Treatment of chronic symptoms following mild traumatic brain injury with transcranial LED: a sham run-in pilot study of photobiomodulation therapy.

PRIMARY OBJECTIVE: We evaluated whether photobiomodulation with red/near infrared light applied transcranially via light emitting diodes (LED) was associated with reduced symptoms and improved cognitive functioning in patients with chronic symptoms following mild traumatic brain injury. RESEARCH DESIGN: Participants (3 men, 6 women; 22-61 years-old) underwent a 6-week intervention involving 18 40-minute transcranial LED treatment sessions. METHODS AND PROCEDURES: Reliable change indices were calculated for 10 neuropsychological test scores and 3 self-report questionnaires of subjective cognition, post-concussion symptoms, and depression at baseline and following treatment. Questionnaires were also administered after 2-week sham and at 1-month and 2-month follow-ups. MAIN OUTCOME AND RESULTS: Only 2 participants improved on neuropsychological testing. On questionnaires, 4 reported improved cognition, 5 reported improved post-concussion symptoms, and 3 reported improved depression. Significant improvement in 2 or more domains was reported by 4 participants and mostly maintained at both follow-ups. CONCLUSIONS: Most participants did not improve on neuropsychological testing. A minority self-reported improvement in symptoms, potentially explained by the intervention, psychiatric medication changes, placebo effects, or other factors. Selecting participants with different clinical characteristics, and dosing and delivery system changes, may produce different results. A study design accounting for placebo effects appears warranted in future trials.

Randomized, controlled clinical trial of acoustic stimulation to reduce postconcussive symptoms.

OBJECTIVE: Effective interventions are needed to address postconcussive symptoms. We report the results of randomized, sham-controlled trial of Cereset Research™ Standard Operating Procedures (CR-SOP), a noninvasive, closed-loop, allostatic, acoustic stimulation neurotechnology previously shown to improve insomnia. METHODS: Military service members, veterans, or their spouses with persistent symptoms (Neurobehavioral Symptom Inventory [NSI] Score ≥23) after mTBI 3 months to 10 years ago, were randomized to receive 10 sessions of engineered tones linked to brainwaves (LB, intervention), or random engineered tones not linked to brainwaves (NL, sham control). The primary outcome was change in NSI, with secondary outcomes of heart rate variability and self-report measures of sleep, mood, and anxiety. RESULTS: Participants (n = 106, 22% female, mean age 37.1, 2.8 deployments, 3.8 TBIs) were randomized 1:1 to LB or NL, with no significant differences between groups at baseline. Among all study participants, the NSI declined from baseline 41.0 to 27.2 after (P < 0.0001), with gains largely sustained at 3 months (31.2) and 6 months (28.4). However, there were no significant differences between the LB (NSI declined from 39.9 at baseline to 28.2 post-intervention, 31.5 at 3 months, and 29.4 at 6 months) and NL (NSI declined from 41.5 at baseline to 26.2, 29.9, and 27.3, respectively. Similar patterns were observed for the PCL5 and PHQ-9 and there was no difference in HRV between groups. INTERPRETATION: Ten hours of acoustic stimulation while resting in a zero-gravity chair improves postconcussive symptoms. However, linking tones to brain electrical activity did not reduce symptoms more than random tones. REGISTRATION: ClinicalTrials.gov - NCT03649958.

A Randomized, Double-Blind, Placebo-Controlled Clinical Trial Evaluating Transcranial Photobiomodulation as Treatment for Concussion.

INTRODUCTION: Literature indicating that transcranial photobiomodulation (tPBM) may enable the brain to recover normal function after concussion, resulting in symptoms reduction, and improved cognitive function after concussion is limited by small sample sizes and lack of controls. METHODS: We conducted a randomized, double-blind, placebo-controlled trial examining the effect of 6 wk of tPBM in patients 11 yr or older who received care for persistent postconcussion symptoms between September 2012 and December 2015. Our primary outcome measure was the mean difference in Postconcussion Symptom Scale total score and the raw Immediate Postconcussion Assessment and Cognitive Testing composite scores between study entry and treatment completion. Participants received two, 10-min sessions either with tPBM units or via two placebo units, three times per week. We screened for potential confounding variables using univariable analyses. We entered covariables that differed between the two groups on univariable screening into a regression analysis. We considered adjusted odds ratio that did not cross one statistically significant. RESULTS: Forty-eight participants completed the study. Most were female (63%), and a majority sustained their injury during sports or exercise (71%). Despite randomization, those that received tPBM therapy reported a greater number of previous concussions. After adjusting for the effect of previous concussions and multiple comparisons, there were no significant differences between tPBM and placebo groups at 3 or 6 wk of treatment. CONCLUSIONS: Despite showing promise in previous investigations, our study did not show benefit to tPBM over placebo therapy in patients experiencing persistent postconcussion symptoms. Further investigation is needed to determine if varying the dose or timing alters the efficacy of tPBM after concussion.

Thalamocortical coherence predicts persistent postconcussive symptoms.

The pathogenetic mechanism of persistent post-concussive symptoms (PCS) following concussion remains unclear. Thalamic damage is known to play a role in PCS prolongation while the evidence and biomarkers that trigger persistent PCS have never been elucidated. We collected longitudinal neuroimaging and behavior data from patients and rodents after concussion, complemented with rodents' histological staining data, to unravel the early biomarkers of persistent PCS. Diffusion tensor imaging (DTI) were acquired to investigated the thalamic damage, while quantitative thalamocortical coherence was derived through resting-state functional MRI for evaluating thalamocortical functioning and predicting long-term behavioral outcome. Patients with prolonged symptoms showed abnormal DTI-derived indices at the boundaries of bilateral thalami (peri-thalamic regions). Both patients and rats with persistent symptoms demonstrated enhanced thalamocortical coherence between different thalamocortical circuits, which disrupted thalamocortical multifunctionality. In rodents, the persistent DTI abnormalities were validated in thalamic reticular nucleus (TRN) through immunohistochemistry, and correlated with enhanced thalamocortical coherence. Strong predictive power of these coherence biomarkers for long-term PCS was also validated using another patient cohort. Postconcussive events may begin with persistent TRN injury, followed by disrupted thalamocortical coherence and prolonged PCS. Functional MRI-based coherence measures can be surrogate biomarkers for early prediction of long-term PCS.

A Framework for Understanding the Contribution of Psychosocial Factors in Biopsychosocial Explanatory Models of Persistent Postconcussion Symptoms.

Biopsychosocial models are currently used to explain the development of persistent postconcussion symptoms (PPCS) following concussion. These models support a holistic multidisciplinary management of postconcussion symptoms. One catalyst for the development of these models is the consistently strong evidence pertaining to the role of psychological factors in the development of PPCS. However, when applying biopsychosocial models in clinical practice, understanding and addressing the influence of psychological factors in PPCS can be challenging for clinicians. Accordingly, the objective of this article is to support clinicians in this process. In this Perspective article, we discuss current understandings of the main psychological factors involved in PPCS in adults and summarize these into 5 interrelated tenets: preinjury psychosocial vulnerabilities, psychological distress following concussion, environment and contextual factors, transdiagnostic processes, and the role of learning principles. With these tenets in mind, an explanation of how PPCS develop in one person but not in another is proposed. The application of these tenets in clinical practice is then outlined. Guidance is provided on how these tenets can be used to identify psychosocial risk factors, derive predictions, and mitigate the development of PPCS after concussion from a psychological perspective within biopsychosocial conceptualizations. IMPACT: This Perspective helps clinicians apply biopsychosocial explanatory models to the clinical management of concussion, providing summary tenets that can guide hypothesis testing, assessment, and treatment.

Acute thalamic connectivity precedes chronic post-concussive symptoms in mild traumatic brain injury.

Chronic post-concussive symptoms are common after mild traumatic brain injury (mTBI) and are difficult to predict or treat. Thalamic functional integrity is particularly vulnerable in mTBI and may be related to long-term outcomes but requires further investigation. We compared structural MRI and resting state functional MRI in 108 patients with a Glasgow Coma Scale (GCS) of 13-15 and normal CT, and 76 controls. We examined whether acute changes in thalamic functional connectivity were early markers for persistent symptoms and explored neurochemical associations of our findings using PET data. Of the mTBI cohort, 47% showed incomplete recovery 6 months post-injury. Despite the absence of structural changes, we found acute thalamic hyperconnectivity in mTBI, with specific vulnerabilities of individual thalamic nuclei. Acute fMRI markers differentiated those with chronic post-concussive symptoms, with time- and outcome-dependent relationships in a sub-cohort followed longitudinally. Moreover, emotional and cognitive symptoms were associated with changes in thalamic functional connectivity to known serotonergic and noradrenergic targets, respectively. Our findings suggest that chronic symptoms can have a basis in early thalamic pathophysiology. This may aid identification of patients at risk of chronic post-concussive symptoms following mTBI, provide a basis for development of new therapies and facilitate precision medicine application of these therapies.

Neck Symptoms and Associated Clinical Outcomes in Patients Following Concussion.

OBJECTIVE: To examine the frequency and association of neck pain symptoms in patients with a concussion. STUDY SETTING AND PARTICIPANTS: Three-hundred and thirty-one consecutively enrolled patients aged 9 to 68 years with a diagnosed concussion 1 to 384 days post-injury were enrolled at a concussion clinic from a single integrated healthcare system in Western Pennsylvania between 2019 and 2021. DESIGN: Retrospective cohort analysis of prospectively collected concussion screening tool intake survey responses and clinical outcomes data. The primary outcome was self-reported neck pain or difficulty with neck movement on the Concussion Clinical Profiles Screening (CP Screen) tool, recovery time, and incidence of treatment referral. Immediate Post-concussion Assessment and Cognitive Testing (ImPACT) composite scores, Vestibular/Ocular Motor Screening (VOMS) item scores, type and severity of neck symptoms, mechanism of injury, time from injury to clinic presentation, medical history, and concussion symptom profile were secondary outcomes. RESULTS: Of the 306 consecutively enrolled eligible patients in the registry, 145 (47%) reported neck pain, 68 (22.2%) reported difficulty moving their neck, and 146 (47.7%) reported either symptom. A total of 47 (15.4%) participants reported more severe neck symptoms, and this group took longer to recover (40 ± 27 days) than those not reporting neck symptoms (30 ± 28 days; U = 8316, P < .001). Stepwise logistic regression predicting more severe neck symptoms was significant (Nagelkerke R2 = 0.174, χ 2 = 9.315, P = .316) with older age ( P = .019) and mechanism of injury including motor vehicle collisions (MVCs) ( P = .047) and falls ( P = .044) as risk factors. MVCs and falls were associated with over 4 times and 2 times greater risk, respectively, for reporting more severe neck symptoms. CONCLUSION: Neck pain and stiffness symptoms are common in patients with a concussion following high-energy mechanisms of injury including MVCs or falls from height. These symptoms are associated with prolonged recovery. Providers should evaluate neck symptoms and consider targeted treatment strategies to limit their effects in patients with a concussion.

Nutritional Supplement and Dietary Interventions as a Prophylaxis or Treatment of Sub-Concussive Repetitive Head Impact and Mild Traumatic Brain Injury: A Systematic Review.

Mild traumatic brain injury (mTBI) affects 42 to 56 million individuals worldwide annually. Even more individuals are affected by sub-concussive repetitive head impacts (SRHIs). Such injuries may result in significant acute and chronic symptoms. A study of how individuals may adjust or augment their nutritional and dietary habits to prevent cumulative neurotrauma and promote post-injury recovery is necessary. The objective of the current study is to systematically review nutritional and dietary interventions for neurotrauma prevention and mTBI recovery to direct clinical decision-making and identify future areas of research. This systematic review, without a specified time-period, was performed in PubMed, Scopus, Cochrane, CINAHL, and Web of Science followed by a manual search of references. Search strings were generated by a research librarian. Studies were included if they: 1) investigate human subjects with mTBI or SRHI; 2) investigate a supplement/ingredient of dietary supplement sold in the U.S. or dietary intervention without classification as a drug or prohibitive statement against use by the U.S. Food and Drug Administration (FDA); 3) assess a quantifiable outcome; and 4) are published in English in a peer-reviewed journal with an accessible full-length article. Studies were excluded if: 1) the study included non-mTBI or SRHI subjects (e.g., moderate/severe TBI, stroke); 2) mTBI is not assessed separately from moderate/severe mTBI; or 3) the studies that required intracranial hemorrhage. Fifteen studies from 12 unique subject populations met inclusion and exclusion criteria. A total of 1139 mTBI or SRHI subjects were enrolled across intervention arms in the study populations. A total of eight intervention were studied. Omega-3 fatty acid (n-3FA), melatonin, and Pinus radiata were the only interventions examined in multiple studies. Studies included 10 randomized-control trials, three prospective observational studies, and two retrospective observational studies. Seven of the 15 studies had a low risk of bias. Eleven studies reported benefit of the intervention. Strongest evidence supports n-3FA utility for neurotrauma prevention in athletes exposed to SRHI. Both Pinus radiata and melatonin may have benefit for persistent post-concussion symptoms; however, additional multi-center studies are necessary prior to making a definitive conclusion on these supplements' efficacy. Future studies should continue to assess both novel interventions and additional interventions examined in this review to bring additional evidence to the burgeoning field of nutritional and dietary interventions for SRHI and mTBI.

Hyperbaric oxygen therapy in children with post-concussion syndrome improves cognitive and behavioral function: a randomized controlled trial.

Persistent post-concussion syndrome (PPCS) is a common and significant morbidity among children following traumatic brain injury (TBI) and the evidence for effective PPCS treatments remains limited. Recent studies have shown the beneficial effects of hyperbaric oxygen therapy (HBOT) in PPCS adult patients. This randomized, sham-control, double blind trial evaluated the effect of hyperbaric oxygen therapy (HBOT) on children (age 8-15) suffering from PPCS from mild-moderate TBI events six months to 10 years prior. Twenty-five children were randomized to receive 60 daily sessions of HBOT (n = 15) or sham (n = 10) treatments. Following HBOT, there was a significant increase in cognitive function including the general cognitive score (d = 0.598, p = 0.01), memory (d = 0.480, p = 0.02), executive function (d = 0.739, p = 0.003), PPCS symptoms including emotional score (p = 0.04, d = - 0.676), behavioral symptoms including hyperactivity (d = 0.244, p = 0.03), global executive composite score (d = 0.528, p = 0.001), planning/organizing score (d = 1.09, p = 0.007). Clinical outcomes correlated with significant improvements in brain MRI microstructural changes in the insula, supramarginal, lingual, inferior frontal and fusiform gyri. The study suggests that HBOT improves both cognitive and behavioral function, PPCS symptoms, and quality of life in pediatric PPCS patients at the chronic stage, even years after injury. Additional data is needed to optimize the protocol and to characterize the children who can benefit the most.

Effects of phytocannabinoids on heart rate variability and blood pressure variability in female post-concussion syndrome patients: case series.

Cannabidiol (CBD) can exert neuroprotective effects without being intoxicating, and in combination with Δ9-tetrahydrocannabinol (THC) CBD has shown to protect against THC psychosis. Acute concussion and post-concussion syndrome (PCS) can result in autonomic dysfunction in heart rate variability (HRV), but less information is available on blood pressure variability (BPV). Furthermore, the effects of phytocannabinoids on HRV and BPV in PCS are unknown. The purpose of this study was to observe the influence of daily administration of CBD or a combination of CBD and THC on HRV and BPV parameters in four female PCS participants. Participants completed a seated 5-min rest followed by six breaths-per-minute paced breathing protocol. Data was collected prior to phytocannabinoid intake and continued over 54 to 70 days. High frequency systolic BPV parameter increased every assessment period, unless altered due to external circumstances and symptoms. HRV parameters showed less consistent and varying responses. These results suggest that CBD can help to improve the altered autonomic dysfunction in those with PCS, and that responses to the drug administration was individualized. Double blinded, randomized controlled trials with greater sample sizes are required to better understand the influences of the varying dosages on human physiology and in PCS.

Effects of CranioSacral therapy upon symptoms of post-acute concussion and Post-Concussion Syndrome: A pilot study.

OBJECTIVE: The purpose of this study was to investigate the utilization of CranioSacral Therapy (CST) in patients with Post-Concussion Syndrome (PCS) and capture patient-reported perceptions of clinical outcomes of lived treatment experiences. DESIGN: Two-part, longitudinal study conducted through a chart review of target group, followed by a Patient-reported Treatment Outcome Survey (PTOS). PARTICIPANTS: A convenience sample of 212 patients with a historical incidence of head trauma not requiring hospitalization was obtained through medical records department dating back ten years. Inclusion criteria for further chart review (n = 67) was determined by identifying patients with a confirmed concussion directly correlated with presenting symptoms and for which CST was specifically sought as a treatment option. Demographics and patient-determined treatment duration data were analyzed by comparison groups extensively suggested in existing literature: Recovery time since injury as either Post-acute concussion (<6 months) or Post-Concussion Syndrome (PCS) (≥6 months); Athletes (A) or Non-athletes (NA); and traditional gender. Final PTOS group criteria was determined by eliminating confounding issues reporting (n = 47): (A, n = 24 and NA, n = 23). RESULTS: Quantitative data was analyzed via Numerical Analysis, and qualitative data was analyzed via Inductive Content Analysis. Symptoms reported in all charts as well as in the PTOS were consistent with identified PCS subtypes. Utilization of CST revealed that most patients determined the treatment effect upon concussion symptoms within 1-3 sessions. Nearly twice as many sessions were attended in the PCS than post-acute groups. Referral sources, studied for a perspective on local concussion after-care discharge planning, ranged from professional to personal recommendation or self-discovery. A majority of patients met goals of reducing post-acute or PCS as reasons cited by self-determined change-in-status or discharge from service. Patients were asked to indicate on the PTOS which pre- and post-treatment symptoms were helped or not helped by this particular intervention. CONCLUSIONS: Patient-reported changes of PCS symptoms is critical when evaluating treatment options. CST is an experiential treatment that addresses subjective levels of dysfunction, thus it is the patient deciding the value of an intervention. A sizable portion of patients in all groups reported a positive effect upon their symptoms by CST. Patients indicated personal meaning to CST through their utilization of multiple sessions. A high percentage indicated the likelihood of referring others with PCS for CST. Of the 212 patient charts first studied, the 145 not meeting inclusion criteria suggest some chronic conditions may present as long-term effects of older head injuries. CST is a low-risk, conservative treatment option for PCS sub-types worthy of further clinical study.

Osteopathic manipulative medicine in the management of headaches associated with postconcussion syndrome.

CONTEXT: Previous studies have demonstrated the effectiveness of osteopathic manipulative treatment (OMT) for various headache types, with limited evidence of its use for headaches related to mild traumatic brain injury (MTBI). No studies prior studies were found regarding OMT for headaches in patients with postconcussion syndrome (PCS), defined as symptom persistence for longer than 3 months after MTBI. OBJECTIVES: To evaluate OMT for headaches in patients with PCS. METHODS: A controlled pilot study was conducted of patients with PCS who presented to an outpatient interdisciplinary rehabilitation clinic; patients with symptoms lasting longer than 3 months were enrolled and randomly assigned to an OMT treatment group or a control group. Primary outcome measures were immediate change in headache scores according to a Visual Analog Scale (VAS) and change in the six item Headache Impact Test (HIT-6) between baseline and follow up visits. The participants in the control group completed the HIT-6 between baseline and follow up visits but did not receive OMT and did not complete the VAS. Mean immediate VAS score change for the treatment group and mean improvement in HIT-6 scores for both groups between baseline and follow up were analyzed for statistical significance. RESULTS: A total of 26 patients were included in this study: 13 (50%) in the treatment group and 13 (50%) in the control group. Six patients (23.1%), three from each group, did not complete the study, so 10 subjects in each group were included in the final analysis. Statistically significant improvement in VAS scores was seen immediately after OMT in the treatment group (mean change, 2.1;p=0.002). Mean HIT-6 scores showed improvement in the treatment group compared with the control group, although the change was not statistically significant (p=0.15) from baseline to follow up visit. No adverse effects from treatments were noted. CONCLUSIONS: Patients with headaches secondary to PCS showed immediate benefit in headache pain intensity after OMT. However, no sustained benefit was found on the follow up visit compared with the control group.

Early Stage Longitudinal Subcortical Volumetric Changes following Mild Traumatic Brain Injury.

Objective: To investigate early brain volumetric changes from acute to 6 months following mild traumatic brain injury (mTBI) in deep gray matter regions and their association with patient 6-month outcome.Methods: Fifty-six patients with mTBI underwent MRI and behavioral evaluation at acute (<10 days) and approximately 1 and 6 months post injury. Regional volume changes were investigated in key gray matter regions: thalamus, hippocampus, putamen, caudate, pallidum, and amygdala, and compared with volumes from 34 healthy control subjects. In patients with mTBI, we further assessed associations between longitudinal regional volume changes with patient outcome measures at 6 months including post-concussive symptoms, cognitive performance, and overall satisfaction with life.Results: Reduction in thalamic and hippocampal volumes was observed at 1 month among patients with mTBI. Such volume reduction persisted in the thalamus until 6 months. Changes in thalamic volumes also correlated with multiple symptom and functional outcome measures in patients at 6 months.Conclusion: Our results indicate that the thalamus may be differentially affected among patients with mTBI, resulting in both structural and functional deficits with subsequent post-concussive sequelae and may serve as a biomarker for the assessment of efficacy of novel therapeutic interventions.

A randomized cohort study of the efficacy of PO magnesium in the treatment of acute concussions in adolescents.

INTRODUCTION/STUDY OBJECTIVE: Concussions are becoming a growing concern in society today with one out of every five adolescents being affected. This accounts for 1.6 to 3.8 million emergency department visits annually. The current standard of care involves an initial period of mental rest with symptomatic care and symptom-based return to daily activities/sports. High dose IV magnesium has been proven to be neuroprotective in severe TBI. We hypothesized that oral magnesium replacement following a concussion will decrease the overall symptomatic period allowing a quicker return to functional baseline. METHODS: We used a randomized cohort study involving patients aged 12-18 who presented within 48 h after a concussion. Our study design had a treatment arm including acetaminophen, ondansetron, and magnesium PO and a placebo arm of acetaminophen and ondansetron. We then utilized the Post- Concussion Severity Score (PCSS) to evaluate the extent of the patient's symptoms. This score was collected immediately prior to obtaining medications, 1 h, 48 h, and 120 h after starting the study. The study relied on outpatient follow up through phone conversations, and a Sports Medicine clinic locally. RESULTS: Our data shows that there was a statistically significant decrease in the PCSS at 48 h (p = 0.016) in the magnesium group relative to the placebo treatment arm. This study does imply that magnesium supplementation has potential benefit in treatment of concussions acutely. CONCLUSION: Oral magnesium replacement decreases symptoms acutely following a concussion and should be provided with symptomatic management following a concussion in the emergency setting.

Perceived Recovery and Self-Reported Functioning in Adolescents with Mild Traumatic Brain Injury: The Role of Sleep, Mood, and Physical Symptoms.

Purpose: To determine the contributions of anxiety, depressive, and concussion symptoms and sleep quality to self-perceived recovery in adolescents with concussion.Method: Adolescents aged 12-20 (n = 298) completed anxiety, depression, concussion symptoms, and sleep measures at an initial concussion clinic visit and three-month follow-up. At follow-up, they reported self-perceived recovery as percent back to normal.Results: Injury-related factors alone did not predict self-perceived recovery (R2Adj =.017, p =.074). More concurrent physical, mental health, and sleep symptoms explained 18.8% additional variance in poorer self-perceived recovery (R2Adj Change =.188, p <.05). Physical symptoms (Bstand = -.292) and anxiety (Bstand = -.260) accounted for the most variance in self-perceived recovery.Conclusion: Post-concussive symptoms, in particular anxiety and self-reported physical symptoms, seem to characterize protracted recovery. Self-perceived recovery as an outcome measure may provide a more holistic understanding of adolescents' experiences after concussion.

Medical Therapies for Concussion.

The medications used in postconcussion syndrome are typically used to help manage or minimize disruptive symptoms while recovery proceeds. These medications are not routinely used in most concussions that recover within days to weeks. However, it is beneficial to be aware of medication options that may be used in athletes with prolonged concussion symptoms or for those that have symptom burdens that preclude entry into basic concussion protocols. Medications and supplements remain a small part of the concussion treatment plan, which may include temporary academic adjustments, physical therapy, vestibular and ocular therapy, psychological support, and graded noncontact exercise.

Changes in attentional processing following neurofeedback in patients with persistent post-concussive symptoms: a pilot study.

OBJECTIVE: Persistent post-concussive symptoms (PPCS) often include attention deficits, particularly orienting and executive attention. Research in other clinical populations has demonstrated that neurofeedback therapy (NFT) is effective at improving orienting and executive attention, although its effects on attentional networks in patients with PPCS are unknown. METHOD: In this single-group pilot study, we examined attention-related event-related potentials (ERPs) - N1 and P3 - and cognitive outcomes following Live Z-score training (LZT), a variant of NFT. RESULTS: No changes in early selective attention, as indexed by N1 amplitude, were observed; however, P3 amplitude, which indexes neural resource allocation, increased following LZT and returned to baseline by 3 months. Cognitive performance improved following treatment, which was sustained at 3 months. The magnitude of change in P3 and ANT performance did not differ between orienting or executive attention, suggesting LZT improved general attentional processing efficiency. CONCLUSION: Our results suggest that LZT may positively affect attention globally, but does not target specific attention networks. These pilot data warrant the initiation of a clinical trial evaluating the effectiveness of LZT for treating attention deficits in patients with PPCS.

Effect of Transcranial Low-Level Light Therapy vs Sham Therapy Among Patients With Moderate Traumatic Brain Injury: A Randomized Clinical Trial.

Importance: Preclinical studies have shown that transcranial near-infrared low-level light therapy (LLLT) administered after traumatic brain injury (TBI) confers a neuroprotective response. Objectives: To assess the feasibility and safety of LLLT administered acutely after a moderate TBI and the neuroreactivity to LLLT through quantitative magnetic resonance imaging metrics and neurocognitive assessment. Design, Setting, and Participants: A randomized, single-center, prospective, double-blind, placebo-controlled parallel-group trial was conducted from November 27, 2015, through July 11, 2019. Participants included 68 men and women with acute, nonpenetrating, moderate TBI who were randomized to LLLT or sham treatment. Analysis of the response-evaluable population was conducted. Interventions: Transcranial LLLT was administered using a custom-built helmet starting within 72 hours after the trauma. Magnetic resonance imaging was performed in the acute (within 72 hours), early subacute (2-3 weeks), and late subacute (approximately 3 months) stages of recovery. Clinical assessments were performed concomitantly and at 6 months via the Rivermead Post-Concussion Questionnaire (RPQ), a 16-item questionnaire with each item assessed on a 5-point scale ranging from 0 (no problem) to 4 (severe problem). Main Outcomes and Measures: The number of participants to successfully and safely complete LLLT without any adverse events within the first 7 days after the therapy was the primary outcome measure. Secondary outcomes were the differential effect of LLLT on MR brain diffusion parameters and RPQ scores compared with the sham group. Results: Of the 68 patients who were randomized (33 to LLLT and 35 to sham therapy), 28 completed at least 1 LLLT session. No adverse events referable to LLLT were reported. Forty-three patients (22 men [51.2%]; mean [SD] age, 50.49 [17.44] years]) completed the study with at least 1 magnetic resonance imaging scan: 19 individuals in the LLLT group and 24 in the sham treatment group. Radial diffusivity (RD), mean diffusivity (MD), and fractional anisotropy (FA) showed significant time and treatment interaction at 3-month time point (RD: 0.013; 95% CI, 0.006 to 0.019; P < .001; MD: 0.008; 95% CI, 0.001 to 0.015; P = .03; FA: -0.018; 95% CI, -0.026 to -0.010; P < .001).The LLLT group had lower RPQ scores, but this effect did not reach statistical significance (time effect P = .39, treatment effect P = .61, and time × treatment effect P = .91). Conclusions and Relevance: In this randomized clinical trial, LLLT was feasible in all patients and did not exhibit any adverse events. Light therapy altered multiple diffusion tensor parameters in a statistically significant manner in the late subacute stage. This study provides the first human evidence to date that light therapy engages neural substrates that play a role in the pathophysiologic factors of moderate TBI and also suggests diffusion imaging as the biomarker of therapeutic response. Trial Registration: ClinicalTrials.gov Identifier: NCT02233413.

Evaluation of current post-concussion protocols.

The growing number of concussions and mild traumatic brain injuries (mTBI) with the lack of evidence-based treatment options is a continuous health concern. This creates problems when evaluating and providing efficacious symptom management to patients suffering from post-concussion syndrome (PCS). Numerous pharmacological and non-pharmacological agents have been utilized in an attempt to treat PCS. Some of these approaches include physical therapy, analgesics, antidepressants, and nutraceuticals. Although these treatments have had some success, there has been inconsistent outcomes, with some examples of patients' symptoms worsening. Among pharmaceutical agents, fluoxetine has been a popular choice for the symptom management of PCS. Although some patients have had symptom resolution with the use of fluoxetine, there is still a lack of conclusive data. Of the several biochemical changes that occur in a patient's brain following a concussion, an increase in reactive oxygen species (ROS) is of particular concern. In order to counteract the responses of the brain, antioxidants, such as ascorbic acid, have been utilized to reverse the damaging cellular effects. However, this may inadvertently cause an increase in ROS, rather than a reduction. Although there is a lack of consistency in exactly when each treatment was used in the post-injury interval, it is important that we analyze the strengths and weaknesses of the most commonly used agents due to the lack of a set protocol. The studies were chosen in a non-exhaustive manner and were not consistent in patients' post-injury intervals, in addition to other baseline characteristics. However, over-arching claims that some treatments may benefit more than others can be made. This review evaluates both the pharmaceutical and non-pharmaceutical protocols that are most commonly utilized in post-concussive patients for their efficacy in treatment of post-concussive syndrome (PCS).

Neural Correlates of Sleep Recovery following Melatonin Treatment for Pediatric Concussion: A Randomized Controlled Trial.

Evidence-based treatments for children with persistent post-concussion symptoms (PPCS) are few and limited. Common PPCS complaints such as sleep disturbance and fatigue could be ameliorated via the supplementation of melatonin, which has significant neuroprotective and anti-inflammatory properties. This study aims to identify neural correlates of melatonin treatment with changes in sleep disturbances and clinical recovery in a pediatric cohort with PPCS. We examined structural and functional neuroimaging (fMRI) in 62 children with PPCS in a randomized, double-blind, placebo-controlled trial of 3 mg or 10 mg of melatonin (NCT01874847). The primary outcome was the total youth self-report Post-Concussion Symptom Inventory (PCSI) score after 28 days of treatment. Secondary outcomes included the change in the sleep domain PCSI score and sleep-wake behavior (assessed using wrist-worn actigraphy). Whole-brain analyses of (1) functional connectivity (FC) of resting-state fMRI, and (2) structural gray matter volumes via voxel-based morphometry were assessed immediately before and after melatonin treatment and compared with placebo to identify neural effects of melatonin treatment. Increased FC of posterior default mode network (DMN) regions with visual, somatosensory, and dorsal networks was detected in the melatonin groups over time. The FC increases also corresponded with reduced wake periods (r = -0.27, p = 0.01). Children who did not recover (n = 39) demonstrated significant FC increases within anterior DMN and limbic regions compared with those who did recover (i.e., PCSI scores returned to pre-injury level, n = 23) over time, (p = 0.026). Increases in GM volume within the posterior cingulate cortex were found to correlate with reduced wakefulness after sleep onset (r = -0.32, p = 0.001) and sleep symptom improvement (r = 0.29, p = 0.02). Although the melatonin treatment trial was negative and did not result in PPCS recovery (with or without sleep problems), the relationship between melatonin and improvement in sleep parameters was linked to changes in function-structure within and between brain regions interacting with the DMN.