The Effects And Mechanisms Of Deep Brain Stimulation In Parkinson's Disease

The Effects and Mechanisms of Deep Brain Stimulation in Parkinson's DiseaseParkinson's disease (PD) is a progressive neurodegenerative disorder. The pathologic hallmark of the disease is the degeneration of dopaminergic neurons of the substantia nigra pars compacta, which leads to severe dopaminergic denervation of the corpus striatum. Deep brain stimulation (DBS) can improve most symptoms of mid or late stage PD patients with less complication, long term symptom regression, and decrease of antiparkinsonian drug dose, which has been accepted by the world. But many issues related to DBS remained to be answered, including basic questions as mechanism of action, long-term outcome. In the present study, the long-trem effects of deep brain stimulation (DBS) in Parkinson's disease (PD) have been investigated using the means of clinical evaluation. Microdialysis, extracellular recording, behavioral test, immunohistochemistry were used to investigate the possible mechanisms involved. The research includes two parts:PartⅠHemiparkinsonian monkey models induced by MPTPObjectiveHemiparkinsonian monkey models can be induced by unilateral internal carotid artery infusion of MPTP with two different methods, endovascular and direct surgical approach, are similar to that of Parkinsonian humans. The objective of this part is to provide PD monkey models for HFS-STN experiment, simultaneously, to compare two kinds of methods.MethodsThree healthy senior rhesus monkeys with weights ranging form 9.8～11.8kg were used in this study, all more than 8-year-old. There are two methods to establish monkey models of hemiparkinsonism with MPTP. Endovascular approach: One monkeys, after general anesthesia, were punctured of femoral artery. The internal carotid artery was catherized and MPTP (10mg) saline was injected slowly under Fluoroscopy. Direct surgical approach: Two monkeys were included in this group. After general anesthesia, the right common carotid artery and bifurcation was exposed by blunt dissection. MPTP (10mg) saline was injected into the right common carotid artery slowly after clipping of the extemal carotid artery. All monkeys were evaluated after surgery according to a disability rating scale. The apomorphine (APO) evoked rotation was also tested. After the death of the monkey models, both sides of substantia nigra of the monkey brain were cut into serial sections, and tyroxine hydroxylase (TH), immunohistochemistry study was performed.ResultsAfter infused of MPTP, endovascular with one time (M1) and surgical approach with 3 times (M2) and 2 times(M3) respectively, monkeys appeared the PD symptoms including automatic action decrease, rigidity of left limbs, bradykinesia and gait abnormlity. The disability scores of hemiparkinsonian monkeys were all higher than 6 at 1 months after the last time of infusion of MPTP. APO could evoke rotation to left. NISSL and TH immunohistochemistry stained sections of nigrostriatal area showed that DA neurons reduced by more than 65% in the lesioned side compared with the unlesioned side.ConclusionsBoth two methods, endovascular and direct surgical approach, can establish satisfactory MPTP monkey models of hemiparkinsonism which is useful for further study on HFS-STN. After infusion of MPTP, monkeys appeared the PD symptoms which be checked by behavior evaluation and APO test. The endovascular method is better than the direct surgical method for. establishing senior animal PD models with less operating time, MPTP dosage and injury.PartⅡThe mechanisms of HFS-STN in PDObjectiveWe used extracellular recording and microdialysis-HPLC approach to investigate the changes of the STN and GPi on the neuronal activity and the level of GLu and GABA in both normal and hemiparkinsonian animals with or without HFS-STN. The objective of this study is to find out the mechanisms of PD and HFS-STN in PD. MethodsThree hemiparkinsonian monkeys respectively were implanted with glass electrodes, stimulating electrodes, microdialysis probe in STN and GPi according to stereotaxic atlas of the monkey brain. Exetracellular recording and intracerebral microdialysis approaches were used to investigate the spikes and analysis of firing activity and detect the GLu and GABA levels with or without HFS-STN.ResultsLesion of the SNc did not significantly change the firing rate of STN and GPi neurons but did induce a dramatic changes in their firing pattern and increase the GLu and GABA levels. And HFS-STN could cause the depression of the neuronal activity of STN and GPi and the increase of GLu and GABA levels.ConclusionsThe changed firing pattern of STN and GPi in hemiparkinsonian animals may be responsible for the pathological situation of the basal ganglia in PD. HFS would to a certain extent suppress the abnormal activity of STN neurons, resulting in a re-equilibrium in the neuronal activity of the basal ganglia motor circuit and the improvement of PD syndromes.PartⅢClinical study of DBS in PDObjectiveTo demonstrate the effects of deep brain stimulation (DBS) in the treatment of Parkinson's disease (PD) postoperative 3-52 months' follow-up.MethodsBetween 04/01 and 12/06, 83 PD patients with DBS were followed up postoperatively in Beijing Tiantan Hospital. All of them were evaluated with Unified Parkinson's Disease Rating Scale (UPDRS) partsⅡ-Ⅴbefore surgery and 3-52 months after surgery. The amelioration of miscellaneous symptoms and decrease of medication dose respectively were compared. Main side effects were observed.ResultsAfter surgery, both the score of activities of daily living (ADL) and the UPDRS motor score decreased significantly (P＜0.001). Among the PD symptoms, tremor was improved best. Rigidity, bradykinesia, axial symptoms, facial expression and dyskinesia were all improved, although to a lesser extent, while speech was not improved very well. Medication dose was decreased 48.2% significantly (P＜0.001). According to the time of follow-up, ADL, UPDRS motor score and dyskinesia subscore improvement were compared among 1 year and 4 years groups postoperatively. No significant difference existed. No life threatening complications occurred. Main side effects included hypophonia, dyskinesia, confusion, depression.ConclusionsDBS is a satisfying surgical method for the treatment of advanced PD. Complications and side effects were rare and usually temporary or reversible.