Low‐frequency rTMS of the unaffected hemisphere in stroke patients: A systematic review

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Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique able to influence cortical excitability. Through rTMS, trains of magnetic stimuli are applied to target brain areas at frequency ranging from 1 to 20 Hz or more. Generally, low‐frequency (LF) rTMS (stimulus rates ≤1 Hz) induces inhibitory effects on motor cortical excitability, whereas high‐frequency (HF) rTMS (≥3 Hz) usually promotes an increase in cortical excitability. Both single‐site or multifocal rTMS protocols have been used, to modulate the function of a single cortex region or the reciprocal interaction between remote but functionally related cortical areas, respectively.1 The cortical activity modulation can last for several minutes beyond the duration of the train itself, thus promoting both short‐ and long‐term neuroplasticity. A rTMS protocol named theta burst stimulation (TBS) employs low intensities and has a robust, long‐lasting effect in normal subjects. Different patterns of delivery of TBS produce opposite effects on synaptic efficiency of the stimulated cortex. Continuous TBS (cTBS) decreases cortical excitability, while intermittent TBS (iTBS) was shown to increase motor cortical excitability.7
Due to the lack of effective neurorepair therapy, application of rTMS to facilitate neural plasticity during stroke rehabilitation has gained increasing attention, in order to increase the functional recovery attainable by physical therapy (PT). Accumulating evidence indicates that rTMS might have positive effects on motor recovery in patients with stroke, especially for those with subcortical lesions.9 However, there remains uncertainty, mainly regarding the effects of rTMS on the mechanisms of functional recovery. As the post‐ischemic phenomena might significantly differ among patients, it is unrealistic to expect that a unique, standardized rTMS approach can exert beneficial effects for every patient with stroke.
Spontaneous post‐stroke motor recovery has been related to molecular and synaptic changes occurring within the central nervous system, which can lead to different degrees of functional improvement. After a stroke, spared tissue in the lesioned cortex, its surrounding areas and the motor cortices of the unlesioned hemisphere are involved in an extensive anatomic and functional reorganization. Non‐primary motor areas of the lesioned hemisphere, which could be spared in middle cerebral artery infarction, can assume functional control of the ipsilesional descending pathways. Furthermore, homologous motor areas of the contralesional hemisphere can be engaged in ipsilateral movements early after the stroke onset,18 or after an experimentally induced cortical dysfunction.19 This capability of some brain areas to mediate the lost or impaired function of other cortical areas represents the basis of the “vicariation model.” This conceptual model is supported by rigorous experimental evidence.20 However, it is not completely descriptive of all the post‐lesional phenomena. Indeed, the unlesioned hemisphere can also exert unfavourable effects on functional recovery, by unbalancing the interhemispheric inhibition (IHI), which is a physiologic mechanism necessary to the execution of skilled movements, and is mediated by transcallosal connections. After unilateral lesion involving the primary motor cortex (M1), the homologous area of the contralesional hemisphere (cM1) continues to exert inhibitory interhemispheric effects, even if this activity becomes unfavourable to the functional recovery. These phenomena are summarized in the “interhemispheric competition model,” which has provided the rational basis for neuromodulation treatments aimed at reducing excitability of cM1, and thus at rebalancing restoring IHI.21 Therefore, these two different models could lead to opposite neuromodulator approaches. Indeed, according to the “vicariation model,” the activity of cM1 needs be further enhanced, rather than inhibited, in order to support functional recovery. Nevertheless, there is increasing evidence that this dualistic view is an oversimplification. Well‐recovered, mildly impaired patients can show, in the chronic phase after left capsular stroke, increased activation in the motor cortices of both the affected and the unaffected hemisphere.

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