Dataset Information

L-DOPA and consolidation of fear extinction learning among women with posttraumatic stress disorder.

ABSTRACT: This study tested whether L-DOPA delivered during the consolidation window following fear extinction learning reduces subsequent fear responding among women with PTSD. Adult women diagnosed with PTSD completed a contextual fear acquisition and extinction task during fMRI and then immediately received either placebo (n?=?34), 100/25?mg L-DOPA/carbidopa (n?=?28), or 200/50?mg L-DOPA/carbidopa (n?=?29). Participants completed a resting-state scan before the task and again 45?min following drug ingestion to characterize effects of L-DOPA on extinction memory neural reactivation patterns during consolidation. Twenty-four hours later, participants returned for tests of context renewal, extinction recall, and reinstatement during fMRI with concurrent skin conductance responding (SCR) assessment. Both active drug groups demonstrated increased reactivation of extinction encoding in the amygdala during the post-task resting-state scan. For SCR data, both drug groups exhibited decreased Day 2 reinstatement across all stimuli compared to placebo, and there was some evidence for decreased context renewal to the fear stimulus in the 100?mg group compared to placebo. For imaging data, both drug groups demonstrated decreased Day 2 reinstatement across stimuli in a bilateral insula network compared to placebo. There was no evidence in SCR or neural activity that L-DOPA improved extinction recall. Reactivation of extinction encodings in the amygdala during consolidation on Day 1 predicted Day 2 activation of the insula network. These results support a role for dopamine during the consolidation window in boosting reactivation of amygdala extinction encodings and reducing reinstatement, but not improving extinction recall, in women with PTSD.

SUBMITTER: Cisler JM

PROVIDER: S-EPMC7429959 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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L-DOPA and consolidation of fear extinction learning among women with posttraumatic stress disorder.

Cisler Josh M JM Privratsky Anthony A AA Sartin-Tarm Anneliis A Sellnow Kyrie K Ross Marisa M Weaver Shelby S Hahn Emily E Herringa Ryan J RJ James George Andrew GA Kilts Clinton D CD

Translational psychiatry 20200815 1

This study tested whether L-DOPA delivered during the consolidation window following fear extinction learning reduces subsequent fear responding among women with PTSD. Adult women diagnosed with PTSD completed a contextual fear acquisition and extinction task during fMRI and then immediately received either placebo (n = 34), 100/25 mg L-DOPA/carbidopa (n = 28), or 200/50 mg L-DOPA/carbidopa (n = 29). Participants completed a resting-state scan before the task and again 45 min following drug inge ...[more]

PMID: 32801342

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Project description:BackgroundFear responding in posttraumatic stress disorder (PTSD) is sexually heterogeneous and varies with hormonal fluctuations throughout the menstrual cycle. While research suggests that estrogen levels affect PTSD symptoms among women, there is a dearth of research on modulatory effects of estrogen on fear responding among women with PTSD, and neural outcome measures are lacking.MethodsA sample of 42 women with PTSD underwent 2 consecutive alternating blocks of fear conditioning and extinction training, during which a CS+ conditioned stimulus, but not a CS-, predicted the occurrence of an electric shock in an acquisition context but not in an extinction context. Assayed saliva determined estradiol levels. Skin conductance response and whole-brain voxelwise activity during functional magnetic resonance imaging were outcome variables in linear mixed-effects models, with estradiol level, PTSD severity, and task contrasts as predictors.ResultsSkin conductance response exhibited a significant estradiol × PTSD severity × habituation interaction (t = 3.180, p = .002), such that PTSD severity was correlated with increased arousal responding between training blocks among women with lower estradiol (t = -3.985, p < .001) but not higher estradiol (t = 0.550, p = .583). Voxelwise activity also demonstrated an identical three-way interaction within dorsomedial prefrontal cortex and anterior insula clusters. The skin conductance response and imaging interactions between PTSD severity and estradiol were not specific to conditioned stimulus type or context.ConclusionsEstradiol moderated the relationship between PTSD severity and arousal response habituation between fear conditioning and extinction training sessions, such that high estradiol protected against the negative impact of severe PTSD symptoms on fear habituation. These findings suggest that estrogen enhances habituation among women with severe PTSD, potentially influencing the efficacy of extinction-based therapies.

Project description:Fear conditioning is an established model for investigating posttraumatic stress disorder (PTSD). However, symptom triggers may vaguely resemble the initial traumatic event, differing on a variety of sensory and affective dimensions. We extended the fear-conditioning model to assess generalization of conditioned fear on fear processing neurocircuitry in PTSD. Military veterans (n=67) consisting of PTSD (n=32) and trauma-exposed comparison (n=35) groups underwent functional magnetic resonance imaging during fear conditioning to a low fear-expressing face while a neutral face was explicitly unreinforced. Stimuli that varied along a neutral-to-fearful continuum were presented before conditioning to assess baseline responses, and after conditioning to assess experience-dependent changes in neural activity. Compared with trauma-exposed controls, PTSD patients exhibited greater post-study memory distortion of the fear-conditioned stimulus toward the stimulus expressing the highest fear intensity. PTSD patients exhibited biased neural activation toward high-intensity stimuli in fusiform gyrus (P<0.02), insula (P<0.001), primary visual cortex (P<0.05), locus coeruleus (P<0.04), thalamus (P<0.01), and at the trend level in inferior frontal gyrus (P=0.07). All regions except fusiform were moderated by childhood trauma. Amygdala-calcarine (P=0.01) and amygdala-thalamus (P=0.06) functional connectivity selectively increased in PTSD patients for high-intensity stimuli after conditioning. In contrast, amygdala-ventromedial prefrontal cortex (P=0.04) connectivity selectively increased in trauma-exposed controls compared with PTSD patients for low-intensity stimuli after conditioning, representing safety learning. In summary, fear generalization in PTSD is biased toward stimuli with higher emotional intensity than the original conditioned-fear stimulus. Functional brain differences provide a putative neurobiological model for fear generalization whereby PTSD symptoms are triggered by threat cues that merely resemble the index trauma.

Dataset Information

L-DOPA and consolidation of fear extinction learning among women with posttraumatic stress disorder.

Publications

L-DOPA and consolidation of fear extinction learning among women with posttraumatic stress disorder.

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