Effect of Theta Burst Stimulation-Patterned rTMS on Motor and Nonmotor Dysfunction of Parkinson's Disease: A Systematic Review and Metaanalysis

Abstract

Background: Theta burst stimulation (TBS), a type of patterned repetitive transcranial magnetic stimulation (rTMS), has several advantages, such as short time of single treatment and low stimulation intensity compared with traditional rTMS. Since the efficacy of TBS on the symptoms of Parkinson's disease (PD) was inconsistent among different studies, we systematically searched these studies and quantitatively analyzed the therapeutic effect of TBS for patients with PD.Methods: We followed the recommended PRISMA guidelines for systematic reviews. Studies from PubMed, EMBASE, CENTRAL, and ClinicalTrials.gov from January 1, 2005 of each database to September 30, 2021 were analyzed. We also manually retrieved studies of reference.Results: Eight eligible studies with 189 participants (received real TBS and/or sham TBS) were included. This metaanalysis found that TBS did not significantly improve Unified Parkinson's Disease Rating Scale part III (UPDRS-III) score in the “on” medicine state (SMD = −0.06; 95% CI, −0.37 to 0.25; p = 0.69; I2 = 0%), while, it brought significant improvement of UPDRS-III scores in the “off” medicine state (SMD = −0.37; 95% CI, −0.65 to −0.09; p < 0.01; I2 = 19%). Subgroup analysis found that merely continuous TBS (cTBS) over the supplementary motor area (SMA) brought significant improvement of UPDRS-III score (SMD = −0.63; 95% CI, −1.02 to −0.25; p < 0.01). TBS had insignificant effectiveness for upper limb movement disorder both in the “on” and “off” medicine status (SMD = −0.07; 95% CI, −0.36 to 0.22; p = 0.64; I2 = 0%; SMD = −0.21; 95% CI, −0.57 to 0.15; p = 0.26; I2 = 0%; respectively). TBS significantly improved slowing of gait in the “off” medicine status (SMD = −0.37; 95% CI, −0.71 to −0.03; p = 0.03; I2 = 0%). Subgroup analysis suggested that only intermittent TBS (iTBS) over the primary motor cortex (M1) + dorsolateral prefrontal cortex (DLPFC) had significant difference (SMD = −0.57; 95% CI, −1.13 to −0.01; p = 0.04). Additionally, iTBS over the M1+ DLPFC had a short-term (within 2 weeks) therapeutic effect on PD depression (MD = −2.93; 95% CI, −5.52 to −0.33; p = 0.03).Conclusion: Our study demonstrated that cTBS over the SMA could significantly improve the UPDRS-III score for PD patients in the “off,” not in the “on,” medicine state. TBS could not bring significant improvement of upper limb movement dysfunction. ITBS over the M1+DLPFC could significantly improve the slowing of gait in the “off” medicine status. Additionally, iTBS over the M1+DLPFC has a short-term (within 2 weeks) therapeutic effect on PD depression. Further RCTs of a large sample, and excellent design are needed to confirm our conclusions.

Neuroimaging and serum biomarkers of neurodegeneration and neuroplasticity in Parkinson’s disease patients treated by intermittent theta-burst stimulation over the bilateral primary motor area: a randomized, double-blind, sham-controlled, crossover trial study

“…In fact, different rTMS modalities are considered a potential therapy for PD, given the safety and lack of side effects after application ( Wagle Shukla et al, 2016 ). Nevertheless, although a variety of rTMS protocols have been demonstrated to be effective, many of them have limited benefits in terms of time and effects ( Chou et al, 2015 ; Zanjani et al, 2015 ); thus, an increasing number of studies has examined the therapeutic impact of TBS, which has a shorter stimulation duration and more intense stimulation sequence, on motor and nonmotor symptoms in PD patients ( Cheng et al, 2022 ). However, inconsistent conclusions have been reported because only a few TBS studies have been performed; hence, the magnitude and persistence of the TBS effect remain debatable.…”

“…Thus, while a single session of cTBS over the M1 did not have any motor or clinical effects in PD patients in the OFF medication state ( Eggers et al, 2010 ), a study using a single session of iTBS over the M1 was promising for alleviating complications in PD patients in the ON medication state ( Degardin et al, 2012 ). However, some disagreements regarding the application of excitatory or inhibitory TBS protocols and the recommended brain targets during the ON medication state still need to be clarified ( Cheng et al, 2022 ).…”

“…Current evidence suggests that the application of iTBS and cTBS patterns to the motor cortex can facilitate or depress corticospinal excitability, respectively, and induce synaptic plasticity, as revealed in experimental models of PD ( Chen and Udupa, 2009 ; Ghiglieri et al, 2012 ; Natale et al, 2021 ) and multiple studies on cortical plasticity in humans, in which the effect lasted from minutes to hours after administration ( Di Lazzaro et al, 2005 ; Huang et al, 2005 , 2017 ; Wischnewski and Schutter, 2015 ). Thus, the majority of PD studies suggest that cTBS over the supplementary motor area (SMA) has strong potential to enhance motor function and that iTBS over the motor primary area (M1) or the dorsolateral prefrontal cortex may improve specific aspects of motor performance, gait, and nonmotor symptoms in PD ( Cheng et al, 2022 ). Nevertheless, despite the undeniable advantages of TBS over conventional TMS, the conclusions of these studies have some inconsistencies, particularly in terms of the duration and variability of the clinical effects in this patient population, the target of stimulation, and the role of dopaminergic medication use.…”

Noninvasive Neuromodulation in Parkinson’s Disease: Insights from Animal Models

“…A considerable body of work has examined rTMS as a potential treatment for motor and cognitive symptoms of PD, with several meta-analyses and reviews on this topic providing evidence of efficacy in treatment of motor, depressive, and cognitive symptoms [9], as shown in Table 1. A number of mechanisms have been proposed to underlie the therapeutic effects of rTMS in PD based on both clinical and preclinical literature, including the induction of plasticity in the stimulated cortical areas and related circuits; a release of dopamine, which may modulate synaptic activity and plasticity; and molecular mecha-nisms bringing about neuroprotective effects [10,11].…”