Gaps and roadmap of novel neuromodulation targets for treatment of gait in Parkinson's disease.
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ABSTRACT:
SUBMITTER: Cury RG
PROVIDER: S-EPMC8752758 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Freezing of gait (FOG) is a devastating axial motor symptom in Parkinson's disease (PD) leading to falls, institutionalization, and even death. The response of FOG to dopaminergic medication and deep brain stimulation (DBS) is complex, variable, and yet to be optimized. Fundamental gaps in the knowledge of the underlying neurobiomechanical mechanisms of FOG render this symptom one of the unsolved challenges in the treatment of PD. Subcortical neural mechanisms of gait impairment and FOG in PD are largely unknown due to the challenge of accessing deep brain circuitry and measuring neural signals in real time in freely-moving subjects. Additionally, there is a lack of gait tasks that reliably elicit FOG. Since FOG is episodic, we hypothesized that dynamic features of subthalamic (STN) beta oscillations, or beta bursts, may contribute to the Freezer phenotype in PD during gait tasks that elicit FOG. We also investigated whether STN DBS at 60 Hz or 140 Hz affected beta burst dynamics and gait impairment differently in Freezers and Non-Freezers. Synchronized STN local field potentials, from an implanted, sensing neurostimulator (Activa® PC + S, Medtronic, Inc.), and gait kinematics were recorded in 12 PD subjects, off-medication during forward walking and stepping-in-place tasks under the following randomly presented conditions: NO, 60 Hz, and 140 Hz DBS. Prolonged movement band beta burst durations differentiated Freezers from Non-Freezers, were a pathological neural feature of FOG and were shortened during DBS which improved gait. Normal gait parameters, accompanied by shorter bursts in Non-Freezers, were unchanged during DBS. The difference between the mean burst duration between hemispheres (STNs) of all individuals strongly correlated with the difference in stride time between their legs but there was no correlation between mean burst duration of each STN and stride time of the contralateral leg, suggesting an interaction between hemispheres influences gait. These results suggest that prolonged STN beta burst durations measured during gait is an important biomarker for FOG and that STN DBS modulated long not short burst durations, thereby acting to restore physiological sensorimotor information processing, while improving gait.
| S-EPMC6422345 | biostudies-literature
Project description:IntroductionFreezing of gait (FoG) is one of the most disabling yet poorly understood symptoms of Parkinson's disease (PD). FoG is an episodic gait pattern characterized by the inability to step that occurs on initiation or turning while walking, particularly with perception of tight surroundings. This phenomenon impairs balance, increases falls, and reduces the quality of life.Materials and methodsClinical-anatomical correlations, electrophysiology, and functional imaging have generated several mechanistic hypotheses, ranging from the most distal (abnormal central pattern generators of the spinal cord) to the most proximal (frontal executive dysfunction). Here, we review the neuroanatomy and pathophysiology of gait initiation in the context of FoG, and we discuss targets of central nervous system neuromodulation and their outcomes so far. The PubMed database was searched using these key words: neuromodulation, freezing of gait, Parkinson's disease, and gait disorders.ConclusionDespite these investigations, the pathogenesis of this process remains poorly understood. The evidence presented in this review suggests FoG to be a heterogenous phenomenon without a single unifying pathologic target. Future studies rigorously assessing targets as well as multimodal approaches will be essential to define the next generation of therapeutic treatments.
| S-EPMC8233405 | biostudies-literature
Project description:BackgroundGait speed is an important outcome that relates to mobility, function, and mortality, and is altered in people with Parkinson's disease (PwPD). However, changes in gait speed may not reflect changes in other important aspects of gait.ObjectiveTo characterize which outcomes change concomitantly with walking speed in PwPD. This information can inform the choice of outcome variables for characterizing and tracking gait performance in this population.Methods67 PwPD and 40 neurotypical adults completed 2-minute overground walking bouts at comfortable and fast self-selected speeds. Eight inertial sensors were used to characterize gait and turning. We identified a subset of participants (38 per group) where the PD participant's "fast" walk was similar speed to neurotypical participants "comfortable" walk, facilitating an across-group gait comparison controlling for gait speed.ResultsWalking at fast gait speed compared to comfortable lead to significant changes in stride length, cadence, and stride time variability, but not in steps to turn, trunk ROM, and trunk and lumbar stability in PwPD. Sub-group analyses showed that despite walking at a similar speed as neurotypical adults, PwPD exhibit altered turning outcomes, lumbar stability, and stride length/cadence.ConclusionsGait speed is a critical outcome for characterizing mobility. However, in PwPD, several important outcomes do not exhibit a uniform relationship with gait speed, and remain altered compared to neurotypical adults despite "normalizing" walking speed. Given the complex relationship between gait speed and other gait quality measures, care should be taken when choosing outcome measures to characterize the breadth of gait abnormality in PwPD.
| S-EPMC7304052 | biostudies-literature
Project description:ObjectiveTreatment of different depression symptoms may require different brain stimulation targets with different underlying brain circuits. The authors sought to identify such targets, which could improve the efficacy of therapeutic brain stimulation and facilitate personalized therapy.MethodsThe authors retrospectively analyzed two independent cohorts of patients who received left prefrontal transcranial magnetic stimulation (TMS) for treatment of depression (discovery sample, N=30; active replication sample, N=81; sham replication sample, N=87). Each patient's TMS site was mapped to underlying brain circuits using functional connectivity MRI from a large connectome database (N=1,000). Circuits associated with improvement in each depression symptom were identified and then clustered based on similarity. The authors tested for reproducibility across data sets and whether symptom-specific targets derived from one data set could predict symptom improvement in the other independent cohort.ResultsThe authors identified two distinct circuit targets effective for two discrete clusters of depressive symptoms. Dysphoric symptoms, such as sadness and anhedonia, responded best to stimulation of one circuit, while anxiety and somatic symptoms responded best to stimulation of a different circuit. These circuit maps were reproducible, predicted symptom improvement in independent patient cohorts, and were specific to active compared with sham stimulation. The maps predicted symptom improvement in an exploratory analysis of stimulation sites from 14 clinical TMS trials.ConclusionsDistinct clusters of depressive symptoms responded better to different TMS targets across independent retrospective data sets. These symptom-specific targets can be prospectively tested in a randomized clinical trial. This data-driven approach for identifying symptom-specific targets may prove useful for other disorders and facilitate personalized neuromodulation therapy.
| S-EPMC8396109 | biostudies-literature
Project description:The mainstay treatments for Parkinson's Disease (PD) have been limited to pharmacotherapy and deep brain stimulation. While these interventions are helpful, a new wave of research is investigating noninvasive neuromodulation methods as potential treatments. Some promising avenues have included transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), electroconvulsive therapy (ECT), and focused ultrasound (FUS). While these methods are being tested in PD patients, investigations in animal models of PD have sought to elucidate their therapeutic mechanisms. In this rapid review, we assess the available animal literature on these noninvasive techniques and discuss the possible mechanisms mediating their therapeutic effects based on these findings.
| S-EPMC10487610 | biostudies-literature
Project description:Background:Anxiety is the most under-recognized nonmotor symptom of Parkinson's disease (PD), yet it is unclear whether motor impairment exacerbates anxiety observed in PD, or vice versa. The current study examined: (1) whether movement (i.e., walking vs. standing) elevates distress in PD; (2) how dopaminergic treatment influences anxiety specifically while walking; and (3) whether these responses are worse in PD patients with gait impairments (compared to those without). Methods:Twenty healthy control participants (HC), 17 PD participants without gait impairments (PD-GI), and 14 PD participants with gait impairments (PD+GI) performed two tasks (stand vs. walk) in two virtual environments: (1) LOW threat; (2) HIGH threat. This protocol was completed in on and off dopaminergic states (to evaluate the effect of exacerbating motor symptoms). Results:PD+GI reported greater levels of anxiety compared to PD-GI and HC overall. All participants reported greater levels of anxiety and had higher skin conductance levels (SCLs) when walking compared to standing. The HIGH threat condition also generated greater levels of anxiety in all participants, compared to LOW threat, especially when required to walk. Notably, only PD+GI reported greater levels of anxiety when walking compared to standing in the LOW threat environment. Dopaminergic medication reduced self-reported levels of anxiety, but did not significantly change SCL. Conclusion:This study provides evidence that movement exacerbates anxiety in all older adults, but is particularly influential in those with gait impairments, which emphasizes the importance of optimally treating movement impairments as a method of reducing movement driven anxiety.
| S-EPMC6178607 | biostudies-literature
Project description:Surgical treatment for Parkinson's disease (PD) has evolved from ablative procedures, within a variety of brain regions, to implantation of electrodes into specific targets of the basal ganglia. Electrode implantation surgery, referred to as deep brain stimulation (DBS), is preferred to ablative procedures by many experts owing to its reversibility, programmability, and the ability to be safely performed bilaterally. Several randomized clinical studies have demonstrated the effectiveness of DBS surgery for control of PD symptoms. Many brain targets, including the subthalamic nucleus and the globus pallidus internus, have emerged as potentially effective, with each target being closely associated with important pros and cons. Selection of appropriate PD candidates through a methodical interdisciplinary screening is considered a prerequisite for a successful surgical outcome. Despite recent growth in DBS knowledge, there is currently no consensus on the ideal surgical technique, the best surgical approach, and the most appropriate surgical target. DBS is now targeted towards treating specific PD-related symptoms in a given individual, and not simply addressing the disease with one pre-defined approach. In this review we will discuss the historical aspects of surgical treatments, the selection of an appropriate DBS candidate, the current surgical techniques, and recently introduced DBS-related technologies. We will address important pre- and postoperative issues related to DBS. We will also discuss the lessons learned from the randomized clinical studies for DBS and the shifting paradigm to tailor to a more patient-centered and symptom-specific approach.
| S-EPMC3899492 | biostudies-literature
Project description:Background:Striatal foot deformity can shorten the stance phase of gait and impair the ability to stand and walk. Botulinum neurotoxin type A (BoNT A) is a treatment option. However, no previous study has included clinical balance testing in the evaluation of treatment effects. The aim of this study was to evaluate gait and balance in patients with striatal foot deformities and Parkinson's disease (PD) before and after treatment with BoNT A injections. Method:The study included 10 patients with PD and striatal foot deformity who visited a neurological clinic. The mean ± standard deviation age and PD-duration was 62.8 ± 8.8 years and 4.9 ± 3.6 years, respectively. Clinical assessment was made before and 4 and 16 weeks after injection and included 5 clinical gait and balance tests. The intensity of distress due to deformities was investigated with a visual analogue scale. Parkinsonian motor status was assessed with the Unified Parkinson's Disease Rating Scale part III (motor part). Based on ordinary clinical examination, electromyography-guided BoNT A injection was given in affected muscles. Clinically effective doses of BoNT A were used. Results:Improvements were observed regarding functional, dynamic, and standing balance as well as intensity of distress at 4 weeks but not at 16 weeks compared with baseline. Conclusions:BoNT A injection treatment improved gait and balance in patients with PD and striatal foot deformities. Multicenter trials are needed; and, to achieve increased power, a randomized, double-blind controlled design is needed and should focus on the ability of tests to capture subtle changes in gait and balance.
| S-EPMC6174462 | biostudies-other
Project description:BackgroundThe discovery of abnormal synchronization of neuronal activity in the basal ganglia in Parkinson's disease (PD) has prompted the development of novel neuromodulation paradigms. Coordinated reset neuromodulation intends to specifically counteract excessive synchronization and to induce cumulative unlearning of pathological synaptic connectivity and neuronal synchrony.MethodsIn this prospective case series, six PD patients were evaluated before and after coordinated reset neuromodulation according to a standardized protocol that included both electrophysiological recordings and clinical assessments.ResultsCoordinated reset neuromodulation of the subthalamic nucleus (STN) applied to six PD patients in an externalized setting during three stimulation days induced a significant and cumulative reduction of beta band activity that correlated with a significant improvement of motor function.ConclusionsThese results highlight the potential effects of coordinated reset neuromodulation of the STN in PD patients and encourage further development of this approach as an alternative to conventional high-frequency deep brain stimulation in PD.
| S-EPMC4282372 | biostudies-literature
Project description:We tested the feasibility of one session of treadmill training using a novel physical therapist assisted system (Mobility Rehab) using wearable sensors on the upper and lower limbs of 10 people with Parkinson's disease (PD). Participants performed a 2-min walk overground before and after 15 min of treadmill training with Mobility Rehab, which included an electronic tablet (to visualize gait metrics) and five Opal sensors placed on both the wrists and feet and on the sternum area to measure gait and provide feedback on six gait metrics (foot-strike angle, trunk coronal range-of-motion (ROM), arm swing ROM, double-support duration, gait-cycle duration, and step asymmetry). The physical therapist used Mobility Rehab to select one or two gait metrics (from the six) to focus on during the treadmill training. Foot-strike angle (effect size (ES) = 0.56, 95% Confidence Interval (CI) = 0.14 to 0.97), trunk coronal RoM (ES = 1.39, 95% CI = 0.73 to 2.06), and arm swing RoM (ES = 1.64, 95% CI = 0.71 to 2.58) during overground walking showed significant and moderate-to-large ES following treadmill training with Mobility Rehab. Participants perceived moderate (60%) and excellent (30%) effects of Mobility Rehab on their gait. No adverse events were reported. One session of treadmill training with Mobility Rehab is feasible for people with mild-to-moderate PD.
| S-EPMC9823339 | biostudies-literature