Procedural Motor Memory Deficits in Patients With Long-COVID.

BACKGROUND AND OBJECTIVES: At least 15% of patients who recover from acute severe acute respiratory syndrome coronavirus 2 infection experience lasting symptoms ("Long-COVID") including "brain fog" and deficits in declarative memory. It is not known if Long-COVID affects patients' ability to form and retain procedural motor skill memories. The objective was to determine the ability of patients with Long-COVID to acquire and consolidate a new procedural motor skill over 2 training days. The primary outcome was to determine difference in early learning, measured as the increase in correct sequence typing speed over the initial 11 practice trials of a new skill. The secondary outcomes were initial and final typing speed on days 1 and 2, learning rate, overnight consolidation, and typing accuracy. METHODS: In this prospective, cross-sectional, online, case-control study, participants learned a sequential motor skill over 2 consecutive days (NCT05746624). Patients with Long-COVID (reporting persistent post-coronavirus disease 2019 [COVID-19] symptoms for more than 4 weeks) were recruited at the NIH. Patients were matched one-to-one by age and sex to controls recruited during the pandemic using a crowd-sourcing platform. Selection criteria included age 18-90 years, English speaking, right-handed, able to type with the left hand, denied active fever or respiratory infection, and no previous task exposure. Data were also compared with an age-matched and sex-matched control group who performed the task online before the COVID-19 pandemic (prepandemic controls). RESULTS: In total, 105 of 236 patients contacted agreed to participate and completed the experiment (mean ± SD age 46 ± 12.8 years, 82% female). Both healthy control groups had 105 participants (mean age 46 ± 13.1 and 46 ± 11.9 years, 82% female). Early learning was comparable across groups (Long-COVID: 0.36 ± 0.24 correct sequences/second, pandemic controls: 0.36 ± 0.53 prepandemic controls: 0.38 ± 0.57, patients vs pandemic controls [CI -0.068 to 0.067], vs prepandemic controls [CI -0.084 to 0.052], and between controls [CI -0.083 to 0.053], p = 0.82). Initial and final typing speeds on days 1 and 2 were slower in patients than controls. Patients with Long-COVID showed a significantly reduced overnight consolidation and a nonsignificant trend to reduced learning rates. DISCUSSION: Early learning was comparable in patients with Long-COVID and controls. Anomalous initial performance is consistent with executive dysfunction. Reduction in overnight consolidation may relate to deficits in procedural memory formation.

A translational roadmap for transcranial magnetic and direct current stimulation in stroke rehabilitation: Consensus-based core recommendations from the third stroke recovery and rehabilitation roundtable.

BACKGROUND AND AIMS: The purpose of this Third Stroke Recovery and Rehabilitation Roundtable (SRRR3) was to develop consensus recommendations to address outstanding barriers for the translation of preclinical and clinical research using the non-invasive brain stimulation (NIBS) techniques Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS) and provide a roadmap for the integration of these techniques into clinical practice. METHODS: International NIBS and stroke recovery experts (N = 18) contributed to the consensus process. Using a nominal group technique, recommendations were reached via a five-stage process, involving a thematic survey, two priority ranking surveys, a literature review and an in-person meeting. RESULTS AND CONCLUSIONS: Results of our consensus process yielded five key evidence-based and feasibility barriers for the translation of preclinical and clinical NIBS research, which were formulated into five core consensus recommendations. Recommendations highlight an urgent need for (1) increased understanding of NIBS mechanisms, (2) improved methodological rigor in both preclinical and clinical NIBS studies, (3) standardization of outcome measures, (4) increased clinical relevance in preclinical animal models, and (5) greater optimization and individualization of NIBS protocols. To facilitate the implementation of these recommendations, the expert panel developed a new SRRR3 Unified NIBS Research Checklist. These recommendations represent a translational pathway for the use of NIBS in stroke rehabilitation research and practice.

A translational roadmap for transcranial magnetic and direct current stimulation in stroke rehabilitation: Consensus-based core recommendations from the third stroke recovery and rehabilitation roundtable.

BACKGROUND AND AIMS: The purpose of this Third Stroke Recovery and Rehabilitation Roundtable (SRRR3) was to develop consensus recommendations to address outstanding barriers for the translation of preclinical and clinical research using the non-invasive brain stimulation (NIBS) techniques Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS) and provide a roadmap for the integration of these techniques into clinical practice. METHODS: International NIBS and stroke recovery experts (N = 18) contributed to the consensus process. Using a nominal group technique, recommendations were reached via a five-stage process, involving a thematic survey, two priority ranking surveys, a literature review and an in-person meeting. RESULTS AND CONCLUSIONS: Results of our consensus process yielded five key evidence-based and feasibility barriers for the translation of preclinical and clinical NIBS research, which were formulated into five core consensus recommendations. Recommendations highlight an urgent need for (1) increased understanding of NIBS mechanisms, (2) improved methodological rigor in both preclinical and clinical NIBS studies, (3) standardization of outcome measures, (4) increased clinical relevance in preclinical animal models, and (5) greater optimization and individualization of NIBS protocols. To facilitate the implementation of these recommendations, the expert panel developed a new SRRR3 Unified NIBS Research Checklist. These recommendations represent a translational pathway for the use of NIBS in stroke rehabilitation research and practice.

Applied strategies of neuroplasticity.

Various levels of somatotopic organization are present throughout the human nervous system. However, this organization can change when needed based on environmental demands, a phenomenon known as neuroplasticity. Neuroplasticity can occur when learning a new motor skill, adjusting to life after blindness, or following a stroke. Following an injury, these neuroplastic changes can be adaptive or maladaptive, and often occur regardless of whether rehabilitation occurs or not. But not all movements produce neuroplasticity, nor do all rehabilitation interventions. Here, we focus on research regarding how to maximize adaptive neuroplasticity while also minimizing maladaptive plasticity, known as applied neuroplasticity. Emphasis is placed on research exploring how best to apply neuroplastic principles to training environments and rehabilitation protocols. By studying and applying these principles in research and clinical practice, it is hoped that learning of skills and regaining of function and independence can be optimized.

Combined low-frequency brain oscillatory activity and behavior predict future errors in human motor skill.

Human skills are composed of sequences of individual actions performed with utmost precision. When occasional errors occur, they may have serious consequences, for example, when pilots are manually landing a plane. In such cases, the ability to predict an error before it occurs would clearly be advantageous. Here, we asked whether it is possible to predict future errors in a keyboard procedural human motor skill. We report that prolonged keypress transition times (KTTs), reflecting slower speed, and anomalous delta-band oscillatory activity in cingulate-entorhinal-precuneus brain regions precede upcoming errors in skill. Combined anomalous low-frequency activity and prolonged KTTs predicted up to 70% of future errors. Decoding strength (posterior probability of error) increased progressively approaching the errors. We conclude that it is possible to predict future individual errors in skill sequential performance.

Reactivation-induced motor skill modulation does not operate at a rapid micro-timescale level.

Abundant evidence shows that consolidated memories are susceptible to modifications following their reactivation. Processes of memory consolidation and reactivation-induced skill modulation have been commonly documented after hours or days. Motivated by studies showing rapid consolidation in early stages of motor skill acquisition, here we asked whether motor skill memories are susceptible to modifications following brief reactivations, even at initial stages of learning. In a set of experiments, we collected crowdsourced online motor sequence data to test whether post-encoding interference and performance enhancement occur following brief reactivations in early stages of learning. Results indicate that memories forming during early learning are not susceptible to interference nor to enhancement within a rapid reactivation-induced time window, relative to control conditions. This set of evidence suggests that reactivation-induced motor skill memory modulation might be dependent on consolidation at the macro-timescale level, requiring hours or days to occur.

Robust enhancement of motor sequence learning with 4 mA transcranial electric stimulation.

BACKGROUND AND OBJECTIVES: Motor learning experiments with transcranial direct current stimulation (tDCS) at 2 mA have produced mixed results. We hypothesize that tDCS boosts motor learning provided sufficiently high field intensity on the motor cortex. METHODS: In a single-blinded design, 108 healthy participants received either anodal (N = 36) or cathodal (N = 36) tDCS at 4 mA total, or no stimulation (N = 36) while they practiced a 12-min sequence learning task. Anodal stimulation was delivered across four electrode pairs (1 mA each), with anodes above the right parietal lobe and cathodes above the right frontal lobe. Cathodal stimulation, with reversed polarities, served as an active control for sensation, while the no-stimulation condition established baseline performance. fMRI-localized targets on the primary motor cortex in 10 subjects were used in current flow models to optimize electrode placement for maximal field intensity. A single electrode montage was then selected for all participants. RESULTS: We found a significant difference in performance with anodal vs. cathodal stimulation (Cohen's d = 0.71) and vs. no stimulation (d = 0.56). This effect persisted for at least 1 h, and subsequent learning for a new sequence and the opposite hand also improved. Sensation ratings were comparable in the active groups and did not exceed moderate levels. Current flow models suggest the new electrode montage can achieve stronger motor cortex polarization than alternative montages. CONCLUSION: The present paradigm shows a medium to large effect size and is well-tolerated. It may serve as a go-to experiment for future studies on motor learning and tDCS.

Barriers to Enrollment in Post-Stroke Brain Stimulation in a Racially and Ethnically Diverse Population.

BACKGROUND AND PURPOSE: Brain stimulation is an adjuvant strategy to promote rehabilitation after stroke. Here, we evaluated the influence of inclusion/exclusion criteria on enrollment in a transcranial direct current stimulation (tDCS) trial in the context of a racially/ethnically diverse acute stroke service at University of Texas Southwestern (UTSW). METHODS: 3124 (59.7 ± 14.5 years) racially/ethnically diverse (38.4% non-Hispanic white, (W), Hispanic (H) 22%, African American (AA) 33.5%, Asian (A) 2.3%) patients were screened in the acute stroke service at UTSW. Demographics, stroke characteristics, and reasons for exclusion were recorded prospectively. RESULTS: 2327 (74.5%) patients had a verified stroke. Only 44 of them (1.9%) were eligible. Causes for exclusion included in order of importance: (1) magnitude of upper extremity (UE) motor impairment, (2) prior strokes (s), (3) hemorrhagic stroke, (4) psychiatric condition or inability to follow instructions, and (5) old age, of these (2) and (4) were more common in AA patients but not in other minorities. 31 of the 44 eligible individuals were enrolled (W 1.68%, H 1.37%, AA .77%, A 3.774%). 90.5% of verified stroke patients did not exhibit contraindications for stimulation. CONCLUSIONS: 3 main conclusions emerged: (a) The main limitations for inclusion in brain stimulation trials of motor recovery were magnitude of UE motor impairments and stroke lesion characteristics, (b) most stroke patients could be stimulated with tDCS without safety concerns and (c) carefully tailored inclusion criteria could increase diversity in enrollment.Clinical Trial Registration-URL: http://clinicaltrials.gov. Unique identifier: NCT01007136.

Identifying transcranial magnetic stimulation induced EEG signatures of different neuronal elements in primary motor cortex.

OBJECTIVE: To investigate the neuronal elements involved in the activation of corticospinal neurons in the primary motor cortex (M1). METHODS: We studied 10 healthy subjects. Cortical evoked potentials with different components induced by monophasic transcranial magnetic stimulation (TMS) in anterior-posterior and posterior-anterior currents recorded with electroencephalography (EEG) were analyzed. RESULTS: EEG signatures with P25 and N45 components recorded at the C3 electrode with posterior-anterior current were larger than those with anterior-posterior current, while the signatures with P180 and N280 components recorded at the FC1 electrode with anterior-posterior current were larger than those with posterior-anterior current. The source localization analysis revealed that the cortical evoked potential with anterior-posterior current distributed both in the M1 and premotor cortex while that with posterior-anterior current only located in the M1. CONCLUSIONS: We conclude that the activation of corticospinal pyramidal neurons in the M1 is affected by various neuronal elements including the local intracortical circuits in the M1 and inputs from premotor cortex with different sensitivities to TMS in opposite current directions. SIGNIFICANCE: Our finding helped answer a longstanding question about how the corticospinal pathway from the M1 is functionally organized and activated.

Breaking the boundaries of interacting with the human brain using adaptive closed-loop stimulation.

The human brain is arguably one of the most complex systems in nature. To understand how it operates, it is essential to understand the link between neural activity and behavior. Experimental investigation of that link requires tools to interact with neural activity during behavior. Human neuroscience, however, has been severely bottlenecked by the limitations of these tools. While invasive methods can support highly specific interaction with brain activity during behavior, their applicability in human neuroscience is limited. Despite extensive development in the last decades, noninvasive alternatives have lacked spatial specificity and yielded results that are commonly fraught with variability and replicability issues, along with relatively limited understanding of the neural mechanisms involved. Here we provide a comprehensive review of the state-of-the-art in interacting with human brain activity and highlight current limitations and recent efforts to overcome these limitations. Beyond crucial technical and scientific advancements in electromagnetic brain stimulation, new frontiers in interacting with human brain activity such as task-irrelevant sensory stimulation and focal ultrasound stimulation are introduced. Finally, we argue that, along with technological improvements and breakthroughs in noninvasive methods, a paradigm shift towards adaptive closed-loop stimulation will be a critical step for advancing human neuroscience.

Reward and plasticity: Implications for neurorehabilitation.

Neuroplasticity follows nervous system injury in the presence or absence of rehabilitative treatments. Rehabilitative interventions can be used to modulate adaptive neuroplasticity, reducing motor impairment and improving activities of daily living in patients with brain lesions. Learning principles guide some rehabilitative interventions. While basic science research has shown that reward combined with training enhances learning, this principle has been only recently explored in the context of neurorehabilitation. Commonly used reinforcers may be more or less rewarding depending on the individual or the context in which the task is performed. Studies in healthy humans showed that both reward and punishment can enhance within-session motor performance; but reward, and not punishment, improves consolidation and retention of motor skills. On the other hand, neurorehabilitative training after brain lesions involves complex tasks (e.g., walking and activities of daily living). The contribution of reward to neurorehabilitation is incompletely understood. Here, we discuss recent research on the role of reward in neurorehabilitation and the needed directions of future research.

Crowdsourcing in Cognitive and Systems Neuroscience.

Behavioral research in cognitive and human systems neuroscience has been largely carried out in-person in laboratory settings. Underpowering and lack of reproducibility due to small sample sizes have weakened conclusions of these investigations. In other disciplines, such as neuroeconomics and social sciences, crowdsourcing has been extensively utilized as a data collection tool, and a means to increase sample sizes. Recent methodological advances allow scientists, for the first time, to test online more complex cognitive, perceptual, and motor tasks. Here we review the nascent literature on the use of online crowdsourcing in cognitive and human systems neuroscience. These investigations take advantage of the ability to reliably track the activity of a participant's computer keyboard, mouse, and eye gaze in the context of large-scale studies online that involve diverse research participant pools. Crowdsourcing allows for testing the generalizability of behavioral hypotheses in real-life environments that are less accessible to lab-designed investigations. Crowdsourcing is further useful when in-laboratory studies are limited, for example during the current COVID-19 pandemic. We also discuss current limitations of crowdsourcing research, and suggest pathways to address them. We conclude that online crowdsourcing is likely to widen the scope and strengthen conclusions of cognitive and human systems neuroscience investigations.

Repetitive Peripheral Sensory Stimulation as an Add-On Intervention for Upper Limb Rehabilitation in Stroke: A Randomized Trial.

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.

Statistical learning occurs during practice while high-order rule learning during rest period.

Knowing when the brain learns is crucial for both the comprehension of memory formation and consolidation and for developing new training and neurorehabilitation strategies in healthy and patient populations. Recently, a rapid form of offline learning developing during short rest periods has been shown to account for most of procedural learning, leading to the hypothesis that the brain mainly learns during rest between practice periods. Nonetheless, procedural learning has several subcomponents not disentangled in previous studies investigating learning dynamics, such as acquiring the statistical regularities of the task, or else the high-order rules that regulate its organization. Here we analyzed 506 behavioral sessions of implicit visuomotor deterministic and probabilistic sequence learning tasks, allowing the distinction between general skill learning, statistical learning, and high-order rule learning. Our results show that the temporal dynamics of apparently simultaneous learning processes differ. While high-order rule learning is acquired offline, statistical learning is evidenced online. These findings open new avenues on the short-scale temporal dynamics of learning and memory consolidation and reveal a fundamental distinction between statistical and high-order rule learning, the former benefiting from online evidence accumulation and the latter requiring short rest periods for rapid consolidation.

The prevalence of the Val66Met polymorphism in musicians: Possible evidence for compensatory neuroplasticity from a pilot study.

The study compared the prevalence of the Val66Met Brain-derived Neurotrophic Factor single nucleotide polymorphism (rs6265) in a sample of musicians (N = 50) to an ethnically matched general population sample from the 1000 Human Genome Project (N = 424). Met-carriers of the polymorphism (Val/Met and Met/Met genotypes) are typically present in 25-30% of the general population and have associated deficits in motor learning and plasticity. Many studies have assessed the benefits of long-term music training for neuroplasticity and motor learning. This study takes a unique genetic approach investigating if the prevalence of the Val66Met BDNF polymorphism, which negatively affects motor learning, is significantly different in musicians from the general population. Our genotype and allele frequency analyses revealed that the distribution of the Val66Met polymorphism was not significantly different in musicians versus the general population (p = 0.6447 for genotype analysis and p = 0.8513 allele analysis). In the Musician sample (N = 50), the prevalence of the Val/Met genotype was 40% and the prevalence of the Met/Met genotype was 2%. In the 1000 Human Genome Project subset (N = 424), the prevalence of Val/Met was 33.25% and the Met/Met genotype prevalence was 4%. Therefore, musicians do exist with the Val66Met polymorphism and the characteristics of long-term music training may compensate for genetic predisposition to motor learning deficits. Since the polymorphism has significant implications for stroke rehabilitation, future studies may consider the implications of the polymorphism in music-based interventions such as Neurologic Music Therapy.

Consolidation of human skill linked to waking hippocampo-neocortical replay.

The introduction of rest intervals interspersed with practice strengthens wakeful consolidation of skill. The mechanisms by which the brain binds discrete action representations into consolidated, highly temporally resolved skill sequences during waking rest are not known. To address this question, we recorded magnetoencephalography (MEG) during acquisition and rapid consolidation of a sequential motor skill. We report the presence of prominent, fast waking neural replay during the same rest periods in which rapid consolidation occurs. The observed replay is temporally compressed by approximately 20-fold relative to the acquired skill, is selective for the trained sequence, and predicts the magnitude of skill consolidation. Replay representations extend beyond the hippocampus and entorhinal cortex to the contralateral sensorimotor cortex. These results document the presence of robust hippocampo-neocortical replay supporting rapid wakeful consolidation of skill.

Phase-dependent offline enhancement of human motor memory.

BACKGROUND: Skill learning engages offline activity in the primary motor cortex (M1). Sensorimotor cortical activity oscillates between excitatory trough and inhibitory peak phases of the mu (8-12 Hz) rhythm. We recently showed that these mu phases influence the magnitude and direction of neuroplasticity induction within M1. However, the contribution of M1 activity during mu peak and trough phases to human skill learning has not been investigated. OBJECTIVE: To evaluate the effects of phase-dependent TMS during mu peak and trough phases on offline learning of a newly-acquired motor skill. METHODS: On Day 1, three groups of healthy adults practiced an explicit motor sequence learning task with their non-dominant left hand. After practice, phase-dependent TMS was applied to the right M1 during either mu peak or mu trough phases. The third group received sham TMS during random mu phases. On Day 2, all subjects were re-tested on the same task to evaluate offline learning. RESULTS: Subjects who received phase-dependent TMS during mu trough phases showed increased offline skill learning compared to those who received phase-dependent TMS during mu peak phases or sham TMS during random mu phases. Additionally, phase-dependent TMS during mu trough phases elicited stronger whole-brain broadband oscillatory power responses than phase-dependent TMS during mu peak phases. CONCLUSIONS: We conclude that sensorimotor mu trough phases reflect brief windows of opportunity during which TMS can strengthen newly-acquired skill memories.

Induction of LTD-like corticospinal plasticity by low-frequency rTMS depends on pre-stimulus phase of sensorimotor µ-rhythm.

BACKGROUND: Neural oscillations reflect rapidly changing brain excitability states. We have demonstrated previously with EEG-triggered transcranial magnetic stimulation (TMS) of human motor cortex that the positive vs. negative peak of the sensorimotor µ-oscillation reflect corticospinal low-vs. high-excitability states. In vitro experiments showed that induction of long-term depression (LTD) by low-frequency stimulation depends on the postsynaptic excitability state. OBJECTIVE/HYPOTHESIS: We tested the hypothesis that induction of LTD-like corticospinal plasticity in humans by 1 Hz repetitive TMS (rTMS) is enhanced when rTMS is synchronized with the low-excitability state, but decreased or even shifted towards long-term (LTP)-like plasticity when synchronized with the high-excitability state. METHODS: We applied real-time EEG-triggered 1-Hz-rTMS (900 pulses) to the hand area of motor cortex in healthy subjects. In a randomized double-blind three-condition crossover design, pulses were synchronized to either the positive or negative peak of the sensorimotor µ-oscillation, or were applied at random phase (control). The amplitude of motor evoked potentials was recorded as an index of corticospinal excitability before and after 1-Hz-rTMS. RESULTS: 1-Hz-rTMS at random phase resulted in a trend towards LTD-like corticospinal plasticity. RTMS in the positive peak condition (i.e., the low-excitability state) induced significant LTD-like plasticity. RTMS in the negative peak condition (i.e., the high-excitability state) showed a trend towards LTP-like plasticity, which was significantly different from the other two conditions. CONCLUSION: The level of corticospinal depolarization reflected by phase of the µ-oscillation determines the degree of corticospinal plasticity induced by low-frequency rTMS, a finding that may guide future personalized therapeutic stimulation.