Neuropharmacology in Traumatic Brain Injury.

One of the primary goals in traumatic brain injury (TBI) treatment is to minimize secondary brain damage and promote neuroprotection. In TBI rehabilitation, we seek to facilitate neurologic recovery and restore what independence is possible given a patient's physical and cognitive impairments. These goals must be balanced with treatment of the various symptoms that may occur following TBI. This is challenging given the fact that many of the typical treatments for certain symptoms also come with side effects which could be problematic in the TBI population.

Comorbidity and polypharmacy impact neurobehavioral symptoms and symptom validity failure among post-9/11 veterans with mild traumatic brain injury.

Objective: The study aimed to examine the association between post-concussive comorbidity burdens [post-traumatic stress disorder (PTSD), depression, and/or headache] and central nervous system (CNS) polypharmacy (five or more concurrent medications) with reported neurobehavioral symptoms and symptom validity screening among post-9/11 veterans with a history of mild traumatic brain injury (mTBI). Setting: Administrative medical record data from the Department of Veterans Affairs (VA) were used in the study. Participants: Post-9/11 veterans with mTBI and at least 2 years of VA care between 2001 and 2019 who had completed the comprehensive traumatic brain injury evaluation (CTBIE) were included in the study. Design: Retrospective cross-sectional design was used in the study. Main measures: Neurobehavioral Symptom Inventory (NSI), International Classification of Diseases, Ninth Revision, and Clinical Modification diagnosis codes were included in the study. Results: Of the 92,495 veterans with a history of TBI, 90% had diagnoses of at least one identified comorbidity (PTSD, depression, and/or headache) and 28% had evidence of CNS polypharmacy. Neurobehavioral symptom reporting and symptom validity failure was associated with comorbidity burden and polypharmacy after adjusting for sociodemographic characteristics. Veterans with concurrent diagnoses of PTSD, depression, and headache were more than six times more likely [Adjusted odds ratio = 6.55 (99% CI: 5.41, 7.92)]. to fail the embedded symptom validity measure (Validity-10) in the NSI. Conclusion: TBI-related multimorbidity and CNS polypharmacy had the strongest association with neurobehavioral symptom distress, even after accounting for injury and sociodemographic characteristics. Given the regular use of the NSI in clinical and research settings, these findings emphasize the need for comprehensive neuropsychological evaluation for individuals who screen positively for potential symptom overreporting, the importance of multidisciplinary rehabilitation to restore functioning following mTBI, and the conscientious utilization of symptom validity measures in research efforts.

Mechanisms of change in posttraumatic headache-related disability: A mediation model.

OBJECTIVE: To explore whether the association between change in headache management self-efficacy and posttraumatic headache-related disability is partially mediated by a change in anxiety symptom severity. BACKGROUND: Many cognitive-behavioral therapy treatments for headache emphasize stress management, which includes anxiety management strategies; however, little is currently known about mechanisms of change in posttraumatic headache-related disability. Increasing our understanding of mechanisms could lead to improvements in treatments for these debilitating headaches. METHODS: This study is a secondary analysis of veterans (N = 193) recruited to participate in a randomized clinical trial of cognitive-behavioral therapy, cognitive processing therapy, or treatment as usual for persistent posttraumatic headache. The direct relationship between headache management self-efficacy and headache-related disability, along with partial mediation through change in anxiety symptoms was tested. RESULTS: The mediated latent change direct, mediated, and total pathways were statistically significant. The path analysis supported a significant direct pathway between headache management self-efficacy and headache-related disability (b = -0.45, p < 0.001; 95% confidence interval [CI: -0.58, -0.33]). The total effect of change of headache management self-efficacy scores on change in Headache Impact Test-6 scores was significant with a moderate-to-strong effect (b = -0.57, p = 0.001; 95% CI [-0.73, -0.41]). There was also an indirect effect through anxiety symptom severity change (b = -0.12, p = 0.003; 95% CI [-0.20, -0.04]). CONCLUSIONS: In this study, most of the improvements in headache-related disability were related to increased headache management self-efficacy with mediation occurring through change in anxiety. This indicates that headache management self-efficacy is a likely mechanism of change of posttraumatic headache-related disability with decreases in anxiety explaining part of the improvement in headache-related disability.

Comparison of veterans affairs and NIDILRR traumatic brain injury model systems participants with disorders of consciousness.

OBJECTIVE: To characterize demographic, pre-injury, and outcome data within the National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR) and Veterans Affairs (VA) Traumatic Brain Injury Model Systems (TBIMS) cohorts with severe traumatic brain injury (TBI) with no command-following ability at time of admission to acute rehabilitation. DESIGN: Retrospective cohort. SETTING: NIDILRR and VA TBI Model Systems (TBIMS) centers. PARTICIPANTS: 396 NIDILRR and 72 VA participants without command-following ability who experienced TBI with subsequent Disorder of Consciousness (DoC). MAIN OUTCOME MEASURE: Pre-injury and injury characteristics, rehabilitation outcomes, and 1-year self-reported outcomes. RESULTS: VA TBIMS cohort included individuals who were active duty or had military service before their injury. The VA cohort were more likely to be re-hospitalized at 1-year follow-up or residing in a long-term care or rehab setting. The NIDILRR TBIMS cohort had higher FIM and DRS scores at rehabilitation discharge, while the VA participants saw longer lengths of stay and higher numbers of "violent" injury types. CONCLUSIONS: This study allows for a better understanding of the comparability between VA and NIDILRR DoC cohorts providing guidance on how veteran and civilian samples might be merged in future TBIMS studies to explore predictors of recovery from a DoC.

Altered lateralization of the cingulum in deployment-related traumatic brain injury: An ENIGMA military-relevant brain injury study.

Traumatic brain injury (TBI) in military populations can cause disruptions in brain structure and function, along with cognitive and psychological dysfunction. Diffusion magnetic resonance imaging (dMRI) can detect alterations in white matter (WM) microstructure, but few studies have examined brain asymmetry. Examining asymmetry in large samples may increase sensitivity to detect heterogeneous areas of WM alteration in mild TBI. Through the Enhancing Neuroimaging Genetics Through Meta-Analysis Military-Relevant Brain Injury working group, we conducted a mega-analysis of neuroimaging and clinical data from 16 cohorts of Active Duty Service Members and Veterans (n = 2598). dMRI data were processed together along with harmonized demographic, injury, psychiatric, and cognitive measures. Fractional anisotropy in the cingulum showed greater asymmetry in individuals with deployment-related TBI, driven by greater left lateralization in TBI. Results remained significant after accounting for potentially confounding variables including posttraumatic stress disorder, depression, and handedness, and were driven primarily by individuals whose worst TBI occurred before age 40. Alterations in the cingulum were also associated with slower processing speed and poorer set shifting. The results indicate an enhancement of the natural left laterality of the cingulum, possibly due to vulnerability of the nondominant hemisphere or compensatory mechanisms in the dominant hemisphere. The cingulum is one of the last WM tracts to mature, reaching peak FA around 42 years old. This effect was primarily detected in individuals whose worst injury occurred before age 40, suggesting that the protracted development of the cingulum may lead to increased vulnerability to insults, such as TBI.

Mindfulness-Based Interdisciplinary Pain Management Program for Complex Polymorbid Pain in Veterans: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the effects of interdisciplinary pain management on pain-related disability and opioid reduction in polymorbid pain patients with 2 or more comorbid psychiatric conditions. DESIGN: Two-arm randomized controlled trial testing a 3-week intervention with assessments at pre-treatment, post-treatment, 6-month, and 12-month follow-up. SETTING: Department of Veterans Affairs medical facility. PARTICIPANTS: 103 military veterans (N=103) with moderate (or worse) levels of pain-related disability, depression, anxiety, and/or posttraumatic stress disorder randomly assigned to usual care (n=53) and interdisciplinary pain management (n=50). All participants reported recent persistent opioid use. Trial participants had high levels of comorbid medical and mental health conditions. INTERVENTIONS: Experimental arm-a 3-week, interdisciplinary pain management program guided by a structured manual; comparison arm-usual care in a large Department of Veterans Affairs medical facility. MAIN OUTCOME MEASURES: Oswestry Disability Index (pain disability); Timeline Followback Interview and Medication Event Monitoring System (opioid use). Analysis used generalized linear mixed model with all posttreatment observations (posttreatment, 6-month follow-up, 12-month follow-up) entered simultaneously to create a single posttreatment effect. RESULTS: Veterans with polymorbid pain randomized to the interdisciplinary pain program reported significantly greater decreases in pain-related disability compared to veterans randomized to treatment as usual (TAU) at posttreatment, 6-month, and 12-month follow-up. Aggregated mean pain disability scores (ie, a summary effect of all posttreatment observations) for the interdisciplinary pain program were -9.1 (95% CI: -14.4, -3.7, P=.001) points lower than TAU. There was no difference between groups in the proportion of participants who resumed opioid use during trial participation (32% in both arms). CONCLUSION: These findings offer the first evidence of short- and long-term interdisciplinary pain management efficacy in polymorbid pain patients, but more work is needed to examine how to effectively decrease opioid use in this population.

Research Letter: Long-Term Outcomes Following Cognitive Rehabilitation for Mild Traumatic Brain Injury: A 5-Year Follow-Up of a Cohort From the SCORE Randomized Clinical Trial.

OBJECTIVE: To examine the functioning of military service members 5 years after completing a randomized controlled trial (RCT) of cognitive rehabilitation for mild traumatic brain injury (mTBI). SETTING: Home-based telephonic interview and internet-based self-ratings. PARTICIPANTS: Sixty-nine of the 126 (55%) active-duty service members who were enrolled in a 4-arm RCT of cognitive rehabilitation 3 to 24 months after mTBI and were successfully contacted by phone 5 years later. Original and 5-year follow-up participants in each of 4 RCT treatment arms included: psychoeducation ( n = 32 original, n = 17 follow-up), computer ( n = 30 original, n = 11 follow-up), therapist-directed ( n = 30 original, n = 23 follow-up), integrated ( n = 34 original, n = 18 follow-up). DESIGN: Inception cohort evaluated 5 years after completion of an RCT of cognitive rehabilitation. MAIN MEASURES: Postconcussion symptoms (Neurobehavioral Symptom Inventory total score), psychological distress (Symptom Checklist-90-revised Global Severity Index score), and functional cognitive/behavioral symptoms (Key Behaviors Change Inventory total average score). RESULTS: Participants' postconcussive symptoms and psychological distress improved at the 5-year follow-up. Functional cognitive/behavioral symptoms were not significantly improved, but therapeutic gains were maintained across time, to 5 years after completing the RCT. CONCLUSION: In this sample of military personnel, postconcussive symptoms and psychological distress significantly improved from posttreatment to 5 years after cognitive rehabilitation, regardless of treatment arm. Functional cognitive/behavioral symptoms significantly improved with treatment while treatment gains were maintained at the 5-year follow-up. Replication of these results with a larger sample and interim data between 18 weeks and 5 years post-treatment is needed.

Cognitive Behavioral Therapy for Veterans With Comorbid Posttraumatic Headache and Posttraumatic Stress Disorder Symptoms: A Randomized Clinical Trial.

Importance: Posttraumatic headache is the most disabling complication of mild traumatic brain injury. Posttraumatic stress disorder (PTSD) symptoms are often comorbid with posttraumatic headache, and there are no established treatments for this comorbidity. Objective: To compare cognitive behavioral therapies (CBTs) for headache and PTSD with treatment per usual (TPU) for posttraumatic headache attributable to mild traumatic brain injury. Design, Setting, and Participants: This was a single-site, 3-parallel group, randomized clinical trial with outcomes at posttreatment, 3-month follow-up, and 6-month follow-up. Participants were enrolled from May 1, 2015, through May 30, 2019; data collection ended on October 10, 2019. Post-9/11 US combat veterans from multiple trauma centers were included in the study. Veterans had comorbid posttraumatic headache and PTSD symptoms. Data were analyzed from January 20, 2020, to February 2, 2022. Interventions: Patients were randomly assigned to 8 sessions of CBT for headache, 12 sessions of cognitive processing therapy for PTSD, or treatment per usual for headache. Main Outcomes and Measures: Co-primary outcomes were headache-related disability on the 6-Item Headache Impact Test (HIT-6) and PTSD symptom severity on the PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (PCL-5) assessed from treatment completion to 6 months posttreatment. Results: A total of 193 post-9/11 combat veterans (mean [SD] age, 39.7 [8.4] years; 167 male veterans [87%]) were included in the study and reported severe baseline headache-related disability (mean [SD] HIT-6 score, 65.8 [5.6] points) and severe PTSD symptoms (mean [SD] PCL-5 score, 48.4 [14.2] points). For the HIT-6, compared with usual care, patients receiving CBT for headache reported -3.4 (95% CI, -5.4 to -1.4; P < .01) points lower, and patients receiving cognitive processing therapy reported -1.4 (95% CI, -3.7 to 0.8; P = .21) points lower across aggregated posttreatment measurements. For the PCL-5, compared with usual care, patients receiving CBT for headache reported -6.5 (95% CI, -12.7 to -0.3; P = .04) points lower, and patients receiving cognitive processing therapy reported -8.9 (95% CI, -15.9 to -1.9; P = .01) points lower across aggregated posttreatment measurements. Adverse events were minimal and similar across treatment groups. Conclusions and Relevance: This randomized clinical trial demonstrated that CBT for headache was efficacious for disability associated with posttraumatic headache in veterans and provided clinically significant improvement in PTSD symptom severity. Cognitive processing therapy was efficacious for PTSD symptoms but not for headache disability. Trial Registration: ClinicalTrials.gov Identifier: NCT02419131.

Complex pain phenotypes: Suicidal ideation and attempt through latent multimorbidity.

BACKGROUND: Given the relatively high rates of suicidal ideation and attempt among people with chronic pain, there is a need to understand the underlying factors to target suicide prevention efforts. To date, no study has examined the association between pain phenotypes and suicide related behaviors among those with mild traumatic brain injuries. OBJECTIVE: To determine if pain phenotypes were independently associated with suicidal ideation / attempt or if comorbidities within the pain phenotypes account for the association between pain phenotypes and suicide related behaviors. METHODS: This is a longitudinal retrospective cohort study of suicide ideation/attempts among pain phenotypes previously derived using general mixture latent variable models of the joint distribution of repeated measures of pain scores and pain medications/treatment. We used national VA inpatient, outpatient, and pharmacy data files for Post-9/11 Veterans with mild traumatic injury who entered VA care between fiscal years (FY) 2007 and 2009. We considered a counterfactual causal modeling framework to assess the extent that the pain phenotypes during years 1-5 of VA care were predictive of suicide ideation/attempt during years 6-8 of VA care conditioned on covariates being balanced between pain phenotypes. RESULTS: Without adjustment, pain phenotypes were significant predictors of suicide related behaviors. When we used propensity scores to balance the comorbidities present in the pain phenotypes, the pain phenotypes were no longer significantly associated with suicide related behaviors. CONCLUSION: These findings suggest that suicide ideation/attempt is associated with pain trajectories primarily through latent multimorbidity. Therefore, it is critical to identify and manage comorbidities (e.g., depression, post-traumatic stress disorder) to prevent tragic outcomes associated with suicide related behaviors throughout the course of chronic pain and mild traumatic brain injury management.

PTSD symptoms and tinnitus severity: An analysis of veterans with posttraumatic headaches.

OBJECTIVE: Tinnitus and posttraumatic stress disorder (PTSD) are among the top service-connected disabilities within the Veterans Health Administration. Extant research shows that there is considerable overlap between tinnitus-related distress and PTSD, including sleep difficulty, irritability, hyperarousal, and concentration problems. However, no studies have prospectively examined the relationship between the two disorders. The purpose of this study was to examine that relationship. METHOD: Participants (N = 112) with posttraumatic headache completed measures of tinnitus and PTSD. Correlational analyses and analyses of variance were conducted to examine the associations with PTSD symptom clusters and factors of tinnitus-related distress. RESULTS: Approximately, half of participants with tinnitus demonstrated severe impairment. Correlational analyses indicated that reexperiencing, avoidance, negative emotions and cognitions, and hyperarousal PTSD symptoms were significantly related to many factors of tinnitus-related distress, including intrusiveness of tinnitus, perceived loudness, awareness, and annoyance. Participants with severe tinnitus demonstrated significantly greater reexperiencing, negative mood/cognitions, hyperarousal, and PTSD total severity compared to those with mild or moderate tinnitus. CONCLUSIONS: Trauma therapists should assess for the presence of tinnitus in order to more fully conceptualize key health problems of help-seeking patients. Heightened psychological symptoms seemingly related to PTSD may be a function of tinnitus-related distress. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The management and rehabilitation of post-acute mild traumatic brain injury.

DESCRIPTION: In June 2021, the U.S. Department of Veterans Affairs (VA) and U.S. Department of Defense (DoD) approved a joint clinical practice guideline for the management and rehabilitation care for those who have symptoms in the post-acute period following mild traumatic brain injury (mTBI). This synopsis describes some of the clinically important recommendations. METHODS: In January 2020, VA and DoD leaders assembled a joint VA/DoD guideline development team of multidisciplinary clinical stakeholders that developed key questions, systematically searched and evaluated the literature, created two 1-page algorithms, and refined 19 recommendations using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. The process closely conformed to the National Academy of Medicine's tenets for trustworthy clinical practice guidelines. RECOMMENDATIONS: This synopsis describes clinically important recommendations for the management and rehabilitation of mTBI. Outpatient primary care providers are the target audience for this synopsis and guideline. The current recommendations are an update from the 2016 VA/DoD Clinical Practice Guidelines for the Management of Concussion-Mild Traumatic Brain Injury.

Health Conditions Among Special Operations Forces Versus Conventional Military Service Members: A VA TBI Model Systems Study.

OBJECTIVE: To examine traumatic brain injury (TBI) characteristics and comorbid medical profiles of Special Operations Forces (SOF) Active Duty Service Member/Veterans (ADSM/Vs) and contrast them with conventional military personnel. SETTING: The 5 Veterans Affairs (VA) Polytrauma Rehabilitation Centers. PARTICIPANTS: A subset of participants in the VA TBI Model Systems multicenter longitudinal study with known SOF status. These included 157 participants who identified as SOF personnel (average age = 41.8 years; 96% male, 81% active duty), and 365 who identified as Conventional Forces personnel (average age = 37.4 years; 92% male, 30% active duty). DESIGN: Retrospective analysis of prospective cohort, cross-sectional. MAIN MEASURES: The Health Comorbidities Interview. RESULTS: SOF personnel were more likely to have deployed to a combat zone, had more years of active duty service, and were more likely active duty at time of TBI. SOF personnel were more likely to have had mild TBI (vs moderate/severe) and their TBI caused by violent mechanism. SOF personnel had a higher number of comorbidities, with more diagnoses of chronic pain, osteoarthritis, hyperlipidemia, hip fractures, and obstructive sleep apnea. CONCLUSION: SOF personnel are at a higher risk for multimorbidity after TBI. Current rehabilitation practices should incorporate early screening and treatment of common conditions in this population, while future practices may benefit from a focus on prevention.

Models of Care for Postacute COVID-19 Clinics: Experiences and a Practical Framework for Outpatient Physiatry Settings.

ABSTRACT: After surviving infection with the SARS-CoV-2 virus, individuals may have persistent symptoms and prolonged impairments that may last for weeks to months. The frequency and heterogeneity of persistent post-COVID conditions have created challenges in care. Specialty clinics are being established in response to an increasing need to care for patients with postacute sequelae of SARS-CoV-2 or long COVID syndrome. Although many post-COVID conditions can be bettered through a comprehensive rehabilitation plan, various clinical settings may benefit from differing models of coordinated care. We present five models of care in varying degrees of development and compare processes and adaptations to address the unique needs of each center and their unique patient populations. Forging a path to recovery will necessitate a multidisciplinary team with physiatry involvement to meet the distinctive needs of patients with postacute sequelae of SARS-CoV-2. Furthermore, it is imperative that there be equitable access to this care and commitment from healthcare institutions to provide resources for these programs.

Persistent posttraumatic headaches and functioning in veterans: Injury type can matter.

OBJECTIVE: To characterize the relationship between head trauma types (blast injury, blunt injury, combined blast+blunt injury) with subsequent headache presentations and functioning. BACKGROUND: Posttraumatic headaches (PTHs), the most common sequelae of traumatic brain injury (TBI), are painful and disabling. More than 400,000 veterans report having experienced a TBI, and understanding the predictors of PTHs may guide treatment developments. METHODS: This study used a nested-cohort design analyzing baseline data from a randomized clinical trial of cognitive behavioral therapy for PTH (N = 190). Participants had PTH (from blast and/or blunt head trauma) and symptoms of posttraumatic stress disorder (PTSD). The Structured Diagnostic Interview for Headache-Revised and Ohio State University Traumatic Brain Injury Identification Method were used to phenotype headaches and head injury histories, respectively. RESULTS: Individuals with persistent PTHs after a combined blast and blunt head trauma were more likely (OR =3.45; 95% CI [1.41, 8.4]) to experience chronic (vs. episodic) PTHs compared with the blunt trauma only group (23/33, 70% vs. 26/65, 40%, respectively); and they were more likely (OR =2.51; 95% CI [1.07, 5.9]) to experience chronic PTH compared with the blast trauma only group (44/92, 48%). There were no differences between head injury type on headache-related disability, depression symptoms, or severity of PTSD symptoms. CONCLUSION: The combination of blast and blunt injuries was associated with headache chronicity, but not headache disability. Considering the refractory nature of chronic headaches, the potential added and synergistic effects of distinct head injuries warrant further study.

The Military Injuries: Understanding Post-Traumatic Epilepsy Study: Understanding Relationships among Lifetime Traumatic Brain Injury History, Epilepsy, and Quality of Life.

Understanding risk for epilepsy among persons who sustain a mild (mTBI) traumatic brain injury (TBI) is crucial for effective intervention and prevention. However, mTBI is frequently undocumented or poorly documented in health records. Further, health records are non-continuous, such as when persons move through health systems (e.g., from Department of Defense to Veterans Affairs [VA] or between jobs in the civilian sector), making population-based assessments of this relationship challenging. Here, we introduce the MINUTE (Military INjuries-Understanding post-Traumatic Epilepsy) study, which integrates data from the Veterans Health Administration with self-report survey data for post-9/11 veterans (n = 2603) with histories of TBI, epilepsy and controls without a history of TBI or epilepsy. This article describes the MINUTE study design, implementation, hypotheses, and initial results across four groups of interest for neurotrauma: 1) control; 2) epilepsy; 3) TBI; and 4) post-traumatic epilepsy (PTE). Using combined survey and health record data, we test hypotheses examining lifetime history of TBI and the differential impacts of TBI, epilepsy, and PTE on quality of life. The MINUTE study revealed high rates of undocumented lifetime TBIs among veterans with epilepsy who had no evidence of TBI in VA medical records. Further, worse physical functioning and health-related quality of life were found for persons with epilepsy + TBI compared to those with either epilepsy or TBI alone. This effect was not fully explained by TBI severity. These insights provide valuable opportunities to optimize the resilience, delivery of health services, and community reintegration of veterans with TBI and complex comorbidity.