Functionally separated networks for self-paced and externally-cued motor execution in Parkinson's disease: Evidence from deep brain recordings in humans.

Spatially segregated cortico-basal ganglia networks have been proposed for the control of goal-directed and habitual behavior. In Parkinson's disease, selective loss of dopaminergic neurons regulating sensorimotor (habitual) behavior might therefore predominantly cause deficits in habitual motor control, whereas control of goal-directed movement is relatively preserved. Following this hypothesis, we examined the electrophysiology of cortico-basal ganglia networks in Parkinson patients emulating habitual and goal-directed motor control during self-paced and externally-cued finger tapping, respectively, while simultaneously recording local field potentials in the subthalamic nucleus (STN) and surface EEG. Only externally-cued movements induced a pro-kinetic event-related beta-desynchronization, whereas beta-oscillations were continuously suppressed during self-paced movements. Connectivity analysis revealed higher synchronicity (phase-locking value) between the STN and central electrodes during self-paced and higher STN to frontal phase-locking during externally-cued movements. Our data provide direct electrophysiological support for the existence of functionally segregated cortico-basal ganglia networks controlling motor behavior in Parkinson patients, and corroborate the assumption of Parkinson patients being shifted from habitual towards goal-directed behavior.

Impact of target depth on safety and efficacy outcomes in MR-guided focused ultrasound thalamotomy for tremor patients.

OBJECTIVE: Target depth, defined by the z-coordinate in the dorsoventral axis relative to the anterior commissure-posterior commissure axial plane of the MR-guided focused ultrasound (MRgFUS) lesion, is considered to be critical for tremor improvement and the occurrence of side effects such as gait impairment. However, although different z-coordinates are used in the literature, there are no comparative studies available with information on optimal lesion placement. This study aimed to compare two different MRgFUS lesion targets (z = +2 mm vs z = 0 mm) regarding efficacy and safety outcomes. METHODS: The authors conducted a retrospective analysis of 52 patients with pharmacoresistant tremor disorders who received unilateral MRgFUS thalamotomy in the ventral intermediate nucleus for the first time between 2017 and 2022 by one neurosurgeon, with two different z-coordinates, either z = +2 mm (+2-mm group; n = 17) or z = 0 mm (0-mm group; n = 35), but otherwise identical parameters. Standardized video-recorded assessments of efficacy (including the Washington Heights-Inwood Genetic Study of Essential Tremor scale) and safety (using a standardized grading system) outcomes at baseline and at 6 months posttreatment were reviewed and compared. Moreover, overall patient satisfaction was extracted as documented by the examiner at 6 months. RESULTS: Based on a multiple logistic regression analysis, the authors found that a more dorsal target with a z-coordinate of +2 mm as compared with 0 mm was associated with a higher incidence of any persistent side effect at 6 months (p = 0.02). Most consistently, sensory disturbances, although mild and nondisturbing in most cases, occurred more frequently in the +2-mm group (35% vs 11%, p = 0.007), while no significant differences were found for gait impairment (29% vs 35%) and arm ataxia (24% vs 11%). On the other hand, average tremor suppression was similar (63.6% vs 60.2%) between the groups. Here, higher efficacy was associated with a higher side effect burden in the 0-mm group but not in the +2-mm group. Despite the occurrence of side effects, general patient satisfaction was high (87% would undergo MRgFUS again) as most patients valued tremor suppression more. CONCLUSIONS: A more ventral MRgFUS target of z = 0 mm seems to be associated with a more favorable safety and a comparable efficacy profile as compared with a more dorsal target of z = +2 mm, but prospective studies are warranted.

Does Subthalamic Deep Brain Stimulation Impact Asymmetry and Dyscoordination of Gait in Parkinson's Disease?

Background. Subthalamic deep brain stimulation (STN-DBS) is an effective treatment for selected Parkinson's disease (PD) patients. Gait characteristics are often altered after surgery, but quantitative therapeutic effects are poorly described. Objective. The goal of this study was to systematically investigate modifications in asymmetry and dyscoordination of gait 6 months postoperatively in patients with PD and compare the outcomes with preoperative baseline and to asymptomatic controls without PD. Methods. A convenience sample of thirty-two patients with PD (19 with postural instability and gait disorder (PIGD) type and 13 with tremor dominant disease) and 51 asymptomatic controls participated. Parkinson patients were tested prior to the surgery in both OFF and ON medication states, and 6-months postoperatively in the ON stimulation condition. Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) I to IV and medication were compared to preoperative conditions. Asymmetry ratios, phase coordination index, and walking speed were assessed. Results. MDS-UPDRS I to IV at 6 months improved significantly, and levodopa equivalent daily dosages significantly decreased. STN-DBS increased step time asymmetry (hedges' g effect sizes [95% confidence interval] between pre- and post-surgery: .27 [-.13, .73]) and phase coordination index (.29 [-.08, .67]). These effects were higher in the PIGD subgroup than the tremor dominant (step time asymmetry: .38 [-.06, .90] vs .09 [-.83, 1.0] and phase coordination index: .39 [-.04, .84] vs .13 [-.76, .96]). Conclusions. This study provides objective evidence of how STN-DBS increases asymmetry and dyscoordination of gait in patients with PD and suggests motor subtypes-associated differences in the treatment response.

Revealing the optimal thresholds for movement performance: A systematic review and meta-analysis to benchmark pathological walking behaviour.

In order to address whether increased levels of movement output variability indicate pathological performance, we systematically reviewed and synthesized meta-analysis data on healthy and pathological motor behavior. After screening up to 24'000 reports from four databases, 85 studies were included containing 2409 patients and 2523 healthy asymptomatic controls. The optimal thresholds of variability with uncertainty boundaries (in % Coefficient of Variation ±â€¯Standard Error) were estimated in 7 parameters: stride time (2.34 ±â€¯0.21), stride length (2.99 ±â€¯0.37), step length (3.34 ±â€¯0.84), swing time (2.94 ±â€¯0.60), step time (3.35 ±â€¯0.23), step width (15.87 ±â€¯1.86), and dual-limb support time (6.08 ±â€¯2.83). All spatio-temporal parameters exhibited a positive effect size (pathology led to increased variability) except step width variability (Effect Size = -0.21). By objectively benchmarking thresholds for pathological motor variability also presented through a case-study, this review provides access to movement signatures to understand neurological changes in an individual that are apparent in movement variability. The comprehensive evidence presented now qualifies stride time variability as a movement biomarker, endorsing its applicability as a viable outcome measure in clinical trials.

Dopamine-responsive pattern in tremor patients.

BACKGROUND: Diagnosis and treatment of tremor are largely based on clinical assessment. Whereas in some patients tremor may respond to dopaminergic treatment, in general l-Dopa response to tremor varies considerably. The aim of this study was to predict l-Dopa response by accelerometry. METHODS: We included 60 tremor patients and measured harmonic oscillations by accelerometry. In addition to neurological assessment, we performed l-Dopa challenge tests and the individual tremor response was compared to the amount of harmonic oscillations. RESULTS: We found a strong correlation between harmonic oscillations and clinical l-Dopa response. Similarly, harmonic oscillations were significantly greater in patients with subjective tremor reduction upon l-Dopa administration. CONCLUSIONS: We conclude that harmonic oscillations are a measure for l-Dopa response to tremor irrespective of the underlying disease. Because of the observational character of the study, any causal relation remains speculative. Nevertheless, we propose a novel, non-invasive approach to predict l-Dopa response in tremor patients.

Subthalamic deep brain stimulation versus best medical therapy for L-dopa responsive pain in Parkinson's disease.

Pain is a frequently observed non-motor symptom of patients with Parkinson's disease. In some patients, Parkinson's-related pain responds to dopaminergic treatment. In the present study, we aimed to elucidate whether subthalamic deep brain stimulation has a similar beneficial effect on pain in Parkinson's disease, and whether this effect can be predicted by a pre-operative l-dopa challenge test assessing pain severity. We prospectively analyzed 14 consecutive Parkinson's patients with severe pain who underwent subthalamic deep brain stimulation. In 8 of these patients, pain severity decreased markedly with high doses of l-dopa, irrespective of the type and localization of the pain symptoms. In these patients, subthalamic deep brain stimulation provided an even higher reduction of pain severity than did dopaminergic treatment, and the majority of this group was pain-free after surgery. This effect lasted for up to 41 months. In the remaining 6 patients, pain was not improved by dopaminergic treatment nor by deep brain stimulation. Thus, we conclude that pain relief following subthalamic deep brain stimulation is superior to that following dopaminergic treatment, and that the response of pain symptoms to deep brain stimulation can be predicted by l-dopa challenge tests assessing pain severity. This diagnostic procedure could contribute to the decision on whether or not a Parkinson's patient with severe pain should undergo deep brain stimulation for potential pain relief.