Relationship between hand stereotypies and purposeful hand use and factors causing skin injuries and joint contractures in individuals with Rett syndrome.

BACKGROUND: Skin injuries and joint contractures in the upper limbs are observed in approximately 50 % of individuals with Rett syndrome, respectively. AIMS: To investigate the relationship between stereotypic hand movements and purposeful hand skills, items related to these, and factors that cause upper extremity skin injuries and joint contractures in individuals with Rett syndrome. STUDY DESIGN: We conducted a cross-sectional observational study in 2020 with families belonging to either of the two largest Rett syndrome organizations in Japan. SUBJECTS: In 2020, we sent a questionnaire to 194 Japanese families. OUTCOME MEASURES: We used descriptive statistics to indicate frequency in each question. We analysed the association between hand stereotypies and purposeful hand use, their associations with each questionnaire item, and the relationship between the occurrence of skin injuries and joint contractures. RESULTS: We acquired information from 72 cases. We found correlations between stereotypy frequency with reaching and between purposeful hand use with intellectual development grade and hand function. Hand and finger skin injuries and elbow and finger joint contractures were associated with wringing/washing, grasping, locomotion, reaching, and intellectual development grade. We identified cut-off points for the occurrence of elbow and finger joint contractures of 10 years 6 months, ability to roll over, finger feeds only, and understanding of simple words. CONCLUSIONS: Direct interventions can reduce hand stereotypies and increase purposeful hand use, while related items can be addressed with indirect interventions. Evaluations of factors that cause skin injuries and joint contractures can prevent their occurrence.

Unilateral cathodal transcranial direct current stimulation over the parietal area modulates postural control depending with eyes open and closed.

OBJECTIVE: Cathodal transcranial direct current stimulation (C-tDCS) is generally assumed to inhibit cortical excitability. The parietal cortex contributes to multisensory information processing in the postural control system, and this processing is proposed to be different between the right and left hemispheres and sensory modality. However, previous studies did not clarify whether the effects of unilateral C-tDCS of the parietal cortex on the postural control system differ depending on the hemisphere. We investigated the changes in static postural stability after unilateral C-tDCS of the parietal cortex. METHODS: Ten healthy right-handed participants were recruited for right- and left-hemisphere tDCS and sham stimulation, respectively. The cathodal electrode was placed on either the right or left parietal area, whereas the anodal electrode was placed over the contralateral orbit. tDCS was applied at 1.5 mA for 15 min. We evaluated static standing balance by measuring the sway path length (SPL), mediolateral sway path length (ML-SPL), anteroposterior sway path length (AP-SPL), sway area, and the SPL per unit area (L/A) after 15-minute C-tDCS under eyes open (EO) and closed (EC) conditions. To evaluate the effects of C-tDCS on pre- and post-offline trials, each parameter was compared using two-way repeated-measures analysis of variance (ANOVA) with factors of intervention and time. A post-hoc evaluation was performed using a paired t-test. The effect sizes were evaluated according to standardized size-effect indices of partial eta-squared (ηp2) and Cohen's d. The power analysis was calculated (1-ß). RESULTS: A significant interaction was observed between intervention and time for SPL (F (2, 27) = 4.740, p = 0.017, ηp2 = 0.260), ML-SPL (F (2, 27) = 4.926, p = 0.015, ηp2 = 0.267), and sway area (F (2, 27) = 9.624, p = 0.001, ηp2 = 0.416) in the EO condition. C-tDCS over the right hemisphere significantly increased the SPL (p < 0.01, d = 0.51), ML-SPL (p < 0.01, d = 0.52), and sway area (p < 0.05, d = 0.83) in the EO condition. In contrast, C-tDCS over the left hemisphere significantly increased the L/A in both the EC and EO condition (EO; p < 0.05, d = 0.67, EC; p < 0.05, d = 0.57). CONCLUSION: These results suggest that the right parietal region contributes to static standing balance through chiefly visual information processing during the EO condition. On the other hand, L/A increase during EC and EO by tDCS over the left parietal region depends more on somatosensory information to maintain static standing balance during the EC condition.

Weighted Blind Source Separation Can Decompose the Frequency Mismatch Response by Deviant Concatenation: An MEG Study.

The mismatch response (MMR) is thought to be a neurophysiological measure of novel auditory detection that could serve as a translational biomarker of various neurological diseases. When recorded with electroencephalography (EEG) or magnetoencephalography (MEG), the MMR is traditionally extracted by subtracting the event-related potential/field (ERP/ERF) elicited in response to "deviant" sounds that occur randomly within a train of repetitive "standard" sounds. However, there are several problems with such a subtraction, which include increased noise and the neural adaptation problem. On the basis of the original theory underlying MMR (i.e., the memory-comparison process), the MMR should be present only in deviant epochs. Therefore, we proposed a novel method called weighted-BSS T/k, which uses only the deviant response to derive the MMR. Deviant concatenation and weight assignment are the primary procedures of weighted-BSS T/k, which maximize the benefits of time-delayed correlation. We hypothesized that this novel weighted-BSS T/k method highlights responses related to the detection of the deviant stimulus and is more sensitive than independent component analysis (ICA). To test this hypothesis and the validity and efficacy of the weighted-BSS T/k in comparison with ICA (infomax), we evaluated the methods in 12 healthy adults. Auditory stimuli were presented at a constant rate of 2 Hz. Frequency MMRs at a sensor level were obtained from the bilateral temporal lobes with the subtraction approach at 96-276 ms (the MMR time range), defined based on spatio-temporal cluster permutation analysis. In the application of the weighted-BSS T/k, the deviant responses were given a constant weight using a rectangular window on the MMR time range. The ERF elicited by the weighted deviant responses demonstrated one or a few dominant components representing the MMR that fitted well with that of the sensor space analysis using the conventional subtraction approach. In contrast, infomax or weighted-infomax revealed many minor or pseudo components as constituents of the MMR. Our single-trial, contrast-free approach may assist in using the MMR in basic and clinical research, and it opens a new and potentially useful way to analyze event-related MEG/EEG data.

Different brain activation patterns in the prefrontal area between self-paced and high-speed driving tasks.

The purpose of this study was to investigate the effects on prefrontal cortex brain activity when participants attempted to stop a car accurately at a stop line when driving at different speeds using functional near-infrared spectroscopy (fNIRS). Twenty healthy subjects with driving experience drove their own cars for a distance of 60 m five times each at their own pace or as fast as possible. The variation in the distance between the stop line and the car was not significantly different between the self-paced and high-speed tasks. However, oxygenated hemoglobin concentration in the prefrontal cortex was significantly higher in the high-speed task than in the self-paced task. These findings suggest that driving at high speed requires more divided attention than driving at self-paced speed, even though the participants were able to stop the car at the same distance from the target. This study shows the advantages and usefulness of fNIRS .

Comparison of the presence and absence of an intervention to reduce hand stereotypies in individuals with Rett syndrome.

BACKGROUND: We investigated how many individuals with Rett syndrome were undergoing interventions to reduce stereotypic hand movements and the factors determining the presence or absence of an intervention. METHOD: A questionnaire was sent to 194 families. Each survey item was compared between the intervention and non-intervention groups according to the presence or absence of interventions to reduce hand stereotypies. RESULTS: Information was acquired from 72 cases; 72.1% of individuals had received an intervention to reduce stereotypies at some point in their lives. An upper limb splint was the most common intervention. Age, locomotor and reaching function, diagnostic age, frequency and type of stereotypy, joint contractures and stereotypy-associated problems separated the presence or absence of a current or past intervention. CONCLUSIONS: Interventions for stereotypy-associated problems are important and there are several variables related to whether an intervention is received.

After-Effects of Intermittent Theta-Burst Stimulation Are Differentially and Phase-Dependently Suppressed by α- and ß-Frequency Transcranial Alternating Current Stimulation.

Intermittent theta-burst stimulation (iTBS) using transcranial magnetic stimulation (TMS) is known to produce excitatory after-effects over the primary motor cortex (M1). Recently, transcranial alternating current stimulation (tACS) at 10 Hz (α) and 20 Hz (ß) have been shown to modulate M1 excitability in a phase-dependent manner. Therefore, we hypothesized that tACS would modulate the after-effects of iTBS depending on the stimulation frequency and phase. To test our hypothesis, we examined the effects of α- and ß-tACS on iTBS using motor evoked potentials (MEPs). Eighteen and thirteen healthy participants were recruited for α and ß tACS conditions, respectively. tACS electrodes were attached over the left M1 and Pz. iTBS over left M1 was performed concurrently with tACS. The first pulse of the triple-pulse burst of iTBS was controlled to match the peak (90°) or trough (270°) phase of the tACS. A sham tACS condition was used as a control in which iTBS was administered without tACS. Thus, each participant was tested in three conditions: the peak and trough of the tACS phases and sham tACS. As a result, MEPs were enhanced after iTBS without tACS (sham condition), as observed in previous studies. α-tACS suppressed iTBS effects at the peak phase but not at the trough phase, while ß-tACS suppressed the effects at both phases. Thus, although both types of tACS inhibited the facilitatory effects of iTBS, only α-tACS did so in a phase-dependent manner. Phase-dependent inhibition by α-tACS is analogous to our previous finding in which α-tACS inhibited MEPs online at the peak condition. Conversely, ß-tACS reduced the effects of iTBS irrespective of its phase. The coupling of brain oscillations and tACS rhythms is considered important in the generation of spike-timing-dependent plasticity. Additionally, the coupling of θ and γ oscillations is assumed to be important for iTBS induction through long-term potentiation (LTP). Therefore, excessive coupling between ß oscillations induced by tACS and γ or θ oscillations induced by iTBS might disturb the coupling of θ and γ oscillations during iTBS. To conclude, the action of iTBS is differentially modulated by neuronal oscillations depending on whether α- or ß-tACS is applied.

A novel time-delayed correlation method decomposes mismatch response without using subtraction.

The mismatch response (MMR) is thought to be a neurophysiological measure of novel auditory detection that could serve as a translational biomarker of various neurological diseases. When recorded with electroencephalography (EEG) or magnetoencephalography (MEG), the MMR is traditionally extracted by subtracting the event-related potential/field (ERP/ERF) elicited in response to "deviant" sounds that occur randomly within a train of repetitive "standard" sounds. To overcome the limitations of this subtraction procedure, we propose a novel method which we call weighted-BSST/k, which uses only the deviant response to derive the MMR. We hypothesized that this novel weighted-BSST/k method highlights responses related to the detection of the deviant stimulus and is more sensitive than independent component analysis (ICA). To test this hypothesis and the validity and efficacy of the weighted-BSST/k in comparison with ICA (infomax), we evaluated the methods in 12 healthy adults. Auditory stimuli were presented at a constant rate of 2 Hz. Frequency MMRs at a sensor level were obtained from the bilateral temporal lobes with the subtraction approach at 96-276 ms (the MMR time range), defined on the basis of spatio-temporal cluster permutation analysis. In the application of the weighted-BSST/k, the deviant responses were given a constant weight on the MMR time range. The ERF elicited by the weighted deviant responses demonstrated one or a few dominant components representing the MMR with a high signal-to-noise ratio and similar topography to that of the sensor space analysis using the subtraction approach. In contrast, infomax or weighted-infomax revealed many minor or pseudo components as constituents of the MMR. Our new approach may assist in using the MMR in basic and clinical research.Clinical Relevance-Our proposed method opens a new and potentially useful way to analyze event-related MEG/EEG data.

Bilateral Representation of Sensorimotor Responses in Benign Adult Familial Myoclonus Epilepsy: An MEG Study.

Patients with cortical reflex myoclonus manifest typical neurophysiologic characteristics due to primary sensorimotor cortex (S1/M1) hyperexcitability, namely, contralateral giant somatosensory-evoked potentials/fields and a C-reflex (CR) in the stimulated arm. Some patients show a CR in both arms in response to unilateral stimulation, with about 10-ms delay in the non-stimulated compared with the stimulated arm. This bilateral C-reflex (BCR) may reflect strong involvement of bilateral S1/M1. However, the significance and exact pathophysiology of BCR within 50 ms are yet to be established because it is difficult to identify a true ipsilateral response in the presence of the giant component in the contralateral hemisphere. We hypothesized that in patients with BCR, bilateral S1/M1 activity will be detected using MEG source localization and interhemispheric connectivity will be stronger than in healthy controls (HCs) between S1/M1 cortices. We recruited five patients with cortical reflex myoclonus with BCR and 15 HCs. All patients had benign adult familial myoclonus epilepsy. The median nerve was electrically stimulated unilaterally. Ipsilateral activity was investigated in functional regions of interest that were determined by the N20m response to contralateral stimulation. Functional connectivity was investigated using weighted phase-lag index (wPLI) in the time-frequency window of 30-50 ms and 30-100 Hz. Among seven of the 10 arms of the patients who showed BCR, the average onset-to-onset delay between the stimulated and the non-stimulated arm was 8.4 ms. Ipsilateral S1/M1 activity was prominent in patients. The average time difference between bilateral cortical activities was 9.4 ms. The average wPLI was significantly higher in the patients compared with HCs in specific cortico-cortical connections. These connections included precentral-precentral, postcentral-precentral, inferior parietal (IP)-precentral, and IP-postcentral cortices interhemispherically (contralateral region-ipsilateral region), and precentral-IP and postcentral-IP intrahemispherically (contralateral region-contralateral region). The ipsilateral response in patients with BCR may be a pathologically enhanced motor response homologous to the giant component, which was too weak to be reliably detected in HCs. Bilateral representation of sensorimotor responses is associated with disinhibition of the transcallosal inhibitory pathway within homologous motor cortices, which is mediated by the IP. IP may play a role in suppressing the inappropriate movements seen in cortical myoclonus.

Effects of a dual task and different levels of divided attention on motor-related cortical potential.

[Purpose] The aim of this study was to investigate the effect of divided attention on motor-related cortical potential (MRCP) during dual task performance while the difficulty of the secondary task was altered. [Participants and Methods] Twenty-two right-handed healthy volunteers participated in the study. MRCPs were recorded during two tasks, a single task (ST) and a simple (S-DT) or complex dual task (C-DT). The ST involved a self-paced tapping task in which the participants extended their right index finger. In the dual task, the participants performed the ST and a visual number counting task simultaneously. [Results] The amplitude and integral value of MRCP from electroencephalography electrode C3 was significantly higher in the S-DT than in the ST, whereas they were similar between the C-DT and the ST. Medium-load divided attention (i.e., S-DT) led to significantly more changes in the MRCP magnitude than did low-load divided attention (i.e., ST). However, the MRCP of high-load divided attention (i.e., C-DT) was similar to that of low-load divided attention. [Conclusion] These results suggest that MRCP reflects the function of or network between the supplementary motor area and the dorsolateral prefrontal cortex, and may serve as a marker for screening the capacity of individuals to perform dual tasks.

'Time-shrinking perception' in the visual system: a psychophysical and high-density ERP study.

'Time-shrinking perception (TSP)' is a unique perceptual phenomenon in which the duration of two successive intervals (T1 and T2) marked by three auditory stimuli is perceived as equal even when they are physically different. This phenomenon provides a link between time and working memory; however, previous studies have mainly been performed on the auditory modality but not the visual modality. To clarify the neural mechanism of visual TSP, we performed a psychophysical experiment and recorded event-related potentials (ERPs) under different T1/T2 combinations. Three successive black/white sinusoidal gratings (30 ms duration) were presented to the participants. In the psychophysical experiment, either T1 or T2 was varied from 240 to 560 ms in 40-ms steps, while T2 or T1 was fixed at 400 ms. Participants judged whether T1 and T2 were equal or not by pressing a button. ERPs were recorded from 128 scalp electrodes, while T1 was varied from 240, 320, and 400 ms with the 400 ms T2 duration, and vice versa. Behavioral data showed asymmetrical assimilation: When -80 ms ≤ (T1 - T2) ≤ +120 ms, TSP was observed in the T1-varied condition. When -120 ms ≤ (T1 - T2) ≤ +80 ms, it was also observed in the T2-varied condition. These asymmetric time ranges in vision were different from those in the auditory modality. ERP data showed that contingent negative variation (CNV) appeared in the fronto-central region at around 300-500 ms during T2 presentation in the T1 < T2 condition. In the /240/400/ pattern, the CNV amplitude was decreased at around 350 ms. In contrast, P3 appeared at the parietal region about 450-650 ms after T2 in the T1 > T2 condition. In the /400/240/ pattern, P3 amplitude was greater than those of other temporal patterns. These neural responses corresponded to participants' perception that T1 and T2 were not equal. The neural responses in the fronto-central region were involved with endogenous temporal attention for discrimination. Moreover, neural responses in the parietal region were engaged in exogenous temporal attention. Therefore, fronto-parietal neural responses underlie temporal perception in vision.

A Potential VEP Biomarker for Mild Cognitive Impairment: Evidence from Selective Visual Deficit of Higher-Level Dorsal Pathway.

Visual dysfunctions are common in Alzheimer's disease (AD). Our aim was to establish a neurophysiological biomarker for amnestic mild cognitive impairment (aMCI). Visual evoked potentials (VEPs) were recorded in aMCI patients who later developed AD (n = 15) and in healthy older (n = 15) and younger controls (n = 15). Visual stimuli were optimized to separately activate lower and higher levels of the ventral and dorsal streams. We compared VEP parameters across the three groups of participants and conducted a linear correlation analysis between VEPs and data from neuropsychological tests. We then used a receiver operating characteristic (ROC) analysis to discriminate those with aMCI from those who were healthy older adults. The latency and phase of VEPs to lower-level stimuli (chromatic and achromatic gratings) were significantly affected by age but not by cognitive decline. Conversely, VEP latencies for higher-ventral (faces and kanji-words) and dorsal (kana-words and optic flow motion) stimuli were not affected by age, but they were significantly prolonged in aMCI patients. Interestingly, VEPs for higher-dorsal stimuli were related to outcomes of neuropsychological tests. Furthermore, the ROC analysis showed that the highest areas under the curve were obtained for VEP latencies in response to higher-dorsal stimuli. These results suggest aMCI-related functional impairment specific to higher-level visual processing. Further, dysfunction in the higher-level of the dorsal stream could be an early indicator of cognitive decline. Therefore, we conclude that VEPs associated with higher-level dorsal stream activity can be a sensitive biomarker for early detection of aMCI.

Periostin promotes the generation of fibrous membranes in proliferative vitreoretinopathy.

Proliferative vitreoretinopathy (PVR) is a severe, vision-threatening disorder characterized by the fibrous membrane formation that leads to tractional retinal detachment. There has been no effective therapeutic approach other than vitreoretinal surgery. In this study, DNA microarray analysis of the fibrous membranes revealed significant up-regulation of periostin. We also found increased periostin expression in the vitreous and retinal pigment epithelial (RPE) cells from fibrous membranes of PVR patients. In vitro, periostin increased proliferation, adhesion, migration, and collagen production in RPE cells through integrin αV-mediated FAK and AKT phosphorylation. Periostin blockade suppressed migration and adhesion induced by TGFß2 and PVR vitreous. In vivo, periostin inhibition had the inhibitory effect on progression of experimental PVR in rabbit eyes without affecting the viability of retinal cells. These results identified periostin as a pivotal molecule for fibrous membrane formation as well as a promising therapeutic target for PVR.

Selective impairment of optic flow perception in amnestic mild cognitive impairment: evidence from event-related potentials.

Alzheimer's disease (AD) patients have visuospatial deficits due to parietal dorsal stream dysfunction. Two distinct dorsal flows have been proposed: the inferior parietal (ventro-dorsal (v-d)) and superior parietal (dorso-dorsal (d-d)) streams. We aimed to elucidate how the two dorsal streams are altered in patients with amnestic mild cognitive impairment (aMCI) and AD. Thus, the psychophysical threshold measurements and visual event-related potentials (ERPs) were recorded in patients with aMCI and AD, and in healthy old and young adults. The visual stimuli included radial optic flow (OF) derived from the v-d stream and horizontal (HO) motion conveyed from the d-d stream. The motion thresholds between aMCI patients and old adults were comparable. However, AD patients showed significantly higher motion thresholds for both stimuli compared with other groups. In lower-level ERPs, there were no significant differences in P1 (100 ms) and N1 (130 ms) for both stimuli among the groups. For higher-level ERPs, aMCI patients showed the prolonged latency of OF-specific P200 (v-d origin) and comparable latency of motion-related N170 (V5/MT origin) for both stimuli compared with old adults. In AD patients, both N170 and P200 latencies were significantly prolonged compared with other groups. P200 latency was closely correlated with the Mini-Mental State Examination score. These findings indicate that the v-d function related to OF perception is selectively impaired in aMCI, whereas AD has impairment of the distributed higher-level dorsal stream. Therefore, OF-specific P200 can be useful for detecting early functional changes of the brain in aMCI.

Pigment epithelium-derived factor gene therapy targeting retinal ganglion cell injuries: neuroprotection against loss of function in two animal models.

Lentiviral vectors are promising tools for the treatment of chronic retinal diseases including glaucoma, as they enable stable transgene expression. We examined whether simian immunodeficiency virus (SIV)-based lentiviral vector-mediated retinal gene transfer of human pigment epithelium-derived factor (hPEDF) can rescue rat retinal ganglion cell injury. Gene transfer was achieved through subretinal injection of an SIV vector expressing human PEDF (SIV-hPEDF) into the eyes of 4-week-old Wistar rats. Two weeks after gene transfer, retinal ganglion cells were damaged by transient ocular hypertension stress (110 mmHg, 60 min) and N-methyl-d-aspartic acid (NMDA) intravitreal injection. One week after damage, retrograde labeling with 4',6-diamidino-2-phenylindole (DAPI) was done to count the retinal ganglion cells that survived, and eyes were enucleated and processed for morphometric analysis. Electroretinographic (ERG) assessment was also done. The density of DAPI-positive retinal ganglion cells in retinal flat-mounts was significantly higher in SIV-hPEDF-treated rats compared with control groups, in both transient ocular hypertension and NMDA-induced models. Pattern ERG examination demonstrated higher amplitude in SIV-hPEDF-treated rats, indicating the functional rescue of retinal ganglion cells. These findings show that neuroprotective gene therapy using hPEDF can protect against retinal ganglion cell death, and support the potential feasibility of neuroprotective therapy for intractable glaucoma.

Neural responses in the occipital cortex to unrecognizable faces.

OBJECTIVE: Event-related potentials (ERPs) were recorded to examine neural responses to face stimuli in a masking paradigm. METHODS: Images of faces (neutral or fearful) and objects were presented in subthreshold, threshold, and suprathreshold conditions (exposure durations of approximately 20, 30 and 300 ms, respectively), followed by a 1000-ms pattern mask. We recorded ERP responses at Oz, T5, T6, Cz and Pz. The effects of physical stimulus features were examined by inverted stimuli. RESULTS: The occipital N1 amplitude (approximately 160 ms) was significantly smaller in response to faces than objects when presented at a subthreshold duration. In contrast, the occipitotemporal N170 amplitude was significantly greater in the threshold and suprathreshold conditions compared with the subthreshold condition for faces, but not for objects. The P1 amplitude (approximately 120 ms) elicited by upright faces in the subthreshold condition was significantly larger than for inverted faces. CONCLUSIONS: P1 and N1 components at Oz were sensitive to subthreshold faces, which suggests the presence of fast face-specific process(es) prior to face-encoding. The N170 reflects the robustness of the face selective response in the occipitotemporal area. SIGNIFICANCE: Even when presented for a subthreshold duration, faces were processed differently to images of objects at an early stage of visual processing.

Transcranial direct current stimulation over the motor association cortex induces plastic changes in ipsilateral primary motor and somatosensory cortices.

OBJECTIVE: This study was performed to elucidate whether transcranial direct current stimulation (tDCS) over the motor association cortex modifies the excitability of primary motor (M1) and somatosensory (S1) cortices via neuronal connectivity. METHODS: Anodal, cathodal, and sham tDCS (1 mA) over the left motor association cortex was applied to 10 subjects for 15 min using electrodes of two sizes (9 and 18 cm(2)). Both motor evoked potentials (MEPs) and somatosensory evoked potentials (SEPs) were recorded before, immediately after, and 15 min after tDCS. Electrode positions were confirmed by overlaying them on MRI anatomical surface images of two individuals. RESULTS: After applying anodal tDCS using the large electrode, amplitudes of MEP components significantly decreased, whereas those of early SEP components (N20 and P25) increase. Opposite effects were observed on MEPs and SEPs after cathodal tDCS. However, a small electrode did not significantly influence either MEPs or SEPs, irrespective of polarity. The small electrode covered mainly the dorsal premotor cortex (PMd) while the large electrode involved the supplementary motor area (SMA) in addition to PMd. CONCLUSIONS: These results suggest that anodal tDCS over PMd together with SMA enhanced the inhibitory input to M1 and excitatory input to S1, and that cathodal tDCS might lead to an opposite effect. SIGNIFICANCE: The finding that only the large electrode modulated M1 and S1 implies that activation of PMd together with SMA by tDCS can induce plastic changes in primary sensorimotor areas.

Bral1: its role in diffusion barrier formation and conduction velocity in the CNS.

At the nodes of Ranvier, excitable axon membranes are exposed directly to the extracellular fluid. Cations are accumulated and depleted in the local extracellular nodal region during action potential propagation, but the impact of the extranodal micromilieu on signal propagation still remains unclear. Brain-specific hyaluronan-binding link protein, Bral1, colocalizes and forms complexes with negatively charged extracellular matrix (ECM) proteins, such as versican V2 and brevican, at the nodes of Ranvier in the myelinated white matter. The link protein family, including Bral1, appears to be the linchpin of these hyaluronan-bound ECM complexes. Here we report that the hyaluronan-associated ECM no longer shows a nodal pattern and that CNS nerve conduction is markedly decreased in Bral1-deficient mice even though there were no differences between wild-type and mutant mice in the clustering or transition of ion channels at the nodes or in the tissue morphology around the nodes of Ranvier. However, changes in the extracellular space diffusion parameters, measured by the real-time iontophoretic method and diffusion-weighted magnetic resonance imaging (MRI), suggest a reduction in the diffusion hindrances in the white matter of mutant mice. These findings provide a better understanding of the mechanisms underlying the accumulation of cations due to diffusion barriers around the nodes during saltatory conduction, which further implies the importance of the Bral1-based extramilieu for neuronal conductivity.

Induction of paranodal myelin detachment and sodium channel loss in vivo by Campylobacter jejuni DNA-binding protein from starved cells (C-Dps) in myelinated nerve fibers.

In an axonal variant of Guillain-Barré syndrome (GBS) associated with Campylobacter jejuni (C. jejuni) enteritis, the mechanism underlying axonal damage is obscure. We purified and characterized a DNA-binding protein from starved cells derived from C. jejuni (C-Dps). This C-Dps protein has significant homology with Helicobacter pylori neutrophil-activating protein (HP-NAP), which is chemotactic for human neutrophils through binding to sulfatide. Because sulfatide is essential for paranodal junction formation and for the maintenance of ion channels on myelinated axons, we examined the in vivo effects of C-Dps. First, we found that C-Dps specifically binds to sulfatide by ELISA and immunostaining of thin-layer chromatograms loaded with various glycolipids. Double immunostaining of peripheral nerves exposed to C-Dps with anti-sulfatide antibody and anti-C-Dps antibody revealed co-localization of them. When C-Dps was injected into rat sciatic nerves, it densely bound to the outermost parts of the myelin sheath and nodes of Ranvier. Injection of C-Dps rapidly induced paranodal myelin detachment and axonal degeneration; this was not seen following injection of PBS or heat-denatured C-Dps. Electron microscopically, C-Dps-injected nerves showed vesiculation of the myelin sheath at the nodes of Ranvier. Nerve conduction studies disclosed a significant reduction in compound muscle action potential amplitudes in C-Dps-injected nerves compared with pre-injection values, but not in PBS-, heat-denatured C-Dps-, or BSA-injected nerves. However, C-Dps did not directly affect Na(+) currents in dissociated hippocampal neurons. Finally, when C-Dps was intrathecally infused into rats, it was deposited in a scattered pattern in the cauda equina, especially in the outer part of the myelin sheath and the nodal region. In C-Dps-infused rats, but not in BSA-infused ones, a decrease in the number of sodium channels, vesiculation of the myelin sheath, axonal degeneration and infiltration of Iba-1-positive macrophages were observed. Thus, we consider that C-Dps damages myelinated nerve fibers, possibly through interference with paranodal sulfatide function, and may contribute to the axonal pathology seen in C. jejuni-related GBS.

Acute toxicity study of a simian immunodeficiency virus-based lentiviral vector for retinal gene transfer in nonhuman primates.

A phase 1 clinical trial evaluating the safety of gene therapy for patients with wet age-related macular degeneration (AMD) or retinoblastoma has been completed without problems. The efficacy of gene therapy for Leber's congenital amaurosis (LCA) was reported by three groups. Gene therapy may thus hold promise as a therapeutic method for the treatment of intractable ocular diseases. However, it will first be important to precisely evaluate the efficiency and safety of alternative gene transfer vectors in a preclinical study using large animals. In the present study, we evaluated the acute local (ophthalmic) and systemic toxicity of our simian immunodeficiency virus from African green monkeys (SIVagm)-based lentiviral vectors carrying human pigment epithelium-derived factor (SIV-hPEDF) for transferring genes into nonhuman primate retinas. Transient inflammation and elevation of intraocular pressure were observed in some animals, but these effects were not dose dependent. Electroretinograms (ERGs), including multifocal ERGs, revealed no remarkable change in retinal function. Histopathologically, SIV-hPEDF administration resulted in a certain degree of inflammatory reaction and no apparent structural destruction in retinal tissue. Regarding systemic toxicity, none of the animals died, and none showed any serious side effects during the experimental course. No vector leakage was detected in serum or urine samples. We thus propose that SIVagm-mediated stable gene transfer might be useful and safe for ocular gene transfer in a clinical setting.

Role of TGF-beta in proliferative vitreoretinal diseases and ROCK as a therapeutic target.

Cicatricial contraction of preretinal fibrous membrane is a cause of severe vision loss in proliferative vitreoretinal diseases such as proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR). TGF-beta is overexpressed in the vitreous of patients with proliferative vitreoretinal diseases and is also detectable in the contractile membranes. Therefore, TGF-beta is presumed to contribute to the cicatricial contraction of the membranes, however, the underlying mechanisms and TGF-beta's importance among various other factors remain to be elucidated. Vitreous samples from PDR or PVR patients caused significantly larger contraction of hyalocyte-containing collagen gels, compared with nonproliferative controls. The contractile effect was strongly correlated with the vitreal concentration of activated TGF-beta2 (r = 0.82, P < 0.0001). PDR or PVR vitreous promoted expression of alpha-smooth muscle actin (alpha-SMA) and phosphorylation of myosin light chain (MLC), a downstream mediator of Rho-kinase (ROCK), both of which were dramatically but incompletely suppressed by TGF-beta blockade. In contrast, fasudil, a potent and selective ROCK inhibitor, almost completely blocked the vitreous-induced MLC phosphorylation and collagen gel contraction. Fasudil disrupted alpha-SMA organization, but it did not affect its vitreal expression. In vivo, fasudil significantly inhibited the progression of experimental PVR in rabbit eyes without affecting the viability of retinal cells by electroretinographic and histological analyses. These results elucidate the critical role of TGF-beta in mediating cicatricial contraction in proliferative vitreoretinal diseases. ROCK, a key downstream mediator of TGF-beta and other factors might become a unique therapeutic target in the treatment of proliferative vitreoretinal diseases.