones. A description of the recruitment strategy, and characteristics of the participant population has been reported elsewhere (Orr et al., 2003). Fourteen pairs of male monozygotic twins participated. One “exposed” (Ex) twin had served in the Vietnam combat theater, whereas his “unexposed” (Ux) co-twin had not. Of the Ex twins, seven developed combat-related PTSD

Acquisition (Day 1)

We examined the maximum SCRs to the CS+ and CS− during the last four of the five acquisition trials (Fig. 1A). There was significant a Stimulus effect, with SCRs to the CS+ greater than to the CS−: F1,11.3 = 8.6, p = 0.007.

Extinction learning (Day 1)

We examined the average SCRs to the last two late Extinction Learning Phase trials (Fig. 1B). Subjects in all groups extinguished approximately 70% of the acquired conditioned responses. There were no significant differences in the levels of extinction across all groups.

Extinction recall (Day 2)

We

Discussion

Although the acquisition and extinction of conditioned fear were intact across all groups on Day 1, the retention of this extinction measured on Day 2 was deficient in the PTSD combat veterans. Moreover, this deficit was not present in their co-twins, suggesting that deficient extinction retention represents an acquired PTSD sign rather than a familial vulnerability factor. The extinction retention index we observed in the present study was lower than what we have previously reported (Milad et

Conflict of interest

Dr. Rauch receives occasional honoraria or consulting fees from Cyberonics, Novartis, Sepracor, and Neurogen; he has also received funding for research at Massachusetts General Hospital from Cephalon and Medtronic Inc.; finally, past fellows in his research division have received funding from Pfizer. Dr. Pitman in the past has received consulting fees from Pfizer, Glaxo-Smith-Kline, Johnson & Johnson, Sanofi Aventis, and Actelion, but he has no ongoing business relationships with any of these

Contributors

Author M.R. Milad designed the experimental protocol, collected the data, conducted preliminary analyses, and wrote the first draft of the manuscript. Author N. Lasko conducted the clinical assessment for all subjects. Author S.P. Orr assisted in statistical analysis and writing of the manuscript. Author S.L. Rauch assisted in the design of the experimental protocol and data interpretation. Author R.K. Pitman conducted the statistical analyses, and participated in the interpretation and writing

Role of funding source

Funding for this study was provided by a grant from the National Institute of Mental Health (2R01MH54636) to R.K.P. The NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Acknowledgements

The United States Department of Veterans Affairs has provided financial support for the development and maintenance of the Vietnam Era Twin (VET) Registry. Numerous organizations have provided invaluable assistance in the conduct of this study, including: Department of Defense; National Personnel Records Center, National Archives and Records Administration; the Internal Revenue Service; National Institutes of Health; National Opinion Research Center; National Research Council, National Academy

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