Faculty Bibliography

Job loss has been associated with the emergence of depression and subsequent long-term diminished labor market participation. In a sample of 500 adults who lost their jobs, trajectories of depression severity from four years before to four years after job loss were identified using Latent Growth Mixture Modeling. Rates of unemployment by trajectory were compared at two and four years following job loss. Four trajectories demonstrated optimal model fit including resilience (72%), chronic pre-to-post job loss depression (9%), emergent depression (10%), and remitting depression (9%). Logistic regression comparing reemployment status by class while controlling for age, gender, and education at two-years post job loss revealed no significant differences by class. An identical logistic regression on four-year reemployment revealed significant differences by class with post-hoc analyses revealing emergent depression resulting in a 33.3% reemployment rate compared to resilient individuals (60.4%) together indicating that depression affects reemployment rather than lack of reemployment causing the emergence of depression. The emergence of depression following job loss significantly increases the risk of continued unemployment. However, observed high rates of resilience with resulting downstream benefits in reemployment mitigates significant concern about the effects of wide spread unemployment on ongoing global economic recovery following the Great Recession.

BACKGROUND: Studies suggest that exaggerated amygdala reactivity is a vulnerability factor for posttraumatic stress disorder (PTSD); however, our understanding is limited by a paucity of prospective, longitudinal studies. Recent studies in healthy samples indicate that, relative to reactivity, habituation is a more reliable biomarker of individual differences in amygdala function. We investigated reactivity of the amygdala and cortical areas to repeated threat presentations in a prospective study of PTSD. METHODS: Participants were recruited from the emergency department of a large level I trauma center within 24 hours of trauma. PTSD symptoms were assessed at baseline and approximately 1, 3, 6, and 12 months after trauma. Growth curve modeling was used to estimate symptom recovery trajectories. Thirty-one individuals participated in functional magnetic resonance imaging around the 1-month assessment, passively viewing fearful and neutral face stimuli. Reactivity (fearful > neutral) and habituation to fearful faces was examined. RESULTS: Amygdala reactivity, but not habituation, 5 to 12 weeks after trauma was positively associated with the PTSD symptom intercept and predicted symptoms at 12 months after trauma. Habituation in the ventral anterior cingulate cortex was positively associated with the slope of PTSD symptoms, such that decreases in ventral anterior cingulate cortex activation over repeated presentations of fearful stimuli predicted increasing symptoms. CONCLUSIONS: Findings point to neural signatures of risk for maintaining PTSD symptoms after trauma exposure. Specifically, chronic symptoms were predicted by amygdala hyperreactivity, and poor recovery was predicted by a failure to maintain ventral anterior cingulate cortex activation in response to fearful stimuli. The importance of identifying patients at risk after trauma exposure is discussed.

BACKGROUND: Systemic inflammation has emerged as a promising marker and potential mechanism underlying post-traumatic stress disorder (PTSD). The relationship between posttraumatic stress pathology and systemic inflammation has not, however, been consistently replicated and is potentially confounded by comorbid illness or injury, common complications of trauma exposure. METHODS: We analyzed a large naturalistic cohort sharing a discrete physical and mental health trauma from the destruction of the World Trade Center (WTC) towers on September 11, 2001 (n = 641). We evaluated the relationship between multiple physical and mental health related indices collected through routine evaluations at the WTC Environmental Health Center (WTC EHC), a treatment program for community members exposed to the disaster. C-Reactive Protein (CRP), a marker of systemic inflammation, was examined in relation to scores for PTSD, PTSD symptom clusters (re-experiencing, avoidance, negative cognitions/mood, arousal), depression and anxiety, while controlling for WTC exposures, lower respiratory symptoms, age, sex, BMI and smoking as potential risks or confounders. RESULTS: CRP was positively associated with PTSD severity (p < 0.001), trending toward association with depression (p = 0.06), but not with anxiety (p = 0.27). CRP was positively associated with re-experiencing (p < 0.001) and avoidance (p < 0.05) symptom clusters, and trended toward associations with negative cognitions/mood (p = 0.06) and arousal (p = 0.08). CONCLUSIONS: In this large study of the relationship between CRP and posttraumatic stress pathology, we demonstrated an association between systemic inflammation and stress pathology (PTSD; trending with depression), which remained after adjusting for potentially confounding variables. These results contribute to research findings suggesting a salient relationship between inflammation and posttraumatic stress pathology.

Deficits in fear extinction learning are hypothesized to underlie the development of posttraumatic stress disorder (PTSD). Such deficits may, in part, be due to genetic and epigenetic variation in the stress related gene FKBP5. Conversely, altering FKBP5 epigenetic responses during memory consolidation may rescue extinction deficits making it a target for acute intervention to prevent the development of PTSD. Study 1 (Humans) examines if FKBP5 single nucleotide polymorphisms (SNPs) and PTSD symptom domains (re-experiencing, avoidance/numbing, hyperarousal) are associated with abnormal fear extinction phenotypes identified using latent growth mixture modeling (LGMM). Study 2 (Mice) tests if increasing doses of dexamethasone administered prior to extinction alters Fkbp5 mRNA production in the amygdala after extinction and recall and prevents the development of abnormal extinction phenotypes. In humans, abnormal extinction was associated with the TT homozygous genotype of FKBP5 SNPs RS9470080 and RS1360780, and hyperarousal symptoms. In mice, dexamethasone 300 mug/kg was associated with increased amygdala Fkbp5 mRNA following extinction and robust extinction learning while lower doses were not associated with amygdala Fkbp5 mRNA or differences in extinction learning. Further, mice that extinguished on dexamethasone 300 mug/kg maintained low levels of freezing behavior during recall training while mRNA levels were no longer elevated. Together, findings indicate that FKBP5 confers risk for fear extinction deficits. However, this risk may be ameliorated by increasing fkbp5 mRNA expression in the amygdala during memory consolidation making this mechanism a plausible point of acute intervention to prevent the development of PTSD.

To date, studies of biological risk factors have revealed inconsistent relationships with subsequent post-traumatic stress disorder (PTSD). The inconsistent signal may reflect the use of data analytic tools that are ill equipped for modeling the complex interactions between biological and environmental factors that underlay post-traumatic psychopathology. Further, using symptom-based diagnostic status as the group outcome overlooks the inherent heterogeneity of PTSD, potentially contributing to failures to replicate. To examine the potential yield of novel analytic tools, we reanalyzed data from a large longitudinal study of individuals identified following trauma in the general emergency room (ER) that failed to find a linear association between cortisol response to traumatic events and subsequent PTSD. First, latent growth mixture modeling empirically identified trajectories of post-traumatic symptoms, which then were used as the study outcome. Next, support vector machines with feature selection identified sets of features with stable predictive accuracy and built robust classifiers of trajectory membership (area under the receiver operator characteristic curve (AUC)=0.82 (95% confidence interval (CI)=0.80-0.85)) that combined clinical, neuroendocrine, psychophysiological and demographic information. Finally, graph induction algorithms revealed a unique path from childhood trauma via lower cortisol during ER admission, to non-remitting PTSD. Traditional general linear modeling methods then confirmed the newly revealed association, thereby delineating a specific target population for early endocrine interventions. Advanced computational approaches offer innovative ways for uncovering clinically significant, non-shared biological signals in heterogeneous samples.

Posttraumatic stress disorder (PTSD) is common in the general population, yet there are limitations to the effectiveness, tolerability, and acceptability of available first-line interventions. We review the extant knowledge on the effects of marijuana and other cannabinoids on PTSD. Potential therapeutic effects of these agents may largely derive from actions on the endocannabinoid system and we review major animal and human findings in this area. Preclinical and clinical studies generally support the biological plausibility for cannabinoids' potential therapeutic effects, but underscore heterogeneity in outcomes depending on dose, chemotype, and individual variation. Treatment outcome studies of whole plant marijuana and related cannabinoids on PTSD are limited and not methodologically rigorous, precluding conclusions about their potential therapeutic effects. Reported benefits for nightmares and sleep (particularly with synthetic cannabinoid nabilone) substantiate larger controlled trials to determine effectiveness and tolerability. Of concern, marijuana use has been linked to adverse psychiatric outcomes, including conditions commonly comorbid with PTSD such as depression, anxiety, psychosis, and substance misuse. Available evidence is stronger for marijuana's harmful effects on the development of psychosis and substance misuse than for the development of depression and anxiety. Marijuana use is also associated with worse treatment outcomes in naturalistic studies, and with maladaptive coping styles that may maintain PTSD symptoms. Known risks of marijuana thus currently outweigh unknown benefits for PTSD. Although controlled research on marijuana and other cannabinoids' effects on PTSD remains limited, rapid shifts in the legal landscape may now enable such studies, potentially opening new avenues in PTSD treatment research.

BACKGROUND: Research has demonstrated a strong link between trauma, posttraumatic stress disorder PTSD and substance use disorders (SUDs) in general and cannabis use disorders in particular. Yet, few studies have examined the impact of cannabis use on treatment outcomes for individuals with co-occurring PTSD and SUDs. METHODS: Participants were 136 individuals who received cognitive-behavioral therapies for co-occurring PTSD and SUD. Multivariate regressions were utilized to examine the associations between baseline cannabis use and end-of-treatment outcomes. Multilevel linear growth models were fit to the data to examine the cross-lagged associations between weekly cannabis use and weekly PTSD symptom severity and primary substance use during treatment. RESULTS: There were no significant positive nor negative associations between baseline cannabis use and end-of-treatment PTSD symptom severity and days of primary substance use. Cross-lagged models revealed that as cannabis use increased, subsequent primary substance use decreased and vice versa. Moreover, results revealed a crossover lagged effect, whereby higher cannabis use was associated with greater PTSD symptom severity early in treatment, but lower weekly PTSD symptom severity later in treatment. CONCLUSION: Cannabis use was not associated with adverse outcomes in end-of-treatment PTSD and primary substance use, suggesting independent pathways of change. The theoretical and clinical implications of the reciprocal associations between weekly cannabis use and subsequent PTSD and primary substance use symptoms during treatment are discussed.

1-octanol is a therapeutic candidate for disorders involving the abnormal activation of the T-type calcium current since it blocks this current specifically. Such disorders include essential tremor and a group of neurological and psychiatric disorders resulting from thalamocortical dysrhythmia (TCD). For example, clinically, the observable phenotype in essential tremor is the tremor itself. The differential diagnostic of TCD is not based only on clinical signs and symptoms. Rather, TCD incorporates an electromagnetic biomarker, the presence of abnormal thalamocortical low frequency brain oscillations. The effect of 1-octanol on brain activity has not been tested. As a preliminary step to such a TCD study, we examined the short-term effects of a single dose of 1-octanol on resting brain activity in 32 healthy adults using magnetoencephalograpy. Visual inspection of baseline power spectra revealed that the subjects fell into those with strong low frequency activity (set 2, n = 11) and those without such activity, but dominated by an alpha peak (set 1, n = 22). Cross-validated linear discriminant analysis, using mean spectral density (MSD) in nine frequency bands as predictors, found overall that 82.5% of the subjects were classified as determined by visual inspection. The effect of 1-octanol on the MSD in narrow frequency bands differed between the two subject groups. In set 1 subjects the MSD increased in the 4.5-6.5Hz and 6.5-8.5 Hz bands. This was consistent with a widening of the alpha peak toward lower frequencies. In the set two subjects the MSD decrease in the 2.5-4.5 Hz and 4.5-6.5 Hz bands. This decreased power is consistent with the blocking effect of 1-octanol on T-type calcium channels. The subjects reported no adverse effects of the 1-octanol. Since stronger low frequency activity is characteristic of patients with TCD, 1-octanol and other T-type calcium channel blockers are good candidates for treatment of this group of disorders following a placebo-controlled study.