Full title: Repetitive transcranial magnetic stimulation for motor, linguistic and cognitive sequelae of stroke
Authors: Rivero-Santana, A, Ramos-García, V, Herrera-Ramos, E, Cazaña-Pérez V, Favaro, F, Rodríguez-Drincount de Elízaga, J, Gómez-Ramos, AM, Duarte-Díaz, A, Arnal-Artiaga, L, Santos-Álvarez, A, Álvarez-Pérez, Y, Varela-Moreno, E, Perestelo-Pérez, L
Contact Person: Amado Rivero Santana (amado.riverosantana@sescs.es)
SUMMARY
Introduction
Cerebrovascular accident (CVA), commonly known as stroke, is an injury caused by the interruption of blood flow to a part of the brain (ischemic stroke) or by bleeding into or around the brain tissue (hemorrhagic stroke). Worldwide, 15 million people suffer a stroke each year; of these, 5 million die and another 5 million are left with severe motor, language, cognitive, or sensory sequelae. In Spain, according to data from the Spanish Society of Neurology (SEN), there are 90,000 new stroke cases and more than 23,000 stroke-related deaths annually, making it the leading cause of disability.
Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique that uses magnetic fields applied to the brain through an electromagnetic coil. When applied with sufficient intensity over the cortex, the induced current depolarizes cortical neuronal assemblies located directly beneath the coil, as well as in nearby or even remote brain regions, thus generating neurophysiological and behavioral effects. The application of repetitive magnetic pulses (repetitive TMS or rTMS) at specific frequencies and patterns allows modulation of cortical excitability beyond the duration of the pulse train, opening the door to therapeutic applications. rTMS protocols involve combinations of two or more stimulation pulses or bursts delivered at a fixed frequency ranging from 0.5 to 20 Hz, with or without stimulation-free intervals, over periods lasting from several seconds to 30–40 minutes. In general, high-frequency stimulation (≥5 Hz) increases cortical excitability, whereas low-frequency stimulation (≤1 Hz) has an inhibitory effect, although there is significant interindividual variability in these effects.
A variant of rTMS is theta burst stimulation (TBS). This protocol is designed to mimic the brain’s natural activation patterns and delivers a burst of 3 pulses at a frequency of 50 Hz. There are two types: intermittent TBS (iTBS) and continuous TBS (cTBS), which generally produce excitatory and inhibitory effects, respectively. In addition, various coil designs exist for delivering rTMS, differing in their ability to produce focal effects (i.e., stimulating only the target area without affecting nearby regions) or deep effects (reaching deeper brain structures).
The clinical application of rTMS has been under investigation for over three decades, with depression being the most extensively studied area. In terms of safety, although more adverse effects have been reported compared to sham (placebo) stimulation, they have generally been mild and transient (e.g., headache or discomfort at the stimulation site, dizziness, insomnia, fatigue), typically resolving once treatment is discontinued, and no significant differences have been found in treatment dropout rates.
rTMS received FDA approval in the United States for the treatment of treatment-resistant major depression (2008), migraine (2013), and major depression in adolescents (2024). Deep rTMS has been approved for treatment-resistant depression (2013), anxious depression (2021), major depression in older adults (2024), obsessive-compulsive disorder (2018), and smoking addiction (2020). A significant number of studies have investigated the use of rTMS to treat stroke-related sequelae.
Objectives
To evaluate the effectiveness and safety of repetitive transcranial magnetic stimulation (rTMS) in the treatment of motor, language, and cognitive sequelae following a stroke.
Methodology
A systematic review (SR) of the literature was conducted by searching the databases Medline, Embase, CINAHL, and CDRS/CENTRAL up to January 2025. Randomized controlled trials (RCTs) comparing any type of rTMS with sham stimulation in patients who had experienced a stroke and presented with motor (limb or dysphagia), language, or cognitive sequelae were included.
The risk of bias of the included studies was assessed using the RoB 2 tool developed by the Cochrane Collaboration, and the quality of the evidence was rated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Where sufficient studies were available, meta-analyses (MAs) were conducted for each effectiveness outcome variable (symptom reduction, activities of daily living (ADLs), health-related quality of life (HRQoL)). Additionally, meta-regressions and/or subgroup analyses were performed to explore the moderating effect of various sociodemographic, clinical, and stimulation protocol-related variables.
Results
The electronic search retrieved 3572 references, of which 130 met the inclusion criteria, including 2 studies identified by manual search (8 on motor sequelae of upper and lower limbs, 57 on upper limbs, 17 on lower limbs, 18 on dysphagia, 19 on aphasia and 11 on cognitive sequelae, of which one also offers results on lower limbs).
UPPER LIMBS
In the case of stimulation over the primary motor cortex (M1), a clinically and statistically significant effect on motor function (measured with the Fugl-Meyer Assessment scale, FMA) was observed for all protocols combined (g = 0.45, 95% CI: 0.25, 0.64; moderate-quality evidence) as well as individually:
– Low-frequency unilateral stimulation applied on average within 60 days post-stroke (g = 0.55, 95% CI: 0.24, 0.85; moderate quality)
– High-frequency unilateral stimulation (g = 0.69, 95% CI: 0.37, 1.01; low quality)
– Intermittent TBS (iTBS) unilateral (g = 0.51, 95% CI: 0.14, 0.87; low quality)
– Continuous TBS (cTBS) unilateral (g = 0.43, 95% CI: 0.08, 0.77; low quality)
– Bilateral stimulation (g = 0.71, 95% CI: 0.18, 1.24; low quality)
Follow-up results (mostly at 1–3 months) remained significant in all cases, except for the single study that assessed follow-up in the iTBS group.
Similarly, for activities of daily living (ADLs) assessed with the Barthel Index, significant improvements were observed:
– All protocols combined: (g = 0.82, 95% CI: 0.46, 1.18; low quality)
– Low-frequency unilateral stimulation within 60 days (g = 0.64, 95% CI: 0.35, 0.94; moderate quality)
– High-frequency unilateral stimulation (g = 0.51, 95% CI: 0.26, 0.76; low quality)
– iTBS unilateral (no meta-analysis performed; very low quality)
– cTBS unilateral (no meta-analysis performed; low quality)
– Bilateral stimulation (g = 1.32, 95% CI: 0.32, 2.32; very low quality)
No significant differences were found in health-related quality of life (HRQoL): 3 studies using low-frequency stimulation (low quality), one study using iTBS (very low quality), one study using cTBS (very low quality).
LOWER LIMBS
No significant effect on the FMA scale was found for all protocols combined (low quality) or separately (quality not assessed) in M1 stimulation, nor for cerebellar iTBS (very low quality).
Among the studies assessing balance/postural control, 4 out of 6 showed significant results (very low quality) using 1 Hz, 10 Hz, or iTBS over M1. A meta-analysis of 4 studies applying cerebellar iTBS found a significant effect (g = 0.46, 95% CI: 0.06, 0.85; moderate quality).
A small but significant effect of stimulation over M1 on ADLs was found (g = 0.36, 95% CI: 0.10, 0.62; moderate quality), while the only study that assessed stroke-specific quality of life found no significant differences.
DYSPHAGIA
Stimulation over M1 (all protocols combined) showed a significant and strong effect on penetration/aspiration (measured with the Penetration-Aspiration Scale, PAS) (g = -0.80, 95% CI: -1.10, -0.50; moderate-quality evidence) and swallowing function (g = 0.82, 95% CI: 0.53, 1.10; moderate quality). These results were maintained at short- to medium-term follow-up. Analyzed separately, all protocols showed clinically relevant effects (g > 0.40), although not all reached statistical significance. Cerebellar stimulation (10 Hz) also showed significant results for PAS (g = -0.70, 95% CI: -1.19, -0.22; low quality) and swallowing function (g = 1.13, 95% CI: 0.32, 1.94; very low quality).
APHASIA
Clinically and statistically significant effects were observed in the improvement of overall aphasia severity with inhibitory stimulation over the right hemisphere homologous language areas: low-frequency stimulation (g = 0.72, 95% CI: 0.39, 1.05; low quality), continuous TBS (cTBS) (g = 1.26, 95% CI: 0.64, 1.88; low quality), and also for intermittent TBS (iTBS) over the left hemisphere (no meta-analysis conducted; low quality)
GENERAL COGNITIVE FUNCTION
A moderate-to-strong significant effect was found for improvement in general cognitive function with unilateral stimulation of the dorsolateral prefrontal cortex (DLPFC) (g = 0.72, 95% CI: 0.34, 1.09; moderate-quality evidence).
SAFETY
Regarding serious adverse events (SAEs), the evidence supporting the good safety profile of the technique is considered high quality. There were 5 reported cases of seizures, representing 0.23% of valid cases across the 97 studies that explicitly reported on safety. In 60% of these studies, no adverse events were reported, or no significant differences were found between groups. The most common adverse effect was headache, followed by dizziness, nausea, and pain or tingling sensations on the scalp, all mild or moderate in intensity and transient in nature.
Conclusions
UPPER LIMBS
• When considering all stimulation protocols together, there is moderate-quality evidence supporting a small-to-moderate significant effect of rTMS over the primary motor cortex (M1) on motor function improvement. All analyzed protocols showed clinically relevant results (statistical significance was not reached for 5 Hz), although the evidence quality is low for each protocol individually, except for low-frequency stimulation applied on average before 60 days post-stroke (moderate quality). At follow-up, mostly short-term (1–3 months), effects were maintained.
• There is low-quality evidence supporting a significant and strong effect of rTMS over M1 on the improvement of activities of daily living (ADL), which is even greater if applied on average before 60 days after stroke. Separately, all protocols showed clinically relevant results (statistical significance was not reached for 5 Hz).
LOWER LIMBS
• There is low-quality evidence indicating that rTMS over M1 does not improve motor function of the lower limbs, when analyzing protocols separately or combined.
• Evidence on the effect of different rTMS protocols over M1 on balance/postural control shows significant effects in a majority of studies, although these are few and the quality of evidence is very low.
• There is moderate-quality evidence that rTMS over M1 produces a small significant effect on improvement in activities of daily living.
• There is low-quality evidence indicating that cerebellar intermittent theta burst stimulation (iTBS) does not produce significant motor function improvement.
• There is moderate-quality evidence of a small-to-moderate effect of cerebellar iTBS on balance improvement.
DYSPHAGIA
• When all stimulation protocols are considered together, there is moderate-quality evidence that rTMS over M1 produces a significant improvement in penetration/aspiration and swallowing function. All protocols analyzed showed clinically relevant effects (g > 0.40), although only 5 Hz, iTBS, and bilateral stimulation reached statistical significance for penetration/aspiration, and 1 Hz, 3 Hz, iTBS, and bilateral stimulation did so for swallowing function. The effect is maintained at short- to medium-term follow-up.
• There is low-quality evidence that 10 Hz cerebellar stimulation produces a small-to-moderate significant effect on penetration/aspiration improvement, and very low-quality evidence indicating a strong effect on swallowing function.
APHASIA
• There is low-quality evidence that 1 Hz stimulation over the right hemisphere produces a small-to-moderate significant effect on global aphasia severity improvement.
• There is low-quality evidence that continuous theta burst stimulation (cTBS) over the right hemisphere produces a strong significant effect on global aphasia severity improvement.
• There is low-quality evidence that intermittent theta burst stimulation (iTBS) over the left hemisphere produces a significant effect on global aphasia severity improvement.
GENERAL COGNITIVE FUNCTION
• There is moderate-quality evidence that unilateral stimulation of the dorsolateral prefrontal cortex (DLPFC) produces a small-to-moderate significant effect on general cognitive function improvement. Significant effects were obtained for all evaluated protocols (1 Hz, 5 Hz, 10 Hz, and iTBS), although evidence quality is low when analyzed separately.
QUALITY OF LIFE
• Very few studies assessed general or stroke-specific health-related quality of life, without finding significant results (low or very low quality depending on stimulation protocol).
SAFETY
• There is high-quality evidence that rTMS does not produce serious adverse effects, except for the small possibility of seizures in a very small percentage of individuals (≤ 0.26%). Mild to moderate adverse effects, mainly headache, may occur with some frequency but are transient or easily resolved.
Keywords: Transcranial magnetic stimulation; Stroke; Sequelae
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