The subthalamic nucleus(STN)is considered the best target for deep brain stimulation treatments of Parkinson’s disease(PD).It is difficult to localize the STN due to its small size and deep location.Multichannel micr...The subthalamic nucleus(STN)is considered the best target for deep brain stimulation treatments of Parkinson’s disease(PD).It is difficult to localize the STN due to its small size and deep location.Multichannel microelectrode arrays(MEAs)can rapidly and precisely locate the STN,which is important for precise stimulation.In this paper,16-channel MEAs modified with multiwalled carbon nanotube/poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate)(MWCNT/PEDOT:PSS)nanocomposites were designed and fabricated,and the accurate and rapid identification of the STN in PD rats was performed using detection sites distributed at different brain depths.These results showed that nuclei in 6-hydroxydopamine hydrobromide(6-OHDA)-lesioned brains discharged more intensely than those in unlesioned brains.In addition,the MEA simultaneously acquired neural signals from both the STN and the upper or lower boundary nuclei of the STN.Moreover,higher values of spike firing rate,spike amplitude,local field potential(LFP)power,and beta oscillations were detected in the STN of the 6-OHDA-lesioned brain,and may therefore be biomarkers of STN localization.Compared with the STNs of unlesioned brains,the power spectral density of spikes and LFPs synchronously decreased in the delta band and increased in the beta band of 6-OHDA-lesioned brains.This may be a cause of sleep and motor disorders associated with PD.Overall,this work describes a new cellular-level localization and detection method and provides a tool for future studies of deep brain nuclei.展开更多
There are many documented sex differences in the clinical course,symptom expression profile,and treatment response of Parkinson’s disease,creating additional challenges for patient management.Although subthalamic nuc...There are many documented sex differences in the clinical course,symptom expression profile,and treatment response of Parkinson’s disease,creating additional challenges for patient management.Although subthalamic nucleus deep brain stimulation is an established therapy for Parkinson’s disease,the effects of sex on treatment outcome are still unclear.The aim of this retrospective observational study,was to examine sex differences in motor symptoms,nonmotor symptoms,and quality of life after subthalamic nucleus deep brain stimulation.Outcome measures were evaluated at 1 and 12 months post-operation in 90 patients with Parkinson’s disease undergoing subthalamic nucleus deep brain stimulation aged 63.00±8.01 years(55 men and 35 women).Outcomes of clinical evaluations were compared between sexes via a Student’s t-test and within sex via a paired-sample t-test,and generalized linear models were established to identify factors associated with treatment efficacy and intensity for each sex.We found that subthalamic nucleus deep brain stimulation could improve motor symptoms in men but not women in the on-medication condition at 1 and 12 months post-operation.Restless legs syndrome was alleviated to a greater extent in men than in women.Women demonstrated poorer quality of life at baseline and achieved less improvement of quality of life than men after subthalamic nucleus deep brain stimulation.Furthermore,Hoehn-Yahr stage was positively correlated with the treatment response in men,while levodopa equivalent dose at 12 months post-operation was negatively correlated with motor improvement in women.In conclusion,women received less benefit from subthalamic nucleus deep brain stimulation than men in terms of motor symptoms,non-motor symptoms,and quality of life.We found sex-specific factors,i.e.,Hoehn-Yahr stage and levodopa equivalent dose,that were related to motor improvements.These findings may help to guide subthalamic nucleus deep brain stimulation patient selection,prognosis,and stimulation programming for optimal therapeutic efficacy in Parkinson’s disease.展开更多
In this study, 23 asymmetrical Parkinson＇s disease patients were treated with unilateral deep brain stimulation of the subthalamic nucleus and followed up for 5 years. At 5 years after stimulation treatment, Unified ...In this study, 23 asymmetrical Parkinson＇s disease patients were treated with unilateral deep brain stimulation of the subthalamic nucleus and followed up for 5 years. At 5 years after stimulation treatment, Unified Parkinson＇s Disease Rating Scale II, III and axial symptom scores in the off-drug condition were significantly increased compared those at baseline. However, total Unified Parkinson＇s Disease Rating Scale II, III and axial symptom scores were significantly lower with stimulation-on compared with the synchronous stimulation-off state in off-drug condition, and the motor symptoms of contralateral side limbs were effectively controlled. Only low Hoehn-Yahr stage was correlated with good long-term postoperative improvement in motor symptoms. The mean levodopa-equivalent daily dose after stimulation treatment was significantly lower than that before treatment, but dyskinesias became worse. Our experimental findings indicate that unilateral deep brain stimulation of the subthalamic nucleus is an effective treatment for improving motor symptoms in well selected asymmetrical Parkinson＇s disease patients presenting no severe axial symptoms and dyskinesias.展开更多
BACKGROUND： Although experimental studies have utilized high-frequency stimulation in animal models, few reports have focused on long-term subthalamic nucleus deep brain stimulation （STN DBS） in Parkinson＇s disea...BACKGROUND： Although experimental studies have utilized high-frequency stimulation in animal models, few reports have focused on long-term subthalamic nucleus deep brain stimulation （STN DBS） in Parkinson＇s disease （PD） animal models. OBJECTIVE： The present study simulated long-term DBS system and utilized microdialysis technology to study the influence of STN DBS on levels of extracellular dopamine （DA） and its metabolites, homovanillic acid （HVA） and dihydroxy phenyl acetic acid, in the corpus striatum of a hemiparkinsonian monkey model. DESIGN, TIME AND SETTING： A controlled animal study was performed at the Neurosurgery Laboratory, Changhai Hospital of the Second Military Medical University of Chinese PLA between January 2004 and December 2007. MATERIALS： 1-methy-4-phenyl-1, 2, 3, 6-tetrahydropyrindinewas （MPTP） purchased from Sigma, USA. Type-3389 DBS electrode and type-7246 pulse generator were provided by Medtronic, USA. METHODS： Hemiparkinsonism was induced in 2 male, adult Rhesus Macaque monkeys through unilateral internal carotid artery infusion of MPTP. Following model establishment, stimulation electrodes were implanted in the right STN, and chronic high-frequency stimulation （60 μs pulse width, 130 Hz frequency, and 1.5 2.0 V pressure） was performed. MAIN OUTCOME MEASURES： Prior to, and 2 hours, 8 hours, 1 week, 1 month, and 2 months after DBS, samples were collected from the caudate nucleus and putamen using microdialysis technology Extracellular levels of DA and its metabolites were measured using high-performance liquid chromatography and electrochemical detection （HPLC-ECD） methods. RESULTS： At 8 hours, 1 week, 1 month, and 2 months after DBS, DA levels in the putamen and caudate nucleus were increased on the electrode-implanted side by 39%, 91%, 111%, and 114% and 31%, 91%, 106%, and 102%, respectively. The DA turnover rate （HVA/DA） was increased in the putamen and caudate nucleus by 186% and 91%, respectively, at 8 hours after DBS, while there was no significant difference at 1 week, 1 month, and 2 months after DBS. CONCLUSION： Effective, chronic, high frequency DBS increased extracellular DA levels in the corpus striatum, which could be one of mechanisms involved in the effects of STN DBS.展开更多
Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is widely performed for medically refractory Parkinson’s disease (PD). Several western studies have examined the long-term outcomes of STN DBS...Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is widely performed for medically refractory Parkinson’s disease (PD). Several western studies have examined the long-term outcomes of STN DBS. However, the long-term outcomes in Japanese patients have not been reported. Methods: We studied the long-term outcomes of STN DBS in Japanese patients with PD. Fifty-five consecutive patients treated with bilateral STN DBS were followed for 5 years after surgery. Each patient underwent Unified Parkinson’s Disease Rating Scale assessments preoperatively and 1 and 5 years after surgery. Results: Twelve patients (22%) were lost to follow up within 5 years. Among them, 7 died and 5 became bed ridden because of PD deterioration. In the 43 patients followed for 5 years, STN DBS significantly improved motor function. The cardinal motor symptoms of tremor, rigidity, and bradykinesia in medication-on periods were significantly better than baseline 5 years after DBS. However, axial motor symptoms of speech, gait and postural stability gradually deteriorated and significantly worsened 5 years after DBS. Motor complications, including dyskinesia and motor fluctuations, significantly improved after DBS with a marked reduction in dopaminergic medication. These effects were maintained 5 years after DBS. Frequently, persisting adverse effects included apraxia of eyelid opening and dysarthria. Conclusions: STN DBS significantly improved motor symptoms in patients with advanced PD. These effects were maintained over 5 years in most patients. However, some showed rapid PD progression even after STN DBS. Other treatments for the axial symptoms and disease progression are needed in long-term PD treatment.展开更多
BACKGROUND： Previous studies have demonstrated that appropriate interventions can alter brain electrical activity of epileptic patients prior to and during a seizure, leading to maintenance of a highly chaotic state,...BACKGROUND： Previous studies have demonstrated that appropriate interventions can alter brain electrical activity of epileptic patients prior to and during a seizure, leading to maintenance of a highly chaotic state, thereby inhibiting abnormal epileptic discharges, and eventually controlling epileptic seizure. OBJECTIVE： This study was designed to observe the effects of chaotic electrical stimulation to the subthalamic nucleus on mossy fiber sprouting, epileptic seizures, and electrical discharges, and to summarize the most suitable intervention. DESIGN, TIME AND SETTING： This randomized grouping, neuroelectrophysiological study was performed at the Laboratory of Neurology, Union Hospital Affiliated to Fujian Medical University in September 2007. MATERIALS： Fifty-five healthy, male, Sprague Dawley rats were subjected to an epileptic model by an intraperitoneal injection of pentylenetetrazol. The YC-2 programmed electrical stimulator was provided by Chengdu Instrument Factory, China; the video electroencephalographic system （KT-88-2400） and 24-hour active electroencephalographic system were products of Contec Medical System Co., Ltd., China; pentylenetetrazol was purchased from Sigma, USA. METHODS： The present interventional method consisted of electrical stimulation to the subthalamic nucleus with an intensity of 500 μA, pulse width 0.05 ms, frequency 30 Hz, and a duration of 20 minutes for 14 successive days. Fifty-five rats were divided into 6 groups： （1） pre-stimulation （n = 10）, pentylenetetrazol was administered and 30 minutes later, chaotic electrical stimulation was performed; （2） synchronous stimulation （n = 10）, rats received pentylenetetrazol and chaotic electrical stimulation concurrently; （3） post-administration stimulation （n = 10）, after pentylenetetrazol administration, chaotic electrical stimulation was performed immediately after cessation of a seizure; （4） sham-stimulation （n = 10）, following pentylenetetrazol administration, an electrode was connected to the stimulator, but electrical stimulation was not performed; （5） control （n = 10）, pentylenetetrazol administration, but no electrode was implanted; （6） blank control （n = 50）, administration of the same amount of physiological saline and chaotic electrical stimulation. MAIN OUTCOME MEASURES： Timm-stained granule change was scored. Simultaneously, electroencephalography was performed to acquire seizure counts and time course of epileptic discharge within 24 hours. RESULTS： Timm scores were lower in the electrically stimulated rats than in the non-stimulated rats （P 〈 0.01）. Timm scores were lowest in the synchronous stimulation group. When the rats suffered from tonic clonic seizure, the electroencephalogram primarily showed a persistent spike-slow wave and sharp wave. For the electrically stimulated rats, the mean values of seizure counts and time course of epileptic discharge during each hour were noticeably decreased compared with the non-stimulated rats. The synchronous stimulation group, however, had the lowest seizure counts and the shortest time course, followed by the pre-stimulation group, and lastly the post-administration stimulation group. Significant differences existed among the groups （P 〈 0.01）. Compared with the pre-stimulation group and the post-administration stimulation group, the latent period of grades Ⅰ and Ⅳ epileptic seizures was significantly prolonged, and the time course of tonic clonic seizure, as well as total time course, were significantly shortened in the synchronous stimulation group （P 〈 0.01）. CONCLUSION： Simultaneous administration of pentylenetetrazol together with chaotic electrical stimulation produced the greatest inhibitory effects on epileptic seizures. This is possibly related to inhibition of abnormal mossy fiber spouting in the hippocampus.展开更多
BACKGROUND： Some investigations have demonstrated that exogenous 5-hydroxytryptamine increases the spontaneous firing rate of subthalamic nucleus （STN） neurons in the rat brain. OBJECTIVE： To validate the effect o...BACKGROUND： Some investigations have demonstrated that exogenous 5-hydroxytryptamine increases the spontaneous firing rate of subthalamic nucleus （STN） neurons in the rat brain. OBJECTIVE： To validate the effect of electrical stimulation to the dorsal raphe nucleus （DRN） on the neuronal activities of the STN in rats, as well as analyze the differences in the effects of electrical stimulation at various frequencies. DESIGN, TIME AND SETTING： Experiments were performed from March 2007 to June 2007 in the Electrophysiology Laboratory of Liaoning Medical University with a randomized controlled animal study design. MATERIALS： Twenty-four healthy male Sprague-Dawley （SD） rats, weighing 250-350 g, were selected for this study. An A320R constant electrical stimulator was purchased from World Precision Instruments Company （USA）; a Spike 2 biological signal acquisition system was purchased from British CED Company. METHODS： Twenty-four SD rats were randomly assigned into a model group and a normal group, with 12 rats in each group. To mimic Parkinson＇s disease, rats in the model group were injected with 4μL of 6-hydroxydopamine into the right striatum, then received deep brain stimulation. Rats in the normal group received deep brain stimulation in same brain region without modeling. Electrical stimulation （width, 0.06 ms; intensity, 0.2-0.6 mA; frequency, 20-130 Hz; train duration, 5 seconds） was delivered to the DRN. MAIN OUTCOME MEASURES： The firing rates of STN neurons were observed by extracellular recording using a biological signal acquisition system. RESULTS： DRN-high-frequency stimulation （DRN-HFS） induced excitation in 59% of the STN neurons in the normal group and 50% of the STN neurons in the model group; mean firing rates increased significantly from （7.14±0.75） and （7.94 ± 0.61） Hz to （11.17 ±1.49） and （12.11 ± 1.05） Hz, respectively （P 〈 0.01）. Spontaneous firing rate increased significantly in 53% of neurons in normal rats in a frequency-dependent manner when stimulation frequency was in the range 80-130 Hz. CONCLUSION： DRN-HFS induced an excitatory effect on the spontaneous activity of STN neurons in both normal and PD rats. There was a frequency-dependent effect of electrical stimulation of the DRN on spontaneous firing activities in STN neurons.展开更多
BACKGROUND： Subthalamic nucleus-high frequency stimulation （STN-HFS） plays an important role in the treatment of Parkinson＇s disease, but the mechanisms underlying STN-HFS remain unclear. Some studies have demonst...BACKGROUND： Subthalamic nucleus-high frequency stimulation （STN-HFS） plays an important role in the treatment of Parkinson＇s disease, but the mechanisms underlying STN-HFS remain unclear. Some studies have demonstrated that STN stimulation inhibits the firing activity of substantia nigra pars reticulata neurons. OBJECTIVE： To investigate the effects of different-frequency STN stimulation and microiontophoresis of gamma-aminobutyric acid （GABA） and its antagonist, bicuculline, on spontaneous firing activity in a rat model of Parkinson＇s disease, and to analyze the action pathway of high frequency stimulation in firing activity inhibition of substantia nigra pars reticulata neurons. DESIGN, TIME AND SETTING： This neuroelectrophysiological, animal experiment was performed at the Electrophysiology Laboratory of Liaoning Medical University, China from March to August 2008. MATERIALS： 6-hydroxydopamine （6-OHDA） （Sigma, USA）, A320R isolated stimulus and DAM80 preamplifier （World Precision Instruments, USA）, 6400A microiontophoresis apparatus （Dagan, USA）, and Spike 2 biological signal acquisition system （CED, UK） were used in this study. METHODS： A total of 20 Sprague Dawley rats were used to establish a Parkinson＇s disease model via injection of 6-OHDA into the right striatum. Electrical stimulation （0.06-ms width, 0.4-mA intensity 20-200-Hz frequency, 5-second train duration） was delivered to the subthalamic nucleus. Peripheral channels were separately filled with GABA （pH 3.5, 0.2 mol/L）, bicuculline （pH 4.0, 0.01 mol/L）, and NaCI （pH 7.0, 3 mol/L）. The electrode was positioned with a WK-2 microelectrode propulsion device, and was slowly inserted into the substantia nigra pars reticulata to record spontaneous firing activity of substantia nigra pars reticulata neurons. MAIN OUTCOME MEASURES： The number and firing rate of substantia nigra pars reticulata neurons which were either inhibited or excited were measured. RESULTS： Substantia nigra pars reticulata neurons were inhibited by STN stimulation. The proportion of inhibited substantia nigra pars reticulata neurons increased with increasing stimulation frequency. GABA had a tonic inhibitory effect on substantia nigra pars reticulata neurons. Microiontophoresis of bicuculline suppressed the inhibitory effect of STN-HFS on 67% （4/6） of substantia nigra pars reticulata neurons. CONCLUSION： STN-HFS ameliorated abnormal activity in substantia nigra pars reticulata neurons via the inhibitory effect of GABA treatment in a rat model of Parkinson＇s disease.展开更多
BACKGROUND： Subthalamic nucleus deep brain stimulation （STN DBS） for Parkinson＇s disease （PD） has achieved good effects, but to date the mechanism of STN DBS remains poorly understood STN DBS may increase dopami...BACKGROUND： Subthalamic nucleus deep brain stimulation （STN DBS） for Parkinson＇s disease （PD） has achieved good effects, but to date the mechanism of STN DBS remains poorly understood STN DBS may increase dopamine levels or metabolic activity of the corpus striatum. OBJECTIVE： To validate the effects of STN DBS on dopamine metabolism and glucose metabolism in the corpus striatum of hemiparkinsonian monkeys using single photon emission computed tomography （SPECT） and position emission tomography （PET）. DESIGN, TIME AND SET＇rING： A controlled animal study was performed at the Neurosurgery Laboratory, Changhai Hospital of the Second Military Medical University of Chinese PLA between January 2004 and December 2007. METHODS： Hemiparkinsonism was induced in adult Rhesus Macaque monkeys, which exhibit similar characteristics of PD in humans, through unilateral internal carotid artery infusion of 1-methy-4-phenyl-1, 2, 3, 6-tetrahydropyrindine. Following model establishment, stimulation electrodes were implanted in the right STN, and chronic high-frequency stimulation （60 μs pulse width, 130 Hz frequency, and 1.5-2.0 V pressure） was performed. MAIN OUTCOME MEASURES： The changes in dopamine transporter （DAT）, D2 receptor （D2R）, and glucose metabolism in the corpus striatum following STN DBS were observed using SPECT and PET. RESULTS： SPECT examination showed that DAT specific binding in the right corpus striatum was increased at 3 months after DBS compared with prior to stimulation, and D2R specific binding in the right corpus striatum gradually decreased near levels on the left （non-electrode-implanted） side within 3 months after DBS. PET examination showed that the glucose metabolism in the right corpus striatum was markedly increased at 3 months after effective DBS. Hemiparkinsonism monkeys showed improved left limb rigidity, increased activities, and stable gait under chronic high-frequency stimulation. CONCLUSION： STN DBS increased striatal DAT, decreased D2R, and enhanced glucose metabolism, suggesting that chronic, high-frequency STN stimulation enhanced the metabolic activity of the corpus striatum, a mechanism for improving the PD symptoms of hemiparkinsonian monkeys.展开更多
Subthalamic nucleus deep brain stimulation (STN DBS) is an effective treatment for medically refractory Parkinson’s disease (PD). However, a minority of patients develop cognitive problems, particularly a decline of ...Subthalamic nucleus deep brain stimulation (STN DBS) is an effective treatment for medically refractory Parkinson’s disease (PD). However, a minority of patients develop cognitive problems, particularly a decline of executive function in the early period after STN DBS. Although this problem is usually transient, it may cause social maladjustment. We investigated factors affecting early decline of executive function after STN-DBS. Fifty-seven patients whose preoperative global cognitive screening was normal (MMSE score;28 or more) were enrolled in this study. Executive function was evaluated with the Trail-Making Test (TMT) preoperatively and 1-month after surgery. We considered a patient to have decline in executive function if the TMT (B-A) was prolonged more than 30 seconds after STN DBS. Among 57 patients, 25 patients were categorized as having decline of executive function. Univariate analysis revealed that high preoperative UPDRS III motor score in the medication-off period and a depressive state evaluated with BDI-II correlated significantly with decline in executive function. Multiple logistic regression analysis revealed that the only significant independent variable related to early decline of executive function was the preoperative BDI-II score. Postoperative factors such as active contact location or dopaminergic medication reduction had no relation with the decline of executive function. Even in cognitively well-selected patients, STN DBS causes early decline in executive function in a significant number of patients. Preoperative simple cognitive screening alone could not predict early decline in executive function. More detailed neuropsychological evaluation, including mood status, should be undertaken before surgery.展开更多
Deep brain stimulation (DBS) has become an effective therapeutic option for neurological and psychiatric disorders such as Parkinson’s disease (PD), dystonia, and obsessive-compulsive disorder. The subthalamic nucleu...Deep brain stimulation (DBS) has become an effective therapeutic option for neurological and psychiatric disorders such as Parkinson’s disease (PD), dystonia, and obsessive-compulsive disorder. The subthalamic nucleus (STN) and internal globus pallidus (GPi) are by far the most commonly used targets for DBS in the treatment of PD. However, STN/GPi stimulation sometimes causes side effects, including motor fluctuations, cognitive declines, and worse emotional experience, which affect patients’ postoperative quality of life. Recent invasive electrophysiological studies are driven by the desire to better understand the mechanisms of therapeutic actions and side effects of STN/GPi stimulation. These studies investigated the function of the STN and GPi in motor, cognitive and affective processes by recording single- neuron firing patterns during the surgery or local field potentials after the surgery. Here we review the relevant studies to provide an integrative picture of the functional roles of the STN and GPi within the basal ganglia loops for motor, cognition, and emotion. Previous studies suggested that STN and GPi gamma oscillations encode the strength and speed of voluntary movements (execution), whereas beta oscillations reflect the effort and demand of potential movements (preparation). In the cognitive domain, oscillatory beta activity in the STN is involved when people have to stop an inappropriate action or to suppress salient but task-irrelevant information, whereas theta/delta activity is associated with the adjustment of decision thresholds and cost-benefit trade-off. In the affective domain, STN activity in the alpha band may represent the valence and arousal of emotional information.展开更多
Degeneration and death of the neurons of the substantia nigra can cause a deficit in brain dopamine, leading to loss of movement control The subthalamic nucleus is a junction of basal ganglia neural circuit and can re...Degeneration and death of the neurons of the substantia nigra can cause a deficit in brain dopamine, leading to loss of movement control The subthalamic nucleus is a junction of basal ganglia neural circuit and can regulate the efferent information of basal ganglia and control motor activity. High-frequency stimulation of the subthalamic nucleus can alter dopamine levels as well as related factor expression in the corpus striatum and thereby improve the symptoms of Parkinson＇s disease.展开更多
Parkinson's disease(PD)is a chronic progressive neurodegenerative disease.Deep brain stimulation(DBS)is an effective treatment for patients with advanced PD.There are many DBS targets for PD,including subthalamic ...Parkinson's disease(PD)is a chronic progressive neurodegenerative disease.Deep brain stimulation(DBS)is an effective treatment for patients with advanced PD.There are many DBS targets for PD,including subthalamic nucleus(STN),globus pallidus(GPi),meso-ventral thalamic nucleus(VIM),pontine peduncle nucleus(PPN),posterior subthalamic region(PSA)and zonation of undetermined zone(ZI).This paper summarizes the efficacy of each target in the treatment of PD with DBS,not only makes a systematic analysis and comparison of motor symptoms,but also makes a detailed description of the efficacy of non-motor symptoms,so as to provide a personalized treatment basis for PD patients to select appropriate target targets in DBS.展开更多
基金funded by the National Natural Science Foundation of China(Nos.L2224042,T2293731,62121003,61960206012,61973292,62171434,61975206,and 61971400)the Frontier Interdisciplinary Project of the Chinese Academy of Sciences(No.XK2022XXC003)+2 种基金the National Key Research and Development Program of China(Nos.2022YFC2402501 and 2022YFB3205602)the Major Program of Scientific and Technical Innovation 2030(No.2021ZD02016030)the Scientific Instrument Developing Project of he Chinese Academy of Sciences(No.GJJSTD20210004).
文摘The subthalamic nucleus(STN)is considered the best target for deep brain stimulation treatments of Parkinson’s disease(PD).It is difficult to localize the STN due to its small size and deep location.Multichannel microelectrode arrays(MEAs)can rapidly and precisely locate the STN,which is important for precise stimulation.In this paper,16-channel MEAs modified with multiwalled carbon nanotube/poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate)(MWCNT/PEDOT:PSS)nanocomposites were designed and fabricated,and the accurate and rapid identification of the STN in PD rats was performed using detection sites distributed at different brain depths.These results showed that nuclei in 6-hydroxydopamine hydrobromide(6-OHDA)-lesioned brains discharged more intensely than those in unlesioned brains.In addition,the MEA simultaneously acquired neural signals from both the STN and the upper or lower boundary nuclei of the STN.Moreover,higher values of spike firing rate,spike amplitude,local field potential(LFP)power,and beta oscillations were detected in the STN of the 6-OHDA-lesioned brain,and may therefore be biomarkers of STN localization.Compared with the STNs of unlesioned brains,the power spectral density of spikes and LFPs synchronously decreased in the delta band and increased in the beta band of 6-OHDA-lesioned brains.This may be a cause of sleep and motor disorders associated with PD.Overall,this work describes a new cellular-level localization and detection method and provides a tool for future studies of deep brain nuclei.
基金support by the National Nature Science Foundation of China,Nos.81830033,61761166004(both to JGZ)。
文摘There are many documented sex differences in the clinical course,symptom expression profile,and treatment response of Parkinson’s disease,creating additional challenges for patient management.Although subthalamic nucleus deep brain stimulation is an established therapy for Parkinson’s disease,the effects of sex on treatment outcome are still unclear.The aim of this retrospective observational study,was to examine sex differences in motor symptoms,nonmotor symptoms,and quality of life after subthalamic nucleus deep brain stimulation.Outcome measures were evaluated at 1 and 12 months post-operation in 90 patients with Parkinson’s disease undergoing subthalamic nucleus deep brain stimulation aged 63.00±8.01 years(55 men and 35 women).Outcomes of clinical evaluations were compared between sexes via a Student’s t-test and within sex via a paired-sample t-test,and generalized linear models were established to identify factors associated with treatment efficacy and intensity for each sex.We found that subthalamic nucleus deep brain stimulation could improve motor symptoms in men but not women in the on-medication condition at 1 and 12 months post-operation.Restless legs syndrome was alleviated to a greater extent in men than in women.Women demonstrated poorer quality of life at baseline and achieved less improvement of quality of life than men after subthalamic nucleus deep brain stimulation.Furthermore,Hoehn-Yahr stage was positively correlated with the treatment response in men,while levodopa equivalent dose at 12 months post-operation was negatively correlated with motor improvement in women.In conclusion,women received less benefit from subthalamic nucleus deep brain stimulation than men in terms of motor symptoms,non-motor symptoms,and quality of life.We found sex-specific factors,i.e.,Hoehn-Yahr stage and levodopa equivalent dose,that were related to motor improvements.These findings may help to guide subthalamic nucleus deep brain stimulation patient selection,prognosis,and stimulation programming for optimal therapeutic efficacy in Parkinson’s disease.
基金supported by the foundation of Science and Technology Commission of Shanghai Municipality,No.101195400
文摘In this study, 23 asymmetrical Parkinson＇s disease patients were treated with unilateral deep brain stimulation of the subthalamic nucleus and followed up for 5 years. At 5 years after stimulation treatment, Unified Parkinson＇s Disease Rating Scale II, III and axial symptom scores in the off-drug condition were significantly increased compared those at baseline. However, total Unified Parkinson＇s Disease Rating Scale II, III and axial symptom scores were significantly lower with stimulation-on compared with the synchronous stimulation-off state in off-drug condition, and the motor symptoms of contralateral side limbs were effectively controlled. Only low Hoehn-Yahr stage was correlated with good long-term postoperative improvement in motor symptoms. The mean levodopa-equivalent daily dose after stimulation treatment was significantly lower than that before treatment, but dyskinesias became worse. Our experimental findings indicate that unilateral deep brain stimulation of the subthalamic nucleus is an effective treatment for improving motor symptoms in well selected asymmetrical Parkinson＇s disease patients presenting no severe axial symptoms and dyskinesias.
基金Supported by: the National Natural Science Foundation of China, No, 30471776
文摘BACKGROUND： Although experimental studies have utilized high-frequency stimulation in animal models, few reports have focused on long-term subthalamic nucleus deep brain stimulation （STN DBS） in Parkinson＇s disease （PD） animal models. OBJECTIVE： The present study simulated long-term DBS system and utilized microdialysis technology to study the influence of STN DBS on levels of extracellular dopamine （DA） and its metabolites, homovanillic acid （HVA） and dihydroxy phenyl acetic acid, in the corpus striatum of a hemiparkinsonian monkey model. DESIGN, TIME AND SETTING： A controlled animal study was performed at the Neurosurgery Laboratory, Changhai Hospital of the Second Military Medical University of Chinese PLA between January 2004 and December 2007. MATERIALS： 1-methy-4-phenyl-1, 2, 3, 6-tetrahydropyrindinewas （MPTP） purchased from Sigma, USA. Type-3389 DBS electrode and type-7246 pulse generator were provided by Medtronic, USA. METHODS： Hemiparkinsonism was induced in 2 male, adult Rhesus Macaque monkeys through unilateral internal carotid artery infusion of MPTP. Following model establishment, stimulation electrodes were implanted in the right STN, and chronic high-frequency stimulation （60 μs pulse width, 130 Hz frequency, and 1.5 2.0 V pressure） was performed. MAIN OUTCOME MEASURES： Prior to, and 2 hours, 8 hours, 1 week, 1 month, and 2 months after DBS, samples were collected from the caudate nucleus and putamen using microdialysis technology Extracellular levels of DA and its metabolites were measured using high-performance liquid chromatography and electrochemical detection （HPLC-ECD） methods. RESULTS： At 8 hours, 1 week, 1 month, and 2 months after DBS, DA levels in the putamen and caudate nucleus were increased on the electrode-implanted side by 39%, 91%, 111%, and 114% and 31%, 91%, 106%, and 102%, respectively. The DA turnover rate （HVA/DA） was increased in the putamen and caudate nucleus by 186% and 91%, respectively, at 8 hours after DBS, while there was no significant difference at 1 week, 1 month, and 2 months after DBS. CONCLUSION： Effective, chronic, high frequency DBS increased extracellular DA levels in the corpus striatum, which could be one of mechanisms involved in the effects of STN DBS.
文摘Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is widely performed for medically refractory Parkinson’s disease (PD). Several western studies have examined the long-term outcomes of STN DBS. However, the long-term outcomes in Japanese patients have not been reported. Methods: We studied the long-term outcomes of STN DBS in Japanese patients with PD. Fifty-five consecutive patients treated with bilateral STN DBS were followed for 5 years after surgery. Each patient underwent Unified Parkinson’s Disease Rating Scale assessments preoperatively and 1 and 5 years after surgery. Results: Twelve patients (22%) were lost to follow up within 5 years. Among them, 7 died and 5 became bed ridden because of PD deterioration. In the 43 patients followed for 5 years, STN DBS significantly improved motor function. The cardinal motor symptoms of tremor, rigidity, and bradykinesia in medication-on periods were significantly better than baseline 5 years after DBS. However, axial motor symptoms of speech, gait and postural stability gradually deteriorated and significantly worsened 5 years after DBS. Motor complications, including dyskinesia and motor fluctuations, significantly improved after DBS with a marked reduction in dopaminergic medication. These effects were maintained 5 years after DBS. Frequently, persisting adverse effects included apraxia of eyelid opening and dysarthria. Conclusions: STN DBS significantly improved motor symptoms in patients with advanced PD. These effects were maintained over 5 years in most patients. However, some showed rapid PD progression even after STN DBS. Other treatments for the axial symptoms and disease progression are needed in long-term PD treatment.
基金Research and Development Foundation of Fujian Medical University, No. FJGXY04041
文摘BACKGROUND： Previous studies have demonstrated that appropriate interventions can alter brain electrical activity of epileptic patients prior to and during a seizure, leading to maintenance of a highly chaotic state, thereby inhibiting abnormal epileptic discharges, and eventually controlling epileptic seizure. OBJECTIVE： This study was designed to observe the effects of chaotic electrical stimulation to the subthalamic nucleus on mossy fiber sprouting, epileptic seizures, and electrical discharges, and to summarize the most suitable intervention. DESIGN, TIME AND SETTING： This randomized grouping, neuroelectrophysiological study was performed at the Laboratory of Neurology, Union Hospital Affiliated to Fujian Medical University in September 2007. MATERIALS： Fifty-five healthy, male, Sprague Dawley rats were subjected to an epileptic model by an intraperitoneal injection of pentylenetetrazol. The YC-2 programmed electrical stimulator was provided by Chengdu Instrument Factory, China; the video electroencephalographic system （KT-88-2400） and 24-hour active electroencephalographic system were products of Contec Medical System Co., Ltd., China; pentylenetetrazol was purchased from Sigma, USA. METHODS： The present interventional method consisted of electrical stimulation to the subthalamic nucleus with an intensity of 500 μA, pulse width 0.05 ms, frequency 30 Hz, and a duration of 20 minutes for 14 successive days. Fifty-five rats were divided into 6 groups： （1） pre-stimulation （n = 10）, pentylenetetrazol was administered and 30 minutes later, chaotic electrical stimulation was performed; （2） synchronous stimulation （n = 10）, rats received pentylenetetrazol and chaotic electrical stimulation concurrently; （3） post-administration stimulation （n = 10）, after pentylenetetrazol administration, chaotic electrical stimulation was performed immediately after cessation of a seizure; （4） sham-stimulation （n = 10）, following pentylenetetrazol administration, an electrode was connected to the stimulator, but electrical stimulation was not performed; （5） control （n = 10）, pentylenetetrazol administration, but no electrode was implanted; （6） blank control （n = 50）, administration of the same amount of physiological saline and chaotic electrical stimulation. MAIN OUTCOME MEASURES： Timm-stained granule change was scored. Simultaneously, electroencephalography was performed to acquire seizure counts and time course of epileptic discharge within 24 hours. RESULTS： Timm scores were lower in the electrically stimulated rats than in the non-stimulated rats （P 〈 0.01）. Timm scores were lowest in the synchronous stimulation group. When the rats suffered from tonic clonic seizure, the electroencephalogram primarily showed a persistent spike-slow wave and sharp wave. For the electrically stimulated rats, the mean values of seizure counts and time course of epileptic discharge during each hour were noticeably decreased compared with the non-stimulated rats. The synchronous stimulation group, however, had the lowest seizure counts and the shortest time course, followed by the pre-stimulation group, and lastly the post-administration stimulation group. Significant differences existed among the groups （P 〈 0.01）. Compared with the pre-stimulation group and the post-administration stimulation group, the latent period of grades Ⅰ and Ⅳ epileptic seizures was significantly prolonged, and the time course of tonic clonic seizure, as well as total time course, were significantly shortened in the synchronous stimulation group （P 〈 0.01）. CONCLUSION： Simultaneous administration of pentylenetetrazol together with chaotic electrical stimulation produced the greatest inhibitory effects on epileptic seizures. This is possibly related to inhibition of abnormal mossy fiber spouting in the hippocampus.
文摘BACKGROUND： Some investigations have demonstrated that exogenous 5-hydroxytryptamine increases the spontaneous firing rate of subthalamic nucleus （STN） neurons in the rat brain. OBJECTIVE： To validate the effect of electrical stimulation to the dorsal raphe nucleus （DRN） on the neuronal activities of the STN in rats, as well as analyze the differences in the effects of electrical stimulation at various frequencies. DESIGN, TIME AND SETTING： Experiments were performed from March 2007 to June 2007 in the Electrophysiology Laboratory of Liaoning Medical University with a randomized controlled animal study design. MATERIALS： Twenty-four healthy male Sprague-Dawley （SD） rats, weighing 250-350 g, were selected for this study. An A320R constant electrical stimulator was purchased from World Precision Instruments Company （USA）; a Spike 2 biological signal acquisition system was purchased from British CED Company. METHODS： Twenty-four SD rats were randomly assigned into a model group and a normal group, with 12 rats in each group. To mimic Parkinson＇s disease, rats in the model group were injected with 4μL of 6-hydroxydopamine into the right striatum, then received deep brain stimulation. Rats in the normal group received deep brain stimulation in same brain region without modeling. Electrical stimulation （width, 0.06 ms; intensity, 0.2-0.6 mA; frequency, 20-130 Hz; train duration, 5 seconds） was delivered to the DRN. MAIN OUTCOME MEASURES： The firing rates of STN neurons were observed by extracellular recording using a biological signal acquisition system. RESULTS： DRN-high-frequency stimulation （DRN-HFS） induced excitation in 59% of the STN neurons in the normal group and 50% of the STN neurons in the model group; mean firing rates increased significantly from （7.14±0.75） and （7.94 ± 0.61） Hz to （11.17 ±1.49） and （12.11 ± 1.05） Hz, respectively （P 〈 0.01）. Spontaneous firing rate increased significantly in 53% of neurons in normal rats in a frequency-dependent manner when stimulation frequency was in the range 80-130 Hz. CONCLUSION： DRN-HFS induced an excitatory effect on the spontaneous activity of STN neurons in both normal and PD rats. There was a frequency-dependent effect of electrical stimulation of the DRN on spontaneous firing activities in STN neurons.
文摘BACKGROUND： Subthalamic nucleus-high frequency stimulation （STN-HFS） plays an important role in the treatment of Parkinson＇s disease, but the mechanisms underlying STN-HFS remain unclear. Some studies have demonstrated that STN stimulation inhibits the firing activity of substantia nigra pars reticulata neurons. OBJECTIVE： To investigate the effects of different-frequency STN stimulation and microiontophoresis of gamma-aminobutyric acid （GABA） and its antagonist, bicuculline, on spontaneous firing activity in a rat model of Parkinson＇s disease, and to analyze the action pathway of high frequency stimulation in firing activity inhibition of substantia nigra pars reticulata neurons. DESIGN, TIME AND SETTING： This neuroelectrophysiological, animal experiment was performed at the Electrophysiology Laboratory of Liaoning Medical University, China from March to August 2008. MATERIALS： 6-hydroxydopamine （6-OHDA） （Sigma, USA）, A320R isolated stimulus and DAM80 preamplifier （World Precision Instruments, USA）, 6400A microiontophoresis apparatus （Dagan, USA）, and Spike 2 biological signal acquisition system （CED, UK） were used in this study. METHODS： A total of 20 Sprague Dawley rats were used to establish a Parkinson＇s disease model via injection of 6-OHDA into the right striatum. Electrical stimulation （0.06-ms width, 0.4-mA intensity 20-200-Hz frequency, 5-second train duration） was delivered to the subthalamic nucleus. Peripheral channels were separately filled with GABA （pH 3.5, 0.2 mol/L）, bicuculline （pH 4.0, 0.01 mol/L）, and NaCI （pH 7.0, 3 mol/L）. The electrode was positioned with a WK-2 microelectrode propulsion device, and was slowly inserted into the substantia nigra pars reticulata to record spontaneous firing activity of substantia nigra pars reticulata neurons. MAIN OUTCOME MEASURES： The number and firing rate of substantia nigra pars reticulata neurons which were either inhibited or excited were measured. RESULTS： Substantia nigra pars reticulata neurons were inhibited by STN stimulation. The proportion of inhibited substantia nigra pars reticulata neurons increased with increasing stimulation frequency. GABA had a tonic inhibitory effect on substantia nigra pars reticulata neurons. Microiontophoresis of bicuculline suppressed the inhibitory effect of STN-HFS on 67% （4/6） of substantia nigra pars reticulata neurons. CONCLUSION： STN-HFS ameliorated abnormal activity in substantia nigra pars reticulata neurons via the inhibitory effect of GABA treatment in a rat model of Parkinson＇s disease.
基金the National Natural Science Foundation of China,No.30471776
文摘BACKGROUND： Subthalamic nucleus deep brain stimulation （STN DBS） for Parkinson＇s disease （PD） has achieved good effects, but to date the mechanism of STN DBS remains poorly understood STN DBS may increase dopamine levels or metabolic activity of the corpus striatum. OBJECTIVE： To validate the effects of STN DBS on dopamine metabolism and glucose metabolism in the corpus striatum of hemiparkinsonian monkeys using single photon emission computed tomography （SPECT） and position emission tomography （PET）. DESIGN, TIME AND SET＇rING： A controlled animal study was performed at the Neurosurgery Laboratory, Changhai Hospital of the Second Military Medical University of Chinese PLA between January 2004 and December 2007. METHODS： Hemiparkinsonism was induced in adult Rhesus Macaque monkeys, which exhibit similar characteristics of PD in humans, through unilateral internal carotid artery infusion of 1-methy-4-phenyl-1, 2, 3, 6-tetrahydropyrindine. Following model establishment, stimulation electrodes were implanted in the right STN, and chronic high-frequency stimulation （60 μs pulse width, 130 Hz frequency, and 1.5-2.0 V pressure） was performed. MAIN OUTCOME MEASURES： The changes in dopamine transporter （DAT）, D2 receptor （D2R）, and glucose metabolism in the corpus striatum following STN DBS were observed using SPECT and PET. RESULTS： SPECT examination showed that DAT specific binding in the right corpus striatum was increased at 3 months after DBS compared with prior to stimulation, and D2R specific binding in the right corpus striatum gradually decreased near levels on the left （non-electrode-implanted） side within 3 months after DBS. PET examination showed that the glucose metabolism in the right corpus striatum was markedly increased at 3 months after effective DBS. Hemiparkinsonism monkeys showed improved left limb rigidity, increased activities, and stable gait under chronic high-frequency stimulation. CONCLUSION： STN DBS increased striatal DAT, decreased D2R, and enhanced glucose metabolism, suggesting that chronic, high-frequency STN stimulation enhanced the metabolic activity of the corpus striatum, a mechanism for improving the PD symptoms of hemiparkinsonian monkeys.
文摘Subthalamic nucleus deep brain stimulation (STN DBS) is an effective treatment for medically refractory Parkinson’s disease (PD). However, a minority of patients develop cognitive problems, particularly a decline of executive function in the early period after STN DBS. Although this problem is usually transient, it may cause social maladjustment. We investigated factors affecting early decline of executive function after STN-DBS. Fifty-seven patients whose preoperative global cognitive screening was normal (MMSE score;28 or more) were enrolled in this study. Executive function was evaluated with the Trail-Making Test (TMT) preoperatively and 1-month after surgery. We considered a patient to have decline in executive function if the TMT (B-A) was prolonged more than 30 seconds after STN DBS. Among 57 patients, 25 patients were categorized as having decline of executive function. Univariate analysis revealed that high preoperative UPDRS III motor score in the medication-off period and a depressive state evaluated with BDI-II correlated significantly with decline in executive function. Multiple logistic regression analysis revealed that the only significant independent variable related to early decline of executive function was the preoperative BDI-II score. Postoperative factors such as active contact location or dopaminergic medication reduction had no relation with the decline of executive function. Even in cognitively well-selected patients, STN DBS causes early decline in executive function in a significant number of patients. Preoperative simple cognitive screening alone could not predict early decline in executive function. More detailed neuropsychological evaluation, including mood status, should be undertaken before surgery.
基金the Thousand Young Talents Program (to Z.Y.)National Natural Science Foundation of China (31771216, to Z.Y.).
文摘Deep brain stimulation (DBS) has become an effective therapeutic option for neurological and psychiatric disorders such as Parkinson’s disease (PD), dystonia, and obsessive-compulsive disorder. The subthalamic nucleus (STN) and internal globus pallidus (GPi) are by far the most commonly used targets for DBS in the treatment of PD. However, STN/GPi stimulation sometimes causes side effects, including motor fluctuations, cognitive declines, and worse emotional experience, which affect patients’ postoperative quality of life. Recent invasive electrophysiological studies are driven by the desire to better understand the mechanisms of therapeutic actions and side effects of STN/GPi stimulation. These studies investigated the function of the STN and GPi in motor, cognitive and affective processes by recording single- neuron firing patterns during the surgery or local field potentials after the surgery. Here we review the relevant studies to provide an integrative picture of the functional roles of the STN and GPi within the basal ganglia loops for motor, cognition, and emotion. Previous studies suggested that STN and GPi gamma oscillations encode the strength and speed of voluntary movements (execution), whereas beta oscillations reflect the effort and demand of potential movements (preparation). In the cognitive domain, oscillatory beta activity in the STN is involved when people have to stop an inappropriate action or to suppress salient but task-irrelevant information, whereas theta/delta activity is associated with the adjustment of decision thresholds and cost-benefit trade-off. In the affective domain, STN activity in the alpha band may represent the valence and arousal of emotional information.
文摘Degeneration and death of the neurons of the substantia nigra can cause a deficit in brain dopamine, leading to loss of movement control The subthalamic nucleus is a junction of basal ganglia neural circuit and can regulate the efferent information of basal ganglia and control motor activity. High-frequency stimulation of the subthalamic nucleus can alter dopamine levels as well as related factor expression in the corpus striatum and thereby improve the symptoms of Parkinson＇s disease.
基金Natural Science Foundation of Hainan Province (No.821RC682)。
文摘Parkinson's disease(PD)is a chronic progressive neurodegenerative disease.Deep brain stimulation(DBS)is an effective treatment for patients with advanced PD.There are many DBS targets for PD,including subthalamic nucleus(STN),globus pallidus(GPi),meso-ventral thalamic nucleus(VIM),pontine peduncle nucleus(PPN),posterior subthalamic region(PSA)and zonation of undetermined zone(ZI).This paper summarizes the efficacy of each target in the treatment of PD with DBS,not only makes a systematic analysis and comparison of motor symptoms,but also makes a detailed description of the efficacy of non-motor symptoms,so as to provide a personalized treatment basis for PD patients to select appropriate target targets in DBS.
