Acupuncture for Combat-Related Posttraumatic Stress Disorder: A Randomized Clinical Trial.

Importance: Current interventions for posttraumatic stress disorder (PTSD) are efficacious, yet effectiveness may be limited by adverse effects and high withdrawal rates. Acupuncture is an emerging intervention with positive preliminary data for PTSD. Objective: To compare verum acupuncture with sham acupuncture (minimal needling) on clinical and physiological outcomes. Design, Setting, and Participants: This was a 2-arm, parallel-group, prospective blinded randomized clinical trial hypothesizing superiority of verum to sham acupuncture. The study was conducted at a single outpatient-based site, the Tibor Rubin VA Medical Center in Long Beach, California, with recruitment from April 2018 to May 2022, followed by a 15-week treatment period. Following exclusion for characteristics that are known PTSD treatment confounds, might affect biological assessment, indicate past nonadherence or treatment resistance, or indicate risk of harm, 93 treatment-seeking combat veterans with PTSD aged 18 to 55 years were allocated to group by adaptive randomization and 71 participants completed the intervention protocols. Interventions: Verum and sham were provided as 1-hour sessions, twice weekly, and participants were given 15 weeks to complete up to 24 sessions. Main Outcomes and Measures: The primary outcome was pretreatment to posttreatment change in PTSD symptom severity on the Clinician-Administered PTSD Scale-5 (CAPS-5). The secondary outcome was pretreatment to posttreatment change in fear-conditioned extinction, assessed by fear-potentiated startle response. Outcomes were assessed at pretreatment, midtreatment, and posttreatment. General linear models comparing within- and between-group were analyzed in both intention-to-treat (ITT) and treatment-completed models. Results: A total of 85 male and 8 female veterans (mean [SD] age, 39.2 [8.5] years) were randomized. There was a large treatment effect of verum (Cohen d, 1.17), a moderate effect of sham (d, 0.67), and a moderate between-group effect favoring verum (mean [SD] Δ, 7.1 [11.8]; t90 = 2.87, d, 0.63; P = .005) in the intention-to-treat analysis. The effect pattern was similar in the treatment-completed analysis: verum d, 1.53; sham d, 0.86; between-group mean (SD) Δ, 7.4 (11.7); t69 = 2.64; d, 0.63; P = .01). There was a significant pretreatment to posttreatment reduction of fear-potentiated startle during extinction (ie, better fear extinction) in the verum but not the sham group and a significant correlation (r = 0.31) between symptom reduction and fear extinction. Withdrawal rates were low. Conclusions and Relevance: The acupuncture intervention used in this study was clinically efficacious and favorably affected the psychobiology of PTSD in combat veterans. These data build on extant literature and suggest that clinical implementation of acupuncture for PTSD, along with further research about comparative efficacy, durability, and mechanisms of effects, is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT02869646.

Acupuncture for combat post-traumatic stress disorder: trial development and methodological approach for a randomized controlled clinical trial.

BACKGROUND: Post-traumatic stress disorder (PTSD) is a significant public health problem, affecting approximately 7% of the general population and 13-18% of the combat Veteran population. The first study using acupuncture for PTSD in a civilian population showed large pre- to post-treatment effects for an empirically developed verum protocol, which was equivalent to group cognitive behavior therapy and superior to a wait-list control. The primary objective of this study is to determine both clinical and biological effects of verum acupuncture for combat-related PTSD in treatment-seeking US Veterans. METHODS: This is a two-arm, parallel-group, prospective randomized placebo-controlled clinical trial. The experimental condition is verum acupuncture and the placebo control is sham (minimal) acupuncture in 1-h sessions, twice a week for 12 weeks. Ninety subjects will provide adequate power and will be allocated to group by an adaptive randomization procedure. The primary outcome is change in PTSD symptom severity from pre- to post-treatment. The secondary biological outcome is change from pre- to post-treatment in psychophysiological response, startle by electromyographic (EMG) eyeblink. Assessments will be conducted at pre-, mid-, post-, and 1-month post-treatment, blind to group allocation. Intent-to-treat analyses will be conducted. DISCUSSION: The study results will be definitive because both clinical and biological outcomes will be assessed and correlated. Issues such as the number needed for recruitment and improvement, use of sham acupuncture, choice of biological measure, and future research need will be discussed. TRIAL REGISTRATION: ClinicalTrials.gov NCT02869646 . Registered on 17 August 2016.

Neuroendocrine biomarkers of prolonged exposure treatment response in military-related PTSD.

Posttraumatic stress disorder (PTSD) is associated with dysregulation of the neuroendocrine system, including cortisol, allopregnanolone, and pregnanolone. Preliminary evidence from animal models suggests that baseline levels of these biomarkers may predict response to PTSD treatment. We report the change in biomarkers over the course of PTSD treatment. Biomarkers were sampled from individuals participating in (1) a randomized controlled trial comparing a web-version of Prolonged Exposure (Web-PE) therapy to in-person Present-Centered Therapy (PCT) and (2) from individuals participating in a nonrandomized effectiveness study testing PE delivered in-person as part of an intensive outpatient PTSD program. We found that higher cortisol reactivity during script-driven imagery was associated with higher baseline PTSD severity and that baseline allopregnanolone, pregnanolone, and cortisol reactivity were associated with PTSD treatment responder status over the course of intensive outpatient treatment. These findings demonstrate that peripherally assessed biomarkers are associated with PTSD severity and likelihood of successful treatment outcome of PE delivered daily over two weeks. These assessments could be used to determine which patients are likely to respond to treatment and which patients require augmentation to increase the likelihood of optimal response to PTSD treatment.

Smaller Hippocampal Volume in Posttraumatic Stress Disorder: A Multisite ENIGMA-PGC Study: Subcortical Volumetry Results From Posttraumatic Stress Disorder Consortia.

BACKGROUND: Many studies report smaller hippocampal and amygdala volumes in posttraumatic stress disorder (PTSD), but findings have not always been consistent. Here, we present the results of a large-scale neuroimaging consortium study on PTSD conducted by the Psychiatric Genomics Consortium (PGC)-Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) PTSD Working Group. METHODS: We analyzed neuroimaging and clinical data from 1868 subjects (794 PTSD patients) contributed by 16 cohorts, representing the largest neuroimaging study of PTSD to date. We assessed the volumes of eight subcortical structures (nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, and lateral ventricle). We used a standardized image-analysis and quality-control pipeline established by the ENIGMA consortium. RESULTS: In a meta-analysis of all samples, we found significantly smaller hippocampi in subjects with current PTSD compared with trauma-exposed control subjects (Cohen's d = -0.17, p = .00054), and smaller amygdalae (d = -0.11, p = .025), although the amygdala finding did not survive a significance level that was Bonferroni corrected for multiple subcortical region comparisons (p < .0063). CONCLUSIONS: Our study is not subject to the biases of meta-analyses of published data, and it represents an important milestone in an ongoing collaborative effort to examine the neurobiological underpinnings of PTSD and the brain's response to trauma.

Relationship between Toxoplasma gondii seropositivity and acoustic startle response in an inner-city population.

Toxoplasma gondii (TOXO) is a neuroinvasive protozoan parasite that induces the formation of persistent cysts in mammalian brains. It infects approximately 1.1million people in the United States annually. Latent TOXO infection is implicated in the etiology of psychiatric disorders, especially schizophrenia (SCZ), and has been correlated with modestly impaired cognition. The acoustic startle response (ASR) is a reflex seen in all mammals. It is mediated by a simple subcortical circuit, and provides an indicator of neural function. We previously reported the association of TOXO with slowed acoustic startle latency, an index of neural processing speed, in a sample of schizophrenia and healthy control subjects. The alterations in neurobiology with TOXO latent infection may not be specific to schizophrenia. Therefore we examined TOXO in relation to acoustic startle in an urban, predominately African American, population with mixed psychiatric diagnoses, and healthy controls. Physiological and diagnostic data along with blood samples were collected from 364 outpatients treated at an inner-city hospital. TOXO status was determined with an ELISA assay for TOXO-specific IgG. A discrete titer was calculated based on standard cut-points as an indicator of seropositivity, and the TOXO-specific IgG concentration served as serointensity. A series of linear regression models were used to assess the association of TOXO seropositivity and serointensity with ASR magnitude and latency in models adjusting for demographics and psychiatric diagnoses (PTSD, major depression, schizophrenia, psychosis, substance abuse). ASR magnitude was 11.5% higher in TOXO seropositive subjects compared to seronegative individuals (p=0.01). This effect was more pronounced in models with TOXO serointensity that adjusted for sociodemographic covariates (F=7.41, p=0.0068; F=10.05, p=0.0017), and remained significant when psychiatric diagnoses were stepped into the models. TOXO showed no association with startle latency (t=0.49, p=0.63) in an unadjusted model, nor was TOXO associated with latency in models that included demographic factors. After stepping in individual psychiatric disorders, we found a significant association of latency with a diagnosis of PTSD (F=5.15, p=0.024), but no other psychiatric diagnoses, such that subjects with PTSD had longer startle latency. The mechanism by which TOXO infection is associated with high startle magnitude is not known, but possible mechanisms include TOXO cyst burden in the brain, parasite recrudescence, or molecular mimicry of a host epitope by TOXO. Future studies will focus on the neurobiology underlying the effects of latent TOXO infection as a potential inroad to the development of novel treatment targets for psychiatric disease.

Heart rate response to fear conditioning and virtual reality in subthreshold PTSD.

Posttraumatic stress disorder (PTSD) is a significant health concern for U.S. military service members (SMs) returning from Afghanistan and Iraq. Early intervention to prevent chronic disability requires greater understanding of subthreshold PTSD symptoms, which are associated with impaired physical health, mental health, and risk for delayed onset PTSD. We report a comparison of physiologic responses for recently deployed SMs with high and low subthreshold PTSD symptoms, respectively, to a fear conditioning task and novel virtual reality paradigm (Virtual Iraq). The high symptom group demonstrated elevated heart rate (HR) response during fear conditioning. Virtual reality sequences evoked significant HR responses which predicted variance of the PTSD Checklist-Military Version self-report. Our results support the value of physiologic assessment during fear conditioning and combat-related virtual reality exposure as complementary tools in detecting subthreshold PTSD symptoms in Veterans.

Dark-enhanced startle responses and heart rate variability in a traumatized civilian sample: putative sex-specific correlates of posttraumatic stress disorder.

OBJECTIVE: Trauma is associated with increased risk for anxiety disorders such as posttraumatic stress disorder (PTSD). To further understand biologic mechanisms of PTSD, we examined the dark-enhanced startle response, a psychophysiological correlate of anxiety, and heart rate variability (HRV) in traumatized individuals with and without PTSD. The associations of these measures with PTSD may be sex-specific because of their associations with the bed nucleus of the stria terminalis, a sexually dimorphic brain structure in the limbic system that is approximately 2.5 times larger in men than in women. METHODS: The study sample (N = 141) was recruited from a highly traumatized civilian population seeking treatment at Grady Memorial Hospital in Atlanta, Georgia. Psychophysiological responses during a dark-enhanced startle paradigm task included startle magnitude, assessed by eyeblink reflex, and measures of high-frequency HRV, during light and dark phases of the startle session. RESULTS: The startle magnitude was higher during the dark phase than the light phase (mean ± standard error = 98.61 ± 10.68 versus 73.93 ± 8.21 µV, p < .001). PTSD was associated with a greater degree of dark-enhanced startle in women (p = .03) but not in men (p = .38, p interaction = .48). Although HRV measures did not differ between phases, high-frequency HRV was greater in men with PTSD compared with men without PTSD (p = .02). CONCLUSIONS: This study demonstrates that the dark-enhanced paradigm provides novel insights into the psychophysiological responses associated with PTSD in traumatized civilian sample. Sex differences in altered parasympathetic and sympathetic function during anxiety regulation tasks may provide further insight into the neurobiological mechanisms of PTSD.

Risk factors for hepatocellular carcinoma: a case-control study in Belgrade (Serbia).

AIMS AND BACKGROUND: The objective of this case-control study was to test the existing hypotheses about factors related to the occurrence of hepatocellular carcinoma in the population of Belgrade (Serbia). METHODS AND STUDY DESIGN: The investigation was conducted between 2004 and 2007 and consisted of 45 newly diagnosed, histologically confirmed hepatocellular carcinoma patients and 90 individually gender- and age-matched hospital controls. Conditional univariate and multivariate logistic regression analyses were applied. RESULTS: A highly statistically significant association (P = 0.001) was demonstrated between hepatocellular carcinoma and HBsAg positivity and the presence of hepatitis C virus antibodies. Diabetes mellitus was significantly (P = 0.018) associated with an increased risk of hepatocellular carcinoma. A statistically significant inverse association was shown between low parity and the risk of hepatocellular carcinoma (P = 0.033). The risk increased significantly with a longer history of cigarette smoking (P = 0.044), as well as the daily consumption of hard liquor (P = 0.049). A weekly intake of fish (P = 0.003) and yogurt (P = 0.003) and daily intake of boiled vegetables (P = 0.001) were reported more frequently by controls than hepatocellular carcinoma cases. In the current study, a high intake of salty food also significantly increased the risk of hepatocellular carcinoma (P = 0.027). Based on multivariate analysis, the presence of hepatitis C virus antibodies (OR = 24.6, P = 0.001) and duration of smoking > or =25 years (OR = 3.8, P = 0.020) were significantly related to hepatocellular carcinoma, whereas the daily consumption of boiled vegetables (OR = 0.1, P = 0.011) was inversely associated with the risk of hepatocellular carcinoma. CONCLUSIONS: The findings obtained in the current study support the hypotheses that non-viral factors, such as lifestyle factors, reproductive factors, and a history of diabetes, might be involved in the etiology of hepatocellular carcinoma.

Posttraumatic stress disorder may be associated with impaired fear inhibition: relation to symptom severity.

One of the central problems in posttraumatic stress disorder (PTSD) is the inability to suppress fear even under safe conditions. The neural underpinnings of fear are clinically relevant but poorly understood. This study assessed fear potentiation and fear inhibition using fear-potentiated startle in a conditional discrimination procedure (AX+/BX-). We hypothesized that patients with PTSD would show normal fear potentiation and impaired fear inhibition. Subjects comprised 28 healthy volunteers and 27 PTSD patients (14 with low current symptoms, 13 with high current symptoms) who were presented with one set of colored lights (AX trials) paired with aversive air blasts to the throat, and a different series of lights (BX trials) presented without air blasts. We then presented A and B together (AB trials) to see whether B would inhibit fear potentiation to A. All groups showed robust fear potentiation in that they had significantly greater startle magnitude on AX trials than on noise-alone trials. However, the high-symptom PTSD group did not show fear inhibition: these subjects had significantly greater fear potentiation on the AB trials than both the controls and the low-symptom PTSD patients.

Altered resting psychophysiology and startle response in Croatian combat veterans with PTSD.

Posttraumatic stress disorder (PTSD) is a prolonged reaction to an extremely traumatic experience. One of the core symptoms of PTSD is hyper-arousal which can be the result of an elevated activation of the autonomic nervous system. Including psychophysiological assessment methods in PTSD research can point to the neurobiological bases of the disorder. The studies of psychophysiology of PTSD to date have mostly measured reactivity. The aim of the current study was to compare resting state psychophysiology and startle reflexes in PTSD patients and controls in a sample of Croatian combat veterans. We measured heart-rate, respiratory sinus arrhythmia, skin conductance, and eyeblink muscle contraction during an acclimation period and during the presentation of startle stimuli in 45 male PTSD patients and 33 male healthy controls. We found that PTSD patient had elevated baseline heart-rate and decreased respiratory sinus arrhythmia compared to the controls. Furthermore, PTSD patients had impaired habituation to the startle probe, but there was no group difference in initial startle magnitude. There was also no group difference in skin conductance level or skin conductance response. Startle habituation and baseline heart-rate appear to offer the most reliable psychophysiological indices of PTSD. This finding replicates trends in the literature in a new population of PTSD patients.

Timing of extinction relative to acquisition: a parametric analysis of fear extinction in humans.

Fear extinction is a reduction in conditioned fear following repeated exposure to the feared cue in the absence of any aversive event. Extinguished fear often reappears after extinction through spontaneous recovery. Animal studies suggest that spontaneous recovery can be abolished if extinction occurs within minutes of acquisition. However, a limited number of human extinction studies have shown that short interval extinction does not prevent the return of fear. For this reason, we performed an in-depth parametric analysis of human fear extinction using fear-potentiated startle. Using separate single-cue and differential conditioning paradigms, participants were fear conditioned and then underwent extinction either 10 min (Immediate) or 72 hr (Delayed) later. Testing for spontaneous recovery occurred 96 hr after acquisition. In the single cue paradigm, the Immediate and Delayed groups exhibited differences in context, but not fear, conditioning. With differential conditioning, there were no differences in context conditioning and the Immediate group displayed less spontaneous recovery. Thus, the results remain inconclusive regarding spontaneous recovery and the timing of extinction and are discussed in terms of performing translational studies of fear in humans.

An fMRI study of the interaction of stress and cocaine cues on cocaine craving in cocaine-dependent men.

Acute stress is associated with relapse in cocaine addiction, possibly through the activation of craving-related neural circuitry. Neural responses to cocaine cues and acute stress were investigated in an fMRI study. Ten male participants mentally re-enacted personalized scripts about cocaine use and a neutral experience both with and without a stressor present (anticipation of electrical shock). Interaction analysis between script type and stress condition revealed greater activation of the posterior cingulate cortex and of the parietal lobe during the cocaine script in the presence of the stressor. These data suggest that stress may precipitate relapse in cocaine addiction by activating brain areas that mediate reward processing and the attentional and mnemonic bias for drug use reminders.

Contingency awareness and fear inhibition in a human fear-potentiated startle paradigm.

Fear-potentiated startle is defined as an increase in the magnitude of the startle reflex in the presence of a stimulus that was previously paired with an aversive event. It has been proposed that a subject's awareness of the contingencies in the experiment may affect fear-potentiated startle. The authors adapted a conditional discrimination procedure (AX+/BX-), previously validated in animals, to a human fear-potentiated startle paradigm in 50 healthy volunteers. This paradigm allows for an assessment of fear-potentiated startle during threat conditions as well as inhibition of fear-potentiated startle during safety conditions. A response keypad was used to assess contingency awareness on a trial-by-trial basis. Both aware and unaware subjects showed fear-potentiated startle. However, awareness was related to stimulus discrimination and fear inhibition.

Menstrual cycle phase effects on prepulse inhibition of acoustic startle.

Prepulse inhibition (PPI) represents an attenuation of the startle reflex following the presentation of a weak prepulse at brief intervals prior to the startle eliciting pulse. It has been shown that increases in striatal dopamine levels decrease PPI; because dopamine release is sensitive to estrogen, it is likely that PPI varies across the menstrual cycle. Cross-sectional studies looking at estrogen effects suggest that this may be true. In this study, we compare effects of menstrual phase on PPI in a between-group design (men, follicular phase women, and luteal phase women) as well as a within-subjects design (women across the two phases). The study found a between-group as well as a within-subjects effect of phase on PPI. PPI in follicular phase women did not differ significantly from PPI in men. However, PPI was reduced in luteal women compared to follicular women. These data provide evidence that ovarian hormones affect sensorimotor gating.