NMDA enhances a depolarization-activated inward current in subthalamic neurons

Previous studies have shown that N-methyl-D-aspartate (NMDA) receptor stimulation evokes Ca2+- and Na+-dependent burst firing in subthalamic nucleus (STN) neurons. Using whole-cell patch pipettes to record currents under voltage-clamp, we identified a time-dependent depolarization-activated inward current (DIC) that may underlie NMDA-induced burst firing in STN neurons in rat brain slices. Continuous superfusion with NMDA (20 microM) elicited a marked TTX-insensitive inward current when the membrane was depolarized to the level of -70 or -50 mV, from a holding potential of -100 mV. This current had a long duration, and its peak amplitude occurred at a test potential of -60 mV. DIC could not be evoked using the non-NMDA receptor agonist D,L-alpha-amino-3-hydroxy-5-methylisoxalone-4-propionic acid (AMPA). DIC was blocked by either intracellular BAPTA or by removal of extracellular Ca2+, but selective blockers of T-type (mibefradil), L-type (nifedipine) and N-type (omega-conotoxin GVIA) Ca2+ channels did not. Perfusing slices with a low extracellular concentration of sodium abolished the NMDA-induced DIC, implying that both Ca2+ and Na+ are necessary for the expression of DIC. Transient receptor potential (TRP) channel blockers flufenamic acid and SKF96365 severely reduced DIC amplitude, whereas NMDA-gated currents were either increased or were unchanged. These results suggest that the activation of NMDA receptors enhances a Ca2+-activated non-selective cation current that may be mediated by a member of the TRP channel family in STN neurons.     

High frequency stimulation of the subthalamic nucleus increases c-fos immunoreactivity in the dorsal raphe nucleus and afferent brain regions

High frequency stimulation (HFS) of the subthalamic nucleus (STN) is the neurosurgical therapy of choice for the management of motor deficits in patients with advanced Parkinson’s disease, but this treatment can elicit disabling mood changes. Our recent experiments show that in rats, HFS of the STN both inhibits the firing of 5-HT (5-hydroxytryptamine; serotonin) neurons in the dorsal raphe nucleus (DRN) and elicits 5-HT-dependent behavioral effects. The neural circuitry underpinning these effects is unknown. Here we investigated in the dopamine-denervated rat the effect of bilateral HFS of the STN on markers of neuronal activity in the DRN as well as DRN input regions. Controls were sham-stimulated rats. HFS of the STN elicited changes in two 5-HT-sensitive behavioral tests. Specifically, HFS increased immobility in the forced swim test and increased interaction in a social interaction task. HFS of the STN at the same stimulation parameters, increased c-fos immunoreactivity in the DRN, and decreased cytochrome C oxidase activity in this region. The increase in c-fos immunoreactivity occurred in DRN neurons immunopositive for the GABA marker parvalbumin. HFS of the STN also increased the number of c-fos immunoreactive cells in the lateral habenula nucleus, medial prefrontal cortex but not significantly in the substantia nigra. Collectively, these findings support a role for circuitry involving DRN GABA neurons, as well as DRN afferents from the lateral habenula nucleus and medial prefrontal cortex, in the mood effects of HFS of the STN.     

A novel approach to investigate neuronal network activity patterns affected by deep brain stimulation in rats

The establishment of new therapeutic indications for deep brain stimulation (DBS) is ambitiously promoted though the underlying mechanisms remain contested. Here, we report that PET-imaging and subsequent c-Fos-immunostaining in rats constitute a new translational approach to further understand DBS-mechanisms and -effectiveness.     

Subthalamic gamma activity in patients with Parkinson's disease

Depth recordings in patients with Parkinson's disease (PD) have demonstrated oscillatory activity in the gamma frequency (60-100 Hz) band in local field potentials (LFPs) recorded from the region of the subthalamic nucleus (STN). Although this activity has been hypothesised to contribute to movement preparation, it is unclear to what extent these LFP oscillations arise in the STN and are synchronous with local neuronal discharge. We therefore recorded LFPs and neuronal activity from microelectrodes inserted into the STN in PD patients during functional neurosurgery. Eight sides in seven patients out of 15 sides in 12 patients were identified that had peaks in the gamma band in spectra of LFPs. As microelectrodes descended towards STN, there was a pronounced increase in gamma frequency band LFP activity 1 mm above the line joining the anterior and posterior commissures and 2 mm above the microelectrode defined dorsal border of the STN. Gamma activity dropped again 3 mm below the microelectrode defined dorsal border of the STN. Spike-triggered averages of LFP activity suggested that the discharges of neurons in this region were locked to gamma oscillations in the LFP. Gamma band oscillations in the LFP are therefore likely to represent synchronous activity in populations of neurons in the upper STN and bordering zona incerta of patients with PD.     

Nonlinear analysis of discharge patterns in monkey basal ganglia

Spontaneous discharge of basal ganglia neurons is often analyzed with time- or frequency-domain methods. However, it has been shown that sequences of inter-spike interval series are not fully described by such linear procedures. We therefore carried out a characterization of the nonlinear features of spontaneous discharge of neurons in the primate basal ganglia. We studied the spontaneous activity of neurons in the subthalamic nucleus (22 cells), as well as neurons in the external and internal pallidal segments (53 and 39 cells, respectively), recorded with standard extracellular recording methods in two awake Rhesus monkeys. As a measure of the statistical irregularity of neuronal discharge, we compared the approximate entropy of inter-spike interval sequences with that of shuffled representations of the same data. In all three basal ganglia structures, approximately 95% of the original data showed lower approximate entropy values than the shuffled data, suggesting a temporal organization in the original sequence. Fano factor analysis confirmed the presence of a temporal organization of inter-spike interval sequences, and indicated the presence of self-similarity in the great majority of them. In addition, Hurst exponent analysis showed that the inter-spike interval series are persistent. Hurst exponents often differ between short and long scaling ranges. Subsequent principal component analyses allowed us to identify three distinct patterns of the temporal evolution of inter-spike interval sequences in the phase space. These types were found in varying distributions in all three nuclei. Our analyses demonstrate that the discharge of most neurons in the basal ganglia of awake monkeys has nonlinear features that may be important for information coding in the basal ganglia.     

双侧丘脑底核脑深部电刺激治疗中晚期帕金森病的疗效

目的 研究双侧丘脑底核(STN)脑深部电刺激(DBS)对中晚期帕金森病(PD)患者的疗效.方法 对2006年8月至2010年1月在中山大学附属第一医院接受双侧STN DBS治疗的中晚期PD患者于术前、术后分别应用统一帕金森病评分量表(UPDRS)、Hoehn&Yahr(H&Y)分级、帕金森病生活质量问卷(PDQ-39)、简易智能状态检查(MMSE)、帕金森病睡眠评估量表中文版(PDSS-CV)、匹兹堡睡眠质量指数(PSQI)及汉密尔顿焦虑量表(HAMA)、汉密尔顿抑郁量表(HAMD)等评价其临床情况;同时记录各时间点抗PD药物的剂量及DBS相关参数.结果 10例患者术后随访满1年,开机未服药及开机服药状态与术前未服药状态相比UPDRS-Ⅲ运动评分、震颤、强直、迟缓及中轴症状得分均显著降低,其中以震颤改善率最高(52.1%与77.7%),与术前服药状态相比差异无统计学意义.觉醒状态"关"期时间由术前6.3 h/d缩短至1.8 h/d(P=0.008),术后H&Y分级及PDQ-39降低,差异均有统计学意义.非运动症状评分无明显变化.术后1年抗PD药物较术前显著减少49.2%.结论 双侧STN DBS术对中晚期PD患者的运动症状疗效肯定,能有效减少抗帕金森病药物用量,提高患者生活质量.手术具有安全性高、并发症较少且可调控的优点.

Abstract：

Objective To study the effects of deep brain stimulation (DBS) of bilateral subthalamic nucleus (STN) on the motor and non-motor symptoms in moderate or advanced Parkinson's disease (PD) patients. Methods From August 2006 to January 2010, 21 consecutive PD patients with refractory motor fluctuations or dyskinesia underwent operations at our hospital. All patients were evaluated by unified Parkinson's disease rating scale (UPDRS), Hoehn & Yahr (H&Y) stage, Parkinson's disease questionnaire (PDQ-39), mini mental state examination (MMSE), Parkinson's disease sleep scale-Chinese vision( PDSS-CV), Pittsburgh sleep quality index ( PSQI), Hamilton depression rating scale (HAMD) and Hamilton anxiety rating scale (HAMA). And the daily dosage of dopaminergic agents was recorded at 1week pre-operation and 3, 6 and 12 months post-operation. Results Ten patients finished a 12-month follow-up. Their motor functions showed significant improvement. And the scores of UPDRS-motor, tremor,rigidity, bradykinesia and axial symptoms reduced significantly in the on-stimulation-off-medication condition and the on-stimulation-on-medication condition vs the on-medication condition pre-operation. And the improvement of tremor was the most pronounced ( 52. 1% and 77.7% respectively ) . The H&Y stage decreased significantly from 3.2 ± 0. 7 to 2. 5 ± 0. 4 post-operation. The activities of daily living improved while PDQ-39 declined significantly from 56 ±9 pre-operation to 32 ± 13 at 12 months follow-up. The score changes of MMSE, PDSS-CV, PSQI, HAMA and HAMD were statistically insignificant. The levo-dopa equivalent dose of 1-year post-operation decreased significantly by 49.2% versus that of pre-operation ( P ＜0.05). Conclusion Bilateral STN-DBS can significant ameliorate the motor symptoms of moderate or advanced PD patients, reduce the dosage of anti-PD medications and improve the quality of life. This procedure has the advantages of a greater safety, minor side effects and an easy controllability.     

Deep brain stimulation: Subthalamic nucleus electrophysiological activity in awake and anesthetized patients

Objective

The purpose of this study was to evaluate changes in subthalamic nucleus (STN) neuronal activity in Parkinson’s disease (PD) patients during deep brain stimulation (DBS) surgery under general anesthesia, and to compare these data with those recorded in the same subjects during previous surgery under local anesthesia.

Methods

Five patients with advanced PD, who had previously undergone bilateral STN-DBS under local anesthesia, underwent re-implantation under general anesthesia (with an anesthetic protocol based on the intravenous infusion of remifentanyl and ketamine) owing to surgical device complications. The microelectrode recording (MER) data obtained were analyzed by an off-line spike-sorting software. Neurophysiological data (number of spikes detected, mean firing rate, pause index and burst index) obtained under local and general anesthesia were then evaluated and compared by means of statistical analysis.

Results

We found no statistically significant difference between the first and second surgical procedures in any of the neurophysiological parameters analyzed.

Conclusions

Bilateral STN-DBS for advanced PD with MER guidance is possible and reliable under a ketamine-based anesthetic protocol.

Significance

General anesthesia can be proposed for those patients who do not accept an “awake surgery” for clinical reasons, such as excessive fear, poor cooperation or severe “off”-medication effects.     

Subthalamic nucleus involvement in children: A neuroimaging pattern-recognition approach

A neuroimaging-based pattern-recognition approach has been shown to be very helpful in the diagnosis of a wide range of pediatric central nervous system diseases. Few disorders may selectively affect the subthalamic nucleus in children including Leigh syndrome, succinic semialdehyde dehydrogenase deficiency, kernicterus, chronic end-stage liver failure and near total hypoxic-ischemic injury in the full-term neonates. The consideration of the constellation of clinical history and findings as well as additional neuroimaging findings should allow planning the appropriate diagnostic tests to make the correct diagnosis in children with involvement of the subthalamic nucleus.     

Neurophysiologisches Monitoring in der funktionellen Neurochirurgie bei Bewegungsstörungen: Intraoperative Mikroelektrodenableitungen

Intraoperative microelectrode recordings serve as an exploratory guide for many stereotactic neurosurgeons in order to objectively localize deep brain sites to be operated for the control of movement disorders. In this context, microelectrode recordings are used to (i) map structural boundaries, (ii) provide a physiologic delineation of the sensorimotor territory within the surgical target and (iii) to identify and localize neuronal activities related to pathologic brain function such as tremor or dystonia. This article provides an overview of discharge characteristics of single cell activity in the three most common targets for movement disorder surgery: subthalamic nucleus (STN), pars interna of the globus pallidus (GPi) and thalamic nucleus ventro-intermedius (Vim).