Subthalamic nucleus local field potential stability in patients with Parkinson's disease.

BACKGROUND: Despite the large body of work on local field potentials (LFPs), a measure of oscillatory activity in patients with Parkinson's disease (PD), the longitudinal evolution of LFPs is less explored. OBJECTIVE: To determine LFP fluctuations collected in clinical settings in patients with PD and STN deep brain stimulation (DBS). METHODS: Twenty-two STN-DBS patients (age: 67.6 ± 8.3 years; 9 females; disease duration: 10.3 ± 4.5 years) completed bilateral LFP recordings over three visits in the OFF-stimulation setting. Peak and band power measures were calculated from each recording. RESULTS: After bilateral LFP recordings, at least one peak was detected in 18 (81.8%), 20 (90.9%), and 22 (100%) patients at visit 1, 2, and 3, respectively. No significant differences were seen in primary peak amplitude (F = 2.91, p = 0.060) over time. Amplitude of the second largest peak (F = 5.49, p = 0.006) and low-beta (F = 6.89, p = 0.002), high-beta (F = 13.23, p < 0.001), and gamma (F = 12.71, p < 0.001) band power demonstrated a significant effect of time. Post hoc comparisons determined low-beta power (Visit 1-Visit 2: t = 3.59, p = 0.002; Visit 1-Visit 3: t = 2.61, p = 0.031), high-beta (Visit 1-Visit 2: t = 4.64, p < 0.001; Visit 1-Visit 3: t = 4.23, p < 0.001) and gamma band power (Visit 1-Visit 2: t = 4.65, p < 0.001; Visit 1-Visit 3: t = 4.00, p < 0.001) were significantly increased from visit 1 recordings to both follow-up visits. CONCLUSION: Our results provide substantial evidence that LFP can reliably be detected across multiple real-world clinical visits in patients with STN-DBS for PD. Moreover, it provides insights on the evolution of these LFPs.

[Basal Ganglia and Circuit Function:How Does the Ablation or Deep Brain Stimulation(DBS)Work?]

The basal ganglia(BG)is composed of four parallel loops: the motor, oculomotor, associative, and limbic loops. The motor loop starts from the cortex, travels through the BG and thalamus, and returns to the same area of the cortex with somatotopic organization. The striatum is the major input nucleus of the cortex, and the internal segment of the globus pallidus(GPi)is the main output nucleus. BG is explained by the direct and indirect pathways, and these excitatory or inhibitory pathways are used for several disease models. In Parkinson's disease(PD), dopamine deficiency acts on both direct and indirect pathways to cause the neuronal activity of GPi to becomes disinhibited. Pallidotomy, an effective surgery to improve Parkinsonism, aimed to destroy this hyperactive state. This is based on the rate model. However, a simian PD model with MPTP-treated monkeys exhibited increased GPi activity during effective stimulation of subtalamic nucleus(STN)-DBS, which makes it difficult to explain the pathophysiology of PD based only on the rate model. Instead, the alterative model is now widely prevailing. Local field potentials recorded from the DBS leads implanted in GPi and/or STN uncovered the abnormally synchronized activity in the ß range(ß oscillation)and abnormal co-synchronization between these nuclei, which is believed to be important in the pathophysiology of PD.

Imbalance in multiple sclerosis and neuromyelitis optica: association with deep sensation disturbance.

Abnormality in balance is one of the most important causes of gait disturbance which has a direct impact to disability and medical cost in multiple sclerosis (MS) and neuromyelitis optica (NMO). However, characteristics of imbalance in these two diseases have not been fully elucidated. The aim of this study was to evaluate the degree and features of imbalance using stabilography, the degree of deep sensation disturbance using tibial nerve somatosensory evoked potentials (SEP), and their association with clinical impairment, in patients with MS and NMO. Seven NMO patients and seven MS patients with balance disturbance were examined. The relationship among stabilography measurements representing the degree and features of imbalance, height-adjusted P38 peak latency of SEP, and neurological functional disability, were analyzed. Stabilography evaluation showed a significantly severer degree of imbalance in NMO than in MS. Romberg quotient of the patients with brainstem lesions was significantly larger than those without them. In all patients, length of excursion per second significantly correlated positively with anterio-posterior-axis power spectra at intermediate frequency band. In all patients and in NMO, P38 peak latency adjusted by height significantly correlated positively with anterio-posterior-axis power spectra at intermediate frequency band. These findings suggest that the degree of imbalance of MS and NMO possibly correlate with deep sensation disturbance, which could be evaluated by anterio-posterior-axis power spectra at intermediate frequency band by stabilography. Severer imbalance in NMO than MS may be associated with the severe longitudinally extensive spinal cord lesions.

The role of interneuron networks in driving human motor cortical plasticity.

The after-effects of repetitive transcranial magnetic stimulation (rTMS) are highly variable between individuals. Because different populations of cortical neurons are stimulated more easily or are more excitable in different people at different times, the variability may not be due to differences between individuals in the plasticity of cortical synapses, but may instead be due to individual differences in the recruitment of cortical neurons. In this study, we examined the effects of rTMS in 56 healthy volunteers. The responses to excitatory and inhibitory theta burst stimulation (TBS) protocols were highly variable between individuals. Surprisingly, the TBS effect was highly correlated with the latency of motor-evoked potentials (MEPs) evoked by TMS pulses that induced an anterior-posterior (AP) directed current across the central sulcus. Finally, we devised a new plasticity protocol using closely timed pairs of oppositely directed TMS current pulses across the central sulcus. Again, the after-effects were related to the latency of MEPs evoked by AP current. Our results are consistent with the idea that variation in response to rTMS plasticity probing protocols is strongly influenced by which interneuron networks are recruited by the TMS pulse.

Opposite effects of weak transcranial direct current stimulation on different phases of short interval intracortical inhibition (SICI).

Short interval intracortical inhibition (SICI) is a common paired-pulse TMS technique that is used to measure GABAa-ergic inhibition in the cerebral motor cortex. However, inhibition evaluated with an interstimulus interval (ISI) between the TMS pulses of 2.5 ms has quite different properties from that seen at 1 ms. It is thought that the latter may represent either (or both) a different type of synaptic inhibition or refractoriness of neural membranes. The present experiments provide further evidence about the early and late components of SICI using transcranial direct current stimulation (tDCS), a technique thought to change neural excitability by polarising the nerve membranes. We assessed SICI using a threshold tracking method at a range of ISIs during concurrent application of tDCS in 11 healthy volunteers (8 males, 27-43 years old). Each subject underwent both anodal and cathodal tDCS with two different intensities of stimulation (1 and 2 mA). Because there was no significant difference between the results at the two intensities, the data were combined. Principal component analysis was used to separate the contributions of early and late SICI to the time course of inhibition from 1 to 5 ms tDCS had opposite effects on early and late SICI. Anodal tDCS reduced late SICI but enhanced early SICI, whereas cathodal tDCS had the opposite effect. This is further evidence that the two phases of SICI are produced by different mechanisms, perhaps involving different sets of neurones or different locations on the same neurone that respond oppositely to tDCS.

Pre-movement gating of somatosensory evoked potentials in Tourette syndrome.

OBJECTIVE: Tourette syndrome (TS) is a neurobehavioral disorder characterized by motor and vocal tics. Simple tics are purposeless involuntary movements that spontaneously resolve during middle adolescence. Complex tics appear to be semi-voluntary movements that may become intractable when associated with obsessive-compulsive disorder (OCD). Sensory tics or urges preceded by tics suggest sensorimotor processing impairment in TS. We aimed to clarify its pathophysiology by exploring the pre-movement gating (attenuation) of somatosensory evoked potentials (SEPs). METHODS: We examined 42 patients (aged 9-48 years), 4 of whom underwent follow-up assessment, along with 19 healthy controls. We defined patients with only simple tics as TS-S and patients with complex tics as TS-C. Pre-movement gating of SEPs was assessed using a previously described method. Frontal N30 (FrN30) amplitudes were compared between pre-movement and resting states. The gating ratio of pre-movement/resting amplitude of the FrN30 component was assessed: the larger the ratio, the less the gating. RESULTS: The gating ratio for TS-C patients was larger than that of TS-S patients and healthy controls, but a statistical difference between TS-S and TS-C appeared after 15 years and over (p < 0.001). There were no significant differences in the gating ratio between TS-S patients and healthy controls. The gating ratio was related to the severity of OCD (p < 0.05). CONCLUSION: Sensorimotor processing was preserved for simple tics but impaired in complex tics, specifically after middle adolescence. Our study supports an age-dependent dysfunction of both motor and non-motor cortico-striato-thalamo-cortical circuits in complex tics. SEP gating seems promising as a tool for assessing age-dependent sensorimotor disintegration in TS.

Cerebellar modulation of human associative plasticity.

Paired associative stimulation (PAS) is a method commonly used in human studies of motor cortex synaptic plasticity. It involves repeated pairs of electrical stimuli to the median nerve and transcranial magnetic stimulation (TMS) of the motor cortex. If the interval between peripheral and TMS stimulation is around 21­25 ms, corticospinal excitability is increased for the following 30­60 min via a long term potentiation (LTP)-like effect within the primary motor cortex. Previous work has shown that PAS depends on the present and previous levels of activity in cortex, and that it can be modified by motor learning or attention. Here we show that simultaneous transcranial direct current stimulation (TDCS; 2 mA) over the cerebellum can abolish the PAS effect entirely. Surprisingly, the effect is seen when the PAS interval is 25 ms but not when it is 21.5 ms. There are two implications from this work. First, the cerebellum influences PAS effects in motor cortex; second, LTP-like effects of PAS have at least two different mechanisms. The results are relevant for interpretation of pathological changes that have been reported in response to PAS in people with movement disorders and to changes in healthy individuals following exercise or other interventions.

Sustained atypical myokymia of the abductor pollicis brevis with a focal slowing of the median nerve motor axons at the wrist.

OBJECTIVE: We report a case of sustained atypical myokymia associated with short bursts of neuromyotonic discharges involving the abductor pollicis brevis (APB) muscle and describe a useful way of detecting a focal slowing involving a small number of median nerve motor fibers with a concentric needle using the filter setting for single fiber electromyography (EMG). METHODS AND RESULTS: A 62-year-old woman developed right thumb twitches at regular interval of 1.7-3.3 s (0.6-0.3 Hz), which continued for more than four months. Muscle twitches remained the same during altered hand position, psychological stress, or sleep. A concentric needle inserted in the active zone of the APB muscle revealed myokymic bursts with a characteristic of neuromyotonic discharges. Inching study, stimulating at 5 mm increment along the median nerve and recording with a concentric needle using a filter setting for single fiber EMG, revealed a focal slowing of the motor fibers at a point 5-10 mm distal from the distal crease of the wrist, an entrapment site occasionally seen in the carpal tunnel syndrome. One injection of botulinum toxin type A eliminated the myokymia, which then recurred two and a half years later, showing less prominent muscle twitches. CONCLUSIONS: Sustained atypical myokymia seen in our case represented bursts of neuromyotonic discharges originated from a focal demyelinating lesion involving a few median nerve motor fibers.

The identified clinical features of Parkinson's disease in homo-, heterozygous and digenic variants of PINK1.

To investigate the prevalence and genotype-phenotype correlations of phosphatase and tensin homolog induced putative kinase 1 (PINK1) variants in Parkinson's disease (PD) patients, we analyzed 1700 patients (842 familial PD and 858 sporadic PD patients from Japanese origin). We screened the entire exon and exon-intron boundaries of PINK1 using Sanger sequencing and target sequencing by Ion torrent system. We identified 30 patients with heterozygous variants, 3 with homozygous variants, and 3 with digenic variants of PINK1-PRKN. Patients with homozygous variants presented a significantly younger age at onset than those with heterozygous variants. The allele frequency of heterozygous variants in patients with age at onset at 50 years and younger with familial PD and sporadic PD showed no differences. [123I]meta-iodobenzylguanidine (MIBG) myocardial scintigraphy indicated that half of patients harboring PINK1 heterozygous variants showed a decreased heart to mediastinum ratio (12/23). Our findings emphasize the importance of PINK1 variants for the onset of PD in patients with age at onset at 50 years and younger and the broad spectrum of clinical symptoms in patients with PINK1 variants.

Deep slow nasal respiration with tight lip closure for immediate attenuation of severe tics.

BACKGROUND: Severe intractable tics, which are associated with Tourette syndrome and chronic tic disorder (TS/CTD), severely affect the quality of life. Common less-invasive treatments are often unable to attenuate tics with deep brain stimulation currently being the only effective treatment. We aimed to assess the anti-tic effect of deep slow nasal respiration with tight lip closure using patients with TS/CTD. METHODS: We retrospectively analyzed 10 consecutive patients (9 men, 1 woman; 23-41 years old). We instructed the patients to perform the procedure for 120 s and to obtain a video recording of before and during the procedure. The videos were used to count tics and determine lip competency or incompetency. The counted tics were rated using the modified Rush Video Rating Scale. RESULTS: Compared with before the procedure, there were significantly lower frequencies of motor and phonic tics, as well as video scored, during the procedure. Eight patients presented with lip incompetency before the procedure and none after the procedure (P = 0.041). There were no side effects associated with the procedure. CONCLUSION: Our findings indicate that deep slow nasal respiration with tight lip closure ameliorates tics in patients with TS/CTD. In accordance with our results, lip opening and oral breathing could be causes of tics, in addition to heritability. Therefore, this novel procedure could improve tics. Furthermore, our findings could contribute toward the development of tic treatments and elucidate their pathophysiology regarding the reward system, hypersensitivity, autonomic nerves, and nasal airway.

[An autopsy case after endovascular thrombectomy for cardioembolic stroke due to nonbacterial thrombotic endocarditis].

A 73-year-old women visited emergency department because of sudden right hemiplegia. She had a history of duodenum papilla cancer terminal stage and multiple liver metastasis. On admission, diffusion weighted images revealed high intensity area at left middle cerebral artery territory. In addition, 3D-TOF MRA depicted proximal part of the left internal carotid artery. We performed endovascular thrombectomy because low platelet count met contraindication of intravenous recombinant tissue plasminogen activator therapy. Although we could get partial recanalization of middle cerebral artery occlusion after thrombectomy, the patient eventually died due to multiple organ failure. Autopsy findings showed white thrombus on mitral valve and also left middle cerebral artery occluded by similar white thrombus without infective findings. The patient was finally diagnosed with nonbacterial thrombotic endocarditis due to white thrombus on the mitral valve. We should select appropriate mechanical thrombectomy devices with a case of cerebral infarction due to nonbacterial thrombotic endocarditis because its thrombus is often white thrombus and would be hard.

Leukoencephalopathy with a case of heterozygous POLG mutation mimicking mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).

Diseases due to mutations of polymerase γ (POLG) usually present with progressive external ophthalmoplegia. However, a few studies have been reported on POLG1 mutations with the mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)-like phenotype. All cases with POLG1 mutations mimicking MNGIE have never shown leukoencephalopathy on brain magnetic resonance imaging (MRI) or demyelinating polyneuropathy. We present a 26-year-old male with gait disturbance, recurrent bowel obstruction, peripheral neuropathy, ophthalmoplegia or ptosis, which represented MNGIE phenotype. Though he displayed demyelinating peripheral neuropathy or leukoencephalopathy on brain MRI, genetic analysis revealed heterozygous mutation in POLG1 gene. We report for the first time two newly characteristics in our patient with heterozygous POLG1 mutations with the MNGIE-like phenotype: leukoencephalopathy and demyelinating polyneuropathy.

Bilateral oculomotor nerve palsy in a case of anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) has a wide disease spectrum and sometimes shows abnormal eye movement with brainstem manifestations. However, bilateral oculomotor nerve palsy with a midbrain lesion has never been reported in a patient with NMOSD. We describe a 61-year-old woman with progressive ptosis and diplopia. She displayed bilateral oculomotor nerve palsy and hypersomnia. Brain MRI demonstrated abnormal signal intensities in the midbrain and around the third ventricle and hypothalamus with a mild contrast enhancement. A cerebrospinal fluid study indicated elevated protein and pleocytosis. Because serum anti-aquaporin-4 IgG antibody was positive, the patient was diagnosed with neuromyelitis optica spectrum disorder with aquaporin-4 IgG. We report for the first time bilateral oculomotor nerve palsy as an initial manifestation in a patient with aquaporin-4 positive NMOSD.

Bilateral deep brain stimulation of the globus pallidus internus in tardive dystonia.

Tardive dystonia is a disabling movement disorder as a consequence of exposure to neuroleptic drugs. We followed 6 patients with medically refractory tardive dystonia treated by bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) for 21 +/- 18 months. At last follow-up, the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) motor score improved by 86% +/- 14%, and the BFMDRS disability score improved by 80% +/- 12%. Bilateral GPi-DBS is a beneficial therapeutic option for the long-term relief of tardive dystonia.

Comparison of monophasic versus biphasic stimulation in rTMS over premotor cortex: SEP and SPECT studies.

OBJECTIVE: To optimize the clinical uses of repetitive transcranial magnetic stimulation (rTMS), we compared the effects of rTMS on somatosensory-evoked potentials (SEPs) and regional cerebral blood flow (rCBF) using different phases (monophasic vs. biphasic) or frequencies (0.2Hz vs. 0.8Hz) of stimulation. METHODS: In the first experiment, different phases were compared (0.2Hz monophasic vs. 0.2Hz biphasic). Biphasic 1Hz or sham condition served as controls. The second experiment was to explore the effect of frequencies (0.2Hz vs. 0.8Hz) using the monophasic stimulation. Substhreshold TMS was applied 250 times over the left premotor cortex. Single photon emission computed tomography (SPECT) was performed before and after monophasic 0.2Hz or biphasic 1Hz rTMS. RESULTS: Monophasic rTMS of both 0.2 and 0.8Hz significantly increased the ratio of N30 amplitudes as compared with sham rTMS, whereas biphasic stimulation showed no significant effects. SPECT showed increased rCBF in motor cortices after monophasic 0.2Hz rTMS, but not after biphasic 1Hz stimulation. CONCLUSIONS: Monophasic rTMS exerted more profound effects on SEPs and rCBF than biphasic rTMS over the premotor cortex. SIGNIFICANCE: Monophasic rTMS over the premotor cortex could be clinically more useful than biphasic rTMS.

[A case of chronic inflammatory demyelinating polyradiculoneuropathy, showing radicular pain due to tuberous hypertrophy of the spinal roots and plexuses after 20 years interval without relapsing sensorimotor symptoms].

A 40-year-old man visited our department because of chest and back pain. He had a history of diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) 20 years ago. He received immunosuppressive therapy and had no relapses after that. On Admission, MRI showed tuberous hypertrophy of the spinal roots, intercostal nerves, and brachial and lumbar plexuses. The genetic analysis showed no mutations in any of Charcot-Marie-Tooth related genes. He was finally diagnosed with CIDP and administration of high dose intravenous methylprednisolone relieved his chest and back pain within a few days. We present a rare case of CIDP in which showed marked enlarged spinal roots in long clinical course and have a relapse with radicular pain without sensorimotor symptoms.

High-Density Lipoprotein Subclasses and Mild Cognitive Impairment: Study of Outcome and aPolipoproteins in Dementia (STOP-Dementia)1.

BACKGROUND: High-density lipoprotein (HDL) containing apolipoprotein A-I is associated with the pathogenesis of Alzheimer's disease (AD). HDL particle size is modified in the presence of pathological conditions, while the significance of the HDL particle size remains controversial. OBJECTIVE: The aim of this study was to investigate the HDL lipoprotein subclasses in mild cognitive impairment (MCI) and AD. METHODS: This cross-sectional study included 20 AD patients, 17 MCI patients, and 17 age-matched controls without cognitive impairment, selected from the database of the Study of Outcome and aPolipoproteins in Dementia (STOP-Dementia) registry. The diagnoses of AD and MCI were performed by expert neurologists according to the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition criteria. Serum HDL subclasses were measured by electrophoretic separation of lipoproteins using the Lipoprint System. The neutrophil-lymphocyte ratio (NLR), a marker of inflammation, was calculated by dividing the neutrophil count by the lymphocyte count. RESULTS: Small-sized HDL particle levels in the MCI group were significantly higher than in the control group, although there was no difference in serum HDL-cholesterol levels between MCI and control groups. NLR in the MCI group was higher than in the control group, but this difference was non-significant (p = 0.09). There was no difference in HDL subclasses or NLR between the AD and control groups. CONCLUSION: These findings suggest that HDL subclasses might be associated with the development of MCI.

Predictors of Cardioembolic Stroke in Japanese Patients with Atrial Fibrillation in the Fushimi AF Registry.

BACKGROUND: Large-scale clinical trials have analyzed risk factors for any ischemic stroke in patients with atrial fibrillation (AF). However, the risk factors for cardioembolic stroke (CES), specifically, have not been reported. To clarify the risk factors for CES and clinically significant cardioembolic infarction, we examined the incidence of CES and larger infarct volume (IV) (> 30 mL) CES, employing the Fushimi AF Registry, a community-based prospective cohort of AF patients in the Fushimi ward, Kyoto, Japan. METHODS: A total of 4,182 Fushimi AF patients were enrolled from March 2011 to December 2014. The risk factors for CES were evaluated using multivariate analysis. RESULTS: Of 4,182 patients enrolled, 3,749 patients were observed for ≥1 year. During the follow-up period (mean duration, 979 ± 7.7 days), 91/3,749 patients experienced a CES (2.43%). Significant risk factors associated with CES were older age (odds ratio [OR], 1.31; 95% confidence interval [CI], 1.01-1.72; p = 0.046), low body weight (OR, 1.30; 95% CI, 1.03-1.65; p = 0.033), sustained AF (OR, 1.67; 95% CI, 1.05-2.71; p = 0.034), and previous stroke or transient ischemic attack (TIA) (OR, 1.94; 95% CI, 1.22-3.06; p = 0.004). Predictors of a large IV were chronic kidney disease (CKD) (OR, 2.08; 95% CI, 1.09-4.05; p = 0.027) and previous stroke/TIA (OR, 2.27; 95% CI, 1.19-4.24; p = 0.011). CONCLUSIONS: In this population-based cohort of Japanese patients with AF, in addition to previous stroke/TIA and older age, sustained AF and low body weight emerged as risk factors for CES, as opposed to any stroke, which may have a different risk profile. Patients with CKD or previous stroke/TIA who developed cardioembolic infarction exhibited more advanced severity. There is a need for direct oral anticoagulants that can be used safely in patients with comorbid AF and CKD.

Dynamic change of proximal conduction in demyelinating neuropathies: a cervical magnetic stimulation combined with maximum voluntary contraction.

OBJECTIVE: To evaluate conduction abnormalities in the nerves innervating the proximal muscles in demyelinating neuropathies (DN) using cervical magnetic stimulation. METHODS: We applied cervical root magnetic stimulation in the biceps brachii muscles and examined its activity-dependent conduction changes produced by maximal voluntary contraction (MVC) in 12 DN patients (seven chronic inflammatory demyelinating polyradiculoneuropathy and five multifocal motor neuropathy), six motor neuron disease (MND) patients, and 12 healthy volunteers. RESULTS: Defining the upper normal limit of motor threshold (31%) and latency (6.7 ms) of the compound muscle action potential (CMAP) as mean+2SD, most DN patients revealed an abnormality in motor threshold (10/12) and latency (11/12) in contrast to MND patients (motor threshold (1/6) and latency (0/6)). These parameters contribute to the differentiation of DN from MND (P<0.01). Furthermore, the MVC maneuver transiently decreased the CMAP amplitude ratio (after MVC/before MVC x 100) in DN (83+/-18 %) compared with MND (P<0.01). Two of three DN patients who showed normal motor threshold or latency as in MND were successfully differentiated from MND by the MVC maneuver. CONCLUSIONS: In DN patients, conduction abnormality in the nerves innervating the proximal muscles was revealed by cervical magnetic stimulation combined with the MVC maneuver. SIGNIFICANCE: Our results suggested that conduction abnormalities in the proximal nerves innervating the proximal muscles could be evaluated by this method.