Morning light treatment for traumatic stress: The role of amygdala reactivity study protocol.

BACKGROUND: Exposure to trauma can result in various mental health disorders including anxiety, depression, and posttraumatic stress disorder (PTSD). Although psychotherapies and pharmacotherapies exist for the treatment of these disorders, many individuals fail to receive treatment and among those who do, many remain symptomatic. Therefore, it is critical to continue developing new interventions for traumatic stress that target underlying mechanisms of pathology and offer a safe and acceptable alternative to current treatments. Morning light treatment has good potential as a novel non-invasive, low risk treatment for traumatic stress. Evidence suggests that morning light may improve traumatic stress by reducing reactivity in the amygdala, a brain region implicated in the pathophysiology of PTSD and anatomically linked to circadian photoreceptors in the eye. METHODS: In this study, we aim to establish a significant dose-response relationship between duration of morning light treatment and reduction in amygdala reactivity among individuals with traumatic stress symptoms (NCT# 04117347). Using a transdiagnostic approach, sixty-six individuals with a history of a DSM-5 criterion A trauma and traumatic stress symptoms will be recruited to participate in a 5-week study. Participants will be randomized across three treatment arms based on morning light treatment duration: 15-minutes, 30-minutes, or 60-minutes of light treatment per day for four weeks. To evaluate amygdala activity, participants will undergo fMRI at pre-treatment, mid-treatment, and post-treatment. Participants will also complete clinical assessments and self-report measures of PTSD, depression, and anxiety at pre-treatment, mid-treatment, and post-treatment. DISCUSSION: Morning light therapy may be an acceptable, feasible, and effective treatment for individuals suffering from traumatic stress. Identifying mechanistically relevant targets, and the doses needed to impact them, are critical steps in developing this new treatment approach for the sequelae of traumatic stress.

Interdependent self-construal predicts increased gray matter volume of scene processing regions in the brain.

Interdependent self-construal (SC) is thought to lead to a more holistic cognitive style that emphasizes the processing of the background scene of a focal object. At present, little is known about whether the structural properties of the brain might underlie this functional relationship. Here, we examined the gray matter (GM) volume of three cortical regions involved in scene processing -- a cornerstone of contextual processing. Study 1 tested 78 European American non-student adults and found that interdependent (vs. independent) SC predicts higher GM volume in the parahippocampal place area (PPA), one of the three target regions. Testing both European American and East Asian college students (total N = 126), Study 2 replicated this association. Moreover, the GM volume of all the three target regions was greater for East Asians than for European Americans. Our findings suggest that there is a structural neural underpinning for the cultural variation in cognitive style.

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.

A Pilot Study of Mindfulness-Based Exposure Therapy in OEF/OIF Combat Veterans with PTSD: Altered Medial Frontal Cortex and Amygdala Responses in Social-Emotional Processing.

Combat-related posttraumatic stress disorder (PTSD) is common among returning veterans, and is a serious and debilitating disorder. While highly effective treatments involving trauma exposure exist, difficulties with engagement and early drop may lead to sub-optimal outcomes. Mindfulness training may provide a method for increasing emotional regulation skills that may improve engagement in trauma-focused therapy. Here, we examine potential neural correlates of mindfulness training and in vivo exposure (non-trauma focused) using a novel group therapy [mindfulness-based exposure therapy (MBET)] in Afghanistan (OEF) or Iraq (OIF) combat veterans with PTSD. OEF/OIF combat veterans with PTSD (N = 23) were treated with MBET (N = 14) or a comparison group therapy [Present-centered group therapy (PCGT), N = 9]. PTSD symptoms were assessed at pre- and post-therapy with Clinician Administered PTSD scale. Functional neuroimaging (3-T fMRI) before and after therapy examined responses to emotional faces (angry, fearful, and neutral faces). Patients treated with MBET had reduced PTSD symptoms (effect size d = 0.92) but effect was not significantly different from PCGT (d = 0.43). Improvement in PTSD symptoms from pre- to post-treatment in both treatment groups was correlated with increased activity in rostral anterior cingulate cortex, dorsal medial prefrontal cortex (mPFC), and left amygdala. The MBET group showed greater increases in amygdala and fusiform gyrus responses to Angry faces, as well as increased response in left mPFC to Fearful faces. These preliminary findings provide intriguing evidence that MBET group therapy for PTSD may lead to changes in neural processing of social-emotional threat related to symptom reduction.

Context Processing and the Neurobiology of Post-Traumatic Stress Disorder.

Progress in clinical and affective neuroscience is redefining psychiatric illness as symptomatic expression of cellular/molecular dysfunctions in specific brain circuits. Post-traumatic stress disorder (PTSD) has been an exemplar of this progress, with improved understanding of neurobiological systems subserving fear learning, salience detection, and emotion regulation explaining much of its phenomenology and neurobiology. However, many features remain unexplained and a parsimonious model that more fully accounts for symptoms and the core neurobiology remains elusive. Contextual processing is a key modulatory function of hippocampal-prefrontal-thalamic circuitry, allowing organisms to disambiguate cues and derive situation-specific meaning from the world. We propose that dysregulation within this context-processing circuit is at the core of PTSD pathophysiology, accounting for much of its phenomenology and most of its biological findings. Understanding core mechanisms like this, and their underlying neural circuits, will sharpen diagnostic precision and understanding of risk factors, enhancing our ability to develop preventive and "personalized" interventions.

Association of Spirituality With Mental Health Conditions in Ohio National Guard Soldiers.

Research exploring spirituality in military populations is a relatively new field with limited published reports. This study used the Spiritual Well-Being Scale to examine the association of spiritual well-being with suicidal ideation/behavior, posttraumatic stress disorder (PTSD), and depression and alcohol use disorders in a randomized sample of Ohio Army National Guard soldiers. The participants were 418 soldiers, mostly white and male, with nearly three-quarters indicating that they had been deployed at least once during their careers. Higher spirituality, especially in the existential well-being subscale, was associated with significantly less lifetime PTSD, depression, and alcohol use disorders and with less suicidal ideation over the past year. Future research in this area may benefit from a longitudinal design that can assess spirituality and mental health behaviors in addition to diagnoses at different time points, to begin to explore spirituality in a larger context.

ALTERED DEFAULT MODE NETWORK (DMN) RESTING STATE FUNCTIONAL CONNECTIVITY FOLLOWING A MINDFULNESS-BASED EXPOSURE THERAPY FOR POSTTRAUMATIC STRESS DISORDER (PTSD) IN COMBAT VETERANS OF AFGHANISTAN AND IRAQ.

BACKGROUND: Recent studies suggest that mindfulness may be an effective component for posttraumatic stress disorder (PTSD) treatment. Mindfulness involves practice in volitional shifting of attention from "mind wandering" to present-moment attention to sensations, and cultivating acceptance. We examined potential neural correlates of mindfulness training using a novel group therapy (mindfulness-based exposure therapy (MBET)) in combat veterans with PTSD deployed to Afghanistan (OEF) and/or Iraq (OIF). METHODS: Twenty-three male OEF/OIF combat veterans with PTSD were treated with a mindfulness-based intervention (N = 14) or an active control group therapy (present-centered group therapy (PCGT), N = 9). Pre-post therapy functional magnetic resonance imaging (fMRI, 3 T) examined resting-state functional connectivity (rsFC) in default mode network (DMN) using posterior cingulate cortex (PCC) and ventral medial prefrontal cortex (vmPFC) seeds, and salience network (SN) with anatomical amygdala seeds. PTSD symptoms were assessed at pre- and posttherapy with Clinician Administered PTSD Scale (CAPS). RESULTS: Patients treated with MBET had reduced PTSD symptoms (effect size d = 0.92) but effect was not significantly different from PCGT (d = 0.46). Increased DMN rsFC (PCC seed) with dorsolateral dorsolateral prefrontal cortex (DLPFC) regions and dorsal anterior cingulate cortex (ACC) regions associated with executive control was seen following MBET. A group × time interaction found MBET showed increased connectivity with DLPFC and dorsal ACC following therapy; PCC-DLPFC connectivity was correlated with improvement in PTSD avoidant and hyperarousal symptoms. CONCLUSIONS: Increased connectivity between DMN and executive control regions following mindfulness training could underlie increased capacity for volitional shifting of attention. The increased PCC-DLPFC rsFC following MBET was related to PTSD symptom improvement, pointing to a potential therapeutic mechanism of mindfulness-based therapies.

Biological and symptom changes in posttraumatic stress disorder treatment: a randomized clinical trial.

BACKGROUND: Understanding cognitive and biological mechanisms of PTSD treatment can help refine treatments and increase rates of response. METHODS: Thirty-six veterans with PTSD were randomly assigned to receive Prolonged exposure therapy (PE) or Present-Centered therapy (PCT). We examined symptoms, trauma-related cognitions, and two indices of HPA axis function (cortisol awakening response and cortisol response to a script-driven imagery task). RESULTS: Thirty veterans started treatment and 26 completed. PE resulted in significantly more symptom reduction than PCT (P = .008). High treatment responders collapsed across treatments showed nominally higher cortisol levels measured at pretreatment 30 min after trauma script exposure compared to low responders (P = .08). At midtreatment, high treatment responders showed higher cortisol levels throughout the imagery task (Ps = .03-.04). There were no differences between high and low treatment responders at posttreatment. Thoughts of incompetence (F (1.6, 35.8) = 16.8, P = .000) and a dangerous world (F (1.3, 29.9) = 8.2, P = .004) significantly improved over time in high treatment responders but showed no change in low responders. Script-associated cortisol response prior to treatment and reductions in thoughts of incompetence accounted for 83% of the variance in reductions in PTSD severity with PE. CONCLUSIONS: Both increased cortisol response to personal trauma script prior to PTSD therapy and reductions in cognitive symptoms of PTSD were significantly and uniquely related to reductions in the core symptoms of PTSD in PE. However, contrary to our hypotheses, cortisol measures were not related to cognitive changes.

Focal and aberrant prefrontal engagement during emotion regulation in veterans with posttraumatic stress disorder.

BACKGROUND: Collectively, functional neuroimaging studies implicate frontal-limbic dysfunction in the pathophysiology of posttraumatic stress disorder (PTSD), as reflected by altered amygdala reactivity and deficient prefrontal responses. These neural patterns are often elicited by social signals of threat (fearful/angry faces) and traumatic reminders (combat sounds, script-driven imagery). Although PTSD can be conceptualized as a disorder of emotion dysregulation, few studies to date have directly investigated the neural correlates of volitional attempts at regulating negative affect in PTSD. METHODS: Using functional magnetic resonance imaging and a well-validated task involving cognitive regulation of negative affect via reappraisal and known to engage prefrontal cortical regions, the authors compared brain activation in veterans with PTSD (n = 21) and without PTSD (n = 21, combat-exposed controls/CEC), following military combat trauma experience during deployments in Afghanistan or Iraq. The primary outcome measure was brain activation during cognitive reappraisal (i.e., decrease negative affect) as compared to passive viewing (i.e., maintain negative affect) of emotionally evocative content of aversive images RESULTS: The subjects in both groups reported similar successful reduction in negative affect following reappraisal. The PTSD group engaged the dorsolateral prefrontal cortex (dlPFC) during cognitive reappraisal, albeit to a lesser extent than the CEC group. Although the amygdala was engaged in both groups during passive viewing of aversive images, neither group exhibited attenuation of amygdala activation during cognitive reappraisal. CONCLUSIONS: Veterans with combat-related PTSD showed less recruitment of the dlPFC involved in cognitive reappraisal, suggesting focal and aberrant neural activation during volitional, self-regulation of negative affective states.

A pilot study of group mindfulness-based cognitive therapy (MBCT) for combat veterans with posttraumatic stress disorder (PTSD).

BACKGROUND: "Mindfulness-based" interventions show promise for stress reduction in general medical conditions, and initial evidence suggests that they are accepted in trauma-exposed individuals. Mindfulness-based cognitive therapy (MBCT) shows substantial efficacy for prevention of depression relapse, but it has been less studied in anxiety disorders. This study investigated the feasibility, acceptability, and clinical outcomes of an MBCT group intervention adapted for combat posttraumatic stress disorder (PTSD). METHODS: Consecutive patients seeking treatment for chronic PTSD at a VA outpatient clinic were enrolled in 8-week MBCT groups, modified for PTSD (four groups, n = 20) or brief treatment-as-usual (TAU) comparison group interventions (three groups, n = 17). Pre and posttherapy psychological assessments with clinician administered PTSD scale (CAPS) were performed with all patients, and self-report measures (PTSD diagnostic scale, PDS, and posttraumatic cognitions inventory, PTCI) were administered in the MBCT group. RESULTS: Intent to treat analyses showed significant improvement in PTSD (CAPS (t(19) = 4.8, P < .001)) in the MBCT condition but not the TAU conditions, and a significant Condition × Time interaction (F[1,35] = 16.4, P < .005). MBCT completers (n = 15, 75%) showed good compliance with assigned homework exercises, and significant and clinically meaningful improvement in PTSD symptom severity on posttreatment assessment in CAPS and PDS (particularly in avoidance/numbing symptoms), and reduced PTSD-relevant cognitions in PTCI (self blame). CONCLUSIONS: These data suggest group MBCT as an acceptable brief intervention/adjunctive therapy for combat PTSD, with potential for reducing avoidance symptom cluster and PTSD cognitions. Further studies are needed to examine efficacy in a randomized controlled design and to identify factors influencing acceptability and efficacy.

Medial prefrontal cortex and right insula activity predict plasma ACTH response to trauma recall.

Neural substrates underlying psychological activation of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis are not well understood in humans. Trauma recall (using autobiographical script-driven imagery) may provide a model to study neural circuitry involved in LHPA axis activation to personally threatening psychological stimuli. This study sought to identify brain activation patterns that differentiated combat veterans who mounted an LHPA response to trauma recall from those who did not. Twenty-five Vietnam combat veterans (14 with current PTSD, 11 with no PTSD history) experienced autobiographic script-driven imagery in an [(15)O] H(2)O positron emission tomography (PET) paradigm with recurrent blood sampling. Trauma recall elicited acute ACTH responses in some but not all veterans, regardless of the PTSD status and independent of emotional responses. ACTH responders (mean ACTH increase of 24+/-7 pg/ml, n=13) were compared to non-responders (mean decrease of -0.6+/-0.6 pg/ml, n=12) in regional cerebral blood flow (rCBF). Both groups activated right insula (BA13) in response to trauma recall. However, ACTH responders deactivated rostral mPFC (BA10)/rostral ACC (BA32), whereas non-responders activated this same mPFC region, and deactivated amygdala, hippocampus, and temporal pole. In group contrasts comparing ACTH responders to non-responders, the responders had significantly higher rCBF in right insula and right temporal pole, whereas non-responders had higher rCBF in rostral mPFC and dorsal ACC. These results support the hypotheses that right insula is involved in psychological activation of the LHPA axis and that rostral mPFC may negatively modulate LHPA axis responses.

Neural correlates of message tailoring and self-relatedness in smoking cessation programming.

BACKGROUND: Smoking leads to illnesses including addiction, cancer, and cardiovascular and respiratory diseases. Different intervention programs have become available. In the past decade, providing tailored smoking cessation messages has been shown to be more effective in inducing smoking cessation than one-size-fits-all interventions. However, little is known about the brain responses of smokers when they receive tailored smoking cessation messages. METHODS: A neuroimaging study using blocked and event-related designs examined neural activity in 24 smokers exposed to high-tailored and low-tailored smoking cessation messages. RESULTS: In both blocked and event-related conditions, rostral medial prefrontal cortex and precuneus/posterior cingulate were engaged more during the processing of high-tailored smoking cessation messages than low-tailored smoking cessation messages. CONCLUSIONS: The activation patterns of smokers to tailored cessation messages show involvement of brain areas commonly implicated in self-related processing. Results seem to add support to the suggested role of self-relevance in tailored cessation programs, where previous studies have shown a potential mediating role of self-relevance on smoking abstinence. The findings are relevant to understanding the cognitive mechanisms underlying tailored message processing and might point to new directions for testing response to health communications programming.

Altered central micro-opioid receptor binding after psychological trauma.

BACKGROUND: Functional neuroimaging studies have detected abnormal limbic and paralimbic activation to emotional probes in posttraumatic stress disorder (PTSD), but few studies have examined neurochemical mechanisms that underlie functional alterations in regional cerebral blood flow. The mu-opioid neurotransmitter system, implicated in responses to stress and suppression of pain, is distributed in and is thought to regulate the function of brain regions that are implicated in affective processing. METHODS: Here we examined the micro-opioid system with positron emission tomography and the micro-opioid receptor-selective radiotracer [11C] carfentanil in 16 male patients with PTSD and two non-PTSD male control groups, with (n = 14) and without combat exposure (n = 15). Differences in micro-opioid receptor binding potential (BP2) were detected within discrete limbic and paralimbic regions. RESULTS: Relative to healthy controls, both trauma-exposed groups had lower micro-opioid receptor BP2 in extended amygdala, nucleus accumbens, and dorsal frontal and insular cortex but had higher BP2 in the orbitofrontal cortex. PTSD patients exhibited reduced BP2 in anterior cingulate cortex compared with both control groups. Micro-opioid receptor BP2 in combat-exposed subjects without PTSD was lower in the amygdala but higher in the orbitofrontal cortex compared with both PTSD patients and healthy controls. CONCLUSIONS: These findings differentiate the general response of the micro-opioid system to trauma from more specific changes associated with PTSD.

Corticolimbic blood flow in posttraumatic stress disorder during script-driven imagery.

BACKGROUND: Functional neuroimaging experiments targeting personal recall of emotional events may help elucidate neural substrates underlying posttraumatic stress disorder (PTSD). Studies suggest that limbic and paralimbic function might be altered in PTSD, as compared with trauma-exposed control subjects; however, little is known about functional changes resulting from traumatic experience itself. The present study examined both PTSD-specific and trauma-specific regional cerebral blood flow (rCBF) patterns during script-driven imagery. METHODS: Sixteen combat veterans with PTSD (PP); 15 combat veterans without PTSD (CC); and 14 healthy, aged-matched noncombat control subjects (NC) underwent [15O] H20 positron emission tomography (PET) scanning during script-driven imagery of emotionally evocative and neutral autobiographic events. RESULTS: Differential patterns of activation were detected in amygdala and medial frontal cortex. Past trauma experience was associated with decreased amygdala activity (i.e., less activity than healthy control subjects); however, combat control subjects deactivated this region (i.e., greater activity to neutral scripts). All subjects deactivated medial frontal cortex; PTSD patients had greater rostral anterior cingulate (rACC) deactivation compared with control groups, who deactivated ventromedial prefrontal cortex (vmPFC). CONCLUSIONS: Trauma-specific patterns may represent potential compensatory changes to traumatic reminders, while patterns observed only in the PTSD group may reflect neural substrates specific to PTSD pathophysiology.

Topiramate attenuates exaggerated acoustic startle in an animal model of PTSD.

RATIONALE: Exaggerated acoustic startle is a prominent symptom of post-traumatic stress disorder (PTSD); however, its physiological basis is not well understood, and there are few available treatments. Neurobiological research has suggested that anti-kindling agents and/or glutamate antagonists can attenuate the acoustic startle response (ASR) in animal models. The anticonvulsant topiramate is an AMPA antagonist that also demonstrates potent anti-kindling effects and may, therefore, have promise in treating trauma-enhanced ASR. OBJECTIVE: To evaluate the ability of topiramate to attenuate stress-induced increases in ASR in a previously validated animal model of PTSD. METHODS: Male Sprague-Dawley rats ( n=36) served as controls or received single prolonged stress (SPS). SPS consisted of 2 h restraint, forced swim and ether anesthesia, then a 7-day "undisturbed" period. Animals then received vehicle, 10 mg/kg or 30 mg/kg of topiramate orally, twice daily for 7 days. ASR was assessed for all animals before and after the study, in light and dark environments. RESULTS: SPS produced a sustained increase in the ASR in both environments, an effect that was significantly reduced by topiramate. Meanwhile the ASR of control animals remained unaffected by topiramate. CONCLUSIONS: The current results provide one of the few demonstrations of a single stress episode producing sustained enhancement of ASR. In addition, topiramate demonstrates promise in treating exaggerated acoustic startle symptoms in PTSD or other stress-related disorders.

Neural correlates of traumatic recall in posttraumatic stress disorder.

Functional activation studies of posttraumatic stress disorder (PTSD) using symptom provocation paradigms have implicated dysfunction in limbic and paralimbic brain regions. Increased or altered cerebral blood flow has been observed in amygdala and insula. Decreased or absent activity has been seen in medial prefrontal and anterior cingulate cortex (ACC). These brain regions comprise a neural circuit that has been demonstrated as important for emotional processing and emotional regulation. We studied combat veterans with PTSD (n=16), combat veterans without PTSD (combat controls, n=15), and age-matched healthy control subjects (n=15) with [O-15] H2O PET under a script-driven imagery paradigm of personalized traumatic/stressful and emotionally neutral events. Preliminary findings show that PTSD patients and combat controls had differential blood flow patterns during emotional recall in amygdala, insula and medial prefrontal cortex. Consistent with and extending prior findings, these preliminary results replicate differential patterns of activation in limbic and paralimbic regions of PTSD patients and trauma exposed controls suggesting that these neural substrates may be involved in the deficits in emotional processing in PTSD on one hand, and in resilience to trauma on the other.