Motor Symptoms Of Parkinson's Disease Research Articles

Linking Invasive and Noninvasive Brain Stimulation in Parkinson's Disease: A Randomized Trial.

Recent imaging studies identified a brain network associated with clinical improvement following deep brain stimulation (DBS) in Parkinson's disease (PD), the PD response network. This study aimed to assess the impact of neuromodulation on PD motor symptoms by targeting this network noninvasively using multifocal transcranial direct current stimulation (tDCS). In a prospective, randomized, double-blinded, crossover trial, 21 PD patients (mean age 59.7 years, mean Hoehn & Yahr [H&Y] 2.4) received multifocal tDCS targeting the a-priorinetwork. Twenty-minute sessions of tDCS and sham were administered on 2 days in randomized order. Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III) scores were assessed. Before intervention, MDS-UPDRS-III scores were comparable in both conditions (stimulation days: 37.38 (standard deviation [SD] = 12.50, confidence interval [CI] = 32.04, 42.73) vs. sham days: 36.95 (SD = 13.94, CI = 30.99, 42.91), P = 0.63). Active stimulation resulted in a reduction by 3.6 points (9.7%) to 33.76 (SD = 11.19, CI = 28.98, 38.55) points, whereas no relevant change was observed after sham stimulation (36.43 [SD = 14.15, CI = 30.38, 42.48], average improvement: 0.5 [1.4%]). Repeated-measures analysis of variance (ANOVA) confirmed significance (main effect of time: F(1,20)=4.35, P < 0.05). Tukey's post hoc tests indicated MDS-UPDRS-III improvement after active stimulation (t [20] = 2.9, P = 0.03) but not after sham (t [20] = 0.42, P > 0.05). In a subset of patients that underwent DBS surgery later, their DBS response correlated with tDCS effects (R = 0.55, P(1) = 0.04). Noninvasive, multifocal tDCS targeting a DBS-derived network significantly improved PD motor symptoms. Despite a small effect size, this study provides proof of principle for the successful noninvasive neuromodulation of an invasively identified network. Future studies should investigate repeated tDCS sessions and their utility for screening before DBS surgery. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Quetiapine, Clozapine, and Pimavanserin Treatment Response in Monogenic Parkinson's Disease Psychosis: A Systematic Review.

Psychotic symptoms frequently occur in idiopathic Parkinson's disease (PD) and often require treatment with antipsychotic therapy. Most antipsychotics have the potential to worsen the motor symptoms of PD; quetiapine, clozapine, and pimavanserin are commonly used for the treatment of idiopathic PD because these medications tend to be comparatively well tolerated. Although psychotic symptoms may also occur in monogenic forms of PD, no reviews have focused on the use of antipsychotic medications in this context. The objective of the present systematic review was to characterize the effectiveness and tolerability of quetiapine, clozapine, and pimavanserin in monogenic PD-associated psychosis. A literature search was performed with PubMed, Scopus, and Embase. The search yielded 24 eligible articles describing 30 individuals, although treatment response with respect to psychotic symptoms was described in only 11 cases; of these, six individuals experienced symptomatic improvement or remission (four with clozapine and two with quetiapine), two exhibited a poor therapeutic response (one to clozapine and one to quetiapine), and the other three responded initially to antipsychotic therapy before experiencing a recurrence of symptoms. The use of quetiapine and clozapine in GBA variant-associated PD is briefly reviewed separately. Notably, no reports of pimavanserin therapy were identified. In keeping with the idiopathic PD literature, relatively low doses of medication were used in most cases. Lastly, side effects were rarely reported. Although quetiapine and particularly clozapine may be effective and well tolerated in the treatment of monogenic PD psychosis, this review highlights the paucity of available evidence to guide clinical decision making in this context.

Khảo sát tình hình điều trị thuốc cho người bệnh parkinson tại Bệnh viện Đại học Y dược TP. Hồ Chí Minh

Background: Parkinson's disease is one of the most common progressive neurodegenerative disorders. There's currently no cure for Parkinson's disease. Current therapies only help patients relieve the symptoms and improve their quality of life. Objectives: To determine the rate of drugs prescribed to treat Parkinson's disease motor symptoms, the rate of the types of drug combinations, and the frequency of drug-induced motor complications in Parkinson's disease patients. Methods: This cross-sectional study was conducted at the University Medical Center HCMC, Ho Chi Minh City. The patient was diagnosed with Parkinson's disease based on the criteria of the International Parkinson's Disease and Movement Disorder Society (IPMDS). Patients' demographic data, information about Parkinson's disease, and medications used to treat Parkinson's disease were collected. Rating scales include MDS-UPRRS (Movement Disorder Society-Unified Parkinson's Disease Rating Scale), and Hoehn &amp; Yahr. Results: Among 218 Parkinson's patients, 33 (15.1%) patients received levodopa monotherapy, 126 (57.8%) patients received combination therapy of levodopa and dopamine agonists, 07 (3.2%) ) patients received combination therapy of levodopa and trihexyphenidyl, 1 (0.5%) patient received combination therapy of dopamine agonist and trihexyphenidyl, and 51 (23.4%) patients received combination therapy of both levodopa, dopamine agonist and trihexyphenidyl. A total of 217 patients were prescribed levodopa at a median dose of 375 mg. The median daily levodopa equivalent dose was 500 mg. A total of 177 patients (81.2%) used the dopamine agonist (pramipexole) with a median dose of 0.75 mg. 27.9 % of patients used an anticholinergic drug (trihexyphenidyl) with a median dose of 2 mg. The proportion of Parkinson's disease patients with motor complications was 32.6%. Conclusion: Levodopa was the medication most commonly prescribed to treat motor symptoms in patients with Parkinson's disease. The combination of levodopa and dopamine agonist was most popularly used. Drug-induced motor complications were common in Parkinson’s disease.

Symptomatic vs. Disease-modifying treatments in neurological diseases: Where next?

Symptomatic vs. Disease-modifying treatments in neurological diseases: Where next? An optimal drug for chronic neurological disease would slow down disease progression in the long term, with short-term symptomatic benefits. This would shorten clinical development timelines and reduce the cost and risk level for drug developers. Henri Huttunen Chief Scientific Officer (CSO) at Herantis Pharma Plc explains. In Parkinson’s disease (PD), the development of motor symptoms is associated with the degeneration of dopamine-producing nerve cells in the midbrain. For decades, motor symptoms of PD have been treated with levodopa, a precursor of dopamine, which helps to replenish dopamine levels in brain areas coordinating movement. Levodopa is an example of a symptomatic treatment as it improves symptoms but does not interfere with the underlying causes or progression of the disease.

Efficacy and Safety of Zonisamide as Adjunctive Therapy in Motor Symptoms of Advanced Parkinson's Disease (PD) in Egyptian Population

Abstract Background Management of motor complications -especially wearing off- in advanced PD is very challenging. Zonisamide (ZNS) is an antiepileptic drug that showed beneficial effects in motor symptoms of PD in previous studies. Methods To determine the efficacy and safety of ZNS in motor symptoms of advanced PD, we conducted a one month double blinded randomized placebo-controlled crossover study in Egypt. PD patients with Hoehn &amp;amp; Yahr stage ≥ 2 (onstate) and at least 2 hours off time daily were randomized to one of three groups: ZNS 25mg, ZNS 50 mg and placebo. Primary outcome measure was change in off time based on part IV MDS-UPDRS (Movement disorders society-Unified Parkinson’s disease rating scale). Secondary outcome measures were: change in on time based on part IV MDS- UPDRS, change in total score MDS-UPDRS, score of part III MDS-UPDRS. Results Of 69 patients enrolled in the study and underwent randomization to the 3 groups, 49 patients completed one month follow-up. Only 26 patients underwent crossover and 20 patients completed one month follow-up. So, the total number of patients analyzed at 1 month was: 69 patients (25 patients ZNS 25 mg group, 18 patients ZNS 50 mg group and 26 patients placebo group). Both ZNS 25 and 50 mg groups showed significant improvement of total MDS-UPDRS score, Tremors ON score and part 4. Except for sedation, there was no significant adverse effects in both ZNS 25,50 mg groups as compared to placebo. Conclusion ZNS (25,50 mg) is safe and effective in improving motor symptoms of advanced PD as adjunctive therapy.

547 Creation of a Machine Learning Model to Predict Cognitive Outcomes Post Deep Brain Stimulation Surgery for Parkinson’s Disease

Abstract Background Parkinson’s disease (PD) is the second most common neurodegenerative disorder and continues to affect an increasingly large portion of the world’s population. Limitations of the medical treatment of PD with levodopa have led to deep brain stimulation (DBS) therapy being used to alleviate symptoms in advanced PD patients. Despite its efficacy with motor symptoms of PD, DBS has been noted to lead to worsening of cognitive outcomes in a percentage of cases. There is currently no predictive model for individual patient cognitive outcomes post DBS. Aim The aim of this study is the creation of a machine learning (ML) model which can help facilitate decision making for clinicians regarding offering DBS to patients. ML has the potential to analyse multiple variables and produce a predictive model for neurocognitive outcomes. The volume of variables analysed by ML is beyond the remit of calculations that can be performed by individual medical professionals for each patient. Method This study used mild cognitive impairment (MCI) as the outcome, at six months post DBS surgery to measure neurocognitive impact. Clinical and radiomics variables were used to train the models. Results Two predictive models were successfully generated – random forest and logistic regression, which showed an accuracy of 0.87 and 0.74 respectively. Conclusions The study concluded that it is possible to use ML to generate a prediction model for outcomes post DBS. The model can help optimise the decision-making process behind offering DBS surgery to patients and lend insight into the possible causes of poor outcomes.

Radiomics score derived from T1-w/T2-w ratio image can predict motor symptom progression in Parkinson's disease.

To clarify the association between a radiomics score (Rad-score) derived from T1-weighted signal intensity to T2-weighted signal intensity (T1-w/T2-w) ratio images and the progression of motor symptoms in Parkinson's disease (PD). This retrospective study included patients with PD enrolled in the Parkinson's Progression Markers Initiative. The Movement Disorders Society-Unified Parkinson's Disease Rating Scale Part III score ≥ 33 and/or Hoehn and Yahr stage ≥ 3 indicated motor function decline. The Rad-score was constructed using radiomics features extracted from T1-w/T2-w ratio images. The Kaplan-Meier analysis and Cox regression analyses were used to assess the time differences in motor function decline between the high and low Rad-score groups. A total of 171 patients with PD were divided into training (n = 101, mean age at baseline, 61.6 ± 9.3 years) and testing (n = 70, mean age at baseline, 61.6 ± 10 years). The patients in the high Rad-score group had a shorter time to motor function decline than those in the low Rad-score group in the training dataset (log-rank test, p < 0.001) and testing dataset (log-rank test, p < 0.001). The multivariate Cox regression using the Rad-score and clinical factors revealed a significant association between the Rad-score and motor function decline in the training dataset (HR = 2.368, 95%CI:1.423-3.943, p < 0.001) and testing dataset (HR = 2.931, 95%CI:1.472-5.837, p = 0.002). Rad-scores based on radiomics features derived from T1-w/T2-w ratio images were associated with the progression of motor symptoms in PD. The radiomics score derived from the T1-weighted/T2-weighted ratio images offers a predictive tool for assessing the progression of motor symptom in patients with PD. Radiomics score derived from T1-weighted/T2-weighted ratio images is correlated with the motor symptoms of Parkinson's disease. A high radiomics score correlated with faster motor function decline in patients with Parkinson's disease. The proposed radiomics score offers predictive insight into the progression of motor symptoms of Parkinson's disease.

The protective effects of repetitive transcranial magnetic stimulation with different high frequencies on motor functions in MPTP/probenecid induced Parkinsonism mouse models.

High-frequency repeated transcranial magnetic stimulation (rTMS) stimulating the primary motor cortex (M1) is an alternative, adjunctive therapy for improving the motor symptoms of Parkinson's disease (PD). However, whether the high frequency of rTMS positively correlates to the improvement of motor symptoms of PD is still undecided. By controlling for other parameters, a disease animal model may be useful to compare the neuroprotective effects of different high frequencies of rTMS. The current exploratory study was designed to compare the protective effects of four common high frequencies of rTMS (5, 10, 15, and 20Hz) and iTBS (a special form of high-frequency rTMS) and explore the optimal high-frequency rTMS on an animal PD model. Following high frequencies of rTMS application (twice a week for 5weeks) in a MPTP/probenecid-induced chronic PD model, the effects of the five protocols on motor behavior as well as dopaminergic neuron degeneration levels were identified. The underlying molecular mechanisms were further explored. We found that all the high frequencies of rTMS had protective effects on the motor functions of PD models to varying degrees. Among them, the 10, 15, and 20Hz rTMS interventions induced comparable preservation of motor function through the protection of nigrostriatal dopamine neurons. The enhancement of brain-derived neurotrophic factor (BDNF), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT-2)and the suppression of TNF-α and IL-1β in the nigrostriatum were involved in the process. The efficacy of iTBS was inferior to that of the above three protocols. The effect of 5Hz rTMS protocol was weakest. Combined with the results of the present study and the possible side effects induced by rTMS, we concluded that 10Hz might be the optimal stimulation frequency for preserving the motor functions of PD models using rTMS treatment.

Increased mean diffusivity of the caudal motor SNc identifies patients with REM sleep behaviour disorder and Parkinson’s disease

Idiopathic rapid eye movement sleep behaviour disorder (iRBD)—a Parkinson’s disease (PD) prodrome—might exhibit neural changes similar to those in PD. Substantia nigra pars compacta (SNc) degeneration underlies motor symptoms of PD. In iRBD and early PD (ePD), we measured diffusion MRI (dMRI) in the caudal motor SNc, which overlaps the nigrosome-1—the earliest-degenerating dopaminergic neurons in PD—and in the striatum. Nineteen iRBD, 26 ePD (1.7 ± 0.03 years), and 46 age-matched healthy controls (HCs) were scanned at Western University, and 47 iRBD, 115 ePD (0.9 ± 0.01 years), and 56 HCs were scanned through the Parkinson’s Progression Markers Initiative, using 3T MRI. We segmented the SNc and striatum into subregions using automated probabilistic tractography to the cortex. We measured mean diffusivity (MD) and fractional anisotropy (FA) along white-matter bundles and subregional surfaces. We performed group-level and classification analyses. Increased caudal motor SNc surface MD was the only iRBD-HCs and ePD-HCs difference replicating across datasets (padj < 0.05). No iRBD-ePD differences emerged. Caudal motor SNc surface MD classified patient groups from HCs at the single-subject level with good-to-excellent balanced accuracy in an independent sample (0.91 iRBD and 0.86 iRBD and ePD combined), compared to fair performance for total SNc surface MD (0.72 iRBD and ePD). Caudal motor SNc surface MD correlated significantly with MDS-UPDRS-III scores in ePD patients. Using dMRI and automated segmentation, we detected changes suggesting altered microstructural integrity in iRBD and ePD in the nigrostriatal subregion known to degenerate first in PD. Surface MD of the caudal motor SNc presents a potential measure for inclusion in neuroimaging biomarkers of iRBD and PD.

Effects of Chronic Exposure to Low Doses of Rotenone on Dopaminergic and Cholinergic Neurons in the CNS of Hemigrapsus sanguineus.

Rotenone, as a common pesticide and insecticide frequently found in environmental samples, may be present in aquatic habitats worldwide. Exposure to low concentrations of this compound may cause alterations in the nervous system, thus contributing to Parkinsonian motor symptoms in both vertebrates and invertebrates. However, the effects of chronic exposure to low doses of rotenone on the activity of neurotransmitters that govern motor functions and on the specific molecular mechanisms leading to movement morbidity remain largely unknown for many aquatic invertebrates. In this study, we analyzed the effects that rotenone poisoning exerts on the activity of dopamine (DA) and acetylcholine (ACh) synthesis enzymes in the central nervous system (CNS) of Asian shore crab, Hemigrapsus sanguineus (de Haan, 1835), and elucidated the association of its locomotor behavior with Parkinson's-like symptoms. An immunocytochemistry analysis showed a reduction in tyrosine hydroxylase (TH) in the median brain and the ventral nerve cord (VNC), which correlated with the subsequent decrease in the locomotor activity of shore crabs. We also observed a variation in cholinergic neurons' activity, mostly in the ventral regions of the VNC. Moreover, the rotenone-treated crabs showed signs of damage to ChAT-lir neurons in the VNC. These data suggest that chronic treatment with low doses of rotenone decreases the DA level in the VNC and the ACh level in the brain and leads to progressive and irreversible reductions in the crab's locomotor activity, life span, and changes in behavior.

Study protocol for the MIND-PD study: a randomized controlled trial to investigate clinical and biological effects of mindfulness-based cognitive therapy in people with Parkinson’s disease

BackgroundPeople with Parkinson’s disease (PD) are very sensitive to the effects of stress. The prevalence of stress-related neuropsychiatric symptoms is high, and acute stress worsens motor symptoms. Animal studies suggest that chronic stress may accelerate disease progression, but evidence for this in humans is lacking. Mindfulness-based interventions (MBIs) train participants to focus on the present moment, on purpose and without judgement. Previous studies suggest that MBIs may alleviate stress and reduce depression and anxiety in PD. We aim to demonstrate the efficacy of Mindfulness-Based Cognitive Therapy (MBCT) as a non-pharmacologic treatment strategy for neuropsychiatric (and motor) symptoms in PD, and to identify the mechanisms underlying stress and stress reduction in PD.MethodsIn a prospective randomized controlled trial (RCT), we investigate whether 8 weeks of MBCT, as compared to care as usual, can reduce symptoms of anxiety and depression in people with PD. We aim to include 124 PD patients, who experience mild-moderate symptoms of anxiety and depression, are eligible for magnetic resonance imaging (MRI) and naïve to mindfulness, and who have a disease duration ≤ 10 years. Every participant is followed for 12 months. Clinical and biochemical assessments take place at baseline (T0), after 2 months (T1), and after 12 months (T2); MRI assessments take place at T0 and T2. Our primary outcome is the total score on the Hospital Anxiety and Depression Scale (HADS) at T1, while correcting for the HADS score at T0, age, and gender. Beyond testing the effects of MBCT on symptoms of anxiety and depression in PD, we explore whether MBCT: (1) has an effect on motor symptom severity, (2) influences cerebral and biochemical markers of stress, and (3) leads to a change in biomarkers of PD progression.DiscussionMIND-PD is one of the first RCTs with a 1-year follow-up to investigate the effects of MBCT on symptoms of anxiety and depression in PD, and to explore possible mechanisms underlying stress and stress reduction in PD. Insight into these mechanisms can pave the way to new treatment methods in the future.Trial registrationClinicalTrials.gov, NCT05779137. Registered on 12 January 2023.

A Comprehensive Study for Assessing the Demand and Supply Dynamics of Parkinson's Disease Medication in Roorkee, Uttarakhand

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta region of the midbrain. This depletion of dopamine, a neurotransmitter crucial for regulating movement, leads to the characteristic motor symptoms of PD, including tremors, rigidity, bradykinesia, and postural instability. In India, the prevalence of PD is increasing, necessitating greater attention to the availability and distribution of appropriate medication. This comprehensive study aims to assess the demand and supply dynamics of PD medication in Roorkee, Uttarakhand. After recording the sales per week of various drugs, brands, dosage forms, and strengths available in Roorkee, it was determined that SINEMET (Carbidopa + Levodopa) is widely accessible in the region, with STALEVO, MIRAPEX (Pramipexole), and ARTANE (Trihexyphenidyl) being the other prominent brands available in local medical stores. These medications are primarily in tablet form. Sales data from different stores indicated that SINEMET (Carbidopa + Levodopa 25/250 mg) is the most popular drug in the Roorkee area for treating PD. In terms of drug type analysis, levodopa-based decarboxylase inhibitors, particularly the combination of Levodopa and Carbidopa, currently hold a dominant position in the PD drug market in the region

Effects of Blood Flow Restriction Resistance Training on Autonomic and Endothelial Function in Persons with Parkinson's Disease.

Autonomic dysfunction precedes endothelial dysfunction in Parkinson's disease (PD) and causes blood pressure and circulation abnormalities that are highly disruptive to one's quality of life. While exercise interventions have proven helpful for motor symptoms of PD, improving associated non-motor symptoms is limited. Low-intensity resistance training with blood flow restriction (LIRT-BFR) improves autonomic dysfunction in non-PD patients and high-intensity resistance training (HIRT) is recommended for motor symptom improvements for people with PD (PwPD). To determine the effects of LIRT-BFR and HIRT on homocysteine and autonomic and endothelial function in PwPD and to determine the hemodynamic loads during LIRT-BFR and HIRT in PwPD using a novel exercise protocol. Thirty-eight PwPD were assigned LIRT-BFR, HIRT or to a control (CNTRL) group. The LIRT-BFR and HIRT groups exercised three days per week for four weeks. The LIRT-BFR protocol used 60% limb occlusion pressure (LOP) and performed three sets of 20 repetitions at 20% of the one-repetition maximum (1RM). The HIRT group performed three sets of eight repetitions at 80% 1RM. The CNTRL group was asked to continue their normal daily routines. LIRT-BFR significantly improved orthostatic hypotension (p = 0.026), homocysteine levels (p < 0.001), peripheral circulation (p = 0.003), supine blood pressure (p = 0.028) and heart rate variability (p = 0.041); LIRT-BFR improved homocysteine levels (p < 0.018), peripheral circulation (p = 0.005), supine blood pressure (p = 0.007) and heart rate variability (p = 0.047) more than HIRT; and hemodynamic loads for LIRT-BFR and HIRT were similar. LIRT-BFR may be more effective than HIRT for autonomic and endothelial function improvements in PwPD and hemodynamic loads may be lessened in LIRT-BFR protocols using single-joint exercises with intermittent blood flow restriction. Further research is needed to determine if non-motor symptoms improve over time and if results are sustainable.

Uses of Fecal Microbiota Transplantation in Neurodegenerative Disease: A Scoping Review.

Fecal microbiota transplantation (FMT) is the administration of fecal bacteria from a healthy donor into the intestinal tract of a recipient in order to directly change the recipient's gut microbial composition and confer a health benefit. The relationship between the gut microbiome and the central nervous system, termed the gut-brain axis, has been a frequent topic of gut microbiome studies. Commensal gut bacteria communicate with the central nervous system through various hormones, cytokines, and neural pathways. Therefore, influencing the gut microbiome via FMT may have the potential in treating symptoms of neurodegenerative conditions. This study aims to identify current uses of FMT in treating neurodegenerative diseases and highlight areas of future investigation. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework, a literature search was conducted of peer-reviewed sources on September 27, 2022, from Embase, MEDLINE, Web of Science, and Cochrane Central. Searchterms were utilized that were related to the application of FMT and neurodegenerative disorders and limited those human studies, those that were published in English, and those that were published between 2017 and 2022. The initial search yielded 450 unique articles, and after the assessment of the title and abstract for inclusion and exclusion criteria, six articles were identified for full-text review. Studies that focused on either Parkinson's disease (PD) or multiple sclerosis (MS) demonstrated improvements in both motor symptoms and non-motor symptoms. FMT was also shown to provide significant relief of constipation and general gastrointestinal (GI) symptoms in all conditions studied. The studies related to MS showed the most mixed results with regard to symptomatic improvement. The data on the use of FMT as a treatment for neurodegenerative disorders is limited; however, studies have shown not only improvement in GI symptoms but also improvement in the cognitive symptoms of PD and dementia. The data on FMT as a treatment to improve the motor symptoms of PD is both more complete and more compelling than the data on the motor symptoms of MS. The studies that were reviewed showed no major adverse effects of FMT and generally promising results. There is a strong case to be made for larger, more well-controlled studies to be done on FMT and its potential use as a treatment not only for GI symptoms but for the motor and cognitive symptoms of neurodegenerative diseases.

Dopamine-mediated plasticity preserves excitatory connections to direct pathway striatal projection neurons and motor function in a mouse model of Parkinson's disease.

The cardinal symptoms of Parkinson's disease (PD) such as bradykinesia and akinesia are debilitating, and treatment options remain inadequate. The loss of nigrostriatal dopamine neurons in PD produces motor symptoms by shifting the balance of striatal output from the direct (go) to indirect (no-go) pathway in large part through changes in the excitatory connections and intrinsic excitabilities of the striatal projection neurons (SPNs). Here, we report using two different experimental models that a transient increase in striatal dopamine and enhanced D1 receptor activation, during 6-OHDA dopamine depletion, prevent the loss of mature spines and dendritic arbors on direct pathway projection neurons (dSPNs) and normal motor behavior for up to 5 months. The primary motor cortex and midline thalamic nuclei provide the major excitatory connections to SPNs. Using ChR2-assisted circuit mapping to measure inputs from motor cortex M1 to dorsolateral dSPNs, we observed a dramatic reduction in both experimental model mice and controls following dopamine depletion. Changes in the intrinsic excitabilities of SPNs were also similar to controls following dopamine depletion. Future work will examine thalamic connections to dSPNs. The findings reported here reveal previously unappreciated plasticity mechanisms within the basal ganglia that can be leveraged to treat the motor symptoms of PD.

Biosensor Strip for Rapid On-site Assessment of Levodopa Pharmacokinetics along with Motor Performance in Parkinson's Disease.

While levodopa (L-Dopa) is the primary treatment for alleviating Parkinson's disease (PD), its efficacy is hindered by challenges such as a short half-life and inconsistent plasma levels. As PD progresses, the rising need for increased and more frequent L-Dopa doses coupled with symptom fluctuations and dyskinesias underscores the urgency for improved comprehension of the interplay between L-Dopa levels and PD motor symptoms. Addressing this critical need, we present a decentralized testing method using a disposable biosensor strip and a universal slope (U-slope) calibration-free approach. This enables reliable, rapid, simple, and cost-effective decentralized L-Dopa measurements from capillary blood. A pilot study with PD persons demonstrates the ability to monitor real-time L-Dopa pharmacokinetics from fingerstick blood after oral L-Dopa-Carbidopa (C-Dopa) tablet administration. Correlating capillary blood L-Dopa levels with PD motor scores revealed a well-defined inverse correlation with temporal motor fluctuations. We compared the resulting dynamic capillary blood L-Dopa levels with plasma L-Dopa levels using the traditional but clinically impractical high-performance liquid chromatography technique. By providing timely feedback on a proper L-Dopa dosing regimen in a decentralized and rapid fashion, this new biosensing platform will facilitate tailored optimal L-Dopa dosing, towards improving symptom management and enhancing health-related quality of life.

Biosensor Strip for Rapid On‐site Assessment of Levodopa Pharmacokinetics along with Motor Performance in Parkinson's Disease

AbstractWhile levodopa (L‐Dopa) is the primary treatment for alleviating Parkinson's disease (PD), its efficacy is hindered by challenges such as a short half‐life and inconsistent plasma levels. As PD progresses, the rising need for increased and more frequent L‐Dopa doses coupled with symptom fluctuations and dyskinesias underscores the urgency for improved comprehension of the interplay between L‐Dopa levels and PD motor symptoms. Addressing this critical need, we present a decentralized testing method using a disposable biosensor strip and a universal slope (U‐slope) calibration‐free approach. This enables reliable, rapid, simple, and cost‐effective decentralized L‐Dopa measurements from capillary blood. A pilot study with PD persons demonstrates the ability to monitor real‐time L‐Dopa pharmacokinetics from fingerstick blood after oral L‐Dopa‐Carbidopa (C–Dopa) tablet administration. Correlating capillary blood L‐Dopa levels with PD motor scores revealed a well‐defined inverse correlation with temporal motor fluctuations. We compared the resulting dynamic capillary blood L‐Dopa levels with plasma L‐Dopa levels using the traditional but clinically impractical high‐performance liquid chromatography technique. By providing timely feedback on a proper L‐Dopa dosing regimen in a decentralized and rapid fashion, this new biosensing platform will facilitate tailored optimal L‐Dopa dosing, towards improving symptom management and enhancing health‐related quality of life.

The lateralized effects of Parkinson’s Disease on motor imagery: Evidence from mental chronometry

Alterations to the content of action representations may contribute to the movement challenges that characterize Parkinson’s Disease (PD). One way to investigate action representations is through motor imagery. As PD motor symptoms typically have a unilateral onset, disease-related deficits related to action representations may follow a similarly lateralized pattern. The present study examined if temporal accuracy of motor imagery in individuals with PD differed according to the side of the body involved in the task. Thirty-eight participants with PD completed a mental chronometry task using their more affected and less affected side. Participants had significantly shorter mental versus physical movement times for the more affected. Higher imagery vividness in the kinaesthetic domain predicted shorter mental versus physical movement times for the more affected side, as did lower imagery vividness in the visual domain and poorer cognitive function. These results indicate that people with PD imagine movements differently when the target actions their more affected versus less affected side. It is additionally possible that side-specific deficits in the accurate processing of kinaesthetic information lead to an increased reliance on visual processes and cognitive resources to successfully execute motor imagery involving the more affected side.

Evaluation of the Parkinson's Remote Interactive Monitoring System in a Clinical Setting: Usability Study.

The fastest-growing neurological disorder is Parkinson disease (PD), a progressive neurodegenerative disease that affects 10 million people worldwide. PD is typically treated with levodopa, an oral pill taken to increase dopamine levels, and other dopaminergic agonists. As the disease advances, the efficacy of the drug diminishes, necessitating adjustments in treatment dosage according to the patient's symptoms and disease progression. Therefore, remote monitoring systems that can provide more detailed and accurate information on a patient's condition regularly are a valuable tool for clinicians and patients to manage their medication. The Parkinson's Remote Interactive Monitoring System (PRIMS), developed by PragmaClin Research Inc, was designed on the premise that it will be an easy-to-use digital system that can accurately capture motor and nonmotor symptoms of PD remotely. We performed a usability evaluation in a simulated clinical environment to assess the ease of use of the PRIMS and determine whether the product offers suitable functionality for users in a clinical setting. Participants were recruited from a user sign-up web-based database owned by PragmaClin Research Inc. A total of 11 participants were included in the study based on the following criteria: (1) being diagnosed with PD and (2) not being diagnosed with dementia or any other comorbidities that would make it difficult to complete the PRIMS assessment safely and independently. Patient users completed a questionnaire that is based on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale. Interviews and field notes were analyzed for underlying themes and topics. In total, 11 people with PD participated in the study (female individuals: n=5, 45%; male individuals: n=6, 55%; age: mean 66.7, SD 7.77 years). Thematic analysis of the observer's notes revealed 6 central usability issues associated with the PRIMS. These were the following: (1) the automated voice prompts are confusing, (2) the small camera is problematic, (3) the motor test exhibits excessive sensitivity to the participant's orientation and position in relation to the cameras, (4) the system poses mobility challenges, (5) navigating the system is difficult, and (6) the motor test exhibits inconsistencies and technical issues. Thematic analysis of qualitative interview responses revealed four central themes associated with participants' perspectives and opinions on the PRIMS, which were (1) admiration of purpose, (2) excessive system sensitivity, (3) video instructions preferred, and (4) written instructions disliked. The average system usability score was calculated to be 69.2 (SD 4.92), which failed to meet the acceptable system usability score of 70. Although multiple areas of improvement were identified, most of the participants showed an affinity for the overarching objective of the PRIMS. This feedback is being used to upgrade the current PRIMS so that it aligns more with patients' needs.

Premotor cortical beta synchronization and the network neuromodulation of externally paced finger tapping in Parkinson's disease

Parkinson's disease (PD) is characterized by the disruption of repetitive, concurrent and sequential motor actions due to compromised timing-functions principally located in cortex-basal ganglia (BG) circuits. Increasing evidence suggests that motor impairments in untreated PD patients are linked to an excessive synchronization of cortex-BG activity at beta frequencies (13–30 Hz). Levodopa and subthalamic nucleus deep brain stimulation (STN-DBS) suppress pathological beta-band reverberation and improve the motor symptoms in PD. Yet a dynamic tuning of beta oscillations in BG-cortical loops is fundamental for movement-timing and synchronization, and the impact of PD therapies on sensorimotor functions relying on neural transmission in the beta frequency-range remains controversial. Here, we set out to determine the differential effects of network neuromodulation through dopaminergic medication (ON and OFF levodopa) and STN-DBS (ON-DBS, OFF-DBS) on tapping synchronization and accompanying cortical activities. To this end, we conducted a rhythmic finger-tapping study with high-density EEG-recordings in 12 PD patients before and after surgery for STN-DBS and in 12 healthy controls. STN-DBS significantly ameliorated tapping parameters as frequency, amplitude and synchrony to the given auditory rhythms. Aberrant neurophysiologic signatures of sensorimotor feedback in the beta-range were found in PD patients: their neural modulation was weaker, temporally sluggish and less distributed over the right cortex in comparison to controls. Levodopa and STN-DBS boosted the dynamics of beta-band modulation over the right hemisphere, hinting to an improved timing of movements relying on tactile feedback. The strength of the post-event beta rebound over the supplementary motor area correlated significantly with the tapping asynchrony in patients, thus indexing the sensorimotor match between the external auditory pacing signals and the performed taps. PD patients showed an excessive interhemispheric coherence in the beta-frequency range during the finger-tapping task, while under DBS-ON the cortico-cortical connectivity in the beta-band was normalized. Ultimately, therapeutic DBS significantly ameliorated the auditory-motor coupling of PD patients, enhancing the electrophysiological processing of sensorimotor feedback-information related to beta-band activity, and thus allowing a more precise cued-tapping performance.