Blast-related traumatic brain injuries have been common in the Iraq and Afghanistan wars, but fundamental questions about the nature of these injuries remain unanswered.
We tested the hypothesis that ...blast-related traumatic brain injury causes traumatic axonal injury, using diffusion tensor imaging (DTI), an advanced form of magnetic resonance imaging that is sensitive to axonal injury. The subjects were 63 U.S. military personnel who had a clinical diagnosis of mild, uncomplicated traumatic brain injury. They were evacuated from the field to the Landstuhl Regional Medical Center in Landstuhl, Germany, where they underwent DTI scanning within 90 days after the injury. All the subjects had primary blast exposure plus another, blast-related mechanism of injury (e.g., being struck by a blunt object or injured in a fall or motor vehicle crash). Controls consisted of 21 military personnel who had blast exposure and other injuries but no clinical diagnosis of traumatic brain injury.
Abnormalities revealed on DTI were consistent with traumatic axonal injury in many of the subjects with traumatic brain injury. None had detectable intracranial injury on computed tomography. As compared with DTI scans in controls, the scans in the subjects with traumatic brain injury showed marked abnormalities in the middle cerebellar peduncles (P<0.001), in cingulum bundles (P=0.002), and in the right orbitofrontal white matter (P=0.007). In 18 of the 63 subjects with traumatic brain injury, a significantly greater number of abnormalities were found on DTI than would be expected by chance (P<0.001). Follow-up DTI scans in 47 subjects with traumatic brain injury 6 to 12 months after enrollment showed persistent abnormalities that were consistent with evolving injuries.
DTI findings in U.S. military personnel support the hypothesis that blast-related mild traumatic brain injury can involve axonal injury. However, the contribution of primary blast exposure as compared with that of other types of injury could not be determined directly, since none of the subjects with traumatic brain injury had isolated primary blast injury. Furthermore, many of these subjects did not have abnormalities on DTI. Thus, traumatic brain injury remains a clinical diagnosis. (Funded by the Congressionally Directed Medical Research Program and the National Institutes of Health; ClinicalTrials.gov number, NCT00785304.).
Chronic opioid usage not only causes addiction behavior through the central nervous system, but also modulates the peripheral immune system. However, how opioid impacts the immune system is still ...barely characterized systematically. In order to understand the immune modulatory effect of opioids in an unbiased way, here we perform single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from opioid-dependent individuals and controls to show that chronic opioid usage evokes widespread suppression of antiviral gene program in naive monocytes, as well as in multiple immune cell types upon stimulation with the pathogen component lipopolysaccharide. Furthermore, scRNA-seq reveals the same phenomenon after a short in vitro morphine treatment. These findings indicate that both acute and chronic opioid exposure may be harmful to our immune system by suppressing the antiviral gene program. Our results suggest that further characterization of the immune modulatory effects of opioid is critical to ensure the safety of clinical opioids.
Blast injury has been identified as the signature injury in the conflicts in Iraq and Afghanistan. However it remains to be determined whether fundamental differences may exist between blast-related ...traumatic brain injury (TBI) and TBI due to other mechanisms.
To determine similarities and differences between clinical outcomes in US military personnel with blast-related vs. non-blast-related concussive TBI and to identify the specific domains of impairment that best correlate with overall disability.
Prospective cohort study involving active duty US Military personnel evacuated from Iraq or Afghanistan to Landstuhl Regional Medical Center, in Landstuhl, Germany. Four groups of participants were enrolled from 2010 to 2013: (1) blast plus impact complex TBI (n=53), (2) non-blast related TBI with injury due to other mechanisms (n=29), (3) blast-exposed controls evacuated for other medical reasons (n=27) (4) non-blast-exposed controls evacuated for other medical reasons (n=69). All patients with TBI met Department of Defense criteria for concussive (mild) TBI. The study participants were evaluated 6-12 months after injury at Washington University in St Louis. In total, 255 subjects were enrolled in the study, and 183 participated in follow-up evaluations, 5 of whom were disqualified.
In-person clinical examinations included evaluation for overall disability, a standardized neurological exam, headache questionnaires, neuropsychological test battery, combat exposure and alcohol use surveys, and structured interview evaluations for post-traumatic stress disorder (PTSD) and depression.
Global outcomes, headache severity, neuropsychological performance, and surprisingly even PTSD severity and depression were indistinguishable between the two TBI groups, independent of mechanism of injury. Both TBI groups had higher rates of moderate to severe overall disability than the respective control groups: 41/53 (77%) of blast plus impact TBI and 23/29 (79%) of nonblast TBI vs. 16/27 (59%) of blast-exposed controls and 28/69 (41%) of non-blast-exposed controls. In addition, blast-exposed controls had worse headaches and more severe PTSD than non-blast-exposed controls. Self-reported combat exposure intensity was higher in the blast plus impact TBI group than in nonblast TBI group and was higher in blast-exposed controls than in non-blast-exposed controls. However, combat exposure intensity did not correlate with PTSD severity in the TBI groups, but a modest positive correlation was observed in the controls. Overall outcomes were most strongly correlated with depression, headache severity, and number of abnormalities on neuropsychological testing. However a substantial fraction of the variance in overall outcome was not explained by any of the assessed measures.
One potential interpretation of these results is that TBI itself, independent of injury mechanism and combat exposure intensity, is a primary driver of adverse outcomes. Many other important factors may be as yet unmeasured, and adverse outcomes following war-time injuries are difficult to fully explain.
clinicaltrials.gov Identifier: NCT01313130.
Opioid addiction (OA) is moderately heritable, yet only rs1799971, the A118G variant in OPRM1, has been identified as a genome-wide significant association with OA and independently replicated. We ...applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data together with published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective sample size of 88,114 individuals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (r
> 0.9). We observed the strongest evidence to date for OPRM1: lead SNP rs9478500 (p = 2.56 × 10
). Gene-based analyses identified novel genome-wide significant associations with PPP6C and FURIN. Variants within these loci appear to be pleiotropic for addiction and related traits.
High rates of adverse outcomes have been reported following blast-related concussive traumatic brain injury in US military personnel, but the extent to which such adverse outcomes can be predicted ...acutely after injury is unknown. We performed a prospective, observational study of US military personnel with blast-related concussive traumatic brain injury (n = 38) and controls (n = 34) enrolled between March and September 2012. Importantly all subjects returned to duty and did not require evacuation. Subjects were evaluated acutely 0-7 days after injury at two sites in Afghanistan and again 6-12 months later in the United States. Acute assessments revealed heightened post-concussive, post-traumatic stress, and depressive symptoms along with worse cognitive performance in subjects with traumatic brain injury. At 6-12 months follow-up, 63% of subjects with traumatic brain injury and 20% of controls had moderate overall disability. Subjects with traumatic brain injury showed more severe neurobehavioural, post-traumatic stress and depression symptoms along with more frequent cognitive performance deficits and more substantial headache impairment than control subjects. Logistic regression modelling using only acute measures identified that a diagnosis of traumatic brain injury, older age, and more severe post-traumatic stress symptoms provided a good prediction of later adverse global outcomes (area under the receiver-operating characteristic curve = 0.84). Thus, US military personnel with concussive blast-related traumatic brain injury in Afghanistan who returned to duty still fared quite poorly on many clinical outcome measures 6-12 months after injury. Poor global outcome seems to be largely driven by psychological health measures, age, and traumatic brain injury status. The effects of early interventions and longer term implications of these findings are unknown.
Despite evidence of substantial comorbidity between psychiatric disorders and substance involvement, the extent to which common genetic factors contribute to their co-occurrence remains understudied. ...In the current study, we tested for associations between polygenic risk for psychiatric disorders and substance involvement (i.e., ranging from ever-use to severe dependence) among 2573 non-Hispanic European-American participants from the Study of Addiction: Genetics and Environment. Polygenic risk scores (PRS) for cross-disorder psychopathology (CROSS) were generated based on the Psychiatric Genomics Consortium's Cross-Disorder meta-analysis and then tested for associations with a factor representing general liability to alcohol, cannabis, cocaine, nicotine, and opioid involvement (GENSUB). Follow-up analyses evaluated specific associations between each of the five psychiatric disorders which comprised CROSS-attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (AUT), bipolar disorder (BIP), major depressive disorder (MDD), and schizophrenia (SCZ)-and involvement with each component substance included in GENSUB. CROSS PRS explained 1.10% of variance in GENSUB in our sample (p < 0.001). After correction for multiple testing in our follow-up analyses of polygenic risk for each individual disorder predicting involvement with each component substance, associations remained between: (A) MDD PRS and non-problem cannabis use, (B) MDD PRS and severe cocaine dependence, (C) SCZ PRS and non-problem cannabis use and severe cannabis dependence, and (D) SCZ PRS and severe cocaine dependence. These results suggest that shared covariance from common genetic variation contributes to psychiatric and substance involvement comorbidity.
•In this treatment sample, onset of opioid use occurred during late adolescence.•Transitions to opioid dependence and treatment-seeking occurred in early adulthood.•Birth cohort, child maltreatment ...and later use predicted rapid onset of dependence.•<10 years school, depression and alcohol dependence predicted treatment delay.•Mid-adolescence is a critical period for targeting interventions.
Little is known about transition pathways among heroin users prior to treatment. This study examined the demographic and clinical predictors of transition speed from heroin use, to dependence, to first treatment episode.
1149 heroin-dependent participants recruited from opioid agonist treatment clinics in Sydney, Australia, underwent a structured interview. Age of onset (AOO) was collected for heroin use, dependence and treatment-seeking, childhood maltreatment, psychiatric history and other substance dependence. Discrete-time survival analyses modelled years from onset of use to dependence, and from dependence to treatment-seeking, including demographic and clinical covariates.
Median AOO for first heroin use, dependence and treatment-seeking was 18 years (inter-quartile range, or IQR = 6), 21 years (IQR = 7), and 24 years (IQR = 10) respectively. In adjusted models, younger birth cohorts (vs. born <1960), greater childhood maltreatment and later AAO of first heroin use were associated with more rapid transitions from heroin use to dependence. Living independently, parental violence, and alcohol dependence were associated with slower transitions. Earlier treatment-seeking was associated with younger birth cohorts, having dependent children and later AOO of dependence. Delayed treatment-seeking was associated with <10 years school education, living independently, depression and alcohol dependence.
In this treatment sample, onset of heroin use occurred during late adolescence, suggesting the need for targeted interventions in mid-adolescence. Transitions to heroin dependence, then treatment-seeking, occurred during early adulthood. Rapid transitions from use to dependence were associated with younger birth cohorts, greater exposure to childhood maltreatment, and later onset of use.
Cannabis is the most widely used illicit drug throughout the developed world and there is consistent evidence of heritable influences on multiple stages of cannabis involvement including initiation ...of use and abuse/dependence. In this paper, we describe the methodology and preliminary results of a large-scale interview study of 3,824 young adult twins (born 1972-1979) and their siblings. Cannabis use was common with 75.2% of males and 64.7% of females reporting some lifetime use of cannabis while 24.5% of males and 11.8% of females reported meeting criteria for DSM-IV cannabis abuse or dependence. Rates of other drug use disorders and common psychiatric conditions were highly correlated with extent of cannabis involvement and there was consistent evidence of heritable influences across a range of cannabis phenotypes including early (≤15 years) opportunity to use (h 2 = 72%), early (≤16 years) onset use (h 2 = 80%), using cannabis 11+ times lifetime (h 2 = 76%), and DSM abuse/dependence (h 2 = 72%). Early age of onset of cannabis use was strongly associated with increased rates of subsequent use of other illicit drugs and with illicit drug abuse/dependence; further analyses indicating that some component of this association may have been mediated by increasing exposure to and opportunity to use other illicit drugs.
Abstract Introduction and aims To examine differences in the characteristics and histories of male and female dependent heroin users, and in the clinical characteristics associated with multiple ...substance dependence diagnoses. Design and methods 1513 heroin dependent participants underwent an interview covering substance use and dependence, psychiatric history, child maltreatment, family background, adult violence and criminal history. Family background, demographic and clinical characteristics were analysed by sex. Ordinal regression was used to test for a relationship between number of substance dependence diagnoses and other clinical variables. Results Women were more likely to experience most forms of child maltreatment, to first use heroin with a boyfriend or partner, to experience ongoing adult violence at the hands of a partner, and to have a poorer psychiatric history than men. Males had more prevalent lifetime substance dependence diagnoses and criminal histories and were more likely to meet the criteria for ASPD. Predictors of multiple substance dependence diagnoses for both sexes were mental health variables, antisocial behaviour, childhood sexual abuse, victim of adult violence, younger age at first cannabis use and overdose. As the number of dependence diagnoses increased, clinical and behavioural problems increased. Childhood emotional neglect was related to increasing dependence diagnoses for females but not males, whereas PTSD was a significant predictor for males but not females. Discussion and conclusions Mental health problems, other substance dependence, childhood and adult trauma were common in this sample, with sex differences indicating different treatment needs and possible different pathways to heroin dependence for men and women.
Care for US military personnel with combat-related concussive traumatic brain injury (TBI) has substantially changed in recent years, yet trends in clinical outcomes remain largely unknown. Our ...prospective longitudinal studies of US military personnel with concussive TBI from 2008-2013 at Landstuhl Regional Medical Center in Germany and twp sites in Afghanistan provided an opportunity to assess for changes in outcomes over time and analyze correlates of overall disability. We enrolled 321 active-duty US military personnel who sustained concussive TBI in theater and 254 military controls. We prospectively assessed clinical outcomes 6-12 months later in 199 with concussive TBI and 148 controls. Global disability, neurobehavioral impairment, depression severity, and post-traumatic stress disorder (PTSD) severity were worse in concussive TBI groups in comparison with controls in all cohorts. Global disability primarily reflected a combination of work-related and nonwork-related disability. There was a modest but statistically significant trend toward less PTSD in later cohorts. Specifically, there was a decrease of 5.9 points of 136 possible on the Clinician Administered PTSD Scale (-4.3%) per year (95% confidence interval, 2.8-9.0 points, p = 0.0037 linear regression, p = 0.03 including covariates in generalized linear model). No other significant trends in outcomes were found. Global disability was more common in those with TBI, those evacuated from theater, and those with more severe depression and PTSD. Disability was not significantly related to neuropsychological performance, age, education, self-reported sleep deprivation, injury mechanism, or date of enrollment. Thus, across multiple cohorts of US military personnel with combat-related concussion, 6-12 month outcomes have improved only modestly and are often poor. Future focus on early depression and PTSD after concussive TBI appears warranted. Adverse outcomes are incompletely explained, however, and additional studies with prospective collection of data on acute injury severity and polytrauma, as well as reduced attrition before follow-up will be required to fully address the root causes of persistent disability after wartime injury.
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