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Background: Ossification of the posterior atlantoaxial membrane (PAAM) is a rare cause of spinal cord compression. Case presentation: A 46-year-old woman with rheumatoid arthritis (RA) and a 2-year history of slowly progressive gait disturbance underwent surgery for right knee stiffness and right lower limb mild weakness. A neurologic examination revealed brisk deep tendon reflexes (DTR) and spasticity in her four limbs. A computed tomography (CT) scan revealed spinal stenosis caused by ossification of the PAAM, a rare cause of spinal cord compression. The patient's lower limbs weakness and walking capability were ameliorated post-surgery. Conclusions: Although the exact mechanism of ossification of PAAM remains unclear, chronic mechanical stress as well as persistent atlantoaxial instability may promote the development of the ossification.

Abstract Background Whole-body vibration (WBV) training can provoke reactive muscle response and thus exert beneficial effects in various neurological patients. This study aimed to investigate the muscles activation and acceleration transmissibility of the lower extremity to try to understand the neuromuscular control in the Parkinson’s disease (PD) patients under different conditions of the WBV training, including position and frequency. Methods Sixteen PD patients and sixteen controls were enrolled. Each of them would receive two WBV training sessions with 3 and 20 Hz mechanical vibration in separated days. In each session, they were asked to stand on the WBV machine with straight and then bended knee joint positions, while the vibration stimulation was delivered or not. The electromyographic (EMG) signals and the segmental acceleration from the lower extremity were recorded and processed. The amplitude, co-contraction indexes (CCI), and normalized median frequency slope (NMFS) from the EMG signals, and the acceleration transmissibility were calculated. Results The results showed larger rectus femoris (RF) amplitudes under 3 Hz vibration than those in 20 Hz and no vibration conditions; larger tibialis anterior (TA) in 20 Hz than in no vibration; larger gastrocnemius (GAS) in 20 Hz than in 3 Hz and no vibration. These results indicated that different vibration frequencies mainly induced reactive responses in different muscles, by showing higher activation of the knee extensors in 3 Hz and of the lower leg muscles in 20 Hz condition, respectively. Comparing between groups, the PD patients reacted to the WBV stimulation by showing larger muscle activations in hamstring (HAM), TA and GAS, and smaller CCI in thigh than those in the controls. In bended knee, it demonstrated a higher RF amplitude and a steeper NMFS but smaller HAM activations than in straight knee position. The higher acceleration transmissibility was found in the control group, in the straight knee position and in the 3 Hz vibration conditions. Conclusion The PD patients demonstrated altered neuromuscular control compared with the controls in responding to the WBV stimulations, with generally higher EMG amplitude of lower extremity muscles. For designing WBV strengthening protocol in the PD population, the 3 Hz with straight or flexed knee protocol was recommended to recruit more thigh muscles; the bended knee position with 20 Hz vibration was for the shank muscles.

Background. Archery exercise exerts a rehabilitative effect on patients with paraplegia and might potentially serve as complementary physiotherapy for patients with Parkinson’s disease. Objective. This study aimed to examine the rehabilitative effects of an archery intervention. Methods. A randomized controlled trial of a 12-week intervention was performed in patients with idiopathic Parkinson’s disease. Thirty-one of the 39 eligible patients recruited from a medical center in Taiwan participated in the trial, of whom 16 were in the experimental group practicing archery exercises and 15 were in the control group at the beginning; twenty-nine completed the whole process. The Purdue pegboard test (PPT), the Unified Parkinson’s Disease Rating Scale I to III (UPDRS I to III), physical fitness test, and timed up and go test (TUG) were used to assess the intervention effects of archery exercise. Results. Compared to the control group, the outcome differences between the posthoc and baseline tests in PPT, UPDRS I to III, lower extremity muscular strength, and TUG in the experimental group (between-group difference in difference’s mean: 2.07, 1.59, 1.36, −2.25, −3.81, −9.10, 3.57, and −1.51, respectively) did show positive changes and their effect sizes examined from Mann–Whitney U tests (η: 0.631, 0.544, 0.555, 0.372, 0.411, 0.470, 0.601, and 0.381, respectively; Ps

ObjectiveThis study evaluated short-term (1-month) and long-term (1-year) mortality risks associated with the glomerular filtration rate (eGFR) on admission for patients with intracerebral hemorrhage.MethodsFrom the Taiwan Stroke Registry data from April 2006 to December 2016, we identified and stratified patients with intracerebral hemorrhage into five subgroups by the eGFR level on admission: ≥90, 60-89, 30-59, 15-29, and ResultsBoth the 1-month and 1-year mortality rates progressively increased with the decrease in eGFR levels. The 1-month mortality rate in patients with eGFR < 15 mL/min/1.73 m2 or on dialysis was approximately 5.5-fold greater than that in patients with eGFR ≥ 90 mL/min/1.73 m2 (8.31 versus 1.50 per 1000 person-days), with an adjusted hazard ratio (HR) of 4.59 [95% confidence interval (CI) = 2.71-7.78]. Similarly, the 1-year mortality in patients with eGFR < 15 mL/min/1.73 m2 or on dialysis was 7.5 times that in patients with eGFR ≥ 90 mL/min/1.73 m2 (2.34 versus 0.31 per 1000 person-days), with an adjusted HR of 4.54 (95% CI 2.95-6.98).ConclusionImpairment of renal function is an independent risk factor for mortality in patients with intracerebral hemorrhage in a gradual way. The eGFR level is a prognostic indicator for patients with intracerebral hemorrhage.

Objective(s): Parkinson’s disease (PD) is a common progressive neurodegeneration disease. Its incidence increases with age and affects about 1% of people over 60. Incidentally, transient receptor potential V1 (TRPV1) and its relation with neuroinflammation in mouse brain has been widely reported.Materials and Methods: We used 6-hydroxydopamine (6-OHDA) to induce PDD in mice. We then used the Morris water maze and Bio-Plex to test learning and inflammatory mediators in mouse plasma. Western blotting and immunostaining were used to examine TRPV1 pathway in the hippocampus and medial prefrontal cortex (mPFC). Results: On acquisition days 3 (Control = 4.40 ± 0.8 sec, PDD = 9.82 ± 1.52 sec, EA = 5.04 ± 0.58 sec, Riva = 4.75 ± 0.87 sec; P=0.001) and 4, reversal learning days 1, 2, 3 (Control = 2.86 ± 0.46 sec, PDD = 9.80 ± 1.83 sec, EA = 4.6 ± 0.82 sec, Riva = 4.6 ± 1.03 sec; P=0.001) and 4, PDD mice showed significantly longer escape latency than the other three groups. Results showed that several cytokines were up-regulated in PDD mice and reversed by EA and rivastigmine. TRPV1 and downstream molecules were up-regulated in PDD mice and further reversed by EA and rivastigmine. Interestingly, α7 nicotinic receptors and parvalbumin levels in both the hippocampus and prefrontal cortex increased in EA-treated mice, but not in rivastigmine-treated mice.Conclusion: Our results showed that TRPV1 played a role in the modulation of neuroinflammation of PDD, and could potentially be a new target for treatment.

Objective: Lower serum low-density lipoprotein cholesterol (LDL-C) levels are associated with increased intracerebral hemorrhage (ICH) risk. However, reverse causality and residual confounding has not attracted public attention. Therefore, we assessed whether people with LDL-C have increased risk of mortality adjusting for potential confounders using two large Taiwan cohorts.Methods: The Mei-Jhao (MJ) cohort has 414,372 adults participating in a medical screening program with 378 ICH deaths within 15 years of follow-up (1994–2008). Cox proportional hazards regressions estimated hazard death ratios according to LDL-C levels. We identified 4,606 ICH patients from the Taiwan Stroke Registry (TSR) and analyzed the impact of LDL-C on 3-month mortality.Results: Low cholesterol (LDL-C

Task-specific dystonia is a neurological movement disorder that abnormal contractions of muscles result in the twisting of fixed postures or muscle spasm during specific tasks. Due to the rareness and the pathophysiology of the disease, there is no test to confirm the diagnosis of task-specific dystonia, except comprehensive observations by the experts. Evidence from neural electrophysiological data suggests that enhanced low frequency (4–12 Hz) oscillations in the subcortical structure of the globus pallidus were associated with the pathological abnormalities concerning β and γ rhythms in motor areas and motor cortical network in patients with task-specific dystonia. However, whether patients with task-specific dystonia have any low-frequency abnormalities in motor cortical areas remains unclear. In this study, we hypothesized that low-frequency abnormalities are present in core motor areas and motor cortical networks in patients with task-specific dystonia during performing the non-symptomatic movements and those low-frequency abnormalities can help the diagnosis of this disease. We tested this hypothesis by using EEG, effective connectivity analysis, and a machine learning method.Fifteen patients with task-specific dystonia and 15 healthy controls were recruited. The machine learning method identified 8 aberrant movement-related network connections concerning low frequency, β and γ frequencies, which enabled the separation of the data of patients from those of controls with an accuracy of 90%. Importantly, 7 of the 8 aberrant connections engaged the premotor area contralateral to the affected hand, suggesting an important role of the premotor area in the pathological abnormities. The patients exhibited significantly lower low frequency activities during the movement preparation and significantly lower β rhythms during movements compared with healthy controls in the core motor areas. Our findings of low frequency- and β-related abnormalities at the cortical level and aberrant motor network could help diagnose task-specific dystonia in the clinical setting, and the importance of the contralesional premotor area suggests its diagnostic potential for task-specific dystonia.

Objective: Stroke in young adults is uncommon, and the etiologies and risk factors of stroke in young adults differ from those in older populations. Smoker's paradox is an unexpected favorable outcome, and age difference is used to explain the association between smoking and the favorable functional outcome. This study aimed to investigate the existence of this phenomenon in young stroke patients.Methods: We analyzed a total of 9,087 young stroke cases registered in the nationwide stroke registry system of Taiwan between 2006 and 2016. Smoking criteria included having a current history of smoking more than one cigarette per day for more than 6 months. After matching for sex and age, a Cox model was used to compare mortality and function outcomes between smokers and non-smokers.Results: Compared with the non-smoker group, smoking was associated with older age, higher comorbidities, and higher alcohol consumption. Patients who report smoking with National Institutes of Health Stroke Scale scores of 11–15 had a worse functional outcome (adjusted odds ratio, 0.81; 95% confidence interval, 0.76 – 0.87).Conclusion: Smokers had a higher risk of unfavorable functional outcomes at 3 months after stroke, and therefore, we continue to strongly advocate the importance of smoking cessation.

Background: Freezing of gait (FOG) in Parkinson's disease (PD) is a devastating clinical phenomenon that has a detrimental impact on patients. It tends to be triggered more often during turning (complex) than during forwarding straight (simple) walking. The neural mechanism underlying this phenomenon remains unclear and requires further elucidation.Objective: To investigate the differences in cerebral functional magnetic resonance imaging responses between PD patients with and without FOG during explicitly video-guided motor imagery (MI) of various complex (normal, freezing) and simple (normal, freezing) walking conditions.Methods: We recruited 34 PD patients, namely, 20 with FOG and 14 without FOG, and 15 normal controls. Participants underwent video-guided MI of turning and straight walking, with and without freezing, while their brain blood oxygen level-dependent (BOLD) activities were measured. Gait analysis was performed.Results: While comparing FOG turning with FOG straight walking, freezers showed higher activation of the superior occipital gyrus, left precentral gyrus, and right postcentral gyrus compared with non-freezers. Normal controls also manifest similar findings compared with non-freezers, except no difference was noted in occipital gyrus activity between the two groups. Freezers also displayed a higher effect size in the locomotor regions than non-freezers during imagery of normal turning.Conclusions: Our findings suggest that freezers require a higher drive of cortical and locomotion regions to overcome the overinhibition of the pathways in freezers than in non-freezers. Compared with simple walking, increased dorsal visual pathway and deep locomotion region activities might play pivotal roles in tackling FOG in freezers during complex walking.

The present study investigated the impact of carnosic acid (CA) from rosemary on the levodopa (L-dopa)-induced dyskinesia (LID) in rats treated with 6-hydroxydopamine (6-OHDA). To establish the model of LID, 6-OHDA-lesioned rats were injected intraperitoneally with 30 mg/kg L-dopa once a day for 36 days. Rats were daily administrated with 3 or 15 mg/kg CA by oral intubation prior to L-dopa injection for 4 days. Rats pretreated with CA had reduced L-dopa-induced abnormal involuntary movements (AIMs) and ALO scores (a sum of axial, limb, and orofacial scores). Moreover, the increases of dopamine D1-receptor, p-DARPP-32, ΔFosB, p-ERK1/2, and p-c-Jun ser63, along with the decrease in p-c-Jun ser73, induced by L-dopa in 6-OHDA-treated rats were significantly reversed by pretreatment with CA. In addition, we used the model of SH-SY5Y cells to further examine the neuroprotective mechanisms of CA on L-dopa-induced cytotoxicity. SH-SY5Y cells were treated with CA for 18 h, and then co-treated with 400 μM L-dopa for the indicated time points. The results showed that pretreatment of CA attenuated the cell death and nuclear condensation induced by L-dopa. By the immunoblots, the reduction of Bcl-2, p-c-Jun ser73, and parkin and the induction of cleaved caspase 3, cleaved Poly (ADP-ribose) polymerase, p-ERK1/2, p-c-Jun ser63, and ubiquitinated protein by L-dopa were improved in cells pretreated with CA. In conclusion, CA ameliorates the development of LID via regulating the D1R signaling and prevents L-dopa-induced apoptotic cell death through modulating the ERK1/2-c-Jun and inducing the parkin. This study suggested that CA can be used to alleviate the adverse effects of LID for PD patients.

Objective: Multiple system atrophy (MSA) is a neurodegenerative disorder manifesting as parkinsonism, cerebellar ataxia, and autonomic dysfunction. It is categorized into MSA with predominant parkinsonism (MSA-P) and into MSA with predominant cerebellar ataxia (MSA-C). The pathophysiology of motor control circuitry involvement in MSA subtype is unclear. Bereitschaftspotential (BP) is a feasible clinical tool to measure electroencephalographic activity prior to volitional motions. We recorded BP in patients with MSA-P and MSA-C to investigate their motor cortical preparation and activation for volitional movement.Methods: We included eight patients with MSA-P, eight patients with MSA-C, and eight age-matched healthy controls. BP was recorded during self-paced rapid wrist extension movements. The electroencephalographic epochs were time-locked to the electromyography onset of the voluntary wrist movements. The three groups were compared with respect to the mean amplitudes of early (1,500–500 ms before movement onset) and late (500–0 ms before movement onset) BP.Results: Mean early BP amplitude was non-significantly different between the three groups. Mean late BP amplitude in the two patient groups was significantly reduced in the parietal area contralateral to the movement side compared with that in the healthy control group. In addition, the late BP of the MSA-C group but not the MSA-P group was significantly reduced at the central parietal area compared with that of the healthy control group.Conclusions: Our findings suggest that patients with MSA exhibit motor cortical dysfunction in voluntary movement preparation and activation. The dysfunction can be practicably evaluated using late BP, which represents the cerebello-dentato-thalamo-cortical pathway.

Background: In most countries, large cerebral artery occlusion is identified as the leading cause of disability. In 2015, five large-scale clinical trials confirmed the benefit of intra-arterial thrombectomy. However, thrombectomy is a highly technical and facility-dependent procedure. Primary stroke centers need to transfer patients to comprehensive stroke centers to perform thrombectomy. The time-lapse during interhospital transfer would decrease the chance of the patient's proper recovery. Communication barriers also contribute to this delay.Aims: We used a smartphone application to overcome communication barriers between hospitals. We aimed to shorten the door-to-puncture time of interhospital transfer patients.Methods: We began using a smartphone application, “LINE,” to facilitate interhospital communication on May 01, 2018. We carried out retrospective data analyses for all the transfer patients (n = 351), with the primary outcome being the door-to-puncture time in our comprehensive stroke center (China Medical University Hospital). We compared the three periods: May 01 to Dec 31, 2017 (before the use of the smartphone application); May 01 to Dec 31, 2018 (the 1st year of using the smartphone application); and May 01 to Dec 31, 2019 (the 2nd year of using the smartphone application). We also compared the transfer data with non-transfer thrombectomies in the same period.Results: We compared 2017, 2018, and 2019 data. The total number of transfer patients increased over the years: 63, 113, 175, respectively. The mean door-to-puncture time decreased significantly, going from 109, through 102, to 92 min. Meanwhile, the mean door-to-puncture time in non-transfer patients were 140.3, 122.1, and 129.3 min. The main reason of time saving was the change of the way of communication, from point-to-point interhospital communication to hub-to-spoke interhospital communication.Conclusions: We used this smartphone application to enhance interhospital communication, changed from the point-to-point to hub-to-spoke method. It made us overcome the communication barrier and build up interhospital connection, thus shortening the door-to-puncture time. Our experience demonstrated the importance of close communication and teamwork in hyperacute stroke care, especially in interhospital transfer for thrombectomy.

Objective: Associative motor cortical plasticity can be non-invasively induced by paired median nerve electric stimulation and transcranial magnetic stimulation (TMS) of the primary motor cortex (M1). This study investigates whether a simultaneous motor reaction of the other hand advances the associative plasticity in M1.Methods: Twenty-four right-handed subjects received conventional paired associative stimulation (PAS) and PAS with simultaneous motor reaction (PASmr) with at least a 1-week interval. The PASmr protocol additionally included left abductor pollicis brevis muscle movement responding to a digital sound. The motor reaction time was individually measured. The M1 excitability was examined by the motor evoked potential (MEP), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF) before and after the PAS protocols.Results: The conventional PAS protocol significantly facilitated MEP and suppressed SICI. A negative correlation between the reaction time and the MEP change, and a positive correlation between the reaction time and the ICF change were found in the PASmr protocol. By subgrouping analysis, we further found significant facilitation of MEP and a reduction of ICF in the subjects with fast reaction times but not in those with slow reaction times.Conclusion: Synchronized motor reaction ipsilateral to the stimulated M1 induces associative M1 motor plasticity through the spike-timing dependent principle. MEP and ICF change could represent this kind of plasticity. The current findings provide a novel insight into designing rehabilitation programs concerning motor function.

Objective: Review and integrate the neurologic manifestations of the Coronavirus Disease 2019 (COVID-19) pandemic, to aid medical practitioners who are combating the newly derived infectious disease.Methods: We reviewed the clinical research, consisting of mainly case series, on reported neurologic manifestations of COVID-19. We also reviewed basic studies to understand the mechanism of these neurologic symptoms and signs.Results: We included 79 studies for qualitative synthesis and 63 studies for meta-analysis. The reported neurologic manifestations were olfactory/taste disorders (35.6%), myalgia (18.5%), headache (10.7%), acute cerebral vascular disease (8.1%), dizziness (7.9%), altered mental status (7.8%), seizure (1.5%), encephalitis, neuralgia, ataxia, Guillain-Barre syndrome, Miller Fisher syndrome, intracerebral hemorrhage, polyneuritis cranialis, and dystonic posture.Conclusions: Neurologic manifestations in COVID-19 may alert physicians and medical practitioners to rule in high-risk patients. The increasing incidence of olfactory/taste disorders, myalgia, headache, and acute cerebral vascular disease renders a possibility that COVID-19 could attack the nervous system. The cytokine secretion and bloodstream circulation (viremia) are among the most possible routes into the nervous system.

Sialidosis is a rare autosomal recessive disorder that affects the intralysosomal catabolism of sialylated glycoconjugates and is involved in cellular immune response. Mutations in NEU1, which encodes the sialidase enzyme, result in sialidosis. Sialidosis is characterized by the progressive lysosomal storage of sialylated glycopeptides and oligosaccharides. In this study, we used Sendai virus reprogramming to generate an induced pluripotent stem cell (iPSC) line carrying the A544G mutation combined with the 667-679 deletion of the NEU1 gene from a sialidosis patient. The patient-specific iPSCs expressed pluripotent markers, possessed a normal karyotype, and displayed the capability to differentiate into three germ layers.

Introduction: Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant, cerebellar degeneration predominant disease caused by excessive CAG repeats. We examined event-related dysynchronization/synchronization (ERD/ERS) in patients with SCA3.Methods: We assessed ERD/ERS of self-paced voluntary hand movements in 15 patients with genetically proven SCA3 in comparison with healthy controls.Results: In ERS, a significant interaction effect between group, frequency, and period (F = 1.591; p = 0.005; ρI = 0.86) was observed. The post-hoc two-tailed independent t-test showed significant differences in high beta and low beta ERS. By contrast, in ERD, no apparent differences were observed in the pattern of patients with SCA3 in comparison with healthy controls (F = 1.01; p = 0.442).Conclusion: The study revealed a decreased ERS in patients with SCA3, especially at the frequency of 20–30 Hz. This study elucidates the significant role of cerebellum in motor control.

Pairing transcutaneous electric nerve stimulation (TENS) and transcranial magnetic stimulation (TMS) with specific stimulus-intervals induces associative motor plasticity at the primary motor cortex (M1). Electroacupuncture (EA) is an established medical technique in the eastern countries. This study investigates whether EA paired with TMS induces distinct M1 motor plasticity. Fifteen healthy, right-handed subjects (aged 23.6 ± 2.0 years, eight women) were studied. Two-hundred and twenty-five pairs of TMS of the left M1 preceded by right EA at acupoint “Neiguan” [Pericardium 6 (PC6), located 2 decimeters proximal from the wrist wrinkle] were respectively applied with the interstimulus interval (ISI) of individual somatosensory evoked potential (SSEP) N20 latency plus 2 ms (N20+2) and minus 5 ms (N20-5) with at least 1-week interval. The paired stimulation was delivered at a rate of 0.25 Hz. Sham TMS with a sham coil was adopted to examine the low-frequency EA influence on M1 in eleven subjects. M1 excitability was assessed by motor-evoked potential (MEP) recruitment curve with five TMS intensity levels, short-interval intracortical inhibition (SICI), intracortical facilitation (ICF) and cerebellar inhibition (CBI) at the abductor pollicis brevis (APB) muscle of the right hand before and after the EA-M1 paired associative stimulation (PAS). In addition, median nerve SSEPs and H-reflex were respectively measured to monitor somatosensory and spinal excitability. The MEP showed significantly facilitated after the sham EA-M1 PAS while tested with 80% of the TMS intensity producing on average 1 mV amplitude (i.e., MEP1 mV) in the resting APB muscle. It was also facilitated while tested with 90% MEP1 mV irrespective of the stimulation conditions. The SSEP showed a higher amplitude from the real EA-M1 PAS compared to that from the sham EA-M1 PAS. No significant change was found on SICI, ICF, CBI and H-reflex. Findings suggest that repetitive low frequency EA paired with real TMS did not induce spike-timing dependent motor plasticity but EA paired with sham TMS induced specific M1 excitability change. Complex sensory afferents with dispersed time locked to the sensorimotor cortical area could hamper instead of enhancing the induction of the spike-timing dependent plasticity (STDP) in M1.

BackgroundDystonia is a neurological syndrome typically resulting in abnormal postures.ObjectivesWe tested the role of physical injury as potential risk factor for development of dystonia using The National Health Insurance Research Database of Taiwan.MethodsWe identified 65704 people who were coded in the database as having had peripheral traumatic injuries (ICD-9-CM 807-848 and 860-959) in the year 2000. Patients with traumatic brain or spine injuries were excluded from analysis. We matched them using purposive sampling with 65704 people in the database who had not suffered peripheral trauma. We looked then at the incidence of dystonia occurring at least 1 year from the date of the peripheral trauma until 2011. Psychiatric symptoms (depression and anxiety) and sleeps difficulties have been investigated as potential covariates.ResultsWe found 189 patients with dystonia (0.28%) in the trauma group, and 52 patients with dystonia (0.08%) in the non-trauma group. Trauma was independently associated with dystonia (adjusted HR = 3.12, 95% CI = 2.30-4.24). The incidence density of dystonia in the trauma group was 2.27 per 10000 person-years, while it was 0.71 per 10000 person-years in the non-trauma group Beyond the peripheral trauma, other variables associated to the incidence of dystonia included female sex, aged 40 years and above, depression and sleep disorders.ConclusionThese data from a large population dataset support traumatic injury as a risk factor for the development of dystonia.

Objectives: Levodopa-carbidopa intestinal gel (LCIG) was developed to reduce motor complications in Parkinson’s disease (PD) caused by pulsatile levodopa plasma concentrations following oral levodopa administration. Dyskinesia and ‘wearing off’ symptoms can vary between Asian and Caucasian patients with PD, thus highlighting the importance of assessing the effectiveness of LCIG in an Asian population. Efficacy and safety of LCIG were previously assessed in a 12-week open-label study; we report the efficacy and safety of at least 52 weeks of LCIG treatment in Japanese, Taiwanese, and Korean patients with advanced PD in the ongoing extension study. Methods: In this interim analysis of a phase III, open-label, multicenter extension study in Japan, South Korea, and Taiwan [ClinicalTrials.gov identifier: NCT02082249/JapiCTI-142482], the mean change from baseline to final visit in ‘off’ time, as reported in the PD symptom diary, was normalized to a 16-h waking day. Changes in Parkinson’s Disease Questionnaire-39 (PDQ-39) summary index and domains scores were also analyzed. Adverse events (AEs) were recorded. Results: Of the 28 patients enrolled (21 Japanese, 3 Taiwanese, 4 Korean), 27 completed at least 52 total weeks of treatment, and 25 patients were continuing in the study at data cutoff. The mean [standard deviation (SD)] ‘off’ time was significantly reduced by 4.6 (3.1) h/day ( p < 0.001, n = 28). Patients experienced significant improvements in quality of life, as recorded by the mean change from baseline in PDQ-39 summary index ( p < 0.001). All patients had at least one AE; three patients (11%) discontinued due to an AE. There were two deaths (sepsis and drowning), both of which the investigator considered unrelated to LCIG treatment. Conclusions: These data suggest that LCIG treatment is efficacious, safe, and well tolerated in Japanese, Taiwanese, and Korean patients with advanced PD, thus confirming the consistency of LCIG treatment in patients with advanced PD.

BackgroundFunctional perturbation of the cerebellum (CB)–motor cortex (M1) interactions may underlie pathophysiology of movement disorders, such as Parkinson’s disease (PD) and spinocerebellar ataxia type 3 (SCA3). Recently, M1 motor excitability can be bidirectionally modulated in young subjects by corticocortical paired associative stimulation (PAS) on CB and contralateral M1 with transcranial magnetic stimulation (TMS), probably through the cerebello–dentato–thalamo–cortical (CDTC) circuit. In this study, we investigated the CB to M1-associative plasticity in healthy elderly PD and SCA3.MethodsTen right-handed PD patients, nine gene-confirmed SCA3 patients, and 10 age-matched healthy controls (HC) were studied. One hundred and twenty pairs of TMS of the left M1 preceded by right lateral CB TMS at an interstimulus interval of 2 (CB → M1 PAS2ms) and 6 ms (CB → M1 PAS6ms) were, respectively, applied with at least 1-week interval. M1 excitability was assessed by motor-evoked potential (MEP) amplitude, short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), and cerebellar inhibition (CBI) at the first dorsal interosseous muscle of the right hand before and after the CB → M1 PAS.ResultsThe M1 excitability represented by MEP amplitude was significantly facilitated and suppressed in the HC group by CB → M1 PAS2ms and CB → M1 PAS6ms, respectively. The bidirectional modulation on MEP amplitude was absent in the PD and SCA3 groups. SICI and the baseline CBI were significantly reduced in the SCA3 group compared to those of the HC group irrespective of the CB → M1 PAS protocols. There was a significant reduction of CBI immediately and 60 min after the CB → M1 PAS protocols in the HC group but not in the patient groups. No significant change of ICF was found.ConclusionCorticocortical CB → M1 PAS can induce bidirectional motor cortical plasticity in M1 for healthy aged subjects. The modulation may be independent of the inhibitory neurocircuits, such as SICI and CBI, and the facilitatory mechanism like ICF. Both patients with PD and SCA3 showed impairment of such plasticity, suggesting significant functional perturbation of the CDTC circuit.

Previous studies revealed that chronic exposure to air pollution can significantly increase the risk of the development of Parkinson's disease (PD), but this relationship is inconclusive as large-scale prospective studies are limited and the results are inconsistent. Therefore, the purpose of this study was to ascertain the adverse health effects of air pollution exposure in a nationwide population using a longitudinal approach.We conducted a nested case-control study using the National Health Insurance Research Dataset (NHIRD), which consisted of 1,000,000 beneficiaries in the National Health Insurance Program (NHI) in the year 2000 and their medical records from 1995 to 2013 and using public data on air pollution concentrations from monitoring stations across Taiwan released from the Environmental Protection Administration to identify people with ages ≥ 40 years living in areas with monitoring stations during 1995-1999 as study subjects. Then, we excluded subjects with PD, dementia, stroke and diabetes diagnosed before Jan. 1, 2000 and obtained 54,524 subjects to follow until Dec. 31, 2013. In this observational period, 1060 newly diagnosed PD cases were identified. 4240 controls were randomly selected from those without PD using a matching strategy for age, sex, the year of PD diagnosis and the year of entering the NHI program at a ratio of 1:4. Ten elements of air pollution were examined, and multiple logistic regression models were used to measure their risks in subsequent PD development.The incidence of PD in adults aged ≥ 40 years was 1.9%, and the median duration for disease onset was 8.45 years. None of the chemical compounds (SO2, O3, CO, NOx, NO, NO2, THC, CH4, or NMHC) significantly affected the incidence of PD except for particulate matter. PM10 exposure showed significant effects on the likelihood of PD development (T3 level: > 65μg/m3 versus T1 level: ≤ 54μg/m3; OR = 1.35, 95% CI = 1.12-1.62, 0.001 ≤ P < 0.01). In addition, comorbid conditions such as dementia (ORs = 3.53-3.93, Ps < 0.001), stroke (ORs = 2.99-3.01, Ps < 0.001), depression (ORs = 2.51-2.64, Ps < 0.001), head injury (ORs = 1.24-1.29, 0.001 ≤ Ps < 0.01 or 0.01 ≤ Ps < 0.05), sleep disorder (OR = 1.23-1.26, 0.001 ≤ Ps < 0.01), and hypertension (ORs = 1.18-1.19, 0.01 ≤ Ps < 0.05) also significantly increased the risk for PD development.Although PM10 plays a significant role in PD development, the associated chemical/metal compounds that are capable of inducing adverse biological mechanisms still warrant further exploration. Because of a link between comorbid conditions and PM exposure, research on the causal relationship between long-term exposure to PM and the development of PD should be considered with caution because other possible modifiers or mediators, comorbid diseases in particular, may be involved.

Because of dopaminergic neurodegeneration, patients with Parkinson’s disease (PD) show impairment in the recognition of negative facial expressions. In the present study, we aimed to determine whether PD patients with more advanced motor problems would show a much greater deficit in recognition of emotional facial expressions than a control group and whether impairment of emotion recognition would extend to positive emotions. Twenty-nine PD patients and 29 age-matched healthy controls were recruited. Participants were asked to discriminate emotions in Experiment 1 and identify gender in Experiment 2. In Experiment 1, PD patients demonstrated a recognition deficit for negative (sadness and anger) and positive faces. Further analysis showed that only PD patients with high motor dysfunction performed poorly in recognition of happy faces. In Experiment 2, PD patients showed an intact ability for gender identification, and the results eliminated possible abilities in the functions measured in Experiment 2 as alternative explanations for the results of Experiment 1. We concluded that patients’ ability to recognize emotions deteriorated as the disease progressed. Recognition of negative emotions was impaired first, and then the impairment extended to positive emotions.

Parkinson's disease (PD) and essential tremor (ET) are characterized with motor dysfunctions. Motor circuit dysfunctions can be complementarily investigated by paired associative stimulation (PAS)-induced long-term potentiation (LTP)-like plasticity and diffusion tensor imaging (DTI) of the corticospinal tract (CST). Three groups of twelve subjects with moderate severity PD, ET with intention tremor and healthy controls (HC) were studied. The primary motor cortex (M1) excitability, measured by motor evoked potential (MEP) amplitude and by short-interval and long-interval intracortical inhibition (SICI and LICI) was compared between the three groups before and after PAS. The DTI measures of fractional anisotropy (FA) and mean diffusivity (MD) were acquired. PAS effects and DTI data were simultaneously examined between groups. PAS increased MEP amplitude in HC but not in PD and ET. SICI and LICI were significantly reduced after PAS irrespective of groups. No significant differences of the mean FA and MD were found between groups. There was no significant correlation between the PAS effects and the DTI measures. Findings suggest that both PD and ET with intention tremor have impairment of the associative LTP-like corticospinal excitability change in M1. The microstructure of the CST is not relevant to the deficiency of M1 associative plasticity in PD and ET.

In our previous study, intracerebral implantation of peripheral blood stem cells (PBSCs) improved functional outcome in rats with chronic cerebral infarction. Based on this finding, a randomized, single blind controlled study was conducted in 30 patients [PBSC group ( n = 15) and control group ( n = 15)] with middle cerebral artery infarction confirmed on a T2-weighted MRI 6 months to 5 years after a stroke. Only subjects with neurological deficits of intermediate severity based on the National Institute of Health Stroke Scale (NIHSS; range: 9–20) that had been stable for at least 3 months were enrolled. Those in the PBSC group received subcutaneous G-CSF injections (15 μg/kg/day) for 5 consecutive days, and then stereotaxic implantation of 3–8 × 10 6 CD34 + immunosorted PBSCs. All 30 patients completed the 12-month follow-up. No serious adverse events were noted during study period. Improvements in stroke scales (NIHSS, ESS, and EMS) and functional outcomes (mRS) from baseline to the end of the 12-month follow-up period were significantly greater in the PBSC than the control group. The fiber numbers asymmetry (FNA) scores based on diffusion tensor image (DTI) tractography were reduced in every PBSC-treated subject, but not in the control group. Reduction in the FNA scores correlated well with the improvement in NIHSS. Furthermore, a positive motor-evoked potential (MEP) response by transcranial magnetic stimulation (TMS) appeared in 9 of the 15 subjects in the PBSC group. This phase II study demonstrated that implantation of autologous CD34 + PBSC was safe, feasible, and effective in improving functional outcome.

Besides movement disorder, patients with Parkinson's disease (PD) are revealed to have non-motor deficits. To fast detect or discriminate emotion stimuli is the basic ability of a human, and this ability implies adaptive value. There were two purposes in this study. The first goal was to investigate the discrimination of facial expressions in PD. The second goal was to investigate whether the fast discrimination of facial expressions in PD related to the level of their motor severities. Twenty-eight PDs and 28 age-matched healthy controls were recruited in this study, and they were asked to discriminate between positive (happiness) and negative (sadness, fear, anger) faces. The results revealed that PD discriminated all faces longer than healthy controls did, and PD also had less accuracy in the condition of happy and sad faces compared with healthy controls. We had further analysis to separate PDs into two subgroups by the cut-off score “35” of UPDRS motor examination (part 3). PDs with lower motor severity performed worse in the condition of sad faces than healthy controls did. Beside the deficits in perceiving negative emotions, the PDs with higher motor severity had dysfunctions in processing happy faces. We concluded that PDs had selective deficits in discriminating facial expressions, and this discriminating ability would be getting worse along with the progress of motor severity.

Hyperuricemia has been identified as an independent risk factor for coronary artery disease (CAD), with a dose-response association. In this study, we explored the causal association between gout and antigout medication and the risk of incidental CAD. We sampled data from the National Health Insurance Research Database and recruited 37,091 patients as the gout cohort, and 37,091 controls. Our primary endpoint was the diagnosis of CAD during follow-up. The overall study population was followed up until CAD diagnosis, withdrawal from the National Health Insurance program, or the end of the study. Cox proportional hazards regression models were used to examine the effect of gout on the risk of CAD, represented by the HR with the 95% CI. Patients with gout were at greater risk of CAD, compared with those without gout: HR=1.49 after adjusting for potential confounders. Non-steroidal anti-inflammatory drugs and prednisolone use was associated with a reduced risk of CAD: HR=0.63 and 0.50, respectively. Patients with gout, treated with antigout medication, exhibited a reduced risk of CAD compared with non-gout patients. Among patients with gout, those on antigout therapy had 32% lower risk compared with those not on antigout therapy: adjusted HR=0.68, 95% CI 0.63 to 0.73. Gout increases the risk of CAD, and the use of antigout medication reduces CAD risk. These results indicate that gout or hyperuricemia is a modifiable risk factor for CAD. [ABSTRACT FROM AUTHOR]

The article discusses a study on the relationship between depression and individuals diagnosed with Parkinson's Disease (PD) in Taiwan. Topics covered include the serotonergic and dopaminergic hypotheses in examining the pathophysiology between the mood disorder and the progressive disease, the neuroendocrine implications of stress found in PD resulting to the onset of depression, and the age of PD patients between 40-49 years as more at risk for the medical condition.

Objectives To compare the clinical judgment of experienced neurologists after interviewing Parkinson's disease (PD) patients and their caregivers with the use of the Pill Questionnaire to determine the presence of impairments on activities of daily living (ADL). Background ADL impairment is a criterion for the diagnosis of dementia associated with PD. The Pill Questionnaire has been recommended as a screening tool to assess ADL impairment in PD patients, but its usefulness and validity have not been fully investigated. Methods We recruited idiopathic PD patients from 12 hospitals in Taiwan, and the patients underwent clinical assessments, a neuropsychological test battery and the Unified Parkinson Disease Rating Scale evaluation. The Pill Questionnaire was administered by study assistants. Patient and caregiver interviews were performed by experienced neurologists who were blinded to the Pill Questionnaire results. Results In total, 284 PD patients (mean age 71.8 ±9 years, mean education 8.7±5.3 years, mean disease duration 5.4±5.3 years) were recruited. 63 patients showed ADL impairment by the Pill Questionnaire, and 108 patients showed ADL impairment by neurologists' clinical interviews. κ Statistics showed moderate agreement between the two methods (κ=0.521, p<0.001). Of the 108 patients who were diagnosed with ADL impairment by neurologists, only 56 patients (51.9%) showed impairment according to the Pill Questionnaire. Most of the missed patients had milder cognitive impairment and lower motor disability. Conclusions A comprehensive interview is essential to determine the presence of ADL impairment in PD patients, especially in patients with early PD. [ABSTRACT FROM AUTHOR]

The cerebellum is crucially important for motor control and adaptation. Recent non-invasive brain stimulation studies have indicated the possibility to alter the excitability of the cerebellum and its projections to the contralateral motor cortex, with behavioral consequences on motor control and adaptation. Here we sought to induce bidirectional spike-timing dependent plasticity (STDP)-like modifications of motor cortex (M1) excitability by application of paired associative stimulation (PAS) in healthy subjects. Conditioning stimulation over the right lateral cerebellum (CB) preceded focal transcranial magnetic stimulation (TMS) of the left M1 hand area at an interstimulus interval of 2 ms (CB→M1 PAS2 ms), 6ms (CB→M1 PAS6 ms) or 10ms (CB→M1 PAS10 ms ) or randomly alternating intervals of 2 and 10 ms (CB→M1 PASControl). Effects of PAS on M1 excitability were assessed by the motor-evoked potential (MEP) amplitude, short-interval intracortical inhibition (SICI), intracortical facilitation (ICF) and cerebellar-motor cortex inhibition (CBI) in the first dorsal interosseous muscle of the right hand. CB→M1 PAS2 ms resulted in MEP potentiation, CB→M1 PAS6 ms and CB→M1 PAS10 ms in MEP depression, and CB→M1 PASControl in no change. The MEP changes lasted for 30-60 min after PAS. SICI and CBI decreased non-specifically after all PAS protocols, while ICF remained unaltered. The physiological mechanisms underlying these MEP changes are carefully discussed. Findings support the notion of bidirectional STDP-like plasticity in M1 mediated by associative stimulation of the cerebello-dentato-thalamo-cortical pathway and M1. Future studies may investigate the behavioral significance of this plasticity. [ABSTRACT FROM AUTHOR]

Background: Little is known about the relationship between polypharmacy and Parkinson's disease (PD). In the present study, we tested the hypothesis that polypharmacy increases the risk of PD in older people in Taiwan. Methods: From a randomly sampled cohort of one million health insurance enrollees, we identified 2827 new cases of PD over the period 2000-2008 aged ≥65 years and selected 11 308 age-matched controls without PD. Medication history and baseline comorbidities were compared between the two groups. We defined 'polypharmacy' as an average daily use of five or more prescribed drugs. Results: Compared with patients using between none and one drug, the odds ratios (ORs) for PD increased to 1.53, 2.08, 2.64, and 2.95 for patients using two to four, five to seven, eight to nine, and ≥10 drugs, respectively. The other conditions associated with PD were dementia (OR 3.43), stroke (OR 2.30), depression (OR 2.15), and alcoholism (OR 2.11). Hyperlipidemia (OR 0.90) was inversely associated with PD. Conclusions: Polypharmacy was shown to increase the risk of PD in older people in Taiwan, with risk increasing with the number of medications taken daily. Dementia, stroke, depression, and alcoholism were also associated with an increased risk of PD, whereas there was an inverse correlation between PD and hyperlipidemia. [ABSTRACT FROM AUTHOR]

Background: The administration of memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has clinically improved the cognitive function of patients with Alzheimer’s disease (AD), indicating that a disturbance in glutamatergic transmission might be involved in a predisposition to developing the disease. Aim: The potential association of polymorphisms in NMDA receptor subunits NR3A and NR3B, encoded by the GRIN3A and GRIN3B genes, with AD was investigated. Methods: We performed a case-control study. Two single nucleotide polymorphisms, 3104 G/A (rs10989563) and 3723 G/A (rs3739722), in the GRIN3A gene and 2 GRIN3B gene polymorphisms, 1210 C/T (rs4807399) and 1730 C/T (rs2240158), were studied. Results: Upon genotyping of the exonic polymorphism in the GRIN3A gene, the G allele was present at a higher rate than the A allele at position 3723 in AD patients compared with normal groups (p < 0.05). Three haplotypes (designated Ht1–3) were identified from these 2 polymorphisms (3104 G/A and 3723 G/A), and the distribution of Ht2 (AG) differed between AD patients and controls (p < 0.05). Additionally, from the 2 GRIN3B gene variants 1210 C/T and 1730 C/T analyzed, no strong association with AD was observed. Conclusion: These observations suggest that the genetic variation of the NR3A, but not NR3B, subunit of the NMDA receptor may be a risk factor for AD pathogenesis among the Taiwanese population. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Sedative-hypnotic medications, including benzodiazepines and non-benzodiazepines, are usually prescribed for the insomniac patients; however, the addiction, dependence and adverse effects of those medications have drawn much attention. In contrast, suanzaorentang, a traditional Chinese herb remedy, has been efficiently used for insomnia relief in China, although its mechanism remains unclear. This study was designed to further elucidate the underlying mechanism of suanzaorentang on sleep regulation. One ingredient of suanzaorentang, zizyphi spinosi semen, exhibits binding affinity for serotonin (5-hydroxytryptamine, 5-HT) receptors, 5-HT1A and 5-HT2, and for GABA receptors. Our previous results have implicated that GABAA receptors, but not GABAB, mediate suanzaorentang-induced sleep alteration. In current study we further elucidated the involvement of serotonin. We found that high dose of suanzaorentang (4 g/kg/2 ml) significantly increased non-rapid eye movement sleep (NREMS) when comparing to that obtained after administering starch placebo, although placebo at dose of 4 g/kg also enhanced NREMS comparing with that obtained from baseline recording. Rapid eye movement sleep (REMS) was not altered. Administration of either 5-HT1A antagonist (NAN-190), 5-HT2 antagonist (ketanserin) or 5-HT3 antagonist (3-(4-Allylpiperazin-1-yl)-2-quinoxalinecarbonitrile) blocked suanzaorentang-induced NREMS increase. These results implicate the hypnotic effect of suanzaorentang and its effects may be mediated through serotonergic activation, in addition to GABAergic system. [ABSTRACT FROM AUTHOR]

The sedative-hypnotic medications, including benzodiazepines and non-benzodiazepines, are the most common treatments for insomnia. However, concerns regarding patterns of inappropriate use, dependence and adverse effects have led to caution in prescribing those sedative-hypnotic medications. On the other hand, a traditional Chinese herb remedy, suanzaorentang, has been efficiently and widely used in clinic for insomnia relief without severe side effects in Asia. Although suanzaorentang has been reported to improve sleep disruption in insomniac patients, its mechanism is still unclear. The present study was designed to elucidate the effects of oral administration of suanzaorentang on physiological sleep-wake architectures and its underlying mechanism in rats. We found that oral administration of suanzaorentang at the beginning of the dark onset dose-dependently increased non-rapid eye movement sleep (NREMS) during the dark period, but had no significant effect on rapid eye movement sleep (REMS). Our results also indicated that intracerebroventricular (ICV) administration of γ-aminobutyric acid (GABA) receptor type A antagonist, bicuculline, significantly blocked suanzaorentang-induced enhancement in NREMS during the dark period, but GABAB receptor antagonist, 2-hydroxysaclofen had no effect. These results implicated that this traditional Chinese herb remedy, suanzaorentang increases spontaneous sleep activity and its effects may be mediated through the GABAA receptors, but not GABAB receptors. [ABSTRACT FROM AUTHOR]

Electroacupuncture (EAc) possesses a broad therapeutic effect, including improvement of sleep disturbances. The mechanism of sleep improvement with EAc, however, is still unclear. The present study investigated the effects of EAc stimulation of ‘Anmian (extra)’ acupoints on sleep organization and the implication of an active structure, the caudal nucleus tractus solitarius (NTS). Rats were implanted with electroencephalogram (EEG) recording electrodes, and 32-gauge acupuncture needles were bilaterally inserted into ‘Anmian (extra)’ acupoints in the rats, followed by electrical stimulation for 20 min. Twenty-three-hour continuous EEGs were then recorded. Results showed that rapid eye movement sleep (REMS) was enhanced during the dark period when a single EAc stimulation was given 25 min prior to the onset of the dark period. REMS and slow-wave sleep (SWS) increased during the dark period after administration of EAc stimuli on 2 consecutive days. Electrical stimulation of non-acupoints produced no change in the sleep pattern. Pharmacological blockade of muscarinic cholinergic receptors by systemic administration of scopolamine dose-dependently attenuated EAc-induced changes in REMS and SWS. Furthermore, electrical lesions in the bilateral caudal NTS produced significant blockade of EAc-induced sleep enhancement. However, in rats without EAc, scopolamine increased SWS during the dark period, but caudal NTS lesions did not alter sleep. In addition, neither EAc nor scopolamine with EAc manipulation produced any change in the slow-wave activity (SWA) during SWS; however, the SWA during SWS was significantly reduced after caudal NTS lesion with EAc. These results suggest that the caudal NTS may be involved in the regulation of EAc-induced sleep alterations. Copyright © 2004 National Science Council, ROC and S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

No abstract available Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

A letter to the editor about the case of a 33-year-old man who was treated with Theta-Burst Stimulation (TBS) for a treatment-resistant type of obsessive-compulsive disorder and major depressive disorder is presented.