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Background: Parkinson’s disease (PD) is the second most common neurodegenerative disorder, with genetic factors accounting for about 15% of cases. There is a significant challenge in tracking disease progression and treatment response, crucial for developing new therapies. Traditional methods like imaging, clinical monitoring, and biomarker analysis have not conclusively tracked disease progression or treatment response in PD. Our previous research indicated that PD patients with increased dopamine transporter (DAT) and tyrosine hydroxylase (TH) in peripheral blood mononuclear cells (PBMCs) might show disease progression and respond to levodopa treatment.Objective: This study evaluates whether DAT- and TH-expressing PBMCs can monitor motor progression in a PD patient with a heterozygous TH mutation.Methods: We conducted a longitudinal follow-up of a 46-year-old female PD patient with a TH mutation, assessing her clinical features over 18 months through DaT scans and PBMC immunophenotyping. This was compared with idiopathic PD patients (130 subjects) and healthy controls (80 age/sex-matched individuals).Results: We found an increase in DAT+ immune cells concurrent with worsening motor scores (UPDRS-III). Following levodopa therapy, unlike idiopathic PD patients, TH+ immune cell levels in this patient remained high even as her motor scores improved.Conclusions: Longitudinal immunophenotyping in this PD patient suggests DAT+ and TH+ PBMCs as potential biomarkers for tracking PD progression and treatment efficacy, supporting further exploration of this approach in PD research.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, with genetic factors accounting for about 15% of cases. There is a significant challenge in tracking disease progression and treatment response, crucial for developing new therapies. Traditional methods like imaging, clinical monitoring, and biomarker analysis have not conclusively tracked disease progression or treatment response in PD. Our previous research indicated that PD patients with increased dopamine transporter (DAT) and tyrosine hydroxylase (TH) in peripheral blood mononuclear cells (PBMCs) might show disease progression and respond to levodopa treatment. This study evaluates whether DAT- and TH-expressing PBMCs can monitor motor progression in a PD patient with a heterozygous TH mutation. We conducted a longitudinal follow-up of a 46-year-old female PD patient with a TH mutation, assessing her clinical features over 18 months through DaT scans and PBMC immunophenotyping. This was compared with idiopathic PD patients (130 subjects) and healthy controls (80 age/sex-matched individuals). We found an increase in DAT+ immune cells concurrent with worsening motor scores (UPDRS-III). Following levodopa therapy, unlike idiopathic PD patients, TH+ immune cell levels in this patient remained high even as her motor scores improved. Longitudinal immunophenotyping in this PD patient suggests DAT+ and TH+ PBMCs as potential biomarkers for tracking PD progression and treatment efficacy, supporting further exploration of this approach in PD research.

IMPORTANCE: The travel required to receive deep brain stimulation (DBS) programming causes substantial burden on patients and limits who can access DBS therapy. OBJECTIVE: To evaluate the efficacy of home health DBS postoperative management in an effort to reduce travel burden and improve access. DESIGN, SETTINGS, AND PARTICIPANTS: This open-label randomized clinical trial was conducted at University of Florida Health from November 2017 to April 2020. Eligible participants had a diagnosis of Parkinson disease (PD) and were scheduled to receive DBS independently of the study. Consenting participants were randomized 1:1 to receive either standard of care or home health postoperative DBS management for 6 months after surgery. Primary caregivers, usually spouses, were also enrolled to assess caregiver strain. INTERVENTIONS: The home health postoperative management was conducted by a home health nurse who chose DBS settings with the aid of the iPad-based Mobile Application for PD DBS system. Prior to the study, the home health nurse had no experience providing DBS care. MAIN OUTCOMES AND MEASURES: The primary outcome was the number of times each patient traveled to the movement disorders clinic during the study period. Secondary outcomes included changes from baseline on the Unified Parkinson’s Disease Rating Scale part III. RESULTS: Approximately 75 patients per year were scheduled for DBS. Of the patients who met inclusion criteria over the entire study duration, 45 either declined or were excluded for various reasons. Of the 44 patients enrolled, 19 of 21 randomized patients receiving the standard of care (mean [SD] age, 64.1 [10.0] years; 11 men) and 23 of 23 randomized patients receiving home health who underwent a minimum of 1 postoperative management visit (mean [SD] age, 65.0 [10.9] years; 13 men) were included in analysis. The primary outcome revealed that patients randomized to home health had significantly fewer clinic visits than the patients in the standard of care arm (mean [SD], 0.4 [0.8] visits vs 4.8 [0.4] visits; P < .001). We found no significant differences between the groups in the secondary outcomes measuring the efficacy of DBS. No adverse events occurred in association with the study procedure or devices. CONCLUSIONS AND RELEVANCE: This study provides evidence supporting the safety and feasibility of postoperative home health DBS management. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02474459

“Deep brain stimulation is a safe and effective therapy for the management of a variety of neurologic conditions with Food and Drug Administration or humanitarian exception approval for Parkinson disease, dystonia, tremor, and obsessive-compulsive disorder. Advances in neurophysiology, neuroimaging, and technology have driven increasing interest in the potential benefits of neurostimulation in other neuropsychiatric conditions including dementia, depression, pain, Tourette syndrome, and epilepsy, among others. New anatomic or combined targets are being investigated in these conditions to improve symptoms refractory to medications or standard stimulation.”

Graphical Abstract

Although earlier studies reported variable speech changes following subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson’s disease (PD) patients, the effects of globus pallidus internus (GPi) DBS on speech performance in PD remain largely unknown. We aimed to characterize speech changes following PD GPi-DBS. We retrospectively analyzed clinical and speech outcomes of 25 PD patients treated with bilateral GPi-DBS at a single center. Outcome measures included the Unified Parkinson’s Disease Rating Scale (UPDRS), speech subsystem domains (respiratory, laryngeal, resonance, orofacial, rate, prosody, rhythm, and naturalness), and overall speech intelligibility. Scores at baseline were compared with those at 6 months, 1 year, and the longest clinical follow-up available. In the off-medication state, activities of daily living and motor function based on UPDRS II and III significantly improved postoperatively. We observed unique patterns of speech changes in patients with PD following GPi-DBS in the short- (n = 25) and longer-term (n = 8) follow-up periods. Velopharyngeal (resonance), laryngeal components, and prosody worsened after bilateral GPi-DBS (p < 0.015). Speech intelligibility did not worsen after GPi-DBS in the short-term, but there was a trend to deteriorate at long-term follow-up (e.g., one year and beyond). We observed worsening of hypokinetic dysarthria in individual patients. Also, a minority of patients developed stuttering, spastic dysarthria, or ataxic dysarthria. Bilateral GPi-DBS worsened several modalities of parkinsonian speech without compromising overall speech intelligibility. GPi-DBS can potentially worsen or induce hypokinetic dysarthria, stuttering, spastic dysarthria, or ataxic dysarthria. GPi-DBS may have different and variable effects on speech function when compared to STN-DBS.

Management of patients with Parkinson disease (PD) during inpatient hospital stays is complex and poses unique challenges for physicians and ancillary staff. Patients with PD have a high risk of complications, encephalopathy, and prolonged hospital stay. Early recognition of complications and implementation of rehabilitation strategies along with appropriate management of medications are critical to improve outcomes. Patients with PD can exhibit worsening mobility and balance, insomnia, orthostatic hypotension, multiple neuropsychiatric symptoms, and gastrointestinal dysfunction while hospitalized. This review summarizes the specific in-hospital concerns observed in patients with PD and discusses potential treatment approaches.

Parkinson’s disease (PD) negatively affects driver fitness. Few studies document the benefits of in-vehicle information systems (IVIS) and advanced-driver assistance systems (ADAS), the focus of this study, for drivers with PD. This study quantified the impact of IVIS and ADAS on the number of on-road driving errors. Drivers with PD (N= 107) drove a vehicle equipped with IVIS and ADAS in traffic. The activation of IVIS and ADAS resulted in fewer driver errors. Specifically, adaptive cruise control reduced the number of speeding errors on the highway. Bradykinesia correlated with driving errors with deactivated systems. Memory impairments correlated with the total number of driving errors with activated systems. Impairments in executive function and visuospatial ability were associated with more errors during system deactivation. IVIS and ADAS reduced the total number of driving errors for PD drivers; ameliorated effects of individual variations; but memory declines posed a challenge while using these technologies.

Pain is a prevalent and debilitating nonmotor symptom of Parkinson's disease (PD) that is often inadequately managed. Deep brain stimulation (DBS) has been shown to relieve pain in PD but an effective method of identifying which types of PD pain respond to DBS has not been established. We examine the effects of DBS on different types of PD pain using the King's Parkinson's disease pain scale (KPDPS), the only validated scale of PD pain. We prospectively followed 18 PD patients undergoing subthalamic nucleus (STN) or Globus pallidus interna (GPi) DBS. Subjects completed the KPDPS, low back disability index (LBDI), and McGill pain questionnaire (MPQ), preoperatively and at six months postoperatively. Subjects underwent the unified Parkinson's disease rating scale‐III (UPDRS‐III) with preoperative scores ON medication and postoperative scores ON medication/DBS stimulation. Of the 18 patients, a total of 12 subjects had STN DBS and 6 had GPi DBS. As a group, subjects showed improvement in total KPDPS score at six‐month postoperative follow‐up (p= 0.004). Fluctuation and nocturnal pain were most significantly improved (p= 0.006, 0.01, respectively). Significant improvements were found in fluctuation‐related pain domain following GPi DBS. In this pilot study, we are the first group to employ KPDPS to monitor pain relief following DBS in PD patients. We demonstrate that fluctuation‐related pain and nocturnal pain significantly improve with DBS. Use of the KPDPS in the future will allow better understanding of how STN and GPi DBS treat PD pain over time.

IMPORTANCE: Selection of the best deep brain stimulation (DBS) target—subthalamic nucleus (STN) or globus pallidus interna (GPi)—for treatment of motor complications in Parkinson disease remains a matter of debate. OBSERVATIONS: Increasing evidence from randomized clinical trials indicates that motor benefit is similar between both targets, including an effect on dyskinesia and improvement in quality of life. Deep brain stimulation of the STN offers consistently greater dopaminergic medication reduction, possible mild benefit in nonmotor domains, and potential economic advantage. Deep brain stimulation of the GPi provides a probable advantage in dyskinesia suppression, management of symptoms with unilateral leads, and flexibility in medications and programming adjustments. Overall, STN DBS is at potentially higher or equal risk for neuropsychiatric changes compared with GPi DBS. CONCLUSIONS AND RELEVANCE: Both GPi and STN DBS provide similar, consistent, marked motor benefits, but subtle target differences exist. Target selection should be tailored to each patient’s clinical presentation, neuropsychiatric profile, and goals of surgery, allowing customization of this therapy and improved individual outcomes.

Subthalamic nucleus deep brain stimulation (STN DBS) is an established treatment in Parkinson's disease (PD). We investigate the effect of eye opening on neuronal activity and local field potentials (LFPs) in the STN. We prospectively enrolled 25 PD patients undergoing STN DBS in our institution. During DBS, single‐unit activity (SUA) and LFPs were measured when eyes were open and closed. As movement is known to result in changes in LFPs, we tested response to eye opening in the presence and absence of movement. Neither eye state nor arm movement has a significant influence on SUA recordings. There is a statistically significant interaction between eye state and arm movement (p< 0.05). In the presence of movement, STN SUA increase when eyes open (p< 0.05). When eyes are closed, STN SUA decrease with movement (p< 0.05). STN theta LFP oscillations decrease when eyes are open compared to closed, irrespective of movement status (p< 0.05). STN activity is influenced by eye state and arm movement. It is unclear whether this is attributed to a change in the STN's role in oculomotor control or from a change in attentional state. Understanding how physiologic normal activity alters neural activity is critical for the optimization of DBS therapy, particularly in closed‐loop neuromodulation.

Deep brain stimulation (DBS) is a well‐established treatment for the management of severe motor fluctuations in advanced Parkinson's disease (PD). Until recently, device regulation, medical, and insurance practices limited DBS to patients with advanced stages of PD. In February 2016 this changed, however, when the US Food and Drug Administration (FDA) granted formal approval for the use of brain stimulator in mid‐stage PD patients. In this article, we examine whether DBS in mid‐stage PD can be ethically justified beyond the FDA approval. We scrutinize the current risk‐benefit profile, the costs‐benefit profile, and the capacity for informed consent requirement, to ask if use of subthalamic nucleus (STN) in mid‐stage DBS is ethically appropriate. We propose that mid‐stage DBS decisions could be appropriate under a shared decision‐making model, which embraces a broad quality of life perspective. Although it might be too premature to know how the FDA decision will affect medical and insurance practices, we conclude by arguing that revisions to persisting guidelines seems justified both on scientific and ethical grounds.

Accuracy of lead placement within the brain can affect the outcome of deep brain stimulation (DBS) surgery. Whether performing unilateral lead implantation, simultaneous bilateral lead implantation, or staged bilateral lead implantation affects accuracy has not yet been assessed. We compare lead placement errors to evaluate whether one approach affords greater lead accuracy. We retrospectively reviewed 205 leads placed in 125 DBS surgeries. The accuracy of lead placement, defined by differences in x, y, and z coordinates and error vector magnitudes, was compared between three surgery groups: unilateral leads, bilateral leads placed simultaneously, and bilateral leads placed in staged surgeries. We also compared accuracies between first and second leads within each bilateral cohort and between second leads of the bilateral cohorts. Finally, we examined the effect of target and age on accuracy. The accuracy of lead placement was comparable among unilateral, simultaneous bilateral, and staged bilateral leads. Timing of placement of the second lead in bilateral cases was not found to affect accuracy. The mean number of microelectrode trajectories was greater for first leads in simultaneous bilateral DBS (p= 0.032). No significant correlation between either age or target and accuracy was found. Although there may be other important reasons for performing DBS in a staged fashion, our study finds that neither laterality nor timing of second lead placement, patient age, or target site have significant impact on DBS lead accuracy, a finding that indicates with appropriate approach selection based on patient factors, accuracy does not have to be significantly compromised.

Ventralis intermedius thalamic deep brain stimulation (VIM DBS) has shown to be safe and effective for medically refractory essential tremor (ET). We evaluate the use of quantitative tremor measurement methods for head tremor in ET using a “smart” hat and a smartphone application. We enrolled 13 ET patients who previously underwent VIM DBS. Head and arm tremor was measured ON and OFF stimulation using the clinical gold standard Fahn‐Tolosa‐Marin Tremor Rating Scale (TRS). Results were then compared to two quantitative measurement techniques: Lift Pulse (smartphone application) and modified Nizet (adapted laser point measurement from Nizet et al.). Spearman's rank correlation was used to compare tremor severity and improvement on stimulation using TRS and quantitative methods to measure tremor. Lift Pulse tremor severity measurement significantly correlated with TRS for head (ρ= 0.53, p< 0.01) and arm tremor (ρ= 0.49, p< 0.01). Modified Nizet tremor severity measurement significantly correlated with TRS for head (ρ= 0.83, p< 0.001) and arm tremor (ρ= 0.50, p< 0.01). Inter‐method correlation for head tremor severity was significant (ρ= 0.45, p< 0.05). Lift Pulse tremor improvement measurement significantly correlated with TRS for arm tremor (ρ= 0.56, p< 0.05). Modified Nizet tremor improvement measurement significantly correlated with TRS for head tremor (ρ= 0.53, p< 0.01). Our results show that Lift Pulse and modified Nizet are both effective techniques to quantitatively measure head and arm tremor severity. We also show the utility of a “smart” hat to measure head tremor. Modified Nizet technique is more effective for measuring head tremor, while Lift Pulse is an effective measure of tremor severity, especially arm tremor improvement.

Chronic pain is a major, debilitating symptom of Parkinson's disease (PD). Although, deep brain stimulation (DBS) has been shown to improve pain outcomes, the mechanisms underlying this phenomenon are unclear. Microelectrode recording allows us to measure both local field potentials (LFPs) and single neuronal unit activity (SUA). In this study, we examined how single unit and LFP oscillatory activity in the basal ganglia are impacted by mechanical and thermal sensory stimuli and explored their role in pain modulation. We assessed changes in LFPs and SUAs in the subthalamic nucleus (STN), globus pallidus interna (Gpi), and globus pallidus externa (Gpe) following exposure with mechanical or thermal stimuli. Sensory thresholds were determined pre‐operatively using quantitative sensory testing. Based on these data, patients were exposed to innocuous and noxious mechanical, pressure, and thermal stimuli at individualized thresholds. In the STN, LFP alpha oscillatory activity and SUA increased in response to innocuous mechanical stimuli; SUA further increased in response to noxious mechanical, noxious pressure, and noxious thermal stimuli (p< 0.05). In the Gpe, LFP low betaactivity and SUA increased with noxious thermal stimuli; SUA also increased in response to innocuous thermal stimuli (p< 0.05). In the Gpi, innocuous thermal stimuli increased LFP gammaactivity; noxious pressure stimuli decreased low betaactivity; SUA increased in response to noxious thermal stimuli (p< 0.05). Our study is the first to demonstrate that mechanical and thermal stimuli alter basal ganglia LFPs and SUAs in PD. While STN SUA increases nearly uniformly to all sensory stimuli, SUA in the pallidal nuclei respond solely to thermal stimuli. Similarly, thermal stimuli yield increases in pallidal LFP activity, but not STN activity. We speculate that DBS may provide analgesia through suppression of stimuli‐specific changes in basal ganglia activity, supporting a role for these nuclei in sensory and pain processing circuits.

Driving is an essential facilitator of independence, community participation, and quality of life. Drivers with Parkinson's Disease (PD) make more driving errors and fail on-road evaluations more than healthy controls. In-vehicle technologies may mitigate PD-related driving impairments and associated driving errors. Establishing a rigorous study protocol will increase the internal validity and the transparency of the scientific work.

We aimed to formulate a practical clinical treatment algorithm for Holmes tremor (HT) by reviewing currently published clinical data.

Graphical Abstract

Some patients with advanced Parkinson's disease (PD) develop refractory axial symptoms and motor complications following initially effective subthalamic nucleus (STN) deep brain stimulation (DBS). We aim to determine whether globus pallidus internus (GPi) stimulation can improve refractory axial symptoms and dyskinesia, as well as psychosocial functioning and quality of life, in this group of patients who no longer benefit from STN DBS.