Re-emergent Tremor in Parkinson's Disease: Evidence of Pathologic ß and Prokinetic γ Activity.

BACKGROUND: Re-emergent tremor is characterized as a continuation of resting tremor and is often highly therapy refractory. This study examines variations in brain activity and oscillatory responses between resting and re-emergent tremors in Parkinson's disease. METHODS: Forty patients with Parkinson's disease (25 males, mean age, 66.78 ± 5.03 years) and 40 age- and sex-matched healthy controls were included in the study. Electroencephalogram and electromyography signals were simultaneously recorded during resting and re-emergent tremors in levodopa on and off states for patients and mimicked by healthy controls. Brain activity was localized using the beamforming technique, and information flow between sources was estimated using effective connectivity. Cross-frequency coupling was used to assess neuronal oscillations between tremor frequency and canonical frequency oscillations. RESULTS: During levodopa on, differences in brain activity were observed in the premotor cortex and cerebellum in both the patient and control groups. However, Parkinson's disease patients also exhibited additional activity in the primary sensorimotor cortex. On withdrawal of levodopa, different source patterns were observed in the supplementary motor area and basal ganglia area. Additionally, levodopa was found to suppress the strength of connectivity (P < 0.001) between the identified sources and influence the tremor frequency-related coupling, leading to a decrease in ß (P < 0.001) and an increase in γ frequency coupling (P < 0.001). CONCLUSIONS: Distinct variations in cortical-subcortical brain activity are evident in tremor phenotypes. The primary sensorimotor cortex plays a crucial role in the generation of re-emergent tremor. Moreover, oscillatory neuronal responses in pathological ß and prokinetic γ activity are specific to tremor phenotypes. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Management of Impulse Control and Related Disorders in Parkinson's Disease: An Expert Consensus.

BACKGROUND: Impulse-control and related behavioral disorders (ICBDs) significantly impact the lives of Parkinson's disease (PD) patients and caregivers, with lasting consequences if undiagnosed and untreated. While ICBD pathophysiology and risk factors are well-studied, a standardized severity definition and treatment evidence remain elusive. OBJECTIVE: This work aimed to establish international expert consensus on ICBD treatment strategies. To comprehensively address diverse treatment availabilities, experts from various continents were included. METHODS: From 2021 to 2023, global movement disorders specialists engaged in a Delphi process. A core expert group initiated surveys, involving a larger panel in three iterations, leading to refined severity definitions and treatment pathways. RESULTS: Experts achieved consensus on defining ICBD severity, emphasizing regular PD patient screenings for early detection. General treatment recommendations focused on continuous monitoring, collaboration with significant others, and seeking specialist advice for legal or financial challenges. For mild to severe ICBDs, gradual reduction in dopamine agonists was endorsed, followed by reductions in other PD medications. Second-line treatment strategies included diverse approaches like reversing the last medication change, cognitive behavior therapy, subthalamic nucleus deep brain stimulation, and specific medications like quetiapine, clozapine, and antidepressants. The panel reached consensus on distinct treatment pathways for punding and dopamine dysregulation syndrome, formulating therapy recommendations. Comprehensive discussions addressed management strategies for the exacerbation of either motor or non-motor symptoms following the proposed treatments. CONCLUSION: The consensus offers in-depth insights into ICBD management, presenting clear severity criteria and expert consensus treatment recommendations. The study highlights the critical need for further research to enhance ICBD management. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

How to Use the New European Academy of Neurology/Movement Disorder Society European Section Guideline for Invasive Therapies in Parkinson's Disease.

BACKGROUND: The decision to choose invasive treatments for Parkinson's disease (PD) is complex and needs careful consideration. OBJECTIVES: Although the recommendations of the European Academy of Neurology/Movement Disorder Society European Section guideline for invasive therapies of PD are useful, the different clinical profiles of people with PD who seek advice for possible invasive therapy need further attention. METHODS AND RESULTS: Here we describe 8 clinical standard situations of people with PD unsatisfied with their current oral treatment where invasive therapies may be considered. These are PD patients presenting with the following symptoms: (1) severe motor fluctuations, (2) beginning of levodopa-responsive fluctuations, severe tremor at (3) young or (4) advanced age, (5) impulse control disorders and related behavioral disorders, (6) hallucinations and psychosis, (7) minimal cognitive impairment or mild dementia, and (8) patients in need of palliative care. For some of these conditions, evidence at lower level or simple clinical considerations exist. CONCLUSIONS: There are no one-fits-all answers, but physician and patient should discuss each option carefully considering symptom profile, psychosocial context, availability of therapy alternatives, and many other factors. The current paper outlines our proposed approach to these circumstances.

Gait asymmetry and symptom laterality in Parkinson's disease: two of a kind?

BACKGROUND: The laterality of motor symptoms is considered a key feature of Parkinson's disease (PD). Here, we investigated whether gait and turning asymmetry coincided with symptom laterality as determined by the MDS-UPRDS part III and whether it was increased compared to healthy controls (HC). METHODS: We analyzed the asymmetry of gait and turning with and without a cognitive dual task (DT) using motion capture systems and wearable sensors in 97 PD patients mostly from Hoehn & Yahr stage II and III and 36 age-matched HC. We also assessed motor symptom asymmetry using the bilateral sub-items of the MDS-UPDRS-III. Finally, we examined the strength of the association between gait asymmetry and symptom laterality. RESULTS: Participants with PD had increased gait but not more turning asymmetry compared to HC (p < 0.05). Only 53.7% of patients had a shorter step length on the more affected body side as determined by the MDS-UPDRS-III. Also, 54% took more time and 29% more steps during turns toward the more affected side. The degree of asymmetry in the different domains did not correlate with each other and was not influenced by DT-load. CONCLUSIONS: We found a striking mismatch between the side and the degree of asymmetry in different motor domains, i.e., in gait, turning, and distal symptom severity in individuals with PD. We speculate that motor execution in different body parts relies on different neural control mechanisms. Our findings warrant further investigation to understand the complexity of gait asymmetry in PD.

Towards a better understanding of anticipatory postural adjustments in people with Parkinson's disease.

INTRODUCTION: Previous studies have shown that anticipatory postural adjustments (APAs) are altered in people with Parkinson's disease but its meaning for locomotion is less understood. This study aims to investigate the association between APAs and gait initiation, gait and freezing of gait and how a dynamic postural control challenging training may induce changes in these features. METHODS: Gait initiation was quantified using wearable sensors and subsequent straight walking was assessed via marker-based motion capture. Additionally, turning and FOG-related outcomes were measured with wearable sensors. Assessments were conducted one week before (Pre), one week after (Post) and 4 weeks after (Follow-up) completion of a training intervention (split-belt treadmill training or regular treadmill training), under single task and dual task (DT) conditions. Statistical analysis included a linear mixed model for training effects and correlation analysis between APAs and the other outcomes for Pre and Post-Pre delta. RESULTS: 52 participants with Parkinson's disease (22 freezers) were assessed. We found that APA size in the medio-lateral direction during DT was positively associated with gait speed (p<0.001) and stride length (p<0.001) under DT conditions at Pre. The training effect was largest for first step range of motion and was similar for both training modes. For the associations between changes after the training (pooled sample) medio-lateral APA size showed a significant positive correlation with first step range of motion (p = 0.033) only in the DT condition and for the non-freezers only. CONCLUSIONS: The findings of this work revealed new insights into how APAs were not associated with first step characteristics and freezing and only baseline APAs during DT were related with DT gait characteristics. Training-induced changes in the size of APAs were related to training benefits in the first step ROM only in non-freezers. Based on the presented results increasing APA size through interventions might not be the ideal target for overall improvement of locomotion.

Deep brain stimulation of the subthalamic nucleus restores spatial reversal learning in patients with Parkinson's disease.

Spatial learning and navigation are supported by distinct memory systems in the human brain such as the hippocampus-based navigational system and the striatum-cortex-based system involved in motor sequence, habit and reversal learning. Here, we studied the role of subthalamic circuits in hippocampus-associated spatial memory and striatal-associated spatial reversal learning formation in patients with Parkinson's disease, who underwent a deep brain stimulation of the subthalamic nucleus. Deep brain stimulation patients (Parkinson's disease-subthalamic nucleus: n = 26) and healthy subjects (n = 15) were tested in a novel experimental spatial memory task based on the Morris water maze that assesses both hippocampal place memory as well as spatial reversal learning. All subjects were trained to navigate to a distinct spatial location hidden within the virtual environment during 16 learning trials in a subthalamic nucleus Stim-On condition. Patients were then randomized into two groups with either a deep brain stimulation On or Off condition. Four hours later, subjects were retested in a delayed recall and reversal learning condition. The reversal learning was realized with a new hidden location that should be memorized during six consecutive trials. The performance was measured by means of an index indicating the improvement during the reversal learning. In the delayed recall condition, neither patients, healthy subjects nor the deep brain stimulation On- versus Off groups showed a difference in place memory performance of the former trained location. In the reversal learning condition, healthy subjects (reversal index 2.0) and patients in the deep brain stimulation On condition (reversal index 1.6) showed a significant improvement. However, patients in the deep brain stimulation Off condition (reversal index 1.1) performed significantly worse and did not improve. There were no differences between all groups in a final visual guided navigation task with a visible target. These results suggest that deep brain stimulation of subthalamic nucleus restores spatial reversal learning in a virtual navigation task in patients with Parkinson's disease and gives insight into the neuromodulation effects on cognition of subthalamic circuits in Parkinson's disease.

Effect of Thalamic versus Pallidal Deep Brain Stimulation on Head Tremor in Dystonic and Essential Tremor Patients-A Retrospective Video-Blinded Study.

BACKGROUND: Head tremor is common in dystonia syndromes and difficult to treat. Deep brain stimulation (DBS) is a therapeutic option in medically-refractory cases. In most DBS-centers, the globus pallidus internus (GPi) is targeted in patients with predominant dystonia and the ventrointermediate nucleus of the thalamus (Vim) in predominant tremor. The aim of the study was to evaluate the effect of GPi- versus Vim-DBS in dystonic or essential head tremor. METHODS: All patients with dystonia or essential tremor (ET) (n = 381) who underwent DBS surgery at our institution between 1999 and 2020 were screened for head tremor in our database according to predefined selection criteria. Of the 33 patients meeting inclusion criteria tremor and dystonia severity were assessed at baseline, short- (mean 10 months) and long-term follow-up (41 months) by two blinded video-raters. RESULTS: Twenty-two patients with dystonic head tremor received either GPi- (n = 12) or Vim-stimulation (n = 10), according to the prevailing clinical phenotype. These two groups were compared with 11 patients with ET, treated with Vim-stimulation. The reduction in head tremor from baseline to short- and long-term follow-up was 60-70% and did not differ significantly between the three groups. CONCLUSIONS: GPi-DBS effectively and sustainably reduced head tremor in idiopathic dystonia. The effect was comparable to the effect of Vim-DBS on head tremor in dystonia patients with predominant limb tremor and to the effect of Vim-DBS on head tremor in ET.

The role of the motor thalamus in deep brain stimulation for essential tremor.

The advent of next-generation technology has significantly advanced the implementation and delivery of Deep Brain Stimulation (DBS) for Essential Tremor (ET), yet controversies persist regarding optimal targets and networks responsible for tremor genesis and suppression. This review consolidates key insights from anatomy, neurology, electrophysiology, and radiology to summarize the current state-of-the-art in DBS for ET. We explore the role of the thalamus in motor function and describe how differences in parcellations and nomenclature have shaped our understanding of the neuroanatomical substrates associated with optimal outcomes. Subsequently, we discuss how seminal studies have propagated the ventral intermediate nucleus (Vim)-centric view of DBS effects and shaped the ongoing debate over thalamic DBS versus stimulation in the posterior subthalamic area (PSA) in ET. We then describe probabilistic- and network-mapping studies instrumental in identifying the local and network substrates subserving tremor control, which suggest that the PSA is the optimal DBS target for tremor suppression in ET. Taken together, DBS offers promising outcomes for ET, with the PSA emerging as a better target for suppression of tremor symptoms. While advanced imaging techniques have substantially improved the identification of anatomical targets within this region, uncertainties persist regarding the distinct anatomical substrates involved in optimal tremor control. Inconsistent subdivisions and nomenclature of motor areas and other subdivisions in the thalamus further obfuscate the interpretation of stimulation results. While loss of benefit and habituation to DBS remain challenging in some patients, refined DBS techniques and closed-loop paradigms may eventually overcome these limitations.