Search

Abstract Background Previous studies showed that anodal transcranial DC stimulation (tDCS) applied to the primary motor cortex of the affected hemisphere (M1affected hemisphere) after subcortical stroke transiently improves performance of complex tasks that mimic activities of daily living (ADL). It is not known if relatively simpler motor tasks are similarly affected. Here we tested the effects of tDCS on pinch force (PF) and simple reaction time (RT) tasks in patients with chronic stroke in a double-blind cross-over Sham-controlled experimental design. Results Anodal tDCS shortened reaction times and improved pinch force in the paretic hand relative to Sham stimulation, an effect present in patients with higher impairment. Conclusion tDCS of M1affected hemisphere can modulate performance of motor tasks simpler than those previously studied, a finding that could potentially benefit patients with relatively higher impairment levels.

The clinical success of brain computer interfaces depends on overcoming both biological and material challenges to ensure a long-term stable connection for neural recording and stimulation. This study systematically quantified damage that microelectrodes sustained during chronical implantation in three people with tetraplegia for 956-2246 days. Using scanning electron microscopy (SEM), we imaged 980 microelectrodes from eleven Neuroport arrays tipped with platinum (Pt, n=8) and sputtered iridium oxide film (SIROF, n=3). Arrays were implanted/explanted from posterior parietal, motor and somatosensory cortices across three clinical sites (Caltech/UCLA, Caltech/USC, APL/Johns Hopkins). From the electron micrographs, we quantified and correlated physical damage with functional outcomes measured in vivo, prior to explant (recording quality, noise, impedance and stimulation ability). Despite greater physical degradation, SIROF electrodes were twice as likely to record neural activity than Pt (measured by SNR). For SIROF, 1 kHz impedance significantly correlated with all physical damage metrics, recording, and stimulation performance, suggesting a reliable measurement of in vivo degradation. We observed a new degradation type, primarily on stimulated electrodes ("pockmarked" vs "cracked") electrodes; however, no significant degradation due to stimulation or amount of charge. We hypothesize erosion of the silicon shank accelerates damage to the electrode / tissue interface, following damage to the tip metal. These findings link quantitative measurements to the microelectrodes' physical condition and their capacity to record/stimulate. These data could lead to improved manufacturing or novel electrode designs to improve long-term performance of BCIs making them are vitally important as multi-year clinical trials of BCIs are becoming more common. STATEMENT OF SIGNIFICANCE: Long-term performance stability of the electrode-tissue interface is essential for clinical viability of Brain Computer Interface (BCI) devices; currently, materials degradation is a critical component for performance loss. Across three human participants, ten micro-electrode arrays (plus one control) were implanted for 956-2246 days. Using scanning electron microscopy (SEM), we analyzed degradation of 980 electrodes, comparing two types of commonly implanted electrode tip metals: Platinum (Pt) and Sputtered Iridium Oxide Film (SIROF). We correlated observed degradation with in vivo electrode performance: recording (signal-to-noise ratio, noise, impedance) and stimulation (evoked somatosensory percepts). We hypothesize penetration of the electrode tip by biotic processes leads to erosion of the supporting silicon core, which then accelerates further tip metal damage. These data could lead to improved manufacturing processes or novel electrode designs towards the goal of a stable BCI electrical interface, spanning a multi-decade participant lifetime., Competing Interests: Declaration of Interest Statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Richard Andersen reports financial support was provided by National Institutes of Health. Richard Andersen reports financial support was provided by Defense Advanced Research Projects Agency. Richard Andersen reports financial support was provided by Tianqiao and Chrissy Chen Brain-machine Interface Center. Richard Andersen reports a relationship with Blackrock Neurotech that includes: funding grants unrelated to this project. Francesco Tenore reports financial support was provided by Defense Advanced Research Projects Agency. David Bjanes reports financial support was provided by Craig H Neilsen Foundation. Richard Andersen reports financial support was provided by James G Boswell Foundation. Loren Rieth reports financial support was provided by Defense Advanced Research Projects Agency. Loren Rieth reports financial support was provided by National Institutes of Health. Nader Pouratian reports a relationship with Boston Scientific and Abbott Laboratories that includes: consulting or advisory. Spencer Kellis reports a relationship with Blackrock Neurotech that includes: employment. Loren Rieth reports a relationship with Blackrock Neurotech that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier Inc.)

A decline in upper limb strength is common with normal aging. However, whether age-related strength decline is paralleled by reduced excitability of descending motor pathways is unclear. The reticulospinal tract is a key subcortical pathway involved in gross motor output and exhibits increased excitability following resistance training. Here, we sought to determine age-related effects on strength and reticulospinal excitability in flexors and extensors of the upper limb in humans. In 15 younger and 14 older adults, we quantified upper limb strength using dynamometry, and reticulospinal excitability by using transcranial magnetic stimulation to elicit ipsilateral motor evoked potentials. We observed a decline in flexion, but not extension strength, in older compared with younger adults. This behavioral pattern was paralleled by an age-related reduction in ipsilateral motor evoked potential presence specific to flexor muscles. Our findings indicate that reduced excitability of the reticulospinal tract, which exhibits strong innervation of flexor muscles, may be a key contributor to upper limb strength decline commonly observed in older adults., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: In humans, most spontaneous recovery from motor impairment after stroke occurs in the first 3 months. Studies in animal models show higher responsiveness to training over a similar time-period. Both phenomena are often attributed to a milieu of heightened plasticity, which may share some mechanistic overlap with plasticity associated with normal motor learning., Objective: Given that neurorehabilitation approaches are frequently predicated on motor learning principles, here we asked if the sensitivity of trial-to-trial learning for 2 kinds of motor learning processes often involved during rehabilitation is also enhanced early post-stroke. In a cross-sectional design, we compared (1) reinforcement and (2) error-based learning in 2 groups: 1 tested within 3 months after stroke (early group, N  = 35) another tested more than 6 months after stroke (late group, N  = 30). These 2 forms of motor learning were assessed with variations of the same visuomotor rotation task. Critically, motor execution was matched between the 2 groups., Results: Reinforcement learning was impaired in the early but not the late group, whereas error-based learning was unimpaired in either group. These findings could not be attributed to differences in baseline execution, cognitive impairment, gender, age, or lesion volume and location., Discussion: The presence of a deficit in reinforcement motor learning in the first 3 months after stroke has important implications for rehabilitation., Conclusion: It might be necessary to either increase reinforcement feedback given early after stroke, increase the dose of rehabilitation to compensate, or delay onset of rehabilitation approaches that may rely on reinforcement, for example, constraint-induced movement therapy, and instead emphasize other forms of motor training in the subacute time period., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: After severe corticospinal tract damage poststroke in humans, some recovery of strength and movement proximally is evident. It is possible that alternate motor pathways, such as the reticulospinal tract, may be upregulated to compensate for the loss of corticospinal tract input. We investigated the extent of reticulospinal tract excitability modulation and its inter-dependence on the severity of corticospinal tract damage after stroke in humans., Methods: We used a novel startle conditioned transcranial magnetic stimulation paradigm to elicit ipsilateral motor evoked potentials, an index of reticulospinal tract excitability, in 22 chronic stroke participants with mild to severe corticospinal tract damage and 14 neurotypical age-matched controls., Results: We found that ipsilateral motor evoked potential presence was higher in the paretic arm of people with severe corticospinal tract damage compared to their non-paretic arm, people with mild corticospinal tract damage, and age-matched controls. Interestingly, ipsilateral motor evoked potential presence was correlated with motor impairment across the entire stroke cohort, whereby individuals with worse impairment exhibited more frequent ipsilateral motor evoked potentials (ie, higher reticulospinal tract excitability)., Interpretation: Following severe corticospinal tract damage, upregulated reticulospinal tract activity may compensate for a loss of corticospinal tract input, providing some proximal recovery of isolated and within-synergy movements, but deficits in performing out of synergy movements and finger fractionation remain. Interventions aimed at modulating the reticulospinal tract could be beneficial or detrimental to ameliorating motor impairment depending on the degree of reliance on this pathway for residual motor output. ANN NEUROL 2024., (© 2024 American Neurological Association.)

This study asked if combining different motor learning mechanisms-adaptation and reinforcement-could produce immediate improvements in over ground walking after stroke. Fifteen adults with stroke engaged in three conditions: (1) reinforcement following adaptation, (2) reinforcement alone, and (3) adaptation alone. Adaptation involved split-belt treadmill walking to produce after-effects that reduce step asymmetry. Reinforcement involved the use of real-time auditory feedback about step length asymmetry. Auditory feedback was binary, signaling whether steps were asymmetric or equal, but not whether to shorten or lengthen either step. Change in step length asymmetry was the outcome assessed during over ground walking. Reinforcement following adaptation led to reductions in step length asymmetry that persisted into an immediate retention period. Importantly, it led to the desired pattern of lengthening the shorter step in a majority of participants. Reinforcement alone led to no significant change in step length asymmetry, and sometimes produced a non-optimal pattern of shortening the longer step. Our control condition of adaptation alone led to more transient reductions in step length asymmetry. These findings reveal the potential for utilizing serial delivery of adaptation and reinforcement to influence a complex movement in the real-world context of over ground walking, in people with stroke., (© 2024. The Author(s).)

Motivation: The clinical success of brain-machine interfaces depends on overcoming both biological and material challenges to ensure a long-term stable connection for neural recording and stimulation. Therefore, there is a need to quantify any damage that microelectrodes sustain when they are chronically implanted in the human cortex., Methods: Using scanning electron microscopy (SEM), we imaged 980 microelectrodes from Neuroport arrays chronically implanted in the cortex of three people with tetraplegia for 956-2246 days. We analyzed eleven multi-electrode arrays in total: eight arrays with platinum (Pt) electrode tips and three with sputtered iridium oxide tips (SIROF); one Pt array was left in sterile packaging, serving as a control. The arrays were implanted/explanted across three different clinical sites surgeries (Caltech/UCLA, Caltech/USC and APL/Johns Hopkins) in the anterior intraparietal area, Brodmann's area 5, motor cortex, and somatosensory cortex.Human experts rated the electron micrographs of electrodes with respect to five damage metrics: the loss of metal at the electrode tip, the amount of separation between the silicon shank and tip metal, tissue adherence or bio-material to the electrode, damage to the shank insulation and silicone shaft. These metrics were compared to functional outcomes (recording quality, noise, impedance and stimulation ability)., Results: Despite higher levels of physical degradation, SIROF electrodes were twice as likely to record neural activity than Pt electrodes (measured by SNR), at the time of explant. Additionally, 1 kHz impedance (measured in vivo prior to explant) significantly correlated with all physical damage metrics, recording, and stimulation performance for SIROF electrodes (but not Pt), suggesting a reliable measurement of in vivo degradation.We observed a new degradation type, primarily occurring on stimulated electrodes ("pockmarked" vs "cracked") electrodes; however, tip metalization damage was not significantly higher due to stimulation or amount of charge. Physical damage was centralized to specific regions of an array often with differences between outer and inner electrodes. This is consistent with degradation due to contact with the biologic milieu, influenced by variations in initial manufactured state. From our data, we hypothesize that erosion of the silicon shank often precedes damage to the tip metal, accelerating damage to the electrode / tissue interface., Conclusions: These findings link quantitative measurements, such as impedance, to the physical condition of the microelectrodes and their capacity to record and stimulate. These data could lead to improved manufacturing or novel electrode designs to improve long-term performance of BMIs making them are vitally important as multi-year clinical trials of BMIs are becoming more common., Competing Interests: Conflicts of Interest NP is a consultant for Boston Scientific and Abbott Laboratories. SK is currently an employee of Blackrock NeuroTech; however, his contribution to this manuscript was in his capacity at the University of Southern California. LR has received grant funding from Blackrock Neurotech for other projects. All other authors have no conflict of interest.

Invasive brain-machine interfaces can help restore function through the control of external devices while the addition of intracortical microstimulation (ICMS) can elicit sensations of touch and help provide further benefits for individuals living with sensorimotor deficits. However, the extent of tactile information that can be conveyed through ICMS has not been fully explored. In a human participant with spinal cord injury and chronically implanted microelectrode arrays, we used ICMS to the somatosensory cortex to provide grip force feedback in the hands during grasping of objects with varying stiffness with a robotic arm. Using only ICMS-evoked touch sensations, the participant was able to identify between two and three objects with an accuracy of 92% and 67%, respectively. In a compliant grasping task with the goal of grasping a delicate object without crushing it, objects were deformed on average only 2.8 mm with ICMS-based touch feedback compared to 8.7 mm without. These results demonstrate that ICMS-evoked touch sensations to the hands can be used to provide force-based feedback for perceiving object properties and enable more precise grasping during closed-loop control of a robotic limb through a cortical interface.

As rehabilitation advances into the era of digital health, remote monitoring of physical activity via wearable devices has the potential to change how we provide care. However, uncertainties about patient adherence and the significant resource requirements needed create challenges to adoption of remote monitoring into clinical care. Here we aim to determine the impact of a novel digital application to overcome these barriers. The Rehabilitation Remote Monitoring Application (RRMA) automatically extracts data about physical activity collected via a Fitbit device, screens the data for adherence, and contacts the participant if adherence is low. We compare adherence and estimate the resources required (i.e., time and financial) to perform remote monitoring of physical activity with and without the RRMA in two patient groups. Seventy-three individuals with stroke or chronic obstructive pulmonary disease completed 28 days of monitoring physical activity with the RRMA, while 62 individuals completed 28 days with the data flow processes being completed manually. Adherence (i.e., the average percentage of the day that the device was worn) was similar between groups (p=0.85). However, the RRMA saved an estimated 123.8 minutes or $50.24 per participant month when compared to manual processes. These results demonstrate that automated technologies like the RRMA can maintain patient adherence to remote monitoring of physical activity while reducing the time and financial resources needed. Applications like the RRMA can facilitate the adoption of remote monitoring in rehabilitation by reducing barriers related to adherence and resource requirements., Competing Interests: Conflicting interests: The Authors declare that there is no conflict of interest.

The cerebellum has demonstrated a critical role during adaptation in motor learning. However, the extent to which it can contribute to the skill acquisition of complex real-world tasks remains unclear. One particularly challenging application in terms of motor activities is robotic surgery, which requires surgeons to complete complex multidimensional visuomotor tasks through a remotely operated robot. Given the need for high skill proficiency and the lack of haptic feedback, there is a pressing need for understanding and improving skill development. We investigated the effect of cerebellar transcranial direct current stimulation applied during the execution of a robotic surgery training task. Study participants received either real or sham stimulation while performing a needle driving task in a virtual (simulated) and a real-world (actual surgical robot) setting. We found that cerebellar stimulation significantly improved performance compared to sham stimulation at fast (more demanding) execution speeds in both virtual and real-world training settings. Furthermore, participants that received cerebellar stimulation more effectively transferred the skills they acquired during virtual training to the real world. Our findings underline the potential of non-invasive brain stimulation to enhance skill learning and transfer in real-world relevant tasks and, more broadly, its potential for improving complex motor learning., (© 2023. The Author(s).)

Subcortical motor pathways, such as the reticulospinal tract, are critical for producing and modulating voluntary movements and have been implicated in neurological conditions. Previous research has described the presence of ipsilateral motor evoked potentials (iMEPs) in the arm to transcranial magentic stimulation (TMS), and suggested they could be mediated by the uncrossed corticospinal tract or by ipsilateral cortico-reticulospinal connections. Here, we sought to elucidate the role of the reticulospinal tract in mediating iMEPs by assessing their modulation by a startling acoustic stimulus and mapping these responses across multiple upper limb effectors. In a first experiment, we delivered TMS at various intervals (1, 5, 10 and 15 ms) after a startling acoustic stimulus, known to excite the reticular formation, to elicit iMEPs in the arm. We observed robust facilitation of iMEP area when startle conditioning preceded TMS at the 10 ms interval. In a second experiment, we replicated our findings showing that both the area and number of iMEPs in the arm increases with startle conditioning. Using this technique, we observed that iMEPs are more prominent in the arm compared with the hand. In a third experiment, we also observed greater presence of iMEPs in flexor compared with extensor muscles. Together, these findings are consistent with properties of the reticulospinal tract observed in animals, suggesting that iMEPs primarily reflect reticulospinal activity. Our findings imply that we can use this approach to track modulation of cortico-reticulospinal excitability following interventions or neurological conditions where the reticulospinal tract may be involved in motor recovery., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest for this manuscript. This research was supported by the National Institutes of Health (R01HD053793)., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Fatigue is the subjective sensation of weariness, increased sense of effort, or exhaustion and is pervasive in neurologic illnesses. Despite its prevalence, we have a limited understanding of the neurophysiological mechanisms underlying fatigue. The cerebellum, known for its role in motor control and learning, is also involved in perceptual processes. However, the role of the cerebellum in fatigue remains largely unexplored. We performed two experiments to examine whether cerebellar excitability is affected after a fatiguing task and its association with fatigue. Using a crossover design, we assessed cerebellar inhibition (CBI) and perception of fatigue in humans before and after "fatigue" and "control" tasks. Thirty-three participants (16 males, 17 females) performed five isometric pinch trials with their thumb and index finger at 80% maximum voluntary capacity (MVC) until failure (force <40% MVC; fatigue) or at 5% MVC for 30 s (control). We found that reduced CBI after the fatigue task correlated with a milder perception of fatigue. In a follow-up experiment, we investigated the behavioral consequences of reduced CBI after fatigue. We measured CBI, perception of fatigue, and performance during a ballistic goal-directed task before and after the same fatigue and control tasks. We replicated the observation that reduced CBI after the fatigue task correlated with a milder perception of fatigue and found that greater endpoint variability after the fatigue task correlated with reduced CBI. The proportional relation between cerebellar excitability and fatigue indicates a role of the cerebellum in the perception of fatigue, which might come at the expense of motor control. SIGNIFICANCE STATEMENT Fatigue is one of the most common and debilitating symptoms in neurologic, neuropsychiatric, and chronic illnesses. Despite its epidemiological importance, there is a limited understanding of the neurophysiological mechanisms underlying fatigue. In a series of experiments, we demonstrate that decreased cerebellar excitability relates to lesser physical fatigue perception and worse motor control. These results showcase the role of the cerebellum in fatigue regulation and suggest that fatigue- and performance-related processes might compete for cerebellar resources., (Copyright © 2023 Casamento-Moran et al.)

Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article.

Abstract: Motor, speech, and cognitive impairments are the most common consequences of neurological disorders. There has been an increasing interest in the use of noninvasive brain stimulation techniques such as transcranial direct current stimulation and transcranial magnetic stimulation to augment the effects of neurorehabilitation. Numerous research studies have shown that transcranial direct current stimulation and transcranial magnetic stimulation are highly promising neuromodulation tools that can work as adjuvants to standard neurorehabilitation services, including physical therapy, occupational therapy, and speech-language pathology. However, to date, there are vast differences in methodology in studies including noninvasive brain stimulation parameters, patient characteristics, time point of intervention after injury, and outcome measures, making it difficult to translate and implement transcranial direct current stimulation and transcranial magnetic stimulation in the clinical setting. Despite this, a series of principles are thought to underlie the effectiveness of noninvasive brain stimulation techniques. We developed a noninvasive brain stimulation rehabilitation program using these principles to provide best practices for applying transcranial direct current stimulation and/or transcranial magnetic stimulation as rehabilitation adjuvants in the clinical setting to help improve neurorehabilitation outcomes. This article outlines our approach, philosophy, and experience., Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Environmental scans determine trends in an organization's or field's internal and external environment. The results can help shape goals, inform strategic decision making, and direct future actions. The Association of Academic Physiatrists convened a strategic planning group in 2020, composed of physiatrists representing a diversity of professional roles, career stages, race and ethnicity, gender, disability status, and geographic areas of practice. This strategic planning group performed an environmental scan to assess the forces, trends, challenges, and opportunities affecting both the Association of Academic Physiatrists and the entire field of academic physiatry (also known as physical medicine and rehabilitation, physical and rehabilitation medicine, and rehabilitation medicine). This article presents aspects of the environmental scan thought to be most pertinent to the field of academic physiatry organized within the following five themes: (1) Macro/Societal Trends, (2) Technological Advancements, (3) Diversity and Global Outreach, (4) Economy, and (5) Education/Learning Environment. The challenges and opportunities presented here can provide a roadmap for the field to thrive within the complex and evolving healthcare systems in the United States and globally., Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Neurorehabilitation approaches are frequently predicated on motor learning principles. However, much is left to be understood of how different kinds of motor learning are affected by stroke causing hemiparesis. Here we asked if two kinds of motor learning often employed in rehabilitation, (1) reinforcement learning and (2) error-based adaptation, are altered at different times after stroke., Methods: In a cross-sectional design, we compared learning in two groups of patients with stroke, matched for their baseline motor execution deficit on the paretic side. The early group was tested within 3 months following stroke (N = 35) and the late group was tested more than 6 months after stroke (N = 30). Two types of task were studied: one based on reinforcement learning and the other on error-based learning., Results: We found that reinforcement learning was impaired in the early but not the late group, whereas error-based learning was unaffected compared to controls. These findings could not be attributed to differences in baseline execution, cognitive impairment, gender, age, or lesion volume and location., Conclusions: The presence of a specific impairment in reinforcement learning in the first 3 months after stroke has important implications for rehabilitation. It might be necessary to either increase the amount of reinforcement feedback given early or even delay onset of certain forms of rehabilitation training, e.g., like constraint-induced movement therapy, and instead emphasize others forms of motor learning in this early time period. A deeper understanding of stroke-related changes in motor learning capacity has the potential to facilitate the development of new, more precise treatment interventions., Competing Interests: Potential conflict of interest None of the authors have a conflict of interest to declare.

The cerebellum is involved in multiple closed-loops circuitry which connect the cerebellar modules with the motor cortex, prefrontal, temporal, and parietal cortical areas, and contribute to motor control, cognitive processes, emotional processing, and behavior. Among them, the cerebello-thalamo-cortical pathway represents the anatomical substratum of cerebellum-motor cortex inhibition (CBI). However, the cerebellum is also connected with basal ganglia by disynaptic pathways, and cerebellar involvement in disorders commonly associated with basal ganglia dysfunction (e.g., Parkinson's disease and dystonia) has been suggested. Lately, cerebellar activity has been targeted by non-invasive brain stimulation (NIBS) techniques including transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) to indirectly affect and tune dysfunctional circuitry in the brain. Although the results are promising, several questions remain still unsolved. Here, a panel of experts from different specialties (neurophysiology, neurology, neurosurgery, neuropsychology) reviews the current results on cerebellar NIBS with the aim to derive the future steps and directions needed. We discuss the effects of TMS in the field of cerebellar neurophysiology, the potentials of cerebellar tDCS, the role of animal models in cerebellar NIBS applications, and the possible application of cerebellar NIBS in motor learning, stroke recovery, speech and language functions, neuropsychiatric and movement disorders., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Effective connectivity between the cerebellum and primary motor cortex (M1) is critical for motor learning and motor control. Despite evidence of cerebellar atrophy and declines in motor learning and motor control with advanced age, recent behavioral studies indicate that cerebellar-dependent motor learning processes are preserved or even enhanced in older adults. However, physiological evidence of heightened cerebellar excitability leading to strengthened cerebellar-M1 connectivity with advanced age is lacking. Here, we used transcranial magnetic stimulation to assess age-related effects on cerebellar inhibition, a measure of cerebellar-M1 connectivity, in 20 young and 19 older adults. We observed stronger cerebellar inhibition in older compared with young adults. The behavioral implications of strengthened cerebellar inhibition with advanced age found in this study remain to be determined., (Copyright © 2022. Published by Elsevier Inc.)

Advances in intelligent robotic systems and brain-machine interfaces (BMI) have helped restore functionality and independence to individuals living with sensorimotor deficits; however, tasks requiring bimanual coordination and fine manipulation continue to remain unsolved given the technical complexity of controlling multiple degrees of freedom (DOF) across multiple limbs in a coordinated way through a user input. To address this challenge, we implemented a collaborative shared control strategy to manipulate and coordinate two Modular Prosthetic Limbs (MPL) for performing a bimanual self-feeding task. A human participant with microelectrode arrays in sensorimotor brain regions provided commands to both MPLs to perform the self-feeding task, which included bimanual cutting. Motor commands were decoded from bilateral neural signals to control up to two DOFs on each MPL at a time. The shared control strategy enabled the participant to map his four-DOF control inputs, two per hand, to as many as 12 DOFs for specifying robot end effector position and orientation. Using neurally-driven shared control, the participant successfully and simultaneously controlled movements of both robotic limbs to cut and eat food in a complex bimanual self-feeding task. This demonstration of bimanual robotic system control via a BMI in collaboration with intelligent robot behavior has major implications for restoring complex movement behaviors for those living with sensorimotor deficits., Competing Interests: DH is inventor on intellectual property pertaining to robotic manipulation. 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 Handelman, Osborn, Thomas, Badger, Thompson, Nickl, Anaya, Wormley, Cantarero, McMullen, Crone, Wester, Celnik, Fifer and Tenore.)

Understanding the cortical representations of movements and their stability can shed light on improved brain-machine interface (BMI) approaches to decode these representations without frequent recalibration. Here, we characterize the spatial organization (somatotopy) and stability of the bilateral sensorimotor map of forearm muscles in an incomplete-high spinal-cord injury study participant implanted bilaterally in the primary motor and sensory cortices with Utah microelectrode arrays (MEAs). We built representation maps by recording bilateral multiunit activity (MUA) and surface electromyography (EMG) as the participant executed voluntary contractions of the extensor carpi radialis (ECR), and attempted motions in the flexor carpi radialis (FCR), which was paralytic. To assess stability, we repeatedly mapped and compared left- and right-wrist-extensor-related activity throughout several sessions, comparing somatotopy of active electrodes, as well as neural signals both at the within-electrode (multiunit) and cross-electrode (network) levels. Wrist motions showed significant activation in motor and sensory cortical electrodes. Within electrodes, firing strength stability diminished as the time increased between consecutive measurements (hours within a session, or days across sessions), with higher stability observed in sensory cortex than in motor, and in the contralateral hemisphere than in the ipsilateral. However, we observed no differences at network level, and no evidence of decoding instabilities for wrist EMG, either across timespans of hours or days, or across recording area. While map stability differs between brain area and hemisphere at multiunit/electrode level, these differences are nullified at ensemble level., (© 2022. The Author(s).)

Background: Intracortical microstimulation (ICMS) of somatosensory cortex can partially restore the sense of touch. Though ICMS bypasses much of the neuraxis, prior studies have found that conscious detection of touch elicited by ICMS lags behind the detection of cutaneous vibration. These findings may have been influenced by mismatched stimulus intensities, which can impact temporal perception., Objective: Evaluate the relative latency at which intensity-matched vibration and ICMS are perceived by a human participant., Methods: One person implanted with microelectrode arrays in somatosensory cortex performed reaction time and temporal order judgment (TOJ) tasks. To measure reaction time, the participant reported when he perceived vibration or ICMS. In the TOJ task, vibration and ICMS were sequentially presented and the participant reported which stimulus occurred first. To verify that the participant could distinguish between stimuli, he also performed a modality discrimination task, in which he indicated if he felt vibration, ICMS, or both., Results: When vibration was matched in perceived intensity to high-amplitude ICMS, vibration was perceived, on average, 48 ms faster than ICMS. However, in the TOJ task, both sensations arose at comparable latencies, with points of subjective simultaneity not significantly different from zero. The participant could discriminate between tactile modalities above chance level but was more inclined to report feeling vibration than ICMS., Conclusions: The latencies of ICMS-evoked percepts are slower than their mechanical counterparts. However, differences in latencies are small, particularly when stimuli are matched for intensity, implying that ICMS-based somatosensory feedback is rapid enough to be effective in neuroprosthetic applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Most patients with stroke experience motor deficits, usually referred to collectively as hemiparesis. Although hemiparesis is one of the most common and clinically recognizable motor abnormalities, it remains undercharacterized in terms of its behavioral subcomponents and their interactions. Hemiparesis comprises both negative and positive motor signs. Negative signs consist of weakness and loss of motor control (dexterity), whereas positive signs consist of spasticity, abnormal resting posture, and intrusive movement synergies (abnormal muscle co-activations during voluntary movement). How positive and negative signs interact, and whether a common mechanism generates them, remains poorly understood. Here, we used a planar, arm-supported reaching task to assess poststroke arm dexterity loss, which we compared with the Fugl-Meyer stroke scale; a measure primarily reflecting abnormal synergies. We examined 53 patients with hemiparesis after a first-time ischemic stroke. Reaching kinematics were markedly more impaired in patients with subacute (<3 mo) compared to chronic (>6 mo) stroke even for similar Fugl-Meyer scores. This suggests a dissociation between abnormal synergies (reflected in the Fugl-Meyer scale) and loss of dexterity, which in turn suggests different underlying mechanisms. Moreover, dynamometry suggested that Fugl-Meyer scores capture weakness as well as abnormal synergies, in line with these two deficits sharing a neural substrate. These findings have two important implications: First, clinical studies that test for efficacy of rehabilitation interventions should specify which component of hemiparesis they are targeting and how they propose to measure it. Metrics used widely for this purpose may not always be chosen appropriately. For example, as we show here, the Fugl-Meyer score may capture some hemiparesis components (abnormal synergies and weakness) but not others (loss of dexterity). Second, there may be an opportunity to design rehabilitation interventions to address specific subcomponents of hemiparesis. NEW & NOTEWORTHY Motor impairment is common after stroke and comprises reduced dexterity, weakness, and abnormal muscle synergies. Here we report that, when matched on an established synergy and weakness scale (Fugl-Meyer), patients with subacute stroke have worse reaching dexterity than chronic ones. This result suggests that the components of hemiparesis are dissociable and have separable mechanisms and, thus, may require distinct assessments and treatments.

Background and Objectives: The restoration of touch to fingers and fingertips is critical to achieving dexterous neuroprosthetic control for individuals with sensorimotor dysfunction. However, localized fingertip sensations have not been evoked via intracortical microstimulation (ICMS)., Methods: Using a novel intraoperative mapping approach, we implanted electrode arrays in the finger areas of left and right somatosensory cortex and delivered ICMS over a 2-year period in a human participant with spinal cord injury., Results: Stimulation evoked tactile sensations in 8 fingers, including fingertips, spanning both hands. Evoked percepts followed expected somatotopic arrangements. The subject was able to reliably identify up to 7 finger-specific sites spanning both hands in a finger discrimination task. The size of the evoked percepts was on average 33% larger than a finger pad, as assessed via manual markings of a hand image. The size of the evoked percepts increased modestly with increased stimulation intensity, growing 21% as pulse amplitude increased from 20 to 80 µA. Detection thresholds were estimated on a subset of electrodes, with estimates of 9.2 to 35 µA observed, roughly consistent with prior studies., Discussion: These results suggest that ICMS can enable the delivery of consistent and localized fingertip sensations during object manipulation by neuroprostheses for individuals with somatosensory deficits., Clinicaltrialsgov Identifier: NCT03161067., (© 2021 American Academy of Neurology.)

Advances in brain-machine interfaces have helped restore function and independence for individuals with sensorimotor deficits; however, providing efficient and effective sensory feedback remains challenging. Intracortical microstimulation (ICMS) of sensorimotor brain regions is a promising technique for providing bioinspired sensory feedback. In a human participant with chronically-implanted microelectrode arrays, we provided ICMS to the primary somatosensory cortex to generate tactile percepts in his hand. In a 3-choice object identification task, the participant identified virtual objects using tactile sensory feedback and no visual information. We evaluated three different stimulation paradigms, each with a different weighting of the grip force and its derivative, to explore the potential benefits of a more bioinspired stimulation strategy. In all paradigms, the participant's ability to identify the objects was above-chance, with object identification accuracy reaching 80% correct when using only sustained grip force feedback and 76.7% when using equal weighting of both sustained grip force and its derivative. These results demonstrate that bioinspired ICMS can provide sensory feedback that is functionally beneficial in sensorimotor tasks. Designing more efficient stimulation paradigms is important because it will allow us to 1) provide safer stimulation delivery methods that reduce overall injected charge without sacrificing function and 2) more effectively transmit sensory information to promote intuitive integration and usage by the human body.

Objective: Connectivity between the cerebellum and primary motor cortex (M1) can be assessed by using transcranial magnetic stimulation to measure cerebellar brain inhibition (CBI). The aim of the present study was to determine the intra- and inter-day measurment error and relative reliability of CBI. The former informs the degree to which repeated measurements vary, whereas the latter informs how well the measure can distinguish individuals from one another within a sample., Methods: We obtained CBI data from 83 healthy young participants (n = 55 retrospective). Intra-day measurements were separated by ~ 30 min. Inter-day measurmenets were separated by a minimum of 24 h., Results: We show that CBI has low measurement error (~15%) within and between sessions. Using the measurment error, we demonstrate that change estimates which exceed measurment noise are large at an individual level, but can be detected with modest sample sizes. Finally, we demonstrate that the CBI measurement has fair to good relative reliability in healthy individuals, which may be deflated by low sample heterogeneity., Conclusions: CBI has low measurement error supporting its use for tracking intra- and inter-day changes in cerebellar-M1 connectivity., Significance: Our findings provide clear reliability guidelines for future studies assessing modulation of cerebellar-M1 connectivity with intervention or disease progression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Learning similar motor skills in close succession is limited by interference, a phenomenon that takes place early after acquisition when motor memories are unstable. Interference can be bidirectional, as the first memory can be disrupted by the second (retrograde interference), or the second memory can be disrupted by the first (anterograde interference). The heightened plastic state of primary motor cortex after learning is thought to underlie interference, as unstable motor memories compete for neural resources. While time-dependent consolidation processes reduce interference, the passage of time (~6 h) required for memory stabilization limits our capacity to learn multiple motor skills at once. Here, we demonstrate in humans that prolonged training at asymptote of an initial motor skill reduces both retrograde and anterograde interference when a second motor skill is acquired in close succession. Neurophysiological assessments via transcranial magnetic stimulation reflect this online stabilization process. Specifically, excitatory neurotransmission in primary motor cortex increased after short training and decreased after prolonged training at performance asymptote. Of note, this reduction in intracortical excitation after prolonged training was proportional to better skill retention the following day. Importantly, these neurophysiological effects were not observed after motor practice without learning or after a temporal delay. Together, these findings indicate that prolonged training at asymptote improves the capacity to learn multiple motor skills in close succession, and that downregulation of excitatory neurotransmission in primary motor cortex may be a marker of online motor memory stabilization., Competing Interests: Declaration of competing interest The authors declare no competing interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Defining eloquent cortex intraoperatively, traditionally performed by neurosurgeons to preserve patient function, can now help target electrode implantation for restoring function. Brain-machine interfaces (BMIs) have the potential to restore upper-limb motor control to paralyzed patients but require accurate placement of recording and stimulating electrodes to enable functional control of a prosthetic limb. Beyond motor decoding from recording arrays, precise placement of stimulating electrodes in cortical areas associated with finger and fingertip sensations allows for the delivery of sensory feedback that could improve dexterous control of prosthetic hands. In this study, the authors demonstrated the use of a novel intraoperative online functional mapping (OFM) technique with high-density electrocorticography to localize finger representations in human primary somatosensory cortex. In conjunction with traditional pre- and intraoperative targeting approaches, this technique enabled accurate implantation of stimulating microelectrodes, which was confirmed by postimplantation intracortical stimulation of finger and fingertip sensations. This work demonstrates the utility of intraoperative OFM and will inform future studies of closed-loop BMIs in humans.

Importance: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor nervous system. Clinical studies have demonstrated cortical and spinal motor neuron hyperexcitability using transcranial magnetic stimulation and threshold tracking nerve conduction studies, respectively, although metrics of excitability have not been used as pharmacodynamic biomarkers in multi-site clinical trials., Objective: To ascertain whether ezogabine decreases cortical and spinal motor neuron excitability in ALS., Design, Setting, and Participants: This double-blind, placebo-controlled phase 2 randomized clinical trial sought consent from eligible participants from November 3, 2015, to November 9, 2017, and was conducted at 12 US sites within the Northeast ALS Consortium. Participants were randomized in equal numbers to a higher or lower dose of ezogabine or to an identical matched placebo, and they completed in-person visits at screening, baseline, week 6, and week 8 for clinical assessment and neurophysiological measurements., Interventions: Participants were randomized to receive 600 mg/d or 900 mg/d of ezogabine or a matched placebo for 10 weeks., Main Outcomes and Measures: The primary outcome was change in short-interval intracortical inhibition (SICI; SICI-1 was used in analysis to reflect stronger inhibition from an increase in amplitude) from pretreatment mean at screening and baseline to the full-dose treatment mean at weeks 6 and 8. The secondary outcomes included levels of cortical motor neuron excitability (including resting motor threshold) measured by transcranial magnetic stimulation and spinal motor neuron excitability (including strength-duration time constant) measured by threshold tracking nerve conduction studies., Results: A total of 65 participants were randomized to placebo (23), 600 mg/d of ezogabine (23), and 900 mg/d of ezogabine (19 participants); 45 were men (69.2%) and the mean (SD) age was 58.3 (8.8) years. The SICI-1 increased by 53% (mean ratio, 1.53; 95% CI, 1.12-2.09; P = .009) in the 900-mg/d ezogabine group vs placebo group. The SICI-1 did not change in the 600-mg/d ezogabine group vs placebo group (mean ratio, 1.15; 95% CI, 0.87-1.52; P = .31). The resting motor threshold increased in the 600-mg/d ezogabine group vs placebo group (mean ratio, 4.61; 95% CI, 0.21-9.01; P = .04) but not in the 900-mg/d ezogabine group vs placebo group (mean ratio, 1.95; 95% CI, -2.64 to 6.54; P = .40). Ezogabine caused a dose-dependent decrease in excitability by several other metrics, including strength-duration time constant in the 900-mg/d ezogabine group vs placebo group (mean ratio, 0.73; 95% CI, 0.60 to 0.87; P < .001)., Conclusions and Relevance: Ezogabine decreased cortical and spinal motor neuron excitability in participants with ALS, suggesting that such neurophysiological metrics may be used as pharmacodynamic biomarkers in multisite clinical trials., Trial Registration: ClinicalTrials.gov Identifier: NCT02450552.

Transcranial direct current stimulation has been shown to increase the efficiency of language therapy in chronic aphasia; however, to date, an optimal stimulation site has not been identified. We investigated whether neuromodulation of the right cerebellum can improve naming skills in chronic aphasia. Using a randomized, double-blind, sham-controlled, within-subject crossover study design, participants received anodal cerebellar stimulation ( n  = 12) or cathodal cerebellar stimulation ( n  = 12) + computerized aphasia therapy then sham + computerized aphasia therapy, or the opposite order. There was no significant effect of treatment (cerebellar stimulation versus sham) for trained naming. However, there was a significant order x treatment interaction, indicating that cerebellar stimulation was more effective than sham immediately post-treatment for participants who received cerebellar stimulation in the first phase. There was a significant effect of treatment (cerebellar stimulation versus sham) for untrained naming immediately post-treatment and the significant improvement in untrained naming was maintained at two months post-treatment. Greater gains in naming (relative to sham) were noted for participants receiving cathodal stimulation for both trained and untrained items. Thus, our study provides evidence that repetitive cerebellar transcranial direct stimulation combined with computerized aphasia treatment can improve picture naming in chronic post-stroke aphasia. These findings suggest that the right cerebellum might be an optimal stimulation site for aphasia rehabilitation and this could be an answer to handle heterogeneous participants who vary in their size and site of left hemisphere lesions., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Anterior-posterior (AP) and posterior-anterior (PA) pulses of transcranial magnetic stimulation (TMS) over the primary motor cortex (M1) appear to activate distinct interneuron networks that contribute differently to two varieties of physiological plasticity and motor behaviors (Hamada et al., 2014). The AP network is thought to be more sensitive to online manipulation of cerebellar (CB) activity using transcranial direct current stimulation. Here we probed CB-M1 interactions using cerebellar brain inhibition (CBI) in young healthy female and male individuals. TMS over the cerebellum produced maximal CBI of PA-evoked EMG responses at an interstimulus interval of 5 ms (PA-CBI), whereas the maximum effect on AP responses was at 7 ms (AP-CBI), suggesting that CB-M1 pathways with different conduction times interact with AP and PA networks. In addition, paired associative stimulation using ulnar nerve stimulation and PA TMS pulses over M1, a protocol used in human studies to induce cortical plasticity, reduced PA-CBI but not AP-CBI, indicating that cortical networks process cerebellar inputs in distinct ways. Finally, PA-CBI and AP-CBI were differentially modulated after performing two different types of motor learning tasks that are known to process cerebellar input in different ways. The data presented here are compatible with the idea that applying different TMS currents to the cerebral cortex may reveal cerebellar inputs to both the premotor cortex and M1. Overall, these results suggest that there are two independent CB-M1 networks that contribute uniquely to different motor behaviors. SIGNIFICANCE STATEMENT Connections between the cerebellum and primary motor cortex (M1) are essential for performing daily life activities, as damage to these pathways can result in faulty movements. Therefore, developing and understanding novel approaches to probe this pathway are critical to advancing our understanding of the pathophysiology of diseases involving the cerebellum. Here, we show evidence for two distinct cerebellar-cerebral interactions using cerebellar stimulation in combination with directional transcranial magnetic stimulation (TMS) over M1. These distinct cerebellar-cerebral interactions respond differently to physiological plasticity and to distinct motor learning tasks, which suggests they represent separate cerebellar inputs to the premotor cortex and M1. Overall, we show that directional TMS can probe two distinct cerebellar-cerebral pathways that likely contribute to independent processes of learning., (Copyright © 2020 the authors.)

Persistent cognitive, affective, and motor symptoms have been associated with sports-related concussions including several neurophysiological changes in the primary motor cortex. In particular, previous research has provided some evidence of altered latencies of the corticomotor pathway and altered motor neuroplasticity. However, to date, no studies have assessed these neurophysiological metrics in a common group of athletes across different phases of injury and recovery. In this study corticomotor latencies and neuroplasticity were assessed in collegiate athletes with or without a history of prior concussion across two different phases of injury: either in an acute state of concussion (within 2 wk of injury) or in a chronic state of concussion (more than 1 yr after injury). Corticomotor latencies were determined by measuring the motor evoked potential (MEP) onset time, and motor neuroplasticity was assessed by measuring MEP amplitudes following application of anodal transcranial direct current stimulation (tDCS) over the primary motor cortex (M1). We found that concussed athletes had slower corticomotor latencies than nonconcussed athletes, and corticomotor latency was also positively correlated with the number of prior concussions. In contrast, there was no evidence of altered motor neuroplasticity in athletes regardless of concussion history. These findings suggest concussions may lead to permanent changes in the corticospinal tract that are exacerbated by repeated injury. NEW & NOTEWORTHY We are the first to assess corticomotor latencies and motor neuroplasticity in a common group of collegiate athletes across different phases of injury and recovery. We found that the number of concussions an individual sustains negatively impacts corticomotor latencies with a higher number of prior concussions correlating positively with longer latencies. Our findings indicate that concussions may lead to permanent changes in the corticospinal tract that are exacerbated by repeated injury.

Background . After stroke, recovery of movement in proximal and distal upper extremity (UE) muscles appears to follow different time courses, suggesting differences in their neural substrates. Objective . We sought to determine if presence or absence of motor evoked potentials (MEPs) differentially influences recovery of volitional contraction and strength in an arm muscle versus an intrinsic hand muscle. We also related MEP status to recovery of proximal and distal interjoint coordination and movement fractionation, as measured by the Fugl-Meyer Assessment (FMA). Methods . In 45 subjects in the year following ischemic stroke, we tracked the relationship between corticospinal tract (CST) integrity and behavioral recovery in the biceps (BIC) and first dorsal interosseous (FDI) muscle. We used transcranial magnetic stimulation to probe CST integrity, indicated by MEPs, in BIC and FDI. We used electromyography, dynamometry, and UE FMA subscores to assess muscle-specific contraction, strength, and inter-joint coordination, respectively. Results . Presence of MEPs resulted in higher likelihood of muscle contraction, greater strength, and higher FMA scores. Without MEPs, BICs could more often volitionally contract, were less weak, and had steeper strength recovery curves than FDIs; in contrast, FMA recovery curves plateaued below normal levels for both the arm and hand. Conclusions . There are shared and separate substrates for paretic UE recovery. CST integrity is necessary for interjoint coordination in both segments and for overall recovery. In its absence, alternative pathways may assist recovery of volitional contraction and strength, particularly in BIC. These findings suggest that more targeted approaches might be needed to optimize UE recovery.

Motor control theories propose that the same motor plans can be employed by different effectors (e.g., the hand and arm). Skills learned with one effector can therefore "transfer" to others, which has potential applications in clinical situations. However, evidence from adaptation suggests this effect is not reciprocal; learning can be generalized from proximal to distal effectors (e.g., arm to hand), but not from distal to proximal effectors (e.g., hand to arm). We propose that skill learning may not follow the same pattern, because it relies on multiple learning processes beyond error detection and correction. Participants learned a skill task involving the production of isometric forces. We assessed their ability to perform the task with the hand and arm. One group then trained to perform the task using only their hand, whereas a second group trained using only their arm. In a final assessment, we found that participants who trained with either effector improved their skill in performing the task with both their hand and arm. There was no change in a control group that did not train between assessments, indicating that gains were related to the training, not the multiple assessments. These results indicate that in contrast to adaptation, motor skills can generalize from both proximal to distal effectors and from distal to proximal effectors. We propose this is due to differences in the processes underlying skill acquisition as compared with adaptation. NEW & NOTEWORTHY Prior research indicates that motor learning transfers from proximal to distal effectors, but not vice versa. However, this work focused on adapting existing behavior; we questioned whether different results would occur during learning of new motor skills. We found that the benefits of training on a skill task with either the hand or arm transferred across both effectors. This highlights important differences between adaptation and skill learning, and may allow therapeutic benefits for patients with impairments in specific effectors.

Objective: Patients with chronic stroke have been shown to have failure to release interhemispheric inhibition (IHI) from the intact to the damaged hemisphere before movement execution (premovement IHI). This inhibitory imbalance was found to correlate with poor motor performance in the chronic stage after stroke and has since become a target for therapeutic interventions. The logic of this approach, however, implies that abnormal premovement IHI is causal to poor behavioral outcome and should therefore be present early after stroke when motor impairment is at its worst. To test this idea, in a longitudinal study, we investigated interhemispheric interactions by tracking patients' premovement IHI for one year following stroke., Methods: We assessed premovement IHI and motor behavior five times over a 1-year period after ischemic stroke in 22 patients and 11 healthy participants., Results: We found that premovement IHI was normal during the acute/subacute period and only became abnormal at the chronic stage; specifically, release of IHI in movement preparation worsened as motor behavior improved. In addition, premovement IHI did not correlate with behavioral measures cross-sectionally, whereas the longitudinal emergence of abnormal premovement IHI from the acute to the chronic stage was inversely correlated with recovery of finger individuation., Interpretation: These results suggest that interhemispheric imbalance is not a cause of poor motor recovery, but instead might be the consequence of underlying recovery processes. These findings call into question the rehabilitation strategy of attempting to rebalance interhemispheric interactions in order to improve motor recovery after stroke. Ann Neurol 2019;85:502-513., (© 2019 American Neurological Association.)

We routinely make fine motor adjustments to maintain optimal motor performance. These adaptations have been attributed to both implicit, error-based mechanisms, and explicit, strategy-based mechanisms. However, little is known about the neural basis of implicit vs. explicit learning. Here, we aimed to use anodal transcranial direct current stimulation (tDCS) to probe the relationship between different brain regions and learning mechanisms during a visuomotor adaptation task in humans. We hypothesized that anodal tDCS over the cerebellum (CB) should increase implicit learning while anodal tDCS over the dorsolateral prefrontal cortex (dlPFC), a region associated with higher-level cognition, should facilitate explicit learning. Using a horizontal visuomotor adaptation task that measures explicit/implicit contributions to learning (Taylor et al., 2014), we found that dlPFC stimulation significantly improved performance compared to the other groups, and weakly increased explicit learning. However, CB stimulation had no effects on either target error or implicit learning. Previous work showed variable CB stimulation effects only on a vertical visuomotor adaptation task (Jalali et al., 2017), so in Experiment 2, we conducted the same study using a vertical context to see if we could find effects of CB stimulation. We found only weak effects of CB stimulation on target error and implicit learning, and now the dlPFC effect did not replicate. To resolve this discrepancy, in Experiment 3, we examined the effect of context (vertical vs. horizontal) on implicit and explicit contributions and found that individuals performed significantly worse and used greater implicit learning in the vertical screen condition compared to the horizontal screen condition. Across all experiments, however, there was high inter-individual variability, with strong influences of a few individuals, suggesting that these effects are not consistent across individuals. Overall, this work provides preliminary support for the idea that different neural regions can be engaged to improve visuomotor adaptation, but shows that each region's effects are highly context-dependent and not clearly dissociable from one another. This holds implications especially in neurorehabilitation, where an intact neural region could be engaged to potentially compensate if another region is impaired. Future work should examine factors influencing interindividual variability during these processes.

Background: Gait impairments after stroke arise from dysfunction of one or several features of the walking pattern. Traditional rehabilitation practice focuses on improving one component at a time, which may leave certain features unaddressed or prolong rehabilitation time. Recent work shows that neurologically intact adults can learn multiple movement components simultaneously., Objective: To determine whether a dual-learning paradigm, incorporating 2 distinct motor tasks, can simultaneously improve 2 impaired components of the gait pattern in people posttroke., Methods: Twelve individuals with stroke participated. Participants completed 2 sessions during which they received visual feedback reflecting paretic knee flexion during walking. During the learning phase of the experiment, an unseen offset was applied to this feedback, promoting increased paretic knee flexion. During the first session, this task was performed while walking on a split-belt treadmill intended to improve step length asymmetry. During the second session, it was performed during tied-belt walking., Results: The dual-learning task simultaneously increased paretic knee flexion and decreased step length asymmetry in the majority of people post-stroke. Split-belt treadmill walking did not significantly interfere with joint-angle learning: participants had similar rates and magnitudes of joint-angle learning during both single and dual-learning conditions. Participants also had significant changes in the amount of paretic hip flexion in both single and dual-learning conditions., Conclusions: People with stroke can perform a dual-learning paradigm and change 2 clinically relevant gait impairments in a single session. Long-term studies are needed to determine if this strategy can be used to efficiently and permanently alter multiple gait impairments.

Our sensorimotor system appears to be influenced by the recent history of our movements. Repeating movements toward a particular direction is known to have a dramatic effect on involuntary movements elicited by cortical stimulation-a phenomenon that has been termed use-dependent plasticity. However, analogous effects of repetition on behavior have proven elusive. Here, we show that movement repetition enhances the generation of similar movements in the future by reducing the time required to select and prepare the repeated movement. We further show that this reaction time advantage for repeated movements is attributable to more rapid, but still flexible, preparation of the repeated movement rather than anticipation and covert advance preparation of the previously repeated movement. Our findings demonstrate a powerful and beneficial effect of movement repetition on response preparation, which may represent a behavioral counterpart to use-dependent plasticity effects in primary motor cortex., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Following a stroke, mirror movements are unintended movements that appear in the non-paretic hand when the paretic hand voluntarily moves. Mirror movements have previously been linked to overactivation of sensorimotor areas in the non-lesioned hemisphere. In this study, we hypothesized that mirror movements might instead have a subcortical origin, and are the by-product of subcortical motor pathways upregulating their contributions to the paretic hand. To test this idea, we first characterized the time course of mirroring in 53 first-time stroke patients, and compared it to the time course of activities in sensorimotor areas of the lesioned and non-lesioned hemispheres (measured using functional MRI). Mirroring in the non-paretic hand was exaggerated early after stroke (Week 2), but progressively diminished over the year with a time course that parallelled individuation deficits in the paretic hand. We found no evidence of cortical overactivation that could explain the time course changes in behaviour, contrary to the cortical model of mirroring. Consistent with a subcortical origin of mirroring, we predicted that subcortical contributions should broadly recruit fingers in the non-paretic hand, reflecting the limited capacity of subcortical pathways in providing individuated finger control. We therefore characterized finger recruitment patterns in the non-paretic hand during mirroring. During mirroring, non-paretic fingers were broadly recruited, with mirrored forces in homologous fingers being only slightly larger (1.76 times) than those in non-homologous fingers. Throughout recovery, the pattern of finger recruitment during mirroring for patients looked like a scaled version of the corresponding control mirroring pattern, suggesting that the system that is responsible for mirroring in controls is upregulated after stroke. Together, our results suggest that post-stroke mirror movements in the non-paretic hand, like enslaved movements in the paretic hand, are caused by the upregulation of a bilaterally organized subcortical system.

Impaired hand function after stroke is a major cause of long-term disability. We developed a novel paradigm that quantifies two critical aspects of hand function, strength, and independent control of fingers (individuation), and also removes any obligatory dependence between them. Hand recovery was tracked in 54 patients with hemiparesis over the first year after stroke. Most recovery of strength and individuation occurred within the first 3 mo. A novel time-invariant recovery function was identified: recovery of strength and individuation were tightly correlated up to a strength level of ~60% of estimated premorbid strength; beyond this threshold, strength improvement was not accompanied by further improvement in individuation. Any additional improvement in individuation was attributable instead to a second process that superimposed on the recovery function. We conclude that two separate systems are responsible for poststroke hand recovery: one contributes almost all of strength and some individuation; the other contributes additional individuation. NEW & NOTEWORTHY We tracked recovery of the hand over a 1-yr period after stroke in a large cohort of patients, using a novel paradigm that enabled independent measurement of finger strength and control. Most recovery of strength and control occurs in the first 3 mo after stroke. We found that two separable systems are responsible for motor recovery of hand: one contributes strength and some dexterity, whereas a second contributes additional dexterity., (Copyright © 2017 the American Physiological Society.)

Background: It is well known that transcranial direct current stimulation (tDCS) is capable of modulating corticomotor excitability. However, a source of growing concern has been the observed inter- and intra-individual variability of tDCS-responses. Recent studies have assessed whether individuals respond in a predictable manner across repeated sessions of anodal tDCS (atDCS). The findings of these investigations have been inconsistent, and their methods have some limitations (i.e. lack of sham condition or testing only one tDCS intensity)., Objective: To study inter- and intra-individual variability of atDCS effects at two different intensities on primary motor cortex (M1) excitability., Methods: Twelve subjects participated in a crossover study testing 7-min atDCS over M1 in three separate conditions (2 mA, 1 mA, sham) each repeated three times separated by 48 h. Motor evoked potentials were recorded before and after stimulation (up to 30min). Time of testing was maintained consistent within participants. To estimate the reliability of tDCS effects across sessions, we calculated the Intra-class Correlation Coefficient (ICC)., Results: AtDCS at 2 mA, but not 1 mA, significantly increased cortical excitability at the group level in all sessions. The overall ICC revealed fair to high reliability of tDCS effects for multiple sessions. Given that the distribution of responses showed important variability in the sham condition, we established a Sham Variability-Based Threshold to classify responses and to track individual changes across sessions. Using this threshold an intra-individual consistent response pattern was then observed only for the 2 mA condition., Conclusion: 2 mA anodal tDCS results in consistent intra- and inter-individual increases of M1 excitability., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Motor skills are required for activities of daily living. Transcranial direct current stimulation (tDCS) applied in association with motor skill learning has been investigated as a tool for enhancing training effects in health and disease. Here, we review the published literature investigating whether tDCS can facilitate the acquisition, retention or adaptation of motor skills. Work in multiple laboratories is underway to develop a mechanistic understanding of tDCS effects on different forms of learning and to optimize stimulation protocols. Efforts are required to improve reproducibility and standardization. Overall, reproducibility remains to be fully tested, effect sizes with present techniques vary over a wide range, and the basis of observed inter-individual variability in tDCS effects is incompletely understood. It is recommended that future studies explicitly state in the Methods the exploratory (hypothesis-generating) or hypothesis-driven (confirmatory) nature of the experimental designs. General research practices could be improved with prospective pre-registration of hypothesis-based investigations, more emphasis on the detailed description of methods (including all pertinent details to enable future modeling of induced current and experimental replication), and use of post-publication open data repositories. A checklist is proposed for reporting tDCS investigations in a way that can improve efforts to assess reproducibility., (Copyright © 2017. Published by Elsevier B.V.)

One of the functions of the cerebellum in motor learning is to predict and account for systematic changes to the body or environment. This form of adaptive learning is mediated by plastic changes occurring within the cerebellar cortex. The strength of cerebellar-to-cerebral pathways for a given muscle may reflect aspects of cerebellum-dependent motor adaptation. These connections with motor cortex (M1) can be estimated as cerebellar inhibition (CBI): a conditioning pulse of transcranial magnetic stimulation delivered to the cerebellum before a test pulse over motor cortex. Previously, we have demonstrated that changes in CBI for a given muscle representation correlate with learning a motor adaptation task with the involved limb. However, the specificity of these effects is unknown. Here, we investigated whether CBI changes in humans are somatotopy specific and how they relate to motor adaptation. We found that learning a visuomotor rotation task with the right hand changed CBI, not only for the involved first dorsal interosseous of the right hand, but also for an uninvolved right leg muscle, the tibialis anterior, likely related to inter-effector transfer of learning. In two follow-up experiments, we investigated whether the preparation of a simple hand or leg movement would produce a somatotopy-specific modulation of CBI. We found that CBI changes only for the effector involved in the movement. These results indicate that learning-related changes in cerebellar-M1 connectivity reflect a somatotopy-specific interaction. Modulation of this pathway is also present in the context of interlimb transfer of learning. SIGNIFICANCE STATEMENT Connectivity between the cerebellum and motor cortex is a critical pathway for the integrity of everyday movements and understanding the somatotopic specificity of this pathway in the context of motor learning is critical to advancing the efficacy of neurorehabilitation. We found that adaptive learning with the hand affects cerebellar-motor cortex connectivity, not only for the trained hand, but also for an untrained leg muscle, an effect likely related to intereffector transfer of learning. Furthermore, we introduce a novel method to measure cerebellar-motor cortex connectivity during movement preparation. With this technique, we show that, outside the context of learning, modulation of cerebellar-motor cortex connectivity is somatotopically specific to the effector being moved., (Copyright © 2017 the authors 0270-6474/17/372377-10$15.00/0.)

Background and Objective: Stroke rehabilitation assumes motor learning contributes to motor recovery, yet motor learning in stroke has received little systematic investigation. Here we aimed to illustrate that despite matching levels of performance on a task, a trained patient should not be considered equal to an untrained patient with less impairment., Methods: We examined motor learning in healthy control participants and groups of stroke survivors with mild-to-moderate or moderate-to-severe motor impairment. Participants performed a series of isometric contractions of the elbow flexors to navigate an on-screen cursor to different targets, and trained to perform this task over a 4-day period. The speed-accuracy trade-off function (SAF) was assessed for each group, controlling for differences in self-selected movement speeds between individuals., Results: The initial SAF for each group was proportional to their impairment. All groups were able to improve their performance through skill acquisition. Interestingly, training led the moderate-to-severe group to match the untrained (baseline) performance of the mild-to-moderate group, while the trained mild-to-moderate group matched the untrained (baseline) performance of the controls. Critically, this did not make the two groups equivalent; they differed in their capacity to improve beyond this matched performance level. Specifically, the trained groups had reached a plateau, while the untrained groups had not., Conclusions: Despite matching levels of performance on a task, a trained patient is not equal to an untrained patient with less impairment. This has important implications for decisions both on the focus of rehabilitation efforts for chronic stroke, as well as for returning to work and other activities.

Repetitive Transcranial Magnetic Stimulation (rTMS) has been successfully used as a non-invasive therapeutic intervention for several neurological disorders in the clinic as well as an investigative tool for basic neuroscience. rTMS has been shown to induce long-term changes in neuronal circuits in vivo. Such long-term effects of rTMS have been investigated using behavioral, imaging, electrophysiological, and molecular approaches, but there is limited understanding of the immediate effects of TMS on neurons. We investigated the immediate effects of high frequency (20 Hz) rTMS on the activity of cortical neurons in an effort to understand the underlying cellular mechanisms activated by rTMS. We used whole-cell patch-clamp recordings in acute rat brain slices and calcium imaging of cultured primary neurons to examine changes in neuronal activity and intracellular calcium respectively. Our results indicate that each TMS pulse caused an immediate and transient activation of voltage gated sodium channels (9.6 ± 1.8 nA at -45 mV, p value < 0.01) in neurons. Short 500 ms 20 Hz rTMS stimulation induced action potentials in a subpopulation of neurons, and significantly increased the steady state current of the neurons at near threshold voltages (at -45 mV: before TMS: I = 130 ± 17 pA, during TMS: I = 215 ± 23 pA, p value = 0.001). rTMS stimulation also led to a delayed increase in intracellular calcium (153.88 ± 61.94% increase from baseline). These results show that rTMS has an immediate and cumulative effect on neuronal activity and intracellular calcium levels, and suggest that rTMS may enhance neuronal responses when combined with an additional motor, sensory or cognitive stimulus. Thus, these results could be translated to optimize rTMS protocols for clinical as well as basic science applications., Competing Interests: The authors have declared that no competing interests exist.

Newly acquired motor skills become stabilized through consolidation [1]. However, we know from daily life that consolidated skills are modified over multiple bouts of practice and in response to newfound challenges [2]. Recent evidence has shown that memories can be modified through reconsolidation, in which previously consolidated memories can re-enter a temporary state of instability through retrieval, and in order to persist, undergo re-stabilization [3-8]. Although observed in other memory domains [5, 6], it is unknown whether reconsolidation leads to strengthened motor skills over multiple episodes of practice. Using a novel intervention after the retrieval of a consolidated skill, we found that skill can be modified and enhanced through exposure to increased sensorimotor variability. This improvement was greatest in those participants who could rapidly adjust their sensorimotor output in response to the relatively large fluctuations presented during the intervention. Importantly, strengthening required the reactivation of the consolidated skill and time for changes to reconsolidate. These results provide a key demonstration that consolidated motor skills continue to change as needed through the remapping of motor command to action goal, with strong implications for rehabilitation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Lateralization of function is an important organizational feature of the motor system. Each effector is predominantly controlled by the contralateral cerebral cortex and the ipsilateral cerebellum. Transcranial magnetic stimulation studies have revealed hemispheric differences in the stimulation strength required to evoke a muscle response from the primary motor cortex (M1), with the dominant hemisphere typically requiring less stimulation than the nondominant. The current study assessed whether the strength of the connection between the cerebellum and M1 (CB-M1), known to change in association with motor learning, have hemispheric differences and whether these differences have any behavioral correlate. We observed, in right-handed individuals, that the connection between the right cerebellum and left M1 is typically stronger than the contralateral network. Behaviorally, we detected no lateralized learning processes, though we did find a significant effect on the amplitude of reaching movements across hands. Furthermore, we observed that the strength of the CB-M1 connection is correlated with the amplitude variability of reaching movements, a measure of movement precision, where stronger connectivity was associated with better precision. These findings indicate that lateralization in the motor system is present beyond the primary motor cortex, and points to an association between cerebellar M1 connectivity and movement execution., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)