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2. Research officer, Department of Neurology,AIIMS, New Delhi, India.
3. Head, Department of Neurology, AIIMS, New Delhi, India.
4. Professor, Department of NMR & MRI facility, AIIMS, New Delhi, India.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) have great therapeutic potential in diagnostic and interventional neuroscience, neurophysiology and psychiatry. These have emerged as a boon for stroke recovery in the last decade. TMS allows neurostimulation and neuromodulation, while tDCS purely converges in neuromodulation. This review on non invasive brain stimulation (NIBS) provides a comprehensive summary of the current evidence in stroke upper motor recovery with most robust reviews, recent trials included at clinicaltrials.gov, pubmed, CINAHL and other search engines. We also expand this review with our experience of both the interventional modalities for post stroke arm and hand function recovery. Our results show that NIBS works on neurophysiological principles of learning & plasticity and aids in motor performance when applied in different stages of stroke recovery.
Keywords: Non invasive stimulation, stroke, neural rehabilitation, upper limb recovery
The amalgamation of bioelectrical and engineering domains with medical sciences has led to the development of newer technologies like noninvasive brain stimulation (NIBS). This has proved to be a valuable tool for interventional neurophysiology applications which modulates brain activity to induce controlled manipulations in function and behavior [1]. Brain stimulation techniques have a theoretical appeal of being able to specifically and selectively enhance adaptive patterns of CNS activity, suppress mal adaptive patterns and restore equilibrium in imbalanced neural networks [2,3].
There is surmounting evidence for the efficacy of noninvasive brain stimulation in various neurological conditions. In this report we present a comprehensive review of non-invasive brain stimulation techniques like transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) in Stroke [4,5]. TMS is a neurostimulation and neuromodulation device, whereas tDCS is a purely neuromodulatory intervention [6,7].
Neuroplasticity refers to the ability of the nervous system to change its structure and function, adapting to environmental changes to recover after any brain lesion [8,9]. The most commonest principles are “recruitment” and “compensation” of other brain areas than the injured one. The stimulation through TMS or tDCS induces behavioral changes and the response of the brain to such behavioral changes is augmented and captured by these modalities [10,11]. NIBS for stroke patients works on two theoretical models as suggested by reviewers: (i) an interhemispheric inhibition of human motor cortices on one another; and (ii) the transcallosal inhibitory effect on the affected motor cortex because of the above said phenomenon [12,13]. Therefore, the approach for applying tDCS and or TMS generally has been to either up-regulate the lesional hemisphere with excitatory anodal stimulation, down-regulate the contralesional hemisphere with inhibitory cathodal tDCS stimulation, or use excitatory TMS on lesional hemisphere or exploit an inhibitory effect on contralesional hemisphere [14,15] (Figures 1 and 2).
Figure 1 : Excitatory and inhibitory effects of non invasive brain stimulation (NIBS).
Figure 2 : PRISMA selection of research articles.
In the present review we focus on these two interventions; an overview of the modalities, past reviews, current trials and our experience in stroke.
Methods
Inclusion criteria are as follows
• Research trials on non-transcranial magnetic stimulation, transcranial direct current stimulation for motor upper limb impairments after stroke.
• Rehabilitation in the acute, sub-acute, and chronic phases after stroke.
• Randomised controlled trials, case reports, case controlled studies were included.
• Articles published from January 2015 till October 2020.
Exclusion criteria are as follows
• Studies written in languages other than English.
• Reports studying the effects of NIBS on lower limb, gait and postural rehabilitation.
Search Strategy
This review was conducted using PRISMA guidelines (Figure 2). An electronic search was performed using PubMed, Web of Science, CINAHL. The search strategy includes keywords combined with following words: TMS, stroke, NIBS, rehabilitation, functional recovery. The selection strategy of the studies is shown in the PRISMA flow chart.
Review Process
The studies were screened by two authors based on their titles and abstracts. All of the full articles were then assessed in order to check the fulfillment of the inclusion criteria. In case of a disagreement between the selection, the decision was made by the corresponding author.
Data Extraction
After the selection of studies, the data were extracted for information on the title, inclusion and exclusion criteria, type of intervention, sample size, study methodology, primary and secondary outcomes, study limitations, feasibility, and adherence. The data collected were mainly divided on the basis of application in stroke rehabilitation, modes of intervention delivery, and types of control and outcome assessment.
Transcranial magnetic stimulation (TMS)
Device and design
Transcranial magnetic stimulation (TMS) is a non-invasive technique of stimulating the cortex using a wired coil placed over the scalp to generate a short-lasting and localised magnetic field [16,17]. The pulsed magnetic field enters the brain and creates an electrical current that flows through neurons, inducing neuronal depolarization. rTMS is defined as repetition of TMS pulses; high-frequency rTMS increases cortical excitability, whereas low-frequency rTMS suppresses cortical excitability (Figure 3). Another module is theta burst stimulation (TBS) which consists of short bursts of 3 stimuli at 50 Hz, repeating at 5 Hz [18]. The continuous pattern (cTBS; 200 bursts, 600 stimuli, 40 s) suppresses cortical excitability and was delivered to the contralesional hemisphere; the intermittent pattern (iTBS; 20 trains of 10 bursts with 8-s intervals, 600 stimuli, 200 s) enhances excitability and was delivered to the ipsilesional hemisphere [19].
Figure 3 : Taken from Auriat et al 2015; Frontiers in Neurology; A schematic of TMS evoked measures of single and paired pulsed corticospinal excitability.
It has been reported that high-frequency rTMS resulted in a significantly increase in the MEP amplitude than the sham rTMS (p<0.01), and the plastic change was positively associated with an enhanced motor performance accuracy (p<0.05). It was concluded that high-frequency rTMS of the affected motor cortex can facilitate practice-dependent plasticity and improve the motor learning performance in chronic strokes [20]. Cellular data show that rTMS modulates excitability of both γ-aminobutyric acid (GABA) and glutamatergic neurons. Repeated 1-Hz stimulation particularly increased gene expression associated with synaptic plasticity and GABA-producing enzymes, as well as GABAergic neurotransmission on the system level [21].
TMS & stroke recovery
A review by Xiang et al 2019 evaluated the effects of repetitive transcranial magnetic stimulation (rTMS) on limb movement recovery and cortex excitability, to explore the optimal parameters of rTMS and suitable stroke population. They found 42 eligible studies involving 1168 stroke patients indicated that rTMS had positive effects on limb motor recovery (SMD=0.50, p<0.00001) and activities of daily living (SMD = 0.82, P<0.00001), and motor-evoked potentials [22]. Another review quoted that rTMS is favorable in acute stroke than sub acute strokes [23]. One review commented on 34 studies and found that five-session rTMS treatment could best improve stroke-induced upper limb function and dyskinesia acutely and in a long-lasting manner [24].
One of our double blind, randomized controlled research trial investigated the role of low-frequency rTMS (10 Hz, 750 pulses with 110%RMT) along with conventional physiotherapy on 60 chronic ischemic stroke patients from 3 to 36 months of index event with atleast 10° of wrist extension & thumb abduction with brunnstorm stage 2-4. Patients were randomized equally to CIMT & rTMS with CIMT groups and were assessed with clinical scales and fMRI at baseline, 21st & 90th day. We observed a significant change in FM showed statistically significant improvement in group B as compared to group A at 3 weeks (95%CI: -12.4 to -9.3, p=0.003) and 3months (95%CI : 7.4 to 4.2, p=0.01. There was an increase in the BOLD cluster activation in rTMS group as compared to the one who received CIMT alone [25].
Our experience with first ever ischemic stroke was carried out with low frequency repetitive TMS stimulation in a double-blind, parallel group, randomized controlled trial. The primary efficacy outcome measures were a change in modified Barthel Index (mBI), Fugl-Meyer score, Hamilton depression Scale, modified Rankin score measured at 90±7 days post recruitment. Patients were randomized after a run-in period of 75±7 days into real rTMS (n=47) and sham rTMS (n=49) groups. Total 10 sessions of low-frequency rTMS on contralesional premotor cortex was administered along with conventional physiotherapy were administered for 2 weeks for 45-50 minutes. Modified intention to treat analysis showed a significant increase in the mBI score in real rTMS group (4.96±4.06) versus sham rTMS group (2.65±3.25). There was no significant difference in proportion of patients with mBI>90 (55% vs 59%; p=0.86) at 3 months between the groups. 1-Hz low-frequency rTMS on contralesional premotor cortex along with conventional physical therapy resulted in significant change in mBI score [26,27].
Transcranial direct current stimulation (tDCS)
Device and design
This device delivers constant direct current (e.g.,0–4mA) while constantly monitoring the resistance in the system. Saline soaked electrodes are applied and secured onto the scalp over desired areas like the left or right precentral gyrus region (corresponding to C3 or C4 of the international 10–20 EEG system) (Figure 4). The relaying currents are put across the scalp and pass through the underlying brain tissue. The direction of the current flow determines the effects on the underlying tissue [28]. With an active electrode over C3 or C4, a reference electrode (e.g. supra-orbital region) is kept distant to complete the circuit. Two modes of TDCS have been used: anodal stimulation which increases in excitability of the lesional hemisphere or cathodal stimulation which decreases the excitability of the contralesional hemisphere. The excitability under anode is increased and when the current flow is reversed, the excitability of the brain tissue under this electrode is decreased [29].
Figure 4 : Taken from Schlaug et al; Arch Neurol 2008. tDCS device and its applications.
The advantages of tDCS over other NIBS methods is its portability, easy usage, electrode size which allows a large neural network for stimulation, a sham mode and simultaneous rehabilitation being administered to subjects. Moreover it is less risky than direct cortical or epidural stimulation and can be performed on an outpatient basis, with optimal montage of electrodes [30,31]. GABAergic and dopaminergic modulation of tDCS-induced effects were reported by Nitsche et al through long-term potentiation (LTP) and long term depression (LTD) [21].
Transcranial direct current stimulation & ischemic stroke
tDCS has a large data bank with most of the studies depicting positive results after stroke [32,33]. These studies mostly applied a single or multiple sessions of tDCS and evaluated the effects comparing performance in pre and post intervention batteries of motor assessments. We came across more than hundred trials of tDCS for motor, cognitive, balance and gait disorders after stroke. In Tables 1 and 2 we have combined the study designs in the last 5 years with special mention to arm recovery. tDCS could be an effective approach to promote adaptive plasticity in the stroke population with significant enhancement of premotor, somatosensory and motor execution areas. In a review by Bornheim et al 2020 two databases (Medline & Scopus) were searched for randomized, double-blinded, sham-controlled trials pertaining to the use of M1 tDCS (20 min of stimulation, at 2 mA with 25 or 35cm2 electrodes) on stroke patients, and its effects were validated on functional motor outcomes. 46 studies with (n=1291 patients) met inclusion criteria. 71.7% of studies found that tDCS has positive results on functional motor outcomes with an ES between 0-1.33 [34]. A randomized controlled trial with combination of tDCS and CIMT led to improvement in FMA, MAL and hand grip scores; the anodal tDCS seems to have greater impact than the cathodal tDCS in increasing the mCIMT effects on motor function of chronic stroke patients. We share our experience with the University of Buffalow (USA) and studied the efficacy of cerebellar transcranial direct current stimulation (ctDCS) of the dentate nuclei to observe standing balance in chronic (>6 months post-stroke) stroke survivors. This pilot study presented promising results on the beneficial effects of deep ctDCS on functional reach during a standing balance task in chronic stroke survivors [35].
Table 1 : Clinical studies of Transcranial Magnetic Stimulation (TMS) in stroke.
Table 2 : Clinical studies of Transcranial direct current stimulation (tDCS) in stroke.
A multicentric trial is underway from our institute to study the role of Fluoxetine or tDCS and /or combination therapy with drug & device (Fluoxetine & tDCS) on postural Stability and gait in stroke patients between 1 -6 months of index event. All subjects had undergone 12 sessions of tDCs with each session lasting 20 minutes. This was followed by 2 extra sessions every other week of active tDCS with session lasting 20 minutes. Additionally, subjects also took placebo or active fluoxetine by mouth two hours before the tDCS and exercise regime. Placebo fluoxetine tablet was identical in form, colour, and odor and packaging. Exercise regime began within 1 hour after each bihemispheric sham tDCS session and lasted for 45 minutes. As it is RCT (CTRI/2017/05/008668) the results of the study are awaited and one of the abstract got published in World Congress of neurorehabilitation congress 2018 [36].
NIBS and newer imaging technologies
Merging NIBS with other brain-imaging techniques provides particularly powerful means to explore brain function in the living human brain, understand brain-behavior relations and optimize the impact of brain stimulation techniques. A non invasive, method to measure the neuroenergetic status of the cortex is assessed through near infrared spectroscopy (NIRS-EEG joint-imaging sensor montages. These are capable of measuring optical changes in tissue brought about by hemoglobin concentration changes. (NIRS) is one technique that studies brain hemoglobin levels in the coil region pre and post NIBS stimulation. A few authors extended the conventional NIRS technique by increasing the number of light emitter and detector pairs (a single pair is normally used in NIRS) [37].
This review focuses on NIBS and stroke with special mention to upper limb function vis a vis other deficits like pain, aphasia, lower limb dysfunction and sensory syndromes. It is apparent that the best intervention for stroke recovery will incorporate a combination of techniques to maximize neuronal plasticity. The usage and efficacy of these modalities is barred by several factors which stroke is associated with like topography, lesion location and pattern, time course post stroke, the type of adjuvant therapy administered and the most of all the stimulation characteristics. A recent Cochrane review suggests that there is very little enhancement of motor activity when NIBS is used alone [37]. Most of our trials were combination therapy with tDCS & TMS with physical or occupational therapy. Our experience elegantly state that TMS is effective in acute and subacute stages of ischemia whereas TDS is relatively a good option for chronic stroke.
The authors declare that they have no competing interests.
| Authors' contributions | AB | NK | MVP | SSK |
| Research concept and design | √ | -- | -- | -- |
| Collection and/or assembly of data | -- | √ | -- | -- |
| Data analysis and interpretation | √ | -- | -- | -- |
| Writing the article | √ | √ | -- | -- |
| Critical revision of the article | -- | -- | √ | √ |
| Final approval of article | -- | -- | √ | √ |
| Statistical analysis | √ | -- | -- | -- |
AB designed the manuscript, NK helped in edits and formatting, SSK and MVP reviewed the line up of manuscript.
Editor: Catherine Ortega, University of Texas Health Science Center, USA.
Received: 05-April-2022 Final Revised: 30-June-2022
Accepted: 04-July-2022 Published: 09-July-2022
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