CTRI

Research Hypothesis

This study proposes a novel strategy for addressing abnormal neuronal synchrony in Parkinson’s disease by neuromodulation through High-definition closed-loop tACS over motor cortex (M1). The hypothesis is that the neuromodulating effect of this intervention will disrupt abnormal neuronal synchrony in PD, enhance neuroplasticity, and alleviate motor symptoms. Closed-loop tACS over M1 is anticipated to induce phase cancellation of the pathological rhythm in PD.

Background and Rationale of the Study

Over 8.5 million people worldwide have Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s. In 2019, about 771,000 people in India had PD, leading to an estimated 45,300 deaths. As Parkinson’s disease progresses, dopamine precursors such as levodopa, regarded as the gold standard for improving movement, lose effectiveness and lead to undesirable side effects. The standard treatment for medically refractory PD is deep brain stimulation (DBS), but it can lead to DBS-induced movement disorders. Even when combined with medication, traditional high-frequency DBS only provides a temporary motor improvement, with symptoms returning almost immediately after cessation of stimulation. Abnormal neuronal synchrony significantly contributes to the motor symptoms of PD, suggesting a potential new target for therapy not fully explored by existing treatments. Developing strategies that can specifically disrupt this abnormal neuronal activity could open a new direction in PD management, especially for medically refractory PD. Increased synchronization of the subthalamic nucleus is often seen in PD patients and is linked to reduced motor function. Brittain et al. (2013) used transcranial alternating current stimulation (tACS) over the motor cortex (M1) to disrupt the rest tremor rhythm in PD. They found that applying tACS at specific phases for each patient effectively suppressed the ongoing tremor, resulting in an average 50% reduction in resting tremor amplitude. This research proposes a novel therapeutic approach of closed-loop high-definition transcranial alternating current stimulation (tACS) over the motor cortex (M1) to enhance the neuroplasticity of the brain, potentially restoring neural synchrony and offering symptomatic relief in PD. The use of closed-loop tACS allows for real-time tuning of stimulation parameters based on the patient’s neuronal activity, ensuring personalized and optimized treatment. Despite the promise of this novel therapeutic approach, the understanding of its efficacy and the underlying neurophysiological mechanisms is unclear. The proposed study aims to address these lacunae by evaluating the short-term effects of tACS over M1 on motor symptoms in patients with medically refractory PD. Additionally, it aims to elucidate the neurophysiological mechanisms driving the therapeutic effects of these interventions through electroimaging (dense array EEG) analysis. This research could lead to a better understanding of Parkinson’s Disease and a personalized, non-invasive treatment that improves outcomes for those affected by it.

Keywords: Transcranial alternating current, Closed-loop, phase cancellation, motor symptoms, neurophysiological mechanisms, Parkinson’s Disease

The relevance and expected outcome of the proposed study

Relevance: Parkinson’s Disease (PD) affects over 8.5 million individuals globally, leading to significant disability and diminished quality of life. While dopaminergic medications and deep brain stimulation provide symptomatic relief, their efficacy diminishes over time and are associated with substantial side effects. Moreover, the existing treatments do not address abnormal neuronal synchrony in PD. Novelty: This study proposes a novel approach of closed- loop transcranial alternating current stimulation (tACS) over motor cortex (M1). This could disrupt the pathological neuronal synchrony of PD. Method: This Double-Blind, Randomized, Sham-Controlled, parallel-group study will enroll 50 patients with medically refractory PD into two groups: (1) Real tACS, (2) Sham tACS. The MDS-UPDRS III off-medication will be used as the primary outcome measure. Electroimaging (dense array EEG) data will be analyzed to determine the neural mechanisms underlying the therapeutic effects. Expected Outcome: This study aims to develop a personalized and effective non-invasive combinatorial neuromodulation approach for treating medically refractory PD.

Objectives

1. To compare the effects of real versus sham closed-loop transcranial alternating current stimulation (tACS) over motor cortex (M1) on motor symptoms and cognitive function in patients with medically refractory PD.

2. To investigate the neurophysiological mechanisms underlying the therapeutic effects of closed-loop tACS over M1 using dense array EEG data.