Interpreting Change in Disorders of Consciousness Using the Coma Recovery Scale-Revised.

The purpose of this study was to differentiate clinically meaningful improvement or deterioration from normal fluctuations in patients with disorders of consciousness (DoC) following severe brain injury. We computed indices of responsiveness for the Coma Recovery Scale-Revised (CRS-R) using data from a clinical trial of 180 participants with DoC. We used CRS-R scores from baseline (enrollment in a clinical trial) and a 4-week follow-up assessment period for these calculations. To improve precision, we transformed ordinal CRS-R total scores (0-23 points) to equal-interval measures on a 0-100 unit scale using Rasch Measurement theory. Using the 0-100 unit total Rasch measures, we calculated distribution-based 0.5 standard deviation (SD) minimal clinically important difference, minimal detectable change using 95% confidence intervals, and conditional minimal detectable change using 95% confidence intervals. The distribution-based minimal clinically important difference evaluates group-level changes, whereas the minimal detectable change values evaluate individual-level changes. The minimal clinically important difference and minimal detectable change are derived using the overall variability across total measures at baseline and 4 weeks. The conditional minimal detectable change is generated for each possible pair of CRS-R Rasch person measures and accounts for variation in standard error across the scale. We applied these indices to determine the proportions of participants who made a change beyond measurement error within each of the two subgroups, based on treatment arm (amantadine hydrochloride or placebo) or categorization of baseline Rasch person measure to states of consciousness (i.e., unresponsive wakefulness syndrome and minimally conscious state). We compared the proportion of participants in each treatment arm who made a change according to the minimal detectable change and determined whether they also changed to another state of consciousness. CRS-R indices of responsiveness (using the 0-100 transformed scale) were as follows: 0.5SD minimal clinically important difference = 9 units, minimal detectable change = 11 units, and the conditional minimal detectable change ranged from 11 to 42 units. For the amantadine and placebo groups, 70% and 58% of participants showed change beyond measurement error using the minimal detectable change, respectively. For the unresponsive wakefulness syndrome and minimally conscious state groups, 54% and 69% of participants changed beyond measurement error using the minimal detectable change, respectively. Among 115 participants (64% of the total sample) who made a change beyond measurement error, 29 participants (25%) did not change state of consciousness. CRS-R indices of responsiveness can support clinicians and researchers in discerning when behavioral changes in patients with DoC exceed measurement error. Notably, the minimal detectable change can support the detection of patients who make a "true" change within or across states of consciousness. Our findings highlight that the continued use of ordinal scores may result in incorrect inferences about the degree and relevance of a change score.

Feasibility of a Combined Neuromodulation and Yoga Intervention for Mild Traumatic Brain Injury and Chronic Pain: Protocol for an Open-label Pilot Trial.

BACKGROUND: Mild traumatic brain injury (mTBI) and chronic pain often co-occur and worsen rehabilitation outcomes. There is a need for improved multimodal nonpharmacologic treatments that could improve outcomes for both conditions. Yoga is a promising activity-based intervention for mTBI and chronic pain, and neuromodulation through transcranial magnetic stimulation is a promising noninvasive, nonpharmacological treatment for mTBI and chronic pain. Intermittent theta burst stimulation (iTBS) is a type of patterned, excitatory transcranial magnetic stimulation. iTBS can induce a window of neuroplasticity, making it ideally suited to boost the effects of treatments provided after it. Thus, iTBS may magnify the impacts of subsequently delivered interventions as compared to delivering those interventions alone and accordingly boost their impact on outcomes. OBJECTIVE: The aim of this study is to (1) develop a combined iTBS+yoga intervention for mTBI and chronic pain, (2) assess the intervention's feasibility and acceptability, and (3) gather preliminary clinical outcome data on quality of life, function, and pain that will guide future studies. METHODS: This is a mixed methods, pilot, open-labeled, within-subject intervention study. We will enroll 20 US military veteran participants. The combined iTBS+yoga intervention will be provided in small group settings once a week for 6 weeks. The yoga intervention will follow the LoveYourBrain yoga protocol-specifically developed for individuals with TBI. iTBS will be administered immediately prior to the LoveYourBrain yoga session. We will collect preliminary quantitative outcome data before and after the intervention related to quality of life (TBI-quality of life), function (Mayo-Portland Adaptability Index), and pain (Brief Pain Inventory) to inform larger studies. We will collect qualitative data via semistructured interviews focused on intervention acceptability after completion of the intervention. RESULTS: This study protocol was approved by Edward Hines Jr Veterans Administration Hospital Institutional Review Board (Hines IRB 1573116-4) and was prospectively registered on ClinicalTrials.gov (NCT04517604). This study includes a Food and Drug Administration Investigational Device Exemption (IDE: G200195). A 2-year research plan timeline was developed. As of March 2022, a total of 6 veterans have enrolled in the study. Data collection is ongoing and will be completed by November 2022. We expect the results of this study to be available by October 2024. CONCLUSIONS: We will be able to provide preliminary evidence of safety, feasibility, and acceptability of a novel combined iTBS and yoga intervention for mTBI and chronic pain-conditions with unmet treatment needs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04517604; https://www.clinicaltrials.gov/ct2/show/NCT04517604. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/37836.

miRNAs as Potential Biomarkers for Traumatic Brain Injury: Pathway From Diagnosis to Neurorehabilitation.

BACKGROUND: Biomarkers that can advance precision neurorehabilitation of the traumatic brain injury (TBI) are needed. MicroRNAs (miRNAs) have biological properties that could make them well suited for playing key roles in differential diagnoses and prognoses and informing likelihood of responsiveness to specific treatments. OBJECTIVE: To review the evidence of miRNA alterations after TBI and evaluate the state of science relative to potential neurorehabilitation applications of TBI-specific miRNAs. METHODS: This scoping review includes 57 animal and human studies evaluating miRNAs after TBI. PubMed, Scopus, and Google Scholar search engines were used. RESULTS: Gold standard analytic steps for miRNA biomarker assessment are presented. Published studies evaluating the evidence for miRNAs as potential biomarkers for TBI diagnosis, severity, natural recovery, and treatment-induced outcomes were reviewed including statistical evaluation. Growing evidence for specific miRNAs, including miR21, as TBI biomarkers is presented. CONCLUSIONS: There is evidence of differential miRNA expression in TBI in both human and animal models; however, gaps need to be filled in terms of replication using rigorous, standardized methods to isolate a consistent set of miRNA changes. Longitudinal studies in TBI are needed to understand how miRNAs could be implemented as biomarkers in clinical practice.

Customizing TMS Applications in Traumatic Brain Injury Using Neuroimaging.

Optimizing transcranial magnetic stimulation (TMS) treatments in traumatic brain injury (TBI) and co-occurring conditions may benefit from neuroimaging-based customization. PARTICIPANTS: Our total sample (N = 97) included 58 individuals with TBI (49 mild, 8 moderate, and 1 severe in a state of disordered consciousness), of which 24 had co-occurring conditions (depression in 14 and alcohol use disorder in 10). Of those without TBI, 6 individuals had alcohol use disorder and 33 were healthy controls. Of our total sample, 54 were veterans and 43 were civilians. DESIGN: Proof-of-concept study incorporating data from 5 analyses/studies that used multimodal approaches to integrate neuroimaging with TMS. MAIN MEASURES: Multimodal neuroimaging methods including structural magnetic resonance imaging (MRI), MRI-guided TMS navigation, functional MRI, diffusion MRI, and TMS-induced electric fields. Outcomes included symptom scales, neuropsychological tests, and physiological measures. RESULTS: It is feasible to use multimodal neuroimaging data to customize TMS targets and understand brain-based changes in targeted networks among people with TBI. CONCLUSIONS: TBI is an anatomically heterogeneous disorder. Preliminary evidence from the 5 studies suggests that using multimodal neuroimaging approaches to customize TMS treatment is feasible. To test whether this will lead to increased clinical efficacy, studies that integrate neuroimaging and TMS targeting data with outcomes are needed.

A Pilot Trial Examining the Merits of Combining Amantadine and Repetitive Transcranial Magnetic Stimulation as an Intervention for Persons With Disordered Consciousness After TBI.

OBJECTIVE: Report pilot findings of neurobehavioral gains and network changes observed in persons with disordered consciousness (DoC) who received repetitive transcranial magnetic stimulation (rTMS) or amantadine (AMA), and then rTMS+AMA. PARTICIPANTS: Four persons with DoC 1 to 15 years after traumatic brain injury (TBI). DESIGN: Alternate treatment-order, within-subject, baseline-controlled trial. MAIN MEASURES: For group and individual neurobehavioral analyses, predetermined thresholds, based on mixed linear-effects models and conditional minimally detectable change, were used to define meaningful neurobehavioral change for the Disorders of Consciousness Scale-25 (DOCS) total and Auditory-Language measures. Resting-state functional connectivity (rsFC) of the default mode and 6 other networks was examined. RESULTS: Meaningful gains in DOCS total measures were observed for 75% of treatment segments and auditory-language gains were observed after rTMS, which doubled when rTMS preceded rTMS+AMA. Neurobehavioral changes were reflected in rsFC for language, salience, and sensorimotor networks. Between networks interactions were modulated, globally, after all treatments. CONCLUSIONS: For persons with DoC 1 to 15 years after TBI, meaningful neurobehavioral gains were observed after provision of rTMS, AMA, and rTMS+AMA. Sequencing and combining of treatments to modulate broad-scale neural activity, via differing mechanisms, merits investigation in a future study powered to determine efficacy of this approach to enabling neurobehavioral recovery.

Safety Considerations for the Use of Transcranial Magnetic Stimulation as Treatment for Coma Recovery in People With Severe Traumatic Brain Injury.

OBJECTIVE: For persons in states of disordered consciousness (DoC) after severe traumatic brain injury (sTBI), we report cumulative findings from safety examinations, including serious adverse events (AEs) of a repetitive transcranial magnetic stimulation (rTMS) parameter protocol in 2 different studies. PARTICIPANTS: Seven persons in states of DoC after sTBI with widespread neuropathology, but no large lesions in proximity to the site of rTMS. One participant had a ventriculoperitoneal shunt with programmable valve. METHODS: Two clinical trials each providing 30 rTMS sessions to the right or left dorsolateral prefrontal cortex, involving 300 to 600 pulses over 1 or 2 sessions daily. One study provided concomitant amantadine. Safety indicators monitored related to sleep, temperature, blood pressure, skin integrity, sweating, weight loss, infections, and seizure. RESULTS: Average changes for monitored indicators were of mild severity, with 75 nonserious AEs and 1 serious AE (seizure). The participant incurring a seizure resumed rTMS while taking antieplieptics without further seizure activity. CONCLUSIONS: Considering elevated risks for this patient population and conservative patient selection, findings indicate a relatively safe profile for the specified rTMS protocols; however, potential for seizure induction must be monitored. Future research for this population can be broadened to include patients previously excluded on the basis of profiles raising safety concerns.

Neural Connectivity Changes Facilitated by Familiar Auditory Sensory Training in Disordered Consciousness: A TBI Pilot Study.

For people with disordered consciousness (DoC) after traumatic brain injury (TBI), relationships between treatment-induced changes in neural connectivity and neurobehavioral recovery have not been explored. To begin building a body of evidence regarding the unique contributions of treatments to changes in neural network connectivity relative to neurobehavioral recovery, we conducted a pilot study to identify relationships meriting additional examination in future research. To address this objective, we examined previously unpublished neural connectivity data derived from a randomized clinical trial (RCT). We leveraged these data because treatment efficacy, in the RCT, was based on a comparison of a placebo control with a specific intervention, the familiar auditory sensory training (FAST) intervention, consisting of autobiographical auditory-linguistic stimuli. We selected a subgroup of RCT participants with high-quality imaging data (FAST n = 4 and placebo n = 4) to examine treatment-related changes in brain network connectivity and how and if these changes relate to neurobehavioral recovery. To discover promising relationships among the FAST intervention, changes in neural connectivity, and neurobehavioral recovery, we examined 26 brain regions and 19 white matter tracts associated with default mode, salience, attention, and language networks, as well as three neurobehavioral measures. Of the relationships discovered, the systematic filtering process yielded evidence supporting further investigation of the relationship among the FAST intervention, connectivity of the left inferior longitudinal fasciculus, and auditory-language skills. Evidence also suggests that future mechanistic research should focus on examining the possibility that the FAST supports connectivity changes by facilitating redistribution of brain resources. For a patient population with limited treatment options, the reported findings suggest that a simple, yet targeted, passive sensory stimulation treatment may have altered functional and structural connectivity. If replicated in future research, then these findings provide the foundation for characterizing the unique contributions of the FAST intervention and could inform development of new treatment strategies. For persons with severely damaged brain networks, this report represents a first step toward advancing understanding of the unique contributions of treatments to changing brain network connectivity and how these changes relate to neurobehavioral recovery for persons with DoC after TBI. Clinical Trial Registry: NCT00557076, The Efficacy of Familiar Voice Stimulation During Coma Recovery (http://www.clinicaltrials.gov).

Self-reported Participation Restrictions Among Male and Female Veterans With Traumatic Brain Injury in Veterans Health Administration Outpatient Polytrauma Programs.

OBJECTIVES: To identify areas of most restricted self-reported participation among veterans with traumatic brain injury (TBI), explore associations among participation restriction and clinical characteristics, and examine differences in participation restrictions by sex. DESIGN: Retrospective cross-sectional design. SETTING: National VA Polytrauma System of Care outpatient settings. PARTICIPANTS: Veterans with a confirmed TBI event (N=6065). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE(S): Mayo-Portland Participation Index (M2PI), a 5-point Likert-type scale with 8 items. Total score was converted to standardized T score for analysis. RESULTS: The sample consisted of 5679 male and 386 female veterans with ≥1 clinically confirmed TBI events (69% white; 74% with blast exposure). The M2PI items with greatest perceived restrictions were social contact, leisure, and initiation. There were no significant differences between men and women on M2PI standardized T scores. Wilcoxon rank-sum analyses showed significant differences by sex on 4 items: leisure, residence, employment, and financial management (all P<.01). In multinomial logistic regression on each item controlling for demographics, injury characteristics, and comorbidities, female veterans had significantly greater relative risk for part-time work and unemployment on the employment item and significantly less risk for impairment on the residence and financial management item. CONCLUSIONS: There was no significant difference between men and women. Veterans on M2PI standardized T scores, which masks differences in response patterns to individual items. Clinical teams should be encouraged to discuss perceived restrictions with patients and target these areas in treatment planning. Future work is needed to investigate the psychometric properties of the M2PI by biological sex.