Abdulhameed Tomeh
Abdul Hanif Khan Yusof Khan
Wan Aliaa Wan Sulaiman- 1Department of Neurology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
- 2Malaysian Research Institute on Ageing (MyAgeing™), Universiti Putra Malaysia, Serdang, Malaysia
Stroke is a leading cause of morbidity and mortality among elderly populations worldwide. During the early phase of stroke, restoring blood circulation is of utmost importance to protect neurons from further injury. Once the initial condition is stabilized, various rehabilitation techniques can be applied to help stroke survivors gradually regain their affected functions. Among these techniques, transcranial magnetic stimulation (TMS) has emerged as a novel method to assess and modulate cortical excitability non-invasively and aid stroke survivors in the rehabilitation process. Different cortical regions have been targeted using TMS based on the underlying pathology and distorted function. Despite the lack of a standard operational procedure, repetitive TMS (rTMS) of the primary motor cortex (M1) is considered a promising intervention for post-stroke motor rehabilitation. However, apart from the motor response, mounting evidence suggests that M1 stimulation can be employed to treat other symptoms such as dysphagia, speech impairments, central post-stroke pain, depression, and cognitive dysfunction. In this mini-review, we summarize the therapeutic uses of rTMS stimulation over M1 in stroke survivors and discuss the potential mechanistic rationale behind it.
Introduction
Stroke is defined as an episode of acute neurological impairment caused by an ischemic infarction or hemorrhage resulting in focal injury to the brain (Sacco et al., 2013). With an estimated ≈ 13 million cases reported annually, stroke is considered one of the major causes of neurological disability worldwide (Saini et al., 2021). Despite advances in stroke management, many stroke survivors suffer from long-term residual effects (Chohan et al., 2019).
Transcranial magnetic stimulation (TMS) has emerged as a painless, non-invasive technique that can stimulate the human brain and aid stroke survivors in rehabilitation after stroke (Hallett, 2007). Therapeutically, TMS is delivered in a repetitive manner with various stimulation parameters in terms of intensity, frequency, and number of sessions. The mechanism of action of repetitive TMS (rTMS) is believed to rely on principles of long-term potentiation/depression (LTP/LTD)- synaptic plasticity that has been extensively studied at the cellular level (Huang et al., 2017). Excitatory protocols consist of high-frequency (5–20 Hz) rTMS and ultra-high frequency (50 Hz) rTMS applied in the form of a patterned protocol called intermittent theta-burst stimulation (iTBS), while inhibitory protocols consist of low-frequency (≤ 1 Hz) rTMS and continuous TBS (cTBS) (Hallett, 2007). As stroke survivors frequently encounter motor impairments with slow recovery, rTMS stimulation of the primary motor cortex (M1) has been widely investigated to promote the motor rehabilitation process with encouraging results.
However, M1 stimulation has shown therapeutic efficacy beyond the conventional motor symptoms to involve dysphagia, speech impairments, central post-stroke pain, depression, and cognitive dysfunction. This mini-review aims to summarize the latest knowledge about M1 stimulation in post-stroke rehabilitation and discuss the mechanistic rationale behind the management of motor and non-motor symptoms.
Motor rehabilitation
The motor impairment after stroke was shown to result from the damaged corticospinal output from the affected M1 along with transcallosal inhibitory drive from the unaffected M1 (Ward and Cohen, 2004). The latter effect is based on the concept of dysbalanced interhemispheric interaction where the unaffected (contralesional) hemisphere becomes “overactive” and slows the recovery process of the affected (ipsilesional) hemisphere (Ward and Cohen, 2004). Therefore, excitatory (high-frequency) rTMS protocols are usually applied over the ipsilesional hemisphere, whereas inhibitory (low-frequency) rTMS protocols are applied over the contralesional hemisphere to restore the interhemispheric balance. A recent meta-analysis revealed that the high-frequency rTMS over the ipsilesional M1 enhanced its excitability without affecting that of the contralesional M1. On the other hand, the low-frequency rTMS protocol not only decreased the contralesional M1 excitability but also enhanced that of the ipsilesional M1, further supporting the bimodal balance recovery model (Bai et al., 2022).
Rehabilitation of upper limbs
Rehabilitation of upper limbs after stroke has been more extensively studied than the lower limbs, presumably due to the easiness of TMS application over the M1 hand homunculus (Rossini et al., 2015). High-quality evidence from recent systematic reviews and meta-analysis has shown that rTMS over M1 significantly improved the upper limb impairments, including fine motor movements, grip strength, and activities of daily living (O’Brien et al., 2018; He et al., 2020), without affecting spasticity levels significantly compared to sham stimulation (McIntyre et al., 2018; Xu P. et al., 2021).
The improvement in motor recovery was sustained for at least 1 month after 5 daily sessions of the rTMS (Zhang et al., 2017). Whereas delivering more than 5 sessions in one meta-analysis (Zhang et al., 2017), or 7 in another (Xiang et al., 2019), did not yield additional improvement in the upper limb recovery. On the other hand, patients with pure subcortical strokes were found to benefit better from the rTMS therapy compared to those with cortical strokes (Zhang et al., 2017; Xiang et al., 2019).
In relation to stimulation frequency, both low- and high-frequency rTMS protocols were effective in the motor recovery after stroke (Zhang et al., 2017; Xiang et al., 2019). While in TBS protocols, iTBS over the ipsilesional M1 was thought to yield better efficacy on the upper limb recovery than cTBS over the contralesional M1 (Zhang et al., 2017), a finding that an ongoing meta-analysis will further investigate with the inclusion of more accumulating TBS studies (Liu et al., 2019). On the other hand, a recent large network meta-analysis has revealed by probability ranking that among all the aforementioned protocols, the high-frequency (≥ 10 Hz) rTMS may be the most effective protocol for improving the upper limb motor function in stroke patients (Xia et al., 2022).
Considering the optimal time window, applying rTMS as early as the first month after stroke has proved to be more beneficial in promoting the upper limb function in comparison to subacute (1–6 months) and chronic (> 6 months) phases of stroke (van Lieshout et al., 2019). This is consistent with neurophysiological and histological findings in patients and animal models showing that there is an early critical time window during which the brain in more likely to be responsive to neurorehabilitation treatments (Krakauer et al., 2012). In addition, it has been shown that most recovery processes take place within the first 3 months following a stroke, after which improvement is thought to reach a plateau phase (Biernaskie et al., 2004; Krakauer et al., 2012).
Noteworthy, the rTMS stimulation in motor rehabilitation is thought to optimize the effects of other interventions rather than provide the brain with all the changes needed for motor skill acquisition. Therefore, rTMS was usually employed in combination with conventional physiotherapy and occupational therapy (Ahmed et al., 2022). In addition, novel combinations have been investigated simultaneously with the rTMS application, including robotic training (Di Lazzaro et al., 2016; Miller et al., 2019) and virtual reality (Zheng et al., 2015) with promising results.
Rehabilitation of lower limbs
Evidence from recent systematic reviews and meta-analyses has shown that rTMS stimulation of the lower limbs representation at M1 significantly enhanced the motor recovery in stroke patients, including walking speed, spasticity, functional balance, and postural control (Tung et al., 2019; Kang et al., 2020; Liu Y. et al., 2021; Krogh et al., 2022). The number of daily sessions ranged between 5–20 sessions, with the higher number of sessions resulting in a cumulative improvement in the treatment effects (Kang et al., 2020).
Concerning stimulation frequency, low-frequency rTMS over the contralesional M1 seemed to improve the lower limb function better than high-frequency rTMS over the ipsilesional M1, according to a recent network meta-analysis (Xie et al., 2021). On the other hand, while iTBS was more effective than sham stimulation in promoting lower limb recovery, data from cTBS studies are lacking (Xie et al., 2021).
In regard to the optimal timing, rTMS application during the subacute (1–6 months post-stroke) and chronic phases (> 6 months post-stroke) is supported by the current evidence to benefit balance and gait recovery, with limited data on the acute phase (< 1 month after stroke onset) (Parikh et al., 2021).
Dysphagia
Dysphagia is a common complication in stroke patients and could result in aspiration pneumonia, malnutrition, and dehydration (Takizawa et al., 2016). Different neuromodulation techniques have been investigated to promote swallowing recovery after stroke, including transcranial direct current stimulation, surface neuromuscular electrical stimulation, and pharyngeal electrical stimulation. However, rTMS stimulation was superior to these techniques in the swallowing recovery based on the results of two recent network meta-analyses (Chiang et al., 2019; Li et al., 2021). The mechanism of action of M1-rTMS on dysphagia rehabilitation depends on enhancing neuroplasticity of the disrupted corticobulbar neural pathways that project to swallowing muscles (Gow et al., 2004).
Stimulation targets of the M1 have varied between the tongue, mylohyoid, pharyngeal, and esophageal representations at the M1 (Yang et al., 2021). In addition, no significant difference in the swallowing recovery was noted between low- and high-frequency rTMS protocols (Yang et al., 2021). Nonetheless, bihemispheric M1-rTMS has shown better effects on the swallowing function compared to unilateral stimulation (Cheng et al., 2020). In addition, it’s recommended to combine rTMS with traditional swallowing rehabilitation training to achieve better outcomes (Dziewas et al., 2021).
Concerning the optimal time window, the effect of therapeutic rTMS was most beneficial when applied within the first 2 weeks of stroke, and the effects were most substantial during the first 2 months following application (Cheng et al., 2020).
Speech rehabilitation
Based on the cortical region affected, stroke can result in impaired speech production in the form of aphasia or dysarthria (Schindel et al., 2022). As a therapeutic approach, rTMS was mainly applied at the inferior frontal gyrus corresponding to Broca’s area in aphasia rehabilitation (Arheix-Parras et al., 2021). Recently, however, a concurrent use of iTBS and functional magnetic resonance imaging (fMRI) has proposed a therapeutic potential for the iTBS protocol targeting the affected M1 at the hand representation in patients with post-stroke aphasia (Xu S. et al., 2021). These results were in accordance with previous reports showing functional connectivity between the cortical language network and the M1 hand representation (Meister et al., 2003, 2006; Meinzer et al., 2016). While in patients with post-stroke dysarthria, applying low-frequency rTMS to the unaffected mouth representation of M1 in combination with speech therapy improved the articulation functionality significantly in comparison to speech therapy alone (Kwon et al., 2015).
Central post-stroke pain
Central post-stroke pain (CPSP) is defined as a pain occurring after a cerebrovascular lesion of the brain or brainstem (Scholz et al., 2019). This pain is felt in the body region corresponding to the central nervous structure affected by stroke (Scholz et al., 2019). It is estimated that more than 50% of patients with a stroke affecting the somatosensory tract will develop CPSP (Liampas et al., 2020). The pathophysiology of CPSP is related to a defective gamma-aminobutyric acid (GABA)-ergic inhibition inside the brain, leading to maladaptive plasticity in multiple cortical regions, including M1 (Tang et al., 2019). Therefore, many studies have targeted the M1 cortex with rTMS to restore the intracortical inhibition in patients with CPSP. As a result, a direct relationship was noted between the analgesic efficacy and the modulation of M1 cortical excitability (Lefaucheur et al., 2006; Hosomi et al., 2013). In addition, the analgesic efficacy of M1 stimulation is believed to stem from the interconnection between M1 and the endogenous opioid system. This relation was evidenced by positron emission tomography scans (Maarrawi et al., 2007; Lamusuo et al., 2017) and pharmacological blocking of the μ-opioid receptors, which minimized the analgesic efficacy of M1 stimulation (de Andrade et al., 2011). On the neural network level, M1 stimulation was found to modulate the excitability of other cortical and subcortical areas related to sensory, cognitive, and emotional components of pain, such as the thalamus, insular cortex, and anterior cingulate gyrus (García-Larrea et al., 1999; Hasan et al., 2014). Recent systematic reviews have shown that 5–10 sessions of high-frequency rTMS over M1 of the affected hemisphere resulted in a significant reduction in the CPSP intensity which lasted for at least 3 weeks post-treatment (Ramger et al., 2019; Liampas et al., 2020).
Depression
Depression is a common complaint after stroke, affecting approximately 30% of stroke survivors (Towfighi et al., 2017). Patients with post-stroke depression are at higher risk of recurrent strokes and mortality (Towfighi et al., 2017). Previous rTMS studies have mainly targeted the dorsolateral prefrontal cortex as a therapeutic approach in patients with post-stroke depression (Shen et al., 2017). However, preliminary evidence has shown that low-frequency stimulation of the contralesional M1 cortex might have an antidepressant effect in depressed stroke patients (Carey et al., 2008; Niimi et al., 2020). The mechanistic rationale for the antidepressant efficacy of M1 stimulation might stem from its effect on the kynurenine levels (Kepplinger et al., 2014; Niimi et al., 2020), a tryptophan metabolite and one implicated pathway in depression (Ogyu et al., 2018). In addition, a recent meta-analysis combined with functional magnetic resonance imaging studies has identified M1 as a region of interest (ROI) for rTMS in depressive disorders (Zhang et al., 2020). Notably, some individual studies have reported an antidepressant efficacy following high-frequency rTMS at unilateral or bilateral M1 in Parkinson’s disease and chronic pain conditions (Khedr et al., 2015; Makkos et al., 2016; Li et al., 2020; Bursali et al., 2021). On the other hand, the antidepressant efficacy was not found in other studies with similar conditions and stimulation parameters (Brys et al., 2016; Lindholm et al., 2016; Hosomi et al., 2020). However, these findings need to be further explored in larger randomized controlled studies. In addition, it is worth mentioning that the emotional improvement following rTMS at M1 might be an indirect effect of the concomitant improvement in other symptoms, such as motor symptoms and pain.
Cognitive impairment
It is estimated that up to 83% of stroke survivors suffer from cognitive impairment in at least one cognitive domain (Jokinen et al., 2015). Similar to depression, the dorsolateral prefrontal cortex has been a conventional target for rTMS in patients with post-stroke cognitive impairments (Liu M. et al., 2021). However, mounting evidence suggests that the M1 is directly involved in higher cognitive processes including, but not limited to, attention, memory, motor imagery, and language comprehension (Tomasino and Gremese, 2016; Vukovic et al., 2017; Bhattacharjee et al., 2021; Vitale et al., 2021). In this context, two recent studies have shown that low-frequency rTMS stimulation over the contralesional M1 improved the measures of global cognition and visuospatial recall memory in stroke patients (D’Agata et al., 2016; Askin et al., 2017). Furthermore, this improvement was associated with reduced latency in the N200 and P300 markers of event-related potentials, indicating an increasing speed in the perceptual and cognitive processes (D’Agata et al., 2016). Noteworthy, the improvement in measures of global cognition along with the reduced latency in P300 following high-frequency bilateral M1-rTMS has also been reported in patients with Parkinson’s disease-related dementia (Khedr et al., 2020). This, in turn, might suggest a consistent procognitive effect of the M1-rTMS regardless of the underlying pathology.
Conclusion and perspective
With the slow and often incomplete recovery from stroke sequelae, rTMS is becoming an increasingly used technique in post-stroke rehabilitation. Stimulation of the M1 cortex has long been employed to treat residual motor symptoms of stroke incidents. However, accumulating evidence suggests that M1 stimulation can ameliorate a variety of non-motor symptoms that stroke patients frequently experience. The mechanistic rationale behind the management of these symptoms varies depending on the neural networks involved in their pathophysiology. Nonetheless, whether applied in the acute or chronic phase, alone or in combination with other interventions, rTMS stimulation over M1 can yield a therapeutic efficacy that extends beyond the movement execution to involve swallowing, speech, pain, mood, and cognition. Therefore, well-conducted randomized controlled trials, in particular studies combining TMS with EEG and neuroimaging techniques, will help expand our knowledge of the cortical and subcortical connections of M1 in health and disease and ultimately tailor the therapeutic use of rTMS based on the constellation of symptoms in each patient. In addition, as we approach the personalized medicine era, accumulating evidence highlights the influence of genetic polymorphisms on the rate of stroke recovery (Math et al., 2019). This might explain, in part, the variability in responses to the TMS in post-stroke rehabilitation. Therefore, future studies should further explore the potential genetic polymorphisms that interact with TMS responses in stroke, bearing in mind that the most investigated one, the brain-derived neurotrophic factor, has not yet proven as a decisive factor in the M1-rTMS literature (Sasaki et al., 2021).
Author contributions
AT devised the idea for this review and prepared the initial manuscript draft. AT, AHKYK, and WAWS wrote, edited, and revised the final manuscript. All authors approved the final version of the manuscript before submission.
Funding
This work was supported by the Fundamental Research Grant Scheme of the Ministry of Higher Education, Malaysia under the award number FRGS/1/2022/SKK01/UPM/02/4.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Ahmed, I., Mustafaoglu, R., Benkhalifa, N., and Yakhoub, Y. H. (2022). 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. Top. Stroke Rehabil. [Epub ahead of print]. doi: 10.1080/10749357.2022.2026278
Arheix-Parras, S., Barrios, C., Python, G., Cogne, M., Sibon, I., Engelhardt, M., et al. (2021). A systematic review of repetitive transcranial magnetic stimulation in aphasia rehabilitation: Leads for future studies. Neurosci. Biobehav. Rev. 127, 212–241. doi: 10.1016/j.neubiorev.2021.04.008
Askin, A., Tosun, A., and Demirdal, U. S. (2017). Effects of low-frequency repetitive transcranial magnetic stimulation on upper extremity motor recovery and functional outcomes in chronic stroke patients: A randomized controlled trial. Somatosens. Mot. Res. 34, 102–107. doi: 10.1080/08990220.2017.1316254
Bai, Z., Zhang, J., and Fong, K. N. K. (2022). Effects of transcranial magnetic stimulation in modulating cortical excitability in patients with stroke: A systematic review and meta-analysis. J. Neuroeng. Rehabil. 19:24. doi: 10.1186/s12984-022-00999-4
Bhattacharjee, S., Kashyap, R., Abualait, T., Annabel Chen, S. H., Yoo, W. K., and Bashir, S. (2021). The role of primary motor cortex: More than movement execution. J. Mot. Behav. 53, 258–274. doi: 10.1080/00222895.2020.1738992
Biernaskie, J., Chernenko, G., and Corbett, D. (2004). Efficacy of rehabilitative experience declines with time after focal ischemic brain injury. J. Neurosci. 24, 1245–1254. doi: 10.1523/jneurosci.3834-03.2004
Brys, M., Fox, M. D., Agarwal, S., Biagioni, M., Dacpano, G., Kumar, P., et al. (2016). Multifocal repetitive TMS for motor and mood symptoms of Parkinson disease: A randomized trial. Neurology 87, 1907–1915. doi: 10.1212/wnl.0000000000003279
Bursali, C., Özkan, F., Kaysin, M. Y., Dortcan, N., Aktas, I., and Külcü, D. G. (2021). Effectiveness of repetitive transcranial magnetic stimulation in patients with failed back surgery syndrome: A double-blind randomized placebo-controlled study. Pain Physician 24, E23–E30.
Carey, J. R., Evans, C. D., Anderson, D. C., Bhatt, E., Nagpal, A., Kimberley, T. J., et al. (2008). Safety of 6-Hz primed low-frequency rTMS in stroke. Neurorehabil. Neural Repair. 22, 185–192. doi: 10.1177/1545968307305458
Cheng, I., Sasegbon, A., and Hamdy, S. (2020). Effects of neurostimulation on poststroke dysphagia: A synthesis of current evidence from randomized controlled trials. Neuromodulation 24, 1388–1401. doi: 10.1111/ner.13327
Chiang, C. F., Lin, M. T., Hsiao, M. Y., Yeh, Y. C., Liang, Y. C., and Wang, T. G. (2019). Comparative efficacy of noninvasive neurostimulation therapies for acute and subacute poststroke Dysphagia: A systematic review and network meta-analysis. Arch. Phys. Med. Rehabil. 100, 739–750.e4. doi: 10.1016/j.apmr.2018.09.117
Chohan, S. A., Venkatesh, P. K., and How, C. H. (2019). Long-term complications of stroke and secondary prevention: An overview for primary care physicians. Singapore Med. J. 60, 616–620. doi: 10.11622/smedj.2019158
D’Agata, F., Peila, E., Cicerale, A., Caglio, M. M., Caroppo, P., Vighetti, S., et al. (2016). Cognitive and neurophysiological effects of non-invasive brain stimulation in stroke patients after motor rehabilitation. Front. Behav. Neurosci. 10:135. doi: 10.3389/fnbeh.2016.00135
de Andrade, D. C., Mhalla, A., Adam, F., Texeira, M. J., and Bouhassira, D. (2011). Neuropharmacological basis of rTMS-induced analgesia: the role of endogenous opioids. Pain 152, 320–326. doi: 10.1016/j.pain.2010.10.032
Di Lazzaro, V., Capone, F., Di Pino, G., Pellegrino, G., Florio, L., Zollo, L., et al. (2016). Combining robotic training and non-invasive brain stimulation in severe upper limb-impaired chronic stroke patients. Front. Neurosci. 10:88. doi: 10.3389/fnins.2016.00088
Dziewas, R., Michou, E., Trapl-Grundschober, M., Lal, A., Arsava, E. M., Bath, P. M., et al. (2021). European stroke organisation and european society for swallowing disorders guideline for the diagnosis and treatment of post-stroke dysphagia. Eur. Stroke J. 6, LXXXIX–CXV. doi: 10.1177/23969873211039721
García-Larrea, L., Peyron, R., Mertens, P., Gregoire, M. C., Lavenne, F., Le Bars, D., et al. (1999). Electrical stimulation of motor cortex for pain control: A combined PET-scan and electrophysiological study. Pain 83, 259–273. doi: 10.1016/s0304-3959(99)00114-1
Gow, D., Rothwell, J., Hobson, A., Thompson, D., and Hamdy, S. (2004). Induction of long-term plasticity in human swallowing motor cortex following repetitive cortical stimulation. Clin. Neurophysiol. 115, 1044–1051. doi: 10.1016/j.clinph.2003.12.001
Hallett, M. (2007). Transcranial magnetic stimulation: A primer. Neuron 55, 187–199. doi: 10.1016/j.neuron.2007.06.026
Hasan, M., Whiteley, J., Bresnahan, R., Maciver, K., Sacco, P., Das, K., et al. (2014). Somatosensory change and pain relief induced by repetitive transcranial magnetic stimulation in patients with central poststroke pain. Neuromodulation 17, 731–736. doi: 10.1111/ner.12198
He, Y., Li, K., Chen, Q., Yin, J., and Bai, D. (2020). Repetitive transcranial magnetic stimulation on motor recovery for patients with stroke: A PRISMA compliant systematic review and meta-analysis. Am. J. Phys. Med. Rehabil. 99, 99–108. doi: 10.1097/phm.0000000000001277
Hosomi, K., Kishima, H., Oshino, S., Hirata, M., Tani, N., Maruo, T., et al. (2013). Cortical excitability changes after high-frequency repetitive transcranial magnetic stimulation for central poststroke pain. Pain 154, 1352–1357. doi: 10.1016/j.pain.2013.04.017
Hosomi, K., Sugiyama, K., Nakamura, Y., Shimokawa, T., Oshino, S., Goto, Y., et al. (2020). A randomized controlled trial of 5 daily sessions and continuous trial of 4 weekly sessions of repetitive transcranial magnetic stimulation for neuropathic pain. Pain 161, 351–360. doi: 10.1097/j.pain.0000000000001712
Huang, Y. Z., Lu, M. K., Antal, A., Classen, J., Nitsche, M., Ziemann, U., et al. (2017). Plasticity induced by non-invasive transcranial brain stimulation: A position paper. Clin. Neurophysiol. 128, 2318–2329. doi: 10.1016/j.clinph.2017.09.007
Jokinen, H., Melkas, S., Ylikoski, R., Pohjasvaara, T., Kaste, M., Erkinjuntti, T., et al. (2015). Post-stroke cognitive impairment is common even after successful clinical recovery. Eur. J. Neurol. 22, 1288–1294. doi: 10.1111/ene.12743
Kang, N., Lee, R. D., Lee, J. H., and Hwang, M. H. (2020). Functional balance and postural control improvements in patients with stroke after noninvasive brain stimulation: A meta-analysis. Arch. Phys. Med. Rehabil. 101, 141–153. doi: 10.1016/j.apmr.2019.09.003
Kepplinger, B., Sedlnitzky-Semler, B., Eigner, S., Kalina, P., Berger, P., and Baran, H. (2014). Stroke Patients after repetitive Transcranial Magnetic Stimulation (rTMS)–alterations of tryptophan metabolites in the serum. Int. J. Neurorehabil. 1:128. doi: 10.4172/2376-0281.1000128
Khedr, E. M., Kotb, H. I., Mostafa, M. G., Mohamad, M. F., Amr, S. A., Ahmed, M. A., et al. (2015). Repetitive transcranial magnetic stimulation in neuropathic pain secondary to malignancy: A randomized clinical trial. Eur. J. Pain 19, 519–527. doi: 10.1002/ejp.576
Khedr, E. M., Mohamed, K. O., Ali, A. M., and Hasan, A. M. (2020). The effect of repetitive transcranial magnetic stimulation on cognitive impairment in Parkinson’s disease with dementia: Pilot study. Restor. Neurol. Neurosci. 38, 55–66. doi: 10.3233/RNN-190956
Krakauer, J. W., Carmichael, S. T., Corbett, D., and Wittenberg, G. F. (2012). Getting neurorehabilitation right: What can be learned from animal models? Neurorehabil. Neural Repair. 26, 923–931. doi: 10.1177/1545968312440745
Krogh, S., Jønsson, A. B., Aagaard, P., and Kasch, H. (2022). Efficacy of repetitive transcranial magnetic stimulation for improving lower limb function in individuals with neurological disorders: A systematic review and meta-analysis of randomized sham-controlled trials. J. Rehabil. Med. 54:jrm00256. doi: 10.2340/jrm.v53.1097
Kwon, Y. G., Do, K. H., Park, S. J., Chang, M. C., and Chun, M. H. (2015). Effect of repetitive transcranial magnetic stimulation on patients with dysarthria after subacute stroke. Ann. Rehabil. Med. 39, 793–799. doi: 10.5535/arm.2015.39.5.793
Lamusuo, S., Hirvonen, J., Lindholm, P., Martikainen, I. K., Hagelberg, N., Parkkola, R., et al. (2017). Neurotransmitters behind pain relief with transcranial magnetic stimulation - positron emission tomography evidence for release of endogenous opioids. Eur. J. Pain 21, 1505–1515. doi: 10.1002/ejp.1052
Lefaucheur, J. P., Drouot, X., Ménard-Lefaucheur, I., Keravel, Y., and Nguyen, J. P. (2006). Motor cortex rTMS restores defective intracortical inhibition in chronic neuropathic pain. Neurology 67, 1568–1574. doi: 10.1212/01.wnl.0000242731.10074.3c
Li, J., Mi, T. M., Zhu, B. F., Ma, J. H., Han, C., Li, Y., et al. (2020). High-frequency repetitive transcranial magnetic stimulation over the primary motor cortex relieves musculoskeletal pain in patients with Parkinson’s disease: A randomized controlled trial. Parkinsonism Relat. Disord. 80, 113–119. doi: 10.1016/j.parkreldis.2020.07.006
Li, L., Huang, H., Jia, Y., Yu, Y., Liu, Z., Shi, X., et al. (2021). Systematic review and network meta-analysis of noninvasive brain stimulation on dysphagia after stroke. Neural Plast. 2021:3831472. doi: 10.1155/2021/3831472
Liampas, A., Velidakis, N., Georgiou, T., Vadalouca, A., Varrassi, G., Hadjigeorgiou, G. M., et al. (2020). Prevalence and management challenges in central post-stroke neuropathic pain: A Systematic review and meta-analysis. Adv. Ther. 37, 3278–3291. doi: 10.1007/s12325-020-01388-w
Lindholm, P., Lamusuo, S., Taiminen, T., Virtanen, A., Pertovaara, A., Forssell, H., et al. (2016). The analgesic effect of therapeutic rTMS is not mediated or predicted by comorbid psychiatric or sleep disorders. Medicine 95:e5231. doi: 10.1097/MD.0000000000005231
Liu, M., Bao, G., Bai, L., and Yu, E. (2021). The role of repetitive transcranial magnetic stimulation in the treatment of cognitive impairment in stroke patients: A systematic review and meta-analysis. Sci. Prog. 104:368504211004266. doi: 10.1177/00368504211004266
Liu, X. B., Zhong, J. G., Xiao, X. L., Li, Y. X., Huang, Y. J., Liu, Y. G., et al. (2019). Theta burst stimulation for upper limb motor dysfunction in patients with stroke: A protocol of systematic review and meta-analysis. Medicine 98:e17929. doi: 10.1097/md.0000000000017929
Liu, Y., Li, H., Zhang, J., Zhao, Q. Q., Mei, H. N., and Ma, J. (2021). A meta-analysis: Whether repetitive transcranial magnetic stimulation improves dysfunction caused by stroke with lower limb spasticity. Evid. Based Complement. Alternat. Med. 2021:7219293. doi: 10.1155/2021/7219293
Maarrawi, J., Peyron, R., Mertens, P., Costes, N., Magnin, M., Sindou, M., et al. (2007). Motor cortex stimulation for pain control induces changes in the endogenous opioid system. Neurology 69, 827–834. doi: 10.1212/01.wnl.0000269783.86997.37
Makkos, A., Pal, E., Aschermann, Z., Janszky, J., Balazs, E., Takacs, K., et al. (2016). High-frequency repetitive transcranial magnetic stimulation can improve depression in Parkinson’s Disease: A randomized, double-blind, placebo-controlled study. Neuropsychobiology 73, 169–177. doi: 10.1159/000445296
Math, N., Han, T. S., Lubomirova, I., Hill, R., Bentley, P., and Sharma, P. (2019). Influences of genetic variants on stroke recovery: A meta-analysis of the 31,895 cases. Neurol. Sci. 40, 2437–2445. doi: 10.1007/s10072-019-04024-w
McIntyre, A., Mirkowski, M., Thompson, S., Burhan, A. M., Miller, T., and Teasell, R. (2018). A systematic review and meta-analysis on the use of repetitive transcranial magnetic stimulation for spasticity Poststroke. PM R 10, 293–302. doi: 10.1016/j.pmrj.2017.10.001
Meinzer, M., Darkow, R., Lindenberg, R., and Floel, A. (2016). Electrical stimulation of the motor cortex enhances treatment outcome in post-stroke aphasia. Brain 139, 1152–1163. doi: 10.1093/brain/aww002
Meister, I. G., Boroojerdi, B., Foltys, H., Sparing, R., Huber, W., and Töpper, R. (2003). Motor cortex hand area and speech: Implications for the development of language. Neuropsychologia 41, 401–406. doi: 10.1016/s0028-3932(02)00179-3
Meister, I. G., Sparing, R., Foltys, H., Gebert, D., Huber, W., Töpper, R., et al. (2006). Functional connectivity between cortical hand motor and language areas during recovery from aphasia. J. Neurol. Sci. 247, 165–168. doi: 10.1016/j.jns.2006.04.003
Miller, K. J., Gallina, A., Neva, J. L., Ivanova, T. D., Snow, N. J., Ledwell, N. M., et al. (2019). Effect of repetitive transcranial magnetic stimulation combined with robot-assisted training on wrist muscle activation post-stroke. Clin. Neurophysiol. 130, 1271–1279. doi: 10.1016/j.clinph.2019.04.712
Niimi, M., Ishima, T., Hashimoto, K., Hara, T., Yamada, N., and Abo, M. (2020). Effect of repetitive transcranial magnetic stimulation on the kynurenine pathway in stroke patients. Neuroreport 31, 629–636. doi: 10.1097/wnr.0000000000001438
O’Brien, A. T., Bertolucci, F., Torrealba-Acosta, G., Huerta, R., Fregni, F., and Thibaut, A. (2018). Non-invasive brain stimulation for fine motor improvement after stroke: A meta-analysis. Eur. J. Neurol. 25, 1017–1026. doi: 10.1111/ene.13643
Ogyu, K., Kubo, K., Noda, Y., Iwata, Y., Tsugawa, S., Omura, Y., et al. (2018). Kynurenine pathway in depression: A systematic review and meta-analysis. Neurosci. Biobehav. Rev. 90, 16–25. doi: 10.1016/j.neubiorev.2018.03.023
Parikh, V., Medley, A., Chung, Y. C., and Goh, H. T. (2021). Optimal timing and neural loci: A scoping review on the effect of non-invasive brain stimulation on post-stroke gait and balance recovery. Top. Stroke Rehabil. [Epub ahead of print]. doi: 10.1080/10749357.2021.1990467
Ramger, B. C., Bader, K. A., Davies, S. P., Stewart, D. A., Ledbetter, L. S., Simon, C. B., et al. (2019). Effects of non-invasive brain stimulation on clinical pain intensity and experimental pain sensitivity among individuals with central post-stroke pain: A systematic review. J. Pain Res. 12, 3319–3329. doi: 10.2147/jpr.s216081
Rossini, P. M., Burke, D., Chen, R., Cohen, L. G., Daskalakis, Z., Di Iorio, R., et al. (2015). Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: Basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee. Clin. Neurophysiol. 126, 1071–1107. doi: 10.1016/j.clinph.2015.02.001
Sacco, R. L., Kasner, S. E., Broderick, J. P., Caplan, L. R., Connors, J. J., Culebras, A., et al. (2013). An updated definition of stroke for the 21st century: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 44, 2064–2089. doi: 10.1161/STR.0b013e318296aeca
Saini, V., Guada, L., and Yavagal, D. R. (2021). Global epidemiology of stroke and access to acute ischemic stroke interventions. Neurology 97, S6–S16. doi: 10.1212/wnl.0000000000012781
Sasaki, R., Kojima, S., and Onishi, H. (2021). Do brain-derived neurotrophic factor genetic polymorphisms modulate the efficacy of motor cortex plasticity induced by non-invasive brain stimulation? A Systematic Review. Front. Hum. Neurosci. 15, 742373. doi: 10.3389/fnhum.2021.742373
Schindel, D., Mandl, L., Schilling, R., Meisel, A., and Schenk, L. (2022). Guideline adherence in speech and language therapy in stroke aftercare. A health insurance claims data analysis. PLoS One 17:e0263397. doi: 10.1371/journal.pone.0263397
Scholz, J., Finnerup, N. B., Attal, N., Aziz, Q., Baron, R., Bennett, M. I., et al. (2019). The IASP classification of chronic pain for ICD-11: Chronic neuropathic pain. Pain 160, 53–59. doi: 10.1097/j.pain.0000000000001365
Shen, X., Liu, M., Cheng, Y., Jia, C., Pan, X., Gou, Q., et al. (2017). Repetitive transcranial magnetic stimulation for the treatment of post-stroke depression: A systematic review and meta-analysis of randomized controlled clinical trials. J. Affect. Disord. 211, 65–74. doi: 10.1016/j.jad.2016.12.058
Takizawa, C., Gemmell, E., Kenworthy, J., and Speyer, R. (2016). A systematic review of the prevalence of oropharyngeal dysphagia in stroke, Parkinson’s disease, Alzheimer’s Disease, head injury, and pneumonia. Dysphagia 31, 434–441. doi: 10.1007/s00455-016-9695-9
Tang, S. C., Lee, L. J., Jeng, J. S., Hsieh, S. T., Chiang, M. C., Yeh, S. J., et al. (2019). Pathophysiology of central poststroke pain: Motor cortex disinhibition and its clinical and sensory correlates. Stroke 50, 2851–2857. doi: 10.1161/strokeaha.119.025692
Tomasino, B., and Gremese, M. (2016). The cognitive side of M1. Front. Hum. Neurosci. 10:298. doi: 10.3389/fnhum.2016.00298
Towfighi, A., Ovbiagele, B., El Husseini, N., Hackett, M. L., Jorge, R. E., Kissela, B. M., et al. (2017). Poststroke depression: A scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 48, e30–e43. doi: 10.1161/STR.0000000000000113
Tung, Y. C., Lai, C. H., Liao, C. D., Huang, S. W., Liou, T. H., and Chen, H. C. (2019). Repetitive transcranial magnetic stimulation of lower limb motor function in patients with stroke: A systematic review and meta-analysis of randomized controlled trials. Clin. Rehabil. 33, 1102–1112. doi: 10.1177/0269215519835889
van Lieshout, E. C. C., Van Der Worp, H. B., Visser-Meily, J. M. A., and Dijkhuizen, R. M. (2019). Timing of repetitive transcranial magnetic stimulation onset for upper limb function after stroke: A systematic review and meta-analysis. Front. Neurol. 10:1269. doi: 10.3389/fneur.2019.01269
Vitale, F., Padron, I., Avenanti, A., and De Vega, M. (2021). Enhancing motor brain activity improves memory for action language: A tDCS Study. Cereb. Cortex 31, 1569–1581. doi: 10.1093/cercor/bhaa309
Vukovic, N., Feurra, M., Shpektor, A., Myachykov, A., and Shtyrov, Y. (2017). Primary motor cortex functionally contributes to language comprehension: An online rTMS study. Neuropsychologia 96, 222–229. doi: 10.1016/j.neuropsychologia.2017.01.025
Ward, N. S., and Cohen, L. G. (2004). Mechanisms underlying recovery of motor function after stroke. Arch. Neurol. 61, 1844–1848. doi: 10.1001/archneur.61.12.1844
Xia, Y., Xu, Y., Li, Y., Lu, Y., and Wang, Z. (2022). Comparative efficacy of different repetitive transcranial magnetic stimulation protocols for stroke: A network meta-analysis. Front. Neurol. 13:918786. doi: 10.3389/fneur.2022.918786
Xiang, H., Sun, J., Tang, X., Zeng, K., and Wu, X. (2019). The effect and optimal parameters of repetitive transcranial magnetic stimulation on motor recovery in stroke patients: A systematic review and meta-analysis of randomized controlled trials. Clin. Rehabil. 33, 847–864. doi: 10.1177/0269215519829897
Xie, Y. J., Chen, Y., Tan, H. X., Guo, Q. F., Lau, B. W., and Gao, Q. (2021). Repetitive transcranial magnetic stimulation for lower extremity motor function in patients with stroke: A systematic review and network meta-analysis. Neural Regen. Res. 16, 1168–1176. doi: 10.4103/1673-5374.300341
Xu, P., Huang, Y., Wang, J., An, X., Zhang, T., Li, Y., et al. (2021). Repetitive transcranial magnetic stimulation as an alternative therapy for stroke with spasticity: A systematic review and meta-analysis. J. Neurol. 268, 4013–4022. doi: 10.1007/s00415-020-10058-4
Xu, S., Yang, Q., Chen, M., Deng, P., Zhuang, R., Sun, Z., et al. (2021). Capturing neuroplastic changes after iTBS in patients with post-stroke Aphasia: A pilot fMRI study. Brain Sci. 11:1451. doi: 10.3390/brainsci11111451
Yang, W., Cao, X., Zhang, X., Wang, X., Li, X., and Huai, Y. (2021). The effect of repetitive transcranial magnetic stimulation on dysphagia after Stroke: A systematic review and meta-analysis. Front. Neurosci. 15:769848. doi: 10.3389/fnins.2021.769848
Zhang, B., Liu, J., Bao, T., Wilson, G., Park, J., Zhao, B., et al. (2020). Locations for noninvasive brain stimulation in treating depressive disorders: A combination of meta-analysis and resting-state functional connectivity analysis. Aust. N. Z. J. Psychiatry 54, 582–590. doi: 10.1177/0004867420920372
Zhang, L., Xing, G., Fan, Y., Guo, Z., Chen, H., and Mu, Q. (2017). Short- and long-term effects of repetitive transcranial magnetic stimulation on upper limb motor function after stroke: A systematic review and meta-analysis. Clin. Rehabil. 31, 1137–1153. doi: 10.1177/0269215517692386
Zheng, C. J., Liao, W. J., and Xia, W. G. (2015). Effect of combined low-frequency repetitive transcranial magnetic stimulation and virtual reality training on upper limb function in subacute stroke: A double-blind randomized controlled trail. J. Huazhong Univ. Sci. Technol. Med. Sci. 35, 248–254. doi: 10.1007/s11596-015-1419-0
Keywords: transcranial magnetic stimulation, primary motor cortex, stroke, motor rehabilitation, non-motor symptoms
Citation: Tomeh A, Yusof Khan AHK and Wan Sulaiman WA (2022) Repetitive transcranial magnetic stimulation of the primary motor cortex in stroke survivors-more than motor rehabilitation: A mini-review. Front. Aging Neurosci. 14:897837. doi: 10.3389/fnagi.2022.897837
Received: 16 March 2022; Accepted: 07 September 2022;
Published: 26 September 2022.
Edited by:
Yen-Feng Lin, National Health Research Institutes, TaiwanReviewed by:
Maria Concetta Pellicciari, Libera Università Maria SS. Assunta University, ItalyCopyright © 2022 Tomeh, Yusof Khan and Wan Sulaiman. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Wan Aliaa Wan Sulaiman, wanaliaa@upm.edu.my