Stroke is a common acute neurovascular disorder that causes disabling long-term limitations to daily living activities. The most common consequence of a stroke is motor deficit of variable degree,1 although nonmotor symptoms are also relevant and often equally disabling.2 To date, to the best of the authors’ knowledge, there is no validated treatment that is able to restore the impaired functions by a complete recovery of the damaged tissue. Indeed, stroke management basically consists of reducing the initial ischemia in the penumbra, preventing future complications, and promoting a functional recovery using physiotherapy, speech therapy, occupational therapy, and other conventional treatments.3,4
Ischemic damage is associated with significant metabolic and electrophysiological changes in cells and neural networks involved in the affected area. From a pure electrophysiological perspective, however, beyond the affected area, there is a local shift in the balance between the inhibition and excitation of both the affected and contralateral hemisphere, consisting of increased excitability and disinhibition (reduced activity of the inhibitory circuits).3,5 In addition, subcortical areas and spinal regions may be altered.3,5 In particular, the role of the uninjured hemisphere seems to be of utmost significance in post-stroke clinical and functional recovery.
Different theoretical models have been proposed to explain the adaptive response of the brain to acute vascular damage. According to the vicariation model, the activity of the unaffected hemisphere contributes to the functional recovery after a stroke through the replacement of the lost functions of the affected areas. The interhemispheric competition model considers the presence of mutual inhibition between the hemispheres, and the damage caused by a stroke disrupts this balance, thus producing a reduced inhibition of the unaffected hemisphere by the affected side. This results in increased inhibition of the affected hemisphere by the unaffected side. More recently, a new model, called bimodal balance recovery, has been proposed.3,5 It introduces the concept of a structural reserve, which describes the extent to which the nondamaged neural pathways contribute to the clinical recovery. The structural reserve determines the prevalence of the interhemispheric imbalance over vicariation. When the structural reserve is high, the interhemispheric competition model can predict the recovery better than the vicariation model, and vice versa.3
Repetitive transcranial magnetic stimulation
One of the proposed interventions to improve stroke recovery, by the induction of neuromodulation phenomena, is based on methods of noninvasive brain stimulation. Among them, transcranial magnetic stimulation (TMS) is a feasible and painless neurophysiological technique widely used for diagnostic, prognostic, research, and, when applied repetitively, therapeutic purposes.6–9 By electromagnetic induction, TMS generates sub or suprathreshold currents in the human cortex in vivo and in real time.10,11
The most common stimulation site is the primary motor cortex (M1), that generates motor evoked potentials (MEPs) recorded from the contralateral muscles through surface electromyography electrodes.11 The intensity of TMS, measured as a percentage of the maximal output of the stimulator, is tailored to each patient based on the motor threshold (MT) of excitability. Resting MT (rMT) is found when the target muscle is at rest, it is defined as the minimal intensity of M1 stimulation required to elicit an electromyography response with a peak-to-peak amplitude > 50 µV in at least 5 out of 10 consecutive trials.11 Alternatively TMS MTAT 2.0 software (http://www.clinicalresearcher.org/software.htm) is a free tool for TMS researchers and practitioners. It provides four adaptive methods based on threshold-tracking algorithms with the parameter estimation by sequential testing, using the maximum-likelihood strategy for estimating MTs. Active MT (aMT) is obtained during a tonic contraction of the target muscle at approximately 20% of the maximal muscular strength.11
The rMT is considered a basic parameter in providing the global excitation state of a central core of M1 neurons.11 Accordingly, rMT is increased by drugs blocking the voltage-gated sodium channels, where the same drugs may not have an effect on the gamma-aminobutyric acid (GABA)-ergic functions. In contrast, rMT is reduced by drugs increasing glutamatergic transmission not mediated by the N-methyl-D-aspartate (NMDA) receptors, suggesting that rMT reflects both neuronal membrane excitability and non-NMDA receptor glutamatergic neurotransmission.12 Finally, the MT increases, being often undetectable, when a substantial portion of M1 or the cortico-spinal tract is damaged (i.e. by stroke or motor neuron disease), and decreases when the motor pathway is hyperexcitable (such as epilepsy).13
Repetitive (rTMS) is a specific stimulation paradigm characterized by the administration of a sequence of consecutive stimuli on the same cortical region, at different frequencies and inter sequence intervals. As known, rTMS can transiently modulate the excitability of the stimulated cortex, with both local and remote effects outlasting the stimulation period. Conventional rTMS modalities include high-frequency (HF-rTMS) stimulation (>1 Hz) and low-frequency (LF-rTMS) stimulation (⩽1 Hz).11 High-frequency stimulation typically increases motor cortex excitability of the stimulated area, whereas low-frequency stimulation usually produces a decrease in excitability.14 The mechanisms by which rTMS modulates the brain are rather complex, although they seem to be related to the phenomena of long-term potentiation (LTP) and long-term depression (LTD).15
When applied after a stroke, rTMS should ideally be able to suppress the so called ‘maladaptive plasticity’16,17 or to enhance the adaptive plasticity during rehabilitation. These goals can be achieved by modulating the local cortical excitability or modifying connectivity within the neuronal networks.10
rTMS in stroke rehabilitation: an overview
According to the latest International Federation of Clinical Neurophysiology (IFCN) guidelines on the therapeutic use of rTMS,10 there is a possible effect of LF-rTMS of the contralesional motor cortex in post-acute motor stroke, and a probable effect in chronic motor stroke. An effect of HF-rTMS on the ipsilesional motor cortex in post-acute and chronic motor stroke is also possible.
The potential role of rTMS in gross motor function recovery after a stroke has been assessed in a recent comprehensive systematic review of 70 studies by Dionisio and colleagues.18 The majority of the publications reviewed report a role of rTMS in improving motor function, although some randomized controlled trials (RCTs) were not able to confirm this result,19–23 as shown by a recent large randomized, sham-controlled, clinical trial of navigated LF-rTMS.24 It has also been suggested that rTMS can specifically improve manual dexterity,10 which is defined as the ability to coordinate the fingers and efficiently manipulate objects, and is of crucial importance for daily living activities.25 Notably, most of the studies focused on motor impairment in the upper limbs, whereas limited data is available on the lower limbs.18 Walking and balance are frequently impaired in stroke patients and significantly affect the quality of life (QoL),26,27 and rTMS might represent a valid aid in the recovery of these functions.28,29 Spasticity is another common complication after a stroke, consisting of a velocity-dependent increase of muscular tone,30 and for which rTMS has been proposed as a rehabilitation tool.31
Dysphagia is highly common in stroke patients, it impairs the global clinical recovery, and predisposes to complications.32 It has been pointed out that rTMS targeting the M1 area representing the muscles involved in swallowing may contribute to the treatment of post-stroke dysphagia.33
Nonmotor deficit is also a relevant post-stroke disability that negatively impacts the QoL. Aphasia is a very common consequence of stroke, affecting approximately 30% of stroke survivors and significantly limiting rehabilitation.34 According to the IFCN guidelines, to date, there is no recommendation for LF-rTMS of the contralesional right inferior frontal gyrus (IFG). Similarly, no recommendation for HF-rTMS or intermittent theta burst stimulation (TBS) of the ipsilesional left IFG or dorsolateral prefrontal cortex (DLPFC) in Broca’s aphasia has been currently approved.10 The same is true for LF-rTMS of the right superior temporal gyrus in Wernicke’s aphasia.10
Neglect is the incapacity to respond to tactile or visual contralateral stimuli that are not caused by a sensory-motor deficit.35 Although hard to treat, rTMS has been proposed as a tool for neglect rehabilitation.36 However, the IFCN guidelines state that currently there is no recommendation for LF-rTMS of the contralesional left posterior parietal cortex, or for HF-rTMS of the ipsilesional right posterior parietal cortex.10 In a recent systematic review, most of the included studies supported the use of TMS for the rehabilitation of aphasia, dysphagia, and neglect, although the heterogeneity of stimulation protocols did not allow definitive conclusions to be drawn.37
Post-stroke depression is a relevant complication of cerebrovascular diseases.38 The role of rTMS in the management of major depressive disorders is well documented,39,40 and currently, rTMS is internationally approved and indicated for the treatment of major depression in adults with antidepressant medication resistance, and in those with a recurrent course of illness, or in cases of moderate-to-severe disease severity.39 In major depression disorders, according to the IFCN guidelines, there is a clear antidepressant effect of HF-rTMS over the left DLPFC, a probable antidepressant effect of LF-rTMS on the right DLPFC, and probably no differential antidepressant effect between right LF-rTMS and left HF-rTMS. Moreover, there is currently no recommendation for bilateral stimulation combining HF-rTMS of the left DLPFC and LF-rTMS of the right DLPFC. The mentioned guidelines also state that the antidepressant effect when stimulating DLPFC is probably additive, and possibly potentiating, to the efficacy of antidepressant drugs.10 However, no specific recommendation currently addresses the use of rTMS in post-stroke depression. Recently, rTMS has been proposed as a treatment option for the late-life depression associated with chronic subcortical ischemic vascular disease, the so called ‘vascular depression’.41–44 Three studies tested rTMS efficacy in vascular depression (one was a follow-up study with citalopram). Although presenting positive findings, further trials should refine clinical and diagnostic criteria to assess its impact on antidepressant efficacy.45
Approximately 25–30% of stroke patients develop an immediate or delayed cognitive impairment or an overt picture of vascular dementia.46 There is evidence of an overall positive effect on cognitive function for both LF-rTMS47 and HF-rTMS,48 supported by studies on experimental models of vascular dementia.49–52 Nonetheless, the few trials examining the effect on stroke-related cognitive deficit produced mixed results.53–56 In particular, two studies found no effect on cognition when stimulating the left DLPFC at 1 Hz and 10 Hz,53,54 whereas a pilot study found a positive effect on the Stroop interference test with HF-rTMS over the left DLPFC in patients with vascular cognitive impairment without dementia.55 However, this finding was not replicated in a follow-up study.56 To summarize, rTMS can induce beneficial effects on specific cognitive domains, although data are limited and their clinical significance needs to be further validated. Major challenges exist in terms of appropriate patient selection and optimization of the stimulation protocols.57
Central post-stroke pain (CPSP) is the pain resulting from an ischemic lesion of the central nervous system.58 It represents a relatively common complication after a stroke, although it is often under-recognized and, therefore, undertreated.59 According to the IFCN guidelines for the use of rTMS in the treatment of neuropathic pain, there is a definite analgesic effect of HF-rTMS of contralateral M1 to the pain side, and LF-rTMS of contralateral M1 to the pain side is probably ineffective. In addition, there is currently no recommendation for cortical targets other than contralateral M1 to the pain side.10 Notably, rTMS might be effective in drug-resistant CPSP patients.58 A recent systematic review that included nine HF-rTMS studies suggested an effect on CPSP relief, but also underlined the insufficient quality of the studies considered.60
In this article, we aim to provide an up-to-date overview of the most recent evidence on the efficacy of rTMS in the rehabilitation of stroke patients. Although several studies have been published, a conclusive statement supporting a systematic use of rTMS in the multifaceted clinical aspects of stroke rehabilitation is still lacking.