Effects of Multi-Session Repetitive Transcranial Magnetic Stimulation on Motor Control and Spontaneous Brain Activity in Multiple System Atrophy: A Pilot Study

Abstract

Background: Impaired motor control is one of the most common symptoms of multiple system atrophy (MSA). It arises from dysfunction of the cerebellum and its connected neural networks, including the primary motor cortex (M1), and is associated with altered spontaneous (i.e., resting-state) brain network activity. Non-invasive repetitive transcranial magnetic stimulation (rTMS) selectively facilitates the excitability of supraspinal networks. Repeated rTMS sessions have been shown to induce long-term changes to both resting-state brain dynamics and behavior in several neurodegenerative diseases. Here, we hypothesized that a multi-session rTMS intervention would improve motor control in patients with MSA, and that such improvements would correlate with changes in resting-state brain activity. Methods: Nine participants with MSA received daily sessions of 5 Hz rTMS for 5 days. rTMS targeted both the cerebellum and the bilateral M1. Before and within 3 days after the intervention, motor control was assessed by the motor item of the Unified Multiple System Atrophy Rating Scale (UMSARS). Resting-state brain activity was recorded by blood-oxygen-level dependency (BOLD) functional magnetic resonance imaging. The "complexity" of resting-state brain activity fluctuations was quantified within seven well-known functional cortical networks using multiscale entropy, a technique that estimates the degree of irregularity of the BOLD time-series across multiple scales of time. Results: The rTMS intervention was well-attended and was not associated with any adverse events. Average motor scores were lower (i.e., better performance) following the rTMS intervention as compared to baseline (t₈ = 2.3, p = 0.003). Seven of nine participants exhibited such pre-to-post intervention improvements. A trend toward an increase in resting-state complexity was observed within the motor network (t₈ = 1.86, p = 0.07). Participants who exhibited greater increases in motor network resting-state complexity demonstrated greater improvement in motor control (r²= 0.72, p = 0.004). Conclusion: This pilot study demonstrated that a five-session rTMS intervention targeting the cerebellum and bilateral M1 is feasible and safe for those with MSA. More definitive, well-controlled trials are warranted to confirm our preliminary results that rTMS may alleviate the severity of motor dysfunction and modulate the multiscale dynamics of motor network brain activity.

Keywords: motor control; multiple system atrophy; multiscale entropy; repetitive transcranial magnetic stimulation; resting-state fMRI.

FIGURE 1

An example time-series of resting-state BOLD fluctuations within one brain voxel (A) and its corresponding multiscale entropy (MSE) curve (B). The complexity of voxel-level BOLD fluctuations was determined by computing sample entropy across multiple time scales and averaging across said scales. Network-level resting-state complexity was then determined by parceling the brain into seven large-scale networks according to Yeo et al. (2011) and averaging the complexity values associated with all voxels within each network.

FIGURE 2

Participant-level motor control before and after rTMS intervention. Motor control was assessed by the Motor Examination Scale within the Unified Multiple System Atrophy Rating Scale (UMSARS), where lower scores reflect better motor control. After five, once-daily sessions of rTMS targeting the cerebellum and bilateral M1, seven of nine participants exhibited lower motor scores (red lines).

FIGURE 3

Participant-level motor network resting-state complexity before and after rTMS intervention. After five, once-daily sessions of rTMS targeting the cerebellum and bilateral M1, six of nine participants exhibited increased resting-state complexity within the motor network (red lines).

FIGURE 4

Relationship between pre-to-post rTMS intervention changes in motor control and motor network resting-state complexity. From pre-to-post intervention, participants who exhibited greater percent decrease in motor item score (i.e., better performance) demonstrated greater percent increase in resting-state complexity within the motor network (r²= 0.72, p = 0.04). No other relationships between motor control and resting-state complexity reached significance.