The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5–20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson’s disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

Observational studies¹ largely support an association of posttraumatic stress disorder (PTSD) with increased peripheral inflammation, as discussed in a recent review of the overall evidence.² For instance, one large cross-sectional community-based study³ found that patients with PTSD had approximately twice the odds of those without this disorder of elevation in the inflammatory marker C-reactive protein (CRP). Similarly, although some case-control studies^4,5 have had negative or equivocal findings, in most such studies^6-11 PTSD cohorts have had significantly greater plasma levels of CRP or interleukin 6, among other inflammatory markers, than did controls. This association is of prognostic significance because low-grade inflammation is likely involved in the pathophysiology of the metabolic syndrome,^12-14 a major cardiovascular risk factor^15,16; indeed, PTSD has been found to be associated with this syndrome.^17-24

There is accumulating evidence for a link between trauma exposure, posttraumatic stress disorder (PTSD) and diminished health status. To assess PTSD-related biological burden, we measured biological factors that comprise metabolic syndrome, an important established predictor of morbidity and mortality, as a correlate of long-term health risk in PTSD.

Well-established in the field of bioelectronic medicine, Spinal Cord Stimulation (SCS) offers an implantable, non-pharmacologic treatment for patients with intractable chronic pain conditions. Chronic pain is a widely heterogenous syndrome with regard to both pathophysiology and the resultant phenotype. Despite advances in our understanding of SCS-mediated antinociception, there still exists limited evidence clarifying the pathways recruited when patterned electric pulses are applied to the epidural space. The rapid clinical implementation of novel SCS methods including burst, high frequency and dorsal root ganglion SCS has provided the clinician with multiple options to treat refractory chronic pain. While compelling evidence for safety and efficacy exists in support of these novel paradigms, our understanding of their mechanisms of action (MOA) dramatically lags behind clinical data. In this review, we reconstruct the available basic science and clinical literature that offers support for mechanisms of both paresthesia spinal cord stimulation (P-SCS) and paresthesia-free spinal cord stimulation (PF-SCS). While P-SCS has been heavily examined since its inception, PF-SCS paradigms have recently been clinically approved with the support of limited preclinical research. Thus, wide knowledge gaps exist between their clinical efficacy and MOA. To close this gap, many rich investigative avenues for both P-SCS and PF-SCS are underway, which will further open the door for paradigm optimization, adjunctive therapies and new indications for SCS. As our understanding of these mechanisms evolves, clinicians will be empowered with the possibility of improving patient care using SCS to selectively target specific pathophysiological processes in chronic pain.

Traumatic brain injury (TBI) is common. According to a 2010 Centers for Disease Control and Prevention report,¹ at least 1.7 million Americans annually sustain TBI. A significant number of injury survivors join more than 5 million (approximately 2%) Americans already living with TBI-related disabilities, which comprise a wide range of medical, cognitive, emotional, and behavioral impairments.^2,3 The estimated economic burden of TBI in the United States in 2000, prior to initiation of the Iraq and Afghanistan conflicts, was approximately $60 billion annually.⁴