Chronic Functional Adaptations Induced by the Application of Transcranial Direct Current Stimulation Combined with Exercise Programs: A Systematic Review of Randomized Controlled Trials.

The present systematic review aimed to determine the chronic effects of the combination of transcranial direct current stimulation (tDCS) and exercise on motor function and performance outcomes. We performed a systematic literature review in the databases MEDLINE and Web of Science. Only randomized control trials that measured the chronic effect of combining exercise (comprising gross motor tasks) with tDCS during at least five sessions and measured any type of motor function or performance outcome were included. A total of 22 interventions met the inclusion criteria. Only outcomes related to motor function or performance were collected. Studies were divided into three groups: (a) healthy population (n = 4), (b) neurological disorder population (n = 14), and (c) musculoskeletal disorder population (n = 4). The studies exhibited considerable variability in terms of tDCS protocols, exercise programs, and outcome measures. Chronic use of tDCS in combination with strength training does not enhance motor function in healthy adults. In neurological disorders, the results suggest no additive effect if the exercise program includes the movements pretending to be improved (i.e., tested). However, although evidence is scarce, tDCS may enhance exercise-induced adaptations in musculoskeletal conditions characterized by pain as a limiting factor of motor function.

The effects of auditory startle and nonstartle stimuli on step initiation in Parkinson's disease.

BACKGROUND: Auditory external cues enhance step initiation in Parkinson's disease (PD) patients. We wanted to explore whether a startle reaction has a comparable effect on step initiation in PD. METHODS: Thirteen PD patients and 13 aged-matched controls participated in this study. Electromyography pattern and onset toe-off time during a step initiation task were recorded in response to three different stimuli: a visual imperative stimulus; visual stimulus simultaneous with a nonstartle auditory stimulus and with a startle auditory stimulus. RESULTS: In all subjects, onset of tibialis anterior was faster in the startle auditory condition, compared with the nonstartle auditory condition. However, in the patient group, there was no difference in onset of soleus and toe-off between the startle and nonstartle conditions. CONCLUSIONS: Startle reaction in PD patients demonstrates a disordered coupling between the anticipatory postural adjustments that initiate the weight shift and the movement to initiate toe-off during step initiation.

The effect of BDNF val66met polymorphism on visuomotor adaptation.

Brain-derived neurotrophic factor (BDNF) plays an important role in learning, memory, and brain plasticity. Humans with a val66met polymorphism in the BDNF gene have reduced levels of BDNF and alterations in motor learning and short-term cortical plasticity. In the current study, we sought to further explore the role of BDNF in motor learning by testing human subjects on a visuomotor adaptation task. In experiment 1, 21 subjects with the polymorphism (val/met) and 21 matched controls (val/val) were tested during learning, short-term retention (45 min), long-term retention (24 h), and de-adaptation of a 60° visuomotor deviation. We measured both mean error as well as rate of adaptation during each session. There was no difference in mean error between groups; however, val/met subjects had a reduced rate of adaptation during learning as well as during long-term retention, but not short-term retention or de-adaptation. In experiment 2, 12 val/met and 12 val/val subjects were tested on a larger 80° deviation, revealing a more pronounced difference in mean error during adaptation than the 60° deviation. These results suggest that BDNF may play an important role in visuomotor adaptive processes in the human.

Variability in non-invasive brain stimulation studies: Reasons and results.

Non-invasive brain stimulation techniques (NIBS), such as Theta Burst Stimulation (TBS), Paired Associative Stimulation (PAS) and transcranial Direct Current Stimulation (tDCS), are widely used to probe plasticity in the human motor cortex (M1). Although TBS, PAS and tDCS differ in terms of physiological mechanisms responsible for experimentally-induced cortical plasticity, they all share the ability to elicit long-term potentiation (LTP) and depression (LTD) in M1. However, NIBS techniques are all affected by relevant variability in intra- and inter-subject responses. A growing number of factors contributing to NIBS variability have been recently identified and reported. In this review, we have readdressed the issue of variability in human NIBS studies. We have first briefly discussed the physiological mechanisms responsible for TBS, PAS and tDCS-induced cortical plasticity. Then, we have provided statistical measures of intra- and inter-subject variability, as calculated in previous studies. Finally, we have reported in detail known sources of variability by categorizing them into physiological, technical and statistical factors. Improving knowledge about sources of variability could lead to relevant advances in designing new tailored NIBS protocols in physiological and pathological conditions.

Solutions for managing variability in non-invasive brain stimulation studies.

In the last three decades, a number of non-invasive brain stimulation (NIBS) protocols, capable of assessing and modulating plasticity in the human motor cortex (M1), have been described. For almost as long, NIBS has delivered the tantalising prospect of non-invasive neuromodulation as a therapeutic intervention for neurorehabilitation, psychiatry, chronic pain and other disease states. Apart from modest effects in depression, this early promise has not been realised since the symptomatic improvements produced by NIBS are generally weak. One key factor explaining this lack of clinical translation concerns variability in response to NIBS. Several studies have demonstrated a number of physiological, technical and statistical factors accounting for intra- and inter-subject variability. However, solutions to overcome this problem are still under debate. In the present review, we have provided a detailed description of methodological and technical solutions to control known factors influencing variability. We have also suggested potential strategies to strengthen and stabilize NIBS-induced after-effects. Finally, we propose new possible outcome variables which better reflect intrinsic cortical activity, allowing a more sensitive measurement and valid interpretation of responses to NIBS.

Postural Stability and Cognitive Performance of Subjects With Parkinson's Disease During a Dual-Task in an Upright Stance.

BACKGROUND: The reviewed studies on center of pressure (COP) displacement in Parkinson's disease (PD) subjects show important methodological differences and contradictory results with regard to healthy subjects. The dual-task paradigm method has been used to examine cognitive prioritization strategies to control concurrent postural and cognitive tasks. The motor requirements, such as pronouncing words, involved in the cognitive tasks used in double-task conditions could be related to the heterogeneity of the results. RESEARCH OBJECTIVE: To compare postural sway and cognitive performance in subjects with PD and controls using a dual-task paradigm with a cognitive task free of motor demands. We tried to examine the prioritization strategy of PD patients regarding healthy adults to control for concurrent postural and cognitive tasks. MATERIALS AND METHODS: 25 subjects with PD and 20 healthy controls carried out a postural task under both single-task and dual-task conditions. The postural task was to stand as still as possible, with eyes first open and then closed. The dual-task condition added a concurrent cognitive task based on phoneme monitoring. COP displacement variables and cognitive performance were compared between the groups and within-subject factors were also examined. RESULTS: PD participants showed higher COP displacement results than the controls. All participants shortened the mean sway radius in dual-task conditions compared with single-task conditions; only healthy subjects presented less transversal COP sway in dual-task conditions than in single-task conditions. The cognitive performance of PD patients on a phoneme monitoring task worsened when they carried it out while maintaining balance in a standing position compared to sitting. The opposite effect occurred in control subjects. CONCLUSION: This study confirms the negative influence of Parkinson's disease on the control of standing stability, increasing the COP sway amplitude. The attentional demands of a postural task, such as standing balance, may be greater in PD patients than in healthy subjects. This would affect the performance of patients during dual-task conditions to be able to control a postural task while performing other cognitive tasks. In these conditions, cognitive performance would be negatively affected. These results suggest that subjects with PD, at least during initial disease stages, prioritize postural control over other concurrent tasks, as is also seen in healthy subjects.

Distributed cortical structural properties contribute to motor cortical excitability and inhibition.

The link between the local structure of the primary motor cortex and motor function has been well documented. However, motor function relies on a network of interconnected brain regions and the link between the structural properties characterizing these distributed brain networks and motor function remains poorly understood. Here, we examined whether distributed patterns of brain structure, extending beyond the primary motor cortex can help classify two forms of motor function: corticospinal excitability and intracortical inhibition. To this effect, we recorded high-resolution structural magnetic resonance imaging scans in 25 healthy volunteers. To measure corticospinal excitability and inhibition in the same volunteers, we recorded motor evoked potentials (MEPs) elicited by single-pulse transcranial magnetic stimulation and short-interval intracortical inhibition (SICI) in a separate session. Support vector machine (SVM) pattern classification was used to identify distributed multi-voxel gray-matter areas, which distinguished subjects who had lower and higher MEPs and SICIs. We found that MEP and SICI classification could be predicted based on a widely distributed, largely non-overlapping pattern of voxels in frontal, parietal, temporal, occipital, and cerebellar regions. Thus, structural properties distributed over the brain beyond the primary motor cortex relate to motor function.

A Preliminary Comparison of Motor Learning Across Different Non-invasive Brain Stimulation Paradigms Shows No Consistent Modulations.

Non-invasive brain stimulation (NIBS) has been widely explored as a way to safely modulate brain activity and alter human performance for nearly three decades. Research using NIBS has grown exponentially within the last decade with promising results across a variety of clinical and healthy populations. However, recent work has shown high inter-individual variability and a lack of reproducibility of previous results. Here, we conducted a small preliminary study to explore the effects of three of the most commonly used excitatory NIBS paradigms over the primary motor cortex (M1) on motor learning (Sequential Visuomotor Isometric Pinch Force Tracking Task) and secondarily relate changes in motor learning to changes in cortical excitability (MEP amplitude and SICI). We compared anodal transcranial direct current stimulation (tDCS), paired associative stimulation (PAS25), and intermittent theta burst stimulation (iTBS), along with a sham tDCS control condition. Stimulation was applied prior to motor learning. Participants (n = 28) were randomized into one of the four groups and were trained on a skilled motor task. Motor learning was measured immediately after training (online), 1 day after training (consolidation), and 1 week after training (retention). We did not find consistent differential effects on motor learning or cortical excitability across groups. Within the boundaries of our small sample sizes, we then assessed effect sizes across the NIBS groups that could help power future studies. These results, which require replication with larger samples, are consistent with previous reports of small and variable effect sizes of these interventions on motor learning.

Enhancing consolidation of a rotational visuomotor adaptation task through acute exercise.

We assessed the effect of a single bout of intense exercise on the adaptation and consolidation of a rotational visuomotor task, together with the effect of the order of exercise presentation relative to the learning task. Healthy adult participants (n = 29) were randomly allocated to one of three experimental groups: (1) exercise before task practice, (2) exercise after task practice, and (3) task practice only. After familiarization with the learning task, participants undertook a baseline practice set. Then, four 60° clockwise rotational sets were performed, comprising an adaptation set and three retention sets at 1 h, 24 h, and 7 days after the adaptation set. Depending on the experimental group, exercise was presented before or after the adaptation sets. We found that error reduction during adaptation was similar regardless of when exercise was presented. During retention, significant error reduction was found in the retention set at 1 h for both exercise groups, but this enhancement was not present during subsequent retention sets, with no differences present between exercise groups. We conclude that an acute bout of intense exercise could positively affect retention, although the order in which exercise is presented does not appear to influence its benefits during the early stages of consolidation.

Relationship Between Non-invasive Brain Stimulation-induced Plasticity and Capacity for Motor Learning.

BACKGROUND: Cortical plasticity plays a key role in motor learning (ML). Non-invasive brain stimulation (NIBS) paradigms have been used to modulate plasticity in the human motor cortex in order to facilitate ML. However, little is known about the relationship between NIBS-induced plasticity over M1 and ML capacity. HYPOTHESIS: NIBS-induced MEP changes are related to ML capacity. METHODS: 56 subjects participated in three NIBS (paired associative stimulation, anodal transcranial direct current stimulation and intermittent theta-burst stimulation), and in three lab-based ML task (serial reaction time, visuomotor adaptation and sequential visual isometric pinch task) sessions. ANALYSIS: After clustering the patterns of response to the different NIBS protocols, we compared the ML variables between the different patterns found. We used regression analysis to explore further the relationship between ML capacity and summary measures of the MEPs change. We ran correlations with the "responders" group only. RESULTS: We found no differences in ML variables between clusters. Greater response to NIBS protocols may be predictive of poor performance within certain blocks of the VAT. "Responders" to AtDCS and to iTBS showed significantly faster reaction times than "non-responders." However, the physiological significance of these results is uncertain. CONCLUSION: MEP changes induced in M1 by PAS, AtDCS and iTBS appear to have little, if any, association with the ML capacity tested with the SRTT, the VAT and the SVIPT. However, cortical excitability changes induced in M1 by AtDCS and iTBS may be related to reaction time and retention of newly acquired skills in certain motor learning tasks.

Intra-individual variability in the response to anodal transcranial direct current stimulation.

OBJECTIVE: To test the intra-individual reliability in response to anodal transcranial direct current stimulation (AtDCS). METHODS: 45 healthy subjects received AtDCS (1 mA, 13 min) in two separate sessions, 6-12 months apart. Motor evoked potentials were collected at baseline and then at 5-min intervals after AtDCS for 1h. Short intracortical inhibition (SICI) was assessed at minutes 6 and 46 after AtDCS. RESULTS: AtDCS increased cortical excitability over minutes 0-30 post-stimulation in both sessions, with fair intra-individual reliability. 60% and 64% of subjects responded with the expected increase in cortical excitability in each session, respectively. 69% of the subjects maintained their response pattern between sessions during this timeframe. However, there were no significant effects on cortical excitability over the full hour post AtDCS in either session. SICI showed fair intra-individual reliability 6 min after AtDCS. CONCLUSION: A change in cortical excitability in the first half-hour post-AtDCS may be a good predictor of the response in a subsequent session. Furthermore, minute 15 post-stimulation showed the maximum increase in cortical excitability in both sessions. SIGNIFICANCE: We show for the first time that intra-individual variability is lower than inter-individual variability, and with fair intra-individual inter-sessional reliability for 30 min after AtDCS-subjects are likely to maintain their response patterns to tDCS between sessions, with implications for experimental and therapeutic applications of tDCS.

Gait Pattern and Cognitive Performance During Treadmill Walking in Parkinson Disease.

OBJECTIVE: The aim of this study was to explore whether attentional demands are involved in gait improvements in Parkinson disease (PD) patients when they walk on a treadmill. DESIGN: Nineteen individuals with idiopathic PD and 19 age-matched healthy controls participated in this study. Participants walked on a treadmill and on overground under single task (walk only) and dual task (walk performing a simultaneous cognitive task) conditions. The dual-task paradigm was used to reveal the attention allocation behavior. Gait pattern and cognitive performance was measured. RESULTS: The PD group showed reduced gait variability when walking on a treadmill in comparison with overground. However, this reduction did not deteriorate during the dual task. Moreover, there were no differences in the cognitive performance between treadmill and overground walking. CONCLUSIONS: This study does not support the proposition attentional resource allocation as a possible mechanism for the treadmill-associated gait improvements observed in PD.

Inter-individual variability in response to non-invasive brain stimulation paradigms.

BACKGROUND: Non-invasive Brain Stimulation (NIBS) paradigms are unique in their ability to safely modulate cortical plasticity for experimental or therapeutic applications. However, increasingly, there is concern regarding inter-individual variability in the efficacy and reliability of these paradigms. HYPOTHESIS: Inter-individual variability in response to NIBS paradigms would be better explained if a multimodal distribution was assumed. METHODS: In three different sessions for each subject (n = 56), we studied the Paired Associative Stimulation (PAS25), Anodal transcranial DC stimulation (AtDCS) and intermittent theta burst stimulation (iTBS) protocols. We applied cluster analysis to detect distinct patterns of response between individuals. Furthermore, we tested whether baseline TMS measures (such as short intracortical inhibition (SICI), resting motor threshold (RMT)) or factors such as time of day could predict each individual's response pattern. RESULTS: All three paradigms show similar efficacy over the first hour post stimulation--there is no significant effect on excitatory or inhibitory circuits for the whole sample, and AtDCS fares no better than iTBS or PAS25. Cluster analysis reveals a bimodal response pattern--but only 39%, 45% and 43% of subjects responded as expected to PAS25, AtDCS, and iTBS respectively. Pre-stimulation SICI accounted for 10% of the variability in response to PAS25, but no other baseline measures were predictive of response. Finally, we report implications for sample size calculation and the remarkable effect of sample enrichment. CONCLUSION: The implications of the high rate of 'dose-failure' for experimental and therapeutic applications of NIBS lead us to conclude that addressing inter-individual variability is a key area of concern for the field.

Treadmill training improves overground walking economy in Parkinson's disease: a randomized, controlled pilot study.

Gait disturbances are one of the principal and most incapacitating symptoms of Parkinson's disease (PD). In addition, walking economy is impaired in PD patients and could contribute to excess fatigue in this population. An important number of studies have shown that treadmill training can improve kinematic parameters in PD patients. However, the effects of treadmill and overground walking on the walking economy remain unknown. The goal of this study was to explore the walking economy changes in response to a treadmill and an overground training program, as well as the differences in the walking economy during treadmill and overground walking. Twenty-two mild PD patients were randomly assigned to a treadmill or overground training group. The training program consisted of 5 weeks (3 sessions/week). We evaluated the energy expenditure of overground walking, before and after each of the training programs. The energy expenditure of treadmill walking (before the program) was also evaluated. The treadmill, but not the overground training program, lead to an improvement in the walking economy (the rate of oxygen consumed per distance during overground walking at a preferred speed) in PD patients. In addition, walking on a treadmill required more energy expenditure compared with overground walking at the same speed. This study provides evidence that in mild PD patients, treadmill training is more beneficial compared with that of walking overground, leading to a greater improvement in the walking economy. This finding is of clinical importance for the therapeutic administration of exercise in PD.

Mirror neuron system and observational learning: behavioral and neurophysiological evidence.

Three experiments were performed to study observational learning using behavioral, perceptual, and neurophysiological data. Experiment 1 investigated whether observing an execution model, during physical practice of a transitive task that only presented one execution strategy, led to performance improvements compared with physical practice alone. Experiment 2 investigated whether performing an observational learning protocol improves subjects' action perception. In experiment 3 we evaluated whether the type of practice performed determined the activation of the Mirror Neuron System during action observation. Results showed that, compared with physical practice, observing an execution model during a task that only showed one execution strategy does not provide behavioral benefits. However, an observational learning protocol allows subjects to predict more precisely the outcome of the learned task. Finally, intersperse observation of an execution model with physical practice results in changes of primary motor cortex activity during the observation of the motor pattern previously practiced, whereas modulations in the connectivity between primary and non primary motor areas (PMv-M1; PPC-M1) were not affected by the practice protocol performed by the observer.

The effects of startle and non-startle auditory stimuli on wrist flexion movement in Parkinson's disease.

Startle stimuli lead to shorter reaction times in control subjects and Parkinson's disease (PD) patients. However, non-startle stimuli also enhance movement initiation in PD. We wanted to examine whether a startle-triggered movement would retain similar kinematic and EMG-related characteristics compared to one induced by a non-startle external cue in PD patients. In this study we investigated the electromyography pattern and the reaction time during a wrist flexion movement in response to three different stimuli: a visual imperative stimulus; visual stimulus simultaneous with a non-startle auditory stimulus and with a startle auditory stimulus. Ten PD patients and ten aged matched controls participated in this study. The reaction times were faster for startle and non-startle stimuli in comparison with the visual imperative stimulus, in both patients and control subjects. The startle cue induced a faster reaction than the non-startle cue. The electromyography pattern remained unchanged across the conditions. The results suggest that the startle reaction effect for upper limb movements are unimpaired in PD patients and has different characteristics than the effect of non-startle stimuli.