[Show abstract][Hide abstract] ABSTRACT: 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 TGFβ2 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.-Ishikawa, K., Yoshida, S., Nakao, S., Nakama, T., Kita, T., Asato, R., Sassa, Y., Arita, R., Miyazaki, M., Enaida, H., Oshima, Y., Murakami, N., Niiro, H., Ono, J., Matsuda, A., Goto, Y., Akashi, K., Izuhara, K., Kudo, A., Kono, T., Hafezi-Moghadam, A., Ishibashi, T. Periostin promotes the generation of fibrous membranes in proliferative vitreoretinopathy.
Full-text · Article · Sep 2013 · The FASEB Journal
[Show abstract][Hide abstract] ABSTRACT: Visual evoked potentials (VEPs) are the electrical responses from the brain concerned with visual information processing. Amplitude of VEPs is smaller than that of background EEG activity, and the stimulus-locked averaging method is usually used for obtained the waveform. VEP response to each stimulus is not completely the same however it is varying with its amplitude and duration. Therefore, amplitude of averaged VEP waveform deteriorates due to their variability in raw data. Feature extraction of background EEG activity during visual stimulation is also a one of significant items in VEP analysis. In that case, separation of VEP component and background EEG component (mainly posterior dominant rhythm) is crucial. In the past, we proposed the method of estimating both amplitude of VEP and dominant rhythm by use of EEG model. This present study, the proposed method was applied to actual recorded VEP data and its effectiveness was evaluated. EEGs with visual stimulus were recorded from nine healthy young adults. Usefulness of the proposed method was investigated by comparing the conventional power spectrum averaging method. The proposed method will be applicable to show an accurate VEP analysis and characteristic analysis of background activity under visual stimulus.
[Show abstract][Hide abstract] ABSTRACT: 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.
Full-text · Article · Nov 2011 · Journal of Alzheimer's disease: JAD
[Show abstract][Hide abstract] ABSTRACT: By constructing Gaussian Naïve Bayes Classifiers, we have re-analyzed data from an earlier event-related potential (ERP) study
of an illusion in time perception known as auditory temporal assimilation. In auditory temporal assimilation, two neighboring
physically unequal time intervals marked by three successive tone bursts are illusorily perceived as equal if the two time
intervals satisfy a certain relationship. The classifiers could discriminate whether or not the subject was engaged in the
task, which was judgment of the subjective equality between the two intervals, at an accuracy of >79%, and from principal
component scores of individual average ERP waveforms, we were able to predict their subjective judgments to each stimulus
at an accuracy of >70%. Chernoff information, unlike accuracy or Kullback–Leibler (KL) distance, suggested brain activation
associated with auditory temporal assimilation at an early pre-decision stage. This may provide us with a simple and useful
neural decoding scheme in analyzing information processing of temporal patterns in the brain.
No preview · Article · Oct 2011 · Neural Computing and Applications
[Show abstract][Hide abstract] ABSTRACT: distribution of vi sual evoked potentials (VEPs) in electroencephalo graphic (EEG) record brings about the significant information for visual pro cessing in human brain. This study proposes a method for estimating topographical distribution of YEP from the separated power spectrum components by combining the models. VEPs with various temporal frequencies were recorded from nine healthy adults. Original power spectrum consisting of YEP, background activities, artifacts and other components were then obtained. To the extract the YEP components from the original power spectrum, models corresponding to background activities especially for posterior dominant alpha rhythm, low frequency component and high frequency component caused from electromyographi c (EMG) artifact were constructed and those parameters were estimated. Finally, YEP components were calculated by subtracting those components from the original power spectrum. Topographical distribution of both first har monic (IF) and second harmonic (2F) components of YEP were obtained by the proposed method. Estimated other components except VEPs were also investigated. Merits and usefulness of the proposed method were analyzed by comparing the conventional stimulus-locked averaging method in the time domain. Proposed method has several advanced points for conventional averaging method. Particularly, posterior dominant alpha rhythm and EMG artifact were directly taken into account in the YEP components estimation. Therefore, accurate estimation of YEP components can be done even if those components were contaminated with raw EEG. To obtain the topographical distribution of IF and 2F components respectively is also possible. Index Terms-Visual Evoked Potentials (VEPs), Topographical mapping, Signal separation
[Show abstract][Hide abstract] ABSTRACT: People with autism spectrum disorder (ASD) often show inferior global motion performance with superior performance in detail form perception, suggesting dysfunction of the dorsal visual stream. To elucidate the neural basis of impaired global motion perception in ASD, we measured psychophysical threshold and visual event-related potentials (ERPs) with a 128-channel system in 12 ASD and 12 healthy control adults. Radial optic flow (OF) and horizontal motion (HO) were used as the visual stimuli. The former was related to the ventro-dorsal stream formed by the inferior parietal lobule, while the latter was conveyed from the dorso-dorsal stream formed by the superior parietal lobule. No significant group differences were observed in the motion thresholds for both OF and HO. N170 and P200 were elicited as major components of ERPs in both groups. However, the latencies of both components for OF but not HO were significantly prolonged in ASD compared with the control group. Our ERP results suggest that ASD has a selective impairment for OF processing even though the psychophysical thresholds are preserved. Therefore, we provide the first electrophysiological evidence for altered function of the higher-level dorsal visual stream in ASD, specifically the ventro-dorsal stream closely related to OF perception.
Full-text · Article · Mar 2011 · Research in Autism Spectrum Disorders
[Show abstract][Hide abstract] ABSTRACT: 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.
Full-text · Article · Dec 2010 · Human gene therapy
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
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.
Full-text · Article · Nov 2010 · Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology
[Show abstract][Hide abstract] ABSTRACT: Event-related potentials (ERPs) were recorded to examine neural responses to face stimuli in a masking paradigm.
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.
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.
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.
Even when presented for a subthreshold duration, faces were processed differently to images of objects at an early stage of visual processing.
No preview · Article · Nov 2010 · Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology
[Show abstract][Hide abstract] ABSTRACT: It is well known that visual evoked potentials (VEPs) are useful for investigating the physiology and pathophysiology of human visual system. VEPs can be used effectively in association with psychophysics to study both normal and abnormal visual functions. Recent progress of VEPs is based on two concepts: 1) visual information is processed simultaneously via multiple parallel pathways or channels and 2) a functional specialization in the visual system exists so that different attributes of the visual scene are processed in an anatomically separate part of the visual cortex. In this study, we first summarize the concepts of the functional anatomy and physiology of human visual system. Then, we emphasize the innovation for the visual stimuli based on the physiological properties of parallel visual pathways.
[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Oct 2009 · Journal of the neurological sciences
[Show abstract][Hide abstract] ABSTRACT: PURPOSE. Our aim was to better understand how to isolate the cone-mediated response in rats. Therefore, we studied the difference of ERGs in the course of light adaptation between 2 and 20 Hz stimulus frequencies. METHODS. A total of 90 rats divided into 18 different groups were used following overnight dark adaptation. ERGs were recorded against 3 different adapting field luminances (1.15, 1.50 or 1.75 log cd/m 2) with a combination of 3 stimulus flash intensities (0.86, 1.30 or 2.03 log cd sec/m 2) . The responses were obtained at 2 minute intervals for 25 minutes of light adaptation. RESULTS. The response of the rat cone ERG was large despite the small number of cones. The mean amplitude increased systematically from the dark-adapted value requiring more than 15 minutes to reach an asymptote at 2 Hz stimulation, but only 10 minutes at 20 Hz stimulation. The 2 Hz adaptation curves had biphasic pattern compared to the monophasic 20 Hz curve. This second increase in the amplitude at 2 Hz appeared at around 7–8 minutes as a function of adaptation time. This tendency was most evident when using a low adapting field luminance with a high flash intensity. CONCLUSIONS. Our results suggest that the rods intrude much more during light adaptation at 2 Hz stimulation in rodents than in humans. Therefore, 20 Hz flicker stimulation can better isolate more the cone-mediated function than 2 Hz stimulation during the course of light adaptation in rats. Furthermore, the functional characteristics of the cone in rats may be different from that in humans.
[Show abstract][Hide abstract] ABSTRACT: 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.
Full-text · Article · Jun 2009 · Human gene therapy
[Show abstract][Hide abstract] ABSTRACT: Purpose: Our aim was to study whether transcranial direct current stimulation (tDCS) over premotor cortex (PM) can modify the excitability of the ipsilateral primary motor (M1) and somatosensory (S1) cortices via cortico-cortical connectivity. Methods: Ten subjects received, anodal, cathodal and sham tDCS (1mA) over left PM for 15min. PM was determined to be 2cm anterior and 3cm medial to the hotspot of right first dorsal interosseus muscle. Motor evoked potentials (MEPs) were recorded from right first dorsal interosseus (FDI) muscle with transcranial magnetic stimulation over left M1. Somatosensory evoked potentials (SEPs) to right median nerve stimulation were also recorded from left C3'. Both MEPs and SEPs were recorded before, immediately after and 15min after tDCS. Results: The amplitudes of MEPs after anodal tDCS were shown to decrease while those of SEPs tended to increase. In contrast, the effects of cathodal tDCS were opposite to those of anodal tDCS. Statistical analysis (ANOVA) revealed that a significant interaction among INTERVENTION (anodal, cathodal) times TIME (before, after, after15 min) on both MEPs (p Lt 0.01) and SEPs (p Lt 0.05). Discussion: We infer that decreased MEP amplitudes resulted from inhibitory input to M1 from PM with anodal tDCS over PM, whereas the opposite effect was mediated from PM to M1 with cathodal tDCS. It is likely that changes in S1 excitability reflect the alternation of input-output modulation between M1 and S1. Conclusion: tDCS is useful for modulating the excitability of PM with which plastic functions of M1 and S1 can be assessed.
[Show abstract][Hide abstract] ABSTRACT: We conducted two event-related potential (ERP) experiments that examined the mechanisms of auditory temporal assimilation. Stimulus patterns consisted of two neighboring time intervals marked by three successive tone bursts (20 ms, 1000 Hz). Six stimulus patterns were used in which the first time interval (T1) varied from 100 to 280 ms, while the second time interval (T2) was fixed at 200 ms. Two other stimulus patterns consisted of different T1/T2 combinations were employed. Participants judged whether T1 and T2 had the same duration or not by pressing a button. ERPs were recorded from 11 electrodes over the scalp. Behavioral data showed symmetrical assimilation; the participants judged the two neighboring time intervals as equal when the difference between the time intervals (T1-T2) was -40 to +40 ms. Electrophysiological data showed that two ERP components (P300 and CNV) emerged related to the temporal judgment. The P300 appeared in the parietal area at 400 ms after the 2nd tone burst, and its amplitude decreased as a function of T1. The CNV component appeared in the frontal area during T2 presentation, and its amplitude increased as a function of T1. In Experiment 2, 11 stimulus patterns were presented. In seven stimulus patterns, T1 varied from 80 to 320 ms, and T2 was fixed at 200 ms. ERPs were recorded from 19 electrodes over the scalp. In this experiment, behavioral data showed asymmetrical assimilation; participants judged the two neighboring time intervals as equal when T1-T2 was -80 to +40 ms. Consistent with the results of Experiment 1, electrophysiological data showed the P300 and the CNV during T2. In addition, a slow negative component (SNCt) appeared in the right prefrontal area after the 3rd tone burst, and continued up to about 400 ms after the stimuli. The magnitude of this component was smaller when temporal assimilation occurred. These three ERP signatures seem to correlate with the process of temporal assimilation; (a) the P300 augmentation, which could be related to the participants' attention to the 1st interval and reflect the monitoring of the passage of time, (b) the CNV in the frontal area, which might have accompanied the process of memorizing the lengths of the time intervals, and (c) the SNCt in the right prefrontal area, which showed a reduction when temporal assimilation occurred. Our results showed spatiotemporal characteristics of the cortical processing of short time intervals and may assist the neurophysiological understanding of illusions in time and time perception in general.
[Show abstract][Hide abstract] ABSTRACT: A portion of the data from an event-related potential (ERP) experiment  on auditory temporal assimilation [2, 3] was reanalyzed
by constructing Gaussian Naïve Bayes Classifiers . In auditory temporal assimilation, two neighboring physically-unequal
time intervals marked by three successive tone bursts are illusorily perceived to have the same duration if the two time intervals
satisfy a certain relationship. The classifiers could discriminate the subject’s task, which was judgment of the equivalence
between the two intervals, at an accuracy of 86–96% as well as their subjective judgments to the physically equivalent stimulus
at an accuracy of 82–86% from individual ERP average waveforms. Chernoff information  provided more consistent interpretations
compared with classification errors as to the selection of the component most strongly associated with the perceptual judgment.
This may provide us with a simple but somewhat robust neurodecoding scheme.
[Show abstract][Hide abstract] ABSTRACT: We previously demonstrated that a new lentiviral vector derived from nonpathogenic simian immunodeficiency virus (SIVagm) was efficient and safe for long-lasting retinal gene transfer, and that it provided the significant therapeutic effect of expressing human pigment epithelium-derived factor (hPEDF) in Royal College of Surgeons (RCS) rats. In the present study, to obtain a more pronounced outcome, we assessed the potential synergistic effect of the simultaneous gene transfer of hPEDF and human fibroblast growth factor-2 (hFGF-2) by improved third-generation SIV on RCS rats and retinal degeneration slow (rds) mice, because the former targets the primary neurons, including photoreceptor cells (PCs), whereas the latter is effective for targeting secondary neural cells, including Muller cells.
Vector solution (SIV-hPEDF, SIV-hFGF-2, a 1 : 1 mixture of SIV-hPEDF and SIV-hFGF-2, or SIV-enhanced green fluorescent protein) was injected into the peripheral subretinal space of 3-week-old RCS rats or rds mice. Histopathological and electroretinographic assessments were made at several points after gene transfer.
Administration of SIV-hPEDF or SIV-hFGF-2 significantly delayed the histological PC degeneration and electrical deficit in RCS rats, and these delays were synergistically and significantly pronounced by SIV-hPEDF + SIV-hFGF-2 (1 : 1 mixture). In rds mice, functional therapeutic effects were observed even by SIV-PEDF, or SIV-FGF-2 alone and, moreover, both SIV-PEDF and SIV-FGF-2 showed higher therapeutic effects.
These synergistic rescues of retinitis pigmentosa (RP) model animals are the 'proof concept' that the 'dual' expression of hPEDF and hFGF-2 dramatically improved therapeutic efficacy by keeping lower titers. This strategy may contribute to safer and more effective gene therapy for RP.
Full-text · Article · Dec 2008 · The Journal of Gene Medicine