Subthalamic stimulation reduces motor disability and improves quality of life in patients with advanced Parkinson's disease who have severe levodopa-induced motor complications. We hypothesized that neurostimulation would be beneficial at an earlier stage of Parkinson's disease.In this 2-year trial, we randomly assigned 251 patients with Parkinson's disease and early motor complications (mean age, 52 years; mean duration of disease, 7.5 years) to undergo neurostimulation plus medical therapy or medical therapy alone. The primary end point was quality of life, as assessed with the use of the Parkinson's Disease Questionnaire (PDQ-39) summary index (with scores ranging from 0 to 100 and higher scores indicating worse function). Major secondary outcomes included parkinsonian motor disability, activities of daily living, levodopa-induced motor complications (as assessed with the use of the Unified Parkinson's Disease Rating Scale, parts III, II, and IV, respectively), and time with good mobility and no dyskinesia.For the primary outcome of quality of life, the mean score for the neurostimulation group improved by 7.8 points, and that for the medical-therapy group worsened by 0.2 points (between-group difference in mean change from baseline to 2 years, 8.0 points; P=0.002). Neurostimulation was superior to medical therapy with respect to motor disability (P<0.001), activities of daily living (P<0.001), levodopa-induced motor complications (P<0.001), and time with good mobility and no dyskinesia (P=0.01). Serious adverse events occurred in 54.8% of the patients in the neurostimulation group and in 44.1% of those in the medical-therapy group. Serious adverse events related to surgical implantation or the neurostimulation device occurred in 17.7% of patients. An expert panel confirmed that medical therapy was consistent with practice guidelines for 96.8% of the patients in the neurostimulation group and for 94.5% of those in the medical-therapy group.Subthalamic stimulation was superior to medical therapy in patients with Parkinson's disease and early motor complications. (Funded by the German Ministry of Research and others; EARLYSTIM ClinicalTrials.gov number, NCT00354133.).
Deep brain stimulation (DBS) of the ventral intermediate nucleus of thalamus (VIM) is a treatment option in medically intractable tremor, such as essential tremor or tremor-dominant Parkinson disease (PD). Although functional studies demonstrated modulation of remote regions, the structural network supporting this is as yet unknown. In this observational study, we analyzed the network mediating clinical tremor modulation.We studied 12 patients undergoing VIM stimulation for debilitating tremor. We initiated noninvasive diffusion tractography from tremor-suppressive VIM electrode contacts. Moreover, we tested for the contribution of primary motor projections in this structural correlate of a functional tremor network, comparing the connectivity of effective DBS contacts with those of adjacent, but clinically ineffective, stimulation sites.VIM stimulation resulted in decrease of tremor and improvement in quality of life. Tractography initiated from the effective stimulation site reconstructed a highly reproducible network of structural connectivity comprising motor cortical, subcortical, and cerebellar sites and the brainstem, forming the anatomic basis for remote effects of VIM stimulation. This network is congruent with functional imaging studies in humans and with thalamic projections found in the animal literature. Connectivity to the primary motor cortex seemed to play a key role in successful stimulation.Patients undergoing DBS provide a unique opportunity to assess an electrophysiologically defined seed region in human thalamus, a technique that is usually restricted to animal research. In the future, preoperative tractography could aid with stereotactic planning of individual subcortical target points for stimulation in tremor and in other disease entities.
Gilles de la Tourette Syndrome (GTS) is the most severe form of chronic tic disorders, characterized by uncontrollable motor actions and vocalizations. While brain stimulation techniques show promise in reducing tic severity, optimal target networks are not well-defined. Here, we leveraged datasets from two independent deep brain stimulation (DBS) cohorts and a cohort of tic-inducing lesions to infer critical networks for treatment and occurrence of tics by mapping stimulation sites and lesions to a functional connectome derived from 1,000 healthy participants. We found that greater tic reduction is linked to higher connectivity of DBS sites (N = 37) with action-related functional resting-state networks, i.e., the cingulo-opercular (R = 0.62; p < 0.001) and somato-cognitive action networks (R = 0.47; p = 0.002). Hubs within the cingulo-opercular network best matched the optimal connectivity profiles of thalamic DBS. We replicated the significance of targeting cingulo-opercular and somato-cognitive action network connectivity in an independent DBS cohort (N = 10). Finally, we demonstrate that tic-inducing brain lesions (N = 22) exhibit similar connectivity to these networks. Collectively, these results suggest a critical role for these action-related networks in the pathophysiology and treatment of GTS.
Acoustic studies have revealed that patients with Essential Tremor treated with thalamic Deep Brain Stimulation (DBS) may suffer from speech deterioration in terms of imprecise oral articulation and reduced voicing control. Based on the acoustic signal one cannot infer, however, whether this deterioration is due to a general slowing down of the speech motor system (e.g., a target undershoot of a desired articulatory goal resulting from being too slow) or disturbed coordination (e.g., a target undershoot caused by problems with the relative phasing of articulatory movements). To elucidate this issue further, we here investigated both acoustics and articulatory patterns of the labial and lingual system using Electromagnetic Articulography (EMA) in twelve Essential Tremor patients treated with thalamic DBS and twelve age- and sex-matched controls. By comparing patients with activated (DBS-ON) and inactivated stimulation (DBS-OFF) with control speakers, we show that critical changes in speech dynamics occur on two levels: With inactivated stimulation (DBS-OFF), patients showed coordination problems of the labial and lingual system in terms of articulatory imprecision and slowness. These effects of articulatory discoordination worsened under activated stimulation, accompanied by an additional overall slowing down of the speech motor system. This leads to a poor performance of syllables on the acoustic surface, reflecting an aggravation either of pre-existing cerebellar deficits and/or the affection of the upper motor fibers of the internal capsule.
Although characteristic motor symptoms of Parkinson's disease such as bradykinesia typically improve under dopaminergic medication, deficits in higher motor control are less responsive. We here investigated the dopaminergic modulation of network dynamics underlying basic motor performance, i.e. finger tapping, and higher motor control, i.e. internally and externally cued movement preparation and selection. Twelve patients, assessed ON and OFF medication, and 12 age-matched healthy subjects underwent functional magnetic resonance imaging. Dynamic causal modelling was used to assess effective connectivity in a motor network comprising cortical and subcortical regions. In particular, we investigated whether impairments in basic and higher motor control, and the effects induced by dopaminergic treatment are due to connectivity changes in (i) the mesial premotor loop comprising the supplementary motor area; (ii) the lateral premotor loop comprising lateral premotor cortex; and (iii) cortico-subcortical interactions. At the behavioural level, we observed a marked slowing of movement preparation and selection when patients were internally as opposed to externally cued. Preserved performance during external cueing was associated with enhanced connectivity between prefrontal cortex and lateral premotor cortex OFF medication, compatible with a context-dependent compensatory role of the lateral premotor loop in the hypodopaminergic state. Dopaminergic medication significantly improved finger tapping speed in patients, which correlated with a drug-induced coupling increase of prefrontal cortex with the supplementary motor area, i.e. the mesial premotor loop. In addition, only in the finger tapping condition, patients ON medication showed enhanced excitatory influences exerted by cortical premotor regions and the thalamus upon the putamen. In conclusion, the amelioration of bradykinesia by dopaminergic medication seems to be driven by enhanced connectivity within the mesial premotor loop and cortico-striatal interactions. In contrast, medication did not improve internal motor control deficits concurrent to missing effects at the connectivity level. This differential effect of dopaminergic medication on the network dynamics underlying motor control provides new insights into the clinical finding that in Parkinson's disease dopaminergic drugs especially impact on bradykinesia but less on executive functions.
<b><i>Background:</i></b> Directional leads are increasingly used in deep brain stimulation. They allow shaping the electrical field in the axial plane. These new possibilities increase the complexity of programming. Thus, optimized programming approaches are needed to assist clinical testing and to obtain full clinical benefit. <b><i>Objectives:</i></b> This simulation study investigates to what extent the electrical field can be shaped by directional steering to compensate for lead malposition. <b><i>Method:</i></b> Binary volumes of tissue activated (VTA) were simulated, by using a finite element method approach, for different amplitude distributions on the three directional electrodes. VTAs were shifted from 0 to 2 mm at different shift angles with respect to the lead orientation, to determine the best compensation of a target volume. <b><i>Results:</i></b> Malpositions of 1 mm can be compensated with the highest gain of overlap with directional leads. For larger shifts, an improvement of overlap of 10–30% is possible, depending on the stimulation amplitude and shift angle of the lead. Lead orientation and shift determine the amplitude distribution of the electrodes. <b><i>Conclusion:</i></b> To get full benefit from directional leads, both the shift angle as well as the shift to target volume are required to choose the correct amplitude distribution on the electrodes. Current directional leads have limitations when compensating malpositions >1 mm; however, they still outperform conventional leads in reducing overstimulation. Further, their main advantage probably lies in the reduction of side effects. Databases like the one from this simulation could serve for optimized lead programming algorithms in the future.
