Safety and Efficacy of IPX203 in Parkinson's Disease: The RISE-PD Open-Label Extension Study.

BACKGROUND: IPX203 is a novel oral extended-release formulation of carbidopa/levodopa (CD/LD) developed to address the short half-life of immediate-release CD/LD. In the phase 3 RISE-PD trial, IPX203 significantly improved "Good On" time in patients with Parkinson's disease compared with immediate-release CD/LD. OBJECTIVES: To evaluate the safety and efficacy of IPX203 in an open-label extension of the pivotal phase 3 study. METHODS: This 9-month extension enrolled patients who completed the randomized, double-blind trial. Key efficacy endpoints included Movement Disorder Society-Unified Parkinson's Disease Rating Scale and Patient and Clinical Global Impression scores. Adverse events (AEs) were recorded. RESULTS: Improvements in efficacy were maintained and dosing frequency and total daily dose remained stable through the trial. A total of 52.7% of patients experienced ≥1 treatment-emergent AE, mostly mild or moderate and occurred within the first 90 days of treatment. CONCLUSIONS: In this phase 3 open-label extension, IPX203 exhibited a favorable safety and tolerability profile and sustained efficacy of comparable magnitude to the end of the double-blind study. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A Randomized Phase 3 Study Comparing P2B001 to its Components (Low-Dose Extended-Release Rasagiline and Pramipexole) and to Optimized Doses of Marketed Extended-Release Pramipexole in Early Parkinson's Disease.

BACKGROUND: There remains uncertainty as to the optimal way to initiate therapy for Parkinson's disease (PD) to maximize benefit and minimize adversity. OBJECTIVES: The objective was to determine if P2B001 (a fixed, low-dose, extended-release [ER] combination of pramipexole 0.6 mg and rasagiline 0.75 mg) is superior to each of its components and compare its safety and efficacy to optimized treatment with marketed doses of pramipexole-ER. METHODS: This was a 12-week, double-blind study (NCT03329508). Total of 544 untreated patients with PD were randomized (2:2:2:1) to treatment with P2B001, its individual components (pramipexole-ER 0.6 mg or rasagiline-ER 0.75 mg), or commercial doses of pramipexole-ER titrated to optimal dose (1.5-4.5 mg). The primary endpoint was change from baseline to week 12 in Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III. The key secondary endpoint was the change from baseline in the Epworth Sleepiness Scale (ESS) for P2B001 versus the titrated dose of pramipexole-ER. RESULTS: P2B001 provided superior efficacy compared to each of its components; mean (95% CI) treatment differences in UPDRS II + III scores were -2.66 (95% CI, -4.33 to -1.00) versus pramipexole-ER 0.6 mg (P = 0.0018) and - 3.30 (95% CI, -4.96 to -1.63) versus rasagiline-ER 0.75 mg (P < 0.0001). P2B001 had comparable efficacy with the titrated dose of pramipexole-ER (mean, 3.2 mg), but significantly less worsening in daytime-sleepiness (ESS treatment difference: -2.66 [95% CI, -3.50 to -1.81]; P < 0.0001). P2B001 was well-tolerated with fewer sleep-related and dopaminergic adverse events than titrated doses of pramipexole-ER including somnolence, orthostatic hypotension, and neuropsychiatric side effects. CONCLUSIONS: P2B001 had superior efficacy to its individual components and was comparable with commercially used doses of pramipexole-ER with less worsening of sleepiness and fewer dopaminergic adverse events. These findings support considering once-daily P2B001 as initial therapy for patients with early PD. © 2023 International Parkinson and Movement Disorder Society.

An Acute Randomized Controlled Trial of Noninvasive Peripheral Nerve Stimulation in Essential Tremor.

OBJECTIVE: To evaluate the safety and effectiveness of a wrist-worn peripheral nerve stimulation device in patients with essential tremor (ET) in a single in-office session. METHODS: This was a randomized controlled study of 77 ET patients who received either treatment stimulation (N = 40) or sham stimulation (N = 37) on the wrist of the hand with more severe tremor. Tremor was evaluated before and immediately after the end of a single 40-minute stimulation session. The primary endpoint compared spiral drawing in the stimulated hand using the Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS) Archimedes spiral scores in treatment and sham groups. Additional endpoints included TETRAS upper limb tremor scores, subject-rated tasks from the Bain and Findley activities of daily living (ADL) scale before and after stimulation as well as clinical global impression-improvement (CGI-I) rating after stimulation. RESULTS: Subjects who received peripheral nerve stimulation did not show significantly larger improvement in the Archimedes spiral task compared to sham but did show significantly greater improvement in upper limb TETRAS tremor scores (p = 0.017) compared to sham. Subject-rated improvements in ADLs were significantly greater with treatment (49% reduction) than with sham (27% reduction; p = 0.001). A greater percentage of ET patients (88%) reported improvement in the stimulation group as compared to the sham group (62%) according to CGI-I ratings (p = 0.019). No significant adverse events were reported; 3% of subjects experienced mild adverse events. CONCLUSIONS: Peripheral nerve stimulation in ET may provide a safe, well-tolerated, and effective treatment for transient relief of hand tremor symptoms.

Awake versus asleep deep brain stimulation for Parkinson's disease: a critical comparison and meta-analysis.

OBJECTIVE: No definitive comparative studies of the efficacy of 'awake' deep brain stimulation (DBS) for Parkinson's disease (PD) under local or general anaesthesia exist, and there remains significant debate within the field regarding differences in outcomes between these two techniques. METHODS: We conducted a literature review and meta-analysis of all published DBS for PD studies (n=2563) on PubMed from January 2004 to November 2015. Inclusion criteria included patient number >15, report of precision and/or clinical outcomes data, and at least 6 months of follow-up. There were 145 studies, 16 of which were under general anaesthesia. Data were pooled using an inverse-variance weighted, random effects meta-analytic model for observational data. RESULTS: There was no significant difference in mean target error between local and general anaesthesia, but there was a significantly less mean number of DBS lead passes with general anaesthesia (p=0.006). There were also significant decreases in DBS complications, with fewer intracerebral haemorrhages and infections with general anaesthesia (p<0.001). There were no significant differences in Unified Parkinson's Disease Rating Scale (UPDRS) Section II scores off medication, UPDRS III scores off and on medication or levodopa equivalent doses between the two techniques. Awake DBS cohorts had a significantly greater decrease in treatment-related side effects as measured by the UPDRS IV off medication score (78.4% awake vs 59.7% asleep, p=0.022). CONCLUSIONS: Our meta-analysis demonstrates that while DBS under general anaesthesia may lead to lower complication rates overall, awake DBS may lead to less treatment-induced side effects. Nevertheless, there were no significant differences in clinical motor outcomes between the two techniques. Thus, DBS under general anaesthesia can be considered at experienced centres in patients who are not candidates for traditional awake DBS or prefer the asleep alternative.

Downward finger displacement distinguishes Parkinson disease dementia from Alzheimer disease.

Purpose/Aim of the study: To study finger displacement in patients with Parkinson disease dementia (PDD) and in patients with Alzheimer disease (AD). METHODS: We examined 56 patients with PDD and 35 with AD. Patients were examined during their regular outpatient clinic visit. Finger displacement was measured by observers not actively involved in the study using a creative grid ruler for all PDD and AD patients. Finger displacement was examined by asking patients to point their index fingers toward the grid ruler with the nails facing upward. Patients were asked to maintain the pointing position for 15 s. After 15 s, patients were asked to close their eyes for another 15 s while maintaining the same position. A positive result was downward index finger displacement of ≥5 cm within the 15-second time window with eyes closed. RESULTS: Of the 56 PDD patients, 53 had bilateral finger displacement of >5 cm. In comparison, of the 35 AD patients, only 1 patient had minimal displacement. CONCLUSIONS: Results of the non-invasive finger displacement test may provide insight, on an outpatient basis, of the integrity of subcortical-cortical circuits. Downward finger displacement, especially bilateral downward displacement, may signal the extensive disruption of subcortical-cortical circuits that occurs in PDD patients. ABBREVIATIONS: AChE: acetylcholinesterase; AD: Alzheimer disease; DLB: dementia with Lewy bodies; ET: essential tremor; MDS-UPDRS: Movement Disorder Society-sponsored Unified Parkinson's Disease Rating Scale; MMSE: Mini-Mental State Examination; PD: Parkinson disease; PDD: Parkinson disease dementia.

National Randomized Controlled Trial of Virtual House Calls for People with Parkinson's Disease: Interest and Barriers.

BACKGROUND: Delivering specialty care remotely directly into people's homes can enhance access for and improve the healthcare of individuals with chronic conditions. However, evidence supporting this approach is limited. MATERIALS AND METHODS: Connect.Parkinson is a randomized comparative effectiveness study that compares usual care of individuals with Parkinson's disease in the community with usual care augmented by virtual house calls with a Parkinson's disease specialist from 1 of 18 centers nationally. Individuals in the intervention arm receive four virtual visits from a Parkinson's disease specialist over 1 year via secure, Web-based videoconferencing directly into their homes. All study activities, including recruitment, enrollment, and assessments, are conducted remotely. Here we report on interest, feasibility, and barriers to enrollment in this ongoing study. RESULTS: During recruitment, 11,734 individuals visited the study's Web site, and 927 unique individuals submitted electronic interest forms. Two hundred ten individuals from 18 states enrolled in the study from March 2014 to June 2015, and 195 were randomized. Most participants were white (96%) and college educated (73%). Of the randomized participants, 73% had seen a Parkinson's disease specialist within the previous year. CONCLUSIONS: Among individuals with Parkinson's disease, national interest in receiving remote specialty care directly into the home is high. Remote enrollment in this care model is feasible but is likely affected by differential access to the Internet.

Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial.

BACKGROUND: Parkinson's disease psychosis, which includes hallucinations and delusions, is frequent and debilitating in people with Parkinson's disease. We aimed to assess safety and efficacy of pimavanserin, a selective serotonin 5-HT2A inverse agonist, in this population. METHODS: In our 6 week, randomised, double-blind, placebo-controlled study, we enrolled adults (aged ≥40 years) with Parkinson's disease psychosis. Antipsychotic treatments were not permitted during the study, but controlled antiparkinsonian medication or deep brain stimulation was allowed. Eligible participants entered a 2 week non-pharmacological lead-in phase to limit the placebo response, after which they were randomly allocated (1:1) to receive pimavanserin 40 mg per day or matched placebo. The primary outcome was antipsychotic benefit as assessed by central, independent raters with the Parkinson's disease-adapted scale for assessment of positive symptoms (SAPS-PD) in all patients who received at least one dose of study drug and had a SAPS assessment at baseline and at least one follow-up. We assessed safety and tolerability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01174004. FINDINGS: Between Aug 11, 2010, and Aug 29, 2012, we randomly allocated 199 patients to treatment groups. For 90 recipients of placebo and 95 recipients of pimavanserin included in the primary analysis, pimavanserin was associated with a -5·79 decrease in SAPS-PD scores compared with -2·73 for placebo (difference -3·06, 95% CI -4·91 to -1·20; p=0·001; Cohen's d 0·50). Ten patients in the pimavanserin group discontinued because of an adverse event (four due to psychotic disorder or hallucination within 10 days of start of the study drug) compared with two in the placebo group. Overall, pimavanserin was well tolerated with no significant safety concerns or worsening of motor function. INTERPRETATION: Pimavanserin may benefit patients with Parkinson's disease psychosis for whom few other treatment options exist. The trial design used in this study to manage placebo response could have applicability to other studies in neuropsychiatric disease. FUNDING: ACADIA Pharmaceuticals.

Validation of CT-MRI fusion for intraoperative assessment of stereotactic accuracy in DBS surgery.

Deep brain stimulation is typically performed with intraoperative microelectrode recording and test stimulation for target confirmation. Recent studies have shown accurate, clinically efficacious results after lead placement without microelectrode recording or test stimulation, using interventional magnetic resonance imaging (MRI) or intraoperative computed tomography (CT; iCT) for verification of accuracy. The latter relies on CT-MRI fusion. To validate CT-MRI fusion in this setting, we compared stereotactic coordinates determined intraoperatively using CT-MRI fusion with those obtained on postoperative MRI. Deep brain stimulation electrodes were implanted with patients under general anesthesia. Direct targeting was performed on preoperative MRI, which was merged with preimplantation iCT images for stereotactic registration and postimplantation iCT images for accuracy confirmation. Magnetic resonance imaging was obtained 6 weeks postoperatively for comparison. Postoperative MRI was obtained for 48 patients, with 94 leads placed over a 1-year period. Vector error of the targeted contact relative to the initial plan was 1.1 ± 0.7 mm on iCT and 1.6 ± 0.7 mm on postoperative MRI. Variance comparisons (F-tests) showed that the discrepancy between iCT- and postoperative MRI-determined errors was attributable to measurement error on postoperative MRI, as detected in inter-rater reliability testing. In multivariate analysis, improved lead placement accuracy was associated with frame-based stereotaxy with the head of the bed at 0° compared with frameless stereotaxy with the head of the bed at 30° (P = 0.037). Intraoperative CT can be used to determine lead placement accuracy in deep brain stimulation surgery. The discrepancy between coordinates determined intraoperatively by CT-MRI fusion and postoperatively by MRI can be accounted for by inherent measurement error.

Finger displacement in Parkinson disease: up? down? sideways?

We previously reported that patients with tremor preponderant Parkinson disease (PD) displayed upward or lateral displacement of their more tremulous finger when they pointed both their index fingers at a target and closed their eyes for 15 seconds. In this study, we examined the phenomenon in 104 PD patients: 72 patients without tremor and 32 with minimal tremor to see if the displacement is related to the disease or the tremor. Sixty-eight of the 72 patients without tremor, 94%, exhibited finger displacement suggesting the phenomenon is related to the disease. None of the 104 patients were demented: mini-mental status examination (MMSE) score 29.0 ± 0. 75. Ninety patients displayed upward displacement (56 patients) or lateral or medial displacement (34 patients). MMSE score of the 90 patients: 29.2 ± 0.74 with no score < 28. Eight patients (6 without tremor) displayed downward displacement. MMSE score of the 8 patients: 27.5 ± 0.35 with 5 having MMSE score of 27. Although not significant the results suggest that patients with downward displacement and lower MMSE score may be evolving a dementia. Upward displacement with eyes closed for 15 seconds requires an ability to "remember" the position of the finger in space and to alter tone to overcome gravity. Downward displacement implies an inability to "remember" the position of the finger in space an inability to overcome the effects of gravity. This may be more likely in patients who are evolving a dementia. Two patients, with PD-like symptoms, and specific anatomical abnormalities are also presented as they illustrate the anatomy of finger displacement.

Distinguishing the tremor of Parkinson's disease from essential tremor: finger displacement.

Although, the tremor of Parkinson's disease (PD) usually, but not always, differs from essential tremor (ET), there is no simple bedside test to distinguish PD from ET. We believe we have made such an observation. We studied 50 consecutive tremor-dominant PD patients (mean age: 63.4 years; mean disease duration: 4.9 years) and 35 consecutive ET patients (mean age: 64.1 years; mean disease duration: 12.5 years). Among PD patients, 31 had a bilateral tremor and among ET patients, 29 patients had a bilateral tremor. Patients sat opposite the examiner and pointed both index fingers at the examiner's index fingers. Then they closed their eyes. Within 15 s, one or rarely both of the patient's index fingers moved, was displaced, either upward or laterally. Finger displacement occurred only with bilateral simultaneous pointing with the patient's eyes closed. All the tremor-dominant PD patients exhibited displacement of an index finger. In 46 patients, it occurred on the side of dominant tremor, in 4, it occurred bilaterally. In 31 of 35 ET patients, no displacement occurred. In 4 of 35 ET patients, it occurred unilaterally on the side of dominant tremor. Odds ratio of distinguishing PD from ET: 89.62 at 95% confidence limits (5.31-1513.4), p = 0. 0018. Sensitivity 100% (0.91-1), specificity 89% (0.72-0.96). Finger displacement can distinguish the tremor of PD from ET. The unilateral movement with eyes closed suggests the tremor of PD unlike ET may impact circuits involving the parietal and supplementary motor cortices.

Safety, tolerability, and efficacy of NLY01 in early untreated Parkinson's disease: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Converging lines of evidence suggest that microglia are relevant to Parkinson's disease pathogenesis, justifying exploration of therapeutic agents thought to attenuate pathogenic microglial function. We sought to test the safety and efficacy of NLY01-a brain-penetrant, pegylated, longer-lasting version of exenatide (a glucagon-like peptide-1 receptor agonist) that is believed to be anti-inflammatory via reduction of microglia activation-in Parkinson's disease. METHODS: We report a 36-week, randomised, double-blind, placebo-controlled study of NLY01 in participants with early untreated Parkinson's disease conducted at 58 movement disorder clinics in the USA. Participants meeting UK Brain Bank or Movement Disorder Society research criteria for Parkinson's disease were randomly allocated (1:1:1) to one of two active treatment groups (2·5 mg or 5·0 mg NLY01) or matching placebo, based on a central computer-generated randomisation scheme using permuted block randomisation with varying block sizes. All participants, investigators, coordinators, study staff, and sponsor personnel were masked to treatment assignments throughout the study. The primary efficacy endpoint for the primary analysis population (defined as all randomly assigned participants who received at least one dose of study drug) was change from baseline to week 36 in the sum of Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) parts II and III. Safety was assessed in the safety population (all randomly allocated participants who received at least one dose of the study drug) with documentation of adverse events, vital signs, electrocardiograms, clinical laboratory assessments, physical examination, and scales for suicidality, sleepiness, impulsivity, and depression. This trial is complete and registered at ClinicalTrials.gov, NCT04154072. FINDINGS: The study took place between Jan 28, 2020, and Feb 16, 2023. 447 individuals were screened, of whom 255 eligible participants were randomly assigned (85 to each study group). One patient assigned to placebo did not receive study treatment and was not included in the primary analysis. At 36 weeks, 2·5 mg and 5·0 mg NLY01 did not differ from placebo with respect to change in sum scores on MDS-UPDRS parts II and III: difference versus placebo -0·39 (95% CI -2·96 to 2·18; p=0·77) for 2·5 mg and 0·36 (-2·28 to 3·00; p=0·79) for 5·0 mg. Treatment-emergent adverse events were similar across groups (reported in 71 [84%] of 85 patients on 2·5 mg NLY01, 79 [93%] of 85 on 5·0 mg, and 73 [87%] of 84 on placebo), with gastrointestinal disorders the most commonly observed class in active groups (52 [61%] for 2·5 mg, 64 [75%] for 5·0 mg, and 30 [36%] for placebo) and nausea the most common event overall (33 [39%] for 2·5 mg, 49 [58%] for 5·0 mg, and 16 [19%] for placebo). No deaths occurred during the study. INTERPRETATION: NLY01 at 2·5 and 5·0 mg was not associated with any improvement in Parkinson's disease motor or non-motor features compared with placebo. A subgroup analysis raised the possibility of motor benefit in younger participants. Further study is needed to determine whether these exploratory observations are replicable. FUNDING: D&D Pharmatech-Neuraly.

Impedance trend from a symptomatic perielectrode cystic cavity following deep brain stimulation: illustrative case.

BACKGROUND: Deep brain stimulation (DBS) is a well-established neurosurgical intervention for a growing number of neurological and psychiatric diseases. Patients who are affected by Parkinson's disease may benefit from DBS of either the subthalamic nucleus or the globus pallidus internus. Patients who undergo DBS often notice a significant reduction in their clinical symptoms; however, the procedure is not without risks. Multicenter studies have reported postoperative complications such as hardware infection, intracranial hemorrhage, and perielectrode edema. OBSERVATIONS: The authors report a case of a perielectrode cyst managed conservatively. Tracking the impedance trend was a novel approach to monitor for changes within the cyst and to herald a clinical change in the patient. Perielectrode cystic formation can be a transient process that resolves spontaneously or with conservative, nonoperative management, and all diagnostic information is valuable in making clinical decisions. LESSONS: Impedance values have provided an appropriate estimation of this patient's clinical picture. The authors suggest treatment of edema and a cyst after DBS lead implantation through conservative management and observation, avoiding the removal of hardware if a patient's clinical picture is either stable or improving and forgoing additional clinical imaging if the impedance values are trending in an appropriate direction.

Improving levodopa delivery: IPX203, a novel extended-release carbidopa-levodopa formulation.

Introduction: IPX203 is a novel oral extended-release (ER) formulation of carbidopa (CD) and levodopa (LD) developed to address the short half-life and limited area for absorption of LD in the gastrointestinal tract. This paper presents the formulation strategy of IPX203 and its relationship to the pharmacokinetics (PK) and pharmacodynamic profile of IPX203 in Parkinson's disease (PD) patients. Methods: IPX203 was developed with an innovative technology containing immediate-release (IR) granules and ER beads that provides rapid LD absorption to achieve desired plasma concentration and maintaining it within the therapeutic range for longer than can be achieved with current oral LD formulations. The PK and pharmacodynamics of IPX203 were compared with IR CD-LD in a Phase 2, open-label, rater-blinded, multicenter, crossover study in patients with advanced PD. Results: Pharmacokinetic data showed that on Day 15, LD concentrations were sustained above 50% of peak for 6.2 h with IPX203 vs. 3.9 h with IR CD-LD (P = 0.0002). Pharmacodynamic analysis demonstrated that mean MDS-UPDRS Part III scores prior to administration of the first daily dose were significantly lower among patients receiving IPX203 than IR CD-LD (LS mean difference -8.1 [25.0], P = 0.0255). In a study conducted in healthy volunteers, a high-fat, high-calorie meal delayed plasma LD Tmax by 2 h, and increased Cmax and AUCtau by approximately 20% compared with a fasted state. Sprinkling capsule contents on applesauce did not affect PK parameters. Conclusion: These data confirm that the unique design of IPX203 addresses some of the limitations of oral LD delivery.

A simple question about falls to distinguish balance and gait difficulties in Parkinson's disease.

Although gait and balance difficulties often occur together in Parkinson's disease (PD) patients, it is believed that they are actually two eparate symptoms. However, there are no simple tests to distinguish them. We have developed the self-administered Barrow Neurological Institute (BNI) question to distinguish between gait and balance issues in PD and it was tested in 102 consecutive PD patients. The responses were compared with those of the walking and balance question (item # 2.12) of the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS), and the MDS-UPDRS motor examination and its subsets such as gait and postural stability (PS). Fifty-five patients reported balance difficulty on the BNI question and 64 reported walking and balance difficulty on the MDS-UPDRS question. Of the patients who reported balance difficulty on the BNI question, 74.5% had a PS score ≥2 and 25.4% fell at least three times per month. Of the patients who reported walking and balance difficulty on the MDS-UPDRS question, only 59.4% had a PS score ≥2 and only 10.9% fell three or more times per month. These statistically significant results suggest that the BNI question is better able to detect balance difficulty and its associated falls in PD and can be a supplement to the MDS-UPDRS or a stand-alone question to evaluate balance difficulty and its associated falls in PD.

Olfactory Deficits in the Freezing of Gait Phenotype of Parkinson's Disease.

Background: Olfactory dysfunction often occurs before motor onset in Parkinson's disease (PD) and can be detected with the University of Pennsylvania Smell Identification Test (UPSIT). Based on the Braak hypothesis, the olfactory bulb is one of two sites where disease pathology may start and spread to deeper brain structures. Objective: To evaluate whether a specific pattern of odorant identification on the UPSIT discriminated Parkinson's disease patients with and without freezing of gait. Methods: One hundred and twenty four consecutive participants (33 controls, 31 non-freezers, and 60 freezers) were administered the UPSIT. Using the chi-square test, each odorant on the UPSIT was ranked based on the differential ability of freezers and non-freezers to identify them correctly. Using predictive statistics and confusion matrices, the best combination of odorants and a cut-off score was determined. Results: Freezers had a shift toward a more severe hyposmia classification based on age and sex based normative values. The correct identification of nine odors (bubblegum, chocolate, smoke, wintergreen, paint thinner, orange, strawberry, grass, and peanut) was significantly worse in freezers compared to non-freezers. Correctly identifying ≤ 2 out of 3-odorants (bubblegum, chocolate, and smoke) had a 77% sensitivity and 61% specificity for categorizing freezers. The 3-odorant score was not correlated with disease duration, motor or total UPDRS scores, MoCA scores or age at testing. The predictive statistics were similar when sexes were separately categorized. Conclusions: A 3-odorant score helped categorize freezers and non-freezers with similar sensitivity and specificity to short odorant Parkinson's disease identification batteries.

Utility of objective gait measures in levodopa-unresponsive freezing in Parkinson's.

Levodopa-unresponsive gait freezing in Parkinson disease is debilitating. Gait kinematics, while time-consuming, can help optimize levodopa's benefit on gait stride length and stride velocity, and thereby improve freezing and falls in these patients.

Electrophysiologic Mapping for Target Acquisition in Deep Brain Stimulation May Become Unnecessary in the Era of Intraoperative Imaging.

OBJECTIVE: Electrophysiologic mapping (EM) has been instrumental in advancing neuroscience and ensuring accurate lead placement for deep brain stimulation. However, EM is associated with increased operative time, expense, and potential risk. Intraoperative imaging to verify lead placement provides an opportunity to reassess the clinical role of EM. We investigated whether EM 1) provides new information that corrects suboptimal preoperative target selection by the physician or 2) simply corrects intraoperative stereotactic error, which can instead be quickly corrected with intraoperative imaging. METHODS: Deep brain stimulation lead location errors were evaluated by measuring whether repositioning leads based on EM directed the final lead placement 1) away from or 2) toward the original target. We retrospectively identified 50 patients with 61 leads that required repositioning directed by EM. The stereotactic coordinates of each lead were determined with intraoperative computed tomography. RESULTS: In 45 of 61 leads (74%), the electrophysiologically directed repositioning moved the lead toward the initial target. The mean radial errors between the preoperative plan and targeted contact coordinates before and after repositioning were 2.2 and 1.5 mm, respectively (P < 0.001). Microelectrode recording was more likely than test stimulation to direct leads toward the initial target (88% vs. 63%; P = 0.03). The nucleus targeted was associated with the likelihood of moving toward the initial target. CONCLUSIONS: Electrophysiologic mapping corrected primarily for errors in lead placement rather than providing new information regarding errors in target selection. Thus, intraoperative imaging and improvements in stereotactic techniques may reduce or even eliminate dependence on EM.

Clinical Efficacy and Dosing of Vibrotactile Coordinated Reset Stimulation in Motor and Non-motor Symptoms of Parkinson's Disease: A Study Protocol.

Enhanced neuronal synchronization of the subthalamic nucleus (STN) is commonly found in PD patients and corresponds to decreased motor ability. Coordinated reset (CR) was developed to decouple synchronized states causing long lasting desynchronization of neural networks. Vibrotactile CR stimulation (vCR) was developed as non-invasive therapeutic that delivers gentle vibrations to the fingertips. A previous study has shown that vCR can desynchronize abnormal brain rhythms within the sensorimotor cortex of PD patients, corresponding to sustained motor relief after 3 months of daily treatment. To further develop vCR, we created a protocol that has two phases. Study 1, a double blinded randomized sham-controlled study, is designed to address motor and non-motor symptoms, sensorimotor integration, and potential calibration methods. Study 2 examines dosing effects of vCR using a remote study design. In Study 1, we will perform a 7-month double-blind sham-controlled study including 30 PD patients randomly placed into an active vCR or inactive (sham) vCR condition. Patients will receive stimulation for 4 h a day in 2-h blocks for 6 months followed by a 1-month pause in stimulation to assess long lasting effects. Our primary outcome measure is the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III off medication after 6 months of treatment. Secondary measures include a freezing of gait (FOG) questionnaire, objective motor evaluations, sensorimotor electroencephalography (EEG) results, a vibratory temporal discrimination task (VTDT), non-motor symptom evaluations/tests such as sleep, smell, speech, quality of life measurements and Levodopa Equivalent Daily Dose (LEDD). Patients will be evaluated at baseline, 3, 6, and 7 months. In the second, unblinded study phase (Study 2), all patients will be given the option to receive active vCR stimulation at a reduced dose for an additional 6 months remotely. The remote MDS-UPDRS part III off medication will be our primary outcome measure. Secondary measures include sleep, quality of life, objective motor evaluations, FOG and LEDD. Patients will be evaluated in the same time periods as the first study. Results from this study will provide clinical efficacy of vCR and help validate our investigational vibrotactile device for the purpose of obtaining FDA clearance. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT04877015.

Coordinated Reset Vibrotactile Stimulation Induces Sustained Cumulative Benefits in Parkinson's Disease.

BACKGROUND: Abnormal synchronization of neuronal activity in dopaminergic circuits is related to motor impairment in Parkinson's disease (PD). Vibrotactile coordinated reset (vCR) fingertip stimulation aims to counteract excessive synchronization and induce sustained unlearning of pathologic synaptic connectivity and neuronal synchrony. Here, we report two clinical feasibility studies that examine the effect of regular and noisy vCR stimulation on PD motor symptoms. Additionally, in one clinical study (study 1), we examine cortical beta band power changes in the sensorimotor cortex. Lastly, we compare these clinical results in relation to our computational findings. METHODS: Study 1 examines six PD patients receiving noisy vCR stimulation and their cortical beta power changes after 3 months of daily therapy. Motor evaluations and at-rest electroencephalographic (EEG) recordings were assessed off medication pre- and post-noisy vCR. Study 2 follows three patients for 6+ months, two of whom received daily regular vCR and one patient from study 1 who received daily noisy vCR. Motor evaluations were taken at baseline, and follow-up visits were done approximately every 3 months. Computationally, in a network of leaky integrate-and-fire (LIF) neurons with spike timing-dependent plasticity, we study the differences between regular and noisy vCR by using a stimulus model that reproduces experimentally observed central neuronal phase locking. RESULTS: Clinically, in both studies, we observed significantly improved motor ability. EEG recordings observed from study 1 indicated a significant decrease in off-medication cortical sensorimotor high beta power (21-30 Hz) at rest after 3 months of daily noisy vCR therapy. Computationally, vCR and noisy vCR cause comparable parameter-robust long-lasting synaptic decoupling and neuronal desynchronization. CONCLUSION: In these feasibility studies of eight PD patients, regular vCR and noisy vCR were well tolerated, produced no side effects, and delivered sustained cumulative improvement of motor performance, which is congruent with our computational findings. In study 1, reduction of high beta band power over the sensorimotor cortex may suggest noisy vCR is effectively modulating the beta band at the cortical level, which may play a role in improved motor ability. These encouraging therapeutic results enable us to properly plan a proof-of-concept study.