Multiple system atrophy (MSA) is an atypical Parkinsonism (AP) distinguished by a constellation of symptoms including severe autonomic dysfunction, Parkinsonian manifestations, ataxia, and pyramidal tract involvement. Clinically, it is categorized into two subtypes based on the predominant symptoms: the Parkinsonian type (MSA-P) and the cerebellar type (MSA-C) [1]. With an estimated incidence of 0.6–0.7 per 100,000 individuals, MSA is a rare neurological disorder typically presenting around the age of 55. The prognosis is moderate, with an average survival span of 6–10 years post-diagnosis, although some patients may survive up to 15 years [2,3,4,5]. The financial implications of MSA are considerable. According to a 2011 survey, the 6-month treatment costs for MSA patients were notably high, with variations across countries: €28,924 in France, €25,645 in Germany, and €19,103 in the UK [6]. The disease’s progression often results in the loss of independent ambulation within a few years, significantly diminishing the quality of life and compressing the survival timeline. The current standard of care is symptomatic treatment, and there is an absence of effective pharmacological or procedural interventions. Notably, therapies effective in Parkinson’s disease, such as levodopa and deep brain stimulation, have demonstrated limited efficacy in MSA [7,8,9,10,11]. Given the paucity of effective treatments, there is an imperative to explore innovative therapeutic strategies, with a particular focus on noninvasive options. Such advancements could potentially prolong survival, ameliorate the quality of life for MSA patients, and mitigate the economic burden borne by individuals, families, and society at large.

Transcranial magnetic stimulation (TMS) is recognized as a safe and efficacious non-invasive technique for nerve stimulation, extensively utilized in both the research and clinical treatment of a spectrum of neurological and psychiatric disorders [12, 13]. While the precise mechanisms of TMS remain to be fully elucidated, it is postulated that TMS exerts its effects by modulating cerebral blood flow, the metabolic milieu, and directly influencing the excitability of the targeted cortical areas and their interconnected networks. This modulation is believed to impact synaptic plasticity and, consequently, alter brain functional connectivity [14, 15]. At the cellular and molecular levels, TMS is capable of modulating synaptic structure and functional plasticity through its effects on neuronal morphology, glutamate receptors, and neurotransmitter activity. Additionally, TMS exerts regulatory influence on the expression of brain-derived neurotrophic factor (BDNF), which in turn modulates the expression of synaptic-associated proteins, ultimately shaping synaptic plasticity [16,17,18]. Synaptic long-term potentiation (LTP), indicative of enhanced synaptic strength, is typically induced by high-frequency TMS stimulation (> 1 Hz), whereas low-frequency TMS stimulation (≤ 1 Hz) is associated with long-term depression (LTD), reflecting a reduction in synaptic efficacy [15, 19,20,21]. These frequency-dependent effects underscore the potential of TMS to facilitate or inhibit synaptic changes, thereby offering a therapeutic avenue for modulating neural circuits implicated in various pathophysiological conditions. Theta burst stimulation (TBS), a variant of repetitive transcranial magnetic stimulation (rTMS), offers distinct advantages in terms of efficiency and efficacy. intermittent theta burst stimulation (iTBS) is recognized for its ability to enhance neuronal excitability, potentially facilitating therapeutic effects in various conditions. Conversely, continuous theta burst stimulation (cTBS) effectively reduces neuronal excitability. It is of note that the plasticity mechanisms of the cerebellum appear to differ from those of the motor cortex. rTMS at 1 Hz targeting the parallel fibers-Purkinje cell synapses in the cerebellum can induce LTP [22, 23]. Therefore, we hypothesize that the neural regulation within the cerebellum may exhibit opposite effects when subjected to the same modulatory approach as the motor cortex. Of course, this hypothesis necessitates further validation through animal experiments and at the cellular and molecular levels of investigation. Published research underscores the benefits of TBS, including a shorter stimulation duration compared to rTMS, a more enduring impact on neurophysiological states, and a closer resemblance to the natural fluctuations of brain activity. These attributes render TBS particularly advantageous in the context of neurological and psychiatric disorders. Moreover, application of TBS has been associated with a minimal incidence of adverse effects, broadening its therapeutic potential [24,25,26,27,28].

In 2019, the International Parkinson and Movement Disorder Society published research progress on the use of transcranial magnetic stimulation (TMS) for the treatment of movement disorders, demonstrating that TMS can ameliorate the motor symptoms and depressive conditions associated with Parkinson’s disease. However, the therapeutic efficacy of TMS on other movement disorders requires further exploration [29]. Based on the currently published studies, MSA, as a subtype of the Parkinsonian syndrome, may also benefit from TMS treatment.

It has been found that TMS can not only improve motor symptoms such as parkinsonism-like and ataxia, but also improve non-motor symptoms such as anxiety and depression. But there is a lack of high-quality multi-center clinical studies to confirm it. At present, there is no consensus on the therapeutic targets for TMS treatment in MSA. In the following discussion, we categorize the research into three main areas: targeting the primary motor cortex, cerebellar targeting, and studies focusing on non-motor symptoms, which will be addressed separately.

During the stage of employing TMS as a research tool, it has been observed that in MSA patients, even with the administration of levodopa, the levels of MEPs exhibit a sustained decrease following the second stimulus when compared to PD patients. This finding suggests a persistent cortical inhibition in MSA patients relative to those with PD [30]. Kawashima et al. utilized paired associative stimulation (PAS) to investigate MEP amplitudes in 10 patients with PD and 10 with MSA-P. The study revealed that dopaminergic therapy in MSA-P patients did not restore the PAS-induced increase in MEP amplitudes. These findings suggest that corticostriatal circuit activation may play a significant role in the cortical plasticity of the human M1 [31]. These findings provide a basis for the therapeutic targeting of M1 with TMS in MSA. Liu Z et al. [32] found that 5 Hz TMS stimulation of M1 and the cerebellum increases the complexity of the brain’s resting state in MSA patients and reduces the severity of motor impairments. Han Wang et al. [33] applied 5 Hz rTMS targeting the M1 in MSA-P patients, with a sham stimulation as control. The study found that high-frequency rTMS ameliorated motor symptoms in MSA and, using task-based fMRI, revealed increased cerebellar activation. Ying-hui Chou et al. [34] demonstrated that 5 Hz rTMS over the M1 region may ameliorate motor symptoms by modulating functional connectivity within the default mode, cerebellar, and limbic networks. Therefore, it can be inferred that high-frequency TMS targeted at the M1 region may alleviate the symptoms of MSA.

According to published research results, there is controversy surrounding cerebellar-targeted TMS treatment. The 2014 non-invasive cerebellar neuromodulation consensus indicates that cerebellar TMS is an effective method for evaluating the function of the cerebellar-thalamocortical circuit and studying the pathophysiology of ataxia [35]. 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 [36]. A double-blind, prospective, randomized, sham-controlled trial involving 18 patients with spinocerebellar ataxia type 3 observed improvements in ICARS scores post-treatment. Additionally, analysis of magnetic resonance spectroscopy (MRS) before and after treatment indicated enhancements in cerebellar local metabolism and microenvironment [37]. Although MSA-C differs etiologically from spinocerebellar ataxia, a shared pathophysiological basis may underlie the ataxia they induce [38]. Interestingly, iTBS with activating effects can also improve motor imbalance in MSA by modulating cerebello-cortical plasticity [39]. Despite the use of opposing stimulation paradigms in these studies, both appear to exert therapeutic effects on MSA. We speculate that the pathways through which these two distinct modes act may differ and warrant further investigation.

In addition to improving motor symptoms in MSA, TMS seems to have some efficacy in non-motor symptoms. Chou et al. [40] used HF-rTMS to stimulate M1 in patients with MSA-P. And found that the functional connectivity of edge networks was increased. This may be noticed as an improvement of some non-motor symptoms (e.g., orthostatic hypotension or urinary and bowel dysfunction). Although the improvement effect of TMS on autonomic symptoms needs to be further confirmed, the study provides new ideas for this. Additionally, high-frequency stimulation of the left dorsolateral prefrontal cortex may ameliorate fatigue in MSA patients [41] Unilateral cerebellar low-frequency stimulation may aid in improving cognition in MSA patients [36]. These findings provide a foundation for the treatment of non-motor symptoms in MSA.

The existed researches are mostly small-sample, single-center studies; the determination of stimulation intensity and mode is ambiguous; the target localization is not accurate enough; the treatment plan lacks a unified standard; and no in-depth mechanistic exploration is performed. Therefore, it is necessary to further carry out high-quality multi-center clinical studies to clarify its effect and explore its mechanism in order to provide a scientific clinical basis for TMS in the treatment of MSA.