Hippocampal volume and volume asymmetry prospectively predict PTSD symptom emergence among Iraq-deployed soldiers.

BACKGROUND: Evidence suggests a link between smaller hippocampal volume (HV) and post-traumatic stress disorder (PTSD). However, there has been little prospective research testing this question directly and it remains unclear whether smaller HV confers risk or is a consequence of traumatization and PTSD. METHODS: U.S. soldiers (N = 107) completed a battery of clinical assessments, including structural magnetic resonance imaging pre-deployment. Once deployed they completed monthly assessments of traumatic-stressors and symptoms. We hypothesized that smaller HV would potentiate the effects of traumatic stressors on PTSD symptoms in theater. Analyses evaluated whether total HV, lateral (right v. left) HV, or HV asymmetry (right - left) moderated the effects of stressor-exposure during deployment on PTSD symptoms. RESULTS: Findings revealed no interaction between total HV and average monthly traumatic-stressors on PTSD symptoms b = -0.028, p = 0.681 [95% confidence interval (CI) -0.167 to 0.100]. However, in the context of greater exposure to average monthly traumatic stressors, greater right HV was associated with fewer PTSD symptoms b = -0.467, p = 0.023 (95% CI -0.786 to -0.013), whereas greater left HV was unexpectedly associated with greater PTSD symptoms b = 0.435, p = 0.024 (95% CI 0.028-0.715). CONCLUSIONS: Our findings highlight the importance of considering the complex role of HV, in particular HV asymmetry, in predicting the emergence of PTSD symptoms in response to war-zone trauma.

CO2 reactivity as a biomarker of exposure-based therapy non-response: study protocol.

BACKGROUND: Exposure-based therapy is an effective first-line treatment for anxiety-, obsessive-compulsive, and trauma- and stressor-related disorders; however, many patients do not improve, resulting in prolonged suffering and poorly used resources. Basic research on fear extinction may inform the development of a biomarker for the selection of exposure-based therapy. Growing evidence links orexin system activity to deficits in fear extinction and we have demonstrated that reactivity to an inhaled carbon dioxide (CO2) challenge-a safe, affordable, and easy-to-implement procedure-can serve as a proxy for orexin system activity and predicts fear extinction deficits in rodents. Building upon this basic research, the goal for the proposed study is to validate CO2 reactivity as a biomarker of exposure-based therapy non-response. METHODS: We will assess CO2 reactivity in 600 adults meeting criteria for one or more fear- or anxiety-related disorders prior to providing open exposure-based therapy. By incorporating CO2 reactivity into a multivariate model predicting treatment non-response that also includes reactivity to hyperventilation as well as a number of related predictor variables, we will establish the mechanistic specificity and the additive predictive utility of the potential CO2 reactivity biomarker. By developing models independently within two study sites (University of Texas at Austin and Boston University) and predicting the other site's data, we will validate that the results are likely to generalize to future clinical samples. DISCUSSION: Representing a necessary stage in translating basic research, this investigation addresses an important public health issue by testing an accessible clinical assessment strategy that may lead to a more effective treatment selection (personalized medicine) for patients with anxiety- and fear-related disorders, and enhanced understanding of the mechanisms governing exposure-based therapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05467683 (20/07/2022).

Technology-enhanced in vivo exposures in Prolonged Exposure for PTSD: A pilot randomized controlled trial.

In vivo exposures (IVEs) are a key component of exposure-based treatments, during which patients approach fear-provoking, yet safe, situations in "real life." This pilot study assessed the use of a wearable technology (Bio Ware) during IVEs to enhance Prolonged Exposure (PE) therapy for PTSD. Bio Ware provides a clinician dashboard with real-time physiological and subjective data for clinicians to use for virtually guided IVEs. Participants (N = 40) were randomized to a Guided group that received standard PE and virtual, clinician-guided IVEs with the Bio Ware device, or a Non-Guided group that received standard PE and used the Bio Ware device on their own for IVEs. Multilevel linear models with bootstrapping were completed on the intent-to-treat (ITT; N = 39) and per-protocol samples (PP; n = 23), defined as completing at least eight sessions of PE and using the Bio Ware system during ≥ 1 IVEs. In the PP sample, there were significant effects of treatment condition (b = -14.55, SE = 1.47, 95% CI [-17.58, -11.78], p < .001) and time (b = -1.98, SE = 0.25, 95% CI [-2.47, -1.48], p < .001). While both groups showed reductions in PTSD symptoms, the Guided group evidenced significantly greater reductions than the Non-Guided group. These findings demonstrate the feasibility and safety of leveraging Bio Ware for virtual, clinician-guided IVEs during PE therapy for PTSD and suggest that virtual, clinician-guided exposures may enhance treatment outcomes. CLINICAL TRIAL REGISTRATION: NCT04471207.

The Role of Social Support in Coping with Psychological Trauma: An Integrated Biopsychosocial Model for Posttraumatic Stress Recovery.

This theoretical review proposes an integrated biopsychosocial model for stress recovery, highlighting the interconnectedness of intra- and interpersonal coping processes. The proposed model is conceptually derived from prior research examining interpersonal dynamics in the context of stressor-related disorders, and it highlights interconnections between relational partner dynamics, perceived self-efficacy, self-discovery, and biological stress responsivity during posttraumatic recovery. Intra- and interpersonal processes are discussed in the context of pre-, peri-, and post-trauma stress vulnerability as ongoing transactions occurring within the individual and between the individual and their environment. The importance of adopting an integrated model for future traumatic stress research is discussed. Potential applications of the model to behavioral interventions are also reviewed, noting the need for more detailed assessments of relational dynamics and therapeutic change mechanisms to determine how relational partners can most effectively contribute to stress recovery.

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.

Emotional Processing of Imaginal Exposures Predicts Symptom Improvement: Therapist Ratings Can Assess Trajectory in Prolonged Exposure for Posttraumatic Stress Disorder.

Research on mechanisms of change in prolonged exposure therapy (PE), an evidence-based treatment for posttraumatic stress disorder (PTSD), is ongoing. Two putative mechanisms of change are engagement during imaginal exposure and trauma-related belief change. The PE Therapist Questionnaire (PETQ), a novel measure based on the emotional processing theory underlying PE, was developed as a practical tool for therapists to use to assess (a) patient engagement during imaginal exposures and (b) perspective shifts during postimaginal processing. Patients (N = 151) at a U.S. Veterans Affairs medical center PTSD specialty clinic completed self-report measures of PTSD and depression symptoms prior to sessions. Study therapists (n = 17) completed the PETQ postsession. Rational construction and psychometric analyses suggested a two-component solution for the PETQ: imaginal and processing. The imaginal factor did not relate to PTSD and depression symptoms. The processing factor correlated with current and next-session PTSD and depression symptoms, with medium effect sizes, rs = -.41 to -.45, ps < .001. Controlling for current-session PTSD and depression, a higher level of processing predicted lower next-session PTSD severity, with a small effect size, ß = -.38, p < .04. Postexposure emotional processing, which supports positive changes in maladaptive trauma-related beliefs and tolerance of emotional distress, predicted future symptom improvement, highlighting the importance of processing components in PE. Further, the use of therapist observations may offer ancillary methods less influenced by correlation of within-patient subjective ratings and concomitant risk of construct overlap in mechanisms research.

Cortisol, Testosterone, and Prospective Risk for War-zone Stress-Evoked Depression.

Introduction: The major challenges of efforts to reveal biological risk factors and biomarkers of depression include the complexity of underlying systems, interactions with other systems, and contextual factors governing their expression. Altered endocrine function is believed to be a central contributor to depressive illness, but across studies, evidence for a link between endocrine markers and depression has been mixed, inconclusive, or conditional in nature. In the present study, we evaluated basal testosterone (T), cortisol (C), and CO2 inhalation-stress-reactivity measures of these hormones (TR, CR) as pre-deployment moderators of the later impact of war-zone stressors on depression symptoms in-theater. Materials and Methods: At pre-deployment, U.S. soldiers (N = 120) completed demographic, clinical and hormone measures, and during deployment, they completed monthly, web-based assessments of war-zone stressors and depression symptoms (N = 533 observations). Mixed effects models estimated the effects of the pre-deployment hormone profiles in moderating war-zone stressors' impact on in-theater depression. Models also tested whether hormonally linked risk for later stress-evoked depression depends on pre-existing depression. Results: Controlling for pre-deployment depression, high T was protective; whereas TR had depressogenic effects that were amplified by pre-deployment depression. Further, high C was protective, but heightened CR was depressogenic, but only among those with elevated pre-deployment depression. Conclusions: Findings highlight the importance of examining basal and reactivity measures of endocrine function, and use of prospective, longitudinal models to test hypothesized causal pathways associated with depression vulnerability in the war-zone. Results also suggest that pre-existing depression and cortisol may work in tandem to increase vulnerability for later stress-evoked depression in the war-zone.

Dual-hormone stress reactivity predicts downstream war-zone stress-evoked PTSD.

BACKGROUND: The crucial role of the hypothalamic-pituitary-adrenal axis (HPA) in stress-related homeostasis suggests dysregulated HPA involvement in the pathogenesis of post-traumatic stress disorder (PTSD), yet most studies examining linkages between HPA axis measures and PTSD have yielded null findings. One untested explanation for this inconsistency is a failure to account for simultaneous adrenal and gonadal influence. Here we tested the singular and interactive effects of cortisol (CR) and testosterone (TR) reactivity as moderators of war-zone stress evoked PTSD emergence in the war-zone. METHODS: U.S. soldiers (N=120) scheduled for deployment to Iraq completed pre-deployment measures of CR and TR stress reactivity to a CO2 inhalation challenge. Once deployed, monthly assessments of exposure to traumatic war-zone stressors and PTSD symptoms were collected via a web-based assessment system. RESULTS: Cortisol hypo-reactivity potentiated the pathogenic impact of war-zone stressors only in soldiers for whom the CO2 challenge did not elevate testosterone, suggesting that the dual hormone stress reactivity profile of blunted cortisol and testosterone may confer increased risk for PTSD emergence by potentiating the pathogenic effects of war-zone stressors. CONCLUSIONS: Findings underscore the utility of assessing both HPA and HPG stress reactivity when assessing PTSD vulnerability and may help inform efforts for enhanced soldier screening and inoculation to war-zone stressors.

The role of perceived threat in the emergence of PTSD and depression symptoms during warzone deployment.

OBJECTIVE: Numerous studies have shown that level of exposure to combat-related stressors is a robust risk factor for posttraumatic stress disorder (PTSD) and depression among military personnel deployed to a warzone. Threat perception of warzone experiences assessed retrospectively has been consistently linked to increased risk for PTSD and depression months or even years after returning from deployment. However, little is known about concurrent relations between perceived threat, deployment stress, and stress-related symptoms during deployment. Using a novel in-theater web-based assessment system, we investigated the unique and joint contribution of threat perception and deployment stressors in predicting the emergence of PTSD and depression symptoms during deployment. METHOD: Soldiers (N = 150) completed assessments of deployment stressors, perceived threat, PTSD symptoms, and depression symptoms throughout deployment to Iraq. RESULTS: Results revealed that perceived threat potentiated the increase in PTSD symptoms as a result of increases in deployment stressors. In contrast, perceived threat, but not warzone stressors, uniquely predicted depression symptoms. CONCLUSIONS: Results highlight the important role of threat perception as a risk marker for the acute experience of depression and PTSD symptoms during deployment. (PsycINFO Database Record

Effects of post-session administration of methylene blue on fear extinction and contextual memory in adults with claustrophobia.

OBJECTIVE: Preclinical studies have shown that low-dose methylene blue increases mitochondrial cytochrome oxidase activity in the brain and improves memory retention after learning tasks, including fear extinction. The authors report on the first controlled experiment to examine the memory-enhancing effects of posttraining methylene blue administration on retention of fear extinction and contextual memory following fear extinction training. METHOD: Adult participants displaying marked claustrophobic fear were randomly assigned to double-blind administration of 260 mg of methylene blue (N=23) or administration of placebo (N=19) immediately following six 5-minute extinction trials in an enclosed chamber. Retesting occurred 1 month later to assess fear renewal as indexed by peak fear during exposure to a nontraining chamber, with the prediction that the effects of methylene blue would vary as a function of fear reduction achieved during extinction training. Incidental contextual memory was assessed 1 and 30 days after training to assess the cognitive-enhancing effects of methylene blue independent of its effects on fear attenuation. RESULTS: Consistent with predictions, participants displaying low end fear posttraining showed significantly less fear at the 1-month follow-up if they received methylene blue posttraining compared with placebo. In contrast, participants displaying moderate to high levels of posttraining fear tended to fare worse at the follow-up if they received methylene blue posttraining. Methylene blue's enhancement of contextual memory was unrelated to initial or posttraining claustrophobic fear. CONCLUSIONS: Methylene blue enhances memory and the retention of fear extinction when administered after a successful exposure session but may have a deleterious effect on extinction when administered after an unsuccessful exposure session.

Sex differences in the cognitive effects of tobacco abstinence: a pilot study.

Despite significant research demonstrating the deleterious effects of tobacco abstinence on memory, and research showing substantial sex differences in nicotine withdrawal and memory processes, there has been scant work on how males and females might differ in the effects of tobacco abstinence on memory and cognition. Using a standard recognition memory task, we conducted a pilot study to examine how 24 hours of tobacco abstinence in moderate to heavy smokers would affect memory in males and females. Twenty-five moderate to heavy smokers were tested following a period of smoking normally and following 24 hours of tobacco abstinence. At each session, participants completed a recognition memory task in which items were studied under full- and divided-attention conditions (a standard manipulation of memory encoding) as well as tests of passive short-term and working memory (forward and backward digit span). Tobacco abstinence significantly reduced memory performance under full attention conditions for males but not for females. A significant main effect of smoking status in which abstinence significantly reduced performance, as well as a main effect of encoding condition (divided attention < full attention), were found. Our results demonstrate that there may be substantial sex differences in the cognitive effects of tobacco abstinence. While preliminary, the data suggest the need for further, more extensive study of how males and females differ during tobacco abstinence. Such information will inform the best strategies for tobacco cessation efforts.

Evidence that episodic memory impairment during tobacco abstinence is independent of attentional mechanisms.

Previous studies have demonstrated reductions in episodic memory during nicotine withdrawal. However, these studies have been unable to dissociate memory reductions from losses in attention associated with tobacco abstinence. In the present study, the authors sought to determine whether episodic memory reduction is a primary effect of nicotine withdrawal during tobacco abstinence. Heavy smokers were tested when smoking normally and following 24 hrs of abstinence. Participants were tested with a recognition memory task in which items were studied under full and divided attention conditions. Forward digit span and backward digit span were also included as control measures. Withdrawal was associated with a reduction in memory performance that was independent of attention at encoding. The authors conclude that impairment of episodic memory is a primary effect of nicotine withdrawal during tobacco abstinence. Further research is required to determine if this is associated with continued use of tobacco and cessation failures.