Motor Function In Parkinson's Disease Patients Research Articles

Motor improvement in Parkinson’s disease patients receiving caffeine adjuvants: A double-blind randomized controlled trial in Indonesia

Parkinson's disease (PD) manifests as a movement and brain function disorder characterized by symptoms such as resting tremors, rigidity, bradykinesia, and postural instability, leading to disability among patients. The use of psychostimulants such as caffeine has been associated with the improvement of motor symptoms in PD patients; however, studies regarding the effect of caffeine adjuvant therapy on motor function among PD patients in the Indonesian population are lacking. The aim of this study was to evaluate motor improvement as measured by the change in scores of the Movement Disorder Society - Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) among PD patients receiving caffeine adjuvant. A double-blind randomized controlled trial (RCT) was conducted among PD patients at Dr. Soetomo General Academic Hospital and Universitas Airlangga Hospital, Surabaya, Indonesia, from April to August 2023. A total of 27 patients were enrolled and randomly assigned to an intervention (receiving caffeine adjuvant, n=15) and control group (receiving placebo, n=12). Motor improvement was measured using the UPDRS III score prior to intervention and three weeks after. The Chi-squared test was used to analyze the difference in UPDRS III scores between the two groups. Motor improvement, as demonstrated by a reduction in the UPDRS III score, was observed in patients receiving caffeine adjuvant compared to those receiving placebo (80.0% vs 16.7%; p=0.004). Regarding the safety profile, only four out of 15 (26.6%) patients treated with caffeine reported minor adverse events. These conditions improved over time during the intervention. None of the 12 patients in the placebo reported adverse events. This study provides valuable insights into the initial dosage of caffeine that improves motor function in PD patients with minimum adverse effects.

Efficacy of Repetitive Transcranial Magnetic Stimulation over the Supplementary Motor Area on Motor Function in Parkinson's Disease: A Meta-Analysis.

The objective of this study was to assess the effect of repetitive transcranial magnetic stimulation (rTMS) on the supplementary motor area (SMA) in motor function in Parkinson's disease (PD) patients. Databases searched included 5 databases from October 7,2022 to January 4, 2023. The Cochrane Bias Risk Assessment Tool was used for quality assessment. Standardized mean differences (SMDs) were calculated using a random-effects model. Outcome measure is the motor function examination of the motor part of Unified Parkinson's Disease Rating Scale (UPDRS-III). Seven studies totaling 374 patients were included. Meta-analysis showed that stimulation of SMA significantly improved motor function in PD patients compared with sham stimulation (SMD = -1.24; 95% CI, -2.24 to -0.24; P = 0.02; I2 = 93%). Stimulation of the same target (SMA), subgroup analysis showed that high-frequency rTMS (HF-rTMS) is more effective than low-frequency rTMS (LF-rTMS) in improving motor function in PD (SMD = -1.39; 95% CI, -2.21 to -0.57; P = 0.04; I2 = 77.2%). Overall, rTMS over SMA had a statistically significant improvement in motor function in PD patients, and HF-rTMS is statistically significantly more effective than LF-rTMS.

Effectiveness of Yijinjing on cognitive and motor functions in patients with Parkinson's disease: study protocol for a randomized controlled trial.

Parkinson's disease (PD) is a common neurodegenerative disorder that affects motor and non-motor functions, significantly reducing patients' quality of life. No effective drug-based treatments are known to solve this problem. Non-drug therapies such as Yijinjing exercise have shown potential in improving cognitive and motor functions in PD patients. However, solid evidence must still be provided to support their clinical efficacy. This study aims to evaluate the clinical efficacy of Yijinjing exercise interventions in PD patients and explore the underlying mechanisms between the cognitive and motor functions in PD. This is a single-center randomized controlled trial in which 96 eligible PD patients will be randomly assigned to receive either Yijinjing exercise group or brisk walking group or control group in a ratio of 1:1:1. Interventions (Yijinjing exercise or brisk walking training, 40 min per session) will be provided in 3 sessions per week (Monday, Wednesday, Friday) for 12 weeks, with a total of 36 sessions. After the treatment, there will be a 1-month follow-up period. The primary outcomes will be measured using the Montreal Cognitive Assessment (MoCA) and the Unified Parkinson's Disease Rating Scale motor section (UPDRS-III). Secondary outcomes include balance function, executive function, walking function, sleep quality, and quality of life. Additionally, the prefrontal cerebral and sensorimotor cortex blood oxygen signal level will be collected to explore the underlying mechanisms. All outcomes will be assessed at baseline, at the end of 12 weeks of treatment and after an additional 1-month follow-up period. The results of the study protocol will provide high-quality evidence for the potential of intervention measures based on the Yijinjing exercise to improve the cognitive and activity levels of Parkinson's disease patients. We envision the Yijinjing exercise as a non-pharmacological family activity that can provide a new and more effective method for the treatment of Parkinson's disease patients or those at risk. This study was approved by the Ethics Committee of the Second Rehabilitation Hospital of Shanghai (2020-05-01). The trial has been registered in the China Clinical Trials Registry (ChiCTR2200055636).

Effects of tDCS and tRNS in two electrode placement methods on the excitability of basal ganglia cells in Parkinson's disease compared to DBS

Despite advances in the drug therapy of neurological disorders in recent decades, it has faced limitations such as resistance to specific drugs or subsequent complications. Nowadays, the studies on cortical stimulations to improve motor function in Parkinson's disease (PD) are increasing. Given the side effects of invasive stimulations to enhance motor function in the disease (e.g., deep brain stimulation (DBS)), non-invasive methods like transcranial direct current (tDCS) and transcranial random noise (tRNS) stimulations have attracted researchers' attention. Treatments are currently applied despite the non-well understood mechanism behind the techniques. The present study aimed to evaluate the effects of tDCS and tRNS on globus pallidus (GP) and subthalamic nucleus (STN) areas in PD patients. Thus, 3D head models were first created using MRI images, and the two stimulations were simulated based on two electrode placements of primary motor cortex (M1) and dorsolateral prefrontal cortex (DLPFC) anodal stimulation. The stimulations were compared using the current distributed in the two regions. Additionally, the effect of basal ganglia (BG) model on the excitation current distributed in the target areas was examined. Considering the membrane potential of each excitation in the two areas of all subjects, each electrode method was compared with tDCS, tRNS, and DBS in order for effectiveness. The results represented more appropriate effectiveness of the tDCS with M1 than the tRNS in the target region. Further, the method results were acceptable compared to the DBS results. The tDCS and non-invasive electrical stimulation were useful in improving the motor function of PD patients.

Oral-diadochokinesis between Parkinson's disease and neurotypical elderly among Malaysian-Malay speakers.

Parkinson's disease (PD) has an impact on speech production, manifesting in various ways including alterations in voice quality, challenges in articulating sounds and a decrease in speech rate. Numerous investigations have been conducted to ascertain the oral-diadochokinesis (O-DDK) rate in individuals with PD. However, the existing literature lacks exploration of such O-DDK rates in Malaysia and does not provide consistent evidence regarding the advantage of real-word repetition. To explore the effect of gender, stimuli type and PD status and their interactions on the O-DDK rates among Malaysian-Malay speakers. O-DDK performance of 62 participants (29 individuals with PD and 33 healthy elderly) using a non-word ('pataka'), a Malay real-word ('patahkan') and an English real-word ('buttercake') was audio recorded. The number of syllables produced in 8s was counted. A hierarchical linear modelling was performed to investigate the effects of stimuli type (non-word, Malay real-word, English real-word), PD status (yes, no), gender (male, female) and their interactions on the O-DDK rate. The model accounted for participants' age as well as the nesting of repeated measurements within participants, thereby providing unbiased estimates of the effects. The stimuli effect was significant (p < 0.0001). Malay real-word showed the lowest O-DDK rate (5.03 ± 0.11 syllables/s), followed by English real-word (5.25 ± 0.11 syllables/s) and non-word (5.42 ± 0.11 syllables/s). Individuals with PD showed a significantly lower O-DDK rate compared to healthy elderly (4.73 ± 0.15 syllables/s vs. 5.74 ± 0.14 syllables/s, adjusted p < 0.001). A subsequent analysis indicated that the O-DDK rate declined in a quadratic pattern. However, neither gender nor age effects were observed. Additionally, no significant two-way interactions were found between stimuli type, PD status and gender (all p > 0.05). Therefore, the choice of stimuli type has no or only limited effect considering the use of O-DDK tests in clinical practice for diagnostic purposes. The observed slowness in O-DDK among individuals with PD can be attributed to the impact of the movement disorder, specifically bradykinesia, on the physiological aspects of speech production. Speech-language pathologists can gain insights into the impact of PD on speech production and tailor appropriate intervention strategies to address the specific needs of individuals with PD according to disease stages. What is already known on this subject The observed slowness in O-DDK rates among individuals with PD may stem from the movement disorder's effects on the physiological aspects of speech production, particularly bradykinesia. However, there is a lack of consistent evidence regarding the influence of real-word repetition and how O-DDK rates vary across different PD stages. What this study adds to existing knowledge The O-DDK rates decline in a quadratic pattern as the PD progresses. The research provides insights into the advantage of real-word repetition in assessing O-DDK rates, with Malay real-word showing the lowest O-DDK rate, followed by English real-word and non-word. What are the potential or actual clinical implications of this work? Speech-language pathologists can better understand the evolving nature of speech motor impairments as PD progresses. This insight enables them to design targeted intervention strategies that are sensitive to the specific needs and challenges associated with each PD stage. This finding can guide clinicians in selecting appropriate assessment tools for evaluating speech motor function in PD patients.

Efficacy of Probiotics in Improving Motor Function and Alleviating Constipation in Parkinson's Disease: A Randomized Controlled Trial.

Parkinson's disease (PD) is one of the common neurodegenerative diseases, and there has been an increasing interest in the potential role of intestinal dysbiosis in its pathogenesis and related gastrointestinal complications such as constipation. This study aims to evaluate the effects of multi-strain probiotics on constipation and motor function in PD patients. This study was a blinded, randomized controlled trial (RCT) that involved 27 PD patients who were diagnosed with constipation according to the ROME IV criteria for functional constipation. The primary outcome measured before and after the intervention in both the placebo and probiotic groups was the frequency of defecation. Secondary outcomes evaluated were laxative use, sense of complete evacuation, Bristol Stool Scale for consistency, and Unified Parkinson's Disease Rating Scale (UPDRS) scale. The study lasted for eight weeks. Both groups also were educated about lifestyle modification. Of 30 included patients (15 in each group), 13 were women, and 17 were men. Three patients dropped out of the study. Between-group analysis showed that the frequency of bowel movements significantly increased in the probiotic group 4 [3 - 5] in comparison with 2 [2 - 3] in placebo (P = 0.02). Stool consistency also improved in the probiotic group (P = 0.04). However, there were no significant differences in other outcomes. The within-group analysis showed improvement in stool consistency in both probiotics and placebo groups (P = 0.01 and P = 0.007, respectively), while stool frequency and sense of complete evacuation significantly improved only in the probiotic group (P < 0.05). This study demonstrated that multi-strain probiotics could improve frequency, consistency, and sense of complete evacuation in PD patients, while there was no significant effect on motor functions in 8 weeks. It is suggested that additional studies be conducted on longer-term effects.

P 15 Long-term subthalamic deep brain stimulation modulates pathological beta oscillations in the AAV-A53T-Synuclein Parkinson's disease rat model

Introduction: Aberrant beta (13-35 Hz) synchrony within the cortico-basal ganglia circuit has been reported as disease-specific hallmark of human Parkinson's disease (PD). The suppression of pathologically enhanced beta oscillations following subthalamic deep brain stimulation (STN-DBS ) is considered to be a crucial mechanism mediating improved motor function in PD patients and animal models. However, it remains unclear how long-term STN-DBS modulates beta oscillations over time in PD models with ongoing dopaminergic neurodegeneration. To clarify, we performed 3 weeks of continuous STN-DBS in a pathologically-relevant preclinical AAV-A53T-αSynuclein PD rat model (A53T). This model is characterized by a gradual nigrostriatal degeneration and reflects clinical hallmarks of human PD, thus allowing us to study neuromodulatory effects of long -term STN-DBS. Materials & methods: In this study, adult male Sprague Dawley rats were randomly assigned to EV (Empty Vector) and A53T groups and additionally divided into 2 subgroups: stim-ON and stim-OFF. During stereotaxic injection of viral vectors (EV or human AAV-A53T-αSynuclein virus), electrophysiological recordings and DBS electrodes were implanted. To obtain the LFP and ECoG data, we conducted monopolar LFP recordings in globus pallidus - external segment (GPe) and electrocorticography (ECoG) in motor cortex during 4 recording sessions - 1, 3, 6, 8 weeks after surgery. Continuous high frequency DBS / sham-DBS was induced from the 3rd week on, lasting for additional 3 weeks. Neuromodulatory effects of long-term STN-DBS on LFP / ECoG were evaluated immediately at stimulation termination in awake, resting state animals, and repeated after wash-out period for 2 weeks. Results: Both A53T groups developed augmented beta activity in MCx and GPe vs. EV at week 3 after surgery (X 2 ≥7.33, p≤0.03; z≥-2.45, p≤0.05). In the A53T stim-ON group, 3 weeks of continuous STN-DBS suppressed the elevated MCx and GPe beta power compared to EV at week 6 (z≥-1.12, p≥0.25). Specifically, in the A53T stim-ON group, the suppressive effect of beta power after the long-term STN-DBS was still present after 2 weeks wash-out period in the GPe (z = -1.41, p = 0.16), but not in the MCx (z = -2.12, p = 0.03) compared to EV. In contrast, the A53T stim-OFF group augmented MCx and GPe beta power sustainably for 8 weeks (z≥-2.45, p≤0.05). Conclusion: Our preliminary results suggest that long-term STN-DBS has a suppressive effect on pathological beta oscillations in the progressive A53T-aSyn PD rat model.

Levodopa/carbidopa/entacapone for the treatment of early Parkinson’s disease: a meta-analysis

Treatment of Parkinson's disease with levodopa/carbidopa/entacapone (LCE) has been studied for a long time. However, the efficacy and safety of LCE in the treatment of early Parkinson's disease (PD) still need to be assessed. Our objective was to do a meta-analysis of relevant randomized controlled trials (RCTs) to evaluate the efficacy and safety of LCE for early PD. PubMed, Embase, the Cochrane Library, and the Web of Science were searched for RCTs with "levodopa/carbidopa/entacapone" and "Parkinson's disease" as keywords. The search period was from inception to October 2018. The quality of included studies was strictly evaluated. We evaluated the quality of included studies strictly and six studies met all inclusion criteria. The results showed that LCE could improve activities of daily living and motor function in PD patients. However, LCE therapy was associated with higher risks of total AEs and single AEs compared with traditional therapy.

Inter-rater variability in motor function assessment in Parkinson's disease between experts in movement disorders and nurses specialising in PD management

Introduction and objectiveIn clinical practice, assessing patients with Parkinson's disease (PD) is a complex, time-consuming task. Our purpose is to provide a rigorous and objective evaluation of how motor function in PD patients is assessed by neurologists specialising in movement disorders, on the one hand, and by nurses specialising in PD management, on the other. MethodsWe conducted an observational, cross-sectional, single-centre study of 50 patients with PD (52% men; mean age: 64.7±8.7 years) who were assessed between 5 January 2016 and 20 July 2016. A neurologist and a nurse evaluated motor function in the early morning hours using the Unified Parkinson's Disease Rating Scale (UPDRS) parts III and IV and Hoehn & Yahr (H&Y) scale. Tests were administered in the same PD periods (in 48 patients during the “off” time and in 2 patients during the “on” time). Inter-rater variability was estimated with the intraclass correlation coefficient (ICC). ResultsForty-nine patients (98%) were classified in the same H&Y stage by both raters. Assessment times were similar for both raters. ICC for UPDRS-IV and UPDRS-III total scores were 0.955 (P<.0001) and 0.954 (P<.0001), respectively. The greatest variability was found for UPDRS-III item 29 (gait; ICC=0.746; P<.0001) and the lowest, for item 30 (postural stability; ICC=0.918; P<.0001). ConclusionsMotor function assessment of PD patients by a trained nurse is equivalent to that made by an expert neurologist and takes the same time to complete.

Quantitative assessment of motor function in patients with Parkinson's disease using wearable sensors

Motor dysfunction is the main clinical symptom and diagnosis basis of patients with Parkinson's disease (PD). A total of 30 subjects were recruited in this study, including 15 PD patients (PD group) and 15 healthy subjects (control group). Then 5 wearable inertial sensor nodes were worn on the bilateral upper limbs, lower limbs and waist of subjects. When completing the 6 paradigm tasks, the acceleration and angular velocity signals from different parts of the body were acquired and analyzed to obtain 20 quantitative parameters which contain information about the amplitude, frequency, and fatigue degree of movements to assess the motor function. The clinical data of the two groups were statistically analyzed and compared, and then Back Propagation (BP) Neural Network was used to classify the two groups and predict the clinical score. The final results showed that most of the parameters had significant difference between the two groups, ten times of 5-fold cross validation showed that the classification accuracy of the BP Neural Network for the two groups was 90%, and the predictive accuracy of Hoehn-Yahr (H-Y) staging and unified PD rating scale (UPDRS) Ⅲ score of the patients were 72.80% and 68.64%, respectively. This study shows the feasibility of quantitative assessment of motor function in PD patients using wearable sensors, and the quantitative parameters obtained in this paper may have reference value for future related research.

The Efficacy of Istradefylline for Treating Mild Wearing-Off in Parkinson Disease

The adenosine A2A antagonist istradefylline has been used to treat Parkinson disease (PD) with symptoms of wearing-off since 2013 in Japan. Previous randomized controlled trials of istradefylline compared with placebo included PD patients experiencing an average daily OFF time of more than 2 hours. The purpose of this study is to assess the efficacy of 20 mg/d istradefylline in PD subjects experiencing an average daily OFF time of 3 hours or less. Fifteen patients were enrolled into this retrospective study. They received 20 mg/d istradefylline for 12 weeks. Changes in the Unified Parkinson's Disease Rating Scale part III scores in the ON state (ON-UPDRS-III) scores and daily OFF time were assessed at baseline and after 4, 8, and 12 weeks of administration of istradefylline. At baseline, all subjects had shorter daily OFF times, lower doses of L-DOPA and higher ON-UPDRS-III scores than those in previous randomized controlled trials. Twelve weeks of istradefylline significantly reduced ON-UPDRS-III scores (P < 0.001, Wilcoxon signed rank test). Eleven patients (73%) showed more than 50% reductions in ON-UPDRS-III scores. Improvement of ON-UPDRS-III was significantly correlated with baseline ON-UPDRS-III, and the mean ON-UPDRS-III score at end point was 12.1. Our result suggests that 20 mg/d istradefylline significantly improved motor functions in PD patients with mild wearing-off.

Variabilidad en la exploración motora de la enfermedad de Parkinson entre el neurólogo experto en trastornos del movimiento y la enfermera especializada

Introduction and objectiveIn clinical practice, assessing patients with Parkinson's disease (PD) is a complex, time-consuming task. Our purpose is to provide a rigorous and objective evaluation of how motor function in PD patients is assessed by neurologists specialising in movement disorders, on the one hand, and by nurses specialising in PD management, on the other. MethodsWe conducted an observational, cross-sectional, single-centre study of 50 patients with PD (52% men; mean age: 64.7 ± 8.7 years) who were assessed between 5 January 2016 and 20 July 2016. A neurologist and a nurse evaluated motor function in the early morning hours using the Unified Parkinson's Disease Rating Scale (UPDRS) parts III and IV and Hoehn & Yahr (H&Y) scale. Tests were administered in the same PD periods (in 48 patients during the ‘off’ time and in 2 patients during the ‘on’ time). Inter-rater variability was estimated with the intraclass correlation coefficient (ICC). ResultsForty-nine patients (98%) were classified in the same H&Y stage by both raters. Assessment times were similar for both raters. ICC for UPDRS-IV and UPDRS-III total scores were 0.955 (P<.0001) and 0.954 (P<.0001), respectively. The greatest variability was found for UPDRS-III item 29 (gait; ICC=0.746; P<.0001) and the lowest, for item 30 (postural stability; ICC=0.918; P<.0001). ConclusionsMotor function assessment of PD patients by a trained nurse is equivalent to that made by an expert neurologist and takes the same time to complete.

Spinal Cord Stimulation for the Treatment of Abnormal Posture and Gait Disorder in Patients With Parkinson's Disease

Patients with advanced Parkinson's disease (PD) often present with axial symptoms, including abnormal posture, postural instability, and gait disorder. Although spinal cord stimulation (SCS) is effective for pain, little is known about the effect of SCS on motor function in PD patients. The present study investigated the effect of SCS on posture and gait in 15 PD patients, 5 men and 10 women aged 63-79 years (mean 71.1 years), with low back pain and leg pain who received SCS. A visual analog scale (VAS) was used for pain evaluation pre- and postoperatively. The Unified Parkinson's Disease Rating Scale, Timed Up and Go tests, and Timed 10-Meter Walk tests were used to evaluate motor function and activities of daily living of patients. Preoperative mean VAS score was 8.9 (range 7.8-10), which showed significant postoperative improvement at 3 months to mean VAS score of 2.0 (range 0-3.3). The improvements in VAS scores persisted at 12 months after surgery with mean VAS score of 2.3 (range 0-4). Posture and postural stability motor subscores were improved at 3 months after SCS, and gait had significantly improved at 3 months and 1 year after surgery. Timed 10-Meter Walk tests also demonstrated that patient gait was significantly improved at 3 months and 12 months after surgery. Most advanced stage PD patients suffer considerable pain that causes abnormal posture and gait disturbance. SCS is expected to lead to both amelioration of pain and improvement of motor function in such patients.

Immediate Versus Delayed Switch From Levodopa/Carbidopa to Levodopa/Carbidopa/Entacapone: Effects on Motor Function and Quality of Life in Patients With Parkinson's Disease With End-of-Dose Wearing Off

ABSTRACTObjective. Assess motor function and quality of life (QoL) in Parkinson's disease (PD) subjects with end-of-dose wearing off (EODWO), comparing immediate and delayed switch (IS, DEL) to levodopa/carbidopa/entacapone (LCE). Background. LCE treatment improves motor function in PD patients with EODWO. Correlations with QoL have not been previously assessed. Methods. A 16-week, prospective, randomized, multicenter, open-label study in PD subjects on stable levodopa/carbidopa (LC) doses with EODWO. The IS subjects switched to LCE at baseline; DEL subjects at week 4. The primary efficacy variable was UPDRS III score (baseline to week 4). QoL measurements (PDQUALIF, PDQ-39) were assessed at baseline, weeks 4, 8, and study endpoint. Results. The intent-to-treat population comprised 350/359 patients (IS, n = 177; DEL, n = 173). A significant decrease in UPDRS III scores at week 4 was observed (IS, 3.7U, p < .0001; DEL, 1.8U, p = .0018). Group differences favored IS (1.9U, p = .0148). At week 8, IS subjects had significant total score decreases in PDQUALIF (2.5U, p = .0133) and PDQ-39 (5.8U, p = .0001). In the mobility and activities of daily living PDQ-39 subdomains, IS subjects had significantly larger week 4 decreases (versus DEL p = .0331 and p = .0125, respectively). Adverse events included diarrhea (14.5%), nausea (12.3%), and dizziness (8.4%). Conclusion. The IS provided greater motor improvement at week 4 and improved QoL at week 8.

Stimulation of the subthalamic nucleus and impulsivity: Release your horses

In Parkinson disease (PD) patients, deep brain stimulation (DBS) of the subthalamic nucleus (STN) may contribute to certain impulsive behavior during high-conflict decisions. A neurocomputational model of the basal ganglia has recently been proposed that suggests this behavioral aspect may be related to the role played by the STN in relaying a "hold your horses" signal intended to allow more time to settle on the best option. The aim of the present study was 2-fold: 1) to extend these observations by providing evidence that the STN may influence and prevent the execution of any response even during low-conflict decisions; and 2) to identify the neural correlates of this effect. We measured regional cerebral blood flow during a Go/NoGo and a control (Go) task to study the motor improvement and response inhibition deficits associated with STN-DBS in patients with PD. Although it improved Unified Parkinson Disease Rating Scale motor ratings and induced a global decrease in reaction time during task performance, STN-DBS impaired response inhibition, as revealed by an increase in commission errors in NoGo trials. These behavioral effects were accompanied by changes in synaptic activity consisting of a reduced activation in the cortical networks responsible for reactive and proactive response inhibition. The present results suggest that although it improves motor functions in PD patients, modulation of STN hyperactivity with DBS may tend at the same time to favor the appearance of impulsive behavior by acting on the gating mechanism involved in response initiation.

Antidopaminergic therapy for managing comorbidities in patients with Parkinson’s disease

A literature evaluation of antidopaminergic therapies in patients with Parkinson's disease (PD) who have developed psychosis, nausea, vomiting, and hiccups was conducted. Complications associated with the use of antiparkinsonian drugs make PD management more difficult given the need for antidopaminergic therapy, which worsens motor functioning in patients with PD. For psychosis, clozapine is the only atypical antipsychotic that has proven effective without worsening motor function in PD patients. However, its use requires the monitoring of agranulocytosis. Newer atypical antipsychotics such as quetiapine have been claimed to be safe in terms of motor functioning, but evidence about their effectiveness is not compelling. The emergency treatment of psychosis in PD would require parenteral administration, only available for olanzapine and ziprasidone. However, no randomized controlled trials have been conducted to establish the efficacy and safety in this setting. For nausea and vomiting, very little domperidone crosses the blood-brain barrier. As a result, the risk of developing extrapyramidal adverse effects is minimal. Metoclopramide blocks central dopamine receptors and worsens motor parkinsonian symptoms. Chlorpromazine, the first-line treatment of intractable hiccups, is contraindicated in PD. Baclofen could be considered as a first-line alternative. Although clozapine can be used to treat psychosis in patients with PD, managing nausea, vomiting, hiccups, and emergent psychotic symptoms in these patients remains a challenge due to a lack of evidence for currently available options.

脳内埋め込み電極と体内埋設型刺激デバイスを用いた不随意運動の治療

In an attempt to control hypokinetic and hyperkinetic movement disorders, deep brain stimulation (DBS) has been developed during the last two decades by several investigators. In 1987, Benabid and his colleagues suggested the usefulness of high-frequency stimulation of the ventral intermediate nucleus of the thalamus for treating drug-resistant tremors and avoiding the adverse effects of thalamotomy. Since then, DBS has been used as an alternative to functional neurosurgery for movement disorders, and more recently, it has been applied to the treatment of epilepsy, obsessive-compulsive disorders and cluster headache, in addition to other applications in experimental models. In regard to the treatment of movement disorders, recent clinical studies have demonstrated that DBS affords great benefits in terms of improvement of the activities of daily living in patients with Parkinson's disease (PD), essential tremor, dystonia and poststroke hyperkinetic movement disorders. We have treated patients with movement disorders by DBS of the thalamic nuclei ventralis oralis (Voa/Vop) et intermedius (Vim), globus pallidus internus (GPi), and subthalamic nucleus (STN). The site of permanent electrode placement was identified using magnetic resonance imaging and multiunit extracellular recording. The implantable pulse generator was internalized after postoperative test stimulation for one week. The stimulation parameters were modified by physicians at each follow-up visit on the basis of the findings on neurological examination, as well as the patient's report concerning the activities of daily living. The advantages of DBS include reversibility and controllability of stimulation. In addition, DBS carries a smaller risk of side effects, particularly when employed bilaterally. Thalamic DBS is useful for controlling tremor that is unresponsive to medication. DBS of the STN and GPi improves the motor functions in PD patients, mainly during the off-period. Moreover, STN-DBS attenuates levodopa-induced dyskinesia through reducing the requirement of DOPA, whereas GPi-DBS directly attenuates DOPA-induced dyskinesia. In addition, GPi-DBS is very useful for controlling the symptoms of idiopatic generalized dystonia. According to reports, DBS is associated with few serious adverse effects associated with DBS. In general, the operative mortality is less than 1%. The incidences of hemorrhage are in the range of about 1-6%, and the incidences of device-related complications, such as infection or skin erosion, are in the range of 3-26%. DBS is clinically effective in well-selected patients and should be considered as a treatment option for patients with medically refractory movement disorders. Despite its clinical usefulness, the mechanism underlying the efficacy of DBS is still unclear. There is no proof currently that long-term DBS can reset neural networks or induce profound modifications of functional organization. Several researchers have proposed hypotheses concerning the mechanism underlying the efficacy of DBS, including 1) jamming of neural transmission, 2) direct inhibition of spike initiation at the level of the membrane that may be due to the activation of inhibitory terminals, 3) functional changes due to a decrease or increase in the amount of neurotransmitter released, and 4) retrograde activation of upstream neural structures. From the viewpoint of basic neuroscience, the development of DBS is intriguing. Investigation regarding the mechanism underlying the efficacy of DBS may provide clues for further clarification of various processes in the central nervous system.

Transcranial magnetic stimulation over dorsolateral prefrontal cortex in Parkinson’s disease

Objective Several studies have shown that repetitive transcranial magnetic stimulation (rTMS) over the dorsolateral prefrontal cortex (DLPFC) is effective in the treatment of depression in patients with Parkinson disease (PD). However, since research into the effect of this type of rTMS regime on motor function is limited, we studied the effect of rTMS over the DLPFC on the motor functions in PD patients. Methods Thirteen patients were randomly assigned into 2 groups, one receiving real-rTMS (90% of resting motor threshold, 10 Hz, 450 pulses-day for 10 consecutive days) over the DLPFC contralateral to the more affected side, and the other group receiving sham-rTMS. Assessment included a clinical motor evaluation using part III of the Unified Parkinson’s Disease Rating Scale (UPDRS), and several motor tasks. The UPDRS was applied before and after 10 days of rTMS. Finger tapping, reach movement, grip movement and gait were measured in each session before and after the rTMS over the 10 day period. Results Statistical analysis (ANOVA for repeated measures; group ∗ day ∗ side ∗ rTMS) only showed a significant effect for finger tapping, reach movement and gait for the factor day. No significant change was reported for the UPDRS in any group. Conclusions Application of rTMS over the DLPFC as a 10 day course had no significant effect on motor functions and clinical motor status, and the improvement in performance of motor tasks can be attributed to the effects of practice. Significance rTMS over the DLPFC did not lead to any motor improvement in PD patients.

Repetitive transcranial magnetic stimulation to improve mood and motor function in Parkinson's disease

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that can produce lasting changes in excitability and activity in cortical regions underneath the stimulation coil (local effect), but also within functionally connected cortical or subcortical regions (remote effects). Since the clinical presentation of Parkinson's disease (PD) is related to abnormal neuronal activity within the basal ganglia and cortical regions, including the primary motor cortex, the premotor cortex and the prefrontal cortex, several studies have used rTMS to improve brain function in PD. Here, we review the studies that have investigated the possible therapeutic effects of rTMS on mood and motor function in PD patients. We highlight some methodological inconsistencies and problems, including the difficulty to define the most effective protocol for rTMS or to establish an appropriate placebo condition. We finally propose future directions of research that may help to improve the therapeutic efficacy of rTMS in PD.

Low-dose Clozapine in the Treatment of Levodopa-Induced Mental Disturbances in Parkinson's Disease

Delusions and other manifestations of psychotic behavior are common side effects in Parkinson's disease (PD) patients chronically treated with dopaminergic drugs. Clozapine, a dibenzodiazepine derivative, is an antipsychotic drug largely devoid of extrapyramidal side effects. We evaluated the effects of low doses of clozapine on the mental and motor functions in PD patients requiring antipsychotic treatment. Twenty-seven PD patients taking dopaminergic drugs and who had psychotic behavior received clozapine at 12.5 to 75 mg/d. Fifteen patients received clozapine for 1 to 11 months (mean, 6.8 months) and seven received it for 12 to 24 months (mean, 18 months). No patient exhibited motor deterioration, and the psychotic features disappeared immediately, allowing discontinuation of clozapine after several months in 10 patients. Fifteen patients are still receiving clozapine and are free of psychiatric symptoms. The clozapine treatment was discontinued after 5 days (25 mg/d) in two patients because of somnolence. No patient developed neutropenia. Clozapine in low doses is effective in the treatment of drug-induced delusions and hallucinations in PD.