Freezing of gait (FOG), especially the levodopa-unresponsive type, is a major challenge in Parkinson's disease (PD) management. The widely accepted "Interference model" posits that FOG stems from cognitive dysfunction and overload of cognitive, limbic, and motor cortical-basal ganglia (BG) pathways. Targeting these networks could potentially restore balance. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation (NIBS) technique capable of modulating brain connectivity within specific networks. The primary motor cortex of the lower leg (M1-LL) is a potential target for gait and FOG treatment, although its efficacy remains limited. Impaired corticomotor inhibition (CI) of the tibialis anterior muscle is associated with FOG. Low-frequency rTMS over M1 can enhance corticospinal inhibition. Transcranial spinal cord stimulation (SCS) also shows promise for FOG treatment, possibly by modulating the supplementary motor area (SMA). This study hypothesized that combining rTMS over bilateral M1-LL with transcutaneous magnetic SCS would be more effective than rTMS alone in treating levodopa-unresponsive FOG.

Existing literature highlights the challenges of treating levodopa-unresponsive FOG in Parkinson's disease. Several studies explored the use of rTMS targeting the M1-LL, with mixed results regarding efficacy. The "Interference model" provides a framework for understanding FOG as arising from network dysfunction. Prior research indicated that low-frequency rTMS could enhance corticospinal inhibition, potentially alleviating FOG symptoms. Furthermore, studies investigating the use of spinal cord stimulation (SCS), both invasive and non-invasive, showed promising improvements in gait and FOG. These previous findings provided the rationale for investigating a combined rTMS and transcutaneous magnetic SCS approach.

This study employed a randomized, double-blind, controlled trial design. Sixty-eight PD patients with levodopa-unresponsive FOG were initially recruited, with 57 completing the trial after exclusions due to various factors (benign paroxysmal positional vertigo, withdrawals, and loss to follow-up). Participants were randomized into three groups: dual-site stimulation (DS: real bilateral M1-LL rTMS + real lumbar spinal cord tSCS), single-site stimulation (SS: real bilateral M1-LL rTMS + sham lumbar spinal cord tSCS), and no-site stimulation (NS: sham rTMS + sham lumbar spinal cord tSCS). Each group received 10 sessions of stimulation over two weeks. Assessments included the Freezing of Gait Questionnaire (FOG-Q), Unified Parkinson's Disease Rating Scale part III (UPDRS-III), objective gait measures (gait speed, stride length, stride time variability, double support time), and electrophysiological measures (corticomotor excitability of upper and lower extremities, including resting motor threshold (RMT), MEP amplitude (AMP), cortical silent period (CSP), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), and short-latency afferent inhibition (SAI)). Statistical analyses included repeated measures ANOVA, ANCOVA, and correlation analyses.

No serious adverse events were reported, although some participants experienced transient headaches. Both the DS and SS groups showed significant improvements in FOG-Q scores, UPDRS-III scores, gait speed, and stride length compared to the NS group at both 1 day and 1 month post-intervention. The DS group exhibited superior improvements in FOG-Q scores and gait parameters compared to the SS group. A significant TIME × GROUP interaction was observed for SICI of the abductor pollicis brevis (APB), with both DS and SS groups showing increased SICIAPB compared to baseline. The DS group showed a more pronounced increase in SICIAPB than the SS group. In the DS group, greater improvement in SICIAPB correlated with greater improvement in gait speed and stride length. Table 1 presents baseline characteristics, and the tables in the supplementary material and the main text provide details on post-intervention changes in FOG assessments and cortical excitability.

The findings demonstrate the safety and efficacy of low-frequency rTMS over bilateral M1-LL in improving FOG, gait, and motor function in PD patients with levodopa-unresponsive FOG. The dual-site cerebrospinal stimulation protocol proved superior to single-site stimulation, suggesting a synergistic effect of combining cortical and spinal stimulation. The increased SICIAPB observed in both DS and SS groups, and particularly the strong correlation between SICIAPB improvement and gait improvement in the DS group, supports the role of cortical inhibition modulation in the therapeutic mechanism. These results align with the "Interference model" of FOG, suggesting that the dual-site stimulation may help to rebalance the connectivity within the affected networks.

This study confirms the efficacy of cumulative low-frequency rTMS over bilateral M1-LL for levodopa-unresponsive FOG in PD. The dual-site approach combining rTMS and transcutaneous magnetic SCS shows greater benefit than rTMS alone. Future research should investigate the optimal parameters for this dual-site stimulation and explore the underlying neural mechanisms using advanced neuroimaging techniques. Further studies with larger sample sizes and longer follow-up periods are warranted to confirm these findings and assess long-term efficacy.

Several limitations warrant consideration. The lack of electro-navigation for rTMS might have affected the precision of stimulation. The sham design could have been optimized to improve blinding. The absence of a dedicated transcutaneous magnetic SCS group prevents a complete assessment of this modality's isolated effects. The double-cone coil's potential for less focality and stimulation of regions beyond the target needs to be acknowledged. Although earplugs were used, optimizing auditory masking strategies could improve blinding. Finally, employing advanced neuroimaging techniques, such as fMRI, could provide more comprehensive insights into the neural mechanisms at play.