Associations Among Environmental Exposures and Physical and Psychiatric Symptoms in a Care-Seeking Sample of U.S. Military Veterans.

INTRODUCTION: Recent research and policy (e.g., the Sergeant First Class (SFC) Heath Robinson Honoring our Promise to Address Comprehensive Toxics (PACT) Act) have highlighted the potential health consequences of toxic environmental exposures. The purpose of the current study was to assess the self-reported prevalence of such exposures among a sample of U.S. military veterans seeking care at a Veterans Affairs facility and to examine associations between exposures and physical and psychiatric symptoms. MATERIALS AND METHODS: Participants were 4,647 newly enrolling post-9/11 veterans at the VA San Diego Healthcare System who completed standard clinical screening processes between January 2015 and April 2019. Electronic health screening data, including demographic information, military history, environmental exposures, and physical and psychiatric symptoms, were assessed. t-Tests for continuous variables and chi-square tests for categorical variables were used to compare exposed to unexposed veterans on demographic and military characteristics as well as physical and psychiatric symptoms. RESULTS: A total of 2,028 veterans (43.6%) reported exposure to environmental toxins during their military service. Analyses revealed a disproportionate burden of exposure on older, male, educated, combat veterans as well as Asian and Native American veterans. Exposure to any type of environmental toxin was associated with more physical symptoms, particularly pain, fatigue, and insomnia, as well as psychiatric symptoms, including moderate depressive symptomology, mild to moderate anxiety, and scores approaching the threshold for likely post-traumatic stress disorder and alcohol misuse. CONCLUSIONS: The high prevalence and detrimental health correlates of environmental exposures underscore the importance of implementing screening for exposures and providing healthcare services that address the multisystemic nature of exposure-related illness.

High executive functioning is associated with reduced posttraumatic stress after trauma exposure among male U.S. military personnel.

Introduction: Evidence suggests that executive function (EF) may play a key role in development of PTSD, possibly influenced by factors such as trauma type and timing. Since EF can be improved through intervention, it may be an important target for promoting resilience to trauma exposure. However, more research is needed to understand the relation between trauma exposure, EF, and PTSD. The goal of this study was to improve understanding of EF as a potential antecedent or protective factor for the development of PTSD among military personnel. Method: In a cohort of U.S. Marines and Navy personnel (N = 1,373), the current study tested the association between exposure to traumatic events (pre-deployment and during deployment) and PTSD severity, and whether EF moderated these associations. Three types of pre-deployment trauma exposure were examined: cumulative exposure, which included total number of events participants endorsed as having happened to them, witnessed, or learned about; direct exposure, which included total number of events participants endorsed as having happened to them; and interpersonal exposure, which included total number of interpersonally traumatic events participants' endorsed. EF was measured using the Penn Computerized Neurocognitive Battery. Results: EF was associated with less PTSD symptom severity at pre-deployment, even when adjusting for trauma exposure, alcohol use, traumatic brain injury, and number of years in the military. EF also moderated the relation between cumulative trauma exposure and interpersonal trauma exposure and PTSD, with higher EF linked to a 20 and 33% reduction in expected point increase in PTSD symptoms with cumulative and interpersonal trauma exposure, respectively. Finally, higher pre-deployment EF was associated with reduced PTSD symptom severity at post-deployment, independent of deployment-related trauma exposure and adjusting for pre-deployment PTSD. Conclusion: Our results suggest that EF plays a significant, if small role in the development of PTSD symptoms after trauma exposure among military personnel. These findings provide important considerations for future research and intervention and prevention, specifically, incorporating a focus on improving EF in PTSD treatment.

Effects of total sleep deprivation on sensorimotor gating in humans.

Sensorimotor gating is a measure of pre-attentional information processing and can be measured by prepulse inhibition (PPI) of the startle reflex. Sleep deprivation has been shown to disrupt PPI in animals and humans, and has been proposed as an early phase 2 model to probe antipsychotic efficacy in heathy humans. To further investigate the reliability and efficacy of sleep deprivation to produce PPI deficits we tested the effects of total sleep deprivation (TSD) on PPI in healthy controls in a highly controlled sleep laboratory environment. Participants spent 4 days and nights in a controlled laboratory environment with their sleep monitored with polysomnography. Participants were randomly assigned to either normal sleep on all 4 nights (N = 17) or 36 h of TSD on the 3rd or 4th night (N = 40). Participants were assessed for sleepiness using the Karolinska Sleepiness Scale (KSS) and underwent a daily PPI task (interstimlulus intervals 30-2000 ms) in the evening. Both within-subject effects (TSD vs. normal sleep in TSD group alone) and between-subject effects (TSD vs. no TSD group) of TSD on PPI were assessed. TSD increased subjective sleepiness measured with the KSS, but did not significantly alter overall startle, habituation or PPI. Sleep measures including duration, rapid eye movement and slow wave sleep duration were also not associated with PPI performance. The current results show that human sensorimotor gating may not be reliably sensitive to sleep deprivation. Further research is required for TSD to be considered a dependable model of PPI disruption for drug discovery in humans.

Prospective longitudinal assessment of sensorimotor gating as a risk/resiliency factor for posttraumatic stress disorder.

Little is understood about cognitive mechanisms that confer risk and resiliency for posttraumatic stress disorder (PTSD). Prepulse Inhibition (PPI) is a measure of pre-attentional response inhibition that is a stable cognitive trait disrupted in many neuropsychiatric disorders characterized by poor behavioral or cognitive inhibition, including PTSD. Differentiating between PTSD-related phenotypes that are pre-existing factors vs. those that emerge specifically after trauma is critical to understanding PTSD etiology and can only be addressed by prospective studies. This study tested the hypothesis that sensorimotor gating performance is associated with risk/resiliency for combat-related PTSD. As part of a prospective, longitudinal study, 1226 active duty Marines and Navy Corpsman completed a PPI test as well as a clinical interview to assess PTSD symptoms both before,  and 3 and 6 months after a combat deployment. Participants that developed PTSD 6 months following deployment (N=46)  showed lower PPI across pre and post-deployment time points compared to participants who did not develop PTSD (N=1182) . Examination of the distribution of PTSD across PPI performance revealed a lower than expected number of cases in the highest performing quartile compared to the rest of the distribution (p < 0.04). When controlling for other factors that predict PTSD in this population, those in the top 25% of PPI performance showed a >50% reduction in chance to develop PTSD (OR = 0.32). Baseline startle reactivity and startle habituation were not significantly different between PTSD risk and control groups. These findings suggest that robust sensorimotor gating may represent a resiliency factor for development of PTSD following trauma.

Prospective examination of pre-trauma anhedonia as a risk factor for post-traumatic stress symptoms.

Background: Anhedonia, the reduction of pleasure and reward-seeking behaviour, is a transdiagnostic symptom with well-described neural circuit mediators. Although typically observed during disease state, extant hypotheses suggest that anhedonia may also be an early risk factor for development of psychopathology. Understanding the contribution of anhedonia to the trauma-response trajectory may bolster inferences about biological mechanisms contributing to pre-trauma risk versus trauma-related symptom expression, knowledge of which could aid in targeted interventions. Objective: Using a prospective, longitudinal design in a population at risk for trauma disorders, we tested the hypothesis that anhedonia may be a pre-trauma risk factor for post-traumatic stress disorder (PTSD) symptoms. Methods: Adult male participants from the Marine Resilience Study (N = 2,593) were assessed across three time-points (pre-deployment, 3-month and 6-month post-deployment). An anhedonia factor was extracted from self-report instruments pre-trauma and tested for its relationship with development of PTSD re-experiencing symptoms after deployment. Results: Higher pre-deployment anhedonia predicted increased PTSD intrusive re-experiencing symptoms at 3- and 6-months post-deployment when controlling for pre-trauma PTSD and depression symptoms. Depression symptoms were not significant predictors of subsequent PTSD intrusive re-experiencing symptoms. Anhedonia at 3 mo also robustly predicted maintenance of PTSD intrusive re-experiencing symptoms at the 6 mo time point. Conclusions: Pre-deployment anhedonia may be a pre-trauma risk factor for PTSD, not simply a state-dependent effect of trauma exposure and PTSD symptom expression. Anhedonia may contribute to persistence and/or chronicity of re-experiencing symptoms after the emergence of PTSD symptoms.

Antecedentes: La anhedonia, reducción del placer y del comportamiento de búsqueda de recompensa, es un síntoma transdiagnóstico con circuitos neurales mediadores bien descritos. Aunque es observada típicamente durante estados patológicos, hipótesis existentes sugieren que la anhedonia puede ser también un factor de riesgo temprano para el desarrollo de psicopatología. La comprensión de la contribución de la anhedonia a la trayectoria de la respuesta al trauma puede reforzar las inferencias sobre los mecanismos biológicos que contribuyen al riesgo pre-trauma versus la expresión sintomática relacionada al trauma, conocimiento que puede ayudar en intervenciones dirigidas.Objetivo: Utilizando un diseño longitudinal prospectivo en una población de riesgo para trastornos traumáticos, probamos la hipótesis de que la anhedonia puede ser un factor de riesgo pre-trauma para síntomas de trastorno de estrés postraumático (TEPT).Métodos: Participantes masculinos adultos del Estudio de Resiliencia de la Marina (N = 2,593) fueron evaluados a lo largo de 3 puntos temporales (antes del despliegue, a los 3 meses, y a los 6 meses post-despliegue). Se extrajo un factor para anhedonia a partir de instrumentos auto-aplicados pre-trauma y fue evaluado por su relación con el desarrollo de síntomas de re-experimentación del TEPT después del despliegue.Resultados: Una anhedonia más alta pre-despliegue predijo un aumento de síntomas de TEPT a los 3 y 6 meses post-despliegue, al controlar con síntomas de TEPT y de depresión pre-trauma. Los síntomas depresivos no fueron predictores significativos de síntomas de TEPT posteriores. La anhedonia a los 3 meses predijo también de forma robusta la mantención de síntomas de TEPT a los 6 meses.Conclusiones: La anhedonia pre-despliegue puede ser un factor de riesgo pre-trauma para TEPT, no sólo como un efecto dependiente del estado de la exposición al trauma y la expresión de síntomas de TEPT. La anhedonia puede contribuir a la persistencia y/o cronicidad de síntomas de re-experimentación tras el inicio de los síntomas de TEPT.

Dissociable impact of childhood trauma and deployment trauma on affective modulation of startle.

Trauma disorders are often associated with alterations in aversive anticipation and disruptions in emotion/fear circuits. Heightened or blunted anticipatory responding to negative cues in adulthood may be due to differential trauma exposure during development, and previous trauma exposure in childhood may also modify effects of subsequent trauma in adulthood. The aim of the current investigation was to examine the contributions of childhood trauma on affective modulation of startle before and after trauma exposure in adulthood (a combat deployment). Adult male participants from the Marine Resilience Study with (n = 1145) and without (n = 1312) a history of reported childhood trauma completed an affective modulation of startle task to assess aversive anticipation. Affective startle response was operationalized by electromyography (EMG) recording of the orbicularis oculi muscle in response to acoustic stimuli when anticipating positive and negative affective images. Startle responses to affective images were also assessed. Testing occurred over three time-points; before going on a 7 month combat deployment and 3 and 6 months after returning from deployment. Startle response when anticipating negative images was greater compared to pleasant images across all three test periods. Across all 3 time points, childhood trauma was consistently associated with significantly blunted startle when anticipating negative images, suggesting reliable effects of childhood trauma on aversive anticipation. Conversely, deployment trauma was associated with increased startle reactivity post-deployment compared to pre-deployment, which was independent of childhood trauma and image valence. These results support the hypothesis that trauma exposure during development vs. adulthood may have dissociable effects on aversive anticipation and arousal mechanisms. Further study in women and across more refined age groups is needed to test generalizability and identify potential developmental windows for these differential effects.

Sleep disturbance at pre-deployment is a significant predictor of post-deployment re-experiencing symptoms.

Background: Insomnia is common in service members and associated with many mental and physical health problems. Recently, longitudinal data have been used to assess the impact of disturbed sleep on mental health outcomes. These studies have consistently shown relationships between sleep disturbance and development of mental illness. Objective: The present study examined the longitudinal relationship between sleep disturbance and PTSD symptomatology in a cohort of Marines and Navy Corpsmen deployed to Iraq and Afghanistan (n = 2,404) assessed prior to deployment, as well as at -3 and 6 months post-deployment. Additionally, we aimed to investigate the extent to which these relationships are moderated by combat-stress severity, and to what extent these findings are replicated in a second, separate cohort of Marines and Navy corpsmen (n = 938) assessed with identical measures prior to deployment and within 3 months of return. Method: The present study employed latent variable path models to examine the relationships between pre-deployment sleep disturbance and post-deployment re-experiencing symptoms. Initial cross-lagged path models were conducted on discovery and replication samples to validate the hypothesized predictive relationships. Follow up moderation path models were then conducted to include the effect of combat-stress severity on these relationships. Results: Initial cross-lagged models supported a significant relationship between pre-deployment sleep disturbance and future re-experiencing PTSD symptoms at all time points. Initial moderation models showed a small moderator effect of combat-stress severity, though the main predictive relationship between pre-deployment sleep disturbance and PTSD symptoms remained significant. The moderator effect was not significant in the replication sample. Conclusions: The results of this study support pre-deployment sleep disturbance as a risk factor for development of post-deployment PTSD symptoms. Interventions aimed at normalizing sleep may be important in preventive measures for PTSD.

Antecedentes: El insomnio es común en los miembros del servicio y está asociado con muchos problemas de salud mental y física. Recientemente, se han utilizado datos longitudinales para evaluar el impacto de las alteraciones del sueño en los resultados de salud mental. Estos estudios han demostrado consistentemente las relaciones entre las alteraciones del sueño y el desarrollo de enfermedades mentales.Objetivo: El presente estudio examinó la relación longitudinal entre el trastorno del sueño y la sintomatología del TEPT en una cohorte de infantes y médicos de Marina desplegados en Irak y Afganistán evaluados antes del despliegue, así como a los 3 y 6 meses posteriores al despliegue. Además, nuestro objetivo fue investigar hasta qué punto estas relaciones son moderadas por la gravedad del estrés de combate, y en qué medida estos hallazgos se replican en una segunda cohorte separada de marinos y médicos de la Marina evaluados con medidas idénticas antes del despliegue y dentro de los 3 meses de regreso.Método: El presente estudio empleó modelos de trayectorias de variables latentes para examinar las relaciones entre la alteración del sueño previa al despliegue y los síntomas de reexperimentación posterior al despliegue. Se llevaron a cabo modelos iniciales de trayectorias de retardo cruzadas en muestras de descubrimiento y replicación para validar las relaciones predictivas hipotéticas. Los modelos de seguimiento de las trayectorias de moderación se llevaron a cabo para incluir el efecto de la gravedad del estrés de combate en estas relaciones.Resultados: Los modelos iniciales de retardo cruzado respaldaron una relación significativa entre la alteración del sueño previa al despliegue y los síntomas futuros de TEPT que se vuelven a experimentar en todos los momentos. Los modelos de moderación iniciales mostraron un efecto moderador pequeño de la gravedad del estrés de combate, aunque la principal relación predictiva entre la alteración del sueño previa al despliegue y los síntomas de TEPT se mantuvo significativa. El efecto moderador no fue significativo en la muestra de replicación.Conclusiones: Los resultados de este estudio respaldan que la alteración del sueño previa al despliegue es un factor de riesgo para el desarrollo de síntomas de TEPT posterior al despliegue. Intervenciones dirigidas a normalizar el sueño pueden ser importantes en cuanto a medidas preventivas para el TEPT.

Characterizing the neural circuitry associated with configural threat learning.

Contextual threat learning is often associated with two processes: elemental and configural learning. Few studies have examined configural learning where subjects form a representation of the threat-related context as a gestalt whole from the individual features in the environment. The goal of the current study was to compare and contrast neural circuitry recruited by variation in demands placed on configural threat encoding. Subjects (N = 25) completed a configural threat learning task, where we manipulated the amount of configural encoding required to learn the threat association (low demand: changes to a discrete element of the context; and high demand: rearrangement of elements). US expectancy ratings, skin conductance responses (SCR), and functional magnetic resonance imaging (fMRI) were collected. Subjects successfully learned the configural threat association as measured by US expectancy ratings, SCR, and BOLD activity. Hippocampal and amygdala region of interest analyses indicated differential configural threat learning and predicted SCR measures of learning. Furthermore, whole brain analyses identified four circuits that were impacted by the amount of differential configural encoding required, but none correlated with SCR. These results set the stage for a more detailed understanding of how configural threat learning is instantiated in the brain-an important mechanism associated with PTSD and other fear-related disorders.

REM sleep and safety signal learning in posttraumatic stress disorder: A preliminary study in military veterans.

BACKGROUND: Posttraumatic Stress Disorder (PTSD) is associated with a number of negative physical and mental health consequences. Fear conditioning plays an important mechanistic role in PTSD, and PTSD patients also show deficits in safety signal learning. Sleep, particularly REM sleep, is linked to improved safety learning and extinction processes in animal models and healthy humans. No studies have examined the link between REM sleep and safety signal learning or extinction memory in clinical populations. METHODS: This study examined the relationship between REM sleep, safety signal learning, and extinction processes in veterans with PTSD (n = 13). Patients' overnight sleep was characterized in the laboratory via polysomnography (PSG). The next day, participants underwent a fear conditioning paradigm during which they acquired fear toward a visual cue. This testing session also included a visual cue that became a safety signal (CS-). Following conditioning, the veterans' sleep was monitored overnight again, after which they underwent extinction training. Following a third night of sleep, extinction recall and safety recall were tested. Bivariate correlations examined the relationship between the slope of safety signal learning and subsequent REM sleep, as well as the relationship between REM sleep and subsequent extinction recall and safety recall on the last day of testing. RESULTS: Veterans learned to differentiate the CS+ and the CS- on the first day of testing. Veterans who underwent safety learning more quickly on the first day of testing showed more efficient REM sleep that night (r = .607, p = .028). On the second day of testing, the patients successfully underwent extinction learning. Patients with a higher percentage of REM sleep on the last night of the study showed more safety recall early on the last day of testing (r = .688, p = .009). CONCLUSION: To our knowledge, this was the first study to examine the relationship between objective sleep and fear-potentiated startle performance in veterans with PTSD. Study methods were well tolerated by participants, supporting feasibility of the experimental design. Results indicated REM sleep was associated with both initial safety learning and subsequent safety recall. Taken together with previous studies in healthy controls, these preliminary results provide additional evidence suggesting REM sleep could play a mechanistic role in the maintenance of PTSD and thus identify a modifiable biological process to target in treatment of PTSD. These findings should be replicated in larger samples.

Neural measures associated with configural threat acquisition.

Contextual threat learning reflects two often competing processes: configural and elemental learning. Configural threat learning is a hippocampal-dependent process of forming a conjunctive representation of a context through binding of several multi-modal elements. In contrast, elemental threat-learning is governed by the amygdala and involves forming associative relationships between individual features within the context. Contextual learning tasks in humans however, rarely probe if a learned fear response is truly due to configural learning vs. simple elemental associations. The aim of the current study was to probe both constructs separately to enable a more refined interpretation of configural vs. elemental threat learning performance and mediating circuits. Subjects (n = 25) performed both a novel feature-identical contextual threat conditioning task and a discrete cue threat acquisition task while undergoing functional magnetic resonance imaging. Results demonstrated increased hippocampus activity for the threat configuration compared to the safe configuration. This pattern was not observed in the amygdala. In contrast, elemental threat learning was associated with increased amygdala, but not hippocampus activity. Whole-brain analyses revealed that both configural and elemental threat acquisition share neural circuitry related to fear expression. These results provide support for the importance of the hippocampus specifically in configural threat acquisition and fear expression.

Individual variation in working memory is associated with fear extinction performance.

PTSD has been associated consistently with abnormalities in fear acquisition and extinction learning and retention. Fear acquisition refers to learning to discriminate between threat and safety cues. Extinction learning reflects the formation of a new inhibitory-memory that competes with a previously learned threat-related memory. Adjudicating the competition between threat memory and the new inhibitory memory during extinction may rely, in part, on cognitive processes such as working memory (WM). Despite significant shared neural circuits and signaling pathways the relationship between WM, fear acquisition, and extinction is poorly understood. Here, we analyzed data from a large sample of healthy Marines who underwent an assessment battery including tests of fear acquisition, extinction learning, and WM (N-back). Fear potentiated startle (FPS), fear expectancy ratings, and self-reported anxiety served as the primary dependent variables. High WM ability (N = 192) was associated with greater CS + fear inhibition during the late block of extinction and greater US expectancy change during extinction learning compared to individuals with low WM ability (N = 204). WM ability was not associated with magnitude of fear conditioning/expression. Attention ability was unrelated to fear acquisition or extinction supporting specificity of WM associations with extinction. These results support the conclusion that individual differences in WM may contribute to regulating fear responses.

The Future of Contextual Fear Learning for PTSD Research: A Methodological Review of Neuroimaging Studies.

There has been a great deal of recent interest in human models of contextual fear learning, particularly due to the use of such paradigms for investigating neural mechanisms related to the etiology of posttraumatic stress disorder. However, the construct of "context" in fear conditioning research is broad, and the operational definitions and methods used to investigate contextual fear learning in humans are wide ranging and lack specificity, making it difficult to interpret findings about neural activity. Here we will review neuroimaging studies of contextual fear acquisition in humans. We will discuss the methodology associated with four broad categories of how contextual fear learning is manipulated in imaging studies (colored backgrounds, static picture backgrounds, virtual reality, and configural stimuli) and highlight findings for the primary neural circuitry involved in each paradigm. Additionally, we will offer methodological recommendations for human studies of contextual fear acquisition, including using stimuli that distinguish configural learning from discrete cue associations and clarifying how context is experimentally operationalized.

COMT val158met polymorphism links to altered fear conditioning and extinction are modulated by PTSD and childhood trauma.

BACKGROUND: Risk for posttraumatic stress disorder (PTSD) is thought to be mediated by gene × environment (G × E) interactions that affect core cognitive processes such as fear learning. The catechol-O-methyltransferase (COMT) val158met polymorphism has been associated with risk for PTSD and impaired fear inhibition. We used a large, relatively homogenous population to (1) replicate previous findings of poor fear inhibition in COMT Met/Met carriers with PTSD; (2) determine if COMT association with fear inhibition is moderated by childhood trauma (CT), an environmental risk factor for PTSD; and (3) determine if COMT is associated with altered fear processes after recent exposure to combat trauma. METHODS: Male Marines and Navy Corpsmen of European-American ancestry were assessed prior to (n = 714) and 4-6 months after deployment to Afghanistan (n = 452). Acquisition and extinction of fear-potentiated startle, childhood and combat trauma history, and PTSD diagnosis were assessed at both time points. RESULTS: Before deployment, Met/Met genotype was associated with fear inhibition deficits in participants with current PTSD; however, this association was dependent on CT exposure. After deployment, combat trauma was associated with a modest reduction in fear extinction in Met/Met compared with Val/Val carriers. There were no associations of COMT genotype with fear extinction within healthy and non-traumatized individuals. CONCLUSIONS: These findings support the hypothesis that G × E interactions underlie associations of COMT val158met with fear inhibition deficits. These studies confirm that Met/Met carriers with PTSD have poor fear inhibition, and support further research in understanding how this polymorphism might impact response to extinction-based therapies.

Sleep Deprivation Disrupts Recall of Conditioned Fear Extinction.

BACKGROUND: Learned fear is crucial in the development and maintenance of posttraumatic stress disorder (PTSD) and other anxiety disorders, and extinction of learned fear is necessary for response to exposure-based treatments. In humans, research suggests disrupted sleep impairs consolidation of extinction, though no studies have examined this experimentally using total sleep deprivation. METHODS: Seventy-one healthy controls underwent a paradigm to acquire conditioned fear to a visual cue. Twenty-four hours after fear conditioning, participants underwent extinction learning. Twenty-four hours after extinction learning, participants underwent extinction recall. Participants were randomized to three groups: 1) well-rested throughout testing ("normal sleep"; n = 21); 2) 36 hours total sleep deprivation before extinction learning ("pre-extinction deprivation"; n = 25); or 3) 36 hours total sleep deprivation after extinction learning and before extinction recall ("post-extinction deprivation"; n = 25). The groups were compared on blink EMG reactivity to the condition stimulus during extinction learning and recall. RESULTS: There were no differences among the three groups during extinction learning. During extinction recall, the pre-extinction deprivation group demonstrated significantly less extinction recall than the normal sleep group. There was no significant difference between the normal sleep and post-extinction deprivation group during extinction recall. Results indicated sleep deprivation prior to extinction training significantly disrupts extinction recall. CONCLUSIONS: These findings suggest that (1) sleep deprivation in the immediate aftermath of trauma could be a potential contributor to PTSD development and maintenance via interference with natural extinction processes and (2) management of sleep symptoms should be considered during extinction-based therapy.

Fear learning alterations after traumatic brain injury and their role in development of posttraumatic stress symptoms.

BACKGROUND: It is unknown how traumatic brain injury (TBI) increases risk for posttraumatic stress disorder (PTSD). One potential mechanism is via alteration of fear-learning processes that could affect responses to trauma memories and cues. We utilized a prospective, longitudinal design to determine if TBI is associated with altered fear learning and extinction, and if fear processing mediates effects of TBI on PTSD symptom change. METHODS: Eight hundred fifty two active-duty Marines and Navy Corpsmen were assessed before and after deployment. Assessments included TBI history, PTSD symptoms, combat trauma and deployment stress, and a fear-potentiated startle task of fear acquisition and extinction. Startle response and self-reported expectancy and anxiety served as measures of fear conditioning, and PTSD symptoms were measured with the Clinician-Administered PTSD Scale. RESULTS: Individuals endorsing "multiple hit" exposure (both deployment TBI and a prior TBI) showed the strongest fear acquisition and highest fear expression compared to groups without multiple hits. Extinction did not differ across groups. Endorsing a deployment TBI was associated with higher anxiety to the fear cue compared to those without deployment TBI. The association of deployment TBI with increased postdeployment PTSD symptoms was mediated by postdeployment fear expression when recent prior-TBI exposure was included as a moderator. TBI associations with increased response to threat cues and PTSD symptoms remained when controlling for deployment trauma and postdeployment PTSD diagnosis. CONCLUSIONS: Deployment TBI, and multiple-hit TBI in particular, are associated with increases in conditioned fear learning and expression that may contribute to risk for developing PTSD symptoms.

HIGH AND LOW THRESHOLD FOR STARTLE REACTIVITY ASSOCIATED WITH PTSD SYMPTOMS BUT NOT PTSD RISK: EVIDENCE FROM A PROSPECTIVE STUDY OF ACTIVE DUTY MARINES.

BACKGROUND: Heightened startle response is a symptom of PTSD, but evidence for exaggerated startle in PTSD is inconsistent. This prospective study aimed to clarify whether altered startle reactivity represents a trait risk-factor for developing PTSD or a marker of current PTSD symptoms. METHODS: Marines and Navy Corpsmen were assessed before (n = 2,571) and after (n = 1,632) deployments to Iraq or Afghanistan with the Clinician-Administered PTSD Scale (CAPS). A predeployment startle-threshold task was completed with startle probes presented over 80-114 dB[A] levels. Latent class mixture modeling identified three growth classes of startle performance: "high," "low," and "moderate" threshold classes. Zero-inflated negative binomial regression was used to assess relationships between predeployment startle threshold and pre- and postdeployment psychiatric symptoms. RESULTS: At predeployment, the low-threshold class had higher PTSD symptom scores. Relative to the moderate-threshold class, low-threshold class membership was associated with decreased likelihood of being symptom-free at predeployment, based on CAPS, with particular associations with numbing and hyperarousal subscales, whereas high-threshold class membership was associated with more severe predeployment PTSD symptoms, in particular avoidance. Associations between low-threshold membership and CAPS symptoms were independent from measures of trauma burden, whereas associations between high-threshold membership and CAPS were not. Predeployment startle threshold did not predict postdeployment symptoms. CONCLUSIONS: This study found that both low startle threshold (heightened reactivity) and high startle threshold (blunted reactivity) were associated with greater current PTSD symptomatology, suggesting that startle reactivity is associated with current PTSD rather than a risk marker for developing PTSD.

Fear extinction memory performance in a sample of stable, euthymic patients with bipolar disorder.

OBJECTIVES: Affective dysregulation is a core feature of bipolar disorder (BD). Abnormalities in neural circuits underlying affect regulation have been observed in BD, specifically in the structure and function of the amygdala and orbital frontal cortex (OFC). Fear extinction is an automatic affect regulatory process relying on neural circuits that are abnormal in BD. Thus, fear extinction might be useful in probing automatic affect regulation deficits in BD. We tested the hypothesis that BD is associated with reduced ability to extinguish fear responses. METHODS: We examined fear conditioning, extinction, and extinction memory recall in a sample of stable, euthymic participants with BD (n=19) vs. healthy comparison participants (n=32). A limited number of subjects (BD: n=12; healthy comparison: n=11) underwent structural MRI scanning to examine cortical size associations with extinction recall. RESULTS: Both healthy comparison and BD participants were successful in acquiring a fear response, but BD participants responded with greater startle to both threat and safety cues. Both groups showed significant extinction. The BD group showed superior extinction recall. Extinction recall was associated with right rostral middle frontal cortex thickness across groups, whereas right OFC surface area was associated with recall only in healthy comparisons. LIMITATIONS: Limitations include use of a stable, highly screened sample and a relatively small number of participants available for MRI analysis. CONCLUSIONS: Increased fear reactivity may be related to a "trait" disruption in BD patients similar to that previously described in anxiety disorders. This task may be useful for probing automatic affect regulatory processes in BD, and understanding treatment response.

Early Adolescent Emergence of Reversal Learning Impairments in Isolation-Reared Rats.

Cognitive impairments appear early in the progression of schizophrenia, often preceding the symptoms of psychosis. Thus, the systems subserving these functions may be more vulnerable to, and mechanistically linked with, the initial pathology. Understanding the trajectory of behavioral and anatomical abnormalities relevant to the schizophrenia prodrome and their sensitivity to interventions in relevant models will be critical to identifying early therapeutic strategies. Isolation rearing of rats is an environmental perturbation that deprives rodents of social contact from weaning through adulthood and produces behavioral and neuronal abnormalities that mirror some pathophysiology associated with schizophrenia, e.g. frontal cortex abnormalities and prepulse inhibition (PPI) of startle deficits. Previously, we showed that PPI deficits in isolation-reared rats emerge in mid-adolescence (4 weeks after weaning; approx. postnatal day 52) but are not present when tested at 2 weeks after weaning (approx. postnatal day 38). Because cognitive deficits are reported during early adolescence, are relevant to the prodrome, and are linked to functional outcome, we examined the putative time course of reversal learning deficits in isolation-reared rats. Separate groups of male Sprague Dawley rats were tested in a two-choice discrimination task at 2 and 8 weeks after weaning, on postnatal day 38 and 80, respectively. The isolation-reared rats displayed impaired reversal learning at both time points. Isolation rearing was also associated with deficits in PPI at 4 and 10 weeks after weaning. The reversal learning deficits in the isolated rats were accompanied by reductions in parvalbumin immunoreactivity, a marker for specific subpopulations of GABAergic neurons, in the hippocampus. Hence, isolation rearing of rats may offer a unique model to examine the ontogeny of behavioral and neurobiological alterations that may be relevant to preclinical models of prodromal psychosis. © 2015 S. Karger AG, Basel.

Intranasal oxytocin administration prior to exposure therapy for arachnophobia impedes treatment response.

BACKGROUND: Recent years have seen the emergence of a new paradigm for treatment of anxiety disorders focusing on development of drugs that facilitate psychotherapies via targeted effects on neuroplasticity. One compound that has generated interest in this regard is oxytocin (OT), a mammalian neuropeptide that modulates activity of the neurocircuit mediating fear extinction and memory processes. Recent research in healthy humans has suggested that intranasal OT administered prior to fear extinction training enhances fear extinction performance, supporting its potential to augment exposure-based psychotherapy. Here, we tested the hypothesis that OT treatment would facilitate response to exposure therapy in patients with specific phobia. METHODS: We conducted a small proof-of-concept trial investigating the effect of pretreatment intranasal OT administration on a brief, single-session exposure treatment for arachnophobia (fear of spiders). The study was randomized, double-blind, and placebo controlled (n = 13 placebo, 11 females; n = 10 OT, 8 females) with 1-week and 1-month follow-up assessments. Dependent measures attended to arachnophobia symptoms (self-report), phobic behavior (behavioral avoidance of spider task), and treatment credibility/therapeutic alliance. RESULTS: Administration of OT prior to exposure therapy tended to impede treatment response as measured by self-report of symptoms at both follow-up periods. OT treatment did not significantly affect behavioral measures of fear. Immediately after OT administration but before therapy, the OT group trended toward less confidence in the treatment. The OT group also trended toward lower ratings of therapeutic alliance than placebo. CONCLUSIONS: These results suggest that OT administration effects on extinction may vary depending on conditions and population.