Elizabeth A. Hoge

Stress reduction correlates with structural changes in the amygdala

Stress has significant adverse effects on health and is a risk factor for many illnesses. Neurobiological studies have implicated the amygdala as a brain structure crucial in stress responses. Whereas hyperactive amygdala function is often observed during stress conditions, cross-sectional reports of differences in gray matter structure have been less consistent. We conducted a longitudinal MRI study to investigate the relationship between changes in perceived stress with changes in amygdala gray matter density following a stress-reduction intervention. Stressed but otherwise healthy individuals (N = 26) participated in an 8-week mindfulness-based stress reduction intervention. Perceived stress was rated on the perceived stress scale (PSS) and anatomical MR images were acquired pre- and post-intervention. PSS change was used as the predictive regressor for changes in gray matter density within the bilateral amygdalae. Following the intervention, participants reported significantly reduced perceived stress. Reductions in perceived stress correlated positively with decreases in right basolateral amygdala gray matter density. Whereas prior studies found gray matter modifications resulting from acquisition of abstract information, motor and language skills, this study demonstrates that neuroplastic changes are associated with improvements in a psychological state variable.

Broad spectrum of cytokine abnormalities in panic disorder and posttraumatic stress disorder

Background: Proinflammatory cytokines have been reported to be elevated in individuals experiencing chronic stress as well as in those with major depressive disorder. Much less is known about cytokines in anxiety disorders such as posttraumatic stress disorder (PTSD) and panic disorder (PD). We hypothesized that PD and PTSD would be associated with a generalized proinflammatory cytokine signature. Method: We utilized Luminex technology to examine 20 cytokines and chemokines in serum from 48 well‐characterized individuals with a primary DSM‐IV PD or PTSD diagnosis, and 48 age‐ and gender‐matched healthy controls. We conservatively employed a Bonferroni correction for multiple testing (α=.05/20=.0025). Results: Individuals with primary PTSD or PD had significantly elevated median peripheral cytokine levels for 18 of 20 different cytokines compared to age‐ and gender‐matched healthy controls (all P<.0025). To assess for the presence of a generalized proinflammatory state, we also examined the proportion of subjects with detectable levels of at least six of nine common proinflammatory cytokines and chemokines (IL‐6, IL‐1α, IL‐1β, IL‐8, MCP‐1, MIP‐1α, Eotaxin, GM‐CSF, and IFN‐α). For men and women, 87% of anxiety patients had six or more detectable levels of these proinflammatory cytokines, compared with only 25% of controls (Fishers Exact Test (FET) P=.000). Confirmatory analysis of the subset of individuals without current psychiatric medication use or comorbid depression was of comparable significance. Conclusions: These findings suggest that a generalized inflammatory state may be present in individuals with PD or PTSD. Depression and Anxiety, 2009.

Oxytocin Levels in Social Anxiety Disorder

Oxytocin is a neuropeptide recently associated with social behavior in animals and humans, but the study of its function in populations with social deficits such as autism, schizophrenia, and social anxiety disorder has only recently begun. We measured plasma oxytocin in 24 patients with Generalized Social Anxiety Disorder (GSAD) and 22 healthy controls using an enzyme‐linked immunosorbent assay. There were no significant differences in oxytocin level (pg/mL) between patients (M = 163.0, SD = 109.4) and controls (M = 145.0, SD = 52.9, z = 0.21, P= 0.8). Within the GSAD sample, however, higher social anxiety symptom severity adjusted for age and gender was associated with higher oxytocin level (R2= 0.21, β= 0.014, SE = 0.006, t = 2.18, P= 0.04). In addition, dissatisfaction with social relationships was associated with higher oxytocin levels (R2= 0.18, β=–0.20, SE = 0.10, t =–2.01, P= 0.05). Our data provide preliminary support for a link between social anxiety severity and plasma oxytocin. These findings may suggest a possible role for oxytocin as a facilitator of social behavior, an effect which may not be fully utilized in individuals with severe social anxiety.

Randomized Controlled Trial of Mindfulness Meditation for Generalized Anxiety Disorder: Effects on Anxiety and Stress Reactivity

OBJECTIVE Mindfulness meditation has met increasing interest as a therapeutic strategy for anxiety disorders, but prior studies have been limited by methodological concerns, including a lack of an active comparison group. This is the first randomized, controlled trial comparing the manualized Mindfulness-Based Stress Reduction (MBSR) program with an active control for generalized anxiety disorder (GAD), a disorder characterized by chronic worry and physiologic hyperarousal symptoms. METHOD Ninety-three individuals with DSM-IV-diagnosed GAD were randomly assigned to an 8-week group intervention with MBSR or to an attention control, Stress Management Education (SME), between 2009 and 2011. Anxiety symptoms were measured with the Hamilton Anxiety Rating Scale (HAMA; primary outcome measure), the Clinical Global Impressions-Severity of Illness and -Improvement scales (CGI-S and CGI-I), and the Beck Anxiety Inventory (BAI). Stress reactivity was assessed by comparing anxiety and distress during pretreatment and posttreatment administration of the Trier Social Stress Test (TSST). RESULTS A modified intent-to-treat analysis including participants who completed at least 1 session of MBSR (n = 48) or SME (n = 41) showed that both interventions led to significant (P < .0001) reductions in HAMA scores at endpoint, but did not significantly differ. MBSR, however, was associated with a significantly greater reduction in anxiety as measured by the CGI-S, the CGI-I, and the BAI (all P values < .05). MBSR was also associated with greater reductions than SME in anxiety and distress ratings in response to the TSST stress challenge (P < .05) and a greater increase in positive self-statements (P = .004). CONCLUSIONS These results suggest that MBSR may have a beneficial effect on anxiety symptoms in GAD and may also improve stress reactivity and coping as measured in a laboratory stress challenge. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01033851.

Effect of Acute Posttrauma Propranolol on PTSD Outcome and Physiological Responses During Script‐Driven Imagery

Introduction: Animal and human research suggests that the development of posttraumatic stress disorder (PTSD) may involve the overconsolidation of memories of a traumatic experience. Previous studies have attempted to use pharmaceutical agents, especially the β‐adrenergic blocker propranolol, to reduce this overconsolidation. Aims: In this randomized, placebo‐controlled study of the efficacy of propranolol in reducing the development of PTSD, we optimized dosages and conducted both psychophysiological and clinical assessments 1 and 3 months after the traumatic event. Forty‐one emergency department patients who had experienced a qualifying acute psychological trauma were randomized to receive up to 240 mg/day of propranolol or placebo for 19 days. At 4 and 12 weeks post‐trauma, PTSD symptoms were assessed. One week later, participants engaged in script‐driven imagery of their traumatic event while psychophysiological responses were measured. Results: Physiological reactivity during script‐driven traumatic imagery, severity of PTSD symptoms, and the rate of the PTSD diagnostic outcome were not significantly different between the two groups. However, post hoc subgroup analyses showed that in participants with high drug adherence, at the 5‐week posttrauma assessment, physiological reactivity was significantly lower during script‐driven imagery in the propranolol than in the placebo subjects. Conclusions: The physiological results provide some limited support for a model of PTSD in which a traumatic conditioned response is reduced by posttrauma propranolol. However, the clinical results from this study do not support the preventive use of propranolol in the acute aftermath of a traumatic event.

Moving Beyond Mindfulness: Defining Equanimity as an Outcome Measure in Meditation and Contemplative Research

In light of a growing interest in contemplative practices such as meditation, the emerging field of contemplative science has been challenged to describe and objectively measure how these practices affect health and well-being. While “mindfulness” itself has been proposed as a measurable outcome of contemplative practices, this concept encompasses multiple components, some of which, as we review here, may be better characterized as equanimity. Equanimity can be defined as an even-minded mental state or dispositional tendency toward all experiences or objects, regardless of their origin or their affective valence (pleasant, unpleasant, or neutral). In this article, we propose that equanimity be used as an outcome measure in contemplative research. We first define and discuss the inter-relationship between mindfulness and equanimity from the perspectives of both classical Buddhism and modern psychology and present existing meditation techniques for cultivating equanimity. We then review psychological, physiological, and neuroimaging methods that have been used to assess equanimity either directly or indirectly. In conclusion, we propose that equanimity captures potentially the most important psychological element in the improvement of well-being, and therefore should be a focus in future research studies.

Neural mechanisms of symptom improvements in generalized anxiety disorder following mindfulness training

Mindfulness training aims to impact emotion regulation. Generalized anxiety disorder (GAD) symptoms can be successfully addressed through mindfulness-based interventions. This preliminary study is the first to investigate neural mechanisms of symptom improvements in GAD following mindfulness training. Furthermore, we compared brain activation between GAD patients and healthy participants at baseline. 26 patients with a current DSM-IV GAD diagnosis were randomized to an 8-week Mindfulness Based Stress Reduction (MBSR, N = 15) or a stress management education (SME, N = 11) active control program. 26 healthy participants were included for baseline comparisons. BOLD response was assessed with fMRI during affect labeling of angry and neutral facial expressions. At baseline, GAD patients showed higher amygdala activation than healthy participants in response to neutral, but not angry faces, suggesting that ambiguous stimuli reveal stronger reactivity in GAD patients. In patients, amygdala activation in response to neutral faces decreased following both interventions. BOLD response in ventrolateral prefrontal regions (VLPFC) showed greater increase in MBSR than SME participants. Functional connectivity between amygdala and PFC regions increased significantly pre- to post-intervention within the MBSR, but not SME group. Both, change in VLPFC activation and amygdala–prefrontal connectivity were correlated with change in Beck Anxiety Inventory (BAI) scores, suggesting clinical relevance of these changes. Amygdala–prefrontal connectivity turned from negative coupling (typically seen in down-regulation of emotions), to positive coupling; potentially suggesting a unique mechanism of mindfulness. Findings suggest that in GAD, mindfulness training leads to changes in fronto-limbic areas crucial for the regulation of emotion; these changes correspond with reported symptom improvements.

Eszopiclone for the Treatment of Posttraumatic Stress Disorder and Associated Insomnia: A Randomized, Double-Blind, Placebo-Controlled Trial

OBJECTIVE The development of novel strategies for the treatment of posttraumatic stress disorder (PTSD) represents a critical public health need. We present the first prospective, randomized, double-blind, placebo-controlled trial of a non-benzodiazepine hypnotic agent for the treatment of PTSD and associated insomnia. METHOD Twenty-four patients with PTSD by DSM-IV criteria and sleep disturbance were treated in a randomized, double-blind, placebo-controlled crossover study of 3 weeks of eszopiclone 3 mg at bedtime compared to placebo. The primary outcome measures were changes in scores on the Short PTSD Rating Interview (SPRINT) and the Pittsburgh Sleep Quality Index (PSQI). The data were collected from April 2006 to June 2008. RESULTS Three weeks of eszopiclone pharmacotherapy was associated with significantly greater improvement than placebo on PTSD symptom measures including the SPRINT (P = .032) and the Clinician-Administered PTSD Scale (P = .003), as well as on measures of sleep including the PSQI (P = .011) and sleep latency (P = .044). Greater improvement with eszopiclone on PTSD measures was present even when specific sleep-related items were excluded. Adverse events were consistent with the known profile of the drug. CONCLUSIONS This study provides initial evidence that pharmacotherapy with eszopiclone may be associated with short-term improvement in overall PTSD severity as well as associated sleep disturbance. Longer, more definitive study of eszopiclone in PTSD is warranted. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00120250.

Generalized anxiety disorder: diagnosis and treatment

#### Summary points Generalized anxiety disorder (GAD) is relatively common, with lifetime prevalence rates of 4-7%. It is a disorder of chronic uncontrollable worry, compounded by physiological symptoms such as disturbed sleep, muscle tension, and difficulty concentrating. The disorder is associated with seriously impaired social and occupational functioning, comorbidity with other disorders, and increased risk for suicide.1 GAD can go undiagnosed because of a focus on physical symptoms and because of the stigma of mental illness. However, the disorder can be treated. This article reviews current knowledge about the diagnosis and treatment of GAD, including pharmacotherapy and psychosocial therapies. #### Sources and selection criteria We based this review on articles found by searching PubMed and the Cochrane Database of Systematic Reviews using the terms “generalized anxiety disorder” and “generalised anxiety disorder”. Our search was limited to English language articles published between 2005 and 2012. Meta-analyses, reviews, and randomised controlled trials were prioritized. GAD is characterized by excessive worry and symptoms of physiological arousal such as restlessness, insomnia, and muscle tension (box). To meet Diagnostic and Statistical Manual of Mental Disorders , fourth edition (DSM-IV) criteria for the disorder, the patient must have excessive and difficult to control anxiety about several different events or activities.2 For example, anxiety confined to concern about personal safety would not qualify (but should elicit inquiries about symptoms of post-traumatic stress disorder or agoraphobia, for example). In addition to worry, patients must have at least three of the six physiological arousal symptoms listed in the box. …

Nest Making and Oxytocin Comparably Promote Wound Healing in Isolation Reared Rats

Background Environmental enrichment (EE) fosters attachment behavior through its effect on brain oxytocin levels in the hippocampus and other brain regions, which in turn modulate the hypothalamic-pituitary axis (HPA). Social isolation and other stressors negatively impact physical healing through their effect on the HPA. Therefore, we reasoned that: 1) provision of a rat EE (nest building with Nestlets®) would improve wound healing in rats undergoing stress due to isolation rearing and 2) that oxytocin would have a similar beneficial effect on wound healing. Methodology/Principal Findings In the first two experiments, we provided isolation reared rats with either EE or oxytocin and compared their wound healing to group reared rats and isolation reared rats that did not receive Nestlets or oxytocin. In the third experiment, we examined the effect of Nestlets on open field locomotion and immediate early gene (IEG) expression. We found that isolation reared rats treated with Nestlets a) healed significantly better than without Nestlets, 2) healed at a similar rate to rats treated with oxytocin, 3) had decreased hyperactivity in the open field test, and 4) had normalized IEG expression in brain hippocampus. Conclusions/Significance This study shows that when an EE strategy or oxytocin is given to isolation reared rats, the peripheral stress response, as measured by burn injury healing, is decreased. The findings indicate an association between the effect of nest making on wound healing and administration of the pro-bonding hormone oxytocin. Further elucidation of this animal model should lead to improved understanding of how EE strategies can ameliorate poor wound healing and other symptoms that result from isolation stress.