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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.

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.

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.

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.307 Veterans were classified as either combat control (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'sThe 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.

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.

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.

Research Objectives To explore the relationship between attention/working memory (WM) performance and grey matter volume in the dorsal attention network (DAN), a neural network in the brain that supports encoding and maintenance of external information. Design Observational. Setting Data obtained from the Parkinson's Progression Marker Initiative (PPMI; www.ppmi-info.org ), an international longitudinal multisite study. Participants Participants with persistent WM impairment (n= 10) and persistent normal WM performance (n=10) were compared. WM was measured using the Letter Number Sequencing (LNS) test. Persistent impairment was defined by a standardized test score of 8 or less for 4 consecutive years since baseline imaging. Normal WM performance was defined by a standardized test score of 10 or more for 4 consecutive years since baseline imaging. Groups were matched on sex, age, years of education, and disease duration. Interventions Not Applicable. Main Outcome Measures Grey matter volume was measured using voxel-based morphometry (VBM) through SPM12 and CAT12. Region of interest analysis within the DAN (Schaeffer et al., 2018 100-parcel atlas), was conducted. Whole brain cluster analysis was conducted for confirmatory evidence. Significant clusters within a DAN mask (Schaeffer et al., 2018 100-parcel atlas) are reported with a FDR (p=0.05). Results For ROI analysis, grey matter atrophy in the bilateral visuomotor cortex (p=0.005), bilateral intraparietal sulcus (p=0.04), and right superior parietal lobule (p=0.021) was found in the impaired WM group compared to the normal WM group. Between groups, differences in several clusters within the DAN masks were observed. Conclusions These promising preliminary findings support the notion that changes in grey matter volume within cognitive neural networks, such as the DAN, can be a biomarker for decline in cognitive function, as well as treatment responsiveness in people living with PD. Author(s) Disclosures None.

Research Objectives To investigate the relative contributions of demographic factors, behavioral health and mood symptoms, and history of mild Traumatic Brain Injury (mTBI) on neuropsychological test performance. Design Cross-sectional Study. Setting Three VA Polytrauma Network Sites. Participants Veterans aged 18 years and older who deployed to Iraq and/or Afghanistan conflicts, and had not received treatment for concussion in the preceding 30 days were eligible for enrollment. Across sites, 454 Veterans were enrolled between August 1, 2010 and September 30, 2011. After excluding Veterans with missing outcome data or with scores below study cutoffs on measures of symptom/performance validity, 250 Veterans remained. Interventions N/A. Main Outcome Measures Cognitive functioning assessed using neuropsychological measures of processing speed, executive functioning, attention, and memory. Results Using separate multiple regression models (i.e., one for each neuropsychological measure), examining specified predictor variables (estimated pre-injury IQ scores, demographics, behavioral health ratings, insomnia, alcohol use, pain, positive mTBI history, anxiety, depression, presence of Posttraumatic Stress Disorder), indicate that current mood symptoms and other behavioral health concerns (e.g., pain/sleep) predict objective cognitive performance over and above mTBI history. Conclusions Some Veterans presenting to neuropsychology clinics with subjective cognitive complaints attribute these to their prior mTBI. However, many also have commonly co-occurring mood, sleep, and pain concerns which are also known to impact cognition. Our findings suggest that these modifiable factors, rather than mTBI history, likely play a greater role in objective cognitive abilities (i.e., performance on neuropsychological tests). These findings inform ongoing efforts to improve patient education regarding the expected recovery course from mTBI and the relationship between mood and health on daily cognitive efficiency. Author(s) Disclosures N/A.

Objective Veterans presenting to neuropsychology clinics with subjective cognitive complaints often attribute these complaints to history of mild Traumatic Brain Injury (mTBI). However, many of these Veterans also have co-occurring mood, sleep, and pain concerns – all of which negatively impact cognition, but are also modifiable. Here, we investigated the relative contributions of demographic factors, behavioral health and mood symptoms, and history of mTBI on neuropsychological test performance. Method Across three Veterans Affairs Polytrauma Network Sites, 250 Veterans who deployed to Iraq and/or Afghanistan conflicts and had not received treatment for concussion in the preceding 30 days were enrolled between 8/1/2010 and 9/30/2011. Separate multiple regression models were used to examine specified predictor variables (estimated pre-injury IQ, demographics, behavioral health ratings, insomnia, alcohol use, pain, positive mTBI history, anxiety, depression, presence of Posttraumatic Stress Disorder [PTSD]) and their impact on neuropsychological test performances. Results When predicting cognitive functioning, history of mTBI was not a significant predictor in any of the cognitive models. Rather, presence of PTSD was a significant predictor for both immediate (p Conclusion Modifiable factors may play a greater role in objective cognitive abilities (i.e., performance on neuropsychological tests) than mTBI history. These findings inform ongoing efforts to improve patient education regarding the expected recovery course from mTBI and the relationship between mood and health on daily cognitive efficiency.

Brain Gaming (BG) Interventions have been shown to improve the cognitive function of older adults with cognitive impairments (CIs). However, rigorous evaluation supporting BG effectiveness is needed. Thus, we used meta-analysis to evaluate the effectiveness of BG. Several search databases (i.e. Pubmed) were used to identify relevant randomized controlled trials (RCTs). Cochrane RoB tool evaluated risk of bias. The main outcome was the composite score of cognitive function. Inverse-variance random effects model was used to compare the pooled standardized mean difference (SMD) across studies. A total of 16 RCTs included 909 participants. The RCTs varied in sample size, gaming platform, training prescription, and cognition. The meta-analysis showed no significant effects of BG on overall cognitive function (pooled SMD = 0.08, 95% CI [-0.24 – 0.41], p = 0.61, I2 = 77%. However, due to high heterogeneity, we cannot confidently refute that BG is an effective cognitive training approach.

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.

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.