Research Articles

Despite the large comorbidity between PTSD and opioid use disorders, as well as the common treatment of physical injuries resulting from trauma with opioids, the ability of opioid treatments to subsequently modify PTSD-related behavior has not been well studied. Using the stress-enhanced fear learning (SEFL) model for PTSD, we characterized the impact of chronic opioid regimens on the sensitization of fear learning seen following traumatic stress in mice. We demonstrate for the first time that chronic opioid pretreatment is able to robustly augment associative fear learning. Highlighting aversive learning as the cognitive process mediating this behavioral outcome, these changes were observed after a considerable period of drug cessation, generalized to learning about multiple aversive stimuli, were not due to changes in stimulus sensitivity or basal anxiety, and correlated with a marker of synaptic plasticity within the basolateral amygdala. Additionally, these changes were not observed when opioids were given after the traumatic event. Moreover, we found that neither reducing the frequency of opioid administration nor bidirectional manipulation of acute withdrawal impacted the subsequent enhancement in fear learning seen. Given the fundamental role of associative fear learning in the generation and progression of PTSD, these findings are of direct translational relevance to the comorbidity between opioid dependence and PTSD, and they are also pertinent to the use of opioids for treating pain resulting from traumas involving physical injuries.

Objective: The study compared delay of treatment for posttraumatic stress disorder (PTSD), major depressive disorder, and alcohol use disorder among post-9/11 veterans versus pre-9/11 veterans and civilians. Methods: The 2012–2013 National Epidemiologic Survey on Alcohol and Related Conditions–III (NESARC-III), a nationally representative survey of U.S. noninstitutionalized adults, was used. Participants included 13,528 civilians, 1,130 pre-9/11 veterans, and 258 post-9/11 veterans with lifetime diagnoses of PTSD, major depression, or alcohol use disorder. Cox proportional hazard models, controlling for relevant demographic characteristics, were used to estimate differences in treatment delay (i.e., time between diagnosis and treatment). Results: Post-9/11 veterans were less likely to delay treatment for PTSD and depression than pre-9/11 veterans (adjusted hazard ratios [AHRs]=0.69 and 0.74, respectively) and civilians (AHRs=0.60 and 0.67, respectively). No differences in treatment delay were observed between post-9/11 veterans and pre-9/11 veterans or civilians for alcohol use disorder. In an exploratory analysis, post-9/11 veterans with past-year military health care coverage (e.g., Veterans Health Administration) had shorter delays for depression treatment compared with post-9/11 veterans without military coverage, pre-9/11 veterans regardless of health care coverage, and civilians, although past-year coverage did not predict treatment delay for PTSD or alcohol use disorder. Conclusions: Post-9/11 veterans were less likely to delay treatment for some common psychiatric conditions compared with pre-9/11 veterans or civilians, which may reflect efforts to engage recent veterans in mental health care. All groups exhibited low initiation of treatment for alcohol use disorder, highlighting the need for further engagement efforts.

Importance: Traumatic brain injury (TBI) has been associated with adverse mental health outcomes, such as posttraumatic stress disorder (PTSD) and major depressive disorder (MDD), but little is known about factors that modify risk for these psychiatric sequelae, particularly in the civilian sector. Objective: To ascertain prevalence of and risk factors for PTSD and MDD among patients evaluated in the emergency department for mild TBI (mTBI). Design, Setting, and Participants: Prospective longitudinal cohort study (February 2014 to May 2018). Posttraumatic stress disorder and MDD symptoms were assessed using the PTSD Checklist for DSM-5 and the Patient Health Questionnaire-9 Item. Risk factors evaluated included preinjury and injury characteristics. Propensity score weights-adjusted multivariable logistic regression models were performed to assess associations with PTSD and MDD. A total of 1155 patients with mTBI (Glasgow Coma Scale score, 13-15) and 230 patients with nonhead orthopedic trauma injuries 17 years and older seen in 11 US hospitals with level 1 trauma centers were included in this study. Main Outcomes and Measures: Probable PTSD (PTSD Checklist for DSM-5 score, ≥33) and MDD (Patient Health Questionnaire-9 Item score, ≥15) at 3, 6, and 12 months postinjury. Results: Participants were 1155 patients (752 men [65.1%]; mean [SD] age, 40.5 [17.2] years) with mTBI and 230 patients (155 men [67.4%]; mean [SD] age, 40.4 [15.6] years) with nonhead orthopedic trauma injuries. Weights-adjusted prevalence of PTSD and/or MDD in the mTBI vs orthopedic trauma comparison groups at 3 months was 20.0% (SE, 1.4%) vs 8.7% (SE, 2.2%) (P < .001) and at 6 months was 21.2% (SE, 1.5%) vs 12.1% (SE, 3.2%) (P = .03). Risk factors for probable PTSD at 6 months after mTBI included less education (adjusted odds ratio, 0.89; 95% CI, 0.82-0.97 per year), being black (adjusted odds ratio, 5.11; 95% CI, 2.89-9.05), self-reported psychiatric history (adjusted odds ratio, 3.57; 95% CI, 2.09-6.09), and injury resulting from assault or other violence (adjusted odds ratio, 3.43; 95% CI, 1.56-7.54). Risk factors for probable MDD after mTBI were similar with the exception that cause of injury was not associated with increased risk. Conclusions and Relevance: After mTBI, some individuals, on the basis of education, race/ethnicity, history of mental health problems, and cause of injury were at substantially increased risk of PTSD and/or MDD. These findings should influence recognition of at-risk individuals and inform efforts at surveillance, follow-up, and intervention.

By combining computational, morphological, and functional analyses, this study relates latent markers of associative threat learning to overt post-traumatic stress disorder (PTSD) symptoms in combat veterans. Using reversal learning, we found that symptomatic veterans showed greater physiological adjustment to cues that did not predict what they had expected, indicating greater sensitivity to prediction errors for negative outcomes. This exaggerated weighting of prediction errors shapes the dynamic learning rate (associability) and value of threat predictive cues. The degree to which the striatum tracked the associability partially mediated the positive correlation between prediction-error weights and PTSD symptoms, suggesting that both increased prediction-error weights and decreased striatal tracking of associability independently contribute to PTSD symptoms. Furthermore, decreased neural tracking of value in the amygdala, in addition to smaller amygdala volume, independently corresponded to higher PTSD symptom severity. These results provide evidence for distinct neurocomputational contributions to PTSD symptoms.

Background: Although post-traumatic stress disorder (PTSD) onset-persistence is thought to vary significantly by trauma type, most epidemiological surveys are incapable of assessing this because they evaluate lifetime PTSD only for traumas nominated by respondents as their 'worst.' Objective: To review research on associations of trauma type with PTSD in the WHO World Mental Health (WMH) surveys, a series of epidemiological surveys that obtained representative data on trauma-specific PTSD. Method: WMH Surveys in 24 countries (n = 68,894) assessed 29 lifetime traumas and evaluated PTSD twice for each respondent: once for the 'worst' lifetime trauma and separately for a randomly-selected trauma with weighting to adjust for individual differences in trauma exposures. PTSD onset-persistence was evaluated with the WHO Composite International Diagnostic Interview. Results: In total, 70.4% of respondents experienced lifetime traumas, with exposure averaging 3.2 traumas per capita. Substantial between-trauma differences were found in PTSD onset but less in persistence. Traumas involving interpersonal violence had highest risk. Burden of PTSD, determined by multiplying trauma prevalence by trauma-specific PTSD risk and persistence, was 77.7 person-years/100 respondents. The trauma types with highest proportions of this burden were rape (13.1%), other sexual assault (15.1%), being stalked (9.8%), and unexpected death of a loved one (11.6%). The first three of these four represent relatively uncommon traumas with high PTSD risk and the last a very common trauma with low PTSD risk. The broad category of intimate partner sexual violence accounted for nearly 42.7% of all person-years with PTSD. Prior trauma history predicted both future trauma exposure and future PTSD risk. Conclusions: Trauma exposure is common throughout the world, unequally distributed, and differential across trauma types with respect to PTSD risk. Although a substantial minority of PTSD cases remits within months after onset, mean symptom duration is considerably longer than previously recognized.

The last decade of neuroimaging research has yielded important information concerning the structure, neurochemistry, and function of the amygdala, medial prefrontal cortex, and hippocampus in posttraumatic stress disorder (PTSD). Neuroimaging research reviewed in this article reveals heightened amygdala responsivity in PTSD during symptomatic states and during the processing of trauma-unrelated affective information. Importantly, amygdala responsivity is positively associated with symptom severity in PTSD. In contrast, medial prefrontal cortex appears to be volumetrically smaller and is hyporesponsive during symptomatic states and the performance of emotional cognitive tasks in PTSD. Medial prefrontal cortex responsivity is inversely associated with PTSD symptom severity. Lastly, the reviewed research suggests diminished volumes, neuronal integrity, and functional integrity of the hippocampus in PTSD. Remaining research questions and related future directions are presented.

This article discusses past research bearing on the question of the etiology of Posttraumatic Stress Disorder (PTSD). It argues that PTSD can be adequately accounted for by a process of emotional sensitization and that this is a more parsimonious explanation than the two-factor learning theory of Mowrer, now postulated by several writers. In brief, the etiology and subsequent development of PTSD is viewed as the result of the sensitization of fear/anxiety which is linked to a variety of to be conditional stimuli by both backward and forward association: these become conditional stimuli (CSi) once paired with the instigating circumstances. It is furthermore assumed that PTSD will not occur in the absence of a genetic susceptibility that may vary from zero to absolute certainty. Thus far, our evidence is limited to a sensitivity to loud sounds, but it is highly probable that touch and other sensory systems are involved (not necessarily in parallel). The fact that abuse often leads to behavioral disorders, including sexually seductive behaviors in children sexually abused, requires a recognition that emotional reactions other than fear may be sensitized. Fear in combination with pleasure or pleasure alone coupled with a loss of self-esteem may explain these acting-out behaviors.

Lesions of the frontotemporal region of the amygdala, which includes lateral and basal nuclei, cause a loss of conditional fear responses, such as freezing, even when the lesions are made over a year and a half from the original training. These amygdala-damaged animals are not hyperactive and show normal reactivity to strong stimuli such as bright lights. After receiving tone-mild shock pairings rats normally display an appropriately weak response when exposed to the tone. Rats' fear of the tone can be inflated by giving them exposure to strong shocks in the absence of the tone between training and testing. This inflation of fear memory is abolished if the frontotemporal amygdala is inactivated by muscimol only during the inflation treatment with strong shocks. Based on such findings we suggest that the frontotemporal amygdala permanently encodes a memory for the hedonic value of the aversive stimulus used to condition fear.

Fear is an adaptive response that initiates defensive behavior to protect animals and humans from danger. However, anxiety disorders, such as Posttraumatic Stress Disorder (PTSD), can occur when fear is inappropriately regulated. Fear conditioning can be used to study aspects of PTSD, and we have developed a model in which pre-exposure to a stressor of repeated footshock enhances conditional fear responding to a single context-shock pairing. The experiments in this chapter address interpretations of this effect including generalization and summation or fear, inflation, and altered pain sensitivity. The results of these experiments lead to the conclusion that pre-exposure to shock sensitizes conditional fear responding to similar less intense stressors. This sensitization effect resists exposure therapy (extinction) and amnestic (NMDA antagonist) treatment. The pattern predicts why in PTSD patients, mild stressors cause reactions more appropriate for the original traumatic stressor and why new fears are so readily formed in these patients. This model can facilitate the study of neurobiological mechanisms underlying sensitization of responses observed in PTSD.

OBJECTIVE: Most research on the effects of severe psychological stress has focused on stress-related psychopathology. Here, the author develops psychobiological models of resilience to extreme stress.
METHOD: An integrative model of resilience and vulnerability that encompasses the neurochemical response patterns to acute stress and the neural mechanisms mediating reward, fear conditioning and extinction, and social behavior is proposed.
RESULTS: Eleven possible neurochemical, neuropeptide, and hormonal mediators of the psychobiological response to extreme stress were identified and related to resilience or vulnerability. The neural mechanisms of reward and motivation (hedonia, optimism, and learned helpfulness), fear responsiveness (effective behaviors despite fear), and adaptive social behavior (altruism, bonding, and teamwork) were found to be relevant to the character traits associated with resilience.
CONCLUSIONS: The opportunity now exists to bring to bear the full power of advances in our understanding of the neurobiological basis of behavior to facilitate the discoveries needed to predict, prevent, and treat stress-related psychopathology.

Most biological findings in posttraumatic stress disorder (PTSD) are compatible with those of the chronic stress response, such as increased corticotropin-releasing factor (CRF) concentrations, catecholamine depletion within the central nervous system, and reduced hippocampal volume. However, over the last 10 years, biological observations have been made in PTSD that are different from what has been typically associated with chronic stress, notably certain hypothalamic-pituitary-adrenal (HPA) axis findings. In particular, urinary and plasma cortisol levels are considerably lower in PTSD patients than in non-PTSD trauma survivors and normal controls. Furthermore, the circadian pattern of cortisol release from the adrenal glands follows a greater dynamic range in PTSD than in patients with major depression or in normal controls. The reduction in cortisol levels results from an enhanced negative feedback by cortisol, which is secondary to an increased sensitivity of glucocorticoid receptors in target tissues. This HPA axis alteration contrasts with the well-known chronic stress cascade in which CRF release results in erosion of negative feedback and down-regulation of glucocorticoid receptors. Sensitization of the HPA axis is consistent with the clinical picture of hyperreactivity and hyperresponsiveness in PTSD.

Traumatic experiences can lead to a range of mental health problems with posttraumatic stress disorder (PTSD) leading as the most documented disorder following trauma. Epidemiological research has found the rate of exposure to trauma to far outweigh the prevalence of PTSD. Indicating that most people do not develop PTSD following a traumatic event, this phenomenon has led to an interest in evaluating risk factors to determine who develops PTSD. Risk factors for the development of psychopathology following trauma exposure fall into three categories: pre-trauma, peri-trauma and post-trauma factors. Pre-trauma factors can include age, gender, race/ethnicity, education, prior psychopathology, and neurobiological factors. Peri-trauma factors can include the duration/severity of trauma experience and the perception that the trauma has ended. Post-trauma factors can include access to needed resources, social support, specific cognitive patterns, and physical activity. To date, several important risk factors have been found to impact the risk of developing PTSD including gender, age, education, IQ, race and ethnicity, sexual orientation, pre-trauma psychopathology, prior trauma exposure, familial psychiatric history, and neurobiological factors. This article outlines the state of research findings on pretraumatic, peritraumatic, and posttraumatic risk factors for the development of PTSD and associated psychopathology following trauma.