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.

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.

[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.

Subregional 6-[18F]fluoro-ʟ-m-tyrosine uptake in the striatum in Parkinson's disease.

BACKGROUND: In idiopathic Parkinson's disease (PD) the clinical features are heterogeneous and include different predominant symptoms. The aim of the present study was to determine the relationship between subregional aromatic l-amino acid decarboxylase (AADC) activity in the striatum and the cardinal motor symptoms of PD using high-resolution positron emission tomography (PET) with an AADC tracer, 6-[18F]fluoro-ʟ-m-tyrosine (FMT). METHODS: We assessed 101 patients with PD and 19 healthy volunteers. PD was diagnosed based on the UK Brain Bank criteria by two experts on movement disorders. Motor symptoms were measured with the Unified Parkinson's Disease Rating Scale (UPDRS). FMT uptake in the subregions of the striatum was analyzed using semi-automated software for region-of-interest demarcation on co-registered magnetic resonance images. RESULTS: In all PD patients, FMT uptake was decreased in the posterior putamen regardless of predominant motor symptoms and disease duration. Smaller uptake values were found in the putamen contralateral to the side with more affected limbs. The severity of bradykinesia, rigidity, and axial symptoms was correlated with the decrease of FMT uptake in the putamen, particularly in the anterior part. No significant correlation was observed between tremors and FMT uptake. CONCLUSIONS: Decrease of FMT uptake in the posterior putamen appears to be most sensitive in mild PD and uptake in the anterior putamen may reflect the severity of main motor symptoms, except for tremor.

A phase I study of aromatic L-amino acid decarboxylase gene therapy for Parkinson's disease.

Gene transfer of dopamine-synthesizing enzymes into the striatal neurons has led to behavioral recovery in animal models of Parkinson's disease (PD). We evaluated the safety, tolerability, and potential efficacy of adeno-associated virus (AAV) vector-mediated gene delivery of aromatic L-amino acid decarboxylase (AADC) into the putamen of PD patients. Six PD patients were evaluated at baseline and at 6 months, using multiple measures, including the Unified Parkinson's Disease Rating Scale (UPDRS), motor state diaries, and positron emission tomography (PET) with 6-[(18)F]fluoro-L-m-tyrosine (FMT), a tracer for AADC. The short-duration response to levodopa was measured in three patients. The procedure was well tolerated. Six months after surgery, motor functions in the OFF-medication state improved an average of 46% based on the UPDRS scores, without apparent changes in the short-duration response to levodopa. PET revealed a 56% increase in FMT activity, which persisted up to 96 weeks. Our findings provide class IV evidence regarding the safety and efficacy of AADC gene therapy and warrant further evaluation in a randomized, controlled, phase 2 setting.

Management of non-motor complications in Parkinson's disease.

This paper summarizes the methods we devised for the treatment of psychosis, orthostatic hypotension, and mood disorders among the various non-motor complications of Parkinson's disease. Psychosis may not manifest when a patient believes in his/her delusions. If left untreated over a prolonged period, however, the delusions progress to paranoia that is very difficult to cure. Accordingly, enquiries should be made during routine examinations to detect the presence of psychosis and facilitate early discovery. Atypical antipsychotics are used when psychosis does not improve after reducing the doses of antiparkinson drugs. We achieved favorable results by using mianserin hydrochloride prior to this step, with efficacy being observed for hallucinations and mild delusions that often manifested at night. This drug does not act as a dopamine receptor blocker, so it has the advantage of not aggravating motor symptoms. With this therapy, it is also possible to improve motor symptoms without inducing psychosis by reducing the doses of antiparkinson drugs and locally stimulating the motor loop by deep brain stimulation of the subthalamic nucleus. We previously introduced leg-holding exercises for the treatment of orthostatic hypotension, through which blood pooled in the veins is returned to the systemic circulation by holding the knees. This can be done easily and is free of adverse reactions. Mood disorders are difficult to cope with in patients with Parkinson's disease, but may be treated by selecting an appropriate dopamine agonist while giving consideration to affinity for the dopamine D3 receptor. However, treatment becomes complicated when the dopamine receptor is overstimulated. Here we report on cases of successfully treated pathological gambling and dopamine dysregulation syndrome, which are considered difficult to manage. The solution may differ depending on a patient's environment, and it is not easy to prescribe therapy based on evidence-based medicine. The best therapy should be selected by maintaining communication with the patient and developing a relationship built on trust.

[Pathological gambling and Parkinson disease].

Pathological gambling (PG) is defined by the DSM IV criteria as inappropriate, persistent, and maladaptive gambling behavior that has repercussions on family, personal, and professional life. It is classified as an impulse control disorder and is widely understood as a nonpharmacological addiction. PG has been reported as a complication in the treatment of Parkinson disease (PD). The prevalence of PG in PD has been reported to range between 1.7 and 7% compared to a prevalence of approximately 1% in the general population. Though there is no survey that indicates the prevalence of PG in Japanese PD patients, problematic gambling behaviors in PD are occasionally observed. In addition to PG other impulse control behaviors and punding (repetitive stereotyped behavior) are recognized as components of the dopamine dysregulation syndrome (DDS), which is characterized by the compulsive use of dopaminergic medications, including levodopa and subcutaneous apomorphine. Though PG can occur with DDS it often occurs in isolation. The vast majority of PG seen in PD is related to dopamine agonists (DA). With regard to the administration of oral DA, pramipexole may induce a higher degree of PG than other types of oral DA due to its disproportionate stimulation of dopamine D3 receptors. However, the differences between the observed effects of various classes of oral DA were insignificant. PG associated with levodopa mono-therapy is uncommon, but in the majority of cases levodopa is co-prescribed. Subthalamic nucleus deep brain stimulation (STN-DBS) was recently introduced to treat advanced PD. An improvement in PG symptoms following STN-DBS has been reported due to a marked decrease in dopaminergic medications. However, in some patients, PG developed following STN-DBS despite the significant reduction or discontinuation of DA. STN-DBS per se may be a potential initiator of PG. Younger age of PD onset, novelty seeking personality traits, history of alcohol abuse, and impulsivity traits were significant predictors of PG. Patients especially those with individual susceptibility to PG should be warned of the potential risks of PG before DA treatment is initiated.

Oscillation and its inhibition in a neuronal network model for tinnitus sound therapy.

Tinnitus is the perception of phantom sounds in the ears or in the head. Sound therapy techniques for tinnitus treatment have been proposed. In order to investigate mechanisms of tinnitus generation and the clinical effects of sound therapy from the viewpoint of neural engineering, we have proposed a computational model using a neural oscillator. In the present paper, we propose another model that is composed of model neurons described by simplified Hodgkin-Huxley equations. By computer simulation it was detected that this model also has a bistable state, i.e., a stable oscillatory state and a stable equilibrium (non-oscillatory) state coexist at a certain parameter region. It was also noticed that the oscillation can be inhibited by supplying constant or pulse train stimuli, which is hypothesized as an afferent signal that is employed as an acoustical signal for tinnitus treatment. By hypothesizing that the oscillation and the equilibrium correspond to generation and inhibition of tinnitus, respectively, these phenomena could explain the fact that the habituated human auditory system temporarily halts perception of tinnitus following sound therapy.