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Background Vagus Nerve Stimulation (VNS) paired with rehabilitation improved upper extremity impairment and function in a recent pivotal, randomized, triple-blind, sham-controlled trial in people with chronic arm weakness after stroke. Objective We aimed to determine whether treatment effects varied across candidate subgroups, such as younger age or less injury. Methods Participants were randomized to receive rehabilitation paired with active VNS or rehabilitation paired with sham stimulation (Control). The primary outcome was the change in impairment measured by the Fugl–Meyer Assessment Upper Extremity (FMA-UE) score on the first day after completion of 6-weeks in-clinic therapy. We explored the effect of VNS treatment by sex, age (≥62 years), time from stroke (>2 years), severity (baseline FMA-UE score >34), paretic side of body, country of enrollment (USA vs UK) and presence of cortical involvement of the index infarction. We assessed whether there was any interaction with treatment. Findings The primary outcome increased by 5.0 points (SD 4.4) in the VNS group and by 2.4 points (SD 3.8) in the Control group ( P = .001, between group difference 2.6, 95% CI 1.03-4.2). The between group difference was similar across all subgroups and there were no significant treatment interactions. There was no important difference in rates of adverse events across subgroups. Conclusion The response was similar across subgroups examined. The findings suggest that the effects of paired VNS observed in the VNS-REHAB trial are likely to be consistent in wide range of stroke survivors with moderate to severe upper extremity impairment.

Background Motor adaptation relies on error-based learning for accurate movements in changing environments. However, the neurophysiological mechanisms driving individual differences in performance are unclear. Transcranial magnetic stimulation (TMS)-evoked potential can provide a direct measure of cortical excitability. Objective To investigate cortical excitability as a predictor of motor learning and motor adaptation in a robot-mediated forcefield. Methods A group of 15 right-handed healthy participants (mean age 23 years) performed a robot-mediated forcefield perturbation task. There were two conditions: unperturbed non-adaptation and perturbed adaptation. TMS was applied in the resting state at baseline and following motor adaptation over the contralateral primary motor cortex (left M1). Electroencephalographic (EEG) activity was continuously recorded, and cortical excitability was measured by TMS-evoked potential (TEP). Motor learning was quantified by the motor learning index. Results Larger error-related negativity (ERN) in fronto-central regions was associated with improved motor performance as measured by a reduction in trajectory errors. Baseline TEP N100 peak amplitude predicted motor learning (P = 0.005), which was significantly attenuated relative to baseline (P = 0.0018) following motor adaptation. Conclusions ERN reflected the formation of a predictive internal model adapted to the forcefield perturbation. Attenuation in TEP N100 amplitude reflected an increase in cortical excitability with motor adaptation reflecting neuroplastic changes in the sensorimotor cortex. TEP N100 is a potential biomarker for predicting the outcome in robot-mediated therapy and a mechanism to investigate psychomotor abnormalities in depression.

BackgroundLoss of arm function is common after stroke. Robot-assisted training may improve arm outcomes.ObjectiveThe objectives were to determine the clinical effectiveness and cost-effectiveness of robot-assisted training, compared with an enhanced upper limb therapy programme and with usual care.DesignThis was a pragmatic, observer-blind, multicentre randomised controlled trial with embedded health economic and process evaluations.SettingThe trial was set in four NHS trial centres.ParticipantsPatients with moderate or severe upper limb functional limitation, between 1 week and 5 years following first stroke, were recruited.InterventionsRobot-assisted training using the Massachusetts Institute of Technology-Manus robotic gym system (InMotion commercial version, Interactive Motion Technologies, Inc., Watertown, MA, USA), an enhanced upper limb therapy programme comprising repetitive functional task practice, and usual care.Main outcome measuresThe primary outcome was upper limb functional recovery ‘success’ (assessed using the Action Research Arm Test) at 3 months. Secondary outcomes at 3 and 6 months were the Action Research Arm Test results, upper limb impairment (measured using the Fugl-Meyer Assessment), activities of daily living (measured using the Barthel Activities of Daily Living Index), quality of life (measured using the Stroke Impact Scale), resource use costs and quality-adjusted life-years.ResultsA total of 770 participants were randomised (robot-assisted training,n = 257; enhanced upper limb therapy,n = 259; usual care,n = 254). Upper limb functional recovery ‘success’ was achieved in the robot-assisted training [103/232 (44%)], enhanced upper limb therapy [118/234 (50%)] and usual care groups [85/203 (42%)]. These differences were not statistically significant; the adjusted odds ratios were as follows: robot-assisted training versus usual care, 1.2 (98.33% confidence interval 0.7 to 2.0); enhanced upper limb therapy versus usual care, 1.5 (98.33% confidence interval 0.9 to 2.5); and robot-assisted training versus enhanced upper limb therapy, 0.8 (98.33% confidence interval 0.5 to 1.3). The robot-assisted training group had less upper limb impairment (as measured by the Fugl-Meyer Assessment motor subscale) than the usual care group at 3 and 6 months. The enhanced upper limb therapy group had less upper limb impairment (as measured by the Fugl-Meyer Assessment motor subscale), better mobility (as measured by the Stroke Impact Scale mobility domain) and better performance in activities of daily living (as measured by the Stroke Impact Scale activities of daily living domain) than the usual care group, at 3 months. The robot-assisted training group performed less well in activities of daily living (as measured by the Stroke Impact Scale activities of daily living domain) than the enhanced upper limb therapy group at 3 months. No other differences were clinically important and statistically significant. Participants found the robot-assisted training and the enhanced upper limb therapy group programmes acceptable. Neither intervention, as provided in this trial, was cost-effective at current National Institute for Health and Care Excellence willingness-to-pay thresholds for a quality-adjusted life-year.ConclusionsRobot-assisted training did not improve upper limb function compared with usual care. Although robot-assisted training improved upper limb impairment, this did not translate into improvements in other outcomes. Enhanced upper limb therapy resulted in potentially important improvements on upper limb impairment, in performance of activities of daily living, and in mobility. Neither intervention was cost-effective.Future workFurther research is needed to find ways to translate the improvements in upper limb impairment seen with robot-assisted training into improvements in upper limb function and activities of daily living. Innovations to make rehabilitation programmes more cost-effective are required.LimitationsPragmatic inclusion criteria led to the recruitment of some participants with little prospect of recovery. The attrition rate was higher in the usual care group than in the robot-assisted training or enhanced upper limb therapy groups, and differential attrition is a potential source of bias. Obtaining accurate information about the usual care that participants were receiving was a challenge.Trial registrationCurrent Controlled Trials ISRCTN69371850.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 24, No. 54. See the NIHR Journals Library website for further project information.

Objective: To report the fidelity of the enhanced upper limb therapy programme within the Robot-Assisted Training for the Upper Limb after stroke (RATULS) randomized controlled trial, the types of goals selected and the proportion of goals achieved. Design: Descriptive analysis of data on fidelity, goal selection and achievement from an intervention group within a randomized controlled trial. Setting: Out-patient stroke rehabilitation within four UK NHS centres. Subjects: 259 participants with moderate-severe upper limb activity limitation (Action Research Arm Test 0–39) between one week and five years post first stroke. Intervention: The enhanced upper limb therapy programme aimed to provide 36 one-hour sessions, including 45 minutes of face-to-face therapy focusing on personal goals, over 12 weeks. Results: 7877/9324 (84%) sessions were attended; a median of 34 [IQR 29–36] per participant. A median of 127 [IQR 70–190] repetitions were achieved per participant per session attended. Based upon the Canadian Occupational Performance Measure, goal categories were: self-care 1449/2664 (54%); productivity 374/2664 (14%); leisure 180/2664 (7%) and ‘other’ 661/2664 (25%). For the 2051/2664 goals for which data were available, 1287 (51%) were achieved, ranging between 27% by participants more than 12 months post stroke with baseline Action Research Arm Test scores 0–7, and 88% by those less than three months after stroke with scores 8–19. Conclusions: Intervention fidelity was high. Goals relating to self-care were most commonly selected. The proportion of goals achieved varied, depending on time post stroke and baseline arm activity limitation.

ObjectiveTo determine whether robot-assisted training is cost-effective compared with an enhanced upper limb therapy (EULT) programme or usual care.DesignEconomic evaluation within a randomised controlled trial.SettingFour National Health Service (NHS) centres in the UK: Queen’s Hospital, Barking, Havering and Redbridge University Hospitals NHS Trust; Northwick Park Hospital, London Northwest Healthcare NHS Trust; Queen Elizabeth University Hospital, NHS Greater Glasgow and Clyde; and North Tyneside General Hospital, Northumbria Healthcare NHS Foundation Trust.Participants770 participants aged 18 years or older with moderate or severe upper limb functional limitation from first-ever stroke.InterventionsParticipants randomised to one of three programmes provided over a 12-week period: robot-assisted training plus usual care; the EULT programme plus usual care or usual care.Main economic outcome measuresMean healthcare resource use; costs to the NHS and personal social services in 2018 pounds; utility scores based on EQ-5D-5L responses and quality-adjusted life years (QALYs). Cost-effectiveness reported as incremental cost per QALY and cost-effectiveness acceptability curves.ResultsAt 6 months, on average usual care was the least costly option (£3785) followed by EULT (£4451) with robot-assisted training being the most costly (£5387). The mean difference in total costs between the usual care and robot-assisted training groups (£1601) was statistically significant (pConclusionsThe cost-effectiveness analysis suggested that neither robot-assisted training nor EULT, as delivered in this trial, were likely to be cost-effective at any of the cost per QALY thresholds considered.Trial registration numberISRCTN69371850.

Summary Background Loss of arm function is a common problem after stroke. Robot-assisted training might improve arm function and activities of daily living. We compared the clinical effectiveness of robot-assisted training using the MIT-Manus robotic gym with an enhanced upper limb therapy (EULT) programme based on repetitive functional task practice and with usual care. Methods RATULS was a pragmatic, multicentre, randomised controlled trial done at four UK centres. Stroke patients aged at least 18 years with moderate or severe upper limb functional limitation, between 1 week and 5 years after their first stroke, were randomly assigned (1:1:1) to receive robot-assisted training, EULT, or usual care. Robot-assisted training and EULT were provided for 45 min, three times per week for 12 weeks. Randomisation was internet-based using permuted block sequences. Treatment allocation was masked from outcome assessors but not from participants or therapists. The primary outcome was upper limb function success (defined using the Action Research Arm Test [ARAT]) at 3 months. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN69371850. Findings Between April 14, 2014, and April 30, 2018, 770 participants were enrolled and randomly assigned to either robot-assisted training (n=257), EULT (n=259), or usual care (n=254). The primary outcome of ARAT success was achieved by 103 (44%) of 232 patients in the robot-assisted training group, 118 (50%) of 234 in the EULT group, and 85 (42%) of 203 in the usual care group. Compared with usual care, robot-assisted training (adjusted odds ratio [aOR] 1·17 [98·3% CI 0·70–1·96]) and EULT (aOR 1·51 [0·90–2·51]) did not improve upper limb function; the effects of robot-assisted training did not differ from EULT (aOR 0·78 [0·48–1·27]). More participants in the robot-assisted training group (39 [15%] of 257) and EULT group (33 [13%] of 259) had serious adverse events than in the usual care group (20 [8%] of 254), but none were attributable to the intervention. Interpretation Robot-assisted training and EULT did not improve upper limb function after stroke compared with usual care for patients with moderate or severe upper limb functional limitation. These results do not support the use of robot-assisted training as provided in this trial in routine clinical practice. Funding National Institute for Health Research Health Technology Assessment Programme.

Motor deficits are common outcomes of neurological conditions such as stroke. In order to design personalised motor rehabilitation programmes such as robot-assisted therapy, it would be advantageous to predict how a patient might respond to such treatment. Spontaneous neural activity has been observed to predict differences in the ability to learn a new motor behaviour in both healthy and stroke populations. This study investigated whether spontaneous resting-state functional connectivity could predict the degree of motor adaptation of right (dominant) upper limb reaching in response to a robot-mediated force field. Spontaneous neural activity was measured using resting-state electroencephalography (EEG) in healthy adults before a single session of motor adaptation. The degree of beta frequency (β; 15–25 Hz) resting-state functional connectivity between contralateral electrodes overlying the left primary motor cortex (M1) and the anterior prefrontal cortex (aPFC) could predict the subsequent degree of motor adaptation. This result provides novel evidence for the functional significance of resting-state synchronization dynamics in predicting the degree of motor adaptation in a healthy sample. This study constitutes a promising first step towards the identification of patients who will likely gain most from using robot-mediated upper limb rehabilitation training based on simple measures of spontaneous neural activity.

Recovery from a stroke is a dynamic time-dependent process, in which the central nervous system reorganises to accommodate for the impact of the injury. The purpose of this paper is to review recent longitudinal studies of changes in brain connectivity after stroke. A systematic review of research papers reporting functional or effective connectivity at two or more time points in stroke patients was conducted. Stroke leads to an early reduction of connectivity in the motor network. With recovery time, the connectivity increases and can reach the same levels as in healthy participants. The increase in connectivity is correlated with functional motor gains. A new, more randomised pattern of connectivity may then emerge in the longer term. In some instances, a pattern of increased connectivity even higher than in healthy controls can be observed, and is related either to a specific time point or to a specific neural structure. Rehabilitation interventions can help improve connectivity between specific regions. Moreover, motor network connectivity undergoes reorganisation during recovery from a stroke and can be related to behavioural recovery. A detailed analysis of changes in connectivity pattern may enable a better understanding of adaptation to a stroke and how compensatory mechanisms in the brain may be supported by rehabilitation.

There is increasing interest in exploring the use of functional MRI neurofeedback (fMRI-NF) as a therapeutic technique for a range of neurological conditions such as stroke and Parkinson's disease (PD). One main therapeutic potential of fMRI-NF is to enhance volitional control of damaged or dysfunctional neural nodes and networks via a closed-loop feedback model using mental imagery as the catalyst of self-regulation. The choice of target node/network and direction of regulation (increase or decrease activity) are central design considerations in fMRI-NF studies. Whilst it remains unclear whether the primary motor cortex (M1) can be activated during motor imagery, the supplementary motor area (SMA) has been robustly activated during motor imagery. Such differences in the regulation potential between primary and supplementary motor cortex are important because these areas can be differentially affected by a stroke or PD, and the choice of fMRI-NF target and grade of self-regulation of activity likely have substantial influence on the clinical effects and cost effectiveness of NF-based interventions. In this study we therefore investigated firstly whether healthy subjects would be able to achieve self-regulation of the hand-representation areas of M1 and the SMA using fMRI-NF training. There was a significant decrease in M1 neural activity during fMRI-NF, whereas SMA neural activity was increased, albeit not with the predicated graded effect. This study has important implications for fMRI-NF protocols that employ motor imagery to modulate activity in specific target regions of the brain and to determine how they may be tailored for neurorehabilitation., Highlights • Graded fMRI neurofeedback can separate self-regulation effects from general cognitive ones. • There is a significant negative BOLD response in M1 during kinaesthetic motor imagery. • SMA shows robust positive BOLD responses during kinaesthetic motor imagery. • Participants can target discrete levels of BOLD response in SMA using kinaesthetic motor imagery. • For our paradigm neurofeedback provides only minimal extra control of BOLD signals in SMA.

Most gait training systems are designed for acute and subacute neurological inpatients. Many systems are used for relearning gait movements (nonfunctional training) or gait cycle training (functional gait training). Each system presents its own advantages and disadvantages in terms of functional outcomes. However, training gait cycle movements is not sufficient for the rehabilitation of ambulation. There is a need for new solutions to overcome the limitations of existing systems in order to ensure individually tailored training conditions for each of the potential users, no matter the complexity of his or her condition. There is also a need for a new, integrative approach in gait rehabilitation, one that encompasses and addresses all aspects of physical as well as psychological aspects of ambulation in real-life multitasking situations. In this respect, a multidisciplinary multinational team performed an overview of the current technology for gait rehabilitation and reviewed the principles of ambulation training.

BACKGROUND: Muscle co-contraction is a strategy of increasing movement accuracy and stability employed in dealing with perturbation of movement. It is often seen in neuropathological populations. The direction of movement influences the pattern of co-contraction, but not all movements are easily achievable for populations with motor deficits. Manipulating the direction of the force instead, may be a promising rehabilitation protocol to train movement with use of a co-contraction reduction strategy. Force field learning paradigms provide a well described procedure to evoke and test muscle co-contraction. OBJECTIVE: The aim of this study was to test the muscle co-contraction pattern in a wide range of arm muscles in different force-field directions utilising a robot-assisted force field learning paradigm of motor adaptation. METHOD: 42 participants volunteered to participate in a study utilising robot-assisted motor adaptation paradigm with clockwise or counter-clockwise force field. Kinematics and surface electromyography (EMG) of eight arm muscles has been measured. RESULTS: Both muscle activation and co-contraction was earlier and stronger in flexors in clockwise condition and in extensors in the counter-clockwise condition. CONCLUSIONS: Manipulating the force field direction leads to changes in the pattern of muscle co-contraction.

Adaptation of arm reaching in a novel force field involves co-contraction of upper limb muscles, but it is not known how the co-ordination of multiple muscle activation is orchestrated. We have used intermuscular coherence (IMC) to test whether a coherent intermuscular coupling between muscle pairs is responsible for novel patterns of activation during adaptation of reaching in a force field. Subjects (N = 16) performed reaching trials during a null force field, then during a velocity-dependent force field and then again during a null force field. Reaching trajectory error increased during early adaptation to the force-field and subsequently decreased during later adaptation. Co-contraction in the majority of all possible muscle pairs also increased during early adaptation and decreased during later adaptation. In contrast, IMC increased during later adaptation and only in a subset of muscle pairs. IMC consistently occurred in frequencies between ~40–100 Hz and during the period of arm movement, suggesting that a coherent intermuscular coupling between those muscles contributing to adaptation enable a reduction in wasteful co-contraction and energetic cost during reaching.

The emergence of smart phones has had a positive impact on society as the range of features and automation has allowed people to become more productive while they are on the move. On the contrary, the use of these devices has also become a distraction and hindrance, especially for pedestrians who use their phones whilst walking on the streets. This is reinforced by the fact that pedestrian injuries due to the use of mobile phones has now exceeded mobile phone related driver injuries. This paper describes an approach that measures the different levels of distraction encountered by pedestrians whilst they are walking. To distinguish between the distractions within the brain the proposed work analyses data collected from mobile sensors (accelerometers for movement, mobile EEG for electroencephalogram signals from the brain). The long-term motivation of the proposed work is to provide pedestrians with notifications as they approach potential hazards while they walk on the street conducting multiple tasks such as using a smart phone.

Purpose of review Recent developments in functional magnetic resonance imaging (fMRI) have catalyzed a new field of translational neuroscience. Using fMRI to monitor the aspects of task-related changes in neural activation or brain connectivity, investigators can offer feedback of simple or complex neural signals/patterns back to the participant on a quasireal-time basis [real-time-fMRI-based neurofeedback (rt-fMRI-NF)]. Here, we introduce some background methodology of the new developments in this field and give a perspective on how they may be used in neurorehabilitation in the future. Recent findings The development of rt-fMRI-NF has been used to promote self-regulation of activity in several brain regions and networks. In addition, and unlike other noninvasive techniques, rt-fMRI-NF can access specific subcortical regions and in principle any region that can be monitored using fMRI including the cerebellum, brainstem and spinal cord. In Parkinson's disease and stroke, rt-fMRI-NF has been demonstrated to alter neural activity after the self-regulation training was completed and to modify specific behaviours. Summary Future exploitation of rt-fMRI-NF could be used to induce neuroplasticity in brain networks that are involved in certain neurological conditions. However, currently, the use of rt-fMRI-NF in randomized, controlled clinical trials is in its infancy.

This study determined whether recovery of upper limb position control using submaximal force production correlates with an improvement in functional arm impairment during early recovery from stroke.Ten consecutive inpatients were recruited from a stroke unit. Each patient was in early recovery (8 weeks post-lesion) from their first ever stroke. Evaluations of submaximal continuous force production and position control, maximal force production at the shoulder and a clinical outcome measure of motor impairment (Fugl-Meyer score; FM) were performed 20 days post-stroke as a baseline and then once a week for the following four weeks.Submaximal force production and its modulation during a position-holding task improved in early recovery after stroke, whereas maximal force production did not. Better modulation of submaximal force production enabled improved arm position control which was significantly correlated to the changes in FM score of motor impairment during recovery.This study demonstrated that improvement in submaximal force modulation can operate as a mechanism enabling better motor behaviour such as arm position control during early recovery from a stroke.Future rehabilitation strategies may benefit from adding submaximal force development and modulation to early interventions after stroke.

Previous studies have shown that the primary motor cortex (M1) may drive part of the feed forward control of well learnt simple movements by specifying patterns of muscle activation. This study explored the role of the M1 in the feed forward control of newly formed movement patterns after motor adaptation. Ten healthy right-handed subjects performed planar, centre-out arm reaching movement trials with a robotic manipulandum in three phases: a null force field (baseline), a velocity-dependent force field (adaptation; 25 Nsm-1) and again in a null force field (deadaptation). Reaching error and voluntary EMG were recorded from the biceps and triceps before, during and after motor adaptation. We also explored the effects of motor adaptation on evoked responses to single and paired pulse Transcranial Magnetic Stimulation from the same muscles at different delays after a visual go command, but before the onset of voluntary muscle activity. After the force field was removed, subjects produced reaching overshoot characteristic of adaptive internal model formation. Following motor adaptation, there was a significant increase in corticospinal excitability, reduction in short interval intracortical inhibition and increase in short interval intracortical facilitation that was associated with a sustained increase in voluntary muscle activity in the biceps. The adaptation-driven increase in reaching overshoot coupled with the increase in voluntary activity, corticospinal and intracortical excitability in the biceps suggests that the M1 may specify some of the feed forward components of newly learnt internal models through the control of specific muscles.

Slowing and loss of muscle power are major factors limiting physical performance but little is known about the molecular mechanisms involved. The slowing might be a consequence of slow detachment of cross bridges and, if this were the case, then a reduction in the ATP cost of an isometric contraction would be expected as the muscle fatigued. The human anterior tibialis muscle was stimulated repeatedly under ischaemic conditions at 50 Hz for 1.6 s with a 50% duty cycle and muscle metabolites measured by 31P magnetic resonance spectroscopy. Over the course of 20 contractions the half-time of relaxation increased from 36.5 ± 0.09 ms (mean ±s.e.m.) to 113 ± 17 ms and isometric force was reduced to 63 ± 3% of the initial value. ATP turnover was determined from the change in high energy phosphates and lactate production, the latter estimated from the change of intracellular pH. ATP turnover over the first three contractions was 2.45 ± 0.09 mm s−1 and decreased to 1.8 ± 0.06 mm s−1 over the last five tetani. However, when this latter value was normalised for the decrease in isometric force, it became 2.56 ± 0.3 mm s−1, which is the same as the turnover of the fresh muscle. The data suggest that the rate of cross bridge detachment is unaffected by fatigue and are consistent the suggestion that it is the rate of attachment which is slowed rather than the rate of detachment. The present results focus attention on stages in the cross bridge cycle concerned with attachment and the transition from low to high force states that may be influenced by metabolic changes in the fatiguing muscle.

Human subjects can quickly adapt and maintain performance of arm reaching when experiencing novel physical environments such as robot-induced velocity-dependent force fields. Using anodal transcranial direct current stimulation (tDCS) this study showed that the primary motor cortex may play a role in motor adaptation of this sort. Subjects performed arm reaching movement trials in three phases: in a null force field (baseline), in a velocity-dependent force field (adaptation; 25 N s m−1) and once again in a null force field (de-adaptation). Active or sham tDCS was directed to the motor cortex representation of biceps brachii muscle during the adaptation phase of the motor learning protocol. During the adaptation phase, the global error in arm reaching (summed error from an ideal trajectory) was similar in both tDCS conditions. However, active tDCS induced a significantly greater global reaching (overshoot) error during the early stage of de-adaptation compared to the sham tDCS condition. The overshoot error may be representative of the development of a greater predictive movement to overcome the expected imposed force. An estimate of the predictive, initial movement trajectory (signed error in the first 150 ms of movement) was significantly augmented during the adaptation phase with active tDCS compared to sham tDCS. Furthermore, this increase was linearly related to the change of the overshoot summed error in the de-adaptation process. Together the results suggest that anodal tDCS augments the development of an internal model of the novel adapted movement and suggests that the primary motor cortex is involved in adaptation of reaching movements of healthy human subjects.

Background Paired-pulse transcranial magnetic stimuli (TMS) applied to the motor cortex enhances motor-evoked potential (MEP) responses at specific interpulse intervals (IPIs), probably from summation of I-waves by the secondary TMS pulse. This study investigated the properties of I-wave periodicity by comparing double-pulse with triple-pulse TMS at varying IPIs and stimulus intensities. Methods TMS was delivered to the optimal scalp position for the resting dominant first dorsal interosseous muscle at either active motor threshold (AMT) or AMT-5% stimulator output. In experiment 1, 4 conditions were tested, a double-pulse (D 1.5 ; IPI=1.5 milliseconds), and triplets comprising D 1.5 with the addition of a third pulse at 1.5, 2.0, or 3.0 milliseconds (T 1.5 1.5 , T 1.5 2.0 , and T 1.5 3.0 , respectively). Each condition was tested at 2 stimulation intensities. In a second experiment, the same protocol was repeated with a single-pulse (giving an MEP equivalent to D 1.5 ) replacing the first 2 pulses in each triplet. Results At AMT, MEP responses were significantly larger for T 1.5 1.5 and T 1.5 3.0 compared with D 1.5 . Triple-pulse stimulation at AMT-5% resulted in no additional increase in MEP amplitude, or effect of IPI. Double-pulse TMS showed similar effects to the triplets when the first pulse was delivered at an intensity equivalent to D 1.5 . Conclusions The results are consistent with an intensity-dependent facilitation of MEPs produced by triple-pulse TMS, possibly through summation of cortical I-waves. Triple-pulse TMS at I-wave periodicity may have application in the investigation of the cortical circuitry involved in the generation of I-waves, or form a basis for the further development of neuromodulatory TMS interventions.

Robot-mediated therapy can help improve walking ability in patients following injuries to the central nervous system. However, the efficacy of this treatment varies between patients, and evidence for the mechanisms underlying functional improvements in humans is poor, particularly in terms of neural changes in the spinal cord. Here, we review the recent literature on spinal plasticity induced by robotic-based training in humans and propose recommendations for the measurement of spinal plasticity using robotic devices. Evidence for spinal plasticity in humans following robotic training is limited to the lower limbs. Body weight-supported (BWS) robotic-assisted step training of patients with spinal cord injury (SCI) or stroke patients has been shown to lead to changes in the amplitude and phase modulation of spinal reflex pathways elicited by electrical stimulation or joint rotations. Of particular importance is the finding that, among other changes to the spinal reflex circuitries, BWS robotic-assisted step training in SCI patients resulted in the re-emergence of a physiological phase modulation of the soleus H-reflex during walking. Stretch reflexes elicited by joint rotations constitute a tool of interest to probe spinal circuitry since the technology necessary to produce these perturbations could be integrated as a natural part of robotic devices. Presently, ad-hoc devices with an actuator capable of producing perturbations powerful enough to elicit the reflex are available but are not part of robotic devices used for training purposes. A further development of robotic devices that include the technology to elicit stretch reflexes would allow for the spinal circuitry to be routinely tested as a part of the training and evaluation protocols.

Repeated trials of hypercapnic exercise [deltaPET CO2 = 7 (1) mmHg] augment the increase in inspired minute ventilation and tidal volume (V(T)) in the early phase of subsequent trials of unencumbered exercise alone. The increase in V(T) in the first 20 s of exercise was correlated to the increase in V(T) evoked during hypercapnic exercise trials, suggesting that the evoked increase in V(T) during conditioning may be a factor in mediating associative conditioning. To test this hypothesis, inspiratory resistive loading (IRL) was employed to evoke an increase in V(T) [deltaV(T) = 0.4 (0.1) I(BTPS)] during conditioning exercise trials [IRL + EX; deltaP(ET)CO2 = 2 (l) mmHg]. IRL + EX associative conditioning elicited a significant augmentation of the early minute ventilation (+46%) and V(T) (+100%) responses to subsequent unencumbered exercise. The latter was correlated to the evoked increase in V(T) during associative conditioning with IRL + EX. The results support the hypothesis that an evoked increase in V(T) during associative conditioning could be a factor in eliciting long-term modulation of minute ventilation in subsequent unencumbered exercise. The results further indicated that the modulation of ventilation early in exercise is not due to sensitisation to repeated trials of either IRL or exercise alone. Associative conditioning may shape the ventilatory response to exercise through a process of motor learning. Data are presented as mean (SEM) unless otherwise stated.

During constant-load exercise above the lactate threshold, oxygen-uptake kinetics deviate from the pattern seen below the threshold, with an additional, delayed component superimposed on the monoexponential pattern. It was hypothesised that this slow component is due to the progressive recruitment of type II muscle fibres. Oxygen uptake was measured for six male power athletes (group P) and six male endurance athletes (group E) during constant-load knee extension exercise tests in order to determine slow component amplitude. In addition, an electrical stimulation protocol was employed in order to assess the functional contractile profile and fatiguability of the knee extensors. The amplitude of the slow component during exercise was significantly ( P0.05) greater in group P than in group E when expressed as an absolute value [mean (SEM)=77 (17) ml min(-1) and 24 (16) ml min(-1)] and when normalised to end-exercise oxygen uptake, VO(2) [8.2 (0.5)% and 2.6 (1.8)%]. Group differences were observed for percentage force loss during the electrical stimulation protocol [50.0 (3.4)% and 31.5 (3.7)% for groups P and E, respectively], increase in relaxation time from start to end of the fatigue test [87.9 (15.5)% and 31.1 (11.9)%], and relaxation time for fresh muscle [32.4 (1.0) ms and 40.6 (2.1) ms]. These contractile parameters may indicate a higher proportion of type II fibres in group P compared with group E. These experiments have shown evidence of a relationship between the amplitude of the slow component and muscle contractile properties, indicating that the origin of the slow component may lie in the pattern of different muscle fibre types.

This study exploited the alterations in pedal speed and joints kinematics elicited by changing crank length (CL) to test how altered task mechanics during cycling will modulate the muscle activation characteristics in human rectus femoris (RF), biceps femoris long head (BF), soleus (SOL) and tibialis anterior (TA). Kinetic (torque), kinematic (joint angle) and muscle activity (EMG) data were recorded simultaneously from both legs of 10 healthy adults (aged 20–38 years) during steady-state cycling at ~60 rpm and 90–100 W with three symmetrical CLs (155 mm, 175 mm and 195 mm). The CL elongation (ΔCL) resulted in similar increases in the knee joint angles and angular velocities during extension and flexion, whilst the ankle joint kinematics was significantly influenced only during extension. ΔCL resulted in significantly reduced amplitude and prolonged duration of BF EMG, increased mean SOL and TA EMG amplitudes, and shortened SOL activity time. RF activation parameters and TA activity duration were not significantly affected by ΔCL. Thus total SOL and RF EMG activities were similar with different CLs, presumably enabling steady power output during extension. Higher pedal speeds demand an increased total TA EMG activity and decreased total BF activity to propel the leg through flexion into extension with a greater degree of control over joint stability. We concluded that the proprioceptive information about the changes in the cycling kinematics is used by central neural structures to adapt the activation parameters of the individual muscles to the kinetic demands of the ongoing movement, depending on their biomechanical function.

Exercise in youth may affect bone "quality" as well as quantity. Using the rat model, 1.5-month-old females were divided into four weight-matched groups, exercised short-term (6 weeks, E(s), n = 20) and long-term (14 weeks, E(L), n = 10) by access to monitored running wheels, and corresponding "sedentary" controls (S(S) short-term, n = 20; S(L) long-term, n = 10). Femora were either plastic-embedded or fresh-frozen. Transverse histological slices, 100 microm thick, were cut midshaft, while similar cryosections, 8 microm thick, were prepared from the same site and also coronal to the femoral neck region. An image analyser measured femoral neck and midshaft microarchitecture, while immunostaining localized collagen type III-rich fibres (CIII, an index of Sharpey fibre insertions) and osteopontin-rich osteons (OPN, an index of remodelling). Exercise increased cortical bone (proximal width +18%, midshaft area +7%). It also raised cancellous bone volume (+25%) by trabecular thickening (+30%) with more intraosseous vascularity and new trabecular interconnections (node-terminus ratio, +57%; trabecular pattern factor, -147%; marrow star volume. -48%). In the cortex a prominent discrete subperiosteal domain became wider (+50% midshaft) with exercise and contained more numerous (+15%) CIII-stained fibres. In contrast the encircled inner bone developed more numerous (+14%) OPN-rich osteons. It is concluded that short-term voluntary exercise augments both cortical and cancellous microarchitecture. It also alters protein composition, such that expanding arrays of Sharpey's fibres within a circumferential proximal domain (Part I) interconnect more powerfully with the musculature and interface more robustly with the core bone that in response becomes more vascular and biodynamic, providing further insight into how muscle mass may be skeletally translated.

This study demonstrated that expiratory resistive loading (ERL) induced an increase in force fluctuation during a unilateral, submaximal isometric contraction of the non-dominant left vastus lateralis (VL), but did not effect force fluctuation during complex bilateral contractions. The increase in force fluctuation in the unilateral left VL contraction during ERL was not accompanied by alterations of average force production, motor unit activation (median power frequency) or airflow rate when compared to the bilateral contraction. Inspiratory RL (IRL) did not significantly affect force fluctuation in unilateral or bilateral contractions. The results concur with previous reports of ERL, but not IRL, effecting VL function and suggest that patients with obstructive diseases may also be vulnerable to reduced fine motor control.

Resistive loaded breathing (RL) can modulate the electromyogram pattern during an isometric arm flexion or leg extension at 70-80% of voluntary maximal contraction (MVC). This study tested the hypothesis that an interaction between the respiratory muscle afferent activity during RL and the descending motor drive may also have a functional impact on voluntary maximal performance. Therefore, muscle contractions (100% of MVC) were performed with four muscles during phase specific expiratory (ERL) or inspiratory (IRL) resistive loading and force or the steadiness of the force produced were compared with non-RL controls. Both IRL and ERL reduced MVC in leg muscles, especially biceps femoris. IRL caused a reduction in steadiness in the same muscle. These results suggest a hitherto understated impact of RL on functional performance in leg muscles.

A model of voluntary exercise, in which rats are given free access to a running wheel over a 14-week period, led to left ventricular hypertrophy. To test whether the hypertrophic response to exercise was uniformly distributed across the ventricular wall, single ventricular myocytes were isolated from the sub-epicardium (EPI) and sub-endocardium (ENDO) of exercised rats and from sedentary rats for comparison. Cellular hypertrophy (approximately 20 % greater cell volume) was seen in ENDO cells from exercised animals, but no significant changes were observed in EPI cells when compared with sedentary controls. This regional effect of exercise may be a response to transmural changes in ventricular wall stress and/or strain. Cell contraction was measured as cell shortening in ENDO and EPI cells at stimulation frequencies between 1 and 9 Hz at 37 °C. Exercise training had no effect on cell shortening. Positive and negative contraction–frequency relationships (CFRs) were found in both EPI and ENDO cells between 1 and 5 Hz; at higher frequencies (5–9 Hz), all myocytes displayed a negative CFR. The CFR of a myocyte was, therefore, independent of regional origin and unaffected by exercise. These results suggest that, in vivo, the rat heart displays a negative CFR. We conclude that increased cell size may be a more important adaptive response to exercise than a modification of excitation– contraction coupling.

The recovery of functional movements following injury to the central nervous system (CNS) is multifaceted and is accompanied by processes occurring in the injured and non-injured hemispheres of the brain or above/below a spinal cord lesion. The changes in the CNS are the consequence of functional and structural processes collectively termed neuroplasticity and these may occur spontaneously and/or be induced by movement practice. The neurophysiological mechanisms underlying such brain plasticity may take different forms in different types of injury, for example stroke vs. spinal cord injury (SCI). Recovery of movement can be enhanced by intensive, repetitive, variable and rewarding motor practice. To this end, robots that enable or facilitate repetitive movements have been developed to assist recovery and rehabilitation. Here, we suggest some elements of robot-mediated training such as assistance, perturbation and unloading may have the potential to enhance neuroplasticity. Together the elemental components for developing integrated robot-mediated training protocols may form part of a neurorehabilitation framework alongside those methods already employed by therapists. Robots could thus open up a wider choice of options for delivering movement rehabilitation grounded on the principles underpinning neuroplasticity in the human CNS.

Expiratory only resistive loaded breathing (RL) reduces high energy electromyogram (EMG) power (EH) during an isometric contraction of a leg extensor muscle, but not an arm flexor. An interaction between afferent activity during expiratory RL and inspiratory non-loaded phases of breathing, which the contraction spanned, could have accounted for the reduced EH in these long contractions. Therefore this study tested the hypothesis that brief arm extensor muscle contractions (70% of maximal force), performed during a single phase of expiratory RL, would also exhibit reduced EH. Surprisingly, EH in triceps, but not biceps brachii was reduced significantly when the contraction was performed during inspiratory RL rather than expiratory RL. The results suggest that either (a) short and prolonged contractions or (b) motor drive to arm and leg extensors are affected differently by RL.

1. The metabolic costs and physiological consequences of shortening contractions of a human muscle working in situ have been compared with those of the muscle maintaining a continuous isometric contraction and when performing repeated brief isometric contractions. 2. After a total of 10 s stimulation, the shortening and intermittent brief isometric protocols had very similar effects, causing a 30% loss of force and a threefold increase in the half-time of relaxation. This was in contrast to the continuous isometric contraction protocol where there was less than 10% loss of force or slowing of relaxation. 3. The ATP cost over the first 5 s of the continuous isometric protocol was 27 mmol (l intracellular water)-1 while for the shortening and repeated brief isometric protocols the costs were 48 and 46 mmol (l intracellular water)-1, respectively. 4. The results show that shortening and repeated brief isometric contractions are considerably more energetically demanding, and hence more fatiguing, than sustained isometric contractions.

The effects of an intermittent high intensity stimulus (running) or a chronic low intensity stimulus (cold acclimation) of oxidative metabolism on maximal oxygen uptake (VO2,max), lung O2 diffusing capacity (DLO2) and skeletal muscle as well as fat tissue mitochondrial content in growing guinea pigs are described. Young male guinea pigs were assigned to three experimental groups (n = 5): control (C), endurance trained (T; at 70% VO2max) or cold acclimated (CA; 5-7 degrees C) for six weeks. Animals were sacrificed at the end of the experimental period and tissue for morphometric analysis of the lung, muscle and interscapular fat was sampled. T and CA animals significantly increased weight specific VO2max by 23% and 29%, respectively. Despite a significant increase in absolute lung volume in T (+10%) and in weight specific lung volume in CA (+20%) neither absolute nor weight specific DLO2 was significantly affected by the experimental treatments. In trained animals the total volume of mitochondria remained unchanged in samples representative for the entire musculature but was significantly increased in M. vastus intermedius (+72%). Intramyocellular lipids increased significantly both in M. vastus intermedius (+244%) as well as in the whole body musculature (+164%). Cold acclimation increased the mitochondrial content of the interscapular fat pad by approximately 20-fold but had no effect on total mitochondrial volume in muscle. We conclude that the increase in oxygen demand resulting from exercise training or from cold acclimation could be accomodated by the existing lung diffusing capacity and did not induce a global change of oxidative capacity in skeletal muscle tissue in growing guinea pigs. Exercise training caused oxidative capacity to increase only in a locomotor muscle activated during running whereas cold acclimation greatly increased interscapular fat tissue oxidative capacity.

A sharp intake of breath followed by a strong vocalisation is widely observed in response to acute pain although its function and mechanism is poorly understood. This study investigated the effect of percutaneous (overlying the tibial bone) electrical stimulation delivered early (20–30% of inspiratory time) during inspiration (INSP) or expiration (EXP) (20–30% of expiratory time) at sensory intensities at (100%), above (125%) and below (50% and 75%) the pre-determined pain threshold (PT), upon within-a-breath respiratory parameters (via pneumotachography). All INSP stimulation intensities provoked significant inspiratory time shortening thereby elevating mean inspiratory flow. Tidal volume, but not peak flow was increased in response to 100% PT and 125% PT stimulation (vs. PRE). Shortening and increased tidal volume combined to evoke significant mean inspiratory airflow increments. In contrast, EXP stimulation failed to evoke any effect. Thus, our study provides evidence of a within-a-breath inspiratory-specific, augmentory response to noxious stimulation.

Small increases in respiratory dead space (VD) augment the exercise ventilatory response by a serotonin-dependent mechanism known as short-term modulation (STM). We tested the hypotheses that the relevant serotonin receptors for STM are in the spinal cord, and are of the 5-HT2-receptor subtype. After preparing adult female goats with a mid-thoracic (T 6 –T8) subarachnoid catheter, ventilation and arterial blood gases were measured at rest and during treadmill exercise (4.8 km/h; 5% grade) with and without an increased VD (0.2–0.3 L). Measurements were made before and after spinal or intravenous administration of a broad-spectrum serotonin receptor antagonist (methysergide, 1–2 mg total) and a selective 5-HT2-receptor antagonist (ketanserin, 5–12 mg total). Although spinal methysergide had no effect on the exercise ventilatory response in control conditions, the augmented response with increased VD was impaired, allowing P a C O 2 to increase from rest to exercise. Spinal methysergide diminished both mean inspiratory flow and frequency responses to exercise with increased VD. Spinal ketanserin impaired P a C O 2 regulation with increased VD, although its ventilatory effects were less clear. Intrathecal dye injections indicated CSF drug distribution was caudal to the upper cervical spinal cord and intravenous drugs at the same total dose did not affect STM. We conclude that spinal 5-HT2 receptors modulate the exercise ventilatory response with increased VD in goats.

The aim of the present investigation was to test the hypothesis that long-term modulation (LTM) of the exercise ventilatory response, evidenced as an augmentation in minute ventilation (V(I)) and tidal volume (VT) during the early phase of exercise, is only evident when the muscle groups recruited are the same during testing and during hypercapnic exercise conditioning. Measurements of cardiorespiratory variables were made at rest and during leg cycling (fH=107+/-5) exercise in eight male subjects, 1 week before and 1 h after conditioning. Conditioning involved either: (a) ten trials of arm cranking exercise (V(I)=29.0+/-4.4), or (b) ten trials of arm cranking exercise paired with external respiratory dead space (1400 ml; V(I)=57.3+/-6.5). Neither arm conditioning paradigm evoked any of the modulatory responses described in previous studies. We, therefore, conclude that the general upregulation of the spinal respiratory motoneuron pool excitability after conditioning (the "final common pathway" hypothesis), may be inadequate to fully explain the underlying mechanisms of LTM of ventilation in humans.

Repeated hypercapnic exercise augmented the ventilatory response to subsequent trials of exercise alone in running goats and in humans performing arm exercise, suggesting a form of associative conditioning or 'long-term modulation' had taken place. These studies did not include 'control' single stimulus conditioning paradigms. This study demonstrated that ten repeated trials of familiar leg bicycling exercise with dead-space induced hypercapnia also elicited similar significant increases in inspired ventilation (+ 22%; P0.009) and tidal volume (VT; + 255 +/- 73 ml(BTPS); mean +/- S.E.M.; P = 0.004) within the first 20 sec of subsequent exercise only trials. Long-term modulation of the early ventilatory response to cycling was not fully replicated by ten trials of 'control' paradigms involving either repeated exercise alone or resting dead space alone. This study thus demonstrated that long term modulation of the early ventilatory response exercise was due to an explicit effect of associative conditioning and not simply sensitisation to repeated trials of a single stimulus.

Previous studies have shown that prolonged vibration of the rectus femoris decreases maximal voluntary knee extension performance in the ipsilateral leg. In the present study, measurements of maximal voluntary isometric knee extension contractions with the ipsilateral (right) leg and the contralateral (left) leg were made immediately before and after vibration treatment. Significant reductions in maximal force and maximum rate of force generation occurred in both the ipsilateral and contralateral legs following 30 minutes of continuous vibration at both 30 Hz and 120 Hz, with 30 Hz causing the greatest ipsilateral effects. However, although the level of neural activation (iEMG) of the vibrated muscle (right rectus femoris) was reduced following 30 Hz vibration ( P=0.026), there were no significant changes occurring in a synergistic muscle (right vastus lateralis) or in either contralateral muscle. It was concluded that muscle vibration may act through spinal reflex pathways to influence the homonymous motoneuron pool. The effects on contralateral force but not specific muscle iEMG suggest an effect on heteronymous motoneuron pools or an effect acting on central descending drive to contralateral muscles. These findings may have implications for the rehabilitation of patients with an immobilised limb.

Short-term (6 weeks) voluntary wheel running exercise in young female rats that were in an active growth phase resulted in whole-heart hypertrophy and myocyte concentric hypertrophy, when compared to sedentary controls. The cross-sectional area of ventricular myocytes from trained rats was significantly greater than for those isolated from sedentary rats, with the greatest change in morphology seen in sub-endocardial cells. There was no statistically significant effect of training on cell shortening in the absence of external mechanical loading, in [Ca2+](i) transients, or in myofilament Ca2+ sensitivity (assessed during re-lengthening following tetanic stimulation). Under the external mechanical load of carbon fibres, absolute force developed in myocytes from trained rats was significantly greater than in those from sedentary rats. This suggests that increased myocyte cross-sectional area is a major contractile adaptation to exercise in this model. Training did not alter the passive mechanical properties of myocytes or the relative distribution of titin isomers, which was exclusively of the short, N2B form. However, training did increase the steepness of the active tension-sarcomere length relationship, suggesting an exercise-induced modulation of the Frank-Starling mechanism. This effect would be expected to enhance cardiac contractility. Training lengthened the action potential duration of sub-epicardial myocytes, reducing the transmural gradient in action potential duration. This observation may be important in understanding the cellular causes of T-wave abnormalities found in the electrocardiograms of some athletes. Our study shows that voluntary exercise modulates the morphological, mechanical and electrical properties of cardiac myocytes, and that this modulation is dependent upon the regional origin of the myocytes.

Previous studies have suggested that motor cortex may be involved in complex control of respiration in man. In this study, we estimated the influence of a simple visuomotor reaction time task (VMT) on the inspiratory airflow curve (IFC) by comparing measurements of standard deviation (SD), C 0 complexity and approximate entropy (ApEn) of the IFC at rest and during VMT conditions. It was found that both C 0 complexity and ApEn, but not SD of the IFC were significantly increased during the VMT challenge. The results suggest that visuomotor pathways may modulate respiratory motor pathways, because an increase in ApEn is suggestive of increased coupling or communication between (motor) systems.

The control of ventilatory responses to mild or moderate dynamic exercise has been the subject of considerable debate for over a century. The prevailing view has been that the ventilatory response to exercise is stereotypical and rather unmalleable. However, paradigms involving novel associations of stimulus inputs have been shown to modulate breathing in short and longer time scales. The scope of this review includes examples of modified ventilatory responses to exercise which have been investigated in terms of neural mechanisms. An attempt to synthesise the available data into a model of neuromodulation is presented.