After decades of focusing on how to alleviate and prevent recurrence of acute CNS injuries, the emphasis has finally shifted towards repairing such devastating events and rehabilitation. This development has been made possible by substantial progress in understanding the scientific underpinnings of recovery as well as by novel diagnostic tools, and most importantly, by emerging therapies awaiting clinical trials. In this publication, several international experts introduce novel areas of neurological reorganization and repair following CNS damage. Principles and methods to monitor and augment neuroplasticity are explored in depth and supplemented by a critical appraisal of neurological repair mechanisms and possibilities to curtail disability using computer or robotic interfaces. Rather than providing a textbook approach of CNS restoration, the editors selected topics where progress is most imminent in this labyrinthine domain of medicine. Moreover, the varied background and origins of the contributors lend this book a truly global perspective on the current state of affairs in neurological recovery.
112 - 121: Role of Repetitive Transcranial Magnetic Stimulation in Stroke Rehabilitation
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Published:2013
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Book Series: Frontiers of Neurology and Neuroscience
Michaela M. Pinter, Michael Brainin, 2013. "Role of Repetitive Transcranial Magnetic Stimulation in Stroke Rehabilitation", Clinical Recovery from CNS Damage, H. Naritomi, D.W. Krieger
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Abstract
In recent years, efforts have focused on investigating the neurophysiological changes that occur in the brain after stroke, and on developing novel strategies such as additional brain stimulation to enhance sensorimotor and cognitive recovery. In the 1990s, repetitive transcranial magnetic stimulation (rTMS) was introduced as a therapeutic tool for improving the efficacy of rehabilitation for recovery after stroke. It is evident that disturbances of interhemispheric processes after stroke result in a pathological hyperactivity of the intact hemisphere. The rationale of using rTMS as a complementary therapy is mainly to decrease the cortical excitability in regions that are presumed to hinder optimal recovery by low-frequency rTMS delivered to the unaffected hemisphere, while high-frequency rTMS delivered to the affected hemisphere facilitates cortical excitability. However, the exact mechanisms of how rTMS works are still under investigation. There is a growing body of research in stroke patients investigating the effect of rTMS on facilitating recovery by modifying cortical and subcortical networks. Clinical trials applying rTMS already yielded promising results in improving recovery of sensorimotor and cognitive functions. Altogether, in combination with conventional therapeutic approaches, rTMS has a potential to become a complementary strategy to enhance stroke recovery by modulating the excitability of targeted brain areas. In future studies, emphasis should be placed on selecting patient populations to determine whether treatment response depends on age, lesion acuteness, or stroke severity. Furthermore, it is important to identify parameters optimizing the beneficial effects of rTMS on stroke recovery, and to monitor their long-term effects.
Stroke is a leading cause of disability and the burden of stroke is borne disproportionately by older people who have a greater incidence and prevalence of ischemic stroke than younger individuals. For each successive 10 years after 55 years of age, the stroke rate more than doubles in both men and women; 65% of all strokes occur in individuals older than 65 years. Five million survivors are left permanently disabled, with complications including motor (50-83%), cognitive (50%) and language impairments (23-36%), as well as psychological disturbances (20%) [1]. Estimates indicate that 33-42% of patients still require assistance for activities of daily living 6 years after stroke, and that 36% of patients remain disabled after 5 years [2].
Recovery after stroke is complex. Many interventions have been developed to support recovery of impairment and associated functions, and a number of randomized controlled trials and systematic reviews investigated their effectiveness in stroke rehabilitation [3].
Additionally to established therapies (e.g. constraint-induced movement therapy, robotic-assisted strategies, repetitive task training, cognitive training and speech therapy), a noninvasive brain stimulation technique, such as transcranial magnetic stimulation (TMS), has been developed. This stimulation interacts with spontaneous brain activity and influences sensorimotor and higher-order cognitive abilities.
In the 1980s, TMS was originally introduced in clinical neurophysiology for the evaluation of the functional state of the corticospinal pathway [4].
In the 1990s, technological advances allowed the delivery of rhythmic trains of magnetic pulses in a rapid sequence up to a 100-Hz repetition rate, which was referred to as repetitive TMS (rTMS). It was reported that rTMS interacts with cortical activity more effectively than TMS. In recent years, rTMS has been rapidly developed as a potential therapeutic tool in many other clinical fields [5].
Principles of Repetitive Transcranial Magnetic Stimulation and Biological Aspects
The primary property of magnetic stimulation is its ability to penetrate all body structures, allowing stimulation of regions below layers of bone (e.g. the brain).
Single-pulse TMS applied on the scalp overlying the primary motor cortex (M1) assesses the excitability and conductivity of corticospinal motor pathways. This approach has primarily been applied in studies of movement physiology in patients with neurological disorders and in postlesion follow-up studies of plastic cerebral reorganization. Paired-pulse techniques have been shown to provide measures of intracortical facilitation and inhibition as well as corticocortical interactions, which are important when evaluating changes in functionality. When multiple stimuli of TMS are delivered in trains, one can differentiate conventional and patterned protocols of repetitive stimulation. For conventional protocols, there is agreement on the term rTMS. Application of rTMS influences neural excitability of selected brain areas. Low-frequency rTMS of ≤1 Hz was found to suppress while high-frequency rTMS of ≥5 Hz was observed to facilitate local neural activities [6]. Nevertheless, it is speculated that low-frequency rTMS to the nonaffected hemisphere reduces interhemispheric inhibition towards the affected hemisphere, leading to facilitation of beneficial functional reorganization in the affected hemisphere [7]. Patterned rTMS refers to a repetitive application of short rTMS bursts at a high inner frequency, which are separated by short pauses of no stimulation. Theta burst stimulation (TBS) is the most commonly used method of patterned rTMS. In TBS, short bursts of 50-Hz rTMS are repeated as a continuous or intermittent train at a rate in the theta range (5 Hz). The excitatory and inhibitory effects of this type of stimulation can be manipulated by continuous or intermittent delivery of these theta bursts over time [8]. The TBS protocol has been used to modulate motor thresholds [8] and cognitive functions [9]. Recently, quadripulse stimulation, which is able to induce long-term changes in cortical excitability, has been added to the patterned rTMS procedures [9].
Moreover, it was reported that 1-Hz cortical inhibitory effects on a stimulated area were dependent on both GABA and NMDA receptor system activity, whereas high-frequency stimulation might rely on the same system but have opposite effects. Both, long-term depression and long-term potentiation have been postulated as likely mechanisms to explain the persistent effects of rTMS on cortical activity.
The use of rTMS in the clinical practice depends mainly on its ability to transiently interact with the stimulated neural network rather than its ability to modulate cortical excitability. Therefore, rTMS can be used with two distinct approaches: on-line stimulation (rTMS is applied during the performance of a task) and off-line stimulation (rTMS is applied before). In general, it is assumed that on-line rTMS induces an alteration of cortical activity within a specific targeted area that can significantly impair performance, and the effect of on-line rTMS is short-lived. In the case of off-line stimulation, rTMS affects the modulation of cortical excitability and aims to change the cognitive and motor performance.
Nevertheless, modification of the activity of a neural network by rTMS carries important behavioral implications for neurorehabilitation, which will be considered later. It was reported that the effects induced by several off-line rTMS approaches were site specific, but not site limited. Thus, the long-term consequences induced by sustained repetitive brain stimulation were most likely due to activity changes in a given network of cortical and subcortical areas rather than a local inhibition or excitation of an individual brain area. In other words, brain stimulation can modulate the ongoing properties of a neuronal network by facilitation or reduction of its activity. Since the brain mainly operates through flexible and interactive distributed networks, we can expect that the modification of a node of the network would affect the entire network.
Repetitive Transcranial Magnetic Stimulation Modifies Sensorimotor and Cognitive Recovery
The most common impairment caused by stroke is motor impairment, appearing as a limitation or loss of function in motor control or a limitation in mobility. Therefore, the focus of stroke rehabilitation is often on the recovery of impaired movement and the associated functions based on the paradigm of motor learning. In recent years, efforts have focused on investigating the neurophysiological changes that occur in the brain after stroke, and on developing novel strategies such as additional brain stimulation to enhance motor recovery. In particular, rTMS is known as a therapeutic tool for improving the efficacy of rehabilitation for motor recovery after stroke. In addition to producing effects on cortical excitability, stroke may affect the balance of transcallosal inhibitory pathways between primary motor areas in both hemispheres: the affected hemisphere may be disrupted not only by the infarct itself but also by the resulting asymmetric inhibition from the unaffected hemisphere. Therefore, rTMS could be used therapeutically to restore the balance of interhemispheric inhibition after stroke. According to the interhemispheric competition model, there are two therapeutic strategies for improvement of motor function using rTMS: downregulation of the excitability of the primary motor cortex in the nonaffected hemisphere with low-frequency stimulation, and upregulation of excitability of the primary motor cortex in the affected hemisphere with high-frequency stimulation [6]. All in all, studies have not determined if the facilitation of the affected hemisphere [10] or the inhibition of the unaffected contralateral hemisphere [11,12,13] is more effective in improving the hampered function.
The downregulation strategy has been proven to be effective in consecutive multisession trials for acute and chronic stroke in children and adults. On the other hand, the upregulation strategy has rarely been applied, primarily due to safety concerns, since it was thought that high-frequency rTMS would increase the risk of seizures. Nevertheless, Corti et al. [14] recently reviewed the evidence regarding the safety, and efficacy of high-frequency rTMS to the motor cortex of the affected hemisphere was collated. The studies included in this systematic review investigated the concurrent effects of rTMS on the excitability of corticospinal pathways and upper-limb motor function in adults after stroke. The authors concluded that rTMS applied to the affected hemisphere is a safe technique and could be considered as an effective approach for modulating brain function and contributing to motor recovery after stroke. Moreover, some researchers studying the motor cortex have suggested that the stimulation of both areas would be the most effective strategy [15].
Another frequent motor symptom following stroke is dysphagia. Up to one third of patients experience swallowing problems in the period immediately after a stroke. Most patients recover swallowing ability within a few weeks, but the extent of recovery varies widely from patient to patient. Previous studies using TMS have demonstrated the presence of a direct corticobulbar projection to swallowing muscles from the motor cortex [16]. The projection is bilateral, but is often asymmetric, independent of handedness. Hamdy [16] has suggested that if a stroke affects the dominant swallowing hemisphere, then dysphagia is more likely to occur than if the nondominant hemisphere is affected. Several lines of evidence show that the cortex retains its potential for reorganization after stroke, both in the damaged and undamaged hemispheres. This offers the possibility to modify the corticobulbar network by stimulation.
A recent study reported that 5 daily sessions of rTMS over the esophageal motor cortex of the affected hemisphere improve clinical recovery of swallowing functions in patients with acute monohemispheric stroke, and that, compared with the sham group, this recovery was maintained for at least 2 months [17]. In addition, the electrophysiological measures on 10 patients who received real rTMS indicate that the recovery is associated with an increase in the excitability of the corticobulbar projections from both hemispheres. Furthermore, Khedr and Abo-Elfetoh [18] have shown in a randomized controlled study that active rTMS applied to each hemisphere (affected and unaffected) - compared with sham rTMS - improved swallowing function in patients with acute lateral medullary or other brainstem infarctions. This improvement was maintained over 2 months of follow-up.
Cognitive impairment is a frequent consequence of stroke, with estimates of 50% of patients presenting cognitive impairment in the early phase after stroke [1], and up to 32% of patients demonstrating persistent cognitive impairment up to 3 years after the onset of their first stroke [19].
Approximately 40-81% of stroke patients after stroke demonstrate hemineglect, and this symptom is sustained in approximately one third of these patients [20]. Hemispatial neglect can result from lesions to different structures within an extended attentional network, such as the inferior and posterior parietal lobe, the superior temporal lobe, the inferior frontal lobe, basal ganglia and thalamus, and connecting fiber tracts [21]. Furthermore, hemineglect interferes with the rehabilitative process and is associated with a poor functional outcome.
rTMS - as a noninvasive technique modulating cortical activity - gains growing importance in the field of hemispatial neglect treatment. In neglect patients after stroke, it has been proposed that neuronal activities in contralesional homologous regions are increased due to a loss of active interhemispheric inhibition [5]. In line with this finding, it has been reported in few small studies that reducing activity in the left nonaffected parietal lobe by applying inhibitory low-frequency rTMS can improve hemineglect by reducing abnormally increased interhemispheric transcallosal inhibition from the nonaffected to the affected cortex [22,23].
In a recent study by Song et al. [24], the effects of repeated applications of low-frequency rTMS over the posterior parietal cortex were investigated in a total of 14 right-hemispheric neglect patients. Seven patients were treated with rTMS during 2 weeks, twice a day, whereas 7 patients had no stimulation. Repeated application of low-frequency rTMS resulted in a significant improvement lasting 2 weeks, whereas no improvement was found in the control group without stimulation. In this study, confounding learning effects were controlled and spontaneous remission was accounted for. However, since the study did not include a sham stimulation group, it is difficult to exclude unspecific placebo-like effects.
Newly developed protocols such as TBS present shorter stimulation times and their repeated application can significantly prolong the effects on cortical excitability. The repeated TBS application has thus a promising future as rehabilitative approach in neglect [25]. Moreover, in a recent review it was concluded that rTMS is a promising approach to reduce the interhemispheric imbalance in neglect patients and to ameliorate symptoms [26].
Aphasia is a frequent consequence of stroke with serious effects on the patient's autonomy. Although speech therapy significantly improves language and communication deficits particularly in very early stroke recovery, residual aphasia has a multifactorial impact on quality of life and participation.
With reference to the theory of transcallosal disinhibition [27], recent studies in stroke patients with chronic aphasia suggest that the restoration of the left-hemispheric language network by inhibition of the overactive right homologous frontal speech areas with rTMS as a complementary treatment is linked to better recovery in language and communication deficits [28]. Moreover, a recent functional imaging study proposed that inhibitory rTMS of the right-hemispheric Broca homolog together with subsequent speech therapy prevents establishing right-hemispheric lateralization and that this normalization of the activation pattern might be accompanied by better clinical improvement [29].
In a recent article, Naeser et al. [30] concluded that new rTMS studies suggested that the use of 1-Hz rTMS for a series of at least 10 rTMS treatments results in significant improvement in naming, and often in phrase length during propositional speech. These improvements are long lasting, up to 2 months, or even as long as 2 years, after TMS. Moreover, when rTMS is combined with speech therapy, additional improvement has been observed, beyond rTMS alone.
Although the stimulation protocol varies (table 1), most of the mentioned studies concluded that rTMS is an effective, safe and feasible complementary therapy for stroke rehabilitation.
Studies mentioned in the article evaluating the effects of rTMS in stroke patients

The idea behind rTMS is that modification of the cortical excitability leads to a reorganization of the functional network responsible for the impaired function. The function may be restored by mechanisms that involve structural as well as functional changes of the neuronal circuits. Following the loss of a part of the neural population after stroke, a reduction of excitability of cortical neurons within the affected area might induce a depression of the circuit underlying the function, resulting in an impaired function. Thus, rTMS can induce a partial recovery of sensorimotor and cognitive abilities, which may be due to a strengthening of the synaptic activity of the surviving neurons in the stimulated network.
Another aspect is that areas - connected or adjacent to the lesion - become ‘silent' due to diaschisis, and therefore lesion-induced effects are weakening the synaptic activity resulting in silent synapses. In line with this, rTMS might induce a readjustment of an intact but ‘functionally' suppressed area due to a reduction in synaptic strength. On the other hand, strengthening the synaptic activity by applying rTMS leads to more effective processing within the functional network.
Finally, it has been suggested that lesion-induced plasticity might be stronger when it occurs shortly after stroke, and this plasticity becomes weaker as more time is over. Several experiments have reported that plasticity changes were not caused by rTMS alone; they also require a focused rehabilitation procedure. Therefore, the best way to facilitate recovery is to stimulate the area and activate the network supporting the specific function. This approach can be achieved by combining exogenously induced plasticity by applying rTMS with a specific training-induced plasticity like focused rehabilitation procedures.
Altogether, rTMS - which as a technique is able to noninvasively modulate cortical activity - gains growing importance in the field of stroke recovery. The possibility of noninvasively interacting with the functioning of the brain and its plasticity mechanisms opens new scenarios in the neurorehabilitation field.
Conclusion
A growing body of research in stroke patients indicated that cortical and subcortical networks are involved in sensorimotor and cognitive dysfunction and that rTMS can facilitate recovery of motor and cognitive functions. The literature provides evidence for the disturbance of interhemispheric rivalry processes as a central pathophysiological mechanism in sensorimotor and cognitive dysfunctions, resulting in a pathological hyperactivity of the intact nonaffected hemisphere. Thus, a reduction of this pathological hyperactivity by means of inhibitory rTMS seems to be an effective approach to improve sensorimotor and cognitive symptoms after stroke. However, it is still debatable which paradigm of rTMS (downregulation with low-frequency rTMS vs. upregulation with high-frequency rTMS) should be applied to enhance recovery after stroke.
Clinical trials applying rTMS already yielded very promising results. The results of rTMS studies suggest that rTMS has a potential role in terms of facilitating motor and cognitive recovery after stroke, and thus findings support the merits of noninvasive cortical interventions as adjuvant strategies during sensorimotor and cognitive rehabilitation. In recent studies, it has been shown that particularly the repeated application of newly developed stimulation protocols such as TBS seems to be able to disproportionately prolong the positive stimulation effects by means of significantly shorter stimulation times than conventional protocols. However, further research is needed to assess stimulation effects not only on clinical testing, but also in terms of disability improvement. Beneficial effects of rTMS on recovery after stroke in the framework of prospective, randomized, double-blind, sham-controlled clinical trials with larger sample sizes are needed to validate this novel therapeutic approach. Moreover, possible interactions in the combination of rTMS with conventional therapeutic approaches should also be assessed.
In future studies, emphasis should be placed on selecting patient populations to determine whether treatment response depends on age, lesion acuteness, or stroke severity. Additional aspects need to be considered, such as the timing of rTMS application after stroke, the duration of the rehabilitation protocol, the type of frequency as well as the ideal area that should be stimulated. Furthermore, it is important to identify parameters optimizing the beneficial effects of rTMS on stroke recovery, and to monitor their long-term effects.