[Abstract + References] Combined noninvasive brain stimulation virtual reality for upper limb rehabilitation poststroke: A systematic review of randomized controlled trials

Abstract

Upper limb impairments are common consequences of stroke. Noninvasive brain stimulation (NIBS) and virtual reality (VR) play crucial roles in improving upper limb function poststroke. This review aims to evaluate the effects of combined NIBS and VR interventions on upper limb function post-stroke and to provide recommendations for future studies in the rehabilitation field. PubMed, MEDLINE, PEDro, SCOPUS, REHABDATA, EMBASE, and Web of Science were searched from inception to November 2023. Randomized controlled trials (RCTs) encompassed patients with a confirmed stroke diagnosis, administrated combined NIBS and VR compared with passive (i.e., rest) or active (conventional therapy), and included at least one outcome assessing upper limb function (i.e., strength, spasticity, function) were selected. The quality of the included studies was assessed using the Cochrane Collaboration tool. Seven studies met the eligibility criteria. In total, 303 stroke survivors (Mean age: 61.74 years) were included in this review. According to the Cochrane Collaboration tool, five studies were classified as “high quality,” while two were categorized as “moderate quality”. There are mixed findings for the effects of combined NIBS and VR on upper limb function in stroke survivors. The evidence for the effects of combined transcranial direct current stimulation and VR on upper limb function post-stroke is promising. However, the evidence regarding the effects of combined repetitive transcranial magnetic stimulation and VR on upper limb function is limited. Further randomized controlled trials with long-term follow-up are strongly warranted.

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[Abstract] Noninvasive brain stimulation for cognitive rehabilitation following traumatic brain injury: a systematic review

Abstract

Traumatic brain injury (TBI) can cause numerous cognitive deficits. These deficits are associated with disability and reduction in quality of life. Noninvasive brain stimulation (NIBS) provides excitatory or inhibitory stimuli to the cerebral cortex. This review aimed to examine the effectiveness of NIBS (i.e., rTMS and tDCS) on cognitive functions in patients with TBI. PubMed, SCOPUS, PEDro, CINAHL, MEDLINE, REHABDATA, and Web of Science were searched from inception to May 2021. The risk of bias in the randomized controlled trials was assessed using the Cochrane Collaboration’s instrument. The Physiotherapy Evidence Database (PEDro) scale was applied to evaluate the risk of bias in the non-randomized controlled trials. Ten studies met our inclusion criteria. Six studies used repetitive Transcranial Magnetic Stimulation (rTMS), and four used transcranial Direct Current Stimulation (tDCS) as cognitive rehabilitation interventions. The results showed heterogenous evidence for the effects of rTMS and tDCS on cognitive function outcomes in individuals with TBI. The evidence for the effects of NIBS on cognition following TBI was limited. TDCS and rTMS are safe and well-tolerated interventions post-TBI. The optimal stimulation sites and stimulation parameters remain unknown. Combining NIBS with traditional rehabilitation interventions may contribute to greater enhancements in cognitive functions post-TBI.

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[ARTICLE] Rehabilitation Interventions Combined with Noninvasive Brain Stimulation on Upper Limb Motor Function in Stroke Patients – Full Text

Abstract

(1) Background: This systematic review aimed to focus on the effects of rehabilitation interventions combined with noninvasive brain stimulation on upper limb motor function in stroke patients.

(2) Methods: PubMed, MEDLINE, and CINAHL were used for the literature research. Articles were searched using the following terms: “Stroke OR CVA OR cerebrovascular accident” AND “upper limb OR upper extremity” AND “NIBS OR Non-Invasive Brain Stimulation” OR “rTMS” OR “repetitive transcranial magnetic stimulation” OR “tDCS” OR “transcranial direct current stimulation” AND “RCT” OR randomized control trial.” In total, 12 studies were included in the final analysis.

(3) Results: Analysis using the Physiotherapy Evidence Database scale for qualitative evaluation of the literature rated eight articles as “excellent” and four as “good.” Combined rehabilitation interventions included robotic therapy, motor imagery using brain–computer interaction, sensory control, occupational therapy, physiotherapy, task-oriented approach, task-oriented mirror therapy, neuromuscular electrical stimulation, and behavior observation therapy.

(4) Conclusions: Although it is difficult to estimate the recovery of upper limb motor function in stroke patients treated with noninvasive brain stimulation alone, a combination of a task-oriented approach, occupational therapy, action observation, wrist robot-assisted rehabilitation, and physical therapy can be effective.

1. Introduction

Stroke is a temporary or permanent neurological functional disorder resulting from local brain damage caused by a lack of oxygen and glucose supply to the brain for a long period of time because of pathological problems such as bleeding and ischemia in the cerebral vessels [1]. Because of limited upper limb motor function recovery, a total of 25–74% of worldwide stroke survivors need help or are completely dependent on assistance in their daily activities because of functional disorders [2,3]. Neurological damage from stroke occasionally decreases motor cortex excitement, which travels down the spinal cord and reduces motor nerve excitement [4]. In particular, the primary motor area (M1) plays an important role in causing peripheral muscle contractions to make movements, such as reaching [5,6]. Generally, each hemisphere of the brain interacts to balance excitement and inhibition. Reduced M1 excitement on the damaged side stimulates excitement of the corresponding area on the other side, which consequently further reduces the M1 activity on the damaged side [7]. This imbalance between excitement and inhibition has negative effects on upper limb motor function [8].

Intensive rehabilitation is an essential factor in recovery from damage after stroke. However, recently, various studies have attempted to seek ways to make use of direct modulation of brain function as a treatment tool to accelerate the recovery of damaged brain function from neurological diseases rather than using therapies that affect the brain indirectly through physiotherapy [9,10,11]. Among them, noninvasive brain stimulation (NIBS), which is one of the major fields of study in cranial nerve rehabilitation and cognitive science, is utilized in the recovery of motor function in the rehabilitation of stroke patients [12]. Transcranial magnetic stimulation and transcranial electrical stimulation are NIBS, and repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are most commonly used in neuroscience and clinical trials [13]. There is a range of NIBS techniques based on their use and their relative advantages and disadvantages [14]. rTMS enables the brain to adapt to environmental and experiential changes through reorganization of the brain based on plasticity [15]. rTMS is a method of generating depolarization of nerve cells in the cerebral cortex by inducing microcurrents in the human brain using magnetic waves, which are generated in a short period of time by placing an electric coil on the outermost skin of the head [16]. rTMS, which is transmitted in a repetitive manner, regulates nerve firing and excites or inhibits brain activity. In healthy volunteers, high-frequency rTMS increased cortical excitability, as measured by a decrease in motor threshold (MT) and an increase in motor evoked potential (MEP) amplitude, whereas low-frequency rTMS inhibited cortical excitability and had the opposite effect on MT and MEP [17,18,19]. Although high-frequency rTMS targeting M1 may improve motor learning of the upper extremities on the opposite side in healthy volunteers, it can reduce motor function of the terminal extremities on the same side [20]. It has been found that low-frequency rTMS improves motor function of the opposite hand through a similar mechanism [21].

In a previous study, task-oriented training after rTMS was effective at relieving upper extremity motor function and stiffness [22]. In addition, combining rTMS and a finger movement program, which sequentially follows instructions, the effectiveness was demonstrated by improvements in hand function [23].

Another NIBS therapy, tDCS, has a positive effect on motor function in the damaged side by inducing neuroplasticity changes in the cerebral cortex caused by changing the excitability of potentials directly in the stimulated part and indirectly in the corresponding part on the other side [7,24]. During tDCS, two electrodes are attached to the scalp, and microcurrents of 1–2 mA are applied, whereby the excitability of the brain nerve is increased under the anodal electrode and decreased under the cathodal electrode [24,25].

tDCS helps restore multiple neurological states by increasing or decreasing cortical excitability in the stimulation region [26]. In stroke patients, many studies have shown that motor function and hand motor tasks can be improved by increasing motor cortical excitability using tDCS [27]. A recent study using functional magnetic resonance imaging (fMRI) reported that motor-related activities increased and motor function improved after using anodal tDCS targeting M1 in a hemisphere with lesions [28]. In addition, a study reported that inhibiting the opposite hemisphere using cathodal tDCS over M1 can improve motor recovery after stroke [29]. A recent study has shown that reducing the excitability of the undamaged hemisphere significantly improves motor learning of paralyzed hands in stroke patients for up to 24 h [30]. In a previous study, the fusion of tDCS and functional electrical stimulation was effective for upper limb motor function [12]. Another study demonstrated the effectiveness of tDCS and virtual reality programs for balance and falls in stroke patients [31].

Previous studies have demonstrated that among the new treatments aimed at improving motor recovery, NIBS techniques such as tDCS and rTMS can induce brain plasticity and are most effective in motor recovery after stroke [32,33]. Recently, studies combining various rehabilitation approaches have been conducted in order to improve functional recovery after stroke [34,35]. Previous studies have shown effective improvement of upper limb motor function with various interventions combined with NIBS [12,22,23,30]. However, the clinical importance of these results are somewhat insignificant, and despite some significant results, two recent systematic reviews have suggested that a lot more information is required to support the use of rTMS and tDCS for stroke recovery [36,37].

Therefore, this study aimed to investigate recent trends and present evidence on the effectiveness of rehabilitation intervention combined with NIBS on upper limb motor function in stroke patients based on academic articles published in the last 10 years. Furthermore, this systematic review of randomized controlled trials (RCTs) investigated the characteristics of the study participants, evaluation tools, application strength and location, application type, and results.[…]

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[ARTICLE] Short-term Effect of Noninvasive Brain Stimulation Techniques on Motor Impairment in Chronic Ischemic Stroke: A Systematic Review with Meta-Analysis – Full Text

Abstract

Background: In recent years, noninvasive brain stimulation (NIBS) has shown promise for stroke rehabilitation as a novel nonpharmaceutical neuromodulatory intervention with attractive neurophysiological theories backing it up.

Objective: To find out the short-term effects of NIBS techniques on motor impairment in chronic ischemic stroke.

Materials and Methods: A systematic review with meta-analysis was performed separately for transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS), and studies that combined both, utilizing various databases for a period spanning from 2001 to 2019. Good-quality randomized controlled trials (RCTs) on chronic ischemic stroke cases with homogeneous clinical upper motor short-term outcome measures were considered for the meta-analysis. RevMan 5.1 software was used for the meta-analysis. Meta-analysis registration: CRD42021196299; https://www.crd.york.ac.uk/PROSPERO

Results: A total of 319 studies were identified initially. After necessary filters to comply with the strict recruitment criteria, only four studies qualified, two each for tDCS and TMS and none qualified for analysis under the combined category. tDCS showed a nonsignificant effect on the upper limb motor function improvement (−0.10 [95% confidence interval {CI}: −0.84 to 0.64; I² 0%; P = 0.8]), whereas the repetitive TMS showed a significant effect (0.75 [95% CI: 0.03–1.48; I² 0%; P = 0.04]). The safety analysis did not reveal any major concerns for several published protocols.

Conclusions: tDCS alone did not significantly benefit motor recovery; rTMS was effective in providing immediate functional benefits in chronic ischemic stroke. While the current stroke rehabilitation protocols with NIBS appear safe, more good-quality stratified RCTs with more innovative experimental protocols are needed to analyze and quantify the efficacy of these techniques in stroke rehabilitation.

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Stroke is a sudden nonconvulsive focal neurological deficit of vascular etiology due to infarction or hemorrhage into brain or spinal cord parenchyma in the anterior or posterior circulation territories. Around 15 million people worldwide suffer from stroke every year. Stroke is the leading cause of adult disability in the elderly, and it leaves around a third of victims permanently disabled. Contingent upon the site and the extent of the brain lesion, post-stroke disabilities vary in survivors, and rehabilitation measures are important to improve the quality of life in stroke survivors. Early rehabilitation is the key for recovery and involves multidisciplinary approaches. However, conventional stroke rehabilitation seldom succeeds in achieving a good recuperation in a vast majority of the cases. Only few rehabilitation techniques have gold standard protocols, and this holds especially true for several newly evolving technologies. Neuromodulation methods such as noninvasive brain stimulation (NIBS) include transcranial electrical stimulation (TES) which in turn can be direct or alternate current stimulation (tDCS/ACS) and transcranial magnetic stimulation (TMS) which all have now been intensively investigated as facilitatory or inhibitory types of stimulations[1] to induce desirable priming effects for routine neurorehabilitation.

A Cochrane review published in 2013 reported unimpressive effects on motor improvement with repetitive transcranial magnetic stimulation rTMS and partly attributed it to the heterogeneity of the trials.^[2] This study covered publications only till 2012, but analysed 19 trials involving a total of 588 participants. It reported meta-analysis of two heterogenous trials with a total of 183 participants which showed rTMS treatment not being associated with any significant increase in the functional status after stroke with a Barthel index score mean difference (MD) of 15.92 with 95% confidence interval (CI) of − 2.11 to 33.95. Four other trials with a total of 73 participants also did not find any statistically significant effect on motor function with MD of 0.51 and 95% CI of − 0.99 to 2.01. Subgroup analyses of different stimulation frequencies or duration of illness also showed no significant difference. But they reported that the adverse events (AEs) in the rTMS groups were mild, with the most common event being transient or mild headaches (2.4%) and local discomfort at the site of the stimulation. They concluded against the routine use of rTMS for the treatment of stroke and recommended further trials with larger sample sizes to determine a suitable rTMS protocol and the long-term functional outcome. Another meta-analysis reported in 2016 covered 23 studies till 2015 and generated 29 comparisons: 14 on tDCS and 15 on rTMS. Using random-effects models, they indicated improvements in paretic limb force after tDCS and rTMS rehabilitation. They reported positive effects on force production with two stimulation protocols, one on increasing cortical activity in the ipsilesional hemisphere and the other on decreasing cortical activity in the contralesional hemisphere. They also reported improved reduction of force across acute, subacute, and chronic phases of stroke with both tDCS and rTMS. While the first meta-analysis was a Cochrane review, the second was a publication in a more technical journal, Brain Stimulation. But the differences between the conclusions are obviously most striking. It is, therefore, important to revisit the studies till date, including those conducted from 2016 till date, and make sense of the reports of quality studies through a fresh systematic review. In order to avoid too much of heterogeneity which makes meta-analysis difficult, we confined our studies to randomized controlled trials (RCTs) of NIBS on upper limb motor rehabilitation in chronic ischemic stroke patients and aimed to determine the effectiveness and safety through a systematic review.[…]

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[Abstract] Does noninvasive brain stimulation combined with other therapies improve upper extremity motor impairment, functional performance, and participation in activities of daily living after stroke? A systematic review and meta-analysis of randomized controlled trial

ABSTRACT

Background

Several studies have investigated the effect of noninvasive brain stimulation (NIBS) on upper limb motor function in stroke, but the evidence so far is conflicting.

Objective

We aimed to determine the effect of NIBS on upper limb motor impairment, functional performance, and participation in activities of daily living after stroke.

Method

Literature search was conducted for randomized controlled trials (RCTs) assessing the effect of “tDCS” or “rTMS” combined with other therapies on upper extremity motor recovery after stroke. The outcome measures were Fugl-Meyer Assessment of Upper Extremity (FMA-UE), Wolf Motor Function Test (WMFT), and Barthel Index (BI). The mean difference (MD) and 95%CI were estimated for motor outcomes. Cochrane risk of bias tool was used to assess the quality of evidence.

Result

Twenty-five RCTs involving 1102 participants were included in the review. Compared to sham stimulation, NIBS combined with other therapies has effectively improved FMA-UE (MD0.97 [95%CI, 0.09 to 1.86; p = .03]) and BI score (MD9.11 [95%CI, 2.27 to 15.95; p = .009]) in acute/sub-acute stroke (MD1.73 [95%CI, 0.61 to 2.85; p = .003]) but unable to modify FMA-UE score in chronic stroke (MD-0.31 [95%CI, -1.77 to 1.15; p = .68]). Only inhibitory (MD3.04 [95%CI, 1.76 to 4.31; I² = 82%, p < .001] protocol is associated with improved FMA-UE score. Twenty minutes of stimulation/session for ≥20 sessions was found to be effective in improving FMA-UE score (Stimulation time: ES0.45; p ≤ .001; Sessions: ES0.33; p ≤ .001). The NIBS did not produce any significant improvement in WMFT as compared to sham NIBS (MD0.91 [95% CI, -0.89 to 2.70; p = .32]).

Conclusion

Moderate to high-quality evidence suggested that NIBS combined with other therapies is effective in improving upper extremity motor impairment and participation in activities of daily living after acute/sub-acute stroke.

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[Abstract] Evidence for a Window of Enhanced Plasticity in the Human Motor Cortex Following Ischemic Stroke

Abstract

Background

In preclinical models, behavioral training early after stroke produces larger gains compared with delayed training. The effects are thought to be mediated by increased and widespread reorganization of synaptic connections in the brain. It is viewed as a period of spontaneous biological recovery during which synaptic plasticity is increased.

Objective

To look for evidence of a similar change in synaptic plasticity in the human brain in the weeks and months after ischemic stroke.

Methods

We used continuous theta burst stimulation (cTBS) to activate synapses repeatedly in the motor cortex. This initiates early stages of synaptic plasticity that temporarily reduces cortical excitability and motor-evoked potential amplitude. Thus, the greater the effect of cTBS on the motor-evoked potential, the greater the inferred level of synaptic plasticity. Data were collected from separate cohorts (Australia and UK). In each cohort, serial measurements were made in the weeks to months following stroke. Data were obtained for the ipsilesional motor cortex in 31 stroke survivors (Australia, 66.6 ± 17.8 years) over 12 months and the contralesional motor cortex in 29 stroke survivors (UK, 68.2 ± 9.8 years) over 6 months.

Results

Depression of cortical excitability by cTBS was most prominent shortly after stroke in the contralesional hemisphere and diminished over subsequent sessions (P = .030). cTBS response did not differ across the 12-month follow-up period in the ipsilesional hemisphere (P = .903).

Conclusions

Our results provide the first neurophysiological evidence consistent with a period of enhanced synaptic plasticity in the human brain after stroke. Behavioral training given during this period may be especially effective in supporting poststroke recovery.

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[Abstract] Effects of Robotic Therapy Associated With Noninvasive Brain Stimulation on Upper-Limb Rehabilitation After Stroke: Systematic Review and Meta-analysis of Randomized Clinical Trials

Abstract

Background

Robot-assisted therapy and noninvasive brain stimulation (NIBS) are promising strategies for stroke rehabilitation.

Objective

This systematic review and meta-analysis aims to evaluate the evidence of NIBS as an add-on intervention to robotic therapy in order to improve outcomes of upper-limb motor impairment or activity in individuals with stroke.

Methods

This study was performed according to the PRISMA Protocol and was previously registered on the PROSPERO Platform (CRD42017054563). Seven databases and gray literature were systematically searched by 2 reviewers, and 1176 registers were accessed. Eight randomized clinical trials with upper-limb body structure/function or activity limitation outcome measures were included. Subgroup analyses were performed according to phase poststroke, device characteristics (ie, arm support, joints involved, unimanual or bimanual training), NIBS paradigm, timing of stimulation, and number of sessions. The Grade-Pro Software was used to assess quality of the evidence.

Results

A nonsignificant homogeneous summary effect size was found both for body structure function domain (mean difference [MD] = 0.15; 95% CI = −3.10 to 3.40; P = 0.93; I² = 0%) and activity limitation domain (standard MD = 0.03; 95% CI = −0.28 to 0.33; P = 0.87; I² = 0%).

Conclusions

According to this systematic review and meta-analysis, at the moment, there are not enough data about the benefits of NIBS as an add-on intervention to robot-assisted therapy on upper-limb motor function or activity in individuals with stroke.

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[Abstract + References] Canadian Platform for Trials in Noninvasive Brain Stimulation (CanStim) Consensus Recommendations for Repetitive Transcranial Magnetic Stimulation in Upper Extremity Motor Stroke Rehabilitation Trials

Abstract

Objective. To develop consensus recommendations for the use of repetitive transcranial magnetic stimulation (rTMS) as an adjunct intervention for upper extremity motor recovery in stroke rehabilitation clinical trials. 

Participants. The Canadian Platform for Trials in Non-Invasive Brain Stimulation (CanStim) convened a multidisciplinary team of clinicians and researchers from institutions across Canada to form the CanStim Consensus Expert Working Group. 

Consensus Process. Four consensus themes were identified: (1) patient population, (2) rehabilitation interventions, (3) outcome measures, and (4) stimulation parameters. Theme leaders conducted comprehensive evidence reviews for each theme, and during a 2-day Consensus Meeting, the Expert Working Group used a weighted dot-voting consensus procedure to achieve consensus on recommendations for the use of rTMS as an adjunct intervention in motor stroke recovery rehabilitation clinical trials. 

Results. Based on best available evidence, consensus was achieved for recommendations identifying the target poststroke population, rehabilitation intervention, objective and subjective outcomes, and specific rTMS parameters for rehabilitation trials evaluating the efficacy of rTMS as an adjunct therapy for upper extremity motor stroke recovery. 

Conclusions. The establishment of the CanStim platform and development of these consensus recommendations is a first step toward the translation of noninvasive brain stimulation technologies from the laboratory to clinic to enhance stroke recovery.

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[REVIEW] Repetitive transcranial magnetic stimulation in stroke rehabilitation: review of the current evidence and pitfalls – Full Text

Abstract

Acute brain ischemia causes changes in several neural networks and related cortico-subcortical excitability, both in the affected area and in the apparently spared contralateral hemisphere. The modulation of these processes through modern techniques of noninvasive brain stimulation, namely repetitive transcranial magnetic stimulation (rTMS), has been proposed as a viable intervention that could promote post-stroke clinical recovery and functional independence. This review provides a comprehensive summary of the current evidence from the literature on the efficacy of rTMS applied to different clinical and rehabilitative aspects of stroke patients. A total of 32 meta-analyses published until July 2019 were selected, focusing on the effects on motor function, manual dexterity, walking and balance, spasticity, dysphagia, aphasia, unilateral neglect, depression, and cognitive function after a stroke. Only conventional rTMS protocols were considered in this review, and meta-analyses focusing on theta burst stimulation only were excluded. Overall, both HF-rTMS and LF-rTMS have been shown to be safe and well-tolerated. In addition, the current literature converges on the positive effect of rTMS in the rehabilitation of all clinical manifestations of stroke, except for spasticity and cognitive impairment, where definitive evidence of efficacy cannot be drawn. However, routine use of a specific paradigm of stimulation cannot be recommended yet due to a significant level of heterogeneity of the studies in terms of protocols to be set and outcome measures that have to be used. Future studies need to preliminarily evaluate the most promising protocols before going on to multicenter studies with large cohorts of patients in order to achieve a definitive translation into daily clinical practice.

Introduction

Background

Stroke is a common acute neurovascular disorder that causes disabling long-term limitations to daily living activities. The most common consequence of a stroke is motor deficit of variable degree,¹ although nonmotor symptoms are also relevant and often equally disabling.² To date, to the best of the authors’ knowledge, there is no validated treatment that is able to restore the impaired functions by a complete recovery of the damaged tissue. Indeed, stroke management basically consists of reducing the initial ischemia in the penumbra, preventing future complications, and promoting a functional recovery using physiotherapy, speech therapy, occupational therapy, and other conventional treatments.^3,4

Ischemic damage is associated with significant metabolic and electrophysiological changes in cells and neural networks involved in the affected area. From a pure electrophysiological perspective, however, beyond the affected area, there is a local shift in the balance between the inhibition and excitation of both the affected and contralateral hemisphere, consisting of increased excitability and disinhibition (reduced activity of the inhibitory circuits).^3,5 In addition, subcortical areas and spinal regions may be altered.^3,5 In particular, the role of the uninjured hemisphere seems to be of utmost significance in post-stroke clinical and functional recovery.

Different theoretical models have been proposed to explain the adaptive response of the brain to acute vascular damage. According to the vicariation model, the activity of the unaffected hemisphere contributes to the functional recovery after a stroke through the replacement of the lost functions of the affected areas. The interhemispheric competition model considers the presence of mutual inhibition between the hemispheres, and the damage caused by a stroke disrupts this balance, thus producing a reduced inhibition of the unaffected hemisphere by the affected side. This results in increased inhibition of the affected hemisphere by the unaffected side. More recently, a new model, called bimodal balance recovery, has been proposed.^3,5 It introduces the concept of a structural reserve, which describes the extent to which the nondamaged neural pathways contribute to the clinical recovery. The structural reserve determines the prevalence of the interhemispheric imbalance over vicariation. When the structural reserve is high, the interhemispheric competition model can predict the recovery better than the vicariation model, and vice versa.³

Repetitive transcranial magnetic stimulation

One of the proposed interventions to improve stroke recovery, by the induction of neuromodulation phenomena, is based on methods of noninvasive brain stimulation. Among them, transcranial magnetic stimulation (TMS) is a feasible and painless neurophysiological technique widely used for diagnostic, prognostic, research, and, when applied repetitively, therapeutic purposes.^6–9 By electromagnetic induction, TMS generates sub or suprathreshold currents in the human cortex in vivo and in real time.^10,11

The most common stimulation site is the primary motor cortex (M1), that generates motor evoked potentials (MEPs) recorded from the contralateral muscles through surface electromyography electrodes.¹¹ The intensity of TMS, measured as a percentage of the maximal output of the stimulator, is tailored to each patient based on the motor threshold (MT) of excitability. Resting MT (rMT) is found when the target muscle is at rest, it is defined as the minimal intensity of M1 stimulation required to elicit an electromyography response with a peak-to-peak amplitude > 50 µV in at least 5 out of 10 consecutive trials.¹¹ Alternatively TMS MTAT 2.0 software (http://www.clinicalresearcher.org/software.htm) is a free tool for TMS researchers and practitioners. It provides four adaptive methods based on threshold-tracking algorithms with the parameter estimation by sequential testing, using the maximum-likelihood strategy for estimating MTs. Active MT (aMT) is obtained during a tonic contraction of the target muscle at approximately 20% of the maximal muscular strength.¹¹

The rMT is considered a basic parameter in providing the global excitation state of a central core of M1 neurons.¹¹ Accordingly, rMT is increased by drugs blocking the voltage-gated sodium channels, where the same drugs may not have an effect on the gamma-aminobutyric acid (GABA)-ergic functions. In contrast, rMT is reduced by drugs increasing glutamatergic transmission not mediated by the N-methyl-D-aspartate (NMDA) receptors, suggesting that rMT reflects both neuronal membrane excitability and non-NMDA receptor glutamatergic neurotransmission.¹² Finally, the MT increases, being often undetectable, when a substantial portion of M1 or the cortico-spinal tract is damaged (i.e. by stroke or motor neuron disease), and decreases when the motor pathway is hyperexcitable (such as epilepsy).¹³

Repetitive (rTMS) is a specific stimulation paradigm characterized by the administration of a sequence of consecutive stimuli on the same cortical region, at different frequencies and inter sequence intervals. As known, rTMS can transiently modulate the excitability of the stimulated cortex, with both local and remote effects outlasting the stimulation period. Conventional rTMS modalities include high-frequency (HF-rTMS) stimulation (>1 Hz) and low-frequency (LF-rTMS) stimulation (⩽1 Hz).¹¹ High-frequency stimulation typically increases motor cortex excitability of the stimulated area, whereas low-frequency stimulation usually produces a decrease in excitability.¹⁴ The mechanisms by which rTMS modulates the brain are rather complex, although they seem to be related to the phenomena of long-term potentiation (LTP) and long-term depression (LTD).¹⁵

When applied after a stroke, rTMS should ideally be able to suppress the so called ‘maladaptive plasticity’^16,17 or to enhance the adaptive plasticity during rehabilitation. These goals can be achieved by modulating the local cortical excitability or modifying connectivity within the neuronal networks.¹⁰

rTMS in stroke rehabilitation: an overview

According to the latest International Federation of Clinical Neurophysiology (IFCN) guidelines on the therapeutic use of rTMS,¹⁰ there is a possible effect of LF-rTMS of the contralesional motor cortex in post-acute motor stroke, and a probable effect in chronic motor stroke. An effect of HF-rTMS on the ipsilesional motor cortex in post-acute and chronic motor stroke is also possible.

The potential role of rTMS in gross motor function recovery after a stroke has been assessed in a recent comprehensive systematic review of 70 studies by Dionisio and colleagues.¹⁸ The majority of the publications reviewed report a role of rTMS in improving motor function, although some randomized controlled trials (RCTs) were not able to confirm this result,^19–23 as shown by a recent large randomized, sham-controlled, clinical trial of navigated LF-rTMS.²⁴ It has also been suggested that rTMS can specifically improve manual dexterity,¹⁰ which is defined as the ability to coordinate the fingers and efficiently manipulate objects, and is of crucial importance for daily living activities.²⁵ Notably, most of the studies focused on motor impairment in the upper limbs, whereas limited data is available on the lower limbs.¹⁸ Walking and balance are frequently impaired in stroke patients and significantly affect the quality of life (QoL),^26,27 and rTMS might represent a valid aid in the recovery of these functions.^28,29 Spasticity is another common complication after a stroke, consisting of a velocity-dependent increase of muscular tone,³⁰ and for which rTMS has been proposed as a rehabilitation tool.³¹

Dysphagia is highly common in stroke patients, it impairs the global clinical recovery, and predisposes to complications.³² It has been pointed out that rTMS targeting the M1 area representing the muscles involved in swallowing may contribute to the treatment of post-stroke dysphagia.³³

Nonmotor deficit is also a relevant post-stroke disability that negatively impacts the QoL. Aphasia is a very common consequence of stroke, affecting approximately 30% of stroke survivors and significantly limiting rehabilitation.³⁴ According to the IFCN guidelines, to date, there is no recommendation for LF-rTMS of the contralesional right inferior frontal gyrus (IFG). Similarly, no recommendation for HF-rTMS or intermittent theta burst stimulation (TBS) of the ipsilesional left IFG or dorsolateral prefrontal cortex (DLPFC) in Broca’s aphasia has been currently approved.¹⁰ The same is true for LF-rTMS of the right superior temporal gyrus in Wernicke’s aphasia.¹⁰

Neglect is the incapacity to respond to tactile or visual contralateral stimuli that are not caused by a sensory-motor deficit.³⁵ Although hard to treat, rTMS has been proposed as a tool for neglect rehabilitation.³⁶ However, the IFCN guidelines state that currently there is no recommendation for LF-rTMS of the contralesional left posterior parietal cortex, or for HF-rTMS of the ipsilesional right posterior parietal cortex.¹⁰ In a recent systematic review, most of the included studies supported the use of TMS for the rehabilitation of aphasia, dysphagia, and neglect, although the heterogeneity of stimulation protocols did not allow definitive conclusions to be drawn.³⁷

Post-stroke depression is a relevant complication of cerebrovascular diseases.³⁸ The role of rTMS in the management of major depressive disorders is well documented,^39,40 and currently, rTMS is internationally approved and indicated for the treatment of major depression in adults with antidepressant medication resistance, and in those with a recurrent course of illness, or in cases of moderate-to-severe disease severity.³⁹ In major depression disorders, according to the IFCN guidelines, there is a clear antidepressant effect of HF-rTMS over the left DLPFC, a probable antidepressant effect of LF-rTMS on the right DLPFC, and probably no differential antidepressant effect between right LF-rTMS and left HF-rTMS. Moreover, there is currently no recommendation for bilateral stimulation combining HF-rTMS of the left DLPFC and LF-rTMS of the right DLPFC. The mentioned guidelines also state that the antidepressant effect when stimulating DLPFC is probably additive, and possibly potentiating, to the efficacy of antidepressant drugs.¹⁰ However, no specific recommendation currently addresses the use of rTMS in post-stroke depression. Recently, rTMS has been proposed as a treatment option for the late-life depression associated with chronic subcortical ischemic vascular disease, the so called ‘vascular depression’.^41–44 Three studies tested rTMS efficacy in vascular depression (one was a follow-up study with citalopram). Although presenting positive findings, further trials should refine clinical and diagnostic criteria to assess its impact on antidepressant efficacy.⁴⁵

Approximately 25–30% of stroke patients develop an immediate or delayed cognitive impairment or an overt picture of vascular dementia.⁴⁶ There is evidence of an overall positive effect on cognitive function for both LF-rTMS⁴⁷ and HF-rTMS,⁴⁸ supported by studies on experimental models of vascular dementia.^49–52 Nonetheless, the few trials examining the effect on stroke-related cognitive deficit produced mixed results.^53–56 In particular, two studies found no effect on cognition when stimulating the left DLPFC at 1 Hz and 10 Hz,^53,54 whereas a pilot study found a positive effect on the Stroop interference test with HF-rTMS over the left DLPFC in patients with vascular cognitive impairment without dementia.⁵⁵ However, this finding was not replicated in a follow-up study.⁵⁶ To summarize, rTMS can induce beneficial effects on specific cognitive domains, although data are limited and their clinical significance needs to be further validated. Major challenges exist in terms of appropriate patient selection and optimization of the stimulation protocols.⁵⁷

Central post-stroke pain (CPSP) is the pain resulting from an ischemic lesion of the central nervous system.⁵⁸ It represents a relatively common complication after a stroke, although it is often under-recognized and, therefore, undertreated.⁵⁹ According to the IFCN guidelines for the use of rTMS in the treatment of neuropathic pain, there is a definite analgesic effect of HF-rTMS of contralateral M1 to the pain side, and LF-rTMS of contralateral M1 to the pain side is probably ineffective. In addition, there is currently no recommendation for cortical targets other than contralateral M1 to the pain side.¹⁰ Notably, rTMS might be effective in drug-resistant CPSP patients.⁵⁸ A recent systematic review that included nine HF-rTMS studies suggested an effect on CPSP relief, but also underlined the insufficient quality of the studies considered.⁶⁰

Study objective

In this article, we aim to provide an up-to-date overview of the most recent evidence on the efficacy of rTMS in the rehabilitation of stroke patients. Although several studies have been published, a conclusive statement supporting a systematic use of rTMS in the multifaceted clinical aspects of stroke rehabilitation is still lacking.

[…]

 

Continue —> Repetitive transcranial magnetic stimulation in stroke rehabilitation: review of the current evidence and pitfalls – Francesco Fisicaro, Giuseppe Lanza, Alfio Antonio Grasso, Giovanni Pennisi, Rita Bella, Walter Paulus, Manuela Pennisi, 2019

[Abstract + References] Motor stroke recovery after tDCS: a systematic review

Abstract

The purpose of the present study was to investigate the effects of transcranial direct current stimulation (tDCS) on motor recovery in adult patients with stroke, taking into account the parameters that could influence the motor recovery responses. The second aim was to identify the best tDCS parameters and recommendations available based on the enhanced motor recovery demonstrated by the analyzed studies. Our systematic review was performed by searching full-text articles published before February 18, 2019 in the PubMed database. Different methods of applying tDCS in association with several complementary therapies were identified. Studies investigating the motor recovery effects of tDCS in adult patients with stroke were considered. Studies investigating different neurologic conditions and psychiatric disorders or those not meeting our methodologic criteria were excluded. The main parameters and outcomes of tDCS treatments are reported. There is not a robust concordance among the study outcomes with regard to the enhancement of motor recovery associated with the clinical application of tDCS. This is mainly due to the heterogeneity of clinical data, tDCS approaches, combined interventions, and outcome measurements. tDCS could be an effective approach to promote adaptive plasticity in the stroke population with significant positive premotor and postmotor rehabilitation effects. Future studies with larger sample sizes and high-quality studies with a better standardization of stimulation protocols are needed to improve the study quality, further corroborate our results, and identify the optimal tDCS protocols.

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