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1.  Tachikawa project for prevention of posttraumatic stress disorder with polyunsaturated fatty acid (TPOP): study protocol for a randomized controlled trial 
BMC Psychiatry  2013;13:8.
Preclinical and clinical studies suggest that supplementation with omega-3 fatty acids after trauma might reduce subsequent posttraumatic stress disorder (PTSD). To date, we have shown in an open trial that PTSD symptoms in critically injured patients can be reduced by taking omega-3 fatty acids, hypothesized to stimulate hippocampal neurogenesis. The primary aim of the present randomized controlled trial is to examine the efficacy of omega-3 fatty acid supplementation in the secondary prevention of PTSD following accidental injury, as compared with placebo. This paper describes the rationale and protocol of this trial.
The Tachikawa Project for Prevention of Posttraumatic Stress Disorder with Polyunsaturated Fatty Acid (TPOP) is a double-blinded, parallel group, randomized controlled trial to assess whether omega-3 fatty acid supplementation can prevent PTSD symptoms among accident-injured patients consecutively admitted to an intensive care unit. We plan to recruit accident-injured patients and follow them prospectively for 12 weeks. Enrolled patients will be randomized to either the omega-3 fatty acid supplement group (1,470 mg docosahexaenoic acid and 147 mg eicosapentaenoic acid daily) or placebo group. Primary outcome is score on the Clinician-Administered PTSD Scale (CAPS). We will need to randomize 140 injured patients to have 90% power to detect a 10-point difference in mean CAPS scores with omega-3 fatty acid supplementation compared with placebo. Secondary measures are diagnosis of PTSD and major depressive disorder, depressive symptoms, physiologic response in the experiment using script-driven imagery and acoustic stimulation, serum brain-derived neurotrophic factor, health-related quality of life, resilience, and aggression. Analyses will be by intent to treat. The trial was initiated on December 13 2008, with 104 subjects randomized by November 30 2012.
This study promises to be the first trial to provide a novel prevention strategy for PTSD among traumatized people.
Trial registration Identifier NCT00671099
PMCID: PMC3598223  PMID: 23289548
Fish oil; Omega-3 fatty acid; Docosahexaenoic acid; Eicosapentaenoic acid; Posttraumatic stress disorder; Accidental injury; Prevention
2.  Potential impact of propofol immediately after motor vehicle accident on later symptoms of posttraumatic stress disorder at 6-month follow up: a retrospective cohort study 
Critical Care  2012;16(5):R196.
Critically injured patients are at risk of developing posttraumatic stress disorder (PTSD). Propofol was recently reported to enhance fear memory consolidation retrospectively. Thus, we investigated here whether administration of propofol within 72 h of a motor vehicle accident (MVA) affects the subsequent development of PTSD symptoms.
We examined data obtained from a prospective cohort study of MVA-related injured patients, admitted to the intensive care unit of a general hospital. We investigated the effect of propofol administration within 72 h of MVA on outcome. Primary outcome was diagnosis of full or partial PTSD as determined by the Clinician-Administered PTSD Scale (CAPS) at 6 months. Secondary outcomes were diagnosis of full or partial PTSD at 1 month and CAPS score indicating PTSD at 1 and 6 months. Multivariate analysis was conducted adjusting for being female, age, injury severity score (ISS), and administration of ketamine or midazolam within 72 h of MVA.
Among 300 patients recruited (mean ISS, 8.0; median Glasgow Coma Scale (GCS) score, 15.0; age, 18 to 69 years), propofol administration showed a higher risk for full or partial PTSD as determined by CAPS at 6 months (odds ratio = 6.13, 95% confidence interval (CI): 1.57 to 23.85, P = 0.009) and at 1 month (odds ratio = 1.31, 95% CI: 0.41 to 4.23, P = 0.647) in the multivariate logistic regression. Multivariate regression analysis showed a trend toward adverse effects of propofol on PTSD symptom development at 6 months after MVA (β = 4.08, 95% CI: -0.49 to 8.64, P = 0.080), but not at 1 month after MVA (β = -0.42, 95% CI: -6.34 to 5.51, P = 0.890).
These findings suggest that using propofol in the acute phase after MVA might be associated with the development of PTSD symptoms 6 months later. However, since the design of this study was retrospective, these findings should be interpreted cautiously and further study is warranted.
PMCID: PMC3682298  PMID: 23075426
3.  Structural and functional plasticity of the human brain in posttraumatic stress disorder 
Progress in brain research  2008;167:171-186.
Posttraumatic stress disorder (PTSD) is associated with long-term changes in neurobiology. Brain areas involved in the stress response include the medial prefrontal cortex, hippocampus, and amygdala. Neurohormonal systems that act on the brain areas to modulate PTSD symptoms and memory include glucocorticoids and norepinephrine. Dysfunction of these brain areas is responsible for the symptoms of PTSD. Brain imaging studies show that PTSD patients have increased amygdala reactivity during fear acquisition. Other studies show smaller hippocampal volume. A failure of medial prefrontal/anterior cingulate activation with re-experiencing of the trauma is hypothesized to represent a neural correlate of the failure of extinction seen in PTSD. The brain has the capacity for plasticity in the aftermath of traumatic stress. Antidepressant treatments and changes in environment can reverse the effects of stress on hippocampal neurogenesis, and humans with PTSD showed increased hippocampal volume with both paroxetine and phenytoin.
PMCID: PMC3226705  PMID: 18037014
PET; depression; cortisol; glucocorticoids; stress; PTSD
4.  Prevalence rate, predictors and long-term course of probable posttraumatic stress disorder after major trauma: a prospective cohort study 
BMC Psychiatry  2012;12:236.
Among trauma patients relatively high prevalence rates of posttraumatic stress disorder (PTSD) have been found. To identify opportunities for prevention and early treatment, predictors and course of PTSD need to be investigated. Long-term follow-up studies of injury patients may help gain more insight into the course of PTSD and subgroups at risk for PTSD. The aim of our long-term prospective cohort study was to assess the prevalence rate and predictors, including pre-hospital trauma care (assistance of physician staffed Emergency Medical Services (EMS) at the scene of the accident), of probable PTSD in a sample of major trauma patients at one and two years after injury. The second aim was to assess the long-term course of probable PTSD following injury.
A prospective cohort study was conducted of 332 major trauma patients with an Injury Severity Score (ISS) of 16 or higher. We used data from the hospital trauma registry and self-assessment surveys that included the Impact of Event Scale (IES) to measure probable PTSD symptoms. An IES-score of 35 or higher was used as indication for the presence of probable PTSD.
One year after injury measurements of 226 major trauma patients were obtained (response rate 68%). Of these patients 23% had an IES-score of 35 or higher, indicating probable PTSD. At two years after trauma the prevalence rate of probable PTSD was 20%. Female gender and co-morbid disease were strong predictors of probable PTSD one year following injury, whereas minor to moderate head injury and injury of the extremities (AIS less than 3) were strong predictors of this disorder at two year follow-up. Of the patients with probable PTSD at one year follow-up 79% had persistent PTSD symptoms a year later.
Up to two years after injury probable PTSD is highly prevalent in a population of patients with major trauma. The majority of patients suffered from prolonged effects of PTSD, underlining the importance of prevention, early detection, and treatment of injury-related PTSD.
PMCID: PMC3558452  PMID: 23270522
Major trauma; Posttraumatic stress disorder; Follow-up study
Depression and anxiety  2012;29(10):833-842.
The high prevalence of trauma exposure and subsequent negative consequences for both survivors and society as a whole emphasize the need for secondary prevention of posttraumatic stress disorder. However, clinicians and relief workers remain limited in their ability to intervene effectively in the aftermath of trauma and alleviate traumatic stress reactions that can lead to chronic PTSD. The scientific literature on early intervention for PTSD is reviewed, including early studies on psychological debriefing, pharmacological, and psychosocial interventions aimed at preventing chronic PTSD. Studies on fear extinction and memory consolidation are discussed in relation to PTSD prevention and the potential importance of immediate versus delayed intervention approaches and genetic predictors are briefly reviewed. Preliminary results from a modified prolonged exposure intervention applied within hours of trauma exposure in an emergency room setting are discussed, along with considerations related to intervention reach and overall population impact. Suggestions for future research are included. Prevention of PTSD, although currently not yet a reality, remains an exciting and hopeful possibility with current research approaches translating work from the laboratory to the clinic.
PMCID: PMC3665083  PMID: 22941845
secondary prevention; early intervention; PTSD; ASD
6.  Attenuating posttraumatic distress with omega-3 polyunsaturated fatty acids among disaster medical assistance team members after the Great East Japan Earthquake: The APOP randomized controlled trial 
BMC Psychiatry  2011;11:132.
On March 11, 2011, a magnitude 9.0 earthquake, the most powerful ever recorded in Japan, and a massive tsunami struck off the coast of the Sanriku region. A Disaster Medical Assistance Team, a mobile medical team with specialized training that is deployed during the acute phase of a disaster, was dispatched to areas with large-scale destruction and multiple injured and sick casualties. Previous studies have reported critical incident stress (i.e. posttraumatic stress disorder symptoms and depressive symptoms) among rescue workers as well as the need for screening and prevention for posttraumatic stress disorder. So far we have shown in an open trial that posttraumatic stress disorder symptoms in critically injured patients can be reduced by taking omega-3 fatty acids intended to stimulate hippocampal neurogenesis.
This study is designed to determine the effectiveness of attenuating posttraumatic distress with omega-3 polyunsaturated fatty acids among Disaster Medical Assistance Team members after the Great East Japan Earthquake, and is named the APOP randomized controlled trial which is currently ongoing. First, we will provide psycho-education on posttraumatic distress, which is common in responders to the Disaster Medical Assistance Team members deployed to the disaster area. Second, observational research will be conducted to evaluate critical incident stress following the completion of medical activities. Third, team members who provide consent to participate in the intervention research will be randomly divided into a group given an omega-3 fatty acid supplement and a group not given the supplements. Outcome will be evaluated at 12 weeks after the supplements are shipped to the team members.
Measures that address critical incident stress in disaster responders are important, but there is no substantial evidence that links such measures with prevention of posttraumatic stress disorder. Thus, any confirmation through this study that the intake of omega-3 fatty acid supplements serves as a simple preventative measure for critical incident stress will be of great significance.
Trial registration
UMIN Clinical Trials Registry, UMIN000005367
PMCID: PMC3167761  PMID: 21846343
7.  Vulnerability Imposed by Diet and Brain Trauma for Anxiety-Like Phenotype: Implications for Post-Traumatic Stress Disorders 
PLoS ONE  2013;8(3):e57945.
Mild traumatic brain injury (mTBI, cerebral concussion) is a risk factor for the development of psychiatric illness such as posttraumatic stress disorder (PTSD). We sought to evaluate how omega-3 fatty acids during brain maturation can influence challenges incurred during adulthood (transitioning to unhealthy diet and mTBI) and predispose the brain to a PTSD-like pathobiology. Rats exposed to diets enriched or deficient in omega-3 fatty acids (n-3) during their brain maturation period, were transitioned to a western diet (WD) when becoming adult and then subjected to mTBI. TBI resulted in an increase in anxiety-like behavior and its molecular counterpart NPY1R, a hallmark of PTSD, but these effects were more pronounced in the animals exposed to n-3 deficient diet and switched to WD. The n-3 deficiency followed by WD disrupted BDNF signaling and the activation of elements of BDNF signaling pathway (TrkB, CaMKII, Akt and CREB) in frontal cortex. TBI worsened these effects and more prominently in combination with the n-3 deficiency condition. Moreover, the n-3 deficiency primed the immune system to the challenges imposed by the WD and brain trauma as evidenced by results showing that the WD or mTBI affected brain IL1β levels and peripheral Th17 and Treg subsets only in animals previously conditioned to the n-3 deficient diet. These results provide novel evidence for the capacity of maladaptive dietary habits to lower the threshold for neurological disorders in response to challenges.
PMCID: PMC3590222  PMID: 23483949
8.  Re-examination of the Controversial Coexistence of Traumatic Brain Injury and Posttraumatic Stress Disorder: Misdiagnosis and Self-Report Measures 
Psychological Injury and Law  2010;3(1):63-76.
The coexistence of traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) remains a controversial issue in the literature. To address this controversy, we focused primarily on the civilian-related literature of TBI and PTSD. Some investigators have argued that individuals who had been rendered unconscious or suffered amnesia due to a TBI are unable to develop PTSD because they would be unable to consciously experience the symptoms of fear, helplessness, and horror associated with the development of PTSD. Other investigators have reported that individuals who sustain TBI, regardless of its severity, can develop PTSD even in the context of prolonged unconsciousness. A careful review of the methodologies employed in these studies reveals that investigators who relied on clinical interviews of TBI patients to diagnose PTSD found little or no evidence of PTSD. In contrast, investigators who relied on PTSD questionnaires to diagnose PTSD found considerable evidence of PTSD. Further analysis revealed that many of the TBI patients who were initially diagnosed with PTSD according to self-report questionnaires did not meet the diagnostic criteria for PTSD upon completion of a clinical interview. In particular, patients with severe TBI were often misdiagnosed with PTSD. A number of investigators found that many of the severe TBI patients failed to follow the questionnaire instructions and erroneously endorsed PTSD symptoms because of their cognitive difficulties. Because PTSD questionnaires are not designed to discriminate between PTSD and TBI symptoms or determine whether a patient's responses are accurate or exaggerated, studies that rely on self-report questionnaires to evaluate PTSD in TBI patients are at risk of misdiagnosing PTSD. Further research should evaluate the degree to which misdiagnosis of PTSD occurs in individuals who have sustained mild TBI.
PMCID: PMC2948674  PMID: 20927197
Posttraumatic stress disorder; Traumatic brain injury
9.  How the Neurocircuitry and Genetics of Fear Inhibition May Inform Our Understanding of PTSD 
The American journal of psychiatry  2010;167(6):648-662.
Exposure to traumatic events that produce extreme fear and horror is all too common in both military and civilian populations, but not all individuals develop posttraumatic stress disorder (PTSD) as a result of the exposure. What mediates risk and resilience in the development of PTSD and other stress-related psychopathology is of paramount importance to our further understanding of trauma-related psychopathology as well as the development of new treatment approaches. Biological factors, such as genotype and neurobiology, interact with environmental factors, such as childhood background and trauma load, to affect vulnerability and resilience in the aftermath of trauma exposure. One of the core symptoms of PTSD is the inability to control fear, which has led some investigators and clinicians to conceptualize PTSD as a disorder of fear or, more importantly, its inhibition. This review focuses on translational methods that have been used to examine fear conditioning and inhibition of fear in PTSD and summarizes genetic and neurobiological factors related to fear inhibition. The authors also discuss different pharmacological approaches that enhance fear inhibition and may improve treatment outcomes for patients with PTSD.
PMCID: PMC3603297  PMID: 20231322
10.  A Randomized Stepped Care Intervention Trial Targeting Posttraumatic Stress Disorder for Surgically Hospitalized Injury Survivors 
Annals of surgery  2013;257(3):390-399.
To test the effectiveness of a stepped care intervention model targeting posttraumatic stress disorder (PTSD) symptoms after injury.
Few investigations have evaluated interventions for injured patients with PTSD and related impairments that can be feasibly implemented in trauma surgical settings.
The investigation was a pragmatic effectiveness trial in which 207 acutely injured hospitalized trauma survivors were screened for high PTSD symptom levels and then randomized to a stepped combined, care management, psychopharmacology, and cognitive behavioral psychotherapy intervention (n = 104) or usual care control (n = 103) conditions. The symptoms of PTSD and functional limitations were reassessed at one-, three-, six-, nine-, and twelve-months after the index injury admission.
Regression analyses demonstrated that over the course of the year after injury, intervention patients had significantly reduced PTSD symptoms when compared to controls (group by time effect, CAPS, F(2, 185) = 5.50, P < 0.01; PCL-C, F(4, 185) = 5.45, P < 0.001). Clinically and statistically significant PTSD treatment effects were observed at the six-, nine-, and twelve-month post-injury assessments. Over the course of the year after injury, intervention patients also demonstrated significant improvements in physical function (MOS SF-36 PCS main effect, F(1, 172) = 9.87, P < 0.01).
Stepped care interventions can reduce PTSD symptoms and improve functioning over the course of the year after surgical injury hospitalization. Orchestrated investigative and policy efforts could systematically introduce and evaluate screening and intervention procedures for PTSD at United States trauma centers. (Trial Registration: identifier: NCT00270959)
PMCID: PMC3582367  PMID: 23222034
11.  Substance Use Attenuates Physiological Responses Associated With PTSD among Individuals with Co-Morbid PTSD and SUDs 
Journal of psychology & psychotherapy  2013;Suppl 7:10.4172/2161-0487.S7-006.
Posttraumatic stress disorder (PTSD) is often conceptualized from a fear conditioning perspective given individuals with PTSD demonstrate a reduced ability to inhibit fear even under safe conditions as compared to those without PTSD. The self-medication hypothesis suggests that individuals with PTSD often develop substance use disorders (SUDs) as an attempt to mitigate trauma-related distressing emotions. This investigation examined this hypothesis in a sample 214 participants, of which 81 did not meet criteria for either PTSD or SUDs (No diagnosis Control group); 33 met criteria for lifetime PTSD, but not SUDs (PTSD only group); 54 met criteria for lifetime SUDs, but not PTSD (SUDs only group); and 46 met lifetime criteria for both disorders (PTSD+SUDs group). PTSD was assessed using the modified PTSD Symptoms Scale (mPSS), SUDs were assessed using the Structured Clinical Interview for DSM-IV-TR (SCID). The startle magnitude was assessed using electromyography (EMG) of the eyeblink muscle in response to an acoustic startle probe. Fear-potentiated startle (FPS) was analyzed by comparing startle magnitude at baseline to startle during a fear conditioned stimulus. Results showed that PTSD significantly increased startle responses. However, there was a significant effect of SUDs on fear-potentiated startle to the danger signal, in that those who met criteria for SUDs had reduced fear compared to those who did not. The individuals who had co-morbid PTSD and SUDs did not differ from the Control group. Findings indicate that SUDs may attenuate exaggerated fear responses associated with PTSD. Consistent with the self-medication hypothesis, results suggest that substance use may co-occur with PTSD because it reduces heightened fear load and may allow normalized function in traumatized individuals.
PMCID: PMC3882311  PMID: 24404418
PTSD; Substance abuse; Hyperarousal; Fear responding; Acoustic startle
12.  Impaired Fear Inhibition is a Biomarker of PTSD but not Depression 
Depression and anxiety  2010;27(3):244-251.
A central problem in posttraumatic stress disorder (PTSD) is a reduced capacity to suppress fear under safe conditions. Previously, we have shown that combat-related PTSD patients have impaired inhibition of fear-potentiated startle. Given the high comorbidity between PTSD and depression, our goal was to see whether this impairment is specific to PTSD, or a nonspecific symptom associated with both disorders.
Fear-potentiated startle (FPS) was assessed in 106 trauma-exposed individuals divided into four groups: a) No diagnosis control, b) PTSD only, c) major depression (MDD) only, and d) comorbid PTSD and MDD. We used a novel conditional discrimination procedure, in which one set of shapes (the danger signal) was paired with aversive airblasts to the throat, and different shapes (the safety signal) were presented without airblasts. The paradigm also included fear inhibition transfer test.
Subjects with comorbid MDD and PTSD had higher FPS to the safety signal and to the transfer test compared to controls and MDD only subjects. In contrast to the control and MDD groups, the PTSD and comorbid PTSD and MDD groups did not show fear inhibition to safety cues.
These results suggest that impaired fear inhibition may be a specific biomarker of PTSD symptoms.
PMCID: PMC2841213  PMID: 20143428
PTSD; Depression; Hyper-arousal Symptoms; Physiology; Fear-Potentiated Startle
13.  Posttraumatic Stress Disorder in patients with traumatic brain injury 
BMC Psychiatry  2004;4:5.
Severe traumatic stressors such as war, rape, or life-threatening accidents can result in a debilitating psychopathological development conceptualised as Posttraumatic Stress Disorder (PTSD). Pathological memory formation during an alarm response may set the precondition for PTSD to occur. If true, a lack of memory formation by extended unconsciousness in the course of the traumatic experience should preclude PTSD.
46 patients from a neurological rehabilitation clinic were examined by means of questionnaires and structured clinical interviews. All patients had suffered a TBI due to an accident, but varied with respect to falling unconscious during the traumatic event.
27% of the sub-sample who were not unconscious for an extended period but only 3% (1 of 31 patients) who were unconscious for more than 12 hours as a result of the accident were diagnosed as having current PTSD (P < .02). Furthermore, intrusive memories proved to be far more frequent in patients who had not been unconscious. This was also the case for other re-experiencing symptoms and for psychological distress and physiological reactivity to reminders of the traumatic event.
TBI and PTSD are not mutually exclusive. However, victims of accidents are unlikely to develop a PTSD if the impact to the head had resulted in an extended period of unconsciousness.
PMCID: PMC395832  PMID: 15113439
14.  Early Intervention May Prevent the Development of PTSD: A Randomized Pilot Civilian Study with Modified Prolonged Exposure 
Biological psychiatry  2012;72(11):957-963.
Posttraumatic stress disorder is a major public health concern with long term sequelae. There are no accepted interventions delivered in the immediate aftermath of trauma. This study tested an early intervention aimed at modifying the memory to prevent the development of PTSD prior to memory consolidation.
Patients (N=137) were randomly assigned to receive 3 sessions of an early intervention beginning in the emergency department (ED) compared to an assessment only control group. Posttraumatic stress reactions (PTSR) were assessed at 4 and 12 weeks post-injury and depression at baseline and week 4. The intervention consisted of modified prolonged exposure including imaginal exposure to the trauma memory, processing of traumatic material, and in vivo and imaginal exposure homework.
Patients were assessed an average of 11.79 hours post-trauma. Intervention participants reported significantly lower PTSR than the assessment group at 4 weeks post-injury, p < 0.01, and at 12 weeks post-injury, p < 0.05, and significantly lower depressive symptoms at Week 4 than the assessment group, p < 0.05. In a subgroup analysis the intervention was the most effective at reducing PTSD in rape victims at Week 4 (p=.004) and Week 12 (p=.05).
These findings suggest that the modified prolonged exposure intervention initiated within hours of the trauma in the ED is successful at reducing PTSR and depression symptoms one and three months after trauma exposure and is safe and feasible. This is the first behavioral intervention delivered immediately post-trauma that has been shown to be effective at reducing PTSR.
PMCID: PMC3467345  PMID: 22766415
early intervention; secondary prevention; PTSD; Acute Stress Disorder; prolonged exposure; memory consolidation
15.  Memory suppression trades prolonged fear and sleep-dependent fear plasticity for the avoidance of current fear 
Scientific Reports  2013;3:2227.
Sleep deprivation immediately following an aversive event reduces fear by preventing memory consolidation during homeostatic sleep. This suggests that acute insomnia might act prophylactically against the development of posttraumatic stress disorder (PTSD) even though it is also a possible risk factor for PTSD. We examined total sleep deprivation and memory suppression to evaluate the effects of these interventions on subsequent aversive memory formation and fear conditioning. Active suppression of aversive memory impaired retention of event memory. However, although the remembered fear was more reduced in sleep-deprived than sleep-control subjects, suppressed fear increased, and seemed to abandon the sleep-dependent plasticity of fear. Active memory suppression, which provides a psychological model for Freud's ego defense mechanism, enhances fear and casts doubt on the potential of acute insomnia as a prophylactic measure against PTSD. Our findings bring into question the role of sleep in aversive-memory consolidation in clinical PTSD pathophysiology.
PMCID: PMC3714646  PMID: 23863955
16.  Stress and Brain Atrophy 
Studies in animals showed that stress is associated with changes in hippocampal function and structure, an effect mediated through decreased neurogenesis, increased glucocorticoids, and/or decreased brain derived neurotrophic factor. Antidepressants and some anticonvulsants block the effects of stress and/or promote neurogenesis in animal studies. Patients with posttraumatic stress disorder (PTSD) have been shown to have smaller hippocampal volume on magnetic resonance imaging and deficits in hippocampal-based memory. Symptom activation is associated with decreased anterior cingulate and medial prefrontal function, which is proposed as the neural correlate of a failure of extinction seen in these patients. Treatment with antidepressants and phenytoin reverse hippocampal volume reduction and memory deficits in PTSD patients, suggesting that these agents may promote neurogenesis in humans.
PMCID: PMC3269810  PMID: 17073653
17.  Amygdala-Dependent Fear Is Regulated by Oprl1 in Mice and Humans with PTSD 
Science translational medicine  2013;5(188):188ra73.
The amygdala-dependent molecular mechanisms driving the onset and persistence of posttraumatic stress disorder (PTSD) are poorly understood. Recent observational studies have suggested that opioid analgesia in the aftermath of trauma may decrease the development of PTSD. Using a mouse model of dysregulated fear, we found altered expression within the amygdala of the Oprl1 gene (opioid receptor–like 1), which encodes the amygdala nociceptin (NOP)/orphanin FQ receptor (NOP-R). Systemic and central amygdala infusion of SR-8993, a new highly selective NOP-R agonist, impaired fear memory consolidation. In humans, a single-nucleotide polymorphism (SNP) within OPRL1 is associated with a self-reported history of childhood trauma and PTSD symptoms (n = 1847) after a traumatic event. This SNP is also associated with physiological startle measures of fear discrimination and magnetic resonance imaging analysis of amygdala-insula functional connectivity. Together, these data suggest that Oprl1 is associated with amygdala function, fear processing, and PTSD symptoms. Further, our data suggest that activation of the Oprl1/NOP receptor may interfere with fear memory consolidation, with implications for prevention of PTSD after a traumatic event.
PMCID: PMC3732318  PMID: 23740899
18.  Internet-Based Early Intervention to Prevent Posttraumatic Stress Disorder in Injury Patients: Randomized Controlled Trial 
Posttraumatic stress disorder (PTSD) develops in 10-20% of injury patients. We developed a novel, self-guided Internet-based intervention (called Trauma TIPS) based on techniques from cognitive behavioral therapy (CBT) to prevent the onset of PTSD symptoms.
To determine whether Trauma TIPS is effective in preventing the onset of PTSD symptoms in injury patients.
Adult, level 1 trauma center patients were randomly assigned to receive the fully automated Trauma TIPS Internet intervention (n=151) or to receive no early intervention (n=149). Trauma TIPS consisted of psychoeducation, in vivo exposure, and stress management techniques. Both groups were free to use care as usual (nonprotocolized talks with hospital staff). PTSD symptom severity was assessed at 1, 3, 6, and 12 months post injury with a clinical interview (Clinician-Administered PTSD Scale) by blinded trained interviewers and self-report instrument (Impact of Event Scale—Revised). Secondary outcomes were acute anxiety and arousal (assessed online), self-reported depressive and anxiety symptoms (Hospital Anxiety and Depression Scale), and mental health care utilization. Intervention usage was documented.
The mean number of intervention logins was 1.7, SD 2.5, median 1, interquartile range (IQR) 1-2. Thirty-four patients in the intervention group did not log in (22.5%), 63 (41.7%) logged in once, and 54 (35.8%) logged in multiple times (mean 3.6, SD 3.5, median 3, IQR 2-4). On clinician-assessed and self-reported PTSD symptoms, both the intervention and control group showed a significant decrease over time (P<.001) without significant differences in trend. PTSD at 12 months was diagnosed in 4.7% of controls and 4.4% of intervention group patients. There were no group differences on anxiety or depressive symptoms over time. Post hoc analyses using latent growth mixture modeling showed a significant decrease in PTSD symptoms in a subgroup of patients with severe initial symptoms (n=20) (P<.001).
Our results do not support the efficacy of the Trauma TIPS Internet-based early intervention in the prevention of PTSD symptoms for an unselected population of injury patients. Moreover, uptake was relatively low since one-fifth of individuals did not log in to the intervention. Future research should therefore focus on innovative strategies to increase intervention usage, for example, adding gameplay, embedding it in a blended care context, and targeting high-risk individuals who are more likely to benefit from the intervention.
Trial Registration
International Standard Randomized Controlled Trial Number (ISRCTN): 57754429; (Archived by WebCite at
PMCID: PMC3742408  PMID: 23942480
early intervention; prevention; Internet; posttraumatic stress disorder; cognitive behavior therapy
19.  Corticotrophin-releasing hormone type 1 receptor gene (CRHR1) variants predict posttraumatic stress disorder onset and course in pediatric injury patients 
Disease markers  2011;30(0):89-99.
Posttraumatic stress disorder (PTSD) is a common and disabling anxiety disorder that may occur in the aftermath of exposure to potentially traumatic life events. PTSD is moderately heritable, but few specific molecular variants accounting for this heritability have been identified. Genes regulating the hypothalamic-pituitary-adrenal (HPA) axis, such as corticotrophin-releasing hormone type 1 receptor gene (CRHR1), have been implicated in traumatic-stress related phenotypes but have yet to be studied in relation to PTSD. The present study sought to examine the relation between 9 single nucleotide polymorphisms (SNPs) in the CRHR1 gene and posttraumatic stress symptoms in a prospective study of pediatric injury patients (n = 103) who were first assessed in the acute aftermath of their injury at the hospital. Results indicated that multiple SNPs were associated with acute symptoms at a univariate level, and after correction for multiple testing, rs12944712 was significantly related to acute PTSD symptoms. Longitudinal latent growth curve analyses suggest that rs12944712 is also related to both acute symptom level and trajectory of symptoms over time. The present study adds support for the role of CRHR1 in the stress response following potentially traumatic event exposure in youth. It should be noted that the sample size in this study was small, and therefore statistical power was low; following, results from this study should be considered preliminary. Although results are not definitive, the findings from this study warrant future replication studies on how variation in this gene relates to response to traumatic event exposure in youth.
PMCID: PMC3722863  PMID: 21508513
Posttraumatic stress disorder; CRHR1; hypothalamic-pituitary-adrenal axis; genetic; injury
20.  Corticotrophin-Releasing Hormone Type 1 Receptor Gene (CRHR1) Variants Predict Posttraumatic Stress Disorder Onset and Course in Pediatric Injury Patients 
Disease markers  2011;30(2-3):89-99.
Posttraumatic stress disorder (PTSD) is a common and disabling anxiety disorder that may occur in the aftermath of exposure to potentially traumatic life events. PTSD is moderately heritable, but few specific molecular variants accounting for this heritability have been identified. Genes regulating the hypothalamic-pituitary-adrenal (HPA) axis, such as corticotrophin-releasing hormone type 1 receptor gene (CRHR1), have been implicated in traumatic-stress related phenotypes but have yet to be studied in relation to PTSD. The present study sought to examine the relation between 9 single nucleotide polymorphisms (SNPs) in the CRHR1 gene and posttraumatic stress symptoms in a prospective study of pediatric injury patients (n = 103) who were first assessed in the acute aftermath of their injury at the hospital. Results indicated that multiple SNPs were associated with acute symptoms at a univariate level, and after correction for multiple testing, rs12944712 was significantly related to acute PTSD symptoms. Longitudinal latent growth curve analyses suggest that rs12944712 is also related to both acute symptom level and trajectory of symptoms over time. The present study adds support for the role of CRHR1 in the stress response following potentially traumatic event exposure in youth. It should be noted that the sample size in this study was small, and therefore statistical power was low; following, results from this study should be considered preliminary. Although results are not definitive, the findings from this study warrant future replication studies on how variation in this gene relates to response to traumatic event exposure in youth.
PMCID: PMC3722863  PMID: 21508513
Posttraumatic stress disorder; CRHR1; hypothalamic-pituitary-adrenal axis; genetic; injury
21.  Reduced Neural Activation During an Inhibition Task is Associated with Impaired Fear Inhibition in a Traumatized Civilian Sample 
Impaired inhibition of fear in the presence of safety cues and a deficiency in the extinction of fear cues are increasingly thought to be important biological markers of Posttraumatic Stress Disorder (PTSD). Other studies have suggested that there may be altered neural activation during behavioral inhibition tasks in subjects with PTSD. The current study aimed to see whether neural activation during inhibition was reduced in a highly traumatized civilian population, and whether atypical activation was associated with impaired fear inhibition.
The participants were 41 traumatized women (20 PTSD+, 21 PTSD−) recruited from Grady Memorial Hospital in Atlanta, GA. We used a Go/NoGo procedure with functional magnetic resonance imaging (fMRI) in a high-resolution 3T scanner. Participants were instructed to press a button whenever an “X” or “O” appeared on the screen, but not if a red square appeared behind the letter. Participants were assessed for trauma history and PTSD diagnosis, and completed a fear-potentiated startle and extinction paradigm.
We found stronger activation in the ventromedial prefrontal cortex (vmPFC) in traumatized subjects without PTSD compared to those with PTSD in the NoGo greater than Go contrast condition. Activation in the vmPFC was negatively correlated with fear-potentiated startle responses during safety signal learning (p=.02) and fear extinction (p=.0002).
These results contribute to understanding of how the neural circuitry involved in inhibitory processes may be deficient in PTSD. Furthermore, the same circuits involved in behavioral inhibition appear to be involved in fear inhibition processes during differential fear conditioning and extinction.
PMCID: PMC3540153  PMID: 23020899
22.  Posttraumatic stress disorder may be associated with impaired fear inhibition: relation to symptom severity 
Psychiatry research  2009;167(1-2):151-160.
One of the central problems in posttraumatic stress disorder (PTSD) is the inability to suppress fear even under safe conditions. The neural underpinnings of fear is a clinically relevant issue that is poorly understood. This study assessed fear potentiation and fear inhibition using fear-potentiated startle in a conditional discrimination procedure (AX+/BX-). We hypothesized that patients with PTSD would show normal fear potentiation and impaired fear inhibition. 28 healthy volunteers and 27 PTSD patients (14 with low current symptoms, 13 with high current symptoms) were presented with one set of colored lights (AX trials) paired with aversive air blasts to the throat, and a different series of lights (BX trials) presented without air blasts. We then presented A and B together (AB trials) to see whether B would inhibit fear potentiation to A. All groups showed robust fear potentiation in that they had significantly greater startle magnitude on AX trials compared to noise alone trials. However, the high symptom PTSD group did not show fear inhibition: these subjects had significantly greater fear potentiation on the AB trials than both the controls and the low symptom PTSD patients.
PMCID: PMC2713500  PMID: 19345420
Acoustic Startle Response; Classical Conditioning; Fear-Potentiated Startle; Electromyography; PTSD; Human
23.  Ethnoracial Variations in Acute PTSD Symptoms Among Hospitalized Survivors of Traumatic Injury 
Journal of traumatic stress  2010;23(3):384-392.
Ethnoracial minority status contributes to an increased risk for posttraumatic stress disorder (PTSD) after trauma exposure, beyond other risk factors. A population-based sampling frame was used to examine the associations between ethnoracial groups and early PTSD symptoms while adjusting for relevant clinical and demographic characteristics. Acutely injured trauma center inpatients (N = 623) were screened with the PTSD Checklist. American Indian and African American patients reported the highest levels of posttraumatic stress and preinjury cumulative trauma burden. African American heritage was independently associated with an increased risk of higher acute PTSD symptom levels. Disparities in trauma history, PTSD symptoms, and event related factors emphasize the need for acute care services to incorporate culturally competent approaches for treating these diverse populations.
PMCID: PMC3947745  PMID: 20564368
24.  Long-Term Treatment with Paroxetine Increases Verbal Declarative Memory and Hippocampal Volume in Posttraumatic Stress Disorder 
Biological psychiatry  2003;54(7):693-702.
Animal studies have shown that stress is associated with damage to the hippocampus, inhibition of neurogenesis, and deficits in hippocampal-based memory dysfunction. Studies in patients with posttraumatic stress disorder (PTSD) found deficits in hippocampal-based declarative verbal memory and smaller hippocampal volume, as measured with magnetic resonance imaging (MRI). Recent preclinical evidence has shown that selective serotonin reuptake inhibitors promote neurogenesis and reverse the effects of stress on hippocampal atrophy. This study assessed the effects of long-term treatment with paroxetine on hippocampal volume and declarative memory performance in PTSD.
Declarative memory was assessed with the Wechsler Memory Scale–Revised and Selective Reminding Test before and after 9–12 months of treatment with paroxetine in PTSD. Hippocampal volume was measured with MRI. Of the 28 patients who started the protocol, 23 completed the full course of treatment and neuropsychological testing. Twenty patients were able to complete MRI imaging.
Patients with PTSD showed a significant improvement in PTSD symptoms with treatment. Treatment resulted in significant improvements in verbal declarative memory and a 4.6% increase in mean hippocampal volume.
These findings suggest that long-term treatment with paroxetine is associated with improvement of verbal declarative memory deficits and an increase in hippocampal volume in PTSD.
PMCID: PMC3233762  PMID: 14512209
Posttraumatic stress disorder; memory; hippocampus; stress; paroxetine; selective serotonin reuptake inhibitors
25.  Posttraumatic stress disorder: The development of effective psychological treatments 
Nordic journal of psychiatry  2008;62(Suppl 47):11-18.
Posttraumatic stress disorder (PTSD) has only relatively recently been introduced into the diagnostic classification of mental disorders. Building on advances in the treatment of other anxiety disorders, a range of effective psychological treatments for PTSD has been developed. The most effective of these treatments focus on the patient’s memory for the traumatic event and its meaning. This paper briefly reviews the currently available evidence for these treatments. It then illustrates the process of developing effective psychological treatments by discussing how a combination of phenomenological, experimental and treatment development studies and theoretical considerations was used to develop a trauma-focused cognitive-behavioral treatment, Cognitive Therapy (CT) for PTSD. This treatment program builds on Ehlers and Clark’s (2000) model of PTSD, which specifies two core cognitive abnormalities in PTSD. First, people with chronic PTSD show idiosyncratic personal meanings (appraisals) of the trauma and/or its sequelae that lead to a sense of serious current threat. Second, the nature of the trauma memory explains the occurrence of reexperiencing symptoms. It is further proposed that the idiosyncratic appraisals motivate a series of dysfunctional behaviors (such as safety-seeking behaviors) and cognitive strategies (such as thought suppression and rumination) that are intended to reduce the sense of current threat, but maintain the problem by preventing change in the appraisals and trauma memory, and/or lead to increases in symptoms. CT addresses the cognitive abnormalities and maintaining behaviors in an individualized, but focused, way. Four randomized controlled trials and two dissemination studies showed that CT for PTSD is acceptable and effective.
PMCID: PMC3059487  PMID: 18752113
Posttraumatic stress disorder; trauma; cognitive behavior therapy; cognitive therapy; randomized controlled trial; clinical trial

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