Non-invasive fluid biomarkers in the diagnosis of mild traumatic brain injury (mTBI): a systematic review.

BACKGROUND: Despite approximately 55.9 million annual mild traumatic brain injuries (mTBIs) worldwide, the accurate diagnosis of mTBI continues to challenge clinicians due to symptom ambiguity, reliance on subjective report and presentation variability. Non-invasive fluid biomarkers of mTBI offer a biological measure to diagnose and monitor mTBI without the need for blood draws or neuroimaging. The objective of this study is to systematically review the utility of such biomarkers to diagnose mTBI and predict disease progression. METHODS: A systematic review performed in PubMed, Scopus, Cochrane and Web of Science followed by a manual search of references without a specified timeframe. Search strings were generated and run (27 June 2022) by a research librarian. Studies were included if they: (1) included human mTBI subjects, (2) assessed utility of a non-invasive biomarker and (3) published in English. Exclusion criteria were (1) non-mTBI subjects, (2) mTBI not assessed separately from moderate/severe TBI, (3) required intracranial haemorrhage or (4) solely assesses genetic susceptibility to mTBI. RESULTS: A total of 29 studies from 27 subject populations (1268 mTBI subjects) passed the inclusion and exclusion criteria. Twelve biomarkers were studied. Salivary RNAs, including microRNA, were assessed in 11 studies. Cortisol and melatonin were assessed in four and three studies, respectively. Eight salivary and two urinary biomarkers contained diagnostic or disease monitoring capability. DISCUSSION: This systematic review identified several salivary and urinary biomarkers that demonstrate the potential to be used as a diagnostic, prognostic and monitoring tool for mTBI. Further research should examine miRNA-based models for diagnostic and predictive utility in patients with mTBI. PROSPERO REGISTRATION NUMBER: CRD42022329293.

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.

Association of Pharmacological Interventions With Symptom Burden Reduction in Patients With Mild Traumatic Brain Injury: A Systematic Review.

Importance: Mild traumatic brain injury (TBI) is experienced by 55.9 million people globally each year. The symptoms of mild TBI are diverse and sometimes long-lasting, requiring frequent use of pharmacological interventions to mitigate them. A thorough understanding of the data supporting pharmacological interventions is important for decision-making among clinicians treating this common injury. Objective: To systematically review studies of pharmacological interventions and their associations with symptom burden reduction among patients with mild TBI and to use an evidence-based model to identify potential directions for future research that may aid in clinical decision-making. Evidence Review: A systematic review was performed in PubMed, Scopus, and Web of Science. Search strings modified for the advanced search interfaces of each search engine were developed in consultation with a librarian and included combinations of search terms, such as brain concussion, post-concussion syndrome, mild traumatic brain injury, and pharmacological treatment. Articles published between January 1, 2000, and July 1, 2020, were analyzed. Studies were included if (1) they were clinical studies with discrete analyses of participants with mild TBI or complicated mild TBI, (2) they were assessments of a pharmacological intervention, (3) they included human participants, and (4) they were published in a peer-reviewed journal in the English language. Studies were excluded if the severity of TBI among participants could not be ascertained (ie, inadequate definition of mild TBI) and the inclusion criteria for the study required intracranial hemorrhage. A total of 23 studies examining 20 pharmacological interventions met the inclusion criteria. Risk of bias was assessed using the Cochrane Risk of Bias for Randomized Trials (for randomized clinical trials) and the Cochrane Risk of Bias in Non-Randomized Studies of Interventions (for all other studies). Data were analyzed from June to September 2020. Findings: A total of 1495 articles were identified; of those, 131 articles were excluded as duplicates. Titles and abstracts were screened for inclusion and exclusion criteria among the remaining 1364 articles, and 134 of those articles received a full-text review. After exclusions, 23 studies (11 randomized clinical trials, 7 prospective observational studies, 3 retrospective observational studies, and 2 case studies) examining 20 pharmacological interventions were identified for inclusion in the systematic review. Studies included 22 distinct participant populations comprising 8277 participants with mild TBI and 45 participants without TBI. Among 23 total studies, 8 studies specifically addressed the pediatric population, 9 studies had a low risk of bias, and 16 studies reported symptom burden reduction. Of the 20 pharmacological interventions examined in the studies, methylphenidate, sertraline hydrochloride, ondansetron, amitriptyline, and melatonin were the only medications included in multiple studies. Conclusions and Relevance: This systematic review found a limited number of high-quality, clinically meaningful studies, particularly among children and individuals in the acute stage of injury; therefore, performing an evidence-based analysis that would inform clinical decision-making was not possible. Future studies are needed to focus on standardizing measures and increasing sample sizes (including large multicenter clinical trials) to generate a body of research that may provide additional options for the treatment of patients with mild TBI.

Long term at-home treatment with transcranial direct current stimulation (tDCS) improves symptoms of cerebellar ataxia: a case report.

BACKGROUND: Progressive cerebellar ataxia is a neurodegenerative disorder without effective treatment options that seriously hinders quality of life. Previously, transcranial direct current stimulation (tDCS) has been demonstrated to benefit cerebellar functions (including improved motor control, learning and emotional processing) in healthy individuals and patients with neurological disorders. While tDCS is an emerging therapy, multiple daily sessions are needed for optimal clinical benefit. This case study tests the symptomatic benefit of remotely supervised tDCS (RS-tDCS) for a patient with cerebellar ataxia. METHODS: We report a case of a 71-year-old female patient with progressive cerebellar ataxia, who presented with unsteady gait and balance impairment, treated with tDCS. tDCS was administered using our RS-tDCS protocol and was completed daily in the patient's home (Monday - Friday) with the help of a trained study technician. tDCS was paired with 20 min of simultaneous cognitive training, followed by 20 min of physical exercises directed by a physical therapist. Stimulation consisted of 20 min of 2.5 mA direct current targeting the cerebellum via an anodal electrode and a cathodal electrode placed over the right shoulder. The patient completed baseline and treatment end visits with neurological, cognitive, and motor (Lafayette Grooved Pegboard Test, 25 ft walk test and Timed Up and Go Test) assessments. RESULTS: The patient successfully completed sixty tDCS sessions, 59 of which were administered remotely at the patient's home with the use of real time supervision as enabled by video conferencing. Mild improvement was observed in the patient's gait with a 7% improvement in walking speed, which she completed without a walking-aid at treatment end, which was in stark contrast to her baseline assessment. Improvements were also achieved in manual dexterity, with an increase in pegboard scores bilaterally compared to baseline. CONCLUSIONS: Results from this case report suggest that consecutively administered tDCS treatments paired with cognitive and physical exercise hold promise for improving balance, gait, and manual dexterity in patients with progressive ataxia. Remotely supervised tDCS provides home access to enable the administration over an extended period. Further controlled study in a large group of those with cerebellar ataxia is needed to replicate these findings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03049969 . Registered 10 February 2017- Retrospectively registered.

Brief Computer-Based Information Processing Measures are Linked to White Matter Integrity in Pediatric-Onset Multiple Sclerosis.

BACKGROUND AND PURPOSE: Pediatric-onset multiple sclerosis (POMS) is a demyelinating disorder with unique clinical challenges. A brief computer-administered cognitive screening battery measuring processing speed (Cogstate) and the Brief International Cognitive Assessment in MS (BICAMS) detect cognitive impairment in POMS. The neuroanatomic correlates of these deficits are incompletely understood. The purpose of this study is to define the neuroanatomic underpinnings of deficits identified with cognitive screening batteries in POMS. METHODS: Participants with POMS and age-matched healthy controls (HCs) were screened with Cogstate and BICAMS. Diffusion tensor imaging assessed region-wise and tractography-based fractional anisotropy (FA). RESULTS: The POMS (n = 15) and HC (n = 21) groups were matched on age (mean ages 17.9 ± 3.2 vs. 17.8 ± 3.3 years, respectively) and on an estimate of general intellectual functioning. The Cogstate composite revealed significant slowing in POMS relative to HCs (P = .004), but the BICAMS composite did not significantly distinguish the groups (P = .10). The Cogstate composite showed moderate-to-strong correlations with regional FA (r = -.67 to -.82) and significantly associated with uncinate fasciculus FA following multiple comparisons correction (P = .002) in POMS. However, the BICAMS composite measure showed only weak-to-moderate correlations with FA in POMS (r = -.19 to -.57), with none surviving multiple comparisons correction. CONCLUSIONS: Computer-administered measures of cognitive processing are particularly sensitive in POMS and are closely linked to white matter FA.

The effect of linguistic background on rapid number naming: implications for native versus non-native English speakers on sideline-focused concussion assessments.

OBJECTIVE: To determine if native English speakers (NES) perform differently compared to non-native English speakers (NNES) on a sideline-focused rapid number naming task. A secondary aim was to characterize objective differences in eye movement behaviour between cohorts. BACKGROUND: The King-Devick (KD) test is a rapid number-naming task in which numbers are read from left-to-right. This performance measure adds vision-based assessment to sideline concussion testing. Reading strategies differ by language. Concussion may also impact language and attention. Both factors may affect test performance. METHODS: Twenty-seven healthy  NNES and healthy NES performed a computerized KD test under high-resolution video-oculography.  NNES also performed a Bilingual Dominance Scale (BDS) questionnaire to weight linguistic preferences (i.e., reliance on non-English language(s)). RESULTS: Inter-saccadic intervals were significantly longer in  NNES (346.3 ± 78.3 ms vs. 286.1 ± 49.7 ms, p = 0.001), as were KD test times (54.4 ± 15.1 s vs. 43.8 ± 8.6 s, p = 0.002). Higher BDS scores, reflecting higher native language dominance, were associated with longer inter-saccadic intervals in  NNES. CONCLUSION: These findings have direct implications for the assessment of athlete performance on vision-based and other verbal sideline concussion tests; these results are particularly important given the international scope of sport. Pre-season baseline scores are essential to evaluation in the event of concussion, and performance of sideline tests in the athlete's native language should be considered to optimize both baseline and post-injury test accuracy.