Classification of Hippocampal Ripples: Convolutional Neural Network Learns Episode-Specific Changes.

The hippocampus is known to play an important role in memory by processing spatiotemporal information of episodic experiences. By recording synchronized multiple-unit firing events (ripple firings with 300 Hz-10 kHz) of hippocampal CA1 neurons in freely moving rats, we previously found an episode-dependent diversity in the waveform of ripple firings. In the present study, we hypothesized that changes in the diversity would depend on the type of episode experienced. If this hypothesis holds, we can identify the ripple waveforms associated with each episode. Thus, we first attempted to classify the ripple firings measured from rats into five categories: those experiencing any of the four episodes and those before experiencing any of the four episodes. In this paper, we construct a convolutional neural network (CNN) to classify the current stocks of ripple firings into these five categories and demonstrate that the CNN can successfully classify the ripple firings. We subsequently indicate partial ripple waveforms that the CNN focuses on for classification by applying gradient-weighted class activation mapping (Grad-CAM) to the CNN. The method of t-distributed stochastic neighbor embedding (t-SNE) maps ripple waveforms into a two-dimensional feature space. Analyzing the distribution of partial waveforms extracted by Grad-CAM in a t-SNE feature space suggests that the partial waveforms may be representative of each category.

Dual-Arm Visuo-Haptic Optical Tweezers for Bimanual Cooperative Micromanipulation of Nonspherical Objects.

Cooperative manipulation through dual-arm robots is widely implemented to perform precise and dexterous tasks to ensure automation; however, the implementation of cooperative micromanipulation through dual-arm optical tweezers is relatively rare in biomedical laboratories. To enable the bimanual and dexterous cooperative handling of a nonspherical object in microscopic workspaces, we present a dual-arm visuo-haptic optical tweezer system with two trapped microspheres, which are commercially available end-effectors, to realize indirect micromanipulation. By combining the precise correction technique of distortions in scanning optical tweezers and computer vision techniques, our dual-arm system allows a user to perceive the real contact forces during the cooperative manipulation of an object. The system enhances the dexterity of bimanual micromanipulation by employing the real-time representation of the forces and their directions. As a proof of concept, we demonstrate the cooperative indirect micromanipulation of single nonspherical objects, specifically, a glass fragment and a large diatom. Moreover, the precise correction method of the scanning optical tweezers is described. The unique capabilities offered by the proposed dual-arm visuo-haptic system can facilitate research on biomedical materials and single-cells under an optical microscope.

[Functional Movement Disorders That Do Not Improve after Explaining the Diagnosis: Do Not Treat the Disease, Treat the Patient].

The most important factor in the treatment of functional movement disorders is the initial discussion between the doctor and the patient, wherein the doctor must inform the patient regarding their diagnosis and obtain their consent. To obtain consent, explanations must be tailored to the patient's knowledge. To do so, it is important to know the patient. In this process, psychological factors may be speculated. The rationale for the diagnosis, including test results, should be presented to the patient. Although the choice of future treatment should be left to the patient, the doctor must assure the patient of their continued support until they recover.

Cost-effectiveness analysis of lemborexant for treating insomnia in Japan: a model-based projection, incorporating the risk of falls, motor vehicle collisions, and workplace accidents.

BACKGROUND: Lemborexant has demonstrated statistically significant improvements in sleep onset and sleep maintenance compared with placebo and zolpidem tartrate extended release, measured both objectively using polysomnography and subjectively using sleep diaries, in the phase 3 clinical trial SUNRISE 1. This study evaluated the cost-effectiveness of lemborexant compared with suvorexant, zolpidem immediate release (IR), and untreated insomnia. METHODS: A decision-tree model was developed for falls, motor vehicle collisions, and workplace accidents associated with insomnia and insomnia treatments from a Japanese healthcare perspective and with a 6-month time horizon. The model extracted subjective sleep onset latency treatment responses and disutility values for non-responders from SUNRISE 1. Cost-effectiveness was assessed using incremental cost per quality-adjusted life year (QALY) gained. One-way and probabilistic sensitivity analyses were conducted to evaluate the impact of parameter uncertainty on the results. RESULTS: In the base-case analysis, the mean estimated QALYs for lemborexant, suvorexant, zolpidem-IR, and untreated insomnia were 0.4220, 0.4204, 0.4113, and 0.4163, and expected medical costs were JPY 34 034, JPY 38 371, JPY 38 139, and JPY 15 383, respectively. Lemborexant saved JPY 4337 and JPY 4105 compared with suvorexant or zolpidem-IR, respectively, while conferring QALY benefits. The incremental cost-effectiveness ratio (ICER) of lemborexant compared with that of untreated insomnia was JPY 3 220 975 /QALY. Lemborexant was dominant over suvorexant and zolpidem-IR and was cost-effective when compared with untreated insomnia. Sensitivity analyses supported the results' robustness. CONCLUSIONS: In a Japanese clinical practice setting, lemborexant may represent a better investment for treating insomnia in the healthcare system in Japan.

Treatment patterns and medical costs after hepatectomy in real-world practice for patients with hepatocellular carcinoma in Japan.

AIM: To examine the treatment patterns and medical costs in real-world practice among patients who received hepatectomy for hepatocellular carcinoma (HCC) in Japan. METHODS: Data of patients who underwent hepatectomy as an initial therapy for primary HCC were extracted from a Japanese medical claims database from April 2008 to December 2019. The types of additional treatments for recurrent HCC and medical costs for up to 3 years from the first hepatectomy were analyzed. The average cumulative cost per patient starting on the date of the first hepatectomy was calculated using the Kaplan-Meier sample-average method. RESULTS: Data from 2 342 patients (median age, 71 years) were analyzed. Overall, 35.6% of patients received at least one HCC treatment within 3 years of the first hepatectomy. The total average cumulative 3-years medical cost was JPY 4 993 300 (95% confidence interval [CI]: 4 804 100 to 5 220 500). Surgical procedures were the most costly components in the first month after hepatectomy, whereas the costs of drugs, which mainly included antiviral and antineoplastic medications, increased thereafter. Patients with advanced stage HCC, hepatitis C, or a higher Charlson Comorbidity Index at hepatectomy, or those who required additional treatment, especially with antineoplastic drugs for recurrent HCC, incurred higher medical costs. CONCLUSIONS: Patients with HCC after hepatectomy experienced a large economic burden, which was more serious for those with advanced stage HCC, higher comorbidities, and hepatitis at baseline and for patients treated with antineoplastic drugs. A treatment selection that considers its medical cost burden would help to reduce some of these economic burdens.

Impact of the Severity of Alzheimer's Disease on the Quality of Life, Activities of Daily Living, and Caregiving Costs for Institutionalized Patients on Anti-Alzheimer Medications in Japan.

BACKGROUND: Alzheimer's disease (AD) increases societal costs and decreases the activities of daily living (ADL) and quality of life (QoL) of the affected individuals. OBJECTIVE: We assess the impact of AD severity on ADL, QoL, and caregiving costs in Japanese facilities for the elderly. METHODS: Patients with AD in facilities for the elderly were included (47 facilities, N = 3,461). The QoL, ADL, and disease severity of patients were assessed using Barthel Index (BI), EuroQoL-5D-5L (EQ-5D-5L), and Mini-Mental State Examination (MMSE), respectively. Annual caregiving costs were estimated using patients' claims data. The patients were subcategorized into the following three groups according to the MMSE score: mild (21≤MMSE≤30), moderate (11≤MMSE≤20), and severe (0≤MMSE≤10). Changes among the three groups were evaluated using the Jonckheere-Terpstra test. RESULTS: Four hundred and one participants were on anti-AD medicines, of whom 287 (age: 86.1±6.4 years, 76.7% women) in the mild (n = 53, 84.0±6.9 years, 71.7%), moderate (n = 118, 86.6±5.9 years, 76.3%), and severe (n = 116, 86.6±6.5 years, 79.3%) groups completed the study questionnaires. The mean BI and EQ-5D-5L scores for each group were 83.6, 65.1, and 32.8 and 0.801, 0.662, and 0.436, respectively. The mean annual caregiving costs were 2.111, 2.470, and 2.809 million JPY, respectively. As AD worsened, the BI and EQ-5D-5L scores decreased and annual caregiving costs increased significantly. CONCLUSION: AD severity has an impact on QoL, ADL, and caregiving costs.

The Prevalence and Characteristics of Older Japanese Adults with Polypharmacy, Based on Regionally Representative Health Insurance Claims Data.

We aimed to clarify the prevalence of polypharmacy among elderly individuals in Japan. We used the data obtained from a large-scale population-based representative database of health insurance claims in a single prefecture in Japan. We examined all of the outpatient and pharmaceutical health insurance claims for National Health Insurance and those for Late-stage Elderly Health Insurance in Nagasaki Prefecture, Japan between April and June 2016. When two or more claim forms were issued for a patient in a single month, we combined the data and identified the number of prescribed drugs for each person. The definition of polypharmacy is a the prescription of six or more drugs per month. We investigated the prevalence of polypharmacy among the beneficiaries of the two insurance systems. Of the 605,406 beneficiaries of the 2 insurance systems, 121,033 (20.0%) patients with polypharmacy were identified. The prevalence of polypharmacy increased with age, especially among the beneficiaries aged > 85 years, with about half of the beneficiaries having polypharmacy status. About half of the people aged > 85 years in the database had polypharmacy status. When a drug is prescribed to an elderly individual, it is necessary to consider the possibility of polypharmacy-related problems.

Coding and prescription rates of osteoporosis are low among distal radius fracture patients in Japan.

INTRODUCTION: This study aimed to clarify the coding and prescription rates for osteoporosis in distal radius fracture patients and to investigate the associated factors to help prevent subsequent osteoporotic fracture. MATERIALS AND METHODS: Between 2014-2015, among 294,374 eligible individuals (42% female) aged 50-75 years in a health insurance claims database, we identified 192 individuals (mean age: 59.8 years, 74% female), counted the coding of distal radius fracture (International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10) code: S525, S526), and determined if the patient had been assigned the code for osteoporosis and been prescribed osteoporosis medications. Logistic regression was performed to identify factors related to each rate. RESULTS: The osteoporosis coding rate and osteoporosis medication prescription rate were 17.2% (n = 33) and 10.9% (n = 21), respectively. Most codes were assigned ≤ 3 months after injury (88%) at the distal radius fracture treatment facilities (84.8%). Patients who were assigned the code for osteoporosis or treated with osteoporosis medications were older (p = 0.08, p = 0.02, respectively), female (p = 0.05, p = 0.06, respectively) and having comorbidity (p = 0.02, p = 0.07, respectively). After adjustment, being female and having comorbidity remained the independent factors for the assignment of the code for osteoporosis (OR: 3.30, 95%, CI: 1.08-10.07, OR: 2.77, 95% CI: 1.24-6.12, respectively). No factor remained significant for the osteoporosis prescription. Active vitamin D analogues were most frequently prescribed medication (67%) followed by bisphosphonates (48%). CONCLUSION: The overall coding and prescription rates for osteoporosis after distal radius fracture were low, which suggested that physician adherence to the osteoporosis guideline was low.

Postural Abnormality in Parkinson's Disease: A Large Comparative Study With General Population.

BACKGROUND: Postural abnormalities in Parkinson's disease (PD) patients and unimpaired elderly are not well differentiated. Factors related to postural abnormality associated with PD are controversial. OBJECTIVE: We assessed differences in postural change between PD patients and unimpaired elderly and elucidated factors related to abnormal posture in PD patients. METHODS: We measured the dropped head angle (DHA), anterior flexion angle (AFA), and lateral flexion angle (LFA) of the thoracolumbar spine of an unprecedented 1,117 PD patients and 2,732 general population participants (GPPs) using digital photographs. Two statistical analyses were used for elucidating factors related to these angles. RESULTS: In GPPs, age was correlated with DHA, AFA, and LFA. DHAs, AFAs, and LFAs of PD patients and age-matched GPPs were 21.70° ± 14.40° and 13.13° ± 10.79°, 5.98° ± 12.67,°and - 3.82° ± 4.04°, and 0.86° ± 4.25° and 1.33° ± 2.16°, respectively. In PD patients, factors related to DHA were age, male sex, and H & Y stage during ON time. Factors related to AFA were age, duration of disease, H & Y stage during ON and OFF times, pain, vertebral disease, and bending to the right. A factor related to LFA was AFA. CONCLUSIONS: DHA and AFA of GGPs correlated with age and were larger in PD patients than those with in GPPs. Some PD patients showed angles far beyond the normal distribution. Thus, factors associated with disease aggravation affected postural abnormality in PD patients.

GCH1 mutations in dopa-responsive dystonia and Parkinson's disease.

Guanosine triphosphate cyclohydrolase I (GCH1) mutations are associated with increased risk for dopa-responsive dystonia (DRD) and Parkinson's disease (PD). Herein, we investigated the frequency of GCH1 mutations and clinical symptoms in patients with clinically diagnosed PD and DRD. We used the Sanger method to screen entire exons in 268 patients with PD and 26 patients with DRD, with the examinations of brain magnetic resonance imaging scans, striatal dopamine transporter scans, and [123I] metaiodobenzylguanidine (MIBG) myocardiac scintigraphy scans. We identified 15 patients with heterozygous GCH1 mutations from seven probands and five sporadic cases. The prevalence of GCH1 mutations in probands was different between PD [1.9% (5/268)] and DRD [26.9% (7/26)] (p value < 0.0001). The onset age tends to be different between PD and DRD patients: 35.4 ± 25.3 and 16.5 ± 13.6, respectively (average ± SD; p = 0.08). Most of the patients were women (14/15). Dystonia was common symptom, and dysautonomia and cognitive decline were uncommon in our PD and DRD. All patients presented mild parkinsonism or dystonia with excellent response to levodopa. Seven of seven DRD and three of five PD presented normal heart-to-mediastinum ratio on MIBG myocardial scintigraphy. Five of six DRD and three of four PD demonstrated normal densities of dopamine transporter. Our findings elucidated the clinical characteristics of PD and DRD patients due to GCH1 mutations. PD patients with GCH1 mutations also had different symptoms from those seen in typical PD. The patients with GCH1 mutations had heterogeneous clinical symptoms.

Persistent Expression of Dopamine-Synthesizing Enzymes 15 Years After Gene Transfer in a Primate Model of Parkinson's Disease.

Restoring dopamine production in the putamen through gene therapy is a straightforward strategy for ameliorating motor symptoms for Parkinson's disease (PD). In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity-based primate model of PD, we previously showed the safety and efficacy of adeno-associated viral (AAV) vector-mediated gene delivery to the putamen of three dopamine-synthesizing enzymes (tyrosine hydroxylase [TH], aromatic l-amino acid decarboxylase [AADC], and guanosine triphosphate cyclohydrolase I [GCH]) up to 10 months postprocedure. Although three of four monkeys in this study have previously undergone postmortem analysis, one monkey was kept alive for 15 years after gene therapy to evaluate long-term effects. Here, we report that this monkey showed behavioral recovery in the right-side limb that remained unchanged for 15 years, at which time euthanasia was carried out owing to onset of senility. Immunohistochemistry of the postmortem brain from this monkey revealed persistent expression of TH, AADC, and GCH genes in the lesioned putamen. Transduced neurons were broadly distributed, with the estimated transduction region occupying 91% of the left postcommissural putamen. No signs of cytotoxicity or Lewy body pathology were observed in the AAV vector-injected putamen. This study provides evidence of long-term safety and efficacy of the triple-transduction method as a gene therapy for PD.

[Patients' Perspective on Parkinson Disease Therapies: Comparative Results of Large-scale Surveys in 2008 and 2013 in Japan].

A large-scale patient survey was conducted in 2013 and results compared with those of a similar scale survey conducted in 2008 to clarify the current status of drug therapy and patients' understanding of Parkinson disease (PD) and therapy. A total of 4,278 and 101 patients respectively participated in primary mail survey and secondary interview surveys. Measures of PD severity, activity level, and level of assistance required in daily life were improved compared with those in the 2008 survey. Average daily dose of levodopa was increased across all disease durations. The treatment compliance rate of monoamine oxidase-B inhibitors was increased in patients with < 6 years of disease duration, but was reduced in patients with ≥ 6 years. The treatment compliance rates of catechol-O-methyltransferase inhibitors and zonisamide were increased. Patients with experience of dyskinesia hoped more to improve their mobility rather than avoid dyskinesia. Since there is no fundamental treatment for PD and drug therapy achieves only symptomatic relief, PD exerted a negative influence on patients' satisfaction. The patients' unsatisfied feelings changed with the severity of OFF time. Physicians are required to not only devise a selection and dosage of PD therapeutic drugs but also empathetically respond to patients, with consideration of their feelings. (Received January 22, 2016; Accepted April 11, 2016; Published September 1, 2016).

Identification of a Japanese family with LRRK2 p.R1441G-related Parkinson's disease.

Leucine-rich repeat kinase 2 (LRRK2) is a causative gene of autosomal dominant familial Parkinson's disease (PD). We screened for LRRK2 mutations in 3 frequently reported exons (31, 41, and 48) in our cohort of 871 Japanese patients with PD (430 with sporadic PD and 441 probands with familial PD). Direct sequencing analysis of LRRK2 revealed 1 proband (0.11%) with a p.R1441G mutation, identified for the first time in Asian countries, besides frequently reported substitutions including, the p.G2019S mutation (0.11%) and p.G2385R variant (11.37%). Several studies have suggested that the LRRK2 p.R1441G mutation, which is highly prevalent in the Basque country, is extremely rare outside of northern Spain. Further analysis of family members of the proband with the p.R1441G mutation revealed that her mother and first cousin shared the same mutation and parkinsonism. Haplotype analysis revealed a different haplotype from that of the original Spanish families. Our patients demonstrated levodopa-responsive parkinsonism with intrafamilial clinical heterogeneity. This is the first report of familial PD because of the LRRK2 p.R1441G mutation in Asia.

[Problem of alternative medicine in Parkinson's disease].

I asked about the usage of alternative medicine to 300 outpatients with Parkinson's disease. 163 patients (54.3%) had experience with health appliance and 128 patients (42.7%) had experience with supplements. There is no health appliance or supplement whose efficacy for Parkinson's disease is approved publicly. Most of the patients understood it but some patients who purchased the goods believed to be effective in Parkinson's disease. In addition some patients feel affected because the purchase price is abnormally high. Continuous usage rate is generally high in supplements, relatively high in massage machine, but significantly low in equipment to move the body, such as muscle training equipment of various types or exercise bike. It seems important to inform this fact to Parkinson's disease patients.

Preoperative high-dose steroid has long-term beneficial effects for myasthenia gravis.

Previous studies addressing preoperative steroid treatment have revealed that control of myasthenia gravis (MG) with steroids prior to surgery appeared to stabilize postoperative status. The purpose of our study was to clarify the clinical benefits of the preoperative programmed high-dose steroid treatment on the long-term outcomes of MG patients. We retrospectively reviewed the records of 171 MG patients who were followed up after undergoing thymectomy in our hospital between 1988 and 2006. One hundred and thirteen patients in the programmed treatment group had received preoperative steroid treatment, while 58 patients received no steroid treatment during the preoperative period. Clinical remission, which was defined as the achievement of the modified pharmacologic remission (PR) for at least 1 year, and clinical benefits were compared between the two groups. With regard to the remission after thymectomy, Kaplan-Meier life-table curves for patients in the preoperative steroid treatment group versus those for patients in the no steroid preoperative treatment group revealed a significantly higher probability of the PR in the preoperative steroid treatment group (log-rank test, P < 0.01). This study might be the first, as per our knowledge, to indicate that preoperative programmed high-dose steroid treatment has long-term beneficial effects for MG patients.

Patient perspectives on Parkinson's disease therapy in Japan and the United States: results of two patient surveys.

BACKGROUND: Despite evidence suggesting that patient attitudes towards therapy may influence treatment outcomes, the impact of these factors on treatment for Parkinson's disease is poorly understood. These two surveys, based in Japan and the US, investigated the attitudes of patients towards antiparkinsonian medications, the complications of these therapies, and how these differ across geographies. METHODS: The US PRELUDE survey collected data from May 13 to May 20, 2003, from 300 interviews with patients with Parkinson's disease from the National Parkinson Foundation. The Japanese survey was carried out from June to December 2008 in a stepwise manner using questionnaires (n = 3548) followed by interviews with those who had consented to participate in the questionnaire (n = 407). Both surveys assessed the attitudes of patients towards therapies for Parkinson's disease and associated complications. RESULTS: Dyskinesia was not a major challenge of therapy for Parkinson's disease, and wearing-off caused greater concern in the US, while hallucinations had a greater emphasis in Japan. Patients who had previously experienced dyskinesia were less concerned about this side effect than those who had not. Although pill burden was thought to be a concern in the US, Japanese patients did not indicate that pill burden would limit their drug intake. There were also discrepancies between the perspectives and concerns of patients and those of their treating physicians. CONCLUSION: Recognizing patient perspectives regarding therapies for Parkinson's disease and associated complications, as well as certain cultural influences, is important in the management of parkinsonian symptoms. Acknowledging these concerns may improve the standard of care in patients with Parkinson's disease. In addition, improved patient education and effective patient-physician communication in both countries may improve compliance and treatment outcomes in patients with the disease.

[Disinhibitory abnormal behavior induced by treatment of Parkinson disease].

The treatment of Parkinson disease has considerably progressed in the last 20 years. However, such treatments results in the adverse event of disinhibitory abnormal behavior, which includes impulse control disorders, punding, and dopamine dysregulation syndrome. Pathological gambling is the most extensively studied among such abnormal behaviors. It has been associated with the use of dopamine agonists and its prevalence increases according to the does of the drugs. The maximum dose of the ergot dopamine agonist pergolide is 1.25 mg/day in Japan, which is a quarter of that used in Western countries. The maximum dose of the non-ergot dopamine agonist, pramipexole is 4.5 mg/day in Japan, which is the same as in Western countries. Pramipexole was launched in 2004 in Japan, and since then cases of pathological gambling associated with dopamine agonists used has been increasing. Because of the excellent health-care system in Japan, patients can easily acquire expensive dopamine agonists. Although the prevalence of these abnormal behaviors has not been studied in Japan, it could be highly proportionate to the amount of dopamine agonists. Disinhibitory abnormal behavior is also induced by deep brain stimulation of the subthalamic nucleus. This technology was approved in 2000 in Japan. The mechanisms by which these behaviors are induced are different between dopamine replacement therapy and deep brain stimulation. Parkinson disease patients and their caregivers occasionally believe the disinhibitory abnormal behavior as arising from the original personality of the patient rather than as an adverse event of treatment. Neurologists should be aware of the occurrence of disinhibitory abnormal behavior in the clinical practice.

Sudden change from chaos to oscillation death in the Bonhoeffer-van der Pol oscillator under weak periodic perturbation.

In this paper, we analyze the sudden change from chaos to oscillation death generated by the Bonhoeffer-van der Pol (BVP) oscillator under weak periodic perturbation. The parameter values of the BVP oscillator are chosen such that a stable focus and a stable relaxation oscillation coexist if no perturbation is applied. In such a system, complicated bifurcation structure is expected to emerge when weak periodic perturbation is applied because the stable focus and the stable relaxation oscillation coexist in close proximity in the phase plane. We draw a bifurcation diagram of the fundamental harmonic entrainment. The bifurcation structure is complex because there coexist two bifurcation sets. One is the bifurcation set generated in the vicinity of the stable focus, and the other is that generated in the vicinity of the stable relaxation oscillation. By analyzing the bifurcation diagram in detail, we can explain the sudden change from chaos with complicated waveforms to oscillation death. We make it clear that this phenomenon is caused by a saddle-node bifurcation.

[Patients' perspective on Parkinson disease therapies: results of a large-scale survey in Japan].

Parkinson's disease (PD) affects 145,000 people in Japan. Most of these patients are treated with levodopa in combination with other anti-PD therapies. In order to maximize efficacy and patient satisfaction, this survey was conducted to investigate patients' perspective of current PD management in Japan. This survey was conducted in 2008 by questionnaire (3,935) and interview (407). The majority of responders were members of the Japan PD Association. Severity of PD, medication, impact of wearing-off, and patients' attitudes to therapy were assessed. Most patients (95%) were on levodopa, with an average dose of 370 mg/day. Although dose increased with duration of treatment, the majority of patients remained within 300-400 mg/day. Patients with wearing-off were less satisfied with their therapy than those without wearing-off (36 vs 49%). Most patients are less concerned by mild dyskinesias. Hallucination is the most distressing side effect. For patients preferring mobility over dyskinesia, levodopa should be dosed sufficiently, and possibly titrated, to maximize clinical benefit and patient satisfaction.