Spinal Neural Mechanism Underlying Parkinsonian Rest Tremor And Effectiveness Of Inhibition By Transcutaneous Electrical Nerve Stimulation

Parkinson’s disease(PD)is a long-term degenerative disorder of the central nervous system,and rest tremor is the most common motor symptom in patients with PD.The pathophysiology of resting tremor of PD has been studied more than one hundred years,and the major progress has been made with the adanvances in neurophysiologic technologies.Many studies have shown that there are multiple oscillators in the cerebral networks and the oscillations most likely are produced in the basal ganglia and cerebellar loops.In the peripheral system,the tremor occurs in one or multiple body segments with the same or similar frequency,the related agonist-antagonist muscles of joints show rhythmic,reciprocal and alternative bursting activities.Signal coherence analysis reveals that the oscillatory activities in the brain have strong coupling with peripheral electromyography(EMG)and tremor movement.However,the spinal mechanism of corticomuscular processing remains unknown.Clinical treatments of Parkinsonian rest tremor focus on dopaminergic medication and neurosurgery.The efficiency of medication could last by simply increasing dose.The invasive neurosurgery,including deep brain stimulation or lesion(pallidotomy and thalamotomy),are usually recommended to pharmaco-resistant patients who live with the tremor symptom at least three years.In addition,the risk and the high cost stand in the way of neurosurgery.Many studies tried to control tremor by intervention at the peripheral system,such as kinematic adjustment and compensation using functional electrical stimulation or changing the extra load,and inhibition based on spinal stretch reflex mechanism via Ib inhibition by low transcutaneous electrical nerve stimulation.Nevertheless,the underlying neural mechanisms or the effectiveness of current interventions need further clarification.This dissertation is aimed at elucidating the spinal mechanism in transmitting cortical signals of Parkinsonian rest tremor and evaluating a novel non-invasive intervention technology for inhibiting the tremor by transcutaneous electrical nerve stimulation.There are three major parts in this dissertation,which are described as follows:1.Extend the Virtual Arm model by adding a propriospinal neuronal(PN)network.The realistic Virtual Arm model was integrated from model components of upper-limb musculoskeletal biomechanics,virtual muscle,muscle spindle,Golgi tendon organ,and spinal reflex circuits.This model could simulate normal and pathological neural motor behaviors.The PN network has been added to this model,so that there are two corticospinal descending pathways to motoneurons,the mono-synaptic pathway and the multi-synaptic pathway,forming the new Cortico-Spinal Virtual Arm(CS-VA)model.2.Test the hypothesis that the signals of Parkinsonian rest tremor are transmitted by way of PN multi-synaptic corticospinal pathway.Kinematics data and surface electromyogram of tremor in upper limb were collected from patients with PD.The tremor behaviors were simulated in SIMULINK with the CS-VA model.By comparing tremor data of patients with PD and the results of model simulation,our simulation supported the hypotheses regarding the corticospinal transmission of oscillatory signals in Parkinsonian tremor.Simulations indicated that without the PN network,the alternating burst patterns of agonist-antagonistic muscle electromyograms could not be reliably generated and with the PN network,the alternating burst patterns of agonist-antagonist electromyograms were naturally reproduced under all conditions of cortical oscillations.The results suggest that cortical commands of single and double tremor frequencies are further processed at PN to compute the alternating burst patterns in flexor and extensor muscles.3.Evaluate inhibition of Parkinsonian rest tremor by cutaneous afferents evoked by transcutaneous electrical nerve stimulation.Cutaneous afferents evoked by electrical stimulation on the dorsal skin of the hand could disrupt the corticospinal transmission of descending tremor signals.Experiments were designed to investigate the inhibition effects.Kinematics data and surface electromyogram of tremor in upper limb were collected from patients with PD.In these trials,data were collected before stimulation,during stimulation and after stimulation.Results showed that at stimulation intensity from 1.5 to 1.75 times of radiating sensation threshold,apparent suppressions of tremor at wrist,forearm and upper arm and in the EMGs were observed immediately at the onset of stimulation.After termination of stimulation,tremor and rhythmic EMG bursts reemerged gradually.Statistical analysis of peak spectral amplitudes showed a significant difference in joint tremors and EMGs during and prior to stimulation in all 8 subjects with PD.The average percentage of suppression was 61.56%±8.90% in tremor across all joints of all subjects,and 47.97%±25.77% in EMG of all muscles.This dissertation discovered the important role of the PN network in spinal level in transmitting the corticospinal tremor signals.This hypothesis was supported by using the CS-VA model that reproduced the Parkinsonian rest tremor.Based on this discovery of spinal neural mechanism,we proposed a novel strategy using electrical stimulation to alleviate Parkinsonian rest tremor.Results in 8 patients with PD provided direct evidence that tremor in the upper extremity of patients with PD can be inhibited to a large extent with evoked cutaneous reflexes via surface stimulation of the dorsal hand skin area innervated by the superficial radial nerve.The technique may suggest a non-invasive intervention to reduce tremor in PD patients with tremor dominant symptoms.