Showing papers by "Israel Liberzon published in 2014"

Impaired Contextual Modulation of Memories in PTSD: An fMRI and Psychophysiological Study of Extinction Retention and Fear Renewal

Abstract: Post-traumatic stress disorder (PTSD) patients display pervasive fear memories, expressed indiscriminately. Proposed mechanisms include enhanced fear learning and impaired extinction or extinction recall. Documented extinction recall deficits and failure to use safety signals could result from general failure to use contextual information, a hippocampus-dependent process. This can be probed by adding a renewal phase to standard conditioning and extinction paradigms. Human subjects with PTSD and combat controls were conditioned (skin conductance response), extinguished, and tested for extinction retention and renewal in a scanner (fMRI). Fear conditioning (light paired with shock) occurred in one context, followed by extinction in another, to create danger and safety contexts. The next day, the extinguished conditioned stimulus (CS+E) was re-presented to assess extinction recall (safety context) and fear renewal (danger context). PTSD patients showed impaired extinction recall, with increased skin conductance and heightened amygdala activity to the extinguished CS+ in the safety context. However, they also showed impaired fear renewal; in the danger context, they had less skin conductance response to CS+E and lower activity in amygdala and ventral-medial prefrontal cortex compared with combat controls. Control subjects displayed appropriate contextual modulation of memory recall, with extinction (safety) memory prevailing in the safety context, and fear memory prevailing in the danger context. PTSD patients could not use safety context to sustain suppression of extinguished fear memory, but they also less effectively used danger context to enhance fear. They did not display globally enhanced fear expression, but rather showed a globally diminished capacity to use contextual information to modulate fear expression.

The Dopamine D4 Receptor Gene (DRD4) Moderates Cultural Difference in Independent Versus Interdependent Social Orientation

Abstract: Prior research suggests that cultural groups vary on an overarching dimension of independent versus interdependent social orientation, with European Americans being more independent, or less interdependent, than Asians Drawing on recent evidence suggesting that the dopamine D4 receptor gene (DRD4) plays a role in modulating cultural learning, we predicted that carriers of DRD4 polymorphisms linked to increased dopamine signaling (7- or 2-repeat alleles) would show higher levels of culturally dominant social orientations, compared with noncarriers European Americans and Asian-born Asians (total N = 398) reported their social orientation on multiple scales They were also genotyped for DRD4 As in earlier work, European Americans were more independent, and Asian-born Asians more interdependent This cultural difference was significantly more pronounced for carriers of the 7- or 2-repeat alleles than for noncarriers Indeed, no cultural difference was apparent among the noncarriers Implications for potential coevolution of genes and culture are discussed

Advancing consumer neuroscience

Abstract: In the first decade of consumer neuroscience, strong progress has been made in understanding how neuroscience can inform consumer decision making. Here, we sketch the development of this discipline and compare it to that of the adjacent field of neuroeconomics. We describe three new frontiers for ongoing progress at both theoretical and applied levels. First, the field will broaden its boundaries to include genetics and molecular neuroscience, each of which will provide important new insights into individual differences in decision making. Second, recent advances in computational methods will improve the accuracy and out-of-sample generalizability of predicting decisions from brain activity. Third, sophisticated meta-analyses will help consumer neuroscientists to synthesize the growing body of knowledge, providing evidence for consistency and specificity of brain activations and their reliability as measurements of consumer behavior.

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

Abstract: 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.

Interaction of the ADRB2 gene polymorphism with childhood trauma in predicting adult symptoms of posttraumatic stress disorder.

Abstract: Posttraumatic stress disorder (PTSD) is a debilitating and highly prevalent (7.6% over a lifetime) consequence of trauma exposure.1,2 Recent large-scale military deployments and high-profile traumatic events have contributed to greater recognition of the PTSD burden both among health professionals3 and the general public.4 Trauma exposure is presumed to constitute a key etiologic factor in PTSD5; however, only a subset of trauma-exposed individuals develops PTSD,2 suggesting that vulnerability and resilience factors might have an important role in PTSD development. Heritable factors and trauma exposure have been implicated in PTSD by twin and family studies,6–8 suggesting that both genetic and environmental factors are involved; however, larger-scale efforts to identify specific genetic factors are relatively nascent. A recent review of the candidate gene studies of PTSD (approximately 40 to date) addressed 18 gene variants9; however, the majority (10 of 18) were based on a single, relatively small discovery cohort each. Only a few (eg, the FKBP5 gene10–14 and the SLC6A4 gene15,16) had more than 1 positive association, showed no reported negative findings, and involved relatively large cohorts. Beyond candidate gene studies, a small genome-wide association study17 (GWAS) identified a single-nucleotide polymorphism (SNP) within the retinoid-related orphan receptor alpha gene (RORA) as associated with PTSD, and a larger GWAS18 identified SNPs near the Tolloid-like 1 gene (TLL1) as associated with PTSD. Given that expected variance contributed by any single genetic factor is small19 and that the likelihood of pleiotropic and polygenic effects in psychiatric disorders is high,20 major effort is required to both replicate the reported findings and to identify novel risk genes if the goal of identifying genetic risk factors for PTSD is to be accomplished. Given the centrality of trauma exposure to the etiology of PTSD, a broad range of environmental exposures has been examined in this context, with early childhood trauma emerging as a risk factor linked to both the incident PTSD and the course of PTSD over time.21,22 Importantly, childhood trauma has been shown to act in interaction with the 2 most consistently replicated PTSD risk alleles in the SLC6A4 and FKBP5 genes,10,13,15,16 suggesting that gene × environment (G × E) approaches utilizing continuous measures of adult PTSD severity might be particularly useful in the study of PTSD pathogenesis. Finally, on the physiological level, while adrenergic and noradrenergic abnormalities have long been believed to have a key etiologic role in PTSD development,23,24 contributing to exaggerated physiological reactivity and hyperarousal symptoms,25–27 direct evidence of genetic variance in noradrenergic and adrenergic function in PTSD has been missing. The PTSD genetic findings so far have mainly implicated serotonin, dopamine, and hypothalamic-pituitary-adrenal axis genes. To address key open questions listed above, we have conducted a candidate gene study in PTSD-relevant pathways, including the adrenergic and noradrenergic systems, using independent discovery and confirmation cohorts and G × E models.

The neurosteroids allopregnanolone and dehydroepiandrosterone modulate resting-state amygdala connectivity.

Abstract: The neurosteroids allopregnanolone and dehydroepiandrosterone (DHEA) are integral components of the stress response and exert positive modulatory effects on emotion in both human and animal studies. Although these antidepressant and anxiolytic effects have been well established, to date, little research has examined their neural correlates, and no research has been conducted into the effects of neurosteroids on large-scale networks at rest. To investigate the neurosteroid impact on intrinsic connectivity networks, participants were administered 400 mg of pregnenolone (N = 16), 400 mg of DHEA (N = 14), or placebo (N = 15) and underwent 3T fMRI. Resting-state brain connectivity was measured using amygdala as a seed region. When compared with placebo, pregnenolone administration reduced connectivity between amygdala and dorsal medial prefrontal cortex, between amygdala and precuneus, and between amygdala and hippocampus. DHEA reduced connectivity between amygdala and periamygdala and between amygdala and insula. Reductions in amygdala to precuneus connectivity were associated with less self-reported negative affect. These results demonstrate that neurosteroids modulate amygdala functional connectivity during resting state and may be a target for pharmacological intervention. Additionally, allopregnanolone and DHEA may shift the balance between salience network and default network, a finding that could provide insight into the neurocircuitry of anxiety psychopathology.

Trauma exposure and sleep: using a rodent model to understand sleep function in PTSD.

Abstract: Post-traumatic stress disorder (PTSD) is characterized by intrusive memories of a traumatic event, avoidance behavior related to cues of the trauma, emotional numbing, and hyper-arousal Sleep abnormalities and nightmares are core symptoms of this disorder In this review, we propose a model which implicates abnormal activity in the locus coeruleus (LC), an important modifier of sleep–wake regulation, as the source of sleep abnormalities and memory abnormalities seen in PTSD Abnormal LC activity may be playing a key role in symptom formation in PTSD via sleep dysregulation and suppression of hippocampal bidirectional plasticity

Validation of lay-administered mental health assessments in a large Army National Guard cohort

Abstract: To report the reliability and validity of key mental health assessments in an ongoing study of the Ohio Army National Guard (OHARNG). The 2616 OHARNG soldiers received hour-long structured telephone surveys including the post-traumatic stress disorder (PTSD) checklist (PCV-C) and Patient Health Questionnaire – 9 (PHQ-9). A subset (N = 500) participated in two hour clinical reappraisals, using the Clinician-Administered PTSD Scale (CAPS) and the Structured Clinical Interview for DSM (SCID). The telephone survey assessment for PTSD and for any depressive disorder were both highly specific [92% (standard error, SE 0.01), 83% (SE 0.02)] with moderate sensitivity [54% (SE 0.09), 51% (SE 0.05)]. Other psychopathologies assessed included alcohol abuse [sensitivity 40%, (SE 0.04) and specificity 80% (SE 0.02)] and alcohol dependence [sensitivity, 60% (SE 0.05) and specificity 81% (SE 0.02)].The baseline prevalence estimates from the telephone study suggest alcohol abuse and dependence may be higher in this sample than the general population. Validity and reliability statistics suggest specific, but moderately sensitive instruments. Copyright © 2014 John Wiley & Sons, Ltd.

Incidence and predictors of acute psychological distress and dissociation after motor vehicle collision: a cross-sectional study

Abstract: Objective: We examined the incidence and predictors of peritraumatic distress and dissociation after one of the most common forms of civilian trauma exposure: motor vehicle collision (MVC). Method: In this study, patients presenting to the emergency department after MVCs who were without serious injury and discharged to home after evaluation (n = 935) completed an emergency department interview evaluating sociodemographic, collision-related, and psychological characteristics. Results: The incidence and predictors of distress (Peritraumatic Distress Inventory score ≥23) and dissociation (Michigan Critical Events Perception Scale score >3) were assessed. Distress was present in 355 of 935 patients (38%), and dissociation was present in 260 of 942 patients (28%). These outcomes showed only moderate correlation (r = .45) and had both shared and distinct predictors. Female gender, anxiety symptoms prior to the MVC, and vehicle damage severity predicted both distress and dissociation. Higher socioeconomic statu...

Stress-related psychological symptoms contribute to axial pain persistence after motor vehicle collision: path analysis results from a prospective longitudinal study.

Abstract: Posttraumatic stress disorder (PTSD) symptoms and pain after traumatic events such as motor vehicle collision (MVC) have been proposed to be mutually promoting. We performed a prospective multicenter study that enrolled 948 individuals who presented to the emergency department within 24 hours of MVC and were discharged home after evaluation. Follow-up evaluations were completed 6 weeks, 6 months, and 1 year after MVC. Path analysis results supported the hypothesis that axial pain after MVC consistently promotes the maintenance of hyperarousal and intrusive symptoms, from the early weeks after injury through 1 year. In addition, path analysis results supported the hypothesis that one or more PTSD symptom clusters had an influence on axial pain outcomes throughout the year after MVC, with hyperarousal symptoms most influencing axial pain persistence in the initial months after MVC. The influence of hyperarousal symptoms on pain persistence was only present among individuals with genetic vulnerability to stress-induced pain, suggesting specific mechanisms by which hyperarousal symptoms may lead to hyperalgesia and allodynia. Further studies are needed to better understand the specific mechanisms by which pain and PTSD symptoms enhance one another after trauma, and how such mechanisms vary among specific patient subgroups, to better inform the development of secondary preventive interventions.

Unit Support Protects Against Sexual Harassment and Assault Among National Guard Soldiers

Abstract: OBJECTIVE: Despite concerns about increased sexual harassment and assault after the 2013 legislation repealing the ban on women in combat, little research has examined military factors that could prevent sexual harassment and assault during deployment This study examined whether unit support, which reflects the quality of service members' relationships within their unit, protects against sexual harassment and assault during deployment METHODS: Participants were 1,674 Ohio Army National Guard service members who reported at least one deployment during a telephone survey conducted in 2008 and 2009 Participants completed measures of sexual harassment/assault, unit support, and psychosocial support Logistic regression was used to model odds of sexual harassment/assault RESULTS: Approximately 132% of men (n = 198) and 435% of women (n = 74) reported sexual harassment, and 11% of men (n = 17) and 188% of women (n = 32) reported sexual assault during their most recent deployment Greater unit support was associated with decreased odds of sexual harassment and assault CONCLUSIONS: A substantial proportion of men and women reported sexual harassment/assault Greater unit support was associated with diminished odds of sexual harassment/assault during deployment Programming designed to improve unit cohesion has the potential to reduce sexual harassment and assault Language: en

Mental Health Service Use in a Representative Sample of National Guard Soldiers

Abstract: Objective:With Operation Iraqi Freedom and Operation Enduring Freedom winding down, large numbers of National Guard members have recently returned from active deployment No prospective, longitudinal studies have examined predictors of mental health service use in a representative sample of National Guard soldiers This study investigated the prevalence and predictors of mental health service use in a representative sample of National Guard soldiersMethods:A representative sample (N=1,189) of Ohio Army National Guard participants was enrolled Demographic characteristics, mental health problems, and deployment status in 2009–2010 and mental health service use during the subsequent one-year period (2010−2011) were assessedResults:Approximately 16% of National Guard members used mental health services during the one-year period Among those with depression, posttraumatic stress disorder, anxiety, alcohol use disorders, or suicidal ideation, a little over one-third (37%) reported using services in the subs

Haplotype-based study of the association of alcohol and acetaldehyde-metabolising genes with alcohol dependence (with or without comorbid anxiety symptoms) in a Cape Mixed Ancestry population.

Abstract: Alcohol dependence (AD) has a large heritable component. Genetic variation in genes involved in the absorption and elimination of ethanol have been associated with AD. However, some of these polymorphisms are not present in an African population. Previous studies have reported that a type of AD which is characterized by anxious behaviour may be a genetically specific subtype of AD. We investigated whether variation in genes encoding cytochrome P450 2E1 (CYP2E1) or acetaldehyde-metabolising enzymes (ALDH1A1, ALDH2) might alter the risk of AD, with and without symptoms of anxiety, in a Cape population with mixed ancestry. Eighty case control pairs (one with AD, one without AD) were recruited and individually matched for potential confounders. Genotype data were available for 29 single-nucleotide polymorphisms (SNPs) across the three genes. Linkage disequilibrium D′ values were evaluated for all pairwise comparisons. Allele and haplotype frequencies were compared between cases and controls using a χ2 test. The ACAG haplotype in block 4 of the ALDH1A1 gene provided evidence of an association with AD (p = 0.03) and weak evidence of an association with AD without symptoms of anxiety (p = 0.06). When a genetic score was constructed using SNPs showing nominal evidence of association with AD, every extra risk allele increased the odds of AD by 35 % (OR 1.35, 95%CI 1.08, 1.68, p = 0.008) and the odds of having AD with anxiety symptoms increased by 53 % (OR 1.53, 95%CI 1.14, 2.05, p = 0.004). Although our results are supported by previous studies in other populations, they must be interpreted with caution due to the small sample size and the potential influence of population stratification.

Preliminary study on the relationship between visitation in the emergency department and posttraumatic mental health

Abstract: This study documented family/friend support to patients in the Emergency Department (ED), including bedside visits and transportation of patients from the ED after discharge, and measured depression, anxiety, and stress symptoms within 2 weeks, 1 month, and 3 months after motor vehicle accidents Stress and depression symptoms significantly decreased during the initial three months Family/friend visitation in the ED was negatively associated with anxiety and depression symptoms within 2 weeks and with stress symptoms months after trauma This pilot study suggests family/friend visitation in the ED is associated with fewer mental health issues in the months following an accident

Identifying Molecular Targets For PTSD Treatment Using Single Prolonged Stress

Abstract: : Our statement of work proposed that in our first year of funding, we would examine whether SPS disrupts extinction retention by disrupting consolidation and/or retrieval of extinction memory, and/or enhancing fear memory reconsolidation or by disrupting contextual modulation of extinction retrieval. Data collection for all of these experiments, detailed in Specific Aim 1, has been completed and data analysis is currently underway. We proposed that work on Specific Aim 2, in which we examine if SPS enhancement in brain GR and -AR expression alters glutamatergic and GABAergic function in neural circuits that mediate SPS-induced deficits in extinction retention, would also have been started during the first year and we have completed the behavior part and tissue collection for 5/8 experiments described in this aim. Scoring of behavioral data is underway for these experiments, with molecular assays planned for the coming year. In addition to completing the above, we have begun some of the work proposed in Specific Aims 3 and 4 that was timetabled for later in the funding period. In this report we detail findings from two of these experiments. We feel confident that we have exceeded the goals set out in our statement of work due to the large numbers of experiments for which data collection is complete, and the progress made on Specific Aims 3 and 4 ahead of schedule.