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Chronic motor impairments are a leading cause of disability after stroke. Previous studies have associated motor outcomes with the degree of damage to predefined structures in the motor system, such as the corticospinal tract. However, such theory-based approaches may not take full advantage of the information contained in clinical imaging data. The present study uses data-driven approaches to model chronic motor outcomes after stroke and compares the accuracy of these associations to previously-identified theory-based biomarkers. Using a cross-validation framework, regression models were trained using lesion masks and motor outcomes data from 789 stroke patients from the Enhancing NeuroImaging Genetics through Meta Analysis (ENIGMA) Stroke Recovery Working Group. Using the explained variance metric to measure the strength of the association between chronic motor outcomes and imaging biomarkers, we compared theory-based biomarkers, like lesion load to known motor tracts, to three data-driven biomarkers: lesion load of lesion-behaviour maps, lesion load of structural networks associated with lesion-behaviour maps, and measures of regional structural disconnection. In general, data-driven biomarkers had stronger associations with chronic motor outcomes accuracy than theory-based biomarkers. Data-driven models of regional structural disconnection performed the best of all models tested ( R 2 = 0.210, P < 0.001), performing significantly better than the theory-based biomarkers of lesion load of the corticospinal tract ( R 2 = 0.132, P < 0.001) and of multiple descending motor tracts ( R 2 = 0.180, P < 0.001). They also performed slightly, but significantly, better than other data-driven biomarkers including lesion load of lesion-behaviour maps ( R 2 = 0.200, P < 0.001) and lesion load of structural networks associated with lesion-behaviour maps ( R 2 = 0.167, P < 0.001). Ensemble models - combining basic demographic variables like age, sex, and time since stroke - improved the strength of associations for theory-based and data-driven biomarkers. Combining both theory-based and data-driven biomarkers with demographic variables improved predictions, and the best ensemble model achieved R 2 = 0.241, P < 0.001. Overall, these results demonstrate that out-of-sample associations between chronic motor outcomes and data-driven imaging features, particularly when lesion data is represented in terms of structural disconnection, are stronger than associations between chronic motor outcomes and theory-based biomarkers. However, combining both theory-based and data-driven models provides the most robust associations., Competing Interests: S.C.C. serves as a consultant for Abbvie, Constant Therapeutics, BrainQ, Myomo, MicroTransponder, Neurolutions, Panaxium, NeuExcell, Elevian, Helius, Omniscient, Brainsgate, Nervgen, Battelle, and TRCare. B.H. has a clinical partnership with Fourier Intelligence. N.J.S. is an inventor for a patent US 10,071,015 B2. C.J. W. is a consultant for Microtransponder, BrainQ, and MedRhythm. G.F.W. sits on Advisory Boards for Myomo and Neuro-innovators., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

We develop a novel metal contact approach using an antimony (Sb)-platinum (Pt) bilayer to mitigate Fermi-level pinning in 2D transition metal dichalcogenide channels. This strategy allows for control over the transport polarity in monolayer WSe 2 devices. By adjustment of the Sb interfacial layer thickness from 10 to 30 nm, the effective work function of the contact/WSe 2 interface can be tuned from 4.42 eV (p-type) to 4.19 eV (n-type), enabling selectable n-/p-FET operation in enhancement mode. The shift in effective work function is linked to Sb-Se bond formation and an emerging n-doping effect. This work demonstrates high-performance n- and p-FETs with a single WSe 2 channel through Sb-Pt contact modulation. After oxide encapsulation, the maximum current density at |V D | = 1 V reaches 170 μA/μm for p-FET and 165 μA/μm for n-FET. This approach shows promise for cost-effective CMOS transistor applications using a single channel material and metal contact scheme.

Background and Objectives: Motor outcomes after stroke relate to corticospinal tract (CST) damage. The brain leverages surviving neural pathways to compensate for CST damage and mediate motor recovery. Thus, concurrent age-related damage from white matter hyperintensities (WMHs) might affect neurologic capacity for recovery after CST injury. The role of WMHs in post-stroke motor outcomes is unclear. In this study, we evaluated whether WMHs modulate the relationship between CST damage and post-stroke motor outcomes., Methods: We used data from the multisite ENIGMA Stroke Recovery Working Group with T1 and T2/fluid-attenuated inversion recovery imaging. CST damage was indexed with weighted CST lesion load (CST-LL). WMH volumes were extracted with Freesurfer's SAMSEG. Mixed-effects beta-regression models were fit to test the impact of CST-LL, WMH volume, and their interaction on motor impairment, controlling for age, days after stroke, and stroke volume., Results: A total of 223 individuals were included. WMH volume related to motor impairment above and beyond CST-LL (β = 0.178, 95% CI 0.025-0.331, p = 0.022). Relationships varied by WMH severity (mild vs moderate-severe). In individuals with mild WMHs, motor impairment related to CST-LL (β = 0.888, 95% CI 0.604-1.172, p < 0.001) with a CST-LL × WMH interaction (β = -0.211, 95% CI -0.340 to -0.026, p = 0.026). In individuals with moderate-severe WMHs, motor impairment related to WMH volume (β = 0.299, 95% CI 0.008-0.590, p = 0.044), but did not significantly relate to CST-LL or a CST-LL × WMH interaction., Discussion: WMHs relate to motor outcomes after stroke and modify relationships between motor impairment and CST damage. WMH-related damage may be under-recognized in stroke research as a factor contributing to variability in motor outcomes. Our findings emphasize the importance of brain structural reserve in motor outcomes after brain injury.

Introduction: Chronic stroke survivors with severe arm impairment have limited options for effective rehabilitation. High intensity, repetitive task practice (RTP) is known to improve upper limb function among stroke survivors who have some volitional muscle activation. However, clients without volitional movement of their arm are ineligible for RTP-based interventions and require hands-on facilitation from a clinician or robotic therapy to simulate task practice. Such approaches can be expensive, burdensome, and have marginal effects. Alternatively, supervised at-home telerehabilitation using muscle biofeedback may provide a more accessible, affordable, and effective rehabilitation option for stroke survivors with severe arm impairment, and could potentially help people with severe stroke regain enough volitional activation to be eligible for RTP-types of therapies. Feedback of muscle activity via electromyography (EMG) has been previously used with clients who have minimal or no movement to improve functional performance. Specifically, training to reduce unintended co-contractions of the impaired hand using EMG biofeedback may modestly improve motor control in people with limited movement. Importantly, these modest and covert functional changes may influence the perceived impact of stroke-related disability in daily life. In this manuscript, we examine whether physical changes following use of a portable EMG biofeedback system (Tele-REINVENT) for severe upper limb hemiparesis also relate to perceived quality of life improvements. Secondarily, we examined the effects of Tele-REINVENT, which uses EMG to quantify antagonistic muscle activity during movement attempt trials and transform individuated action into computer game control, on several different domains of stroke recovery., Methods: For this pilot study, nine stroke survivors (age = 37-73 years) with chronic impairment (Fugl-Meyer = 14-40/66) completed 30 1-hour sessions of home-based training, consisting of six weeks of gaming that reinforced wrist extensor muscle activity while attenuating coactivation of flexor muscles. To assess motor control and performance, we measured changes in active wrist ranges of motion, the Fugl-Meyer Assessment, and Action Research Arm Test. We also collected an EMG-based test of muscle control to examine more subtle changes. To examine changes in perceived quality of life, we utilized the Stroke Impact Scale along with participant feedback., Results: Results from our pilot data suggest that 30 sessions of remote training can induce modest changes on clinical and functional assessments, showing a statistically significant improvement of active wrist ranges of motion at the group level, changes that could allow some people with severe stroke to be eligible for other therapeutic approaches, such as RTP. Additionally, changes in motor control were correlated with the perceived impact of stroke on participation and impairment after training. We also report changes in corticomuscular coherence, which showed a laterality change from the ipsilesional motor cortex towards the contralesional hemisphere during wrist extension attempts. Finally, all participants showed high adherence to the protocol and reported enjoying using the system., Conclusion: Overall, Tele-REINVENT represents a promising telerehabilitation intervention that might improve sensorimotor outcomes in severe chronic stroke, and that improving sensorimotor abilities even modestly may improve quality of life. We propose that Tele-REINVENT may be used as a precursor to help participants gain enough active movement to participate other occupational therapy interventions, such as RTP. Future work is needed to examine if home-based telerehabilitation to provide feedback of individuated muscle activity could increase meaningful rehabilitation accessibility and outcomes for underserved populations., Competing Interests: S-LL, OM-P, and CP reported having a patent pending as “2024, Neurofeedback rehabilitation system US20240057926A1”. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Marin-Pardo, Donnelly, Phanord, Wong and Liew.)

The elderly are considered a high-risk group for severe outcomes and death from COVID-19 infection. Given the emergence of new COVID variants and the immunity provided by vaccines waning over time, booster doses of the vaccine have been advocated for those at risk to stay protected. This study aimed to determine the factors associated with hesitancy toward the second booster of the COVID-19 vaccine among the elderly residing in residential care homes. A cross-sectional study was conducted in 24 residential care homes in the Klang Valley using a face-to-face interview questionnaire. The study population included individuals aged 60 and above who had been fully vaccinated against COVID-19 up to the first booster dose. Second-booster hesitancy was assessed using the Oxford Vaccine Hesitancy Scale with seven items, the aggregate score of which ranges from seven to thirty-five; the higher the score, the greater the level of hesitancy. Multivariate linear regression was employed to determine factors associated with second-booster hesitancy, and a p -value < 0.05 was considered statistically significant. Data from 401 elderly individuals were included for analysis. The mean score of the Oxford Vaccine Hesitancy Scale was 21.6 ± 7.2. Predictors of second booster hesitancy were identified. Age, Indian ethnicity, being a recipient of the Sinovac vaccine as the first COVID-19 booster, experiencing the death of close friends or immediate family members following COVID-19 vaccination, and negative messages (indicating that taking a booster dose is harmful) from caregivers, friends, or family members were found to be associated with an increased second-booster-hesitancy score. Conversely, positive messages (indicating that taking a booster is helpful) from the government and caregivers, friends, or family members were identified as predictors associated with a reduction in the second-booster-hesitancy score. While vaccines effectively combat severe COVID-19, the majority of the elderly hesitate before taking the second booster. Their hesitancy, rooted in the perception of a low self risk and reliance on protection from the initial doses, emphasizes the need for intervention by relevant bodies. Taking into consideration the risk, albeit relatively low, of potentially serious side effects following COVID-19 vaccinations, it is imperative that transparent, appropriate, and positive messaging regarding booster vaccines, particularly in the context of the elderly from residential care homes, be available. Encouraging this high-risk group to embrace the second booster aligns with the goal of maximizing protection within the vulnerable elderly population.

The articles in this Special Issue on Recovery of Function After Neurological Injury include an impressive range of clinical diagnoses, scientific approaches, and theoretical frameworks that demonstrate the breadth and depth of occupational therapy in the restoration of function after neurological injury. An emerging theme throughout is the need for the profession of occupational therapy to identify and use more efficient methods for diagnosing and treating people with neurological injuries to improve their quality of life and the impact of care., (Copyright © 2024 by the American Occupational Therapy Association, Inc.)

Importance: Complex telehealth interventions can facilitate remote occupational therapy services and improve access for people living with chronic neurological conditions. Understanding the factors that influence the uptake of these technologies is important., Objective: To explore the fit between electromyography (EMG) biofeedback and telerehabilitation for stroke survivors, optimize EMG biofeedback interventions, and, more broadly, support other efforts to develop complex telerehabilitation interventions., Design: Pre-implementation mixed-methods analysis of usability and acceptability data collected during a pilot and feasibility study., Setting: Community., Participants: Adult stroke survivors with hemiparesis (N = 11; M age = 54 yr)., Intervention: Game-based EMG biofeedback system for arm sensorimotor rehabilitation, delivered via telehealth., Outcomes and Measures: Post-Study System Usability Questionnaire, an extended Unified Theory of Acceptance and Use of Technology model questionnaire, and semistructured interview. We coded the interview data using questionnaire constructs., Results: Participants used an EMG biofeedback intervention at home. Quantitative measures show high levels of perceived usability and acceptability, supported by qualitative findings describing specific facilitators and barriers., Conclusions and Relevance: Pre-implementation studies can improve the design and relevance of complex telehealth interventions. One major conclusion from this study is the influence of therapy providers on acceptability and usability of complex telehealth interventions. Plain-Language Summary: This study contributes to an emerging body of literature that examines the use of complex telehealth interventions with survivors of neurological injury. The findings highlight the value and support the development and use of complex telehealth interventions, which have the potential to improve remote access to occupational therapy for clients living with chronic neurological conditions. Complex telehealth interventions can open doors for survivors of neurological injury who face barriers to accessing occupational therapy and would benefit from technology-enabled therapy at home., (Copyright © 2024 by the American Occupational Therapy Association, Inc.)

In this article, a 0.7 nm thick monolayer MoS 2 nanosheet gate-all-around field effect transistors (NS-GAAFETs) with conformal high- κ metal gate deposition are demonstrated. The device with 40 nm channel length exhibits a high on-state current density of ~410 μ A μ m -1 with a large on/off ratio of 6 × 10 8 at drain voltage = 1 V. The extracted contact resistance is 0.48 ± 0.1 kΩ μ m in monolayer MoS 2 NS-GAAFETs, thereby showing the channel-dominated performance with the channel length scaling from 80 to 40 nm. The successful demonstration of device performance in this work verifies the integration potential of transition metal dichalcogenides for future logic transistor applications., (© 2024 IOP Publishing Ltd.)

Background: Microstructural changes in the corpus callosum (CC) are associated with more severe motor impairment in the paretic hand, poor recovery, and general disability. The purpose of this study was to determine if CC microstructure predicts bimanual motor performance in chronic stroke survivors., Methods: We examined the relationship between the fractional anisotropy (FA) across the CC, in both the sensorimotor and non-sensorimotor regions, and movement times for two self-initiated and self-paced bimanual tasks in 41 chronic stroke survivors. Using publicly available control datasets (n = 52), matched closely for imaging acquisition parameters, we also explored the effect of stroke and age on callosal microstructure., Results: In mild-to-moderate chronic stroke survivors with relatively localized lesions to the motor areas, lower callosal FA values, suggestive of a more disorganized microstructure, were associated with slower bimanual performance. Associations were strongest for the primary motor fibers ( b = -2.19 ± 1.03, p = .035), followed closely by premotor/supplementary motor ( b = -2.07 ± 1.07, p = .041) and prefrontal ( b = -1.92 ± 0.97, p = .05) fibers of the callosum. Secondary analysis revealed that compared to neurologically age-similar adults, chronic stroke survivors exhibited significantly lower mean FA in all regions of the CC, except the splenium., Conclusion: Remote widespread changes in the callosal genu and body are associated with slower performance on cooperative bimanual tasks that require precise and interdependent coordination of the hands. Measures of callosal microstructure may prove to be a useful predictor of real-world bimanual performance in chronic stroke survivors.

Background: Integrity of the corticospinal tract (CST) is an important biomarker for upper limb motor function following stroke. However, when structurally compromised, other tracts may become relevant for compensation or recovery of function., Methods: We used the ENIGMA Stroke Recovery data set, a multicenter, retrospective, and cross-sectional collection of patients with upper limb impairment during the chronic phase of stroke to test the relevance of tracts in individuals with less and more severe (laterality index of CST fractional anisotropy ≥0.25) CST damage in an observational study design. White matter integrity was quantified using fractional anisotropy for the CST, the superior longitudinal fascicle, and the callosal fibers interconnecting the primary motor cortices between hemispheres. Optic radiations served as a control tract as they have no a priori relevance for the motor system. Pearson correlation was used for testing correlation with upper limb motor function (Fugl-Meyer upper extremity)., Results: From 1235 available data sets, 166 were selected (by imaging, Fugl-Meyer upper extremity, covariates, stroke location, and stage) for analyses. Only individuals with severe CST damage showed a positive association of fractional anisotropy in both callosal fibers interconnecting the primary motor cortices ( r [21]=0.49; P= 0.025) and superior longitudinal fascicle ( r [21]=0.51; P=0 .018) with Fugl-Meyer upper extremity., Conclusions: Our data support the notion that individuals with more severe damage of the CST depend on residual pathways for achieving better upper limb outcome than those with less affected CST., Competing Interests: Disclosures Dr Hordacre has a clinical partnership with Fourier Intelligence. Dr Conforto is a consultant for Boehringer Ingelheim. Dr Kautz reports grants from US Department of Veterans Affairs and grants from National Institute of General Medical Sciences. Dr Thompson has received research grant support from Biogen, Inc, for research unrelated to this article. Dr Warach is a consultant for Genentech and BrainsGate. The other authors report no conflicts.

Electromyography (EMG) biofeedback delivered via telerehabilitation can increase access to occupational therapy services for stroke survivors with severe impairment, but there is limited research on its acceptability. This study identified factors influencing the acceptability of a complex, muscle biofeedback system (Tele-REINVENT) for upper extremity sensorimotor stroke telerehabilitation among stroke survivors. We conducted interviews with stroke survivors ( n = 4) who used Tele-REINVENT at home for 6 weeks and analyzed the data with reflexive thematic analysis. Biofeedback, customization, gamification, and predictability affected the acceptability of Tele-REINVENT among stroke survivors. Across themes, features and experiences that gave participants agency and control were more acceptable. Our findings contribute to the design and development of at-home EMG biofeedback interventions, which can improve access to advanced occupational therapy treatment options for those who need it most.

Background and Objectives: Functional outcomes after stroke are strongly related to focal injury measures. However, the role of global brain health is less clear. In this study, we examined the impact of brain age, a measure of neurobiological aging derived from whole-brain structural neuroimaging, on poststroke outcomes, with a focus on sensorimotor performance. We hypothesized that more lesion damage would result in older brain age, which would in turn be associated with poorer outcomes. Related, we expected that brain age would mediate the relationship between lesion damage and outcomes. Finally, we hypothesized that structural brain resilience, which we define in the context of stroke as younger brain age given matched lesion damage, would differentiate people with good vs poor outcomes., Methods: We conducted a cross-sectional observational study using a multisite dataset of 3-dimensional brain structural MRIs and clinical measures from the ENIGMA Stroke Recovery. Brain age was calculated from 77 neuroanatomical features using a ridge regression model trained and validated on 4,314 healthy controls. We performed a 3-step mediation analysis with robust mixed-effects linear regression models to examine relationships between brain age, lesion damage, and stroke outcomes. We used propensity score matching and logistic regression to examine whether brain resilience predicts good vs poor outcomes in patients with matched lesion damage., Results: We examined 963 patients across 38 cohorts. Greater lesion damage was associated with older brain age (β = 0.21; 95% CI 0.04-0.38, p = 0.015), which in turn was associated with poorer outcomes, both in the sensorimotor domain (β = -0.28; 95% CI -0.41 to -0.15, p < 0.001) and across multiple domains of function (β = -0.14; 95% CI -0.22 to -0.06, p < 0.001). Brain age mediated 15% of the impact of lesion damage on sensorimotor performance (95% CI 3%-58%, p = 0.01). Greater brain resilience explained why people have better outcomes, given matched lesion damage (odds ratio 1.04, 95% CI 1.01-1.08, p = 0.004)., Discussion: We provide evidence that younger brain age is associated with superior poststroke outcomes and modifies the impact of focal damage. The inclusion of imaging-based assessments of brain age and brain resilience may improve the prediction of poststroke outcomes compared with focal injury measures alone, opening new possibilities for potential therapeutic targets., (Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

White matter hyperintensities (WMHs) are a risk factor for stroke. Consequently, many individuals who suffer a stroke have comorbid WMHs. The impact of WMHs on stroke recovery is an active area of research. Automated WMH segmentation methods are often employed as they require minimal user input and reduce risk of rater bias; however, these automated methods have not been specifically validated for use in individuals with stroke. Here, we present methodological validation of automated WMH segmentation methods in individuals with stroke. We first optimized parameters for FSL's publicly available WMH segmentation software BIANCA in two independent (multi-site) datasets. Our optimized BIANCA protocol achieved good performance within each independent dataset, when the BIANCA model was trained and tested in the same dataset or trained on mixed-sample data. BIANCA segmentation failed when generalizing a trained model to a new testing dataset. We therefore contrasted BIANCA's performance with SAMSEG, an unsupervised WMH segmentation tool available through FreeSurfer. SAMSEG does not require prior WMH masks for model training and was more robust to handling multi-site data. However, SAMSEG performance was slightly lower than BIANCA when data from a single site were tested. This manuscript will serve as a guide for the development and utilization of WMH analysis pipelines for individuals with stroke., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ferris, Lo, Khlif, Brodtmann, Boyd and Liew.)

Although automated methods for stroke lesion segmentation exist, many researchers still rely on manual segmentation as the gold standard. Our detailed, standardized protocol for stroke lesion tracing on high-resolution 3D T1-weighted (T1w) magnetic resonance imaging (MRI) has been used to trace over 1,300 stroke MRI. In the current study, we describe the protocol, including a step-by-step method utilized for training multiple individuals to trace lesions ("tracers") in a consistent manner and suggestions for distinguishing between lesioned and non-lesioned areas in stroke brains. Inter-rater and intra-rater reliability were calculated across six tracers trained using our protocol, resulting in an average intraclass correlation of 0.98 and 0.99, respectively, as well as a Dice similarity coefficient of 0.727 and 0.839, respectively. This protocol provides a standardized guideline for researchers performing manual lesion segmentation in stroke T1-weighted MRI, with detailed methods to promote reproducibility in stroke research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lo, Donnelly, Barisano and Liew.)

Magnetic resonance imaging (MRI) is an important imaging modality in stroke. Computer based automated medical image processing is increasingly finding its way into clinical routine. The Ischemic Stroke Lesion Segmentation (ISLES) challenge is a continuous effort to develop and identify benchmark methods for acute and sub-acute ischemic stroke lesion segmentation. Here we introduce an expert-annotated, multicenter MRI dataset for segmentation of acute to subacute stroke lesions ( https://doi.org/10.5281/zenodo.7153326 ). This dataset comprises 400 multi-vendor MRI cases with high variability in stroke lesion size, quantity and location. It is split into a training dataset of n = 250 and a test dataset of n = 150. All training data is publicly available. The test dataset will be used for model validation only and will not be released to the public. This dataset serves as the foundation of the ISLES 2022 challenge ( https://www.isles-challenge.org/ ) with the goal of finding algorithmic methods to enable the development and benchmarking of automatic, robust and accurate segmentation methods for ischemic stroke., (© 2022. The Author(s).)

Stroke is a leading cause of adult disability in the United States. High doses of repeated task-specific practice have shown promising results in restoring upper limb function in chronic stroke. However, it is currently challenging to provide such doses in clinical practice. At-home telerehabilitation supervised by a clinician is a potential solution to provide higher-dose interventions. However, telerehabilitation systems developed for repeated task-specific practice typically require a minimum level of active movement. Therefore, severely impaired people necessitate alternative therapeutic approaches. Measurement and feedback of electrical muscle activity via electromyography (EMG) have been previously implemented in the presence of minimal or no volitional movement to improve motor performance in people with stroke. Specifically, muscle neurofeedback training to reduce unintended co-contractions of the impaired hand may be a targeted intervention to improve motor control in severely impaired populations. Here, we present the preliminary results of a low-cost, portable EMG biofeedback system (Tele-REINVENT) for supervised and unsupervised upper limb telerehabilitation after stroke. We aimed to explore the feasibility of providing higher doses of repeated task-specific practice during at-home training. Therefore, we recruited 5 participants (age = 44-73 years) with chronic, severe impairment due to stroke (Fugl-Meyer = 19-40/66). They completed a 6-week home-based training program that reinforced activity of the wrist extensor muscles while avoiding coactivation of flexor muscles via computer games. We used EMG signals to quantify the contribution of two antagonistic muscles and provide biofeedback of individuated activity, defined as a ratio of extensor and flexor activity during movement attempt. Our data suggest that 30 1-h sessions over 6 weeks of at-home training with our Tele-REINVENT system is feasible and may improve individuated muscle activity as well as scores on standard clinical assessments (e.g., Fugl-Meyer Assessment, Action Research Arm Test, active wrist range of motion) for some individuals. Furthermore, tests of neuromuscular control suggest modest changes in the synchronization of electroencephalography (EEG) and EMG signals within the beta band (12-30 Hz). Finally, all participants showed high adherence to the training protocol and reported enjoying using the system. These preliminary results suggest that using low-cost technology for home-based telerehabilitation after severe chronic stroke is feasible and may be effective in improving motor control via feedback of individuated muscle activity., Competing Interests: S-LL, OM-P, and CP reported having a patent pending as “2022, S-LL, OM-P, and CS. Neurofeedback rehabilitation system. International Publication No. WO 2022/183009 A1.” The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Marin-Pardo, Donnelly, Phanord, Wong, Pan and Liew.)

Background: Complex motor tasks in immersive virtual reality using a head-mounted display (HMD-VR) have been shown to increase cognitive load and decrease motor performance compared to conventional computer screens (CS). Separately, visuomotor adaptation in HMD-VR has been shown to recruit more explicit, cognitive strategies, resulting in decreased implicit mechanisms thought to contribute to motor memory formation. However, it is unclear whether visuomotor adaptation in HMD-VR increases cognitive load and whether cognitive load is related to explicit mechanisms and long-term motor memory formation., Methods: We randomized 36 healthy participants into three equal groups. All groups completed an established visuomotor adaptation task measuring explicit and implicit mechanisms, combined with a dual-task probe measuring cognitive load. Then, all groups returned after 24-h to measure retention of the overall adaptation. One group completed both training and retention tasks in CS (measuring long-term retention in a CS environment), one group completed both training and retention tasks in HMD-VR (measuring long-term retention in an HMD-VR environment), and one group completed the training task in HMD-VR and the retention task in CS (measuring context transfer from an HMD-VR environment). A Generalized Linear Mixed-Effect Model (GLMM) was used to compare cognitive load between CS and HMD-VR during visuomotor adaptation, t-tests were used to compare overall adaptation and explicit and implicit mechanisms between CS and HMD-VR training environments, and ANOVAs were used to compare group differences in long-term retention and context transfer., Results: Cognitive load was found to be greater in HMD-VR than in CS. This increased cognitive load was related to decreased use of explicit, cognitive mechanisms early in adaptation. Moreover, increased cognitive load was also related to decreased long-term motor memory formation. Finally, training in HMD-VR resulted in decreased long-term retention and context transfer., Conclusions: Our findings show that cognitive load increases in HMD-VR and relates to explicit learning and long-term motor memory formation during motor learning. Future studies should examine what factors cause increased cognitive load in HMD-VR motor learning and whether this impacts HMD-VR training and long-term retention in clinical populations., (© 2022. The Author(s).)

Scaling of monolayer transition metal dichalcogenide (TMD) field-effect transistors (FETs) is an important step toward evaluating the application space of TMD materials. Although some work on ultrashort channel monolayer (ML) TMD FETs has been published, there exist no comprehensive studies that assess their performance in a statistically relevant manner, providing critical insights into the impact of the device geometry. Part of the reason for the absence of such a study is the substantial variability of TMD devices when processes are not carefully controlled. In this work, we show a statistical study of ultrashort channel double-gated ML WS 2 FETs exhibiting excellent device performance and limited device-to-device variations. From a detailed analysis of cross-sectional scanning transmission electron microscopy (STEM) images and careful technology computer aided design (TCAD) simulations, we evaluated, in particular, an unexpected deterioration of the subthreshold characteristics for our shortest devices. Two potential candidates for the observed behavior were identified, i.e., buckling of the TMD on the substrate and loss of gate control due to the source geometry and the high- k dielectric between the metal gate and the metal source electrode.

Pemphigus is a rare autoimmune bullous disease which affects the mucous membranes and skin. Pemphigus vulgaris (PV) is the most prevalent type of pemphigus. PV presents with extremely painful, non-healing oral erosions. However, there are only a handful of reports addressing the pain management of PV. We would like to present a case of a painful PV, which was successfully managed., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: It is difficult to predict poststroke outcome for individuals with severe motor impairment because both clinical tests and corticospinal tract (CST) microstructure may not reliably indicate severe motor impairment. Here, we test whether imaging biomarkers beyond the CST relate to severe upper limb (UL) impairment poststroke by evaluating white matter microstructure in the corpus callosum (CC). In an international, multisite hypothesis-generating observational study, we determined if (1) CST asymmetry index (CST-AI) can differentiate between individuals with mild-moderate and severe UL impairment and (2) CC biomarkers relate to UL impairment within individuals with severe impairment poststroke. We hypothesized that CST-AI would differentiate between mild-moderate and severe impairment, but CC microstructure would relate to motor outcome for individuals with severe UL impairment., Methods: Seven cohorts with individual diffusion imaging and motor impairment (Fugl-Meyer Upper Limb) data were pooled. Hand-drawn regions-of-interest were used to seed probabilistic tractography for CST (ipsilesional/contralesional) and CC (prefrontal/premotor/motor/sensory/posterior) tracts. Our main imaging measure was mean fractional anisotropy. Linear mixed-effects regression explored relationships between candidate biomarkers and motor impairment, controlling for observations nested within cohorts, as well as age, sex, time poststroke, and lesion volume., Results: Data from 110 individuals (30 with mild-moderate and 80 with severe motor impairment) were included. In the full sample, greater CST-AI (i.e., lower fractional anisotropy in the ipsilesional hemisphere, p < 0.001) and larger lesion volume ( p = 0.139) were negatively related to impairment. In the severe subgroup, CST-AI was not reliably associated with impairment across models. Instead, lesion volume and CC microstructure explained impairment in the severe group beyond CST-AI ( p 's < 0.010)., Discussion: Within a large cohort of individuals with severe UL impairment, CC microstructure related to motor outcome poststroke. Our findings demonstrate that CST microstructure does relate to UL outcome across the full range of motor impairment but was not reliably associated within the severe subgroup. Therefore, CC microstructure may provide a promising biomarker for severe UL outcome poststroke, which may advance our ability to predict recovery in individuals with severe motor impairment after stroke., (© 2022 American Academy of Neurology.)

Accurate lesion segmentation is critical in stroke rehabilitation research for the quantification of lesion burden and accurate image processing. Current automated lesion segmentation methods for T1-weighted (T1w) MRIs, commonly used in stroke research, lack accuracy and reliability. Manual segmentation remains the gold standard, but it is time-consuming, subjective, and requires neuroanatomical expertise. We previously released an open-source dataset of stroke T1w MRIs and manually-segmented lesion masks (ATLAS v1.2, N = 304) to encourage the development of better algorithms. However, many methods developed with ATLAS v1.2 report low accuracy, are not publicly accessible or are improperly validated, limiting their utility to the field. Here we present ATLAS v2.0 (N = 1271), a larger dataset of T1w MRIs and manually segmented lesion masks that includes training (n = 655), test (hidden masks, n = 300), and generalizability (hidden MRIs and masks, n = 316) datasets. Algorithm development using this larger sample should lead to more robust solutions; the hidden datasets allow for unbiased performance evaluation via segmentation challenges. We anticipate that ATLAS v2.0 will lead to improved algorithms, facilitating large-scale stroke research., (© 2022. The Author(s).)

Background Persistent sensorimotor impairments after stroke can negatively impact quality of life. The hippocampus is vulnerable to poststroke secondary degeneration and is involved in sensorimotor behavior but has not been widely studied within the context of poststroke upper-limb sensorimotor impairment. We investigated associations between non-lesioned hippocampal volume and upper limb sensorimotor impairment in people with chronic stroke, hypothesizing that smaller ipsilesional hippocampal volumes would be associated with greater sensorimotor impairment. Methods and Results Cross-sectional T1-weighted magnetic resonance images of the brain were pooled from 357 participants with chronic stroke from 18 research cohorts of the ENIGMA (Enhancing NeuoImaging Genetics through Meta-Analysis) Stroke Recovery Working Group. Sensorimotor impairment was estimated from the FMA-UE (Fugl-Meyer Assessment of Upper Extremity). Robust mixed-effects linear models were used to test associations between poststroke sensorimotor impairment and hippocampal volumes (ipsilesional and contralesional separately; Bonferroni-corrected, P <0.025), controlling for age, sex, lesion volume, and lesioned hemisphere. In exploratory analyses, we tested for a sensorimotor impairment and sex interaction and relationships between lesion volume, sensorimotor damage, and hippocampal volume. Greater sensorimotor impairment was significantly associated with ipsilesional ( P =0.005; β=0.16) but not contralesional ( P =0.96; β=0.003) hippocampal volume, independent of lesion volume and other covariates ( P =0.001; β=0.26). Women showed progressively worsening sensorimotor impairment with smaller ipsilesional ( P =0.008; β=-0.26) and contralesional ( P =0.006; β=-0.27) hippocampal volumes compared with men. Hippocampal volume was associated with lesion size ( P <0.001; β=-0.21) and extent of sensorimotor damage ( P =0.003; β=-0.15). Conclusions The present study identifies novel associations between chronic poststroke sensorimotor impairment and ipsilesional hippocampal volume that are not caused by lesion size and may be stronger in women.

A new generation of compact and high-speed electronic devices, based on carbon, would be enabled through the development of robust gate oxides with sub-nanometer effective oxide thickness (EOT) on carbon nanotubes or graphene nanoribbons. However, to date, the lack of dangling bonds on sp 2 oriented graphene sheets has limited the high precursor nucleation density enabling atomic layer deposition of sub-1 nm EOT gate oxides. It is shown here that by deploying a low-temperature AlO x (LT AlO x ) process, involving atomic layer deposition (ALD) of Al 2 O 3 at 50 °C with a chemical vapor deposition (CVD) component, a high nucleation density layer can be formed, which templates the growth of a high- k dielectric, such as HfO 2 . Atomic force microscopy (AFM) imaging shows that at 50 °C, the Al 2 O 3 spontaneously forms a pinhole-free, sub-2 nm layer on graphene. Density functional theory (DFT) based simulations indicate that the spreading out of AlO x clusters on the carbon surface enables conformal oxide deposition. Device applications of the LT AlO x deposition scheme were investigated through electrical measurements on metal oxide semiconductor capacitors (MOSCAPs) with Al 2 O 3 /HfO 2 bilayer gate oxides using both standard Ti/Pt metal gates as well as TiN/Ti/Pd gettering gates. In this study, LT AlO x was used to nucleate HfO 2 and it was shown that bilayer gate oxide stacks of 2.85 and 3.15 nm were able to achieve continuous coverage on carbon nanotubes (CNTs). The robustness of the bilayer was tested through deployment in a CNT-based field-effect transistor (FET) configuration with a gate leakage of less than 10 -8 A/μm per CNT.

Low-intensity transcranial electrical stimulation (tES), including alternating or direct current stimulation, applies weak electrical stimulation to modulate the activity of brain circuits. Integration of tES with concurrent functional MRI (fMRI) allows for the mapping of neural activity during neuromodulation, supporting causal studies of both brain function and tES effects. Methodological aspects of tES-fMRI studies underpin the results, and reporting them in appropriate detail is required for reproducibility and interpretability. Despite the growing number of published reports, there are no consensus-based checklists for disclosing methodological details of concurrent tES-fMRI studies. The objective of this work was to develop a consensus-based checklist of reporting standards for concurrent tES-fMRI studies to support methodological rigor, transparency and reproducibility (ContES checklist). A two-phase Delphi consensus process was conducted by a steering committee (SC) of 13 members and 49 expert panelists through the International Network of the tES-fMRI Consortium. The process began with a circulation of a preliminary checklist of essential items and additional recommendations, developed by the SC on the basis of a systematic review of 57 concurrent tES-fMRI studies. Contributors were then invited to suggest revisions or additions to the initial checklist. After the revision phase, contributors rated the importance of the 17 essential items and 42 additional recommendations in the final checklist. The state of methodological transparency within the 57 reviewed concurrent tES-fMRI studies was then assessed by using the checklist. Experts refined the checklist through the revision and rating phases, leading to a checklist with three categories of essential items and additional recommendations: (i) technological factors, (ii) safety and noise tests and (iii) methodological factors. The level of reporting of checklist items varied among the 57 concurrent tES-fMRI papers, ranging from 24% to 76%. On average, 53% of checklist items were reported in a given article. In conclusion, use of the ContES checklist is expected to enhance the methodological reporting quality of future concurrent tES-fMRI studies and increase methodological transparency and reproducibility., (© 2022. © The Author(s).)

Lesion load of the corticospinal tract (CST-LL), a measure of overlap between a stroke lesion and the CST, is one of the strongest predictors of motor outcomes following stroke. CST-LL is typically calculated by using a probabilistic map of the CST originating from the primary motor cortex (M1). However, higher order motor areas also have projections that contribute to the CST and motor control. In this retrospective study, we examined whether evaluating CST-LL from additional motor origins is more strongly associated with post-stroke motor severity than using CST-LL originating from M1 only. We found that lesion load to both the ventral premotor (PMv) cortex and M1 were more strongly related to stroke motor severity indexed by Fugl-Meyer Assessment cut-off scores than CST-LL of M1 alone, suggesting that higher order motor regions add clinical relevance to motor impairment.

The goal of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Stroke Recovery working group is to understand brain and behavior relationships using well-powered meta- and mega-analytic approaches. ENIGMA Stroke Recovery has data from over 2,100 stroke patients collected across 39 research studies and 10 countries around the world, comprising the largest multisite retrospective stroke data collaboration to date. This article outlines the efforts taken by the ENIGMA Stroke Recovery working group to develop neuroinformatics protocols and methods to manage multisite stroke brain magnetic resonance imaging, behavioral and demographics data. Specifically, the processes for scalable data intake and preprocessing, multisite data harmonization, and large-scale stroke lesion analysis are described, and challenges unique to this type of big data collaboration in stroke research are discussed. Finally, future directions and limitations, as well as recommendations for improved data harmonization through prospective data collection and data management, are provided., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

As stroke mortality rates decrease, there has been a surge of effort to study poststroke dementia (PSD) to improve long-term quality of life for stroke survivors. Hippocampal volume may be an important neuroimaging biomarker in poststroke dementia, as it has been associated with many other forms of dementia. However, studying hippocampal volume using MRI requires hippocampal segmentation. Advances in automated segmentation methods have allowed for studying the hippocampus on a large scale, which is important for robust results in the heterogeneous stroke population. However, most of these automated methods use a single atlas-based approach and may fail in the presence of severe structural abnormalities common in stroke. Hippodeep, a new convolutional neural network-based hippocampal segmentation method, does not rely solely on a single atlas-based approach and thus may be better suited for stroke populations. Here, we compared quality control and the accuracy of segmentations generated by Hippodeep and two well-accepted hippocampal segmentation methods on stroke MRIs (FreeSurfer 6.0 whole hippocampus and FreeSurfer 6.0 sum of hippocampal subfields). Quality control was performed using a stringent protocol for visual inspection of the segmentations, and accuracy was measured as volumetric correlation with manual segmentations. Hippodeep performed significantly better than both FreeSurfer methods in terms of quality control. All three automated segmentation methods had good correlation with manual segmentations and no one method was significantly more correlated than the others. Overall, this study suggests that both Hippodeep and FreeSurfer may be useful for hippocampal segmentation in stroke rehabilitation research, but Hippodeep may be more robust to stroke lesion anatomy., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Introduction: Repetitive peripheral sensory stimulation (RPSS) followed by 4-hour task-specific training (TST) improves upper limb motor function in subjects with stroke who experience moderate to severe motor upper limb impairments. Here, we compared effects of RPSS vs sham followed by a shorter duration of training in subjects with moderate to severe motor impairments in the chronic phase after stroke., Methods: This single-center, randomized, placebo-controlled, parallel-group clinical trial compared effects of 18 sessions of either 1.5 h of active RPSS or sham followed by a supervised session that included 45 min of TST of the paretic upper limb. In both groups, subjects were instructed to perform functional tasks at home, without supervision. The primary outcome measure was the Wolf Motor Function Test (WMFT) after 6 weeks of treatment. Grasp and pinch strength were secondary outcomes., Results: In intention-to-treat analysis, WMFT improved significantly in both active and sham groups at 3 and 6 weeks of treatment. Grasp strength improved significantly in the active, but not in the sham group, at 3 and 6 weeks. Pinch strength improved significantly in both groups at 3 weeks, and only in the active group at 6 weeks., Conclusions: The between-group difference in changes in WMFT was not statistically significant. Despite the short duration of supervised treatment, WMFT improved significantly in subjects treated with RPSS or sham. These findings are relevant to settings that impose constraints in duration of direct contact between therapists and patients. In addition, RPSS led to significant gains in hand strength.Trial Registry Name: Peripheral Nerve Stimulation and Motor Training in Stroke Clinical Trials.gov identifier: NCT0265878 https://clinicaltrials.gov/ct2/show/NCT02658578.

Importance: Virtual reality in head-mounted displays (HMD-VR) may be a valuable tool in occupational therapy to address anxiety. Findings from the virtual reality exposure therapy (VRET) literature may facilitate translation of HMD-VR to occupational therapy psychosocial practice., Objective: To explore how HMD-VR has been used to treat anxiety through VRET and could be translated to occupational therapy., Data Sources: We searched seven electronic databases for articles published between 2000 and 2020: CINAHL, Cochrane Library, Embase, ERIC, Ovid MEDLINE, PsycINFO, and Web of Science. Search terms included HMD-VR constructs, products, and therapy concepts. Study Selection and Data Collection: We used Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to report studies implementing VRET to treat anxiety. At least two reviewers assessed each citation, and a third resolved disagreements. Articles were included if they were in English, reported experimental data, and used HMD-VR. Letters, commentaries, book chapters, technical descriptions, theoretical papers, conference proceedings (≤4 pages), and reviews were excluded., Findings: Twenty-eight studies used HMD-VR to treat posttraumatic stress disorder (n = 3), specific phobias (n = 19), and performance-based social anxiety (n = 6); protocols and levels of evidence varied (randomized controlled trials, n = 11; controlled trials without randomization, n = 6; case-control or cohort studies, n = 11). Qualitative examination indicates HMD-VR is an effective treatment tool., Conclusions and Relevance: HMD-VR can be a valuable tool for occupational therapy to simulate environments where clients with anxiety disorders participate. Eliciting presence through multisensory features and body representation may enhance outcomes. What This Article Adds: Drawing from the VRET literature, this scoping review suggests that HMD-VR can be used by occupational therapy practitioners to simulate ecologically valid environments, evaluate client responses to fearful stimuli, and remediate anxiety though immersion in virtual tasks when participation in natural contexts is unfeasible. Having ecologically valid environments is particularly important for people with anxiety disorders because they need support to cope when they encounter triggers in everyday life environments., (Copyright © 2021 by the American Occupational Therapy Association, Inc.)

Up to two-thirds of stroke survivors experience persistent sensorimotor impairments. Recovery relies on the integrity of spared brain areas to compensate for damaged tissue. Deep grey matter structures play a critical role in the control and regulation of sensorimotor circuits. The goal of this work is to identify associations between volumes of spared subcortical nuclei and sensorimotor behaviour at different timepoints after stroke. We pooled high-resolution T 1 -weighted MRI brain scans and behavioural data in 828 individuals with unilateral stroke from 28 cohorts worldwide. Cross-sectional analyses using linear mixed-effects models related post-stroke sensorimotor behaviour to non-lesioned subcortical volumes (Bonferroni-corrected, P  < 0.004). We tested subacute (≤90 days) and chronic (≥180 days) stroke subgroups separately, with exploratory analyses in early stroke (≤21 days) and across all time. Sub-analyses in chronic stroke were also performed based on class of sensorimotor deficits (impairment, activity limitations) and side of lesioned hemisphere. Worse sensorimotor behaviour was associated with a smaller ipsilesional thalamic volume in both early ( n  = 179; d  =   0.68) and subacute ( n  = 274, d  =   0.46) stroke. In chronic stroke ( n  = 404), worse sensorimotor behaviour was associated with smaller ipsilesional putamen ( d  =   0.52) and nucleus accumbens ( d  =   0.39) volumes, and a larger ipsilesional lateral ventricle ( d  =   -0.42). Worse chronic sensorimotor impairment specifically (measured by the Fugl-Meyer Assessment; n  = 256) was associated with smaller ipsilesional putamen ( d  =   0.72) and larger lateral ventricle ( d  = -0.41) volumes, while several measures of activity limitations ( n  = 116) showed no significant relationships. In the full cohort across all time ( n  = 828), sensorimotor behaviour was associated with the volumes of the ipsilesional nucleus accumbens ( d  =   0.23), putamen ( d  =   0.33), thalamus ( d  =   0.33) and lateral ventricle ( d  = -0.23). We demonstrate significant relationships between post-stroke sensorimotor behaviour and reduced volumes of deep grey matter structures that were spared by stroke, which differ by time and class of sensorimotor measure. These findings provide additional insight into how different cortico-thalamo-striatal circuits support post-stroke sensorimotor outcomes., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Combination therapy emerges as a fundamental scheme in cancer. Many targeted therapeutic agents are developed to be used with chemotherapy or radiation therapy to enhance drug efficacy and reduce toxicity effects. ABT-263, known as navitoclax, mimics the BH3-only proteins of the BCL-2 family and has a high affinity towards pro-survival BCL-2 family proteins (i.e., BCL-XL, BCL-2, BCL-W) to induce cell apoptosis effectively. A single navitoclax action potently ameliorates several tumor progressions, including blood and bone marrow cancer, as well as small cell lung carcinoma. Not only that, but navitoclax alone also therapeutically affects fibrotic disease. Nevertheless, outcomes from the clinical trial of a single navitoclax agent in patients with advanced and relapsed small cell lung cancer demonstrated a limited anti-cancer activity. This brings accumulating evidence of navitoclax to be used concomitantly with other chemotherapeutic agents in several solid and non-solid tumors that are therapeutically benefiting from navitoclax treatment in preclinical studies. Initially, we justify the anti-cancer role of navitoclax in combination therapy. Then, we evaluate the current evidence of navitoclax in combination with the chemotherapeutic agents comprehensively to indicate the primary regulator of this combination strategy in order to produce a therapeutic effect.

Real-time fMRI neurofeedback is an increasingly popular neuroimaging technique that allows an individual to gain control over his/her own brain signals, which can lead to improvements in behavior in healthy participants as well as to improvements of clinical symptoms in patient populations. However, a considerably large ratio of participants undergoing neurofeedback training do not learn to control their own brain signals and, consequently, do not benefit from neurofeedback interventions, which limits clinical efficacy of neurofeedback interventions. As neurofeedback success varies between studies and participants, it is important to identify factors that might influence neurofeedback success. Here, for the first time, we employed a big data machine learning approach to investigate the influence of 20 different design-specific (e.g. activity vs. connectivity feedback), region of interest-specific (e.g. cortical vs. subcortical) and subject-specific factors (e.g. age) on neurofeedback performance and improvement in 608 participants from 28 independent experiments. With a classification accuracy of 60% (considerably different from chance level), we identified two factors that significantly influenced neurofeedback performance: Both the inclusion of a pre-training no-feedback run before neurofeedback training and neurofeedback training of patients as compared to healthy participants were associated with better neurofeedback performance. The positive effect of pre-training no-feedback runs on neurofeedback performance might be due to the familiarization of participants with the neurofeedback setup and the mental imagery task before neurofeedback training runs. Better performance of patients as compared to healthy participants might be driven by higher motivation of patients, higher ranges for the regulation of dysfunctional brain signals, or a more extensive piloting of clinical experimental paradigms. Due to the large heterogeneity of our dataset, these findings likely generalize across neurofeedback studies, thus providing guidance for designing more efficient neurofeedback studies specifically for improving clinical neurofeedback-based interventions. To facilitate the development of data-driven recommendations for specific design details and subpopulations the field would benefit from stronger engagement in open science research practices and data sharing., Competing Interests: Declaration of Competing Interest SHK receives payment from Mendi Innovations AB, Stockholm, Sweden., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The right hemisphere is involved with the integrative processes necessary to achieve global coherence during reasoning and discourse processing. Specifically, the right temporal lobe has been proven to facilitate the processing of distant associate relationships, such as generating novel ideas. Previous studies showed a specific swing of alpha and gamma oscillatory activity over the right parieto-occipital lobe and the right anterior temporal lobe respectively, when people solve semantic problems with a specific strategy, i.e., insight problem-solving. In this study, we investigated the specificity of the right parietal and temporal lobes for semantic integration using transcranial Random Noise Stimulation (tRNS). We administered a set of pure semantics (i.e., Compound Remote Associates [CRA]) and visuo-semantic problems (i.e., Rebus Puzzles) to a sample of 31 healthy volunteers. Behavioral results showed that tRNS stimulation over the right temporal lobe enhances CRA accuracy (+12%), while stimulation on the right parietal lobe causes a decrease of response time on the same task (-2,100 ms). No effects were detected for Rebus Puzzles. Our findings corroborate the involvement of the right temporal and parietal lobes when solving purely semantic problems but not when they involve visuo-semantic material, also providing causal evidence for their postulated different roles in the semantic integration process and promoting tRNS as a candidate tool to boost verbal reasoning in humans., (© 2021. The Psychonomic Society, Inc.)

Everyday decision-making is supported by a dual-system of control comprised of parallel goal-directed and habitual systems. Over the past decade, the two-stage Markov decision task has become popularized for its ability to dissociate between goal-directed and habitual decision-making. While a handful of studies have implemented decision-making tasks online, only one study has validated the task by comparing in-person and web-based performance on the two-stage task in children and young adults. To date, no study has validated the dissociation of goal-directed and habitual behaviors in older adults online. Here, we implemented and validated a web-based version of the two-stage Markov task using parameter simulation and recovery and compared behavioral results from online and in-person participation on the two-stage task in both young and healthy older adults. We found no differences in estimated free parameters between online and in-person participation on the two-stage task. Further, we replicate previous findings that young adults are more goal-directed than older adults both in-person and online. Overall, this work demonstrates that the implementation and use of the two-stage Markov decision task for remote participation is feasible in the older adult demographic, which would allow for the study of decision-making with larger and more diverse samples., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ito, Cao, Reinberg, Keller, Monterosso, Schweighofer and Liew.)

Hypokalaemic periodic paralysis secondary to subclinical hyperthyroidism is an uncommon clinical phenomenon characterised by lower limb paralysis secondary to hypokalaemia in the background of subclinical hyperthyroidism. In this article, we report a patient who presented with progressive lower limb muscle weakness secondary to hypokalaemia that was refractory to potassium replacement therapy. He has no diarrhoea, no reduced appetite and was not taking any medication that can cause potassium wasting. Although he was clinically euthyroid, his thyroid function test revealed subclinical hyperthyroidism. His 24-hour urine potassium level was normal, which makes a rapid transcellular shift of potassium secondary to subclinical hyperthyroidism as the possible cause. He was successfully treated with potassium supplements, non-selective beta-blockers and anti-thyroid medication. This case report aimed to share an uncommon case of hypokalaemic periodic paralysis secondary to subclinical hyperthyroidism, which to our knowledge, only a few has been reported in the literature., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Stroke is a leading cause of long-term disability in the United States. Recent studies have shown that high doses of repeated task-specific practice can be effective at improving upper-limb function at the chronic stage. Providing at-home telerehabilitation services with therapist supervision may allow higher dose interventions targeted to this population. Additionally, muscle biofeedback to train patients to avoid unwanted simultaneous activation of antagonist muscles (co-contractions) may be incorporated into telerehabilitation technologies to improve motor control. Here, we present the development and feasibility of a low-cost, portable, telerehabilitation biofeedback system called Tele-REINVENT. We describe our modular electromyography acquisition, processing, and feedback algorithms to train differentiated muscle control during at-home therapist-guided sessions. Additionally, we evaluated the performance of low-cost sensors for our training task with two healthy individuals. Finally, we present the results of a case study with a stroke survivor who used the system for 40 sessions over 10 weeks of training. In line with our previous research, our results suggest that using low-cost sensors provides similar results to those using research-grade sensors for low forces during an isometric task. Our preliminary case study data with one patient with stroke also suggest that our system is feasible, safe, and enjoyable to use during 10 weeks of biofeedback training, and that improvements in differentiated muscle activity during volitional movement attempt may be induced during a 10-week period. Our data provide support for using low-cost technology for individuated muscle training to reduce unintended coactivation during supervised and unsupervised home-based telerehabilitation for clinical populations, and suggest this approach is safe and feasible. Future work with larger study populations may expand on the development of meaningful and personalized chronic stroke rehabilitation.

B-cell lymphoma 2 (BCL-2) family proteins primarily work as a programmed cell death regulator, whereby multiple interactions between them determine cell survival. This explains the two major classes of BCL-2 proteins which are anti-apoptotic and pro-apoptotic proteins. The anti-apoptotic proteins are attractive targets for BCL-2 family inhibitors, which result in the augmentation of the intrinsic apoptotic pathway. BCL-2 family inhibitors have been studied extensively for novel targeted therapies in various cancer types, fibrotic diseases, aging-related as well as autoimmune diseases. Navitoclax is one of them and it has been discovered to have a high affinity toward BCL-2 anti-apoptotic proteins, including BCL-2, BCL-W and B-cell lymphoma-extra-large. Navitoclax has been demonstrated as a single agent or in combination with other drugs to successfully ameliorate tumor progression and fibrosis development. To date, navitoclax has entered phase I and phase II clinical studies. Navitoclax alone potently treats small cell lung cancer and acute lymphocytic leukemia, whilst in combination therapy for solid tumors, it enhances the therapeutic effect of other chemotherapeutic agents. A low platelet count has always associated with single navitoclax treatments, though this effect is tolerable. Moreover, the efficacy of navitoclax is determined by the expression of several BCL-2 family members. Here, we elucidate the complex mechanisms of navitoclax as a pro-apoptotic agent, and review the early and current clinical studies of navitoclax alone as well as with other drugs. Additionally, some suggestions on the development of navitoclax clinical studies are presented in the future prospects section., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Mohamad Anuar, Ugusman, Nor Hisam and Liew.)

Neurofeedback training has been shown to influence behavior in healthy participants as well as to alleviate clinical symptoms in neurological, psychosomatic, and psychiatric patient populations. However, many real-time fMRI neurofeedback studies report large inter-individual differences in learning success. The factors that cause this vast variability between participants remain unknown and their identification could enhance treatment success. Thus, here we employed a meta-analytic approach including data from 24 different neurofeedback studies with a total of 401 participants, including 140 patients, to determine whether levels of activity in target brain regions during pretraining functional localizer or no-feedback runs (i.e., self-regulation in the absence of neurofeedback) could predict neurofeedback learning success. We observed a slightly positive correlation between pretraining activity levels during a functional localizer run and neurofeedback learning success, but we were not able to identify common brain-based success predictors across our diverse cohort of studies. Therefore, advances need to be made in finding robust models and measures of general neurofeedback learning, and in increasing the current study database to allow for investigating further factors that might influence neurofeedback learning., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Importance: Head-mounted displays for virtual reality (HMD-VR) may be used as a therapeutic medium in physical rehabilitation because of their ability to immerse patients in safe, controlled, and engaging virtual worlds., Objective: To explore how HMD-VR has been used in adult physical rehabilitation., Data Sources: A systematic search of MEDLINE, Embase, Cochrane Library, CINAHL, Web of Science, PsycINFO, and ERIC produced 11,453 abstracts, of which 777 underwent full-text review., Study Selection and Data Collection: This scoping review includes 21 experimental studies that reported an assessment or intervention using HMD-VR in a physical rehabilitation context and within the scope of occupational therapy practice., Findings: HMD-VR was used for assessment and intervention for patients with a range of disorders, including stroke, multiple sclerosis, spinal cord injury, and Parkinson's disease., Conclusions and Relevance: HMD-VR is an emerging technology with many uses in adult physical rehabilitation. Higher quality clinical implementation studies are needed to examine effects on patient outcomes., What This Article Adds: We review existing research on how immersive virtual reality (e.g., using head-mounted displays) has been used for different clinical populations in adult physical rehabilitation and highlight emerging opportunities in this field for occupational therapists., (Copyright © 2020 by the American Occupational Therapy Association, Inc.)

Severe impairment of limb movement after stroke can be challenging to address in the chronic stage of stroke (e.g., greater than 6 months post stroke). Recent evidence suggests that physical therapy can still promote meaningful recovery after this stage, but the required high amount of therapy is difficult to deliver within the scope of standard clinical practice. Digital gaming technologies are now being combined with brain-computer interfaces to motivate engaging and frequent exercise and promote neural recovery. However, the complexity and expense of acquiring brain signals has held back widespread utilization of these rehabilitation systems. Furthermore, for people that have residual muscle activity, electromyography (EMG) might be a simpler and equally effective alternative. In this pilot study, we evaluate the feasibility and efficacy of an EMG-based variant of our REINVENT virtual reality (VR) neurofeedback rehabilitation system to increase volitional muscle activity while reducing unintended co-contractions. We recruited four participants in the chronic stage of stroke recovery, all with severely restricted active wrist movement. They completed seven 1-hour training sessions during which our head-mounted VR system reinforced activation of the wrist extensor muscles without flexor activation. Before and after training, participants underwent a battery of clinical and neuromuscular assessments. We found that training improved scores on standardized clinical assessments, equivalent to those previously reported for brain-computer interfaces. Additionally, training may have induced changes in corticospinal communication, as indexed by an increase in 12-30 Hz corticomuscular coherence and by an improved ability to maintain a constant level of wrist muscle activity. Our data support the feasibility of using muscle-computer interfaces in severe chronic stroke, as well as their potential to promote functional recovery and trigger neural plasticity.

Background: Virtual reality viewed using a head-mounted display (HMD-VR) has the potential to be a useful tool for motor learning and rehabilitation. However, when developing tools for these purposes, it is important to design applications that will effectively transfer to the real world. Therefore, it is essential to understand whether motor skills transfer between HMD-VR and conventional screen-based environments and what factors predict transfer., Methods: We randomized 70 healthy participants into two groups. Both groups trained on a well-established measure of motor skill acquisition, the Sequential Visual Isometric Pinch Task (SVIPT), either in HMD-VR or in a conventional environment (i.e., computer screen). We then tested whether the motor skills transferred from HMD-VR to the computer screen, and vice versa. After the completion of the experiment, participants responded to questions relating to their presence in their respective training environment, age, gender, video game use, and previous HMD-VR experience. Using multivariate and univariate linear regression, we then examined whether any personal factors from the questionnaires predicted individual differences in motor skill transfer between environments., Results: Our results suggest that motor skill acquisition of this task occurs at the same rate in both HMD-VR and conventional screen environments. However, the motor skills acquired in HMD-VR did not transfer to the screen environment. While this decrease in motor skill performance when moving to the screen environment was not significantly predicted by self-reported factors, there were trends for correlations with presence and previous HMD-VR experience. Conversely, motor skills acquired in a conventional screen environment not only transferred but improved in HMD-VR, and this increase in motor skill performance could be predicted by self-reported factors of presence, gender, age and video game use., Conclusions: These findings suggest that personal factors may predict who is likely to have better transfer of motor skill to and from HMD-VR. Future work should examine whether these and other predictors (i.e., additional personal factors such as immersive tendencies and task-specific factors such as fidelity or feedback) also apply to motor skill transfer from HMD-VR to more dynamic physical environments.

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.

Electroencephalography (EEG)-based brain-computer interfaces (BCIs) for motor rehabilitation aim to "close the loop" between attempted motor commands and sensory feedback by providing supplemental information when individuals successfully achieve specific brain patterns. Existing EEG-based BCIs use various displays to provide feedback, ranging from displays considered more immersive (e.g., head-mounted display virtual reality (HMD-VR)) to displays considered less immersive (e.g., computer screens). However, it is not clear whether more immersive displays improve neurofeedback performance and whether there are individual performance differences in HMD-VR versus screen-based neurofeedback. In this pilot study, we compared neurofeedback performance in HMD-VR versus a computer screen in 12 healthy individuals and examined whether individual differences on two measures (i.e., presence, embodiment) were related to neurofeedback performance in either environment. We found that, while participants' performance on the BCI was similar between display conditions, the participants' reported levels of embodiment were significantly different. Specifically, participants experienced higher levels of embodiment in HMD-VR compared to a computer screen. We further found that reported levels of embodiment positively correlated with neurofeedback performance only in HMD-VR. Overall, these preliminary results suggest that embodiment may relate to better performance on EEG-based BCIs and that HMD-VR may increase embodiment compared to computer screens.

The effectiveness of transcranial direct current stimulation (tDCS) placed over the motor hotspot (thought to represent the primary motor cortex (M1)) to modulate motor network excitability is highly variable. The premotor cortex-particularly the dorsal premotor cortex (PMd)-may be a promising alternative target to reliably modulate motor excitability, as it influences motor control across multiple pathways, one independent of M1 and one with direct connections to M1. This double-blind, placebo-controlled preliminary study aimed to differentially excite motor and premotor regions using high-definition tDCS (HD-tDCS) with concurrent functional magnetic resonance imaging (fMRI). HD-tDCS applied over either the motor hotspot or the premotor cortex demonstrated high inter-individual variability in changes on cortical motor excitability. However, HD-tDCS over the premotor cortex led to a higher number of responders and greater changes in local fMRI-based complexity than HD-tDCS over the motor hotspot. Furthermore, an analysis of individual motor hotspot anatomical locations revealed that, in more than half of the participants, the motor hotspot is not located over anatomical M1 boundaries, despite using a canonical definition of the motor hotspot. This heterogeneity in stimulation site may contribute to the variability of tDCS results. Altogether, these preliminary findings provide new considerations to enhance tDCS reliability.

Accurate stroke lesion segmentation is a critical step in the neuroimaging processing pipeline for assessing the relationship between poststroke brain structure, function, and behavior. Many multimodal segmentation algorithms have been developed for acute stroke neuroimaging, yet few algorithms are effective with only a single T1-weighted (T1w) anatomical MRI. This is a critical gap because multimodal MRI is not commonly available due to time and cost constraints in the stroke rehabilitation setting. Although several attempts to automate the segmentation of chronic lesions on single-channel T1w MRI have been made, these approaches have not been systematically evaluated on a large dataset. We performed an exhaustive review of the literature and identified one semiautomated and three fully automated approaches for segmentation of chronic stroke lesions using T1w MRI within the last 10 years: Clusterize, automated lesion identification (ALI), Gaussian naïve Bayes lesion detection (lesionGnb), and lesion identification with neighborhood data analysis (LINDA). We evaluated each method on a large T1w stroke dataset (N = 181). LINDA was the most computationally expensive approach, but performed best across the three main evaluation metrics (median values: dice coefficient = 0.50, Hausdorff's distance = 36.34 mm, and average symmetric surface distance = 4.97 mm). lesionGnb had the highest recall/least false negatives (median = 0.80). However, across the automated methods, many lesions were either misclassified (ALI: 28, lesionGnb: 39, LINDA: 45) or not identified (ALI: 24, LINDA: 23, lesionGnb: 0). Segmentation accuracy in all automated methods were influenced by size (small: worst) and stroke territory (brainstem, cerebellum: worst) of the lesion. To facilitate reproducible science, our analysis files have been made publicly available online., (© 2019 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)