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.

Impulsivity and Psychiatric Diagnoses as Mediators of Suicidal Ideation and Suicide Attempts Among Veterans With Traumatic Brain Injury.

OBJECTIVE: Traumatic brain injury (TBI) is a risk factor for suicide, but questions related to mechanisms remain unanswered. Impulsivity is a risk factor for suicide and is a common sequela of TBI. The authors explored the relationships between TBI and both suicidal ideation and suicide attempts and explored whether impulsivity and comorbid psychiatric diagnoses mediate these relationships. METHODS: This cross-sectional retrospective chart review study included 164 veterans enrolled in a previous study. Sixty-nine veterans had no TBI history, and 95 had a TBI history (mild, N=44; moderate, N=13; severe, N=12; and unclear severity, N=26). To examine the associations between TBI and suicidal ideation or suicide attempts, as well as potential mediators of these relationships, chi-square tests, t tests, and logistic regression models were used. RESULTS: Unadjusted analyses indicated that veterans with TBI were more likely to report suicidal ideation; however, in analyses controlling for mediators, this relationship was no longer significant. Among veterans with TBI, suicidal ideation was related most strongly to high impulsivity (odds ratio=15.35, 95% CI=2.43-96.79), followed by depression (odds ratio=5.73, 95% CI=2.53-12.99) and posttraumatic stress disorder (odds ratio=2.57, 95% CI=1.03-6.42). TBI was not related to suicide attempts, yet suicide attempts were related to high impulsivity (odds ratio=6.95, 95% CI=1.24-38.75) and depression (odds ratio=3.89, 95% CI=1.56-9.40). CONCLUSIONS: These findings suggest that impulsivity, followed by psychiatric diagnoses, most strongly mediate the relationships between TBI and both suicidal ideation and suicide attempts. Impulsivity may be mechanistically related to, and serve as a future treatment target for, suicidality among veterans with TBI.

Comparing indices of responsiveness for the Coma Near-Coma Scale with and without pain items: An Exploratory study.

INTRODUCTION: This study aimed to establish the indices of responsiveness for the Coma/Near-Coma (CNC) scale without (8 items) and with (10 items) pain test stimuli. A secondary purpose was to examine whether the CNC 8 items and 10 items differ when detecting change in neurobehavioral function. METHODS: We analyzed CNC data from three studies of participants with disorders of consciousness: one observational study and two intervention studies. We generated Rasch person measures using the CNC 8 items and CNC 10 items for each participant at two time points 14 ± 2 days apart using Rasch Measurement Theory. We calculated the distribution-based minimal clinically important difference (MCID) and minimal detectable change using 95% confidence intervals (MDC95 ). RESULTS: We used the Rasch transformed equal-interval scale person measures in logits. For the CNC 8 items: Distribution-based MCID 0.33 SD = 0.41 logits and MDC95  = 1.25 logits. For the CNC 10 items: Distribution-based MCID 0.33 SD = 0.37 logits and MDC95  = 1.03 logits. Twelve and 13 participants made a change beyond measurement error (MDC95 ) using the CNC 8-item and 10-item scales, respectively. CONCLUSION: Our preliminary evidence supports the clinical and research utility of the CNC 8-item scale for measuring the responsiveness of neurobehavioral function, and that it demonstrates comparable responsiveness to the CNC 10-item scale without administering the two pain items. The distribution-based MCID can be used to evaluate group-level changes while the MDC95 can support clinical, data-driven decisions about an individual patient.

An Initial miRNA Profile of Persons With Persisting Neurobehavioral Impairments and States of Disordered Consciousness After Severe Traumatic Brain Injury.

OBJECTIVE: To examine the merits of using microRNAs (miRNAs) as biomarkers of disorders of consciousness (DoC) due to traumatic brain injury (TBI). SETTINGS: Acute and subacute beds. PARTICIPANTS: Patients remaining in vegetative and minimally conscious states (VS, MCS), an average of 1.5 years after TBI, and enrolled in a randomized clinical trial ( n = 6). Persons without a diagnosed central nervous system disorder, neurotypical controls ( n = 5). DESIGN: Comparison of whole blood miRNA profiles between patients and age/gender-matched controls. For patients, correlational analyses between miRNA profiles and measures of neurobehavioral function. MAIN MEASURES: Baseline measures of whole blood miRNAs isolated from the cellular and fluid components of blood and measured using miRNA-seq and real-time polymerase chain reaction (RT-PCR). Baseline neurobehavioral measures derived from 7 tests. RESULTS: For patients, relative to controls, 48 miRNA were significantly ( P < .05)/differentially expressed. Cluster analysis showed that neurotypical controls were most similar to each other and with 2 patients (VS: n = 1; and MCS: n = 1). Three patients, all in MCS, clustered separately. The only female in the sample, also in MCS, formed an independent group. For the 48 miRNAs, the enriched pathways identified are implicated in secondary brain damage and 26 miRNAs were significantly ( P < .05) correlated with measures of neurobehavioral function. CONCLUSIONS: Patients remaining in states of DoC an average of 1.5 years after TBI showed a different and reproducible pattern of miRNA expression relative to age/gender-matched neurotypical controls. The phenotypes, defined by miRNA profiles relative to persisting neurobehavioral impairments, provide the basis for future research to determine the miRNA profiles differentiating states of DoC and the basis for future research using miRNA to detect treatment effects, predict treatment responsiveness, and developing targeted interventions. If future research confirms and advances reported findings, then miRNA profiles will provide the foundation for patient-centric DoC neurorehabilitation.

The diagnostic intersection of cognitive-communication disorders and aphasia secondary to TBI.

BACKGROUND & AIMS: The present retrospective study examines veterans and military personnel who have sustained a cognitive-communication deficit/disorder (CCD) and/or aphasia secondary to traumatic brain injury (TBI). The prevalence of each disorder secondary to TBI is identified and demographic factors are analysed to determine whether specific characteristics (age, gender, race and/or ethnicity) differentially influenced diagnosis (CCD or aphasia). METHODS & PROCEDURES: A retrospective analysis examining the prevalence of CCD and aphasia among US service personnel with a complicated mild-to-severe TBI treated over a 4-year period (1 January 2016-31 December 2019) was conducted. Medical diagnoses and demographic factors were obtained from administrative data repositories and a logistic regression was performed to identify the relationship between demographic factors and diagnoses. OUTCOMES & RESULTS: Analyses revealed that 8.8% of individuals studied had a secondary diagnosis of CCD (6.9%), aphasia (1.5%) or both (0.4%). This signifies 6863 cases of CCD, 1516 cases of aphasia and 396 cases of CCD and aphasia (dual diagnosis) per 100,000 individuals who have sustained a complicated mild-to-severe TBI. The proportion of cases observed with these diagnoses was consistent with the racial, gender and ethnic demographics of those diagnosed with TBI. Statistical modelling revealed that increased age is predictive of a diagnosis of aphasia relative to CCD. CONCLUSIONS & IMPLICATIONS: Service personnel sustaining TBIs are at increased risk of communication impairments with deficits observed across all gender, racial and ethnic demographics. CCD is more commonly observed than aphasia, though clinicians should be cognisant of both when performing assessments. Age is a factor that can influence diagnosis. WHAT THIS PAPER ADDS: What is already known on the subject Military personnel are at increased risk of communication disorders (CCDs) with TBI associated with multiple types of communication impairments including CCD, aphasia, dysarthria and apraxia of speech. What this paper adds to existing knowledge This paper examines CCD and aphasia occurring following TBI. The proportion of observed cases of CCD and aphasia secondary to TBI are calculated over a 4-year period and the prevalence of these disorders is provided. Additionally, statistical modelling is used to identify differences in the diagnosis of CCD relative to aphasia using the demographic factors of age, racial identity and ethnicity. What are the potential or actual clinical implications of this work? CCD is a frequently occurring issue following TBI, and the findings of this study demonstrate that it is a concern observed across gender, racial and ethnic lines. Advanced age is linked with the diagnosis of aphasia relative to CCD following TBI and should be a consideration during evaluation of patients who have sustained significant head trauma.

rTMS/iTBS and Cognitive Rehabilitation for Deficits Associated With TBI and PTSD: A Theoretical Framework and Review.

Rehabilitation of cognitive and psychosocial deficits resulting from traumatic brain injury (TBI) continues to be an area of concern in health care. Commonly co-occurring psychiatric disorders, such as major depressive disorder and posttraumatic stress disorder, create additional hurdles when attempting to remediate cognitive sequelae. There is increased need for procedures that will yield consistent gains indicative of recovery of function. Intermittent theta-burst stimulation (iTBS), a form of repetitive transcranial magnetic stimulation, has potential as an instrument that can be tailored to aid cognitive processes and support functional gains. The use of iTBS enables direct stimulation of desired neural systems. iTBS, performed in conjunction with behavioral interventions (e.g., cognitive rehabilitation, psychotherapy), may result in additive success in facilitating cognitive restoration and adaptation. The purpose of this theoretical review is to illustrate how the technical and physiological aspects of iTBS may enhance other forms of neurorehabilitation for individuals with TBI. Future research on combinatorial iTBS interventions has the potential to translate to other complex neuropsychiatric conditions.

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.

Mapping outcomes for recovery of consciousness in studies from 1986 to 2020: a scoping review protocol.

INTRODUCTION: Historically, heterogeneous outcome assessments have been used to measure recovery of consciousness in patients with disorders of consciousness (DoC) following traumatic brain injury (TBI), making it difficult to compare across studies. To date, however, there is no comprehensive review of clinical outcome assessments that are used in intervention studies of adults with DoC. The objective of this scoping review is to develop a comprehensive inventory of clinical outcome assessments for recovery of consciousness that have been used in clinical studies of adults with DoC following TBI. METHODS AND ANALYSIS: The methodological framework for this review is: (1) identify the research questions, (2) identify relevant studies, (3) select studies, (4) chart the data, (5) collate, summarise and report results and (6) consult stakeholders to drive knowledge translation. We will identify relevant studies by searching the following electronic bibliographic databases: PubMed, Scopus, EMBASE, PsycINFO and The Cochrane Library (including Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials and Cochrane Methodology Register). Criteria for article inclusion are published in the English-language, peer-reviewed studies of interventions aimed at facilitating recovery of consciousness among adults (> 18 years) with DoC following a severe TBI, published from January 1986 to December 2020. Articles meeting inclusion criteria at this stage will undergo a full text review. We will chart the data by applying the WHO International Classification of Functioning, Disability and Health Framework to identify the content areas of clinical outcome assessments. To support knowledge translation efforts, we will involve clinicians and researchers experienced in TBI care throughout the project from conceptualisation of the study through dissemination of results. ETHICS AND DISSEMINATION: No ethical approval is required for this study as it is not determined to be human subjects research. Results will be presented at national conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: CRD42017058383.

Determining the Hierarchy of Coma Recovery Scale-Revised Rating Scale Categories and Alignment with Aspen Consensus Criteria for Patients with Brain Injury: A Rasch Analysis.

This study aimed to empirically evaluate the hierarchical structure of the Coma Recovery Scale-Revised (CRS-R) rating scale categories and their alignment with the Aspen consensus criteria for determining disorders of consciousness (DoC) following a severe brain injury. CRS-R data from 262 patients with DoC following a severe brain injury were analyzed applying the partial credit Rasch Measurement Model. Rasch Analysis produced logit calibrations for each rating scale category. Twenty-eight of the 29 CRS-R rating scale categories were operationalized to the Aspen consensus criteria. We expected the hierarchical order of the calibrations to reflect Aspen consensus criteria. We also examined the association between the CRS-R Rasch person measures (indicative of performance ability) and states of consciousness as determined by the Aspen consensus criteria. Overall, the order of the 29 rating scale category calibrations reflected current literature regarding the continuum of neurobehavioral function: category 6 "Functional Object Use" of the Motor item was hardest for patients to achieve; category 0 "None" of the Oromotor/Verbal item was easiest to achieve. Of the 29 rating scale categories, six were not ordered as expected. Four rating scale categories reflecting the Vegetative State (VS)/Unresponsive Wakefulness Syndrome (UWS) had higher calibrations (reflecting greater neurobehavioral function) than the easiest Minimally Conscious State (MCS) item (category 2 "Fixation" of the Visual item). Two rating scale categories, one reflecting MCS and one not operationalized to the Aspen consensus criteria, had higher calibrations than the easiest eMCS item (category 2 "Functional: Accurate" of the Communication item). CRS-R person measures (indicating amount of neurobehavioral function) and states of consciousness, based on Aspen consensus criteria, showed a strong correlation (rs = 0.86; p < 0.01). Our study provides empirical evidence for revising the diagnostic criteria for MCS to also include category 2 "Localization to Sound" of the Auditory item and for Emerged from Minimally Conscious State (eMCS) to include category 4 "Consistent Movement to Command" of the Auditory item.

"Fluctuation is the norm": Rehabilitation practitioner perspectives on ambiguity and uncertainty in their work with persons in disordered states of consciousness after traumatic brain injury.

The purpose of this study is to describe the clinical lifeworld of rehabilitation practitioners who work with patients in disordered states of consciousness (DoC) after severe traumatic brain injury (TBI). We interviewed 21 practitioners using narrative interviewing methods from two specialty health systems that admit patients in DoC to inpatient rehabilitation. The overarching theme arising from the interview data is "Experiencing ambiguity and uncertainty in clinical reasoning about consciousness" when treating persons in DoC. We describe practitioners' practices of looking for consistency, making sense of ambiguous and hard to explain patient responses, and using trial and error or "tinkering" to care for patients. Due to scientific uncertainty about diagnosis and prognosis in DoC and ambiguity about interpretation of patient responses, working in the field of DoC disrupts the canonical meaning-making processes that practitioners have been trained in. Studying the lifeworld of rehabilitation practitioners through their story-making and story-telling uncovers taken-for-granted assumptions and normative structures that may exist in rehabilitation medical and scientific culture, including practitioner training. We are interested in understanding these canonical breaches in order to make visible how practitioners make meaning while treating patients.

Health Care Resource Utilization and Costs for Adults With Mild Traumatic Brain Injury With Chronic Vestibular Impairment.

OBJECTIVE: To quantify the economic burden of all-cause health care resource utilization (HCRU) among adults with and without chronic vestibular impairment (CVI) after a mild traumatic brain injury (mTBI). DESIGN: Retrospective matched cohort study. SETTING: IQVIA Integrated Data Warehouse. PARTICIPANTS: People with mTBI+CVI (n=20,441) matched on baseline age, sex, year of mTBI event, and Charlson Comorbidity Index (CCI) score to people with mTBI only (n=20,441) (N=40,882). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: All-cause health HCRU and costs at 12 and 24 months post mTBI diagnosis. RESULTS: People with mTBI+CVI had significantly higher all-cause HCRU and costs at both time points than those with mTBI only. Multivariable regression analysis showed that, when controlling for baseline variables, costs of care were 1.5 times higher for mTBI+CVI than mTBI only. CONCLUSIONS: People who developed CVI after mTBI had greater overall HCRU and costs for up to 2 years after the injury event compared with people who did not develop CVI after controlling for age, sex, region, and CCI score. Further research on access to follow-up services and effectiveness of interventions to address CVI is warranted.

Psychometric Properties and Sex Differences on the Mayo-Portland Adaptability Inventory Participation Subscale (M2PI) in Veterans With Traumatic Brain Injury.

OBJECTIVE: To evaluate the structural validity of the Mayo-Portland Adaptability Inventory Participation Index (M2PI) in a sample of veterans and to assess whether the tool functioned similarly for male and female veterans. DESIGN: Rasch analysis of M2PI records from the National Veterans Traumatic Brain Injury Health Registry database from 2012-2018. SETTING: National VA Polytrauma System of Care outpatient settings. PARTICIPANTS: Veterans with a clinically confirmed history of traumatic brain injury (TBI) (N=6065; 94% male). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: M2PI, a 5-point Likert-type scale with 8 items. For this analysis, the 2 employment items were treated individually for a total of 9 items. RESULTS: The employment items misfit the Rasch Measurement model (paid employment mean square [MnSq]=1.40; other employment MnSq=1.34) and were removed from subsequent iterations. The final model had eigenvalue 1.87 on the first contrast, suggesting unidimensionality of the remaining 7 items. Item order from least to most participation restriction was transportation, self-care, residence management, financial management, initiation, leisure, and social contact. Wright's person separation reliability for nonnormal distributions was 0.93, indicating appropriateness of M2PI for making individual-level treatment decisions. Mean person measure was -0.92±1.34 logits, suggesting that participants did not report restrictions on most items (item mean=0 logits). A total of 3.8% of the sample had the minimum score (no impairment on all items), and 0.2% had the maximum score. Four items had different item calibrations (≥0.25 logits) for female compared with male veterans, but the hierarchy of items was unchanged when the female sample was examined separately. CONCLUSIONS: These findings suggest that, although employment is a poor indicator of participation restrictions among veterans with TBI, the M2PI is unidimensional. Because of subtle differences in scale function between male and female participants, M2PI should be part of a more thorough clinical interview about participation strengths and restrictions.

Psychometric measurement properties of the world health organization disability assessment schedule 2.0 (WHODAS) evaluated among veterans with mild traumatic brain injury and behavioral health conditions.

PURPOSE: Examine the psychometric properties of the World Health Organization Disability Assessment Schedule 2.0 among U.S. Iraq/Afghanistan Veterans with a combination of mild traumatic brain injury and behavioral health conditions using Rasch analysis. METHODS: 307 Veterans were classified as either combat control (n = 141), or one of three clinical groups: mild traumatic brain injury (n = 10), behavioral health conditions (n = 24), or both (n = 128). Data from the three clinical groups were used to establish step and item calibrations serving as anchors when including the control group. RESULTS: Measurement precision was excellent (person separation reliability = 0.93). Ordering of item calibrations formed a logical hierarchy. Test items were off-target (too easy) for the clinical groups. Principal component analysis indicated unidimensionality although 4/36 items misfit the measurement model. No meaningful differential item functioning was detected. There was a moderate effect size (Hedge's g = 1.64) between the control and clinical groups. CONCLUSIONS: The World Health Organization Disability Assessment Schedule was suitable for our study sample, distinguishing 4 levels of functional ability. Although items may be easy for some Veterans with mild traumatic brain injury and/or behavioral health conditions, the World Health Organization Disability Assessment Schedule can be used to capture disability information for those with moderate to severe disability.Implications for rehabilitationPersistent functional disability is seen in military and civilian populations with mild traumatic brain injury which often co-occurs with behavioral health conditions.A comprehensive measure of disability is needed to distinguish between levels of disability to inform clinical decisions for individual patients and to detect treatment effects between groups in research.Results of this analysis indicate the World Health Organization Disability Assessment Schedule items are sufficiently unidimensional to evaluate level of disability in the moderate and severe range among persons with mild traumatic brain injury with and without behavioral health conditions.Further examination of the psychometric properties of the World Health Organization.Disability Assessment Schedule is necessary before measurement of disability is recommended for those with less than moderate levels of disability.

Cognition and Other Predictors of Functional Disability Among Veterans With Mild Traumatic Brain Injury and Posttraumatic Stress Disorder.

BACKGROUND: Limitations in everyday functioning are frequently reported by veterans with a history of mild traumatic brain injury (mTBI) and/or posttraumatic stress disorder (PTSD). Multiple factors are associated with functional disability among veterans, including depression, poor social support, cognition, and substance use. However, the degree to which these factors, particularly cognitive capacities, contribute to functional limitations remains unclear. METHODS: We evaluated performance on tests of processing speed, executive functioning, attention, and memory as predictors of functioning on the World Health Organization Disability Assessment Scale (WHODAS) 2.0 in 288 veterans. Participants were placed in one of the following groups: PTSD-only, mTBI-only, mTBI + PTSD, and neither PTSD nor mTBI (deployed control group). Cognitive test performances were evaluated as predictors of WHODAS 2.0 functional ratings in regression models that included demographic variables and a range of mood, behavioral health, and postconcussive symptom ratings. RESULTS: Multiple cognitive test performances predicted WHODAS 2.0 scores in the deployed control group, but they generally did not predict functioning in the clinical groups when accounting for demographics, mood, behavioral health, and postconcussive symptoms. CONCLUSIONS: In veterans with mTBI and/or PTSD, cognitive test performances are less associated with everyday functioning than mood and postconcussive symptoms.

Psychometric Properties of the Coma Near-Coma Scale for Adults in Disordered States of Consciousness: A Rasch Analysis.

OBJECTIVES: To examine the construct validity and measurement precision of the Coma Near-Coma scale (CNC) in measuring neurobehavioral function (NBF) in patients with disorders of consciousness receiving postacute care rehabilitation. DESIGN: Rasch analysis of retrospective data. PARTICIPANTS: Participants (N=48) with disordered consciousness who were admitted to postacute care rehabilitation. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: CNC. RESULTS: Assessment with CNC repeated weekly until the participant was conscious or discharged from the postacute care facility (451 participant records). Rating scale steps were ordered for all items. Eight of the 10 CNC items evaluated in this study fit the measurement model (χ2=5332.58; df=11; P=.17); pain items formed a distinct construct. The ordering of the 8 items from most to least challenging makes clinical sense and compares favorably with other published hierarchies of NBF. Tactile items are more easily responded to. Visual and auditory items requiring higher cognitive processing were more challenging. In the full sample, the CNC achieved good measurement precision, with a person separation reliability of 0.87. CONCLUSIONS: The items of the CNC reflect good construct validity and acceptable interrater reliability. The measurement precision achieved indicates that the CNC may be used to make decisions about groups of individuals but that these items may not be sufficiently precise for individual patient treatment decision-making.

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.