Development of Cortical Electrical Stimulation Technique for Improving Neuroplasticity and Motor Function in Parkinsonian Rats

Parkinson's disease (PD) is the second most common neurodegenerative disease of the elderly which affects approximately seven million people worldwide and thirty thousand people in Taiwan. Although dopamine agonists therapy provides benefits to most PD patients, the symptom relief is often incomplete, and chronic drug treatment is often limited by adverse effects. Thus, new therapeutic and alternative strategies are clearly needed for PD disorders. Various brain stimulation techniques such as repetitive magnetic stimulation (rTMS) or cortical electrical stimulation (CES), have been increasingly developed for modulating cortical plasticity which are considered having therapeutic potentials in PD. However, the therapeutic value of such cortical stimulation approach for PD is still unclear and controversial due to the clinical heterogeneity in patients, long-term pharmacological effects, different severity of the disease and the variability of stimulus protocols. Accordingly, an disease animal model would be helpful for solving this formidable impediment and enabling translational research for better understanding the mechanistic insight of cortical stimulation in PD treatment. The purpose of this three-year research is to develop a CES scheme which mimics the situation of rTMS and CES in humans via neural engineering approaches and conduct the series of experiments to test the therapeutic potential of CES in a PD animal model, as an early step toward possible eventual clinical use of CES in PD. In the first year, we will design of long-term implantable CES module which has the advantages with high accuracy and spatial resolution for stimulating a specific area of the motor cortex in freely moving PD rats. The dysfunctions of neuroplasticity and neuromodulation in PD rats will be verified by electrophysiological measurements of motor evoked potential (MEP) during CES-theta burst paradigm and paired-pulse CES, respectively. For motor behavioral tests, several quantitative platforms will be adapted to assess the impairment of muscular rigidity, tremor, akinesa and locomotor function of hemiparkinsonian rats following 6-hydroxydopamine (6-OHDA) lesion. In the second year, we will investigate the efficacy of CES treatment in PD rats at three major levels: motor behavioral (as measured by targeted tasks), synaptic (as reflected in cortical plasticity and neuromodulation) and molecular (as assayed by immunohistochemistry). In the last year, with the help of this model, we will identify the therapeutic effects of long-term CES treatment for improving neuroprotection and neurogenesis in PD rats. This integrated neural engineering approaches will provide a unique opportunity to detect the beneficial effects of neuroplasticity, neuromodulation as well as motor performance after CES interventions in the PD rat model, which may enhance for promising possibility of potential use of CES and may serve as a translational platform bridging human and animal studies for developing therapeutic strategies of cortical stimulation such as rTMS for PD or other neurological disorders.