Genome-wide association studies with experimental validation identify a protective role for B lymphocytes against chronic post-surgical pain.

BACKGROUND: Chronic post-surgical pain (CPSP) significantly impacts patients' recovery and quality of life. Although environmental risk factors are well-established, genetic risk remains less understood. METHODS: A meta-analysis of genome-wide association studies followed by partitioned heritability was performed on 1350 individuals across five surgery types: hysterectomy, mastectomy, abdominal, hernia, and knee. In subsequent animal studies, withdrawal thresholds to evoked mechanical stimulation were measured in Rag1 null mutant and wild-type mice after plantar incision and laparotomy. Cell sorting by flow cytometry tracked recruitment of immune cell types. RESULTS: We discovered 77 genome-wide significant single-nucleotide polymorphism (SNP) hits, distributed among 24 loci and 244 genes. Meta-analysis of all cohorts estimated a SNP-based narrow-sense heritability for CPSP at ∼39%, indicating a substantial genetic contribution. Partitioned heritability analysis across a wide variety of tissues revealed enrichment of heritability in immune system-related genes, particularly those associated with B and T cells. Rag1 null mutant mice lacking both T and B cells exhibited exacerbated and prolonged allodynia up to 42 days after surgery, which was rescued by B-cell transfer. Recruitment patterns of B cells but not T cells differed significantly during the first 7 days after injury in the footpad, lymph nodes, and dorsal root ganglia. CONCLUSIONS: These findings suggest a key protective role for the adaptive immune system in the development of chronic post-surgical pain.

Genome-wide association study suggests a critical contribution of the adaptive immune system to chronic post-surgical pain.

Chronic post-surgical pain affects a large proportion of people undergoing surgery, delaying recovery time and worsening quality of life. Although many environmental variables have been established as risk factors, less is known about genetic risk. To uncover genetic risk factors we performed genome-wide association studies in post-surgical cohorts of five surgery types- hysterectomy, mastectomy, abdominal, hernia, and knee- totaling 1350 individuals. Genetic associations between post-surgical chronic pain levels on a numeric rating scale (NRS) and additive genetic effects at common SNPs were evaluated. We observed genome-wide significant hits in almost all cohorts that displayed significance at the SNP, gene, and pathway levels. The cohorts were then combined via a GWAS meta-analysis framework for further analyses. Using partitioned heritability, we found that loci at genes specifically expressed in the immune system carried enriched heritability, especially genes related to B and T cells. The relevance of B cells in particular was then demonstrated in mouse postoperative pain assays. Taken altogether, our results suggest a role for the adaptive immune system in chronic post-surgical pain.

Coping during socio-political uncertainty.

Introduction: Well-being of young adults is known to be compromised in times of significant changes, such as economic and political turmoil. This study focuses on university students in Lebanon during one of the most prominent social unrests of its modern history to determine potential understudied protective factors that would predict the youth capacity to strive. Methods: A sample of 489 university students were asked to fill an online survey including standardized questionnaires of wellbeing (WEMWBS), depression (PHQ-9), anxiety (HAM-A), intolerance of uncertainty (IUS-12), coping (Brief COPE) in addition to demographics and questions about their attitudes and future perspectives. Results: We found increased rates of mental distress, predominantly in women, with around 80% of the sample being highly intolerant to the uncertainty climate. Results unsurprisingly show that well-being negatively correlated with anxiety, depression and intolerance of uncertainty. Overall, mental distress was found to mediate the relation between uncertainty and wellbeing, and the relation between maladaptive coping and wellbeing. Students who were intolerant of uncertainty and who used maladaptive coping strategies were more likely develop anxiety and depression and subsequently report poorer wellbeing. Conversely, having adaptive strategies was directly linked to higher well-being. Discussion: In spite of increased distress, some university students managed to preserve their well-being within a climate of severe socio-political uprise. These findings suggest that modifying subjective experience of events and using soft skillset could alleviate young adults' emotional distress in unstable societies.

Brain-specific genes contribute to chronic but not to acute back pain.

Introduction: Back pain is the leading cause of disability worldwide. Although most back pain cases are acute, 20% of acute pain patients experience chronic back pain symptoms. It is unclear whether acute pain and chronic pain have similar or distinct underlying genetic mechanisms. Objectives: To characterize the molecular and cellular pathways contributing to acute and chronic pain states. Methods: Cross-sectional observational genome-wide association study. Results: A total of 375,158 individuals from the UK Biobank cohort were included in the discovery of genome-wide association study. Of those, 70,633 (19%) and 32,209 (9%) individuals met the definition of chronic and acute back pain, respectively. A total of 355 single nucleotide polymorphism grouped into 13 loci reached the genome-wide significance threshold (5x10-8) for chronic back pain, but none for acute. Of these, 7 loci were replicated in the Nord-Trøndelag Health Study (HUNT) cohort (19,760 chronic low back pain cases and 28,674 pain-free controls). Single nucleotide polymorphism heritability was 4.6% (P=1.4x10-78) for chronic back pain and 0.81% (P=1.4x10-8) for acute back pain. Similar differences in heritability estimates between acute and chronic back pain were found in the HUNT cohort: 3.4% (P=0.0011) and 0.6% (P=0.851), respectively. Pathway analyses, tissue-specific heritability enrichment analyses, and epigenetic characterization suggest a substantial genetic contribution to chronic but not acute back pain from the loci predominantly expressed in the central nervous system. Conclusion: Chronic back pain is substantially more heritable than acute back pain. This heritability is mostly attributed to genes expressed in the brain.

Sodium-calcium exchanger-3 regulates pain "wind-up": From human psychophysics to spinal mechanisms.

Repeated application of noxious stimuli leads to a progressively increased pain perception; this temporal summation is enhanced in and predictive of clinical pain disorders. Its electrophysiological correlate is "wind-up," in which dorsal horn spinal neurons increase their response to repeated nociceptor stimulation. To understand the genetic basis of temporal summation, we undertook a GWAS of wind-up in healthy human volunteers and found significant association with SLC8A3 encoding sodium-calcium exchanger type 3 (NCX3). NCX3 was expressed in mouse dorsal horn neurons, and mice lacking NCX3 showed normal, acute pain but hypersensitivity to the second phase of the formalin test and chronic constriction injury. Dorsal horn neurons lacking NCX3 showed increased intracellular calcium following repetitive stimulation, slowed calcium clearance, and increased wind-up. Moreover, virally mediated enhanced spinal expression of NCX3 reduced central sensitization. Our study highlights Ca2+ efflux as a pathway underlying temporal summation and persistent pain, which may be amenable to therapeutic targeting.

Genome-wide analysis identifies impaired axonogenesis in chronic overlapping pain conditions.

Chronic pain is often present at more than one anatomical location, leading to chronic overlapping pain conditions. Whether chronic overlapping pain conditions represent a distinct pathophysiology from the occurrence of pain at only one site is unknown. Using genome-wide approaches, we compared genetic determinants of chronic single-site versus multisite pain in the UK Biobank. We found that different genetic signals underlie chronic single-site and multisite pain with much stronger genetic contributions for the latter. Among 23 loci associated with multisite pain, nine loci replicated in the HUNT cohort, with the DCC netrin 1 receptor (DCC) as the top gene. Functional genomics identified axonogenesis in brain tissues as the major contributing pathway to chronic multisite pain. Finally, multimodal structural brain imaging analysis showed that DCC is most strongly expressed in subcortical limbic regions and is associated with alterations in the uncinate fasciculus microstructure, suggesting that DCC-dependent axonogenesis may contribute to chronic overlapping pain conditions via corticolimbic circuits.

Single cell transcriptomics of primate sensory neurons identifies cell types associated with chronic pain.

Distinct types of dorsal root ganglion sensory neurons may have unique contributions to chronic pain. Identification of primate sensory neuron types is critical for understanding the cellular origin and heritability of chronic pain. However, molecular insights into the primate sensory neurons are missing. Here we classify non-human primate dorsal root ganglion sensory neurons based on their transcriptome and map human pain heritability to neuronal types. First, we identified cell correlates between two major datasets for mouse sensory neuron types. Machine learning exposes an overall cross-species conservation of somatosensory neurons between primate and mouse, although with differences at individual gene level, highlighting the importance of primate data for clinical translation. We map genomic loci associated with chronic pain in human onto primate sensory neuron types to identify the cellular origin of chronic pain. Genome-wide associations for chronic pain converge on two different neuronal types distributed between pain disorders that display different genetic susceptibilities, suggesting both unique and shared mechanisms between different pain conditions.

Multi-ethnic GWAS and meta-analysis of sleep quality identify MPP6 as a novel gene that functions in sleep center neurons.

Poor sleep quality can have harmful health consequences. Although many aspects of sleep are heritable, the understandings of genetic factors involved in its physiology remain limited. Here, we performed a genome-wide association study (GWAS) using the Pittsburgh Sleep Quality Index (PSQI) in a multi-ethnic discovery cohort (n = 2868) and found two novel genome-wide loci on chromosomes 2 and 7 associated with global sleep quality. A meta-analysis in 12 independent cohorts (100 000 individuals) replicated the association on chromosome 7 between NPY and MPP6. While NPY is an important sleep gene, we tested for an independent functional role of MPP6. Expression data showed an association of this locus with both NPY and MPP6 mRNA levels in brain tissues. Moreover, knockdown of an orthologue of MPP6 in Drosophila melanogaster sleep center neurons resulted in decreased sleep duration. With convergent evidence, we describe a new locus impacting human variability in sleep quality through known NPY and novel MPP6 sleep genes.

Sex- and age-specific genetic analysis of chronic back pain.

ABSTRACT: Sex differences for chronic back pain (cBP) have been reported, with females usually exhibiting greater morbidity, severity, and poorer response to treatment. Genetic factors acting in an age-specific manner have been implicated but never comprehensively explored. We performed sex- and age-stratified genome-wide association study and single nucleotide polymorphism-by-sex interaction analysis for cBP defined as "Back pain for 3+ months" in 202,077 males and 237,754 females of European ancestry from UK Biobank. Two and 7 nonoverlapping genome-wide significant loci were identified for males and females, respectively. A male-specific locus on chromosome 10 near SPOCK2 gene was replicated in 4 independent cohorts. Four loci demonstrated single nucleotide polymorphism-by-sex interaction, although none of them were formally replicated. Single nucleotide polymorphism-explained heritability was higher in females (0.079 vs 0.067, P = 0.006). There was a high, although not complete, genetic correlation between the sexes (r = 0.838 ± 0.041, different from 1 with P = 7.8E-05). Genetic correlation between the sexes for cBP decreased with age (0.858 ± 0.049 in younger people vs 0.544 ± 0.157 in older people; P = 4.3E-05). There was a stronger genetic correlation of cBP with self-reported diagnosis of intervertebral disk degeneration in males than in females (0.889 vs 0.638; P = 3.7E-06). Thus, the genetic component of cBP in the UK Biobank exhibits a mild sex- and age-dependency. This provides an insight into the possible causes of sex- and age-specificity in epidemiology and pathophysiology of cBP and chronic pain at other anatomical sites.

A genetic polymorphism that is associated with mitochondrial energy metabolism increases risk of fibromyalgia.

Alterations in cellular energy metabolism have been implicated in chronic pain, suggesting a role for mitochondrial DNA. Previous studies reported associations of a limited number of mitochondrial DNA polymorphisms with specific pain conditions. In this study, we examined the full mitochondrial genomes of people with a variety of chronic pain conditions. A discovery cohort consisting of 609 participants either with or without a complex persistent pain conditions (CPPCs) was examined. Mitochondrial DNA was subjected to deep sequencing for identification of rare mutations, common variants, haplogroups, and heteroplasmy associated with 5 CPPCs: episodic migraine, irritable bowel syndrome, fibromyalgia, vulvar vestibulitis, or temporomandibular disorders. The strongest association found was the presence of the C allele at the single nucleotide polymorphism m.2352T>C (rs28358579) that significantly increased the risk for fibromyalgia (odds ratio [OR] = 4.6, P = 4.3 × 10). This relationship was even stronger in women (OR = 5.1, P = 2.8 × 10), and m.2352T>C was associated with all other CPPCs in a consistent risk-increasing fashion. This finding was replicated in another cohort (OR = 4.3, P = 2.6 × 10) of the Orofacial Pain: Prospective Evaluation and Risk Assessment study consisting of 1754 female participants. To gain insight into the cellular consequences of the associated genetic variability, we conducted an assay testing metabolic reprogramming in human cell lines with defined genotypes. The minor allele C was associated with decreased mitochondrial membrane potential under conditions where oxidative phosphorylation is required, indicating a role of oxidative phosphorylation in pathophysiology of chronic pain. Our results suggest that cellular energy metabolism, modulated by m.2352T>C, contributes to fibromyalgia and possibly other chronic pain conditions.

The dichotomous role of epiregulin in pain.

It has recently been shown that epidermal growth factor receptor (EGFR) contributes to the pathogenesis of pain. We scanned genetic markers within genes coding for receptors of the EGFR family (EGFR, ERBB2, ERBB3, and ERBB4) and their ligands (AREG, BTC, EGF, EPGN, EREG, HBEGF, MUC4, NRG1, NRG2, NRG3, NRG4, and TGFA) for association with self-reported pain intensity in patients with chronic facial pain who participated in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) cohort. We found that only epiregulin (EREG) was associated with pain. The strongest effect was observed for a minor allele at rs6836436 in EREG, which was associated with lower chronic pain intensity. However, the same allele was associated with higher facial pain intensity among cases with recent onset of facial pain. Similar trends were observed in an independent cohort of UK Biobank (UKB) where the minor allele at rs6836436 was associated with a higher number of acute pain sites but a lower number of chronic pain sites. Expression quantitative trait loci analyses established rs6836436 as a loss-of-function variant of EREG. Finally, we investigated the functional role of EREG using mouse models of chronic and acute pain. Injecting mice with an EREG monoclonal antibody reversed established mechanosensitivity in the complete Freund's adjuvant and spared nerve injury models of chronic pain. However, the EREG monoclonal antibody prolonged allodynia when administered during the development of complete Freund's adjuvant-induced mechanosensitivity and enhanced pain behavior in the capsaicin model of acute pain.

A functional polymorphism in the ATP-Binding Cassette B1 transporter predicts pharmacologic response to combination of nortriptyline and morphine in neuropathic pain patients.

Many genetic markers have been associated with variations in treatment response to analgesics, but none have been assessed in the context of combination therapies. In this study, the treatment effects of nortriptyline and morphine were tested for an association with genetic markers relevant to pain pathways. Treatment effects were determined for single and combination therapies. A total of 24 functional single nucleotide polymorphisms were tested within the gene loci of mu-opioid receptor (OPRM1) gene locus, ATP-Binding Cassette B1 Transporter (ABCB1), Cytochrome P450 gene family (CYP2C19 and CYP2D6), catecholamine inactivator Catechol-O-Methyl Transferase (COMT), and serotonin receptor 2A (HTR2A). Genotyping was performed in a population of neuropathic pain patients who previously participated in a clinical trial. For monotherapy, neither nortriptyline nor morphine responses were associated with single nucleotide polymorphisms. However, for nortriptyline + morphine combination therapy, the single nucleotide polymorphism rs1045642 within the drug efflux pump ABCB1 transporter significantly predicted analgesic response. The presence of the C allele accounted for 51% of pain variance in this subgroup in response to combination treatment. The T-allele homozygotes demonstrated only 20% improvement in pain scores, whereas the C-allele homozygotes 88%. There was no significant contribution of rs1045642 to the medication side effects under all treatment conditions. The UK Biobank data set was then used to validate this genetic association. Here, patients receiving similar combination therapy (opioid + tricyclic antidepressant) carrying the C allele of rs1045642 displayed 33% fewer body pain sites than patients without that allele, suggesting better pain control. In all, our results show a robust effect of the rs1045642 polymorphism in response to chronic pain treatment with a nortriptyline + morphine combination.

Anatomical selectivity in overlap of chronic facial and bodily pain.

BACKGROUND: Chronic facial pain often overlaps with pain experienced elsewhere in the body, although previous studies have focused on a few, selected pain conditions when assessing the degree of overlap. AIM: To quantify the degree of overlap between facial pain and pain reported at multiple locations throughout the body. METHODS: Data were from a case-control study of US adults participating in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) project. They were interviewed to determine the presence of chronic facial pain (n = 424 cases) or its absence (n = 912 controls). A mailed questionnaire with a body drawing asked about pain at other locations. Odds ratios (ORs) and 95% confidence limits (95% CLs) quantified the degree of overlap between facial pain and pain at other locations. For replication, cross-sectional data were analyzed from the UK Biobank study (n = 459,604 participants) and the US National Health Interview Survey (n = 27,731 participants). RESULTS: In univariate analysis, facial pain had greatest overlap with headache (OR = 14.2, 95% CL = 9.7-20.8) followed by neck pain (OR = 8.5, 95% CL = 6.5-11.0), whereas overlap decreased substantially (ORs of 4.4 or less) for pain at successively remote locations below the neck. The same anatomically based ranking of ORs persisted in multivariable analysis that adjusted for demographics and risk factors for facial pain. Findings were replicated in the UK Biobank study and the US National Health Interview Survey. The observed anatomical selectivity in the degree of overlap could be a consequence of neurosensory and/or affective processes that differentially amplify pain according to its location.

The Effect of Intraoperative Dexmedetomidine Versus Morphine on Postoperative Morphine Requirements After Laparoscopic Bariatric Surgery.

BACKGROUND: Dexmedetomidine is an α2 receptor agonist with sedative and analgesic properties. During bariatric surgery, its use may reduce postoperative opioid requirements, reduce their side effects, and improve quality of recovery. The aim of this prospective randomized controlled trial was to compare the effect of dexmedetomidine bolus and infusion versus morphine bolus given prior to the end of laparoscopic bariatric surgery. METHODS: Sixty morbidly obese patients (BMI > 40 kg m-2) aged 18 to 60 years, undergoing laparoscopic sleeve gastrectomy, received morphine sulfate (bolus 0.08 mg kg-1 followed by a saline infusion) (group M, n = 30) or dexmedetomidine (loading dose of 1 µg kg-1 followed by 0.5 µg kg-1 h-1) (group D, n = 30) 30 min before the end of surgery. Data collected included morphine consumption in the post-anesthesia care unit (PACU) (primary outcome) and at 24 h, pain intensity, nausea, heart rate, blood pressure, vomiting, sedation, and quality of recovery. RESULTS: There was no significant difference in morphine consumption in the PACU (group D 12.2 ± 5.44 mg, group M 13.28 ± 6.64 mg, P = 0.54) or at 24 h (group D 40.67 ± 24.78 mg, group M 43.28 ± 27.79 mg, P = 0.75); when accounting for intraoperative morphine given group M had significantly higher morphine consumption when compared to group D (23.48 ± 6.22 mg vs. 12.22 ± 5.54 mg, respectively, P < 0.01). Group D patients had more cardiovascular stability. CONCLUSIONS: Dexmedetomidine given prior to end of laparoscopic sleeve gastrectomy provides the same level of postoperative analgesia as morphine with better hemodynamic profile.

A functional substitution in the L-aromatic amino acid decarboxylase enzyme worsens somatic symptoms via a serotonergic pathway.

OBJECTIVE: Heightened somatic symptoms are reported by a wide range of patients with chronic pain and have been associated with emotional distress and physical dysfunction. Despite their clinical significance, molecular mechanisms leading to their manifestation are not understood. METHODS: We used an association study design based on a curated list of 3,295 single nucleotide polymorphisms mapped to 358 genes to test somatic symptoms reporting using the Pennebaker Inventory of Limbic Languidness questionnaire from a case-control cohort of orofacial pain (n = 1,607). A replication meta-analysis of 3 independent cohorts (n = 3,189) was followed by functional validation, including in silico molecular dynamics, in vitro enzyme assays, and measures of serotonin (5-HT) plasma concentration. RESULTS: An association with the T allele of rs11575542 coding for an arginine to glutamine substitution in the L-aromatic amino acid decarboxylase (AADC) enzyme was replicated in a meta-analysis of 3 independent cohorts. In a combined meta-analysis of all cohorts, this association reached p = 6.43 × 10-8 . In silico studies demonstrated that this substitution dramatically reduces the conformational dynamics of AADC, potentially lowering its binding capacity to a cofactor. in vitro enzymatic assays showed that this substitution reduces the maximum kinetic velocity of AADC, hence lowering 5-HT levels. Finally, plasma samples from 90 subjects showed correlation between low 5-HT levels and heightened somatic symptoms. INTERPRETATION: Using functional genomics approaches, we identified a polymorphism in the AADC enzyme that contributes to somatic symptoms through reduced levels of 5-HT. Our findings suggest a molecular mechanism underlying the pathophysiology of somatic symptoms and opens up new treatment options targeting the serotonergic system. ANN NEUROL 2019;86:168-180.

Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males.

Painful temporomandibular disorders (TMDs) are the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. Although many environmental factors have been associated with higher risk of developing painful TMD, family and twin studies support a heritable genetic component as well. We performed a genome-wide association study assuming an additive genetic model of TMD in a discovery cohort of 999 cases and 2031 TMD-free controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Using logistic models adjusted for sex, age, enrollment site, and race, we identified 3 distinct loci that were significant in combined or sex-segregated analyses. A single-nucleotide polymorphism on chromosome 3 (rs13078961) was significantly associated with TMD in males only (odds ratio = 2.9, 95% confidence interval: 2.02-4.27, P = 2.2 × 10). This association was nominally replicated in a meta-analysis of 7 independent orofacial pain cohorts including 160,194 participants (odds ratio = 1.16, 95% confidence interval: 1.0-1.35, P = 2.3 × 10). Functional analysis in human dorsal root ganglia and blood indicated this variant is an expression quantitative trait locus, with the minor allele associated with decreased expression of the nearby muscle RAS oncogene homolog (MRAS) gene (beta = -0.51, P = 2.43 × 10). Male mice, but not female mice, with a null mutation of Mras displayed persistent mechanical allodynia in a model of inflammatory pain. Genetic and behavioral evidence support a novel mechanism by which genetically determined MRAS expression moderates the resiliency to chronic pain. This effect is male-specific and may contribute to the lower rates of painful TMD in men.

Human pain genetics database: a resource dedicated to human pain genetics research.

The Human Pain Genetics Database (HPGDB) is a comprehensive variant-focused inventory of genetic contributors to human pain. After curation, the HPGDB currently includes 294 studies reporting associations between 434 distinct genetic variants and various pain phenotypes. Variants were then submitted to a comprehensive analysis. First, they were validated in an independent high-powered replication cohort by testing the association of each variant with 10 different pain phenotypes (n = 1320-26,973). One hundred fifty-five variants replicated successfully (false discovery rate 20%) in at least one pain phenotype, and the association P values of the HPGDB variants were significantly lower compared with those of random controls. Among the 155 replicated variants, 21 had been included in the HPGDB because of their association with analgesia-related and 13 with nociception-related phenotypes, confirming analgesia and nociception as pathways of vulnerability for pain phenotypes. Furthermore, many genetic variants were associated with multiple pain phenotypes, and the strength of their association correlated between many pairs of phenotypes. These genetic variants explained a considerable amount of the variance between different pairs of pain phenotypes, indicating a shared genetic basis among pain phenotypes. In addition, we found that HPGDB variants show many pleiotropic associations, indicating that genetic pathophysiological mechanisms are also shared among painful and nonpainful conditions. Finally, we demonstrated that the HPGDB data set is significantly enriched for functional variants that modify gene expression, are deleterious, and colocalize with open chromatin regions. As such, the HPGDB provides a validated data set that represents a valuable resource for researchers in the human pain field.

Pain with traumatic brain injury and psychological disorders.

Traumatic brain injury (TBI) is the cause for long-term disability in more than 3 million patients in the US alone, with chronic pain being the most frequently reported complain. To date, predisposing mechanisms for chronic pain in TBI patients are largely unknown. Psychological disorders, including post-traumatic stress disorder, depression and anxiety following TBI are commonly reported comorbidities to post-traumatic pain. Long term consequences can be debilitating and affect quality of life even when the injury is mild. In this review, we present the most commonly reported chronic pain conditions across the spectrum of severity of TBI, mainly focusing on mild TBI. We discuss chronic post- traumatic headaches, widespread pain as well as post-traumatic central pain. We discuss pain in the context of injury severity and military versus civilian populations. We are only starting to understand the biological mechanisms behind post-traumatic pain and associated psychological distress following TBI, with genetic, biochemical and imaging studies pointing to the dopaminergic, neurotrophic factors and the role of Apolipoprotein. Physiological and neurological mechanisms are proposed to partially explain this interaction between post-traumatic pain and psychological distress. Nevertheless, the evidence for the role of structural brain damage remains incomplete and to a large extent debatable, as it is still difficult to establish clear causality between brain trauma and chronic pain. Finally, general aspects of management of chronic pain post-TBI are addressed.

Does Sleep Bruxism Contribute to Headache-Related Disability After Mild Traumatic Brain Injury? A Case-Control Study.

AIMS: To explore whether traumatic brain injury (TBI) patients have a higher prevalence of sleep bruxism (SB) and a higher level of orofacial muscle activity than healthy controls and whether orofacial muscle activity in the context of mild TBI (mTBI) increases the risk for headache disability. METHODS: Sleep laboratory recordings of 24 mTBI patients (15 males, 9 females; mean age ± standard deviation [SD]: 38 ± 11 years) and 20 healthy controls (8 males, 12 females; 31 ± 9 years) were analyzed. The primary variables included degree of headache disability, rhythmic masticatory muscle activity (RMMA) index (as a biomarker of SB), and masseter and mentalis muscle activity during quiet sleep periods. RESULTS: A significantly higher prevalence of moderate to severe headache disability was observed in mTBI patients than in controls (50% vs 5%; P = .001). Although 50% and 25% of mTBI patients had a respective RMMA index of ≥ 2 episodes/hour and ≥ 4 episodes/hour, they did not present more evidence of SB than controls. No between-group differences were found in the amplitude of RMMA or muscle tone. Logistic regression analyses suggested that while mTBI is a strong predictor of moderate to severe headache disability, RMMA frequency is a modest but significant mediator of moderate to severe headache disability in both groups (odds ratios = 21 and 2, respectively). CONCLUSION: Clinicians caring for mTBI patients with poorly controlled headaches should screen for SB, as it may contribute to their condition.