Fear Extinction in Traumatized Civilians with Posttraumatic Stress Disorder: Relation to Symptom Severity

Norrholm, Seth D.; Jovanović, Tanja; Olin, Ilana W.; Sands, Lauren; Karapanou, India; Bradley, Bekh; Ressler, Kerry J.

doi:10.1016/j.biopsych.2010.09.013

Cited by 347 publications

(383 citation statements)

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“…In addition, IMO possesses construct validity in that both human PTSD patients and severely stressed animals show alterations in the regulation of the HPA axis (Yehuda, 2009). Further, EXT impairments have been reported in clinical populations with fear-related disorders (Wessa and Flor 2007;Norrholm et al, 2011;Milad et al, 2013). Concordantly, a single IMO exposure also leads to a deficit in EXT of conditioned fear and enhanced anxiety-like behavior evaluated with the elevated plus maze (Andero et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

Sawamura

Klengel

Armario

et al. 2015

Neuropsychopharmacol

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Posttraumatic stress disorder (PTSD) is both a prevalent and debilitating trauma-related disorder associated with dysregulated fear learning at the core of many of its signs and symptoms. Improvements in the currently available psychological and pharmacological treatments are needed in order to improve PTSD treatment outcomes and to prevent symptom relapse. In the present study, we used a putative animal model of PTSD that included presentation of immobilization stress (IMO) followed by fear conditioning (FC) a week later. We then investigated the acute effects of GR receptor activation on the extinction (EXT) of conditioned freezing, using dexamethasone administered systemically which is known to result in suppression of the HPA axis. In our previous work, IMO followed by tone-shockmediated FC was associated with impaired fear EXT. In this study, we administered dexamethasone 4 h before EXT training and then examined EXT retention (RET) 24 h later to determine whether dexamethasone suppression rescued EXT deficits. Dexamethasone treatment produced dose-dependent enhancement of both EXT and RET. Dexamethasone was also associated with reduced amygdala Fkbp5 mRNA expression following EXT and after RET. Moreover, DNA methylation of the Fkbp5 gene occurred in a dose-dependent and time course-dependent manner within the amygdala. Additionally, we found dynamic changes in epigenetic regulation, including Dnmt and Tet gene pathways, as a function of both fear EXT and dexamethasone suppression of the HPA axis. Together, these data suggest that dexamethasone may serve to enhance EXT by altering Fkbp5-mediated glucocorticoid sensitivity via epigenetic regulation of Fkbp5 expression.

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Section: Discussionmentioning

confidence: 99%

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

Sawamura

Klengel

Armario

et al. 2015

Neuropsychopharmacol

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“…We conducted this pilot study to test the following hypotheses: (1) whether active tDCS during extinction learning compared to sham stimulation would augment late extinction learning, and (2) whether the effects of tDCS during extinction learning vs. during extinction consolidation, that is, immediately after extinction learning, on early extinction recall tested 24 hr later would differ. This idea of stimulating immediately after extinction learning, during consolidation, was based on reports that PTSD is associated with impairments in extinction recall (Garfinkel et al., 2014; Milad et al., 2008, 2009; Norrholm et al., 2011), even though extinction can be acquired. Therefore, testing the effects of tDCS during consolidation of fear extinction provides a first step to examining various possibly important time points in which noninvasive brain stimulation could be used to enhance components of extinction learning and memory (Marin & Milad, 2015).…”

Section: Introductionmentioning

confidence: 99%

Transcranial direct current stimulation may modulate extinction memory in posttraumatic stress disorder

et al. 2017

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BackgroundAbnormalities in fear extinction and recall are core components of posttraumatic stress disorder (PTSD). Data from animal and human studies point to a role of the ventromedial prefrontal cortex (vmPFC) in extinction learning and subsequent retention of extinction memories. Given the increasing interest in developing noninvasive brain stimulation protocols for psychopathology treatment, we piloted whether transcranial direct current stimulation (tDCS) during extinction learning, vs. during consolidation of extinction learning, might improve extinction recall in veterans with warzone‐related PTSD.MethodsTwenty‐eight veterans with PTSD completed a 2‐day Pavlovian fear conditioning, extinction, and recall paradigm. Participants received one 10‐min session of 2 mA anodal tDCS over AF3, intended to target the vmPFC. Fourteen received tDCS that started simultaneously with extinction learning onset, and the remaining 14 participants received tDCS during extinction consolidation. Normalized skin conductance reactivity (SCR) was the primary outcome measure. Linear mixed effects models were used to test for effects of tDCS on late extinction and early extinction recall 24 hr later.ResultsDuring early recall, veterans who received tDCS during extinction consolidation showed slightly lower SCR in response to previously extinguished stimuli as compared to veterans who received tDCS simultaneous with extinction learning (p = .08), generating a medium effect size (Cohen's d = .38). There was no significant effect of tDCS on SCR during late extinction.ConclusionsThese preliminary findings suggest that testing the effects of tDCS during consolidation of fear extinction may have promise as a way of enhancing extinction recall.

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“…Other studies have tested for sex differences in fear extinction learning, a form of learning through which animals learn to inhibit responding to cues that once signaled an aversive event. Over the last several years, the study of fear extinction has received considerable attention (Milad and Quirk 2012) due in part to the fact that humans with PTSD display impaired extinction (Milad et al 2009b;Norrholm et al 2011). Recent findings in rodents are mixed with regard to sex differences in fear extinction with several studies reporting no difference between males and females (Milad et al 2009a;Rey et al 2014;Gruene et al 2015a), while others have found that females show weaker fear extinction (Baran et al 2009(Baran et al , 2010Matsuda et al 2015;Fenton et al 2016).…”

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confidence: 99%

Response-specific sex difference in the retention of fear extinction

Voulo

Parsons

2017

Learn. Mem.

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Fear conditioning studies in rodents allow us to assess vulnerability factors which might underlie fear-based psychopathology such as post-traumatic stress disorder (PTSD). Despite PTSD being more prevalent in females than males, very few fear conditioning studies in rodents have tested females. Our study assessed fear conditioning and extinction in male and female rats using both fear-potentiated startle and freezing behavior as measures. Rats were trained to fear cues that predicted the occurrence of shock and then subsequently exposed to an extinction training procedure where the cue was presented repeatedly in the absence of shock. Retention of the extinction memory was assessed the next day. Our results showed that females exhibited less retention of fear extinction, but only when measured by fear-potentiated startle. Our results highlight the importance of using multiple indices of fear behavior, particularly when comparing sexes on measures of extinction learning.Not all individuals who experience trauma during their lifetime will develop post-traumatic stress disorder (PTSD). One of the greatest risk factors for developing this disorder is being female, with the lifetime prevalence rate twice as high for women as it is for men (Kessler et al. 1995;Kilpatrick et al. 2013). Fear conditioning studies in rodents allow us to study the behavioral and neural mechanisms that may underlie PTSD (Parsons and Ressler 2013), yet very few fear conditioning studies in rodents have used females as subjects (Lebron-Milad and Milad 2012). Despite the increased prevalence of PTSD and other fear and anxiety-based disorders in females, nonhuman animal studies testing for sex differences in fear conditioning have largely failed to capture this difference.Fear conditioning studies typically use a procedure in which a discrete cue (e.g., auditory stimulus) signals the occurrence of an aversive stimulus, usually a brief shock. Under normal circumstances, animals learn to fear the discrete cue associated with shock and will also learn to fear the context (i.e., place) in which shock occurs. A handful of studies have directly compared animals of both sexes on tests of cued and contextual fear conditioning. Some of these reports have shown that while males and females exhibit equivalent levels of fear conditioning to discrete cues (Maren et al. 1994;Baran et al. 2009;Milad et al. 2009a;Barker and Galea 2010;Gruene et al. 2015a;Fenton et al. 2016), males often show evidence of better contextual conditioning (Maren et al. 1994;Chang et al. 2009;Barker and Galea 2010). Other studies have tested for sex differences in fear extinction learning, a form of learning through which animals learn to inhibit responding to cues that once signaled an aversive event. Over the last several years, the study of fear extinction has received considerable attention (Milad and Quirk 2012) due in part to the fact that humans with PTSD display impaired extinction (Milad et al. 2009b;Norrholm et al. 2011). Recent findings in rodents are mixed with regard t...

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Fear Extinction in Traumatized Civilians with Posttraumatic Stress Disorder: Relation to Symptom Severity

Cited by 347 publications

References 35 publications

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

Transcranial direct current stimulation may modulate extinction memory in posttraumatic stress disorder

Response-specific sex difference in the retention of fear extinction

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