Posts Tagged NIBS

[ARTICLE] Technological Approaches for Neurorehabilitation: From Robotic Devices to Brain Stimulation and Beyond – Full Text

Neurological diseases causing motor/cognitive impairments are among the most common causes of adult-onset disability. More than one billion of people are affected worldwide, and this number is expected to increase in upcoming years, because of the rapidly aging population. The frequent lack of complete recovery makes it desirable to develop novel neurorehabilitative treatments, suited to the patients, and better targeting the specific disability. To date, rehabilitation therapy can be aided by the technological support of robotic-based therapy, non-invasive brain stimulation, and neural interfaces. In this perspective, we will review the above methods by referring to the most recent advances in each field. Then, we propose and discuss current and future approaches based on the combination of the above. As pointed out in the recent literature, by combining traditional rehabilitation techniques with neuromodulation, biofeedback recordings and/or novel robotic and wearable assistive devices, several studies have proven it is possible to sensibly improve the amount of recovery with respect to traditional treatments. We will then discuss the possible applied research directions to maximize the outcome of a neurorehabilitation therapy, which should include the personalization of the therapy based on patient and clinician needs and preferences.


According to the World Health Organization (WHO), neurological disorders and injuries account for the 6.3% of the global burden of disease (GBD) (12). With more than 6% of DALY (disability-adjusted life years) in the world, neurological disorders represent one of the most widespread clinical condition. Among neurological disorders, more than half of the burden in DALYs is constituted by cerebral-vascular disease (55%), such as stroke. Stroke, together with spinal cord injury (SCI), accounts for 52% of the adult-onset disability and, over a billion people (i.e., about a 15% of the population worldwide) suffer from some form of disability (3). These numbers are likely to increase in the coming years due to the aging of the population (4), since disorders affecting people aged 60 years and older contribute to 23% of the total GBD (5).

Standard physical rehabilitation favors the functional recovery after stroke, as compared to no treatment (6). However, the functional recovery is not always satisfactory as only 20% of patients fully resume their social life and job activities (7). Hence, the need of more effective and patient-tailored rehabilitative approaches to maximize the functional outcome of neurological injuries as well as patients’ quality of life (8). Modern technological methodologies represent one of the most recent advances in neurorehabilitation, and an increasing body of evidence supports their role in the recovery from brain and/or medullary insults. This manuscript provides a perspective on how technologies and methodologies could be combined in order to maximize the outcome of neurorehabilitation.

Current Systems and Therapeutic Approaches for Neurorehabilitation

The great progress made in interdisciplinary fields, such as neural engineering (910), has allowed to investigate many neural mechanisms, by detecting and processing the neural signals at high spatio-temporal resolution, and by interfacing the nervous system with external devices, thus restoring neurological functions lost due to disease/injury. The progress continues in parallel to technological advancements. The last two decades there has seen a large proliferation of technological approaches for human rehabilitation, such as robots, wearable systems, brain stimulation, and virtual environments. In the next sections, we will focus on: robotic therapy, non-invasive brain stimulation (NIBS), and neural interfaces.

Robotic Devices

Robots for neurorehabilitation are designed to support the administration of physical exercises to the upper or lower extremities, with the purpose of promoting neuro-motor recovery. This technology has a relatively long history, dating back to the early 1990s (11). Robot devices for rehabilitation differ widely in terms of mechanical design, number of degrees of freedom, and control architectures. As regards the mechanical design, robots may have either a single point of interaction (i.e., end effector) with the user body (endpoint robots or manipulanda) or multiple points of interaction (exoskeletons and wearable robots) (12).

Endpoint robots for the upper extremity, include Inmotion2 (IMT, USA) (13), KINARM End-Point (BKIN, Canada), and Braccio di Ferro (14) (Figure 1A1, left). Only some of these devices have been tested in randomized clinical trials (15), confirming an improvement of upper limb motor function after stroke (16). However, convincing evidence in favor of significant changes in activities of daily living (ADL) indicators is lacking (17), possibly because performance in ADL is highly affected by hand functionality. A good example of lower limb endpoint robot is represented by gait trainer GT1 (Reha-Stim, Germany). Its efficacy was tested by Picelli et al. (18), who demonstrated an improvement in multiple clinical measures in subjects with Parkinson’s disease following robotic-assisted rehabilitation when compared to physical rehabilitation alone (18). Endpoint robots are also available for postural rehabilitation. For instance, Hunova (Movendo Technology, Italy, launched in 2017) is equipped with a seat and a platform that induce multidirectional movements to improve postural stability (Figure 1A1, right).


Figure 1. Neurorehabilitation therapies. (A1) Endpoint robots: on the left the “Braccio di Ferro” manipulandum, on the right the postural robot Hunova. Braccio di ferro (14) is a planar manipulandum with 2-DOF, developed at the University of Genoa (Italy). It is equipped with direct-drive brushless motors and is specially designed to minimize endpoint inertia. It uses the H3DAPI programming environment, which allows to share exercise protocol with other devices. Written informed consent was obtained from the subject depicted in the panel. Movendo Technology’s Hunova is a robotic device that permits full-body rehabilitation. It has two 2-DOF actuated and sensorized platforms located under the seat and on the floor level that allow it to rehabilitate several body districts, including lower limb (thanks to the floor-level platform), the core, and the back, using the platform located underneath the seat. Different patient categories (orthopedic, neurological, and geriatric) can be treated, and interact with the machine through a GUI based on serious games. (A2) Wearable device: the recent exoskeleton Twin. Twin is a fully modular device developed at IIT and co-funded by INAIL (the Italian National Institute for Insurance against Accidents at Work). The device can be easily assembled/disassembled by the patient/therapist. It provides total assistance to patients in the 5–95th percentile range with a weight up to 110 kg. Its modularity is implemented by eight quick release connectors, each located at both mechanical ends of each motor, that allow mechanical and electrical connection with the rest of the structure. It can implement three different walking patterns that can be fully customized according to the patient’s needs viaa GUI on mobile device, thus enabling personalization of the therapy. Steps can be triggered via an IMU-based machine state controller. (B1) Repetitive transcranial magnetic stimulation (rTMS) representation. rTMS refers to the application of magnetic pulses in a repetitive mode. Conventional rTMS applied at low frequency (0.2–1 Hz) results in plastic inhibition of cortical excitability, whereas when it is applied at high frequency (≥5Hz), it leads to excitation (19). rTMS can also be applied in a “patterned mode.” Theta burst stimulation involves applying bursts of high frequency magnetic stimulation (three pulses at 50 Hz) repeated at intervals of 200 ms (20). Intermittent TBS increases cortical excitability for a period of 20–30 min, whereas continuous TBS leads to a suppression of cortical activity for approximately the same amount of time (20). (B2) Transcranial current stimulation (tCS) representation. tCS uses ultra-low intensity current, to manipulate the membrane potential of neurons and modulate spontaneous firing rates, but is insufficient on its own to discharge resting neurons or axons (21). tCS is an umbrella term for a number of brain modulating paradigms, such as transcranial direct current stimulation (22), transcranial alternating current stimulation (23), and transcranial random noise stimulation (24). (C) A typical BCI system. Five stages are represented: brain-signal acquisition, preprocessing, feature extraction/selection, classification, and application interface. In the first stage, brain-signal acquisition, suitable signals are acquired using an appropriate modality. Since the acquired signals are normally weak and contain noise (physiological and instrumental) and artifacts, preprocessing is needed, which is the second stage. In the third stage, some useful data or so-called “features” are extracted. These features, in the fourth stage, are classified using a suitable classifier. Finally, in the fifth stage, the classified signals are transmitted to a computer or other external devices for generating the desired control commands to the devices. In neurofeedback applications, the application interface is a real-time display of brain activity, which enables self-regulation of brain functions (25).

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[Abstract+References] Restoring Motor Functions After Stroke: Multiple Approaches and Opportunities

More than 1.5 million people suffer a stroke in Europe per year and more than 70% of stroke survivors experience limited functional recovery of their upper limb, resulting in diminished quality of life. Therefore, interventions to address upper-limb impairment are a priority for stroke survivors and clinicians. While a significant body of evidence supports the use of conventional treatments, such as intensive motor training or constraint-induced movement therapy, the limited and heterogeneous improvements they allow are, for most patients, usually not sufficient to return to full autonomy. Various innovative neurorehabNIBSilitation strategies are emerging in order to enhance beneficial plasticity and improve motor recovery. Among them, robotic technologies, brain-computer interfaces, or noninvasive brain stimulation (NIBS) are showing encouraging results. These innovative interventions, such as NIBS, will only provide maximized effects, if the field moves away from the “one-fits all” approach toward a “patient-tailored” approach. After summarizing the most commonly used rehabilitation approaches, we will focus on  and highlight the factors that limit its widespread use in clinical settings. Subsequently, we will propose potential biomarkers that might help to stratify stroke patients in order to identify the individualized optimal therapy. We will discuss future methodological developments, which could open new avenues for poststroke rehabilitation, toward more patient-tailored precision medicine approaches and pathophysiologically motivated strategies.


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<via Restoring Motor Functions After Stroke: Multiple Approaches and OpportunitiesThe Neuroscientist – Estelle Raffin, Friedhelm C. Hummel, 2017>

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[ARTICLE] Plasticity induced by non-invasive transcranial brain stimulation: A position paper – Full Text


Several techniques and protocols of non-invasive transcranial brain stimulation (NIBS), including transcranial magnetic and electrical stimuli, have been developed in the past decades. Non-invasive transcranial brain stimulation may modulate cortical excitability outlasting the period of non-invasive transcranial brain stimulation itself from several minutes to more than one hour. Quite a few lines of evidence, including pharmacological, physiological and behavioral studies in humans and animals, suggest that the effects of non-invasive transcranial brain stimulation are produced through effects on synaptic plasticity. However, there is still a need for more direct and conclusive evidence. The fragility and variability of the effects are the major challenges that non-invasive transcranial brain stimulation currently faces. A variety of factors, including biological variation, measurement reproducibility and the neuronal state of the stimulated area, which can be affected by factors such as past and present physical activity, may influence the response to non-invasive transcranial brain stimulation. Work is ongoing to test whether the reliability and consistency of non-invasive transcranial brain stimulation can be improved by controlling or monitoring neuronal state and by optimizing the protocol and timing of stimulation.

1. Introduction

Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) are the most commonly used methods of non-invasive transcranial brain stimulation that has been abbreviated by previous authors as either as NIBS or NTBS. Here we use NIBS since it seems to be the most common term at the present time. When it was first introduced in 1985, TMS was employed primarily as a tool to investigate the integrity and function of the human corticospinal system (Barker et al., 1985). Single pulse stimulation was used to elicit motor evoked potentials (MEPs) that were easily evoked and measured in contralateral muscles (Rothwell et al., 1999). The robustness and repeatability of measures of conduction time, stimulation threshold and “hot spot” location allowed TMS to be developed into a standard tool in clinical neurophysiology.

As we review below, a number of NIBS protocols can lead to effects on brain excitability that outlast the period of stimulation. These may reflect basic synaptic mechanisms involving long-term potentiation (LTP)- or long-term depression (LTD)-like plasticity, and because of this there has been great interest in using the methods as therapeutic interventions in neurological and psychiatric diseases. Furthermore, recently they are more frequently applied to modify memory processes and to enhance cognitive function in healthy individuals. However, apart from success in treating some patients with depression (Lefaucheur et al., 2014; Padberg et al., 2002, 1999), there is little consensus that they have improved outcomes in a clinically meaningful fashion in any other conditions. The reason for this is probably linked to the reason why many other protocols failed to reach routine clinical neurophysiology: they are too variable both within and between individuals to make them practically useful in a health service setting (Goldsworthy et al., 2014; Hamada et al., 2013; Lopez-Alonso et al., 2014, 2015).

Below we review the evidence for the mechanisms underlying the “neuroplastic” effects of NIBS, and then consider the problems in reproducibility and offer some potential ways forward in research. […]

Continue —> Plasticity induced by non-invasive transcranial brain stimulation: A position paper – ScienceDirect

There are three major lines of evidence supporting NIBS produces effects…

Fig. 1. There are three major lines of evidence supporting NIBS produces effects through mechanisms of synaptic plasticity: (1) Drugs that modulate the function of critical receptors/channels for plasticity, e.g. Ca2+ channels and NMDA receptors, alter the effect of NIBS; (2) NIBS mainly changes I-waves rather than the D-wave in the epidural recording of descending volleys evoked by TMS, suggesting the effect of NIBS occurs trans-synaptically; and (3) NIBS interacts between protocols and with motor practice and cognitive learning processes, suggesting the effect of NIBS is involves in plasticity-related motor and psychological processes.

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[ARTICLE] Transcranial direct current stimulation as a motor neurorehabilitation tool: an empirical review – Full Text


The present review collects the most relevant empirical evidence available in the literature until date regarding the effects of transcranial direct current stimulation (tDCS) on the human motor function. tDCS in a non-invasive neurostimulation technique that delivers a weak current through the brain scalp altering the cortical excitability on the target brain area. The electrical current modulates the resting membrane potential of a variety of neuronal population (as pyramidal and gabaergic neurons); raising or dropping the firing rate up or down, depending on the nature of the electrode and the applied intensity. These local changes additionally have shown long-lasting effects, evidenced by its promotion of the brain-derived neurotrophic factor. Due to its easy and safe application and its neuromodulatory effects, tDCS has attracted a big attention in the motor neurorehabilitation field among the last years. Therefore, the present manuscript updates the knowledge available about the main concept of tDCS, its practical use, safety considerations, and its underlying mechanisms of action. Moreover, we will focus on the empirical data obtained by studies regarding the application of tDCS on the motor function of healthy and clinical population, comprising motor deficiencies of a variety of pathologies as Parkinson’s disease, stroke, multiple sclerosis and cerebral palsy, among others. Finally, we will discuss the main current issues and future directions of tDCS as a motor neurorehabilitation tool.


The central nervous system (CNS) works thanks to the communication between more than 100,000 millions of neurons, whose activity and networking is modulated by chemical and electrical processes [1]. Across history, humans have been trying to alter the electrical brain processes to enhance human’s brain function, for the treatment of psychopathologies and for a better understanding of the brain physiology. For example, in the antiquity, modulation of the electrical processes of the brain started with the use of electrical impulses of torpedo fishes applied directly on the CNS, for therapeutic purposes [2]. In 1746, Musschenbroek (1692–1761) used Leyde jars and electrostatic devices to treat neuralgia, contractures and paralysis. The discovery of biometallic electricity and the invention of the voltaic battery augmented the interest in the therapeutic effects of galvanism. Afterwards, Duchenne de Boulogne (1806–1875) upgraded the electrotherapy with volta and magnetofaradaic apparatuses. Fortunately, in the past Century, the technological advances and its integration in health sciences have let us go from uncontrolled and unsafe interventions with side effects to well-controlled, more effective and safe stimulation devices [3].

Currently, the most used stimulation devices can be divided into invasive techniques, such as deep brain stimulation (DBS), and non-invasive brain stimulation (NiBS) techniques, whose most representative methods are transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) [4].

Although results are variable [5], DBS has reported positive results over the motor function, especially on the motor symptoms of Parkinson’s disease. However, DBS is a technique that needs the implantation of the electrodes on the stimulated area, which is associated with the typical risk derived from surgery, as infections. Therefore, there is an increasing tendence on the search for non-invasive brain stimulation techniques, which can modulate the motor function avoiding those risks.

Hence, NiBS are characterized for its easy and safe use and relatively cheap price, demonstrating also successful results in the treatment of neurological and psychiatric alterations [4]. In the last decades, TMS has been the most researched and developed neuromodulation technique. TMS generates fast changes in the magnetic field delivering electrical currents through the brain, allowing the specific modulation of the cortical excitability through the initiation of action potentials [6]. Multiple studies have already shown its efficacy and safe use for the treatment of multiple pathologies [7], serving also as a useful tool for the functional location of brain areas, especially regarding the motor cortex [8, 9]. However, TMS requires the participation of the participant, and due to its functioning, it is difficult to perform a sham condition, which is highly desirable especially in the research field. In addition, TMS produces in most of the cases undesirable side-effects, as headache [10].

Therefore, the tDCS technique is attracting a strong interest in the neuroscience research field. tDCS has supposed a revolution in the last 15 years of research, solving most of the disadvantages of TMS [10]. tDCS is a neuromodulation tool consisting on a battery connected to two electrodes, the anode and cathode, which are placed directly over the brain scalp and over extracephalic regions. The current flows between both electrodes and induces the depolarization or hyperpolarization of the membrane of the underlying neurons, which depends of the anodal or cathodal nature of the electrode [11], altering the neuronal excitability resulting in the modification of the brain activity [12]. This device is completely portable, as it is provided by built-in rechargeable battery with duration of approximately 6 h stimulation time at 1 mA (0.5–1.5 W of power consumption), and needs approximately 7 h for complete recharging. In addition, including battery, it has a weight of 0.8 kg. Its portability is one of the biggest advantages of tDCS in the context of NiBS. Therefore, tDCS can be considered as a suitable complementary technique on motor rehabilitation therapy, allowing its application in different contexes, during the motor training and even combined with aerobic exercise [13, 14].

This non-invasive brain manipulation has opened the doors for a variety of potential treatments for the major neurological and psychiatry diseases [15], as depression [16], schizophrenia [17], Obsessive–Compulsive disorder [18] and addictions [19], among others.

However, motor functions are the major target for clinical and non-clinical studies regarding tDCS, serving mainly as a potential tool in post-stroke rehabilitation [20], but also in pathologies like Parkinson’s disease [21]. In addition, numerous studies have shown that tDCS produces changes in the brain plasticity processes, generating long-lasting effects that enhances even further its applicability in the neurorehabilitation field [22, 23].

The purpose of this review is to assess the current and future stage of tDCS regarding its use on the human motor function, identifying the empirical cues that point out its benefits as well as its potential limitation, providing a comprehensive framework for designing future research in the field of brain stimulation with tDCS and human motor rehabilitation. The present review is divided in four parts. The first part is based on a detailed definition on what we know about tDCS, the protocols of montage and parameters of stimulation, comprising the mechanisms of action of tDCS, what differs tDCS from other non-invasive neuromodulation techniques, and the main need to-know safety standards. Given the conciseness of this first part, we will present the recent studies focusing exclusively on the empirical data obtained from the use of tDCS in the human motor function, regarding, in the second part, healthy humans; in the third part, its clinical application on deteriorated human motor functions across different pathologies as Parkinson disease, stroke and cerebral palsy. Finally, in the fourth part of this review, we will discuss the main current issues of tDCS applied on the human motor function.[…]

Continue —> Transcranial direct current stimulation as a motor neurorehabilitation tool: an empirical review | BioMedical Engineering OnLine | Full Text

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[Abstract] Basic and functional effects of transcranial Electrical Stimulation (tES)—An introduction


    – Clinical and research interest in noninvasive brain stimulation has grown exponentially.– Here, we present the main findings on the physiological basis of transcranial electric stimulation (tES).– In a second part, we discuss evidence for applications of tES in behavioral research and clinical settings.– We note several challenges which need to be addressed before extensive clinical use of tES.


Non-invasive brain stimulation (NIBS) has been gaining increased popularity in human neuroscience research during the last years. Among the emerging NIBS tools is transcranial electrical stimulation (tES), whose main modalities are transcranial direct, and alternating current stimulation (tDCS, tACS). In tES, a small current (usually less than 3 mA) is delivered through the scalp. Depending on its shape, density, and duration, the applied current induces acute or long-lasting effects on excitability and activity of cerebral regions, and brain networks. tES is increasingly applied in different domains to (a) explore human brain physiology with regard to plasticity, and brain oscillations, (b) explore the impact of brain physiology on cognitive processes, and (c) treat clinical symptoms in neurological and psychiatric diseases. In this review, we give a broad overview of the main mechanisms and applications of these brain stimulation tools.

Source: Basic and functional effects of transcranial Electrical Stimulation (tES)—An introduction – ScienceDirect

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[ARTICLE] Does non-invasive brain stimulation modify hand dexterity? Protocol for a systematic review and meta-analysis – Full Text



Introduction Dexterity is described as coordinated hand and finger movement for precision tasks. It is essential for day-to-day activities like computer use, writing or buttoning a shirt. Integrity of brain motor networks is crucial to properly execute these fine hand tasks. When these networks are damaged, interventions to enhance recovery are frequently accompanied by unwanted side effects or limited in their effect. Non-invasive brain stimulation (NIBS) are postulated to target affected motor areas and improve hand motor function with few side effects. However, the results across studies vary, and the current literature does not allow us to draw clear conclusions on the use of NIBS to promote hand function recovery. Therefore, we developed a protocol for a systematic review and meta-analysis on the effects of different NIBS technologies on dexterity in diverse populations. This study will potentially help future evidence-based research and guidelines that use these NIBS technologies for recovering hand dexterity.

Methods and analysis This protocol will compare the effects of active versus sham NIBS on precise hand activity. Records will be obtained by searching relevant databases. Included articles will be randomised clinical trials in adults, testing the therapeutic effects of NIBS on continuous dexterity data. Records will be studied for risk of bias. Narrative and quantitative synthesis will be done.

Strengths and limitations of this study

  • This is a novel systematic review and meta-analysis focusing specifically on dexterity.

  • We use continuous data not dependent on the evaluator or participant.

  • This work will potentially help future evidence-based research and guidelines to refine non-invasive brain stimulation.


The hand’s somatotopy is extensively represented in the human motor cortex.1 2 Phylogenetically, this relates to the development of corticomotoneuronal cells that specialise in creating patterns of muscle activity that synergises into highly skilled movements.3 This organised hand-and-finger movement to use objects during a specific task is known as dexterity.4 Evolutionary, dexterity played a pivotal role in human survival and is fundamental to actives of daily living, and hence quality of life.5 6

This precision motor movement relies on integration of information from the cerebral cortex, the spinal cord, several neuromusculoskeletal systems and the external world to coordinate finger force control, finger independence, timing and sequence performance.7 During these tasks, multivoxel pattern decoding shows bilateral primary motor cortex activation (M1), which was responsible for muscle recruitment timing and hand movement coordination.8 9 This is related to motor cortex connectivity through the corpus callosum, to motor regions of the cerebellum and white matter integrity.10–15 Adequate motor output translates into successfully executed tasks, like picking up objects, turning over cards, manipulating cutlery, writing, using computer–hand interfaces like smartphones, playing an instrument and performing many other similarly precise skills.16

These motor tasks are negatively impacted when motor output networks are affected, as seen in stroke or Parkinson’s disease.17 18 Therapeutic interventions that restore these damaged motor networks can be vital to restore fine motor movement after injury occurs. Pharmaceutical approaches often lead to adverse effects such as dyskinesias in Parkinson’s disease. Moreover, even after intensive rehabilitation programmes, only about 5%–20% of patients with stroke fully recover their motor function.19–21 Non-invasive brain stimulation (NIBS) techniques, like transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), are proposed adjuvant or stand-alone interventions to target these affected areas and improve fine motor function.22 23 Briefly, these NIBS interventions are shown to influence the nervous system’s excitability and modulate long-term plasticity, which may be beneficial to the brain’s recovery of functions after injury.24–27

Fine hand motor ability is not studied as much in previous reviews of NIBS. Specifically, one narrative review focuses on rTMS in affected hand recovery poststroke; however, it does not consider the implications of varying International Classification of Functioning, Disability and Health (ICF) domains, data types and rater dependent outcomes, and its interpretability is limited without quantitative synthesis.28–31 The overarching conclusion was supportive of rTMS for paretic hand recovery, though with limited data to support its regular use, and a pressing need to study individualised patient parameters.28 One meta-analysis had positive and significant results when specifically studying the effects of rTMS on finger coordination and hand function after stroke.32 However, while various meta-analysis, and another systematic review, studied upper-limb movement after NIBS in distinct populations, they did not focus on precise hand function, pooled upper-limb outcomes with hand outcomes and presented mixed results.33–38

Motivated by this gap in the evidence for NIBS in dexterity, we will do a systematic review and meta-analysis of the literature on these brain stimulation technologies using outcomes that focus exactly on manual dexterity. These outcomes will be continuous and not dependent on the participant’s or rater’s observation (ie, they will be measured in seconds, or number of blocks/pegs placed, and not by an individual’s interpretation). They will be comprised of multiple domains as defined by the ICF, providing an appreciation of function rather than only condition or disease.29–31 By focusing on the ICF model, we will be able to study dexterity across a larger sample of studies, NIBS techniques and conditions in order to provide a better understanding of brain stimulation efficacy on hand function in various populations.[…]

Continue —. Does non-invasive brain stimulation modify hand dexterity? Protocol for a systematic review and meta-analysis | BMJ Open

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[ARTICLE] Repetitive reaching training combined with transcranial Random Noise Stimulation in stroke survivors with chronic and severe arm paresis is feasible: a pilot, triple-blind, randomised case series – Full Text



Therapy that combines repetitive training with non-invasive brain stimulation is a potential avenue to enhance upper limb recovery after stroke. This study aimed to investigate the feasibility of transcranial Random Noise Stimulation (tRNS), timed to coincide with the generation of voluntary motor commands, during reaching training.


A triple-blind pilot RCT was completed. Four stroke survivors with chronic (6-months to 5-years) and severe arm paresis, not taking any medications that had the potential to alter cortical excitability, and no contraindications to tRNS or MRI were recruited. Participants were randomly allocated to 12 sessions of reaching training over 4-weeks with active or sham tRNS delivered over the lesioned hemisphere motor representation. tRNS was triggered to coincide with a voluntary movement attempt, ceasing after 5-s. At this point, peripheral nerve stimulation enabled full range reaching. To determine feasibility, we considered adverse events, training outcomes, clinical outcomes, corticospinal tract (CST) structural integrity, and reflections on training through in-depth interviews from each individual case.


Two participants received active and two sham tRNS. There were no adverse events. All training sessions were completed, repetitive practice performed and clinically relevant improvements across motor outcomes demonstrated. The amount of improvement varied across individuals and appeared to be independent of group allocation and CST integrity.


Reaching training that includes tRNS timed to coincide with generation of voluntary motor commands is feasible. Clinical improvements were possible even in the most severely affected individuals as evidenced by CST integrity.

Trial registration

This study was registered on the Australian and New Zealand Clinical Trials Registry (ANZCTR) Registration date 4 September 2014, first participant date 9 September 2014


It is estimated that 30% of stroke survivors have severe upper limb impairment [1], whereby the functional capacity of the paretic arm is diminished to the extent that it cannot be moved against gravity [2]. For these individuals, who do not have sufficient movement with which to work, the provision of effective therapy can be challenging. The associated consequences are poor prospects for recovery [3], limited rehabilitation opportunities [4], and ultimately reduced quality of life (QoL) [5]. Yet, if task-oriented practice can be made possible by some means, there exists the potential to promote motor recovery, and in turn make a significant positive impact upon individual QoL and alleviate burden of care. In seeking to achieve levels of task-oriented practice beyond those that are possible through traditional therapy alone, attention has therefore turned to enabling technologies, including “assistive” devices, and adjuvant methods such as peripheral nerve and brain stimulation.

Best evidence syntheses [67] suggest that goal-directed movements can be assisted by minimizing the mechanical degrees of freedom to be controlled, in combination with the augmentation of voluntary muscle activity via peripheral nerve stimulation of target muscles, or the use of mechanical actuators. To encourage positive changes in motor performance, the capacity to increase task difficulty through small, yet incremental progressions and provision of meaningful real-time visual and auditory feedback have also been highlighted [89]. The authors have previously sought to implement these principles, using the Sensorimotor Active Rehabilitation Training of the Arm (SMART Arm) device to promote functional recovery in severely impaired stroke survivors [8910]. It has been shown that 4-weeks (12-h) of community-based training of reaching in people greater than 6-months post stroke improved upper limb function (and increased reaching distance) [8], enhanced the specificity of muscle recruitment (elevated ratio of biceps to triceps activation during reaching) [11], and accentuated corticospinal reactivity (decreased motor evoked potential [MEP] onset latency) [12]. Of particular interest in the context of the current study is the observation that not all individuals achieved functional gains. In these cases, the intrinsic neurobiological reserve of the injured brain may have been insufficient for repetitive training alone to drive recovery of motor function.

A variety of non-invasive brain stimulation (NIBS) techniques are now being used with the aim of altering the excitability of brain networks that have the potential to be engaged during the execution of motor tasks. The most commonly applied NIBS techniques are transcranial-direct current stimulation (tDCS) and repetitive-transcranial magnetic stimulation (rTMS) [13]. In general, the application of these techniques is predicated on the assumption that by altering the state of circuits within (contralateral) primary motor cortex (M1) in a manner that produces sustained increases in the excitability of corticospinal projections to the impaired limb (or by decreasing the excitability of circuits in the M1 ipsilateral to the impaired limb), therapeutic gains will be realised. The fact that these approaches have limited efficacy in severely impaired stroke survivors notwithstanding [14], there exist other forms of therapeutic NIBS that are motivated by a different premise.

It is well established that in some circumstances, the addition of random interference or noise, enhances the detection of weak stimuli, or the information content of a signal (e.g., trains of action potentials) [15]. In light of this phenomenon, it has been proposed that the application of transcranial random noise stimulation (tRNS) may boost the adaptive potential of cortical tissue [16]. The present investigation is motivated by the conjecture that: if the delivery of random noise stimulation is timed to occur simultaneously with the generation of voluntary motor commands, it may serve to amplify functional adaptations invoked by the intrinsic neural activity.

Implemented through a triple-blind pilot randomised control design, the specific aim of this study was to establish the feasibility of delivering tRNS, timed to coincide with the generation of the voluntary motor commands, in the context of reaching movements performed by individuals with chronic and severe upper limb paresis after stroke. Recognising that the response to any therapeutic intervention is constrained by the state of pathways that can convey signals from the brain to the periphery, diffusion-weighted magnetic resonance imaging (DW-MRI) was performed to characterize the structural integrity of the descending corticospinal tract (CST) projections for each participant.

Continue —>  Repetitive reaching training combined with transcranial Random Noise Stimulation in stroke survivors with chronic and severe arm paresis is feasible: a pilot, triple-blind, randomised case series | Journal of NeuroEngineering and Rehabilitation | Full Text

Fig. 1 Representation of the training setup including horizontal reaching track, trunk restraint, visual feedback, transcranial random noise stimulation application, and electrical stimulation application to lateral head of triceps


Fig. 2 Corticospinal tract streamline reconstructions: the corticospinal tract is indicated for each of the four participants, displayed on coronal (x view) slices of T1 weighted anatomical scans with direction encoded fractional anisotropy (FA) colour maps superimposed. Images are shown in radiological format (ie. right on the image is the patient’s left side). The reconstructed streamlines for the corticospinal tract are also superimposed, and indicated by red circles. The posterior limb of the internal capsule (PLIC) within the corticospinal tract was the region of interest that was delineated manually for each scan, using anatomical landmarks. No tracts were detected in the PLIC region in the right hemisphere for P03, or the left hemisphere for P04

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[Abstract] The treatment of fatigue by non-invasive brain stimulation


The use of non-invasive brain neurostimulation (NIBS) techniques to treat neurological or psychiatric diseases is currently under development. Fatigue is a commonly observed symptom in the field of potentially treatable pathologies by NIBS, yet very little data has been published regarding its treatment. We conducted a review of the literature until the end of February 2017 to analyze all the studies that reported a clinical assessment of the effects of NIBS techniques on fatigue. We have limited our analysis to repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). We found only 15 studies on this subject, including 8 tDCS studies and 7 rTMS studies. Of the tDCS studies, 6 concerned patients with multiple sclerosis while 6 rTMS studies concerned fibromyalgia or chronic fatigue syndrome. The remaining 3 studies included patients with post-polio syndrome, Parkinson’s disease and amyotrophic lateral sclerosis. Three cortical regions were targeted: the primary sensorimotor cortex, the dorsolateral prefrontal cortex and the posterior parietal cortex. In all cases, tDCS protocols were performed according to a bipolar montage with the anode over the cortical target. On the other hand, rTMS protocols consisted of either high-frequency phasic stimulation or low-frequency tonic stimulation. The results available to date are still too few, partial and heterogeneous as to the methods applied, the clinical profile of the patients and the variables studied (different fatigue scores) in order to draw any conclusion. However, the effects obtained, especially in multiple sclerosis and fibromyalgia, are really carriers of therapeutic hope.

Source: The treatment of fatigue by non-invasive brain stimulation

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[ARTICLE] Cognitive and Neurophysiological Effects of Non-invasive Brain Stimulation in Stroke Patients after Motor Rehabilitation – Full Text

The primary aim of this study was to evaluate and compare the effectiveness of two specific Non-Invasive Brain Stimulation (NIBS) paradigms, the repetitive Transcranial Magnetic Stimulation (rTMS), and transcranial Direct Current Stimulation (tDCS), in the upper limb rehabilitation of patients with stroke.

Short and long term outcomes (after 3 and 6 months, respectively) were evaluated. We measured, at multiple time points, the manual dexterity using a validated clinical scale (ARAT), electroencephalography auditory event related potentials, and neuropsychological performances in patients with chronic stroke of middle severity.

Thirty four patients were enrolled and randomized. The intervention group was treated with a NIBS protocol longer than usual, applying a second cycle of stimulation, after a washout period, using different techniques in the two cycles (rTMS/tDCS). We compared the results with a control group treated with sham stimulation. We split the data analysis into three studies. In this first study we examined if a cumulative effect was clinically visible. In the second study we compared the effects of the two techniques. In the third study we explored if patients with minor cognitive impairment have most benefit from the treatment and if cognitive and motor outcomes were correlated.

We found that the impairment in some cognitive domains cannot be considered an exclusion criterion for rehabilitation with NIBS. ERP improved, related to cognitive and attentional processes after stimulation on the motor cortex, but transitorily. This effect could be linked to the restoration of hemispheric balance or by the effects of distant connections. In our study the effects of the two NIBS were comparable, with some advantages using tDCS vs. rTMS in stroke rehabilitation. Finally we found that more than one cycle (2–4 weeks), spaced out by washout periods, should be used, only in responder patients, to obtain clinical relevant results.


Motor and cognitive impairment are frequent aftermaths of brain damage after a stroke. Many authors reports cognitive deficits in 12–56% of stroke patients and reduced performances in several cognitive domains in 32% (Ebrahim et al., 1985; Tatemichi et al., 1994; Patel et al., 2002). Moreover, dysfunctions in the use of upper limb and in functional walking are among the more common consequences for many stroke survivors. Of note, only 5% of adult stroke survivors regain full function of the upper limb and 20% do not recover any functional use.

The severity of cognitive impairment negatively correlates with motor and functional recovery achieved in stroke patients after rehabilitation. Indeed, a cognitive assessment should be used to select patients that could have the best benefits from rehabilitation (Patel et al., 2002; Mehta et al., 2003; Saxena et al., 2007; Rabadi et al., 2008).

Event Related Potentials (ERP) are a reproducible electrophysiological response to an external stimulus (visual or auditory), representing the brain activity associated with various cognitive processes such as selective attention, memory, or decision making. Interestingly, ERP can be valuable in the diagnosis of cognitive impairment and are able to track the cognitive changes during the follow-up in stroke patients (Trinka et al., 2000; Alonso-Prieto et al., 2002; Yamagata et al., 2004; Stahlhut et al., 2014).

Recently, Non-Invasive Brain Stimulation (NIBS) techniques have been proposed as support of standard cognitive and motor rehabilitation. The application of NIBS in stroke rehabilitation arises from the observation that cortical excitability can be modulated after electrical or magnetic brain stimulation. It can be reduced or enhanced (Miniussi et al., 2008; Sandrini and Cohen, 2013) depending on many factors (stimulation parameters, type of stimulation technique, timing of the stimulation, brain target region, and state of mind).

The physiological mechanisms underlying brain stimulation effects are still partially unknown, but several evidences explain these effects with Long Term Potentiation (LTP) and Long Term Depression (LTD) like mechanisms (Thickbroom, 2007; Fritsch et al., 2010; Bliss and Cooke, 2011).

Repetitive Transcranial Magnetic Stimulation (rTMS) and transcranial Direct Current Stimulation (tDCS) are the most used NIBS techniques in rehabilitation (Hummel et al., 2005; Miniussi et al., 2008; Bolognini et al., 2009). Both can induce long lasting effect on cortical plasticity (30–90 min). Modification of cortical activity may improve the subject’s ability to relearn or acquire new strategies for carrying out motor or behavioral task, by facilitating perilesional activity or by suppressing maladaptive interfering activity from other brain areas (Miniussi et al., 2008). Even if most of the effects are transient, NIBS during or before a learning process may yield the behavioral improvements more robust and stable (Rossi and Rossini, 2004;Pascual-Leone, 2006). Indeed, during motor learning not only the fast (intra-sessions) and slow (inter-sessions) learning during training are relevant, but also the memory consolidation and the savings (Wessel et al., 2015). Plasticity induced by NIBS could thus have important effects not only in the online phase of motor rehabilitation, but also in the offline phases.

A growing number of studies indicates that NIBS could be useful in chronic stroke rehabilitation (Hummel and Cohen, 2006;Sandrini and Cohen, 2013; Liew et al., 2014; Wessel et al., 2015), but no one compared directly the two techniques or explored the link between cognitive and motor improvement. TMS is able to directly induce action potentials in the axons while the currents used in tDCS (1–2 mA) cannot. The first technique is, therefore, best suited to be used offline, while the second can be used online in conjunction with other rehabilitation techniques or tasks (Wessel et al., 2015). Simis et al. (2013) compared rTMS and tDCS in healthy subjects, observing that both techniques induced similar motor gains. The comparison of brain plasticity induced by NIBS in pathologic subjects could thus extend significantly the Simis’ results.

In this paper, the primary aim was to evaluate and compare the motor and cognitive changes induced by rTMS and tDCS in the upper limb rehabilitation in patients with stroke, both in short and in long term outcome. Secondarily we searched for a possible link between motor and cognitive measures.

We chose the most effective paradigm of rTMS in chronic stroke according to meta-analyses and consensus papers (Lefaucheur et al., 2014), a low-frequency protocol applied onto the controlesional motor cortex (M1). For tDCS, in the absence of a gold standard, we chose a paradigm with a dual sites montage validated in non-inferiority trials (Schlaug et al., 2008; Lüdemann-Podubecká et al., 2014). The tDCS was performed in conjunction with a cognitive training focused on the brain representation of the hands, the mirror-box therapy (MT), to direct the neuromodulation effect as wished. Our aim was to create a paradigm easy to apply in a clinical setting.

To compare the NIBS techniques in the same patients we created a treatment longer than usual applying a second cycle of stimulation, after a washout period, using different techniques in the two cycles (rTMS/tDCS).

A randomized clinical trial divided into three studies was designed to explore the following issues:

A longer NIBS stimulation could be beneficial in stroke rehabilitation?

What are the differences between rTMS and tDCS in stroke rehabilitation?

NIBS motor stimulation effects can modulate or be modulated by patients’ cognitive status?

In the first study we evaluated if a cumulative effect, mediated by an offline improvement (consolidation or savings), was clinically detectable. We also evaluated the differences between a first priming cycle with rTMS followed by tDCS and first priming with tDCS followed by rTMS.

In the second study we compared the effects of the two techniques to test if brain plasticity effects could depend on the type of NIBS. In the third study, we searched for a possible link between motor and cognition changes, evaluating if cognitive measures changed in patients with motor improvement differently from the patients without motor improvement.

Continue —> Frontiers | Cognitive and Neurophysiological Effects of Non-invasive Brain Stimulation in Stroke Patients after Motor Rehabilitation | Frontiers in Behavioral Neuroscience

Figure 1. Experimental design. After screening the patients were randomized into three groups with different interventions: MT, Mirror Therapy; tDCS, transcranial Direct Current Stimulation; rTMS, repetitive Transranial Magnetic Stimulation. In the scheme the outcome measures: ARAT, Action Research Arm Test; P300, cognitive auditory evoked response potentials; NPS, neuropsychological test where assessed in multiple time frames; w, week; mos, months.

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Stroke is a leading cause of long-term adult motor disability. While current rehabilitation strategies carry promise, gains in function are modest where approximately 60-80% of survivors continue to experience motor impairments of the upper-limb well into the chronic phase of recovery. One reason for the modest recovery of upper-limb function is the diminishing time available for rehabilitation, where therapists are required to administer best practice in a limited number of sessions. Therefore, current research emphasizes the need for maximizing and accelerating outcomes of rehabilitation within constraints of time permitted for outpatient clinical therapy.

One strategy to maximize rehabilitative outcomes emphasizes the importance of engaging the paretic upper-limb in intensive movements/activities, defined operationally here as ‘unilateral therapies.’ Examples include constraint-induced movement therapy (CIMT) that requires patients to use the paretic upper-limb in tasks of daily living while restraining use of the non-paretic upper-limb, or electrical stimulation that targets weaker muscles to elicit more movement of the paretic upper-limb. Unilateral therapies are emphasized because they are derived from a popular, standard neurophysiologic model of stroke recovery commonly referred to as the ‘interhemispheric competition model’ (figure 1). According to this model, paresis originates from loss of output to the paretic upper-limb, but it persists due to inter-hemispheric imbalances.

The contralesional hemisphere excessively inhibits the ipsilesional hemisphere that is too weak to counter. As patients rely on using the non-paretic upper-limb to compensate for failures in using the paretic upper-limb, inter-hemispheric ‘competition’ intensifies. Output from the ipsilesional hemisphere weakens further, while excitability and inhibition imposed from the contralesional hemisphere continues to rise.

To maximize output to the paretic upper-limb, the model recommends emphasizing use of the paretic upper-limb in unilateral therapies and disregarding or de-incentivizing use of the non-paretic upper-limb. …

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