Transcranial magnetic stimulation (TMS) is emerging as a potential therapeutic intervention for multiple system atrophy (MSA), a rare and debilitating neurodegenerative disorder characterized by autonomic dysfunction, parkinsonism, ataxia, and pyramidal tract involvement. With an estimated incidence of 0.6–0.7 per 100,000 individuals, MSA presents significant challenges due to its moderate prognosis and the lack of effective pharmacological or procedural interventions. Current treatments primarily focus on symptomatic relief, as therapies effective in Parkinson’s disease, such as levodopa and deep brain stimulation, have shown limited efficacy in MSA. Given the imperative to explore innovative therapeutic strategies, TMS is being investigated for its ability to modulate neural circuits and potentially improve the quality of life for MSA patients.
TMS Mechanisms and Applications
TMS is a non-invasive technique that uses magnetic fields to stimulate nerve cells in the brain. While the precise mechanisms of TMS are still being elucidated, it is believed to modulate cerebral blood flow, metabolic activity, and the excitability of targeted cortical areas and their interconnected networks. This modulation can impact synaptic plasticity and alter brain functional connectivity. At the cellular level, TMS can influence synaptic structure and function by affecting neuronal morphology, glutamate receptors, neurotransmitter activity, and the expression of brain-derived neurotrophic factor (BDNF), which plays a crucial role in synaptic plasticity.
Theta burst stimulation (TBS), a variant of repetitive TMS (rTMS), offers advantages in terms of efficiency and efficacy. Intermittent TBS (iTBS) is known to enhance neuronal excitability, while continuous TBS (cTBS) reduces neuronal excitability. Notably, the plasticity mechanisms of the cerebellum may differ from those of the motor cortex, with rTMS at 1 Hz targeting the cerebellum potentially inducing long-term potentiation (LTP). These findings suggest that TMS can facilitate or inhibit synaptic changes, offering a therapeutic avenue for modulating neural circuits implicated in MSA.
TMS for Motor Symptoms in MSA
Research suggests that TMS can improve motor symptoms associated with MSA. Studies have shown that high-frequency TMS targeting the primary motor cortex (M1) can ameliorate motor symptoms in MSA patients. For example, Liu et al. found that 5 Hz TMS stimulation of M1 and the cerebellum increased the complexity of the brain’s resting state and reduced the severity of motor impairments. Han Wang et al. demonstrated that 5 Hz rTMS targeting the M1 in MSA-P patients improved motor symptoms and increased cerebellar activation, as revealed by task-based fMRI. Chou et al. showed that 5 Hz rTMS over the M1 region may improve motor symptoms by modulating functional connectivity within the default mode, cerebellar, and limbic networks.
There is some controversy surrounding cerebellar-targeted TMS treatment. Low-frequency TMS targeting the cerebellum can reduce the Scale for Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS) scores of patients with MSA-C. Chen et al. observed improvements in ICARS scores and enhancements in cerebellar local metabolism and microenvironment in patients with spinocerebellar ataxia type 3 after low-frequency TMS. Interestingly, iTBS with activating effects can also improve motor imbalance in MSA by modulating cerebello-cortical plasticity.
TMS for Non-Motor Symptoms in MSA
In addition to improving motor symptoms, TMS has shown promise in alleviating non-motor symptoms in MSA. Chou et al. found that high-frequency rTMS stimulation of M1 in patients with MSA-P increased the functional connectivity of edge networks, potentially improving autonomic symptoms such as orthostatic hypotension or urinary and bowel dysfunction. High-frequency stimulation of the left dorsolateral prefrontal cortex may also ameliorate fatigue in MSA patients, while unilateral cerebellar low-frequency stimulation may aid in improving cognition.
Ongoing Research and Future Directions
While these findings are promising, the existing research is limited by small sample sizes and single-center designs. The determination of stimulation intensity and mode is often ambiguous, target localization may lack precision, and treatment plans lack a unified standard. Therefore, there is a need for high-quality, multi-center clinical studies to clarify the efficacy of TMS and explore its mechanisms of action in MSA. Such studies could provide a scientific clinical basis for TMS in the treatment of MSA and potentially improve the lives of individuals affected by this challenging disorder.
