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.
