Repetitive transcranial magnetic stimulation (rTMS), combined with hand therapy, is currently a research-based treatment. It is intended to help people with stroke achieve greater recovery of hand function. The hand weakness following a stroke stems from brain neurons destroyed by the stroke, as well as from surviving neurons. The surviving neurons become dormant (not active) through inactivity and suppression from the non-stroke hemisphere. In some patients, rTMS can help dormant neurons reactivate and thereby improve voluntary hand function.
To summarize and systematically review the efficacy and safety of high frequency repetitive transcranial magnetic stimulation (HF-rTMS) for depression in stroke patients.
Six databases (Wanfang, CNKI, PubMed, Embase, Cochrane Library, and Web of Science) were searched from inception until November 15, 2018.
Seventeen randomized controlled trials were included for meta-analysis.
Two independent reviewers selected potentially relevant studies based on the inclusion criteria, extracted data, and evaluated the methodological quality of the eligible trials using the Physiotherapy Evidence Database (PEDro).
We calculated the combined effect size (standardized mean difference [SMD] and odds ratio [OR]) for the corresponding effects models. Physiotherapy Evidence Database scores ranged from 7 to 8 points (mean = 7.35). The study results indicated that HF-rTMS had significantly positive effects on depression in stroke patients. The effect sizes of the SMD ranged from small to large (SMD = −1.01; 95% confidence interval [95% CI], −1.36 to −0.66; P < .001; I2 = 85%; n = 1053), and the effect sizes of the OR were large (response rates: 58.43% VS 33.59%; OR = 3.31; 95% CI, 2.25 to 4.88; P < .001; I2 = 0%; n = 529; remission rates: 26.59% VS 12.60%; OR = 2.72; 95% CI, 1.69 to 4.38; P < .001; I2 = 0%; n = 529). In terms of treatment side-effects, the HF-rTMS group was more prone to headache than the control group (OR = 3.53; 95% CI, 1.85 to 8.55; P < .001; I2 = 0%; n = 496).
HF-rTMS is an effective intervention for post-stroke depression, although treatment safety should be further verified via large sample multi-center trials.
The aim of this study was to evaluate the effects of repetitive transcranial magnetic stimulation (rTMS) on the post-stroke recovery of lower limb motor function.
We searched the databases of PubMed, Cochrane Library, and Embase. The randomized controlled trials were published by 25 January 2019.
We included randomized controlled trials that evaluated the effects of rTMS on lower limb motor recovery in patients with stroke. Two reviewers independently screened the searched records, extracted data, and assessed the risk of bias. The treatment effect sizes were pooled in a meta-analysis by using the RevMan 5.3 software. The internal validity was assessed using topics suggested by the Physiotherapy Evidence Database (PEDro).
Eight studies with 169 participants were included in the meta-analysis. Pooled estimates demonstrated that rTMS significantly improved the body function of the lower limbs (standardized mean difference (SMD) = 0.66; P < 0.01), lower limb activity (SMD = 0.66; P < 0.01), and motor-evoked potential (SMD = 1.13; P < 0.01). The subgroup analyses results also revealed that rTMS improved walking speed (SMD = 1.13) and lower limb scores on the Fugl-Meyer Assessment scale (SMD = 0.63). We found no significant differences between the groups in different mean post-stroke time or stimulation mode over lower limb motor recovery. Only one study reported mild adverse effects.
rTMS may have short-term therapeutic effects on the lower limbs of patients with stroke. Furthermore, the application of rTMS is safe. However, this evidence is limited by a potential risk of bias.
The primary aim of this meta-analysis was to evaluate the effects of repetitive transcranial magnetic stimulation (rTMS) on limb movement recovery post-stroke and cortex excitability, to explore the optimal parameters of rTMS and suitable stroke population. Second, adverse events were also included.
The databases of PubMed, EBSCO, MEDLINE, the Cochrane Central Register of Controlled Trials, EBM Reviews-Cochrane Database, the Chinese National Knowledge Infrastructure, and the Chinese Science and Technology Journals Database were searched for randomized controlled trials exploring the effects of rTMS on limb motor function recovery post-stroke before December 2018.
The effect sizes of rTMS on limb motor recovery, the effect size of rTMS stimulation parameters, and different stroke population were summarized by calculating the standardized mean difference (SMD) and the 95% confidence interval using fixed/random effect models as appropriate.
For the motor function assessment, 42 eligible studies involving 1168 stroke patients were identified. The summary effect size 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 of the stimulated hemisphere differed according to the stimulation frequency, that is, the high-frequency group (SMD = 0.57, P = 0.0006), except the low-frequency group (SMD = –0.27, P = 0.05). No significant differences were observed among the stimulation parameter subgroups except for the sessions subgroup (P = 0.02). Only 10 included articles reported transient mild discomfort after rTMS.
rTMS promoted the recovery of limb motor function and changed the cortex excitability. rTMS may be better for early and pure subcortical stroke patients. Regarding different stimulation parameters, the number of stimulation sessions has an impact on the effect of rTMS.
Objective: To investigate the effects of low frequency transcranial magnetic stimulation (LF-rTMS) combined with motor imagery (MI) on upper limb motor function during stroke rehabilitation.
Background: Hemiplegic upper extremity activity obstacle is a common movement disorder after stroke. Compared with a single intervention, sequential protocol or combination of several techniques has been proven to be better for alleviating motor function disorder. Non-invasive neuromodulation techniques such as repetitive transcranial magnetic stimulation (rTMS) and motor imagery (MI) have been verified to augment the efficacy of rehabilitation.
Methods:Participants were randomly assigned to 2 intervention cohorts: (1) experimental group (rTMS+MI group) was applied at 1 Hz rTMS over the primary motor cortex of the contralesional hemisphere combined with audio-based MI; (2) control group (rTMS group) received the same therapeutic parameters of rTMS combined with audiotape-led relaxation. LF-rTMS protocol was conducted in 10 sessions over 2 weeks for 30 min. Functional measurements include Wolf Motor Function Test (WMFT), the Fugl-Meyer Assessment Upper Extremity (UE-FMA) subscore, the Box and Block Test (BBT), and the Modified Barthel index (MBI) were conducted at baseline, the second week (week 2) and the fourth week (week 4).
Results: All assessments of upper limb function improved in both groups at weeks 2 and 4. In particular, significant differences were observed between two groups at end-intervention and after intervention (p < 0.05). In these findings, we saw greater changes of WMFT (p < 0.01), UE-FMA (p < 0.01), BBT (p < 0.01), and MBI (p < 0.001) scores in the experimental group.
Conclusions: LF-rTMS combined with MI had a positive effect on motor function of upper limb and can be used for the rehabilitation of upper extremity motor recovery in stroke patients.
Decreased mobility of hemiplegic upper limb is a common dyskinesia after stroke. At present, clinical researchers have established a number of treatments to improve upper extremity motor function (1). Compared with a single intervention, a combination approach of different techniques has been proven to be better for alleviating movement disorder (2). Lots of trials have shown that movement function improvement after stroke can be enhanced by non-invasive brain stimulation techniques combined with conventional clinical practice (3–6).
Repetitive transcranial magnetic stimulation (rTMS) is one of non-invasive brain stimulations, and could modulate cortical activity. Stroke is considered to be one possible reason for imbalance of interhemispheric cortical inhibition. rTMS could rebulid the interhemisphere balance by down-regulating the excitability of the non-lesioned hemisphere with low frequency stimulation or up-regulating the lesioned excitability by high frequency stimulation (6). Randomized controlled trials have shown that short courses of inhibitory, contralesional rTMS can improve the motor function of hemiplegia after stroke (7, 8). Evidence suggested that maximum control of the lesioned hemisphere is associated with better function (9, 10). Early damage affected the ability of upper motor neurons to compete with lateral neurons to dominate motor neurons (11). Inhibition of contralateral primary motor cortex (M1) with 1 Hz rTMS may enhance hemispheric motor function. This method has revealed efficacy in the stroke rehabilitation for adults although they do not share the same models (8). Recently, the positive effects of HF-rTMS and LF-rTMS on movement disorder after stroke have been supported by accumulating evidence (7). And LF-rTMS has been confirmed to be in correlation with improved function in patients with chronic stroke (12, 13). Nowadays, a meta-analysis by Zhang et al. evaluated the therapeutic potential of LF-rTMS on stroke-induced upper limb movement disorder and cortex plasticity. This research supported that, as an add-on therapy, LF-rTMS successfully alleviated the hemiplegic upper limb motor deficit and significantly promoted upper limb function improvement after stroke (14).
Another non-invasive neuromodulation technique-motor imagery (MI), has been validated to increase the efficacy of rehabilitation and improve the performance of tasks associated with MI in patients after stroke (15–17). The functional recovery of most stroke patients occurred mainly in the first 3 months, and the functional gain obtained in the chronic phase was limited (18). A possible cause of limited functional recovery in the chronic phase is learned nouse. Patients with severe impairment cannot use their paretic limbs in daily activities may be the reason (19). MI is a dynamic state during which the subject mentally simulates a specific movement without any obvious movement (20). It means that MI has no strict restrictions on the patient’s upper limb motor function, so it can be applied to stroke patients with poor function in chronic phase. According to previous studies, MI and motor execution share the same neural networks related to motor function (17, 21, 22). These findings support the idea that MI can be used as a substitute for physical exercise which is difficult for patients to do (23). MI training was assumed to enhance motor recovery in stroke rehabilitation (24). Based on traditional rehabilitation training, MI training is more effective than conventional training alone (17). For example, Kang et al. and Xu et al. demonstrated an increase in neural activity in the motor area during MI training (25, 26). And Kawakami et al. also investigated changes of cortex in reciprocal inhibition following MI in patients with chronic stroke, and reported positive plastic changes during mental practice with MI (27). In another pilot study, Mihara et al. demonstrated that NIRS-mediated neurofeedback MI could enhance the ipsilesional premotor area activation in correlation with MI training and could have significant effects on the motor deficit recovery in stroke patients. Besides these findings, they also found that the change of cortical activation was related to the recovery of the hand function (19).
In view of the fact that rTMS and MI have no strict restrictions on the limb function of patients with chronic stroke, this study intends to combine the two interventions to maximize the motor function recovery of patients. As the author know, few studies explore whether the effect of LF-rTMS can be enhanced by combining with MI on upper extremity activity. In this study, we hypothesize that combination therapy of LF-rTMS with MI training will promote recovery from upper limb movement disorder in patients after chronic stroke; we also predict that activities of daily living might improve accordingly.
Therefore, the objective was to investigate the effects of LF-rTMS combined with MI on improving motor functions of hemiplegic upper extremity in chronic stroke patients.[…]
We reported the case of a patient WLX, who had one ischemic stroke more than 3 years ago, and had underwent intermittent rehabilitation since then. He still had profound right upper limb paralysis and moderate spasm, accompanied with non-fluent aphasia when came to our department; and complained that his recovery had been rather slow for about two years. In addition to the custom rehabilitation, we applied a peripheral plus central rTMS paradigm to him, which included 3 sessions of peripheral magnetic stimulation to his paralyzed right forearm, followed by a session of high frequency rTMS to the bilateral sensorimotor cortex region. The total magnetic stimulation therapy lasted about 30 min a day, and was applied 5 days/week for 4 weeks.
After 4 weeks’ treatment, the patient’s Fulg–Meyer upper limb assessment (FMA) score was obviously improved (from 27 to 37 points), and the spasm was largely relieved in his right hand and arm.
Peripheral plus central rTMS might be an effective treatment for motor dysfunction of chronic stroke patients.
•1-Hz repetitive transcranial magnetic stimulation with rehabilitation immediately after botulinum toxin type A injection in a stroke patient.
•The spasticity, motor function, and usefulness of the paretic hand improved.
•This is a possibility of shortening the intervention period of combined therapy.
Single case report.
A previous study clarified that spasticity and motor function were improved by combined treatment with botulinum toxin type A (BTX) injection and 1-Hz repetitive transcranial magnetic stimulation (rTMS) with intensive motor training at 4 weeks after injection. However, it is not clear whether 1-Hz rTMS with intensive motor training immediately after BTX injection also improves spasticity and motor function in stroke patients.
Purpose of the Case Report
The purpose of this case report is to test the short- and long-term effects of BTX injection and rTMS with intensive motor training on the spasticity, motor function, and usefulness of the paretic hand in a stroke patient.
A 64-year-old male, who suffered from a right cerebral hemorrhage 53 months previously, participated in the present study. BTX was injected into the spastic muscles of the affected upper limb. He then received the new protocol for a total of 24 sessions. The Modified Ashworth Scale (MAS), Fugl-Meyer Assessment (FMA), and Motor Activity Log, consisting of the amount of use and quality of movement scales, were assessed before and immediately after BTX injection, at discharge, and monthly for up to 5 months after discharge.
For the short-term effects of the therapy, the MAS scores of the elbow and wrist, FMA score, and quality of movement score improved. For the long-term effects of the therapy, the MAS score of the fingers, FMA score, and amount of use score improved for up to 5 months after discharge.
The present case report showed the improvement of all assessments performed in the short and/or long term and suggest the possibility of shortening the intervention period of combined therapy of BTX and rTMS with intensive motor training.
Objective: The objective of this study is to review current literature for the efficacy of Repetitive Transcranial Magnetic Stimulation (rTMS) treatment for cognitive deficits after Traumatic Brain Injury (TBI)/concussion.
Background: TBI is a major public health problem and can cause substantial disability. TBI can lead to Post Concussive Syndrome (PCS) which consists of neuro-motor, cognitive, behavioral/affective, and emotional symptoms. Cognitive deficits can significantly impact functionality. The outcome of neuropsychopharmacological treatment is limited, with risk for side effects. TMS is a form of non-invasive neuromodulation which is FDA-approved for treatment-resistant depression. However, there is limited understanding about its application in addressing cognitive deficits after TBI. We therefore sought to examine current research pertaining to the application of TMS in post-TBI cognitive deficits.
Methods: We searched the PubMed research database with the specific terms “TMS in cognitive deficits after TBI”, “rTMS” and “post concussive syndrome.” We assessed clinical trials where cognition was measured either as a primary or secondary variable. Case studies/reports were excluded.
Results: One non-controlled, pilot study was found that assessed cognition after TMS as a secondary variable in TBI. The aim of the study was to assess safety, tolerability and efficacy of repetitive TMS for treatment of PCS after mild TBI (mTBI). Patients who had sustained mTBI over three months prior and had a PCS Symptom Scale score of over 21 were selected. Repetitive TMS (rTMS) was used as the intervention with 20 sessions of rTMS using a figure-8 coil attached to MagPro stimulator. Cognitive symptoms were assessed using subjective self-report scales and objective tests for attention and speed of processing domains. Neuropsychological tests that were used include Trails A & B, Ruff’s 2 & 7 Automatic speed test, Stroop test, Language test for phonemic, and category fluency, Rey AVLT test. The study showed a reduction in overall severity of PCS symptoms but no significant changes on the cognitive symptoms questionnaire or on the majority of neuropsychological test scores.
Conclusion: Despite the limitation in this study with the lack of a control group, there appears to be a good signal for the clinical application of TMS for post-concussive syndrome after TBI/concussion. A more robust, large well-controlled study may be very reasonable approach in the future to evaluate efficacy of rTMS.
1. Koski L1, Kolivakis T, Yu C, Chen JK, Delaney S, Ptito A. Noninvasive brain stimulation for persistent postconcussion symptoms in mild traumatic brain injury. J Neurotrauma. 2015 Jan 1;32(1):38-44. https://doi.org/10.1089/neu.2014.3449.
2. Bashir S1, Vernet M, Yoo WK, Mizrahi I, Theoret H, Pascual-Leone A. Changes in cortical plasticity after mild traumatic brain injury. Restor Neurol Neurosci. 2012;30(4):277-82. https://doi.org/10.3233/RNN-2012-110207.
3. Demirtas-Tatlidede A1, Vahabzadeh-Hagh AM, Bernabeu M, Tormos JM, Pascual-Leone A.Noninvasive brain stimulation in traumatic brain injury. J Head Trauma Rehabil. 2012 Jul-Aug;27(4):274-92. https://doi.org/10.1097/HTR.0b013e318217df55.
4. Neville IS, Hayashi CY, El Hajj SA, Zaninotto AL, Sabino JP, Sousa LM Jr, Nagumo MM, Brunoni AR, Shieh BD, Amorim RL, Teixeira MJ, Paiva WS. Repetitive Transcranial Magnetic Stimulation (rTMS) for the cognitive rehabilitation of traumatic brain injury (TBI) victims: study protocol for a randomized controlled trial. Trials. 2015 Oct 5;16:440. https://doi.org/10.1186/s13063-015-0944-2.
Americans spend billions of dollars each year on antidepressants, but the National Institutes of Health estimates that those medications work for only 60 percent to 70 percent of people who take them. In addition, the number of people with depression has increased 18 percent since 2005, according to the World Health Organization, which this year launched a global campaign encouraging people to seek treatment.
The Semel Institute for Neuroscience and Human Behavior at UCLA is one of a handful of hospitals and clinics nationwide that offer a treatment that works in a fundamentally different way than drugs. The technique, transcranial magnetic stimulation, beams targeted magnetic pulses deep inside patients’ brains — an approach that has been likened to rewiring a computer.
TMS has been approved by the FDA for treating depression that doesn’t respond to medications, and UCLA researchers say it has been underused. But new equipment being rolled out this summer promises to make the treatment available to more people.
“We are actually changing how the brain circuits are arranged, how they talk to each other,” said Dr. Ian Cook, director of the UCLA Depression Research and Clinic Program. “The brain is an amazingly changeable organ. In fact, every time people learn something new, there are physical changes in the brain structure that can be detected.”
Nathalie DeGravel, 48, of Los Angeles had tried multiple medications and different types of therapy, not to mention many therapists, for her depression before she heard about magnetic stimulation. She discussed it with her psychiatrist earlier this year, and he readily referred her to UCLA.
Within a few weeks, she noticed relief from the back pain she had been experiencing; shortly thereafter, her depression began to subside. DeGravel says she can now react more “wisely” to life’s daily struggles, feels more resilient and is able to do much more around the house. She even updated her resume to start looking for a job for the first time in years.
During TMS therapy, the patient sits in a reclining chair, much like one used in a dentist’s office, and a technician places a magnetic stimulator against the patient’s head in a predetermined location, based on calibrations from brain imaging.
The stimulator sends a series of magnetic pulses into the brain. People who have undergone the treatment commonly report the sensation is like having someone tapping their head, and because of the clicking sound it makes, patients often wear earphones or earplugs during a session.
TMS therapy normally takes 30 minutes to an hour, and people typically receive the treatment several days a week for six weeks. But the newest generation of equipment could make treatments less time-consuming.
“There are new TMS devices recently approved by the FDA that will allow patients to achieve the benefits of the treatment in a much shorter period of time,” said Dr. Andrew Leuchter, director of the Semel Institute’s TMS clinical and research service. “For some patients, we will have the ability to decrease the length of a treatment session from 37.5 minutes down to 3 minutes, and to complete a whole course of TMS in two weeks.”
Leuchter said some studies have shown that TMS is even better than medication for the treatment of chronic depression. The approach, he says, is underutilized.
“We are used to thinking of psychiatric treatments mostly in terms of either talk therapies, psychotherapy or medications,” Leuchter said. “TMS is a revolutionary kind of treatment.”
Bob Holmes of Los Angeles is one of the 16 million Americans who report having a major depressive episode each year, and he has suffered from depression his entire life. He calls the TMS treatment he received at UCLA Health a lifesaver.
“What this did was sort of reawaken everything, and it provided that kind of jolt to get my brain to start to work again normally,” he said.
Doctors are also exploring whether the treatment could also be used for a variety of other conditions including schizophrenia, epilepsy, Parkinson’s disease and chronic pain.
“We’re still just beginning to scratch the surface of what this treatment might be able to do for patients with a variety of illnesses,” Leuchter said. “It’s completely noninvasive and is usually very well tolerated.”
Orlando Swayne completed a PhD at UCL and a fellowship at the NINDS in the US, investigating mechanisms of post-stroke neuroplasticity. He is a Consultant Neurologist at the National Hospital for Neurology & Neurosurgery (NHNN) on the Neurorehabilitation Unit. He also works as a Neurologist at Northwick Park Hospital and is an Honorary Senior Lecturer at the UCL Institute of Neurology.
Correspondence to: Orlando Swayne, National Hospital for Neurology & Neurosurgery, Queen Square, London WC1N 3BG, UK. Acknowledgments: Orlando received funding from the UCLH Biomedical Research Centre. Conflicts of interest statement: None declared Provenance and peer review: Submitted and externally reviewed. Date submitted: 20/8/17 Date submitted after peer review: 27/10/17 Acceptance date: 9/11/17 To cite: Swayne O. ACNR 2017;17(2):11-13. Published online: 11/12/17
Transcranial Magnetic Stimulation (TMS) is a non-invasive technique whereby an electro-magnetic coil held over the scalp is used to induce a brief electrical current in the cortex of the underlying brain. TMS may be used in a number of ways to gain in vivo insights into brain physiology and has provided a window into the cascade of physiological changes that occur following stroke. When stimulating the primary motor cortex in a healthy subject stimuli of an intensity above the motor threshold will give rise to a detectable evoked potential in a peripheral muscle. As the stimulus intensity is gradually increased the evoked potentials increase in amplitude up to a maximum, giving rise to a measurable recruitment curve. The motor threshold and the recruitment curve both provide measures of the excitability of the corticospinal tract. This incorporates the excitability of axons within the motor cortex, synaptic inputs onto pyramidal cells and the spinal alpha motor neuron pool. In paired pulse TMS a sub-threshold pulse is delivered a few milliseconds before a second suprathreshold pulse, both through the same coil. The first pulse conditions the response to the second, resulting in inhibition or facilitation depending upon the inter-stimulus interval and reflecting the activity in intracortical regulatory circuits. If two separate TMS coils are used then one may use a similar test-conditioning approach to explore inter-regional interactions, such as interhemispheric inhibition between the two primary motor cortices (Figure 1). Alternatively pulses may be delivered during a motor task, and the resulting effect on behaviour used to infer the stimulated region’s role in task performance, for example during a simple reaction time or movement selection task. See Reis et al1 for a summary of these techniques and their physiological basis.
Figure 1. TMS measures of motor cortical physiology. a) Eliciting a Motor Evoked Potential (MEP) from the primary motor cortex, b) Measures of corticospinal tract excitability, c) Using paired pulse stimulation to measure Intracortical inhibition, d) Using two TMS coils to measure Interhemispheric Inhibition.
Paired pulse measures have fairly reliably shown reduced inhibitory activity in the intracortical circuits after stroke. Such apparent disinhibition is hard to interpret in the stroke hemisphere, as these measures depend upon an unconditioned evoked potential of reasonable amplitude which may not be available or may require high stimulus intensities. However no such technical issue affects the intact hemisphere, and the absence or reduction of inhibition when tested in the contralesional primary motor cortex suggests a reduction in the tonic level of GABA-ergic inhibitory activity in intracortical circuits that extends far beyond the site of the stroke. In one study such intracortical disinhibition of the non-stroke hemisphere was seen in patients with cortical but not subcortical infarction,5 suggesting that this phenomenon may relate to interruption of the transcallosal projection between the motor cortices. Few longitudinal studies of intra-cortical excitability have been performed but on the basis of the data available it seems that in the acute period disinhibition is seen regardless of clinical status, but that by three months it has resolved in those patients with a better clinical outcome, such that a clinical–physiological correlation emerges at around that time.6 A recent meta-analysis of TMS studies has shown no overall abnormality of excitability in the intact hemisphere:7 however if disinhibition were seen only in more severely affected patients then one may see clinical correlation without a group effect.
It is recognised that in healthy humans there is tonic inhibition of each hemisphere by its opposite, a situation that is likely to be important in the generation of unimanual versus bimanual movements. When this inter-hemispheric interaction is measured at rest with two TMS coils using a paired pulse conditioning approach there is robust inhibition. When tested in healthy subjects during a reaction time paradigm the baseline inhibition disappears or reverses as the onset of movement approaches. Murase and colleagues8 found that such switching-off of interhemispheric inhibition was impaired in stroke patients, and that the extent of residual interhemispheric inhibition was greater in more severely affected patients. This result has been interpreted as suggesting that after stroke there is an imbalance of such interhemispheric interactions, with pathological inhibition of the recovering stroke hemisphere by the non-stroke hemisphere.
Interpretation of the physiological changes observed after stroke remains a matter of debate. TMS as a technique operates at the level of the whole system, drawing inferences from the effect of manipulations on the overall corticospinal output, but the pathological changes observed may be the result of dysfunction at one or more of several levels. These may include the effects of cytotoxic changes on local neurochemistry, altered inhibitory vs excitatory synaptic activity, or diaschisis due to disruption of inter-regional tracts. The TMS finding of wide- spread intracortical disinhibition is in keeping with MR Spectroscopy studies that show reduced cortical GABA content during this period after stroke.9 A rapid reduction in GABA is also seen in healthy humans as a response to motor training or to experimental deafferentation of one arm by ischaemic nerve block, which likewise causes intracortical disinhibition as assessed by TMS. In those contexts it is felt that such disinhibition creates a more favourable environment for synaptic plasticity to occur, and it is tempting to conclude that the same is occurring in the post-stroke period as a way of driving reorganisation of the motor output. It is also conceivable that disinhibition allows cortical regions that are disconnected from their usual corticospinal output projection to access instead the horizontal cortico-cortical connections that are prevalent in cortical layers 2 and 3, thereby reaching an alternative output projection. Such a phenomenon would allow for the shifts in cortical motor output maps that are well documented after stroke.10 In one longitudinal study the correlation between disinhibition and clinical status was strong at three months but then became weaker in the chronic phase.6 We interpreted this as suggesting that ongoing disinhibition becomes less important for motor function as the reorganised motor network becomes better established with time. Direct evidence for such a process is lacking however, and some would argue that disinhibition is an epiphenomenon rather than an adaptive response to injury. This alternative conclusion would be supported by the observation that reduced intracortical inhibition as measured by paired pulse TMS may be observed in other pathological states, including dystonia and Attention Deficit Hyperactivity Disorder.
The concept of an imbalance between the two hemispheres and of excessive interhemispheric inhibition of the stroke hemisphere has gained a lot of traction and has provided the rationale for therapeutic approaches that aim to redress it. Non-invasive brain stimulation, either by repetitive TMS or transcranial direct current stimulation (tDCS), can induce measurable changes in cortical excitability that outlast the period of stimulation. Depending on the stimulation paradigm used one can induce either increases or reductions lasting minutes or in some cases hours. The most common approaches are either to apply excitatory stimulation to the stroke hemisphere or alternatively inhibitory stimulation to the non-stroke hemisphere (Figure 2), the aim being to enhance the response to conventional therapy by stimulating either before or during treatment. The concept of an overactive non-stroke hemisphere resonates with the widely reproduced functional imaging finding of increased movement-related brain activation on that side in more severely affected patients, which may normalise as clinical recovery progresses.6
Figure 2. The interhemispheric rivalry model, whereby the intact hemisphere exerts a pathological degree of interhemispheric inhibition on the stroke hemisphere and hinders motor function in the paretic limb. This has given rise to the therapeutic strategies of either increasing excitability in the stroke hemisphere or reducing it in the intact hemisphere.
It is by no means clear however that this contralesional activity is the same phenomenon as that which generates pathological inhibition of the recovering hemisphere, or that it is necessarily maladaptive. There is evidence that at least some regions on the non-stroke side may support movement of the paretic side, such as the contralesional dorsal premotor cortex which displays increased functional connectivity to the primary motor cortex of the stroke in more affected patients and appears to support hand movement.11,12Furthermore a recent study suggested that reducing intact hemisphere excitability may in fact be detrimental to upper limb function in more impaired patients.3
As the role of contralesional brain regions in movement appears to differ depending upon factors such as clinical severity, extent of corticospinal tract disruption and possibly stroke location it would seem that reducing excitability on that side equally in all stroke patients may represent rather a blunt therapeutic approach. This is especially true of tDCS, whose effects incorporate most of the stimulated hemisphere. However, positive studies may be found in the literature for both repetitive TMS and tDCS when applied to either side of the brain (sometimes both), and although a comprehensive review of the outcomes is beyond the scope of this article the most promising approach appears to be inhibition of the non-stroke hemisphere by tDCS.13 Non-invasive brain stimulation has not as yet entered routine clinical practice however, and there are a number of reasons why this may be, such as the large number of stimulation protocols available and uncertainty regarding the optimal time to apply stimulation. However, for the reasons discussed above it is important to consider the heterogeneity of the clinical syndrome when designing further trials. Opinions differ as to whether progress will be made using a ‘one size fits all’ design, the hope being that larger sample sizes will take care of heterogeneity, or alternatively whether targeting stimulation according to clinical and physiological factors would have a greater chance of success. This is likely to be worth getting right, as a large negative study would present an obstacle to further investigation in this field. It is likely to be the case that applying brain stimulation to the right patients could significantly enhance the outcome of post-stroke rehabilitation, with a clinically meaningful reduction in resulting impairment and disability.
Reis J, Swayne OB, Vandermeeren Y, Camus M, Dimyan MA, Harris-Love M, Perez MA, Ragert P, Rothwell JC, Cohen LG. Contribution of transcranial magnetic stimulation to the understanding of cortical mechanisms involved in motor control. J Physiol 2008; 586(2):325-51.
Stinear CM, Barber PA, Smale PR, Coxon JP, Fleming MK, Byblow WD. Functional Potential in chronic stroke patients depends on corticospinal tract integrity. Brain 2007;130:170-180.
Bradnam LV, Stinear CM, Barber PA, Byblow WD. Contralesional hemisphere control of the proximal paretic upper limb following stroke. Cereb Cortex. 2012 Nov;22(11):2662-71.
Traversa R, Cicinelli P, Pasqualetti P, Filippi M, Rossini PM. Follow-up of interhemispheric differences of motor evoked potentials from the ‘affected’ and ‘unaffected’ hemispheres in human stroke. Brain Research 1998; 803:1-8.
Manganotti P, Patuzzo S, Cortese F, Palermo A, Smania N, Fiaschi A. Motor disinhibition in affected and unaffected hemisphere in the early period of recovery after stroke. Clin Neurophysiol 2002; 113:936-943.
Swayne OB, Rothwell JC, Ward NS, Greenwood RJ. Stages of Motor Output Reorganization after Hemispheric Stroke Suggested by Longitudinal Studies of Cortical Physiology. Cereb Cortex 2008; 18:1909- 1922.
McDonnell MN, Stinear CM. TMS measures of motor cortex function after stroke: A meta-analysis. Brain Stimul. 2017 Jul – Aug;10(4):721-734.
Murase N, Duque J, Mazzocchio R, Cohen LG. Influence of interhemispheric interactions on motor function in chronic stroke. Ann Neurol 2004; 55:400-409.
Blicher JU, Near J, Næss-Schmidt E, Stagg CJ, Johansen-Berg H, Nielsen JF, Østergaard L, Ho YC. GABA levels are decreased after stroke and GABA changes during rehabilitation correlate with motor improvement. Neurorehabil Neural Repair 2015 Mar-Apr;29(3):278-86.
Delvaux V, Alagona G, Gerard P, De Pasqua V, Pennisi G, de Noordhout AM. Post-stroke reorganization of hand motor area: a 1-year prospective follow-up with focal transcranial magnetic stimulation. Clin Neurophysiol 2003; 114:1217-1225
Bestmann S, Swayne O, Blankenburg F, Ruff CC, Teo J, Weiskopf N, Driver J, Rothwell JC, Ward NS. The role of contralesional dorsal premotor cortex after stroke as studied with concurrent TMS-fMRI. J Neurosci 2010; 30(36):11926-37.
Johansen-Berg H, Rushworth MF, Bogdanovic MD, Kischka U, Wimalaratna S, Matthews PM. The role of ipsilateral premotor cortex in hand movement after stroke. Proc Natl Acad Sci U S A 2002; 99:14518- 14523.
Kang N, Summers JJ, Cauraugh JH. Transcranial direct current stimulation facilitates motor learning post- stroke: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2016 Apr;87(4):345-55.