Fatigue in children using motor imagery and P300 brain-computer interfaces.

BACKGROUND: Brain-computer interface (BCI) technology offers children with quadriplegic cerebral palsy unique opportunities for communication, environmental exploration, learning, and game play. Research in adults demonstrates a negative impact of fatigue on BCI enjoyment, while effects on BCI performance are variable. To date, there have been no pediatric studies of BCI fatigue. The purpose of this study was to assess the effects of two different BCI paradigms, motor imagery and visual P300, on the development of self-reported fatigue and an electroencephalography (EEG) biomarker of fatigue in typically developing children. METHODS: Thirty-seven typically-developing school-aged children were recruited to a prospective, crossover study. Participants attended three sessions: (A) motor imagery-BCI, (B) visual P300-BCI, and (C) video viewing (control). The motor imagery task involved an imagined left- or right-hand squeeze. The P300 task involved attending to one square on a 3 × 3 grid during a random single flash sequence. Each paradigm had respective calibration periods and a similar visual counting game. Primary outcomes were self-reported fatigue and the power of the EEG alpha band both collected during resting-state periods pre- and post-task. Self-reported fatigue was measured using a 10-point visual analog scale. EEG alpha band power was calculated as the integrated power spectral density from 8 to 12 Hz of the EEG spectrum. RESULTS: Thirty-two children completed the protocol (age range 7-16, 63% female). Self-reported fatigue and EEG alpha band power increased across all sessions (F(1,155) = 33.9, p < 0.001; F = 5.0(1,149), p = 0.027 respectively). No differences in fatigue development were observed between session types. There was no correlation between self-reported fatigue and EEG alpha band power change. BCI performance varied between participants and paradigms as expected but was not associated with self-reported fatigue or EEG alpha band power. CONCLUSION: Short periods (30-mintues) of BCI use can increase self-reported fatigue and EEG alpha band power to a similar degree in children performing motor imagery and P300 BCI paradigms. Performance was not associated with our measures of fatigue; the impact of fatigue on useability and enjoyment is unclear. Our results reflect the variability of fatigue and the BCI experience more broadly in children and warrant further investigation.

The effects of D-Cycloserine on corticospinal excitability after repeated spaced intermittent theta-burst transcranial magnetic stimulation: A randomized controlled trial in healthy individuals.

Repeated spaced TMS protocols, also termed accelerated TMS protocols, are of increasing therapeutic interest. The long-term potentiation (LTP)-like effects of repeated spaced intermittent theta-burst transcranial magnetic stimulation (iTBS) are presumed to be N-Methyl-D-Aspartate receptor (NMDA-R) dependent; however, this has not been tested. We tested whether the LTP-like effects of repeated spaced iTBS are influenced by low-dose D-Cycloserine (100 mg), an NMDA-R partial-agonist. We conducted a randomized, double-blind, placebo-controlled crossover trial in 20 healthy adults from August 2021-Feb 2022. Participants received repeated spaced iTBS, consisting of two iTBS sessions 60 minutes apart, to the primary motor cortex. The peak-to-peak amplitude of the motor evoked potentials (MEP) at 120% resting motor threshold (RMT) was measured after each iTBS. The TMS stimulus-response (TMS-SR; 100-150% RMT) was measured at baseline, +30 min, and +60 min after each iTBS. We found evidence for a significant Drug*iTBS effect in MEP amplitude, revealing that D-Cycloserine enhanced MEP amplitudes relative to the placebo. When examining TMS-SR, pairing iTBS with D-Cycloserine increased the TMS-SR slope relative to placebo after both iTBS tetani, and this was due to an increase in the upper bound of the TMS-SR. This indicates that LTP-like and metaplastic effects of repeated-spaced iTBS involve NMDA-R, as revealed by two measures of corticospinal excitability, and that low-dose D-Cycloserine facilitates the physiological effects of repeated spaced iTBS. However, extension of these findings to clinical populations and therapeutic protocols targeting non-motor regions of cortex requires empirical validation.

Reliability of active robotic neuro-navigated transcranial magnetic stimulation motor maps.

Transcranial magnetic stimulation (TMS) motor mapping is a safe, non-invasive method used to study corticomotor organization and intervention-induced plasticity. Reliability of resting maps is well established, but understudied for active maps and unestablished for active maps obtained using robotic TMS techniques. The objective of  this study was to determine the reliability of robotic neuro-navigated TMS motor map measures during active muscle contraction. We hypothesized that map area and volume would show excellent short- and medium-term reliability. Twenty healthy adults were tested on 3 days. Active maps of the first dorsal interosseous muscle were created using a 12 × 12 grid (7 mm spacing). Short- (24 h) and medium-term (3-5 weeks) relative (intra-class correlation coefficient) and absolute (minimal detectable change (MDC); standard error of measure) reliabilities were evaluated for map area, volume, center of gravity (CoG), and hotspot magnitude (peak-to-peak MEP amplitude at the hotspot), along with active motor threshold (AMT) and maximum voluntary contraction (MVC). This study found that AMT and MVC had good-to-excellent short- and medium-term reliability. Map CoG (x and y) were the most reliable map measures across sessions with excellent short- and medium-term reliability (p < 0.001). Map area, hotspot magnitude, and map volume followed with better reliability medium-term than short-term, with a change of 28%, 62%, and 78% needed to detect a true medium-term change, respectively. Therefore, robot-guided neuro-navigated TMS active mapping is relatively reliable but varies across measures. This, and MDC, should be considered in interventional study designs.

Robotic lower extremity exoskeleton use in a non-ambulatory child with cerebral palsy: a case study.

PURPOSE: With few treatment options available for non-ambulatory children with cerebral palsy (CP), a robotic lower extremity gait trainer may provide a non-invasive addition to conventional treatment options. This case study investigates the usage and impact of robotic lower extremity gait trainer use in a participant with CP over the initial 3 months of use. MATERIALS AND METHODS: This prospective case study involves a 7-year old female (GMFCS V) with CP (registered clinical trial: NCT04251390). The participant used a Trexo Home robotic gait trainer (Trexo) in the community with assessments occurring in the home and school. Trexo usage and bowel movements (BMs) were tracked daily. Postural control and lower extremity range of motion (ROM) and spasticity were evaluated prior to Trexo use and weekly to biweekly thereafter. RESULTS: The participant used the device an average of 46 min/week, over 3.3 d/week. BM frequency increased from 0.4/d at baseline, to 1.2 (±0.5)/d during Trexo use. There were no diffuse systematic changes in postural stability, ROM or muscle spasticity, but specifically head control and spasticity in the knee flexors had improvements. CONCLUSIONS: Data and anecdotal reports suggest that regular use of the Trexo Home robotic gait trainer has positive outcomes on frequency and quality of BMs, and may improve head control, and knee flexor spasticity. Larger controlled studies are needed to evaluate the impacts of Trexo use in children with CP.Implications for RehabilitationNon-ambulatory children with CP can use and may experience benefits from using a robot-assisted gait trainer (RAGT).Constipation, aspects of balance and focal spasticity may improve.

"I feel like my body is broken": exploring the experiences of people living with long COVID.

PURPOSE: Long COVID, an illness affecting a subset of individuals after COVID-19, is distressing, poorly understood, and reduces quality of life. The objective of this sub-study was to better understand and explore individuals' experiences with long COVID and commonly reported symptoms, using qualitative data collected from open-ended survey responses. METHODS: Data were collected from adults living with long COVID who participated in a larger observational online survey. Participants had the option of answering seven open-ended items. Data from the open-ended items were analyzed following guidelines for reflective thematic analysis. RESULTS: From 213 participants who were included in the online survey, 169 participants who primarily self-identified as women (88.2%), aged 40-49 (33.1%), who had been experiencing long COVID symptoms for ≥ 6 months (74%) provided open-ended responses. Four overlapping and interconnected themes were identified: (1) Long COVID symptoms are numerous and wearing, (2) The effects of long COVID are pervasive, (3) Physical activity is difficult and, in some cases, not possible, and (4) Asking for help when few are listening, and little is working. CONCLUSION: Findings reaffirm prior research, highlighting the complex nature of long COVID. Further, results show the ways individuals affected by the illness are negatively impacted and have had to alter their daily activities. Participants recounted the challenges faced when advocating for themselves, adapting to new limitations, and navigating healthcare systems. The varied relapsing-remitting symptoms, unknown prognosis, and deep sense of loss over one's prior identity suggest interventions are needed to support this population.

Differences in neurometabolites and transcranial magnetic stimulation motor maps in children with attention-deficit/hyperactivity disorder.

BACKGROUND: Although much is known about cognitive dysfunction in attention-deficit/hyperactivity disorder (ADHD), few studies have examined the pathophysiology of disordered motor circuitry. We explored differences in neurometabolite levels and transcranial magnetic stimulation (TMS)-derived corticomotor representations among children with ADHD and typically developing children. METHODS: We used magnetic resonance spectroscopy (MRS) protocols to measure excitatory (glutamate + glutamine [Glx]) and inhibitory (γ-aminobutyric acid [GABA]) neurometabolite levels in the dominant primary motor cortex (M1) and the supplementary motor area (SMA) in children with ADHD and typically developing children. We used robotic neuronavigated TMS to measure corticospinal excitability and create corticomotor maps. RESULTS: We collected data from 26 medication-free children with ADHD (aged 7-16 years) and 25 typically developing children (11-16 years). Children with ADHD had lower M1 Glx (p = 0.044, d = 0.6); their mean resting motor threshold was lower (p = 0.029, d = 0.8); their map area was smaller (p = 0.044, d = 0.7); and their hotspot density was higher (p = 0.008, d = 0.9). M1 GABA levels were associated with motor map area (p = 0.036).Limitations: Some TMS data were lost because the threshold of some children exceeded 100% of the machine output. The relatively large MRS voxel required to obtain sufficient signal-to-noise ratio and reliably measure GABA levels encompassed tissue beyond the M1, making this measure less anatomically specific. CONCLUSION: The neurochemistry and neurophysiology of key nodes in the motor network may be altered in children with ADHD, and the differences appear to be related to each other. These findings suggest potentially novel neuropharmacological and neuromodulatory targets for ADHD.

Active versus resting neuro-navigated robotic transcranial magnetic stimulation motor mapping.

Transcranial magnetic stimulation (TMS) motor mapping is a safe, non-invasive method that can be used to study corticomotor organization. Motor maps are typically acquired at rest, and comparisons to maps obtained during muscle activation have been both limited and contradictory. Understanding the relationship between functional activation of the corticomotor system as recorded by motor mapping is crucial for their use clinically and in research. The present study utilized robotic TMS paired with personalized neuro-navigation to examine the relationship between resting and active motor map measures and their relationship with motor performance. Twenty healthy right-handed participants underwent resting and active robotic TMS motor mapping of the first dorsal interosseous to 10% maximum voluntary contraction. Motor map parameters including map area, volume, and measures of map centrality were compared between techniques using paired sample tests of difference and Bland-Altman plots and analysis. Map area, volume, and hotspot magnitude were larger in the active motor maps, while map center of gravity and hotspot locations remained consistent between both maps. No associations were observed between motor maps and motor performance as measured by the Purdue Pegboard Test. Our findings support previous suggestions that maps scale with muscle contraction. Differences in mapping outcomes suggest rest and active motor maps may reflect functionally different corticomotor representations. Advanced analysis methods may better characterize the underlying neurophysiology of both types of motor mapping.

Robotic mapping of motor cortex in children with perinatal stroke and hemiparesis.

Brain stimulation combined with intensive therapy may improve hand function in children with perinatal stroke-induced unilateral cerebral palsy (UCP). However, response to therapy varies and underlying neuroplasticity mechanisms remain unclear. Here, we aimed to characterize robotic motor mapping outcomes in children with UCP. Twenty-nine children with perinatal stroke and UCP (median age 11 ± 2 years) were compared to 24 typically developing controls (TDC). Robotic, neuronavigated transcranial magnetic stimulation was employed to define bilateral motor maps including area, volume, and peak motor evoked potential (MEP). Map outcomes were compared to the primary clinical outcome of the Jebsen-Taylor Test of Hand Function (JTT). Maps were reliably obtained in the contralesional motor cortex (24/29) but challenging in the lesioned hemisphere (5/29). Within the contralesional M1 of participants with UCP, area and peak MEP amplitude of the unaffected map were larger than the affected map. When comparing bilateral maps within the contralesional M1 in children with UCP to that of TDC, only peak MEP amplitudes were different, being smaller for the affected hand as compared to TDC. We observed correlations between the unaffected map when stimulating the contralesional M1 and function of the unaffected hand. Robotic motor mapping can characterize motor cortex neurophysiology in children with perinatal stroke. Map area and peak MEP amplitude may represent discrete biomarkers of developmental plasticity in the contralesional M1. Correlations between map metrics and hand function suggest clinical relevance and utility in studies of interventional plasticity.

Walking and Fatigue in People with Cerebral Palsy: Brief Report.

The aim of this study was to examine the relationship between perceived fatigue and perceptions of walking abilities and difficulty in people with cerebral palsy (CP). Twenty individuals with CP (range 10-21y; mean age 14.8y) who usually walk in the community were recruited. Community mobility was assessed using the Functional Mobility Scale. Participants were asked about their walking ability and frequency, perceived effort during walking (using the Children's Effort Rating Table), and perceived fatigue (using the Fatigue Impact and Severity Self-Assessment). Community mobility, frequency, and perceived effort during walking were significantly related to fatigue. No relationship was found between time spent walking (maximum walking time) and fatigue. Here we demonstrate that perceived fatigue is related to walking in people with CP.

Chronic Fatigue and Postexertional Malaise in People Living With Long COVID: An Observational Study.

OBJECTIVE: People living with long COVID describe a high symptom burden, and a more detailed assessment is needed to inform rehabilitation recommendations. The objectives were to use validated questionnaires to measure the severity of fatigue and compare this with normative data and thresholds for clinical relevance in other diseases; measure and describe the impact of postexertional malaise (PEM); and assess symptoms of dysfunctional breathing, self-reported physical activity, and health-related quality of life. METHODS: This was an observational study with a cross-sectional survey design (data collection from February 2021 to April 2021). Eligible participants were adults experiencing persistent symptoms due to COVID-19 that did not predate the confirmed or suspected infection. Questionnaires included the Functional Assessment of Chronic Illness Therapy-Fatigue Scale and the DePaul Symptom Questionnaire-Post-Exertional Malaise. RESULTS: After data cleaning, 213 participants were included in the analysis. The total Functional Assessment of Chronic Illness Therapy-Fatigue Scale score was 18 (SD = 10) (where the score can range from 0 to 52, and a lower score indicates more severe fatigue), and 71.4% were experiencing chronic fatigue. Postexertional symptom exacerbation affected most participants, and 58.7% met the PEM scoring thresholds used in people living with myalgic encephalomyelitis/chronic fatigue syndrome. CONCLUSION: Long COVID is characterized by chronic fatigue that is clinically relevant and at least as severe as fatigue in several other clinical conditions. PEM is a significant challenge for this patient group. Because of the potential for setbacks and deteriorated function following overexertion, fatigue and postexertional symptom exacerbation must be monitored and reported in clinical practice and in studies involving interventions for people with long COVID. IMPACT: Physical therapists working with people with long COVID should measure and validate the patient's experience. Postexertional symptom exacerbation must be considered, and rehabilitation needs to be carefully designed based on individual presentation. Beneficial interventions might first ensure symptom stabilization via pacing, a self-management strategy for the activity that helps minimize postexertional malaise.

Effect of the subjective intensity of fatigue and interoception on perceptual regulation and performance during sustained physical activity.

BACKGROUND: The subjective experience of fatigue impairs an individual's ability to sustain physical endurance performance. However, precise understanding of the specific role perceived fatigue plays in the central regulation of performance remains unclear. Here, we examined whether the subjective intensity of a perceived state of fatigue, pre-induced through prior upper body activity, differentially impacted performance and altered perceived effort and affect experienced during a sustained, isometric contraction in lower body. We also explored whether (cardiac) interoception predicted the intensity of experienced perceptual and affective responses and moderated the relationships between constructs during physical activity. METHODS: Using a repeated-measures study design, thirty male participants completed three experimental conditions, with the intensity of a pre-induced state of fatigue manipulated to evoke moderate (MOD), severe (SEV) and minimal (control; CON) intensity of perceptions prior to performance of the sustained contraction. RESULTS: Performance of the sustained contraction was significantly impaired under a perceived state of fatigue, with reductions of 10% and 14% observed in the MOD and SEV conditions, respectively. Performance impairment was accompanied by greater perceived effort and more negative affective valence reported during the contraction. However, effects were limited to comparisons to CON, with no difference evident between the two experimental trials (i.e. MOD vs. SEV). Individuals' awareness of their accuracy in judging resting heartbeats was shown to predict the subjective intensity of fatigue experienced during the endurance task. However, interoception did not moderate the relationships evident between fatigue and both perceived effort and affective valence. CONCLUSIONS: A perceived state of fatigue limits endurance performance, influencing both how effortful activity is perceived to be and the affective experience of activity. Though awareness of interoceptive representations of bodily states may be important to the subjective experience of fatigue, interoception does not modulate the relationships between perceived fatigue and other perceptual (i.e. effort) and affective constructs.

Physiological and psychosocial correlates of cancer-related fatigue.

PURPOSE: Cancer-related fatigue (CRF) is a common and distressing symptom of cancer that may persist for years following treatment completion. However, little is known about the pathophysiology of CRF. Using a comprehensive group of gold-standard physiological and psychosocial assessments, this study aimed to identify correlates of CRF in a heterogenous group of cancer survivors. METHODS: Using a cross-sectional design to determine the physiological and psychosocial correlates of CRF, ninety-three cancer survivors (51 fatigued, 42 non-fatigued) completed assessments of performance fatigability (i.e. the decline in muscle strength during cycling), cardiopulmonary exercise testing, venous blood samples for whole blood cell count and inflammatory markers and body composition. Participants also completed questionnaires measuring demographic, treatment-related, and psychosocial variables. RESULTS: Performance fatigability, time-to-task-failure, peak oxygen uptake (V̇O2peak), tumor necrosis factor-α (TNF-α), body fat percentage, and lean mass index were associated with CRF severity. Performance fatigability, V̇O2peak, TNF-α, and age explained 35% of the variance in CRF severity. Those with clinically-relevant CRF reported more pain, more depressive symptoms, less perceived social support, and were less physically active than non-fatigued cancer survivors. CONCLUSIONS: The present study utilised a comprehensive group of gold-standard physiological and psychosocial assessments and the results give potential insight into the mechanisms underpinning the association between physical inactivity, physical deconditioning and CRF. IMPLICATIONS FOR CANCER SURVIVORS: Given the associations between CRF and both physiological and psychosocial measures, this study identifies targets that can be measured by rehabilitation professionals and used to guide tailored interventions to reduce fatigue.

Effects of Transcranial Direct Current Stimulation and High-Definition Transcranial Direct Current Stimulation Enhanced Motor Learning on Robotic Transcranial Magnetic Stimulation Motor Maps in Children.

Introduction: Conventional transcranial direct current stimulation (tDCS) and high-definition tDCS (HD-tDCS) may improve motor learning in children. Mechanisms are not understood. Neuronavigated robotic transcranial magnetic stimulation (TMS) can produce individualised maps of primary motor cortex (M1) topography. We aimed to determine the effects of tDCS- and HD-tDCS-enhanced motor learning on motor maps. Methods: Typically developing children aged 12-18 years were randomised to right M1 anodal tDCS, HD-tDCS, or Sham during training of their left-hand on the Purdue Pegboard Task (PPT) over 5 days. Bilateral motor mapping was performed at baseline (pre), day 5 (post), and 6-weeks retention time (RT). Primary muscle was the first dorsal interosseous (FDI) with secondary muscles of abductor pollicis brevis (APB) and adductor digiti minimi (ADM). Primary mapping outcomes were volume (mm2/mV) and area (mm2). Secondary outcomes were centre of gravity (COG, mm) and hotspot magnitude (mV). Linear mixed-effects modelling was employed to investigate effects of time and stimulation type (tDCS, HD-tDCS, Sham) on motor map characteristics. Results: Twenty-four right-handed participants (median age 15.5 years, 52% female) completed the study with no serious adverse events or dropouts. Quality maps could not be obtained in two participants. No effect of time or group were observed on map area or volume. LFDI COG (mm) differed in the medial-lateral plane (x-axis) between tDCS and Sham (p = 0.038) from pre-to-post mapping sessions. Shifts in map COG were also observed for secondary left-hand muscles. Map metrics did not correlate with behavioural changes. Conclusion: Robotic TMS mapping can safely assess motor cortex neurophysiology in children undergoing motor learning and neuromodulation interventions. Large effects on map area and volume were not observed while changes in COG may occur. Larger controlled studies are required to understand the role of motor maps in interventional neuroplasticity in children.

Perinatal stroke: mapping and modulating developmental plasticity.

Most cases of hemiparetic cerebral palsy are caused by perinatal stroke, resulting in lifelong disability for millions of people. However, our understanding of how the motor system develops following such early unilateral brain injury is increasing. Tools such as neuroimaging and brain stimulation are generating informed maps of the unique motor networks that emerge following perinatal stroke. As a focal injury of defined timing in an otherwise healthy brain, perinatal stroke represents an ideal human model of developmental plasticity. Here, we provide an introduction to perinatal stroke epidemiology and outcomes, before reviewing models of developmental plasticity after perinatal stroke. We then examine existing therapeutic approaches, including constraint, bimanual and other occupational therapies, and their potential synergy with non-invasive neurostimulation. We end by discussing the promise of exciting new therapies, including novel neurostimulation, brain-computer interfaces and robotics, all focused on improving outcomes after perinatal stroke.

Robotic transcranial magnetic stimulation motor maps and hand function in adolescents.

INTRODUCTION: Transcranial magnetic stimulation (TMS) motor mapping can characterize the neurophysiology of the motor system. Limitations including human error and the challenges of pediatric populations may be overcome by emerging robotic systems. We aimed to show that neuronavigated robotic motor mapping in adolescents could efficiently produce discrete maps of individual upper extremity muscles, the characteristics of which would correlate with motor behavior. METHODS: Typically developing adolescents (TDA) underwent neuronavigated robotic TMS mapping of bilateral motor cortex. Representative maps of first dorsal interosseous (FDI), abductor pollicis brevis (APB), and abductor digiti minimi (ADM) muscles in each hand were created. Map features including area (primary), volume, and center of gravity were analyzed across different excitability regions (R100%, R75%, R50%, R25%). Correlations between map metrics and validated tests of hand motor function (Purdue Pegboard Test as primary) were explored. RESULTS: Twenty-four right-handed participants (range 12-18 years, median 15.5 years, 52% female) completed bilateral mapping and motor assessments with no serious adverse events or dropouts. Gender and age were associated with hand function and motor map characteristics. Full motor maps (R100%) for FDI did not correlate with motor function in either hand. Smaller excitability subset regions demonstrated reduced variance and dose-dependent correlations between primary map variables and motor function in the dominant hemisphere. CONCLUSIONS: Hand function in TDA correlates with smaller subset excitability regions of robotic TMS motor map outcomes. Refined motor maps may have less variance and greater potential to quantify interventional neuroplasticity. Robotic TMS mapping is safe and feasible in adolescents.

Bilateral transcranial magnetic stimulation of the supplementary motor area in children with Tourette syndrome.

AIM: To explore the feasibility and possible effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) delivered to the supplementary motor area (SMA) on tic severity and motor system neurophysiology in children with Tourette syndrome. METHOD: Ten children with Tourette syndrome (eight males, two females; 9-15y) participated in this open-label, phase 1 clinical trial. Treatment consisted of 1800 low-frequency (1Hz) neuronavigated robotic rTMS (100% resting motor threshold) to the SMA, bilaterally for 15 sessions. The primary outcome was a change in Yale Global Tic Severity Scale (YGTSS) total score from baseline to posttreatment. Secondary outcome measures included changes in magnetic resonance spectroscopy metabolite concentrations, TMS neurophysiology measures, TMS motor maps, and clinical assessments (anxiety, depression) from baseline to the end of treatment. RESULTS: The YGTSS score decreased from baseline after treatment (p<0.001; Cohen's d=2.9). All procedures were well-tolerated. INTERPRETATION: Robot-driven, neuronavigated bilateral rTMS of the SMA is feasible in children with Tourette syndrome and appears to reduce tic severity. What this paper adds Repetitive transcranial magnetic stimulation (rTMS) is feasible to use in children with Tourette syndrome. rTMS is tolerated by children with Tourette syndrome. Precise targeting of the supplementary motor area using functional magnetic resonance imaging is also feasible in these children.

Coordination between motor and cognitive tasks in dual task gait.

BACKGROUND: Dual Task (DT) paradigms are frequently used by researchers and clinicians to examine the integrity of motor processes in many movement disorders. However, the mechanism of this interaction is not fully understood. Therefore, the aim of this study was to examine the within-stride interactions between cognitive and motor processes during dual task gait (DT). RESEARCH QUESTION: Do healthy young adults coordinate gait with secondary task processing? If so, is cognitive task processing capability associated with the coordination observed? METHODS: Nineteen healthy young adults walked for two minutes on a motorized treadmill whilst counting backwards in sevens from three-digit numbers. The coordination of calculation verbalizations with gait parameters were assessed across six phases of the gait cycle. Mid verbalization time points (VERMid) were used as points of high cognitive processing of the dual task and compared with the end of the verbalizations (VEREnd) as points of low cognitive processing. RESULTS: VERMid and VEREnd did not systematically occur in any phase of the gait cycle. However, 10/19 and 9/19 participants showed non-random distributions of verbalizations for VERMid and VEREnd time points respectively (p < 0.01), indicating that these walkers coordinated gait with the cognitive task. Analysis of subgroups of Verbalization Coordinators and Non-Coordinators showed slower verbalization response durations (VRD) for VERMid Coordinators compared to VERMid Non-Coordinators, indicating that VERMid Coordinators found the cognitive tasks more demanding. No differences were found in VRD for VEREnd Coordinators and VEREnd Non-Coordinators. SIGNIFICANCE: It was found that cognitive processing is coordinated with gait phases in some but not all healthy young adults during DT gait. When demands on cognitive processes are high, healthy young adults coordinate cognitive processing with phases of gait. Analysis of within-stride coordination may be of use for studying clinical conditions where gait and attentional cognition performance breaks down.

Reliability of robotic transcranial magnetic stimulation motor mapping.

Robotic transcranial magnetic stimulation (TMS) is a noninvasive and safe tool that produces cortical motor maps using neuronavigational and neuroanatomical images. Motor maps are individualized representations of the primary motor cortex (M1) topography that may reflect developmental and interventional plasticity. Results of TMS motor map reliability testing have been variable, and robotic measures are undefined. We aimed to determine the short- and long-term reliability of robotic TMS motor maps. Twenty healthy participants underwent motor mapping at baseline, 24 h, and 4 wk. A 12 × 12 grid (7-mm spacing) was placed over the left M1, centered over the hand knob area. Four suprathreshold stimulations were delivered at each grid point. First dorsal interosseous (FDI) motor-evoked potentials (MEPs) were analyzed offline to generate map characteristics of area, volume, center of gravity (COG), and hotspot magnitude. Subsets of each outcome corresponding to 75%, 50%, and 25% of each map were determined. Reliability measures including intraclass correlation coefficient (ICC), minimal detectable change (MDC), and standard error of measure (SEM) were calculated. Map volume, COG, and hotspot magnitude were the most reliable measures (good-to-excellent) over both short- and long-term sessions. Map area reliability was poor-to-moderate for short- and long-term sessions. Smaller map percentile subsets showed decreased variability but only minimal improvements in reliability. MDC for most outcomes was >50%. Procedures were well tolerated with no serious adverse events. Robotic TMS motor mapping is relatively reliable over time, but careful consideration of specific outcomes is required for this method to interrogate plasticity in the human motor system.NEW & NOTEWORTHY Robotic transcranial magnetic stimulation (TMS) is a noninvasive and safe tool that produces cortical motor maps-individualized representations of the primary motor cortex (M1) topography-that may reflect developmental and interventional plasticity. This study is the first to evaluate short- and long-term relative and absolute reliability of TMS mapping outcomes at various M1 excitability levels using novel robotic neuronavigated TMS.

An Oligonucleotide Delivery Platform to Enable Assessment of Intracellular Transcripts in Live Cells by Flow Cytometry.

The measurement of mRNA transcripts in live cells has been limited by inefficient delivery vehicles for oligonucleotides. Using a delivery platform which utilizes fluorophores capable of forming intramolecular H-type excitonic dimers, we show that antisense oligonucleotides (ASOs) can be delivered across the plasma membrane directly into the cytosol without receptor mediation. With HIV infection of CD4+ lymphocytes as a model system, we quantitate the level of viral infection present in live single cells with flow cytometry by measuring the hybridization of ASOs to viral sequences; we then compare this measurement with a standard HIV analysis, that is, binding of an antibody against the HIV cell surface protein gp120. The nucleic acids delivery platform described herein also enables inhibition of HIV infection by addition of ASO constructs targeting sequences in the virus' highly conserved 5'-untranslated region. Our analysis quantitates the level of inhibition by comparing both the MFI values and the mean fluorescence intensity as calculated by integration under each curve. Thus, a means for measuring intracellular transcripts at the live single cell level and the potential for delivery of a new class of antiviral agents is described. © 2020 International Society for Advancement of Cytometry.

Mechanisms of neuromuscular fatigue and recovery in unilateral versus bilateral maximal voluntary contractions.

The aim of this study was to investigate differences in neuromuscular function and corticospinal excitability in response to sustained unilateral (UNIL) and bilateral (BIL) isometric maximal voluntary contraction (IMVC) of the knee extensors. Eleven men performed a 1-min sustained IMVC of the knee extensors with one or both legs. Central and peripheral measures of neuromuscular function and corticospinal excitability were assessed via surface electromyography (EMG), peripheral nerve stimulation, and transcranial magnetic stimulation before, immediately after, and during recovery from IMVC. IMVC force and root-mean-squared EMG decreased during the fatiguing 1-min IMVC, with a larger decrease in EMG during BIL. All neuromuscular function indexes decreased significantly after the IMVC (P < 0.005), but the magnitude of these decreases did not differ between conditions. Changes in corticospinal excitability (motor evoked potential) and inhibition (silent period) did not differ between conditions. In contrast to previous studies utilizing submaximal exercise, no more peripheral fatigue was found after UNIL vs. BIL conditions, even though central drive was lower after BIL 1-min IMVC. Corticospinal excitability and inhibition were not found to be different between UNIL and BIL conditions, in line with maximal voluntary activation.NEW & NOTEWORTHY The present experiment used peripheral nerve stimulation and transcranial magnetic stimulations during a sustained isometric maximal voluntary contraction to investigate the influence of muscle mass on neuromuscular fatigue. Contrary to previous studies that used submaximal exercise, peripheral fatigue was not found to be greater in unilateral vs. bilateral knee extensions even though central drive was lower during bilateral contractions. Corticospinal excitability and inhibition were not found to be different between unilateral and bilateral conditions.