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.

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.

Variable abnormality of the melanopsin-derived portion of the pupillary light reflex (PLR) in patients with Parkinson's disease (PD) and parkinsonism features.

OBJECTIVES: Ascertain and quantify abnormality of the melanopsin-derived portion of the pupillary light reflex (PLR) in patients with Parkinson's disease (PD) and parkinsonism features based on a statistical predictive modeling strategy for PLR classification. METHODS: Exploratory cohort analysis of pupillary kinetics in non-disease controls, PD subjects, and subjects with parkinsonism features using chromatic pupillometry. Receiver operating characteristic (ROC) curve interpretation of pupillary changes consistent with abnormality of intrinsically photosensitive retinal ganglion cells (ipRGCs) was employed using a thresholding algorithm to discriminate pupillary abnormality between study groups. RESULTS: Twenty-eight subjects were enrolled, including 17 PD subjects (age range 64-85, mean 70.65) and nine controls (age range 48-95, mean 63.89). Two subjects were described as demonstrating parkinsonism symptoms due to presumed Lewy body dementia and motor system atrophy (MSA) respectively. On aggregate analysis, PD subjects demonstrated abnormal but variable pupillary dynamics suggestive of ipRGC abnormality. Subjects with parkinsonism features did not demonstrate pupillary changes consistent with ipRGC abnormality. There was no relationship between levodopa equivalent dosage or PD severity and ipRGC abnormality. The pupillary test sensitivity in predicting PD was 0.75 and likelihood ratio was 1.2. CONCLUSIONS: ipRGC deficit is demonstrated in PD subjects; however, the degree and constancy of abnormality appear variable.

Effectiveness of Brain Gaming in Older Adults With Cognitive Impairments: A Systematic Review and Meta-Analysis.

OBJECTIVE: This systematic review and meta-analysis evaluates the evidence from randomized clinical trials (RCTs) that designed brain gaming interventions to improve cognitive functions of older adults with cognitive impairments, including mild cognitive impairments and dementia. DESIGN: Systematic review and meta-analysis. SETTING AND PARTICIPANTS: N/A. MEASURES: N/A. METHODS: Data sources-relevant randomized control trials (RCTs) were identified by a systematic search of databases including Medline, PubMed, PsycINFO, Embase, CINAHL, Web of Science, and Cochrane. RCTs were selected first based on title and abstract review and then on full-text review by independent reviewers using predefined eligibility criteria. Risk of bias (RoB) was assessed using the Cochrane RoB tool and funnel plots. The primary outcome variable was the composite score of global cognitive function. RESULTS: A total of 909 participants with mild cognitive impairment or dementia from 16 RCTs were included in the systematic review. The study quality was modest, and the RoB assessment showed bias in blinding the participants and personnel. Funnel plots showed no evidence of publication bias. The meta-analysis of 14 RCTs revealed no superior effect of brain gaming compared to other interventions on global cognitive function (pooled standardized mean difference = 0.08, 95% confidence interval -0.24, 0.41, P = .61, I2 = 77%). Likewise, no superior effects were found on the cognitive domains of memory, executive function, visuospatial skills, and language. CONCLUSION AND IMPLICATIONS: The findings of this meta-analysis suggest that brain gaming compared with the control intervention does not show significant improvement in standardized tests of cognitive function. Because of considerable heterogeneity in sample size, gaming platform, cognitive status, study design, assessment tools, and training prescription, we cannot confidently refute the premise that brain gaming is an effective cognitive training approach for older adults with cognitive impairments. Recommendations for future research are included.

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.

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.

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).

Directional Bias in Line Orientation Test Errors in Parkinson's Disease.

OBJECTIVE: Value in evaluating error subtypes on visuospatial line orientation tests has been reported. Directional bias metrics for line orientation test errors represent easily quantifiable data that have not previously been studied. We evaluated whether patients with a clinical condition known to affect visuospatial functioning (Parkinson's disease [PD]) exhibited unique directional error patterns on the RBANS Line Orientation test relative to other neuropsychology-referred patients. METHOD: We compared overall directional bias in errors, directional bias by line location (left or right line and visual field), and absolute error rates (regardless of direction) by line location in a retrospective sample of patients with PD and a sample of neuropsychology-referred patients without PD. Groups were roughly matched on age, education, gender, and overall level of cognitive impairment. RESULTS: Patients with PD exhibited higher rates of leftward bias in errors, both overall and for the left stimulus line in each pair. Directional bias error scores better predicted PD versus non-PD group status than RBANS Line Orientation raw scores. Classification accuracy data for these variables were modest in the entire sample but stronger in a subsample of patients with mild levels of overall cognitive impairment. CONCLUSIONS: Directional bias metrics for line orientation tests represent easily quantifiable data with potential theoretical and clinical value. In our sample, patients with PD made more left-biased line orientation errors than other neuropsychology-referred patients. By themselves, directional bias scores may have limited diagnostic potential, but they may be useful in diagnostic classification models and may have implications for clinical care.

Nonimmersive Brain Gaming for Older Adults With Cognitive Impairment: A Scoping Review.

BACKGROUND: Technological advances have allowed a variety of computerized cognitive training tools to be engineered in ways that are fun and entertaining yet challenging at a level that can maintain motivation and engagement. This revolution has created an opportunity for gerontological scientists to evaluate brain gaming approaches to improve cognitive and everyday function. The purpose of this scoping review is to provide a critical overview of the existing literature on nonimmersive, electronic brain gaming interventions in older adults with mild cognitive impairment or dementia. RESEARCH DESIGN AND METHODS: Systematic search was conducted using 7 electronic databases from inception through July 2017. A comprehensive 2-level eligibility process was used to identify studies for inclusion based on PRISMA guidelines. RESULTS: Seventeen studies met eligibility criteria. Majority of the studies were randomized controlled trials (n = 13) and incorporated an active control (n = 9). Intervention doses ranged from 4 to 24 weeks in duration with an average of 8.4 (±5.1 standard deviation [SD]) weeks. Session durations ranged from 30 to 100 min with an average of 54 (±25 SD) minutes. Nearly half of studies included a follow-up, ranging from 3 months to 5 years (n = 8). For most studies, brain gaming improved at least one cognitive outcome (n = 12); only one study reported improvement in activities of daily living. DISCUSSION AND IMPLICATIONS: This scoping review conveys the breadth of an emerging research field, which will help guide future research to develop standards and recommendations for brain gaming interventions which are currently lacking.

Evaluating the performance of the Montreal Cognitive Assessment in early stage Parkinson's disease.

INTRODUCTION: Mild cognitive impairment is common in Parkinson's disease, even in the early stages, and can be a risk for developing dementia. To properly track development and progression of cognitive impairment, reliable measurement tools are necessary. The Montreal Cognitive Assessment is currently used as a global cognitive screening tool and has been recommended as an abbreviated diagnostic tool to measure mild cognitive impairment in the context of global cognitive function. However psychometric properties of the Montreal Cognitive Assessment in PD have not been assessed in this context. METHODS: Data were obtained from the Parkinson's Progression Markers Initiative (n = 395). We examine psychometric properties of the Montreal Cognitive Assessment among newly diagnosed Parkinson's disease patients using Rasch analysis. RESULTS: Only one item misfit the measurement model and principle component analysis indicated the Montreal Cognitive Assessment was unidimensional. Distribution of items calibrations formed a logical hierarchy from least to most challenging. Test items were markedly off-target (i.e., too easy) for this sample; this was also reflected in low person separation reliability. While 37% of participants performed all items correctly indicating a large ceiling effect, 22% of participants obtained a raw score in the range of 21-25 indicating mild cognitive impairment. No meaningful differential item functioning was detected. CONCLUSION: Results suggest that in the context of early stage Parkinson's disease, the Montreal Cognitive Assessment is a unidimensional measure of global cognitive function. Implications for the use of the Montreal Cognitive Assessment in early stage Parkinson's disease and potential improvements to the assessment are discussed.

Transcranial magnetic stimulation: potential treatment for co-occurring alcohol, traumatic brain injury and posttraumatic stress disorders.

Alcohol use disorder (AUD), mild traumatic brain injury (mTBI), and posttraumatic stress disorder (PTSD) commonly co-occur (AUD + mTBI + PTSD). These conditions have overlapping symptoms which are, in part, reflective of overlapping neuropathology. These conditions become problematic because their co-occurrence can exacerbate symptoms. Therefore, treatments must be developed that are inclusive to all three conditions. Repetitive transcranial magnetic stimulation (rTMS) is non-invasive and may be an ideal treatment for co-occurring AUD + mTBI + PTSD. There is accumulating evidence on rTMS as a treatment for people with AUD, mTBI, and PTSD each alone. However, there are no published studies to date on rTMS as a treatment for co-occurring AUD + mTBI + PTSD. This review article advances the knowledge base for rTMS as a treatment for AUD + mTBI + PTSD. This review provides background information about these co-occurring conditions as well as rTMS. The existing literature on rTMS as a treatment for people with AUD, TBI, and PTSD each alone is reviewed. Finally, neurobiological findings in support of a theoretical model are discussed to inform TMS as a treatment for co-occurring AUD + mTBI + PTSD. The peer-reviewed literature was identified by targeted literature searches using PubMed and supplemented by cross-referencing the bibliographies of relevant review articles. The existing evidence on rTMS as a treatment for these conditions in isolation, coupled with the overlapping neuropathology and symptomology of these conditions, suggests that rTMS may be well suited for the treatment of these conditions together.