Singular and combined effects of transcranial infrared laser stimulation and exposure therapy on pathological fear: a randomized clinical trial.

BACKGROUND: Preclinical findings suggest that transcranial infrared laser stimulation (TILS) improves fear extinction learning and cognitive function by enhancing prefrontal cortex (PFC) oxygen metabolism. These findings prompted our investigation of treating pathological fear using this non-invasive stimulation approach either alone to the dorsolateral PFC (dlPFC), or to the ventromedial PFC (vmPFC) in combination with exposure therapy. METHODS: Volunteers with pathological fear of either enclosed spaces, contamination, public speaking, or anxiety-related bodily sensations were recruited for this randomized, single-blind, sham-controlled trial with four arms: (a) Exposure + TILS_vmPFC (n = 29), (b) Exposure + sham TILS_vmPFC (n = 29), (c) TILS_dlPFC alone (n = 26), or (d) Sham TILS _dlPFC alone (n = 28). Post-treatment assessments occurred immediately following treatment. Follow-up assessments occurred 2 weeks after treatment. RESULTS: A total of 112 participants were randomized [age range: 18-63 years; 96 females (85.71%)]. Significant interactions of Group × Time and Group × Context indicated differential treatment effects on retention (i.e. between time-points, averaged across contexts) and on generalization (i.e. between contexts, averaged across time-points), respectively. Among the monotherapies, TILS_dlPFC outperformed SHAM_dlPFC in the initial context, b = -13.44, 95% CI (-25.73 to -1.15), p = 0.03. Among the combined treatments, differences between EX + TILS_vmPFC and EX + SHAM_vmPFC were non-significant across all contrasts. CONCLUSIONS: TILS to the dlPFC, one of the PFC regions implicated in emotion regulation, resulted in a context-specific benefit as a monotherapy for reducing fear. Contrary to prediction, TILS to the vmPFC, a region implicated in fear extinction memory consolidation, did not enhance exposure therapy outcome.

Use of Cannabidiol (CBD) oil in the treatment of PTSD: Study design and rationale for a placebo-controlled randomized clinical trial.

BACKGROUND: The burden of illness for PTSD is staggering and confers significant interference in work, social functioning, as well as increased risk for other physical and mental health problems. Recently, there's been considerable attention paid to the potential therapeutic use of cannabidiol (CBD) products in the treatment of a variety of physical and mental health problems. The endocannabinoid system (ECS) is a logical therapeutic target for combating PTSD and other fear-based disorders given that cannabinoid receptors and other molecular mediators crucial for ECS signaling are richly expressed in a variety of brain regions that govern the regulation of learned fear and defensive behavior. METHODS: This is an 8-week single-site Phase II randomized double-blind placebo-controlled fixed dose clinical trial. Participants recruited throughout the United States (N = 150) meeting DSM-5 criteria for posttraumatic stress disorder are randomly assigned to one of three treatment arms: (a) 300 mg CBD Isolate; (b) 300 mg CBD Broad Spectrum; and (c) Placebo oil. The primary outcome is PTSD symptom severity as indexed by the PTSD Checklist for DSM-5 (PCL-5) assessed at post treatment (Week 9) and follow-up (Week 13). Secondary outcomes including patient-rated depression, overall disability, anxiety, quality of life, and alcohol use are assessed weekly throughout the trial. Safety and CBD adherence are assessed daily throughout the trial. CONCLUSION: This is the first placebo-controlled clinical trial investigating (a) CBD for the treatment of PTSD; and (b) the first study to test the relative efficacy of CBD Isolate vs CBD Broad Spectrum. Trial registration ClinicalTrials.gov registered (12/12/2019), trial identifier NCT04197102. PROTOCOL VERSION: issued 08/04/2022, protocol amendment number #2019-05-0123.

Impact of cannabidiol-rich hemp extract oil on reconsolidation disruption of naturalistic interoceptive aversive memory in humans: Protocol for a randomized clinical trial.

BACKGROUND: Preclinical experiments with rodents demonstrate that cannabidiol (CBD), the non-psychotomimetic constituent of the Cannabis sativa plant, disrupts reconsolidation of aversive memories conditioned in the laboratory when administered within the memory reconsolidation window (< 6 h. post-retrieval) by indirectly activating cannabinoid type-1 (CB1) receptors in the dorsal anterior cingulate cortex (dACC). Based on these findings, we aim to test whether administration of 300 mg CBD-rich hemp extract oil following fear reactivation of an aversive interoceptive threat memory can disrupt reconsolidation of naturalistic aversive memories in humans. More specifically, naturalistic interoceptive aversive memories, a form of transdiagnostic fear memory that contributes to the pathogenesis of fear-related disorders such as panic disorder, posttraumatic stress disorder (PTSD), and illness anxiety disorder. METHODS: For this proof-of-concept, placebo-controlled double-blind trial, volunteers (n = 99) reporting elevated fears of somatic sensations will be stratified on biological sex and randomized to one of three intervention arms: (a). CBD-rich oil administered within the reconsolidation window, (b) Placebo oil administered within the reconsolidation window; or (c) CBD-rich oil administered outside of the reconsolidation window. Change in emotional reactivity to a 35% CO2 challenge from baseline to two-week follow-up will serve as our primary outcome. CONCLUSION: Study findings may contribute towards the development of a novel brief transdiagnostic intervention guided by reconsolidation theory for individuals prone to fear-related psychiatric disorders. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04726475.

Exploratory and Confirmatory Bayesian Networks Identify the Central Role of Non-judging in Symptoms of Depression.

OBJECTIVES: Depression is a highly heterogeneous disorder, and meta-analyses of mindfulness-based interventions show moderate efficacy for reducing depressive symptoms. However, the mechanisms governing their efficacy remain unclear, highlighting the need for hypothesis-generating analyses to guide future research. METHODS: We used Bayesian network analysis in three cross-sectional samples (N = 1135) of undergraduates and participants from the community to identify links between individual symptoms of depression and specific facets of mindfulness. In two exploratory studies, we assessed depression using the Patient Health Questionnaire (n = 384) or the Depression Anxiety and Stress Scale (n = 350) and mindfulness using the Five-Facet Mindfulness Scale. RESULTS: Across these samples and measures, exploratory analyses indicated that non-judging was a central bridge between facets of mindfulness and symptoms of depression. We confirmed this finding in a pre-registered replication (n = 401) using a recently developed confirmatory testing framework for network analysis. Non-judging was consistently a central bridge in the networks and specifically linked to the symptoms of depression related to feelings of failure and worthlessness. CONCLUSIONS: These findings provide strong evidence that non-judging is an essential feature of mindfulness in the context of depression and provides direction for future research testing mindfulness-oriented treatment prescriptions for depression. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12671-021-01726-1.

tDCS-Augmented in vivo exposure therapy for specific fears: A randomized clinical trial.

Exposure therapy is highly effective for anxiety-related disorders, but there is a need for enhancement. Recent trials of adjunctive neuromodulation have shown promise, warranting evaluation of transcranial direct current stimulation (tDCS) as an augmentation. In a double-blind, placebo-controlled trial, contamination- and animal-phobic participants (N = 49) were randomized to active tDCS (1.7 mA, 20 min; n = 27), or sham tDCS (1.7 mA, 30 s; n = 22), followed by 30 min of in-vivo exposure. Active tDCS targeted excitation of the left mPFC and inhibition of the right dlPFC; polarity was counterbalanced for controls. We predicted tDCS would result in accelerated and better maintained gains, contingent on the subsequent in-session response, and baseline negative prognostic indicators. Consistent with predictions, tDCS promoted engagement and reductions in threat appraisals during exposure, and greater reductions in distress and threat appraisals through 1-month, although effects did not uniformly generalize. tDCS was most beneficial given high phobic severity, anxiety sensitivity, and a suboptimal early response. tDCS may promote engagement and response among individuals who are resistant or refractory to standard treatment. tDCS should be applied to more severe anxiety-related disorders, with parameters yoked to individual differences to improve outcomes in exposure-based interventions.

Singular and combined effects of transcranial infrared laser stimulation and exposure therapy: A randomized clinical trial.

This RCT will test whether transcranial infrared laser stimulation (TILS) administered immediately following standard exposure therapy enhances the retention of fear extinction for naturally acquired pathological fear. A second aim is to investigate the efficacy of TILS as a stand-alone intervention for reducing pathological fear. Participants with elevated fear in any one of the following four domains: (a) fear of enclosed spaces, (b) fear of contamination, (c) fear of public speaking, or (d) fear of anxiety (i.e., anxiety sensitivity) will be recruited from introductory psychology classes and the greater Austin community. Participants displaying marked fear responding will be stratified on baseline fear responding and fear domain and randomized to one of four treatment arms: (1) Exposure + TILS, (2) Exposure + sham TILS, (3) TILS alone, or (4) Sham TILS alone. We anticipate that TILS will enhance exposure therapy outcome relative to sham TILS and that this enhancement effect will be most pronounced for (a) those displaying higher baseline fear responding, and (b) those showing greater fear reduction during exposure. Study rationale as well as additional predictions and clinical implications are discussed.