Dataset Information

Deep Brain Stimulation in Animal Models of Fear, Anxiety, and Posttraumatic Stress Disorder.

ABSTRACT: Although medications and psychotherapy are often effective for the treatment of posttraumatic stress disorder (PTSD), 20-30% of patients do not respond to these conventional therapies. In psychiatry, DBS has been either approved or is currently under investigation for different disorders. At present, whether DBS may be used to treat PTSD remains unknown. Preclinical research may provide the scientific rationale for helping conceive and further improve such trials. Some of the animal models commonly used to date are more suitable for investigating mechanisms of anxiety and fear than the long-lasting behavior that characterized PTSD. That said, mechanisms and neurocircuits involved in paradigms such as fear conditioning and extinction share several common features with those of PTSD. In this article, we review preclinical studies in which electrical stimulation has been delivered to animal models of PTSD-like behavior. In those studies, commonly targeted regions were the basolateral amygdala, ventral striatum, hippocampus, and prefrontal cortex. Overall, stimulation delivered at high frequencies to most of these targets improved fear extinction and anxiety-like behavior. Though further research is certainly needed, promising findings from DBS studies in animals are encouraging and suggest a positive future perspective for the field.

SUBMITTER: Reznikov R

PROVIDER: S-EPMC5061888 | biostudies-other | 2016 Nov

REPOSITORIES: biostudies-other

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Deep Brain Stimulation in Animal Models of Fear, Anxiety, and Posttraumatic Stress Disorder.

Reznikov Roman R Binko Mary M Nobrega José N JN Hamani Clement C

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20160302 12

Although medications and psychotherapy are often effective for the treatment of posttraumatic stress disorder (PTSD), 20-30% of patients do not respond to these conventional therapies. In psychiatry, DBS has been either approved or is currently under investigation for different disorders. At present, whether DBS may be used to treat PTSD remains unknown. Preclinical research may provide the scientific rationale for helping conceive and further improve such trials. Some of the animal models commo ...[more]

PMID: 26932819

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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.

Project description:OBJECTIVE:Posttraumatic stress disorder (PTSD) is a highly prevalent psychiatric disorder associated with disruption in social and occupational function. Transcranial magnetic stimulation (TMS) represents a novel approach to PTSD, and intermittent theta-burst stimulation (iTBS) is a new, more rapid administration protocol with data supporting efficacy in depression. The authors conducted a sham-controlled study of iTBS for PTSD. METHODS:Fifty veterans with PTSD received 10 days of sham-controlled iTBS (1,800 pulses/day), followed by 10 unblinded sessions. Primary outcome measures included acceptability (retention rates), changes in PTSD symptoms (clinician- and self-rated), quality of life, social and occupational function, and depression, obtained at the end of 2 weeks; analysis of variance was used to compare active with sham stimulation. Secondary outcomes were evaluated 1 month after treatment, using mixed-model analyses. Resting-state functional MRI was acquired at pretreatment baseline on an eligible subset of participants (N=26) to identify response predictors. RESULTS:Retention was high, side effects were consistent with standard TMS, and blinding was successful. At 2 weeks, active iTBS was significantly associated with improved social and occupational function (Cohen's d=0.39); depression was improved with iTBS compared with the sham treatment (d=-0.45), but the difference fell short of significance, and moderate nonsignificant effect sizes were observed on self-reported PTSD symptoms (d=-0.34). One-month outcomes, which incorporated data from the unblinded phase of the study, indicated superiority of active iTBS on clinician- and self-rated PTSD symptoms (d=-0.74 and -0.63, respectively), depression (d=-0.47), and social and occupational function (d=0.93) (all significant). Neuroimaging indicated that clinical improvement was significantly predicted by stronger (greater positive) connectivity within the default mode network and by anticorrelated (greater negative) cross-network connectivity. CONCLUSIONS:iTBS appears to be a promising new treatment for PTSD. Most clinical improvements from stimulation occurred early, which suggests a need for further investigation of optimal iTBS time course and duration. Consistent with previous neuroimaging studies of TMS, default mode network connectivity played an important role in response prediction.

Dataset Information

Deep Brain Stimulation in Animal Models of Fear, Anxiety, and Posttraumatic Stress Disorder.

Publications

Deep Brain Stimulation in Animal Models of Fear, Anxiety, and Posttraumatic Stress Disorder.

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