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Background: Non-motor symptoms (NMS) are important factors when selecting treatments for patients with advanced Parkinson's disease (PD). We sought to elucidate the prescribing practices for advanced PD patients with NMS in Japanese clinical practice., Methods: We examined the prescription rates and doses of anti-PD drugs, and the use of non-steroidal anti-inflammatory drugs (NSAIDs) in post hoc analyses of a 52-week observational study of 996 PD patients with wearing-off on levodopa-containing therapy and ≥1 NMS., Results: Dopamine agonists were the most frequently prescribed drugs combined with levodopa-containing drugs, followed by entacapone, zonisamide, istradefylline, selegiline, and amantadine. The daily dose of levodopa-containing drugs, rotigotine, entacapone, istradefylline, and droxidopa, and the levodopa-equivalent dose increased during the observation period. In a subgroup analysis of patients stratified by NMS status (improved/unchanged/deteriorated), the deteriorated group had higher prescription rates of entacapone and istradefylline, whereas the improved group had higher prescription rates of NSAIDs and zonisamide at Week 52. Prescriptions varied by geographical region for anti-PD drugs and by NMS status for NSAIDs., Conclusions: There were significant changes in the prescriptions and dosing of selected anti-PD drugs, especially newer drugs. Anti-PD drug and NSAID prescriptions also varied by changes in NMS status and geographic region., Competing Interests: Masahiro Nomoto reported research funds from Kyowa Kirin in relation to this study; and reported employment by The Social Welfare Organization Imperial Gift Foundation Inc. Saiseikai Imabari Hospital; honoraria from Ehime University, Takeda Pharmaceutical, Kyowa Kirin, Eisai, and Ono Pharmaceutical; consultancies for Kissei Pharmaceutical and SNLD; and has served on advisory boards for the Pharmaceuticals and Medical Devices Agency and Ehime Prefecture. Yoshio Tsuboi reported research funds from Kyowa Kirin in relation to this study; and reported lecture fees from Sumitomo Pharma, Takeda Pharmaceutical, Novartis Pharma, Ono Pharmaceutical, and Eisai; and contributes to courses organized by SUNWELS and Nipro Corporation. Kenichi Kashihara reported research funds from Kyowa Kirin in relation to this study; and reported employment by Okayama Neurology Clinic; and honoraria from Kyowa Kirin, Takeda Pharmaceutical, Ono Pharmaceutical, Sumitomo Pharma, FP Corporation, AbbVie GK, and Eisai. Shih-Wei Chiu reported research funds from Kyowa Kirin in relation to this study. Tetsuya Maeda reported research funds from Kyowa Kirin in relation to this study; and reported lecture fees and scholarship donations from Sumitomo Pharma, Takeda Pharmaceutical Company, Ono Pharmaceutical, Eisai, Otsuka Pharmaceutical, Nippon Boehringer Ingelheim, Daiichi Sankyo, and Japan Medtronic; lecture fees from AbbVie, FP Corporation, Biogen, and Chugai Pharmaceutical; scholarship donations from Bayer Yakuhin, Teijin, and CSL Behring; and consulting fees from Kyowa Kirin and Ono Pharmaceutical. Hidemoto Saiki reported editorial support from Kyowa Kirin in relation to this study; and reported honoraria from Eisai, Sumitomo Pharma, Ono Pharmaceutical, Takeda Pharmaceutical, and Medtronic Japan; and grants from Otsuka Pharmaceutical and PDRadiopharma Inc. Hirohisa Watanabe reported research funds from Kyowa Kirin in relation to this study; and reported honoraria from Takeda Pharmaceutical, AbbVie, Kyowa Kirin, Sumitomo Pharma, Novartis Pharma, Otsuka Pharmaceutical, and FP Corporation. Yasushi Shimo reported honoraria from Takeda Pharmaceutical, Abbott Japan, Otsuka Pharmaceutical, Medtronic Japan, Kyowa Kirin, Eisai, MDS, Boston Scientific Japan, Sumitomo Pharma, Daiichi Sankyo, Nihon Medi-Physics, and EA Pharma; and a grant from Japan Society for the Promotion of Science (JSPS KAKENHI no. 21K07282). Nobutaka Hattori reported research grants, support for attending advisory boards, and support for a joint research department from Kyowa Kirin; and reported research contracts with Sumitomo Pharma and CellSource; consultancy fees from PARKINSON Laboratories; honoraria from Sumitomo Pharma, AbbVie, Otsuka Pharmaceutical, Novartis Pharma, Ono Pharmaceutical, FP Pharmaceutical, Eisai, and Daiichi Sankyo; support for attending advisory boards from Sumitomo Pharma, Novartis Pharma, Ono Pharmaceutical, Teijin Pharma, and Mitsubishi Tanabe Pharma Corporation; support for an endowed department from Nippon Boehringer Ingelheim, FP Pharmaceutical, Teijin Pharma, Fujifilm Wako Pure Chemical Corporation, and Meiji Seika Pharma; support for a joint research department from Kyowa Kirin, Sumitomo Pharma, Parkinson Laboratories, Takeda Pharmaceutical, Otsuka Pharmaceutical, Ono Pharmaceutical, Nihon Medi-Physics, Mitsubishi Tanabe Pharma Corporation, and Sunwels; scholarship donations from FP Pharmaceutical; holds stock in Parkinson Laboratories; honoraria for a team leader role at RIKEN Center for Brain Science; and is a coauthor on patent applications by Juntendo University. Takuhiro Yamaguchi reported grants from Otsuka Pharmaceutical, Solasia Pharma, Japan Tobacco Inc., Daiichi Sankyo, Eisai, and Cordis Corporation; and personal fees from Intellim Corporation, Chugai Pharmaceutical, SONIRE Therapeutics Inc., Merck and Co Inc., EPS Corporation, Japan Tobacco Inc., Ono Pharmaceutical, Kowa Company, Daiichi Sankyo, Eisai, 3H Clinical Trial Inc., and Incyte Biosciences Japan. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Nomoto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Orthostatic hypotension (OH) frequently accompanies autonomic dysfunction and is an important risk factor for cognitive impairment in Parkinson's disease (PD). While OH is usually diagnosed based on an orthostatic blood pressure drop, the association between the heart rate response and cognitive impairment remains unclear. We retrospectively analyzed 143 cases of clinically diagnosed PD to determine the association between the absence of a heart rate response and cognitive impairment in PD with OH. Among the patients with OH, neurogenic OH was diagnosed in cases without a heart rate increase, while all other patients were diagnosed with non-neurogenic OH. Dementia was found in 23 of 143 PD cases (16.1%) in this cohort. The presence of OH was an independent risk factor for dementia in PD in addition to the disease severity, years of education and beta-blockers use. Neurogenic OH was significantly associated with dementia compared to the no OH group (hazard ratio [HR] 7.3, 95% confidence interval [CI] 2.2-24.6, P<0.01), an association that was preserved after adjusting for age, gender and other covariant factors. However, no such association was observed for non-neurogenic OH (HR 2.9, 95%CI 0.8-10.9, P = 0.12). While the cognitive impairment was significantly worse in the neurogenic OH group than the no-OH group, the groups were otherwise similar. The blood pressure decrease was significantly lower in both OH groups than in the no-OH group, despite no significant differences between the OH groups. Our finding showed that OH without a heart rate response was an important predictor of cognitive impairment in PD., Competing Interests: The authors have read the journal’s policy and have the following competing interests: RT received honoraria for work unrelated to this study from Takeda Pharmaceutical Co.,Ltd., Nippon Boehringer Ingelheim,Co.,Ltd, Dai-Nippon Sumitomo Pharma Co.,Ltd., Bayer Yakuhin, Ltd, Otsuka Pharmaceutical, Co.,Ltd, Pfizer Japan Inc., DAIICHI SANKYO Co.,Ltd., Eisai Co.,Ltd., Bristol-Myers Squibb Co., Stryker Japan K.K., CSL Behring K.K,. and Kowa Co.,Ltd. KY received honoraria for work unrelated to this study from Pfizer Inc., Takeda Pharmaceutical Co.,Ltd., Dai-Nippon Sumitomo Pharma Co.,Ltd., Bayer Yakuhin, Ltd., Otsuka Pharmaceutical, Co.,Ltd., DAIICHI SANKYO Co.,Ltd., and Novartis Pharma K.K. KN received a research grant for work unrelated to this study from Biogen Japan, Ltd.GO received honoraria for work unrelated to this study from Medtronic, Boston Scientific, Otsuka Pharmaceutical, Sumitomo Dainippon Pharma, Novartis Pharma, MSD, Nihon Medi-Physics, FP Pharmaceutical Corporation, Kyowa Hakko Kirin, and AbbVie, Inc. AU received a research grant from Novartis Pharma K.K, consultancy fees from Boston Scientific Japan, and honoraria from Medtronic Japan Inc., Novartis Pharma K.K, Kyowa Hakko-Kirin Co.,Ltd., Takeda Pharmaceutical Co.,Ltd. and AbbVie, Inc. all for work unrelated to this study. YS received honoraria for work unrelated to this study from Medtronic, Boston Scientific, Otsuka Pharmaceutical, Takeda Pharmaceutical CO, Sumitomo Dainippon Pharma, Novartis Pharma, MSD, FP Pharmaceutical Corporation, Kyowa Hakko Kirin, and AbbVie, Inc. NH received grants from AbbVie GK, FP Pharma. Co, Dai-Nippon Sumitomo Pharma Co.,Ltd, Eisai Co.,Ltd. and honoraria from Kyowa Kirin Co., Ltd., Dai-Nippon Sumitomo Pharma Co., Ltd, Takeda Pharmaceutical Co., Ltd., Otsuka Pharmaceutical, Co., Ltd, AbbVie GK, Eisai Co., Ltd., FP Pharma. Co, Mitsubishi Tanabe Pharma Co., Otsuka Pharmaceutical, Novartis Pharma, MSD, Nihon Medi-Physics, Bristol-Myers Squibb Company, Ono Pharmaceutical Co., Ltd., EA Pharma Co., Ltd, Asahi Kasei Medical Co., Ltd., and Chugai Pharma Manufacturing Co., Ltd., all for work unrelated to this study. NH also received honoraria from Biogen Japan, Ltd. for subcontracting (trial cases) and has the Equity stock (8%) of PARKINSON Laboratories Co. Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Repetitive transcranial magnetic stimulation (rTMS) induces changes in cortical excitability for minutes to hours after the end of intervention. However, it has not been precisely determined to what extent cortical plasticity prevails spatially in the cortex. Recent studies have shown that rTMS induces changes in "interhemispheric" functional connectivity, the resting-state functional connectivity between the stimulated region and the symmetrically corresponding region in the contralateral hemisphere. In the present study, quadripulse stimulation (QPS) was applied to the index finger representation in the left primary motor cortex (M1), while the position of the stimulation coil was constantly monitored by an online navigator. After QPS application, resting-state functional magnetic resonance imaging was performed, and the interhemispheric functional connectivity was compared with that before QPS. A cluster of connectivity changes was observed in the stimulated region in the central sulcus. The cluster was spatially extended approximately 10 mm from the center [half width at half maximum (HWHM): approximately 3 mm] and was extended approximately 20 mm long in depth (HWHM: approximately 7 mm). A localizer scan of the index finger motion confirmed that the cluster of interhemispheric connectivity changes overlapped spatially with the activation related to the index finger motion. These results indicate that cortical plasticity in M1 induced by rTMS was relatively restricted in space and suggest that rTMS can reveal functional dissociation associated with adjacent small areas by inducing neural plasticity in restricted cortical regions., Competing Interests: The authors have declared that no competing interests exist.

The objective of this study is to test the feasibility of a semi-automated scoring system for the Toronto Western Spasmodic Torticollis Scale (TWSTRS) severity scale in patients with cervical dystonia. The TWSTRS requires training and experience. We previously developed a system to measure neck angle by analyzing three-dimensional position, obtained using Kinect, a marker-less three-dimensional depth sensor. The system can track patients' faces and bodies, automatically analyze neck angles, and semi-automatically calculate the TWSTRS severity scale score. We compared the TWSTRS severity scale scores calculated by the system with the video-based scores calculated by a neurologist trained in movement disorders. A correlation coefficient analysis was then conducted. Absolute accuracy was measured using intra-class correlation (ICC) (3,1), with 95% limits of agreement. To analyze the subscales, Cohen's kappa coefficient (κ) was calculated. A p-value of < .05 was considered statistically significant. Thirty patients were enrolled. Their average age was 52.3±16.0 years, and the male to female ratio was 3:2. The average disease duration was 11.3±12.7 years. Total score measurements by the system were significantly correlated with those rated by the movement disorder-trained neurologist (r = .596, p < .05). There was a significant correlation (r = .655, p < .05) with regard to the automated part of the scale. An adequate ICC (3,1) of .562 was obtained for total severity score (p < .001, 95% confidence interval [CI]: .259-.765), while the equivalent score was .617 for the total automated part (p < .001, 95% CI .336-.798). Our three-dimensional motion capture system, which can measure head angles and semi-automatically calculate the TWSTRS severity scale score utilizing a single-depth camera, demonstrated adequate validity and reliability. This low-cost and portable system could be applied by general practitioners treating cervical dystonia to obtain objective measurements., Competing Interests: NH has received speaker honoraria from Dai-Nippon Sumitomo, Otsuka, Takeda, Kyowa Hakko-Kirin, GSK, Nippon Boehringer Ingelheim, FP, Eisai, Kissei, Nihon Medi-physics, Novartis, Biogen Idec Japan, AbbVie, Astellas, Boston Scientific Japan, Sanofi, Pfizer Japan, Alexion, Mylan N.V, MSD, Daiichi Sankyo, and MDS. NH has received consultancies and subcontracting from Dai-Nippon Sumitomo, Biogen Idec, Otsuka, Takeda, Kyowa Hakko-Kirin, Meiji Seika, Hisamitsu, Kao. GO has received speaker honoraria from Medtronic, Boston Scientific, Otsuka Pharmaceutical, Sumitomo Dainippon Pharma, Novartis Pharma, MSD, Nihon Medi-Physics, FP Pharmaceutical Corporation, and Kyowa Hakko Kirin, and Abbvie. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Transcranial magnetic stimulation (TMS) of the human lateral prefrontal cortex, particularly the ventral region, often causes considerable discomfort to subjects. To date, in contrast to abundant literature on stimulations to the dorsolateral prefrontal cortex, the ventrolateral prefrontal cortex has been less frequently stimulated, partly because some subjects are intolerable of stimulation to the ventrolateral prefrontal cortex. To predict the additional number of subjects required for the stimulation of the dorsolateral and ventrolateral prefrontal cortices, 20 young healthy subjects reported two evaluation scores: the discomfort caused by TMS and the resulting intolerability to complete the TMS experiments. Single-pulse stimulation (SPS) or theta-burst stimulation (TBS) was administered to the lateral prefrontal cortex. The high-resolution extended 10-20 system was used to provide accurate estimation of the voxelwise scores. The discomfort ratings with the SPS and TBS were relatively higher in the ventrolateral prefrontal cortex than those in the dorsolateral prefrontal cortex. Both the SPS and TBS elicited maximal discomfort at the stimulation position F8. The SPS and TBS to F8 under the standard TMS protocols were intolerable for approximately one half (11 and 10, respectively) of the subjects. The intolerability was further calculated for all voxels in the lateral prefrontal cortex, which enabled us to estimate the additional number of subjects required for specific target areas. These results suggest that prior knowledge of subjects' discomfort during stimulation of the lateral prefrontal cortex can be of practical use in the experimental planning of the appropriate number of recruited subjects and provide the database for the probability of intolerability that can be used to predict the additional number of subjects., Competing Interests: The authors have declared that no competing interests exist.

It is generally accepted that the basal ganglia play an important role in interval timing that requires the measurement of temporal durations. By contrast, it remains controversial whether the basal ganglia play an essential role in temporal order judgment (TOJ) of successive stimuli, a behavior that does not necessarily require the measurement of durations in time. To address this issue, we compared the effects of idiopathic Parkinson's disease (PD) on the TOJ of two successive taps delivered to each hand, with the arms uncrossed in one condition and crossed in another. In addition to age-matched elderly participants without PD (non-PD), we examined young healthy participants so that the effect of aging could serve as a control for evaluating the effects of PD. There was no significant difference between PD and non-PD participants in any parameter of TOJ under either arm posture, although reaction time was significantly longer in PD compared with non-PD participants. By contrast, the effect of aging was apparent in both conditions. With their arms uncrossed, the temporal resolution (the interstimulus interval that yielded 84% correct responses) in elderly participants was significantly worse compared with young participants. With their arms crossed, elderly participants made more errors at longer intervals (~1 s) than young participants, although both age groups showed similar judgment reversal at moderately short intervals (~200 ms). These results indicate that the basal ganglia and dopaminergic systems do not play essential roles in tactile TOJ involving both hands and that the effect of aging on TOJ is mostly independent of the dopaminergic systems.