Cerebellar Transcranial Alternating Current Stimulation (tACS) to Modulate Parkinson's Disease Tremor

Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by progressive neurodegeneration, especially in the substantia nigra. Clinically, PD is characterized by motor impairment, including bradykinesia, rigidity, postural instability, and tremor, with hand trem-or being particularly challenging due to its heterogeneity and the incomplete understanding of its underlying neurophysiological mechanisms. Emerging evidence suggests that pathological activity in the cortico-thalamo-cortical (CTC) network is associated with PD tremor amplitude. In recent years, the cerebellum has been recognized for its direct involvement in tremor dynamics within the CTC network. Addressing the abnormal oscillatory activity within this network could potentially modu-late tremor pathophysiology.

Current therapeutic approaches for PD tremor focus on dopaminergic replacement, however some patients exhibit minimal response to this treatment. Deep brain stimulation (DBS) has shown effi-cacy in alleviating tremor, but its invasive nature and associated risks limit its widespread use. Con-sequently, there has been growing interest in non-invasive brain stimulation techniques as poten-tial alternatives for tremor management. Among these techniques, transcranial alternating current stimulation (tACS) has gained significant attention due to its ability to modulate endogenous brain oscillations. Phase-specific tACS, which involves aligning the stimulation phase with the intrinsic tremor rhythms, has demonstrated potential in entraining and reducing PD tremor. However, the application of this technique has been constrained by the complexities associated with phase ad-justment algorithms and the need for a responsive closed-loop system capable of real-time phase synchronization.

For the current project, a novel closed-loop device has been developed together with the collabo-rator neuroConn GmbH that is specifically designed to target PD tremor. This device is capable of real-time monitoring of hand tremor, rapid signal processing, and delivering phase-locked tACS within safe operational parameters. The central hypothesis is that phase-locked tACS of the cere-bellum can modulate the oscillatory dynamics within the CTC network and thereby reduce tremor amplitude in PD patients.

The study will involve PD patients with moderate to severe hand tremor, as assessed using the Movement Disorders Unified Parkinson's Disease Rating Scale (MDS-UPDRS). The experimental design involves two sessions, both utilizing closed-loop tACS at an intensity of 2 to 4 mA.

In each session, a baseline recording of PD hand tremor will be collected before stimulation. In the first session, the phase alignment between the tremor and tACS signals will be systematically varied across 60° phase bins; plus a sham (zero stimulation amplitude) and an unlocked stimulation proto-col (open-loop). The data from this session will be analyzed to determine the optimal phase align-ment. In the second session, tACS will be applied using the optimal phase alignment identified in the first session. After each block of stimulation, a post-stimulation baseline recording will be con-ducted to evaluate the immediate effects of the intervention. This design enables the assessment of phase-specific effects of closed-loop tACS on PD hand tremor.

This study aims to assess the extent and duration of tremor reduction achieved by closed-loop phase-adaptive cerebellar tACS, enhancing our understanding of the CTC network and potentially offering new insights into non-invasive therapeutic strategies for managing PD tremor.

• Tremor entrainment [Time frame: During the stimulation]