Subthalamic stimulation and levodopa modulate cortical reactivity in Parkinson's patients

BackgroundThe effects of deep brain stimulation of the subthalamic nucleus (DBS-STN) and L-dopa (LD) on cortical activity in Parkinson's disease (PD) are poorly understood.ObjectivesBy combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) we explored the effects of STN-DBS, either alone or in combination with L-Dopa (LD), on TMS-evoked cortical activity in a sample of implanted PD patients.MethodsPD patients were tested in three clinical conditions: i) LD therapy with STN-DBS turned on (ON/ON condition); ii) without LD therapy with STN-DBS turned on (OFF/ON condition); iii) without LD therapy with STN-DBS turned off (OFF/OFF condition). TMS pulses were delivered over left M1 while simultaneously acquiring EEG. Eight age-matched healthy volunteers (HC) were tested as a control group.ResultsSTN-DBS enhanced early global TMS-evoked activity (∼45–80ms) and high-alpha TMS-evoked oscillations (11–13 Hz) as compared to OFF/OFF condition, independently from concomitant LD therapy. LD intake (ON/ON condition) produced a further increase of late TMS-evoked activity (∼80–130ms) and beta TMS-evoked oscillations (13–30 Hz), as compared to OFF/OFF and OFF/ON conditions, that normalized reactivity as compared to HC range of values.ConclusionsOur data reveal that bilateral STN-DBS and LD therapy induce a modulation of specific cortical components and specific ranges of frequency. These findings demonstrate that STN-DBS and LD therapy may have synergistic effects on motor cortical activity.     

Subthalamic oscillatory activities at beta or higher frequency do not change after high-frequency DBS in Parkinson's disease

This study aimed to assess whether changes in the patterns of local field potential (LFP) oscillations of the subthalamic nucleus (STN) underlie to the clinical improvement within 60 s after turning off subthalamic DBS. We studied by spectral analysis the STN LFPs recorded in 13 nuclei from 7 patients with Parkinson's disease before and immediately after unilateral high-frequency (130 Hz) stimulation of the same nucleus, when the clinical benefit of DBS was unchanged. The results were compared with LFP data previously reported [A. Priori, G. Foffani, A. Pesenti, F. Tamma, A.M. Bianchi, M. Pellegrini et al., Rhythm-specific pharmacological modulation of subthalamic activity in Parkinson's disease. Exp. Neurol. 189 (2004) 369-379]--namely 13 STN from 9 parkinsonian patients recorded before and after levodopa administration--which were used as a control. Before DBS, in the 'off' clinical state after overnight withdrawal of dopaminergic therapy, the STN spectrum did not significantly differ from the control nuclei, showing prominent activity at beta frequencies (13-20 and 20-35 Hz). After DBS (10-15 min) of the STN, the recorded nuclei significantly differed from the control, failing to show significant changes either in the beta bands or at higher frequencies (60-90 and 250-350 Hz). The patterns of subthalamic LFP oscillations after DBS therefore differ from those after dopaminergic medication. These results suggest (1) that subthalamic LFP modulations are not the epiphenomenon of peripheral motor improvement and (2) that the transitory clinical efficacy maintained after discontinuation of subthalamic DBS is not associated with local modulation of LFP activity at beta or higher frequencies within the STN.     

重复经颅磁刺激治疗帕金森病2年随访

目的随访观察重复经颅磁刺激(r TMS)治疗帕金森病(PD)患者的疗效。方法应用统一PD评分量表第Ⅲ部分(UPDRSⅢ)、Hoehn-Yahr(H-Y)分级、PD非运动症状(NMS)筛查问卷(NMSQ)、PD睡眠量表(PDSS)、汉密尔顿抑郁量表(HAMD)、汉密尔顿焦虑量表(HAMA)和简易智能量表(MMSE)对37例应用药物和r TMS治疗的PD患者(r TMS+药物组)及45例单纯药物治疗的PD患者(药物组)在基线和2年随访末的运动症状(MS)和非运动症状(NMS)进行评估,对比分析两组患者病情进展。结果 r TMS+药物组2年随访末H-Y分级较基线显著升高(P 0.05);药物组2年随访末UPDRSⅢ、H-Y分级、HAMD、HAMA评分及左旋多巴等效剂量(LED)较基线均显著升高(P 0.05);对两组2年随访末的症状进行比较,药物组的UPDRSⅢ、H-Y分级、HAMD评分及LED较r TMS+药物组升高显著(P 0.05)。结论规律的r TMS辅助常规抗PD药物治疗可减缓PD进展,优于单纯抗PD药物治疗。     

Unmasking levodopa resistance in Parkinson's disease

Some motor and nonmotor features associated with Parkinson's disease (PD) do not seem to respond well to levodopa (or other forms of dopaminergic medication) or appear to become resistant to levodopa treatment with disease progression and longer disease duration. In this narrative review, we elaborate on this issue of levodopa resistance in PD. First, we discuss the possibility of pseudoresistance, which refers to dopamine‐sensitive symptoms or signs that falsely appear to be (or have become) resistant to levodopa, when in fact other mechanisms are at play, resulting in suboptimal dopaminergic efficacy. Examples include interindividual differences in pharmacodynamics and pharmacokinetics and underdosing because of dose‐limiting side effects or because of levodopa phobia. Moreover, pseudoresistance can emerge as not all features of PD respond adequately to the same dosage of levodopa. Second, we address that for several motor features (eg, freezing of gait or tremor) and several nonmotor features (eg, specific cognitive functions), the response to levodopa is fairly complex, with a combination of levodopa‐responsive, levodopa‐resistant, and even levodopa‐induced characteristics. A possible explanation relates to the mixed presence of underlying dopaminergic and nondopaminergic brain lesions. We suggest that clinicians take these possibilities into account before concluding that symptoms or signs of PD are totally levodopa resistant. © 2016 International Parkinson and Movement Disorder Society     

Long-term follow-up of DBS of thalamus for tremor and STN for Parkinson's disease

In 1994 we commenced deep brain stimulation (DBS) of the thalamus for patients with severe tremor. This was done under the guidance of Professor Alim Benabid from Grenoble, France, who pioneered the technique. In the beginning we commenced DBS of the thalamus for patients with severe tremulous Parkinson's disease, essential tremor, and in one case, severe post-traumatic tremor. In all, we had 28 patients for whom the procedure was performed for tremulous Parkinson's disease, six patients with essential tremor and one patient with post-traumatic tremor. In 1997, again under the guidance of Professor Benabid, we commenced bilateral subthalamic nucleus stimulation (STN) for patients with severe Parkinson's disease. We were the second unit in Australia to become established for these procedures. A total of 45 patients have undergone STN DBS and have been followed up on a regular basis by the same neurologist (DOS). The surgical complications and long-term complications, including hardware problems will be reviewed retrospectively, as well as the long-term benefits of these surgical procedures.     

丘脑底核高频刺激治疗帕金森病

目的：研究脑深部刺激（DBS）对帕金森病（PD）的治疗作用。观察术中丘脑底核（STN）刺激对PD震颤,肌僵直、运动缓慢的缓解效果及对语言的影响,探讨植入刺激电极的最佳位置。方法：17例帕金森病患者,利用MRI及微电极导向立体定向方法将刺激电极植入丘脑底核,其靶点：X=11mm,Y=-1mm,Z=-7mm。术中予以高频刺激（频率为150Hz,脉宽为150μz,脉宽为150μs,电压自0.5V开始,逐渐增至6-8V）;其中有2例进行了STN电极永久性植入慢性电刺激,术后随访6-8月,结果：17例术中刺激发现,STN中上部是其刺激、改善病人症状的最佳位置,而电极过深及过外则易引起言语障碍,2例永久性植入慢性电刺激经随访观察对肌僵直的控制非常满意,对运动缓慢有明显改善,并减少美多巴的服药量,UPDRS运动评分下降50%。结论：STN的高频刺激能改善PD的震颤,僵直,运动缓慢等主要症状,是PD慢性刺激的最理想靶点,其中上部是刺激效果的最佳位置。     

Subthalamic somatosensory evoked potentials in Parkinson's disease.

Deep brain stimulation (DBS) of subthalamic nucleus (STN) is an effective treatment for advanced Parkinson's disease. It also provides an opportunity to record neural activity from the human basal ganglia. In this study, to investigate the involvement of the human STN in sensory functions, we recorded somatosensory evoked potentials (SEPs) elicited by contralateral median-nerve stimulation, from STN electrodes implanted for DBS in patients with Parkinson's disease. We suggest that the STN N18 component of SEPs in Parkinson's disease is a mainly local field potential elicited by muscle afferent input to the nucleus.     

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.     

Effects of DBS,premotor rTMS,and levodopa on motor function and silent period in advanced Parkinson's disease

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a widely used and highly effective treatment for patients with advanced Parkinson's disease (PD). Repetitive TMS (rTMS) applied to motor cortical areas has also been shown to improve symptoms in PD and modulate motor cortical excitability. Here, we compared clinical and neurophysiological effects of STN stimulation with those of 1 Hz rTMS given to the dorsal premotor cortex (PMd) and those following intake of levodopa in a group of PD patients with advanced disease. Ten PD patients were studied on 2 consecutive days before and after surgery. Clinical effects were determined using the UPDRS motor score. Motor thresholds, motor‐evoked potential (MEP) amplitudes during slight voluntary contraction, and the cortical silent periods (SP) were measured using TMS. Before surgery effects of levodopa and 1 Hz PMd rTMS and after surgery those of STN stimulation with or without additional levodopa were determined. Levodopa significantly improved clinical symptoms and increased the SP duration. STN stimulation improved clinical symptoms without changing the SP duration. In contrast, 1 Hz PMd rTMS was not effective clinically but normalized the SP duration. Whereas levodopa had widespread effects at different levels of an abnormally active motor network in PD, STN stimulation and PMd rTMS led to either clinical improvement or SP normalization, i.e., only partially reversed abnormal motor network activity. © 2009 Movement Disorder Society     

Cardiovascular effects of levodopa in Parkinson's disease

Levodopa is one of the most effective symptomatic treatment options for Parkinsonism with a favorable safety and tolerability profile. In some patients, particularly those suffering from orthostatic intolerance, the hypotensive effect of levodopa limits its therapeutic use.We used continuous noninvasive cardiovascular and ventilatory monitoring in 17 patients suffering from moderate Parkinson's disease to quantify the hypotensive effect of levodopa and to determine whether this effect is rather vasodepressor or cardioinhibitory.Oral administration of 200 mg levodopa/50 mg benserazide induced a significant decrease in mean arterial pressure (−15%, p < 0.001), cardiac stroke volume (−13%, p < 0.01) and measures of cardiac contractility (dP/dt: −18%, p < 0.001). Systemic vascular resistance, heart rate and ventilatory parameters remained preserved.Our data indicate that the hypotensive blood pressure response to levodopa is caused primarily by a negative inotropic mechanism rather than peripheral vasodilation. Whether this effect is triggered peripherally at the level of the heart or is mediated via central sympathoinhibition remains unsolved.