Shinichiro Kumagaya

Cyclic strain induces mouse embryonic stem cell differentiation into vascular smooth muscle cells by activating PDGF receptor β

Embryonic stem (ES) cells are exposed to fluid-mechanical forces, such as cyclic strain and shear stress, during the process of embryonic development but much remains to be elucidated concerning the role of fluid-mechanical forces in ES cell differentiation. Here, we show that cyclic strain induces vascular smooth muscle cell (VSMC) differentiation in murine ES cells. Flk-1-positive (Flk-1+) ES cells seeded on flexible silicone membranes were subjected to controlled levels of cyclic strain and examined for changes in cell proliferation and expression of various cell lineage markers. When exposed to cyclic strain (4-12% strain, 1 Hz, 24 h), the Flk-1+ ES cells significantly increased in cell number and became oriented perpendicular to the direction of strain. There were dose-dependent increases in the VSMC markers smooth muscle alpha-actin and smooth muscle-myosin heavy chain at both the protein and gene expression level in response to cyclic strain, whereas expression of the vascular endothelial cell marker Flk-1 decreased, and there were no changes in the other endothelial cell markers (Flt-1, VE-cadherin, and platelet endothelial cell adhesion molecule 1), the blood cell marker CD3, or the epithelial marker keratin. The PDGF receptor beta (PDGFR beta) kinase inhibitor AG-1296 completely blocked the cyclic strain-induced increase in cell number and VSMC marker expression. Cyclic strain immediately caused phosphorylation of PDGFR beta in a dose-dependent manner, but neutralizing antibody against PDGF-BB did not block the PDGFR beta phosphorylation. These results suggest that cyclic strain activates PDGFR beta in a ligand-independent manner and that the activation plays a critical role in VSMC differentiation from Flk-1+ ES cells.

Restoring movement representation and alleviating phantom limb pain through short-term neurorehabilitation with a virtual reality system

We developed a quantitative method to measure movement representations of a phantom upper limb using a bimanual circle‐line coordination task (BCT). We investigated whether short‐term neurorehabilitation with a virtual reality (VR) system would restore voluntary movement representations and alleviate phantom limb pain (PLP).

Reduced Personal Space in Individuals with Autism Spectrum Disorder

Maintaining an appropriate distance from others is important for establishing effective communication and good interpersonal relations. Autism spectrum disorder (ASD) is a developmental disorder associated with social difficulties, and it is thus worth examining whether individuals with ASD maintain typical or atypical degrees of social distance. Any atypicality of social distancing may impact daily social interactions. We measured the preferred distances when individuals with ASD and typically developing (TD) individuals approached other people (a male experimenter) and objects (a coat rack with clothes) or when other people approached them. Individuals with ASD showed reduced interpersonal distances compared to TD individuals. The same tendency was found when participants judged their preferred distance from objects. In addition, when being approached by other people, both individuals with ASD and TD individuals maintained larger interpersonal distances when there was eye contact, compared to no eye contact. These results suggest that individuals with ASD have a relatively small personal space, and that this atypicality exists not only for persons but also for objects.

Dissociation in accessing space and number representations in pathologic pain patients

Space is represented by integrating egocentric and allocentric reference frames; however, little is known about the role of these independent reference frames in number representation. Using patients with unilateral pathologic pain in one limb, we investigated whether number representation is closely linked to space representation by evaluating visual subjective body-midline judgments in dark and light conditions (egocentric and allocentric space, respectively). To evaluate the number representation, pairs of numbers were read aloud to the participant, who was then asked to state the midpoint number that they intuitively perceived to be at the middle of each interval. All of the patients perceived allocentric space accurately in the light condition. However, each of the patients showed perceptual shifts in egocentric space and number representation in the dark as compared with control subjects. Direct comparison showed a consistent relationship between number representation and egocentric space. We suggest that numbers are represented spatially by integrating these independent reference frames.

Multimodal virtual reality platform for the rehabilitation of phantom limb pain

Amputees usually perceive vivid awareness of their lost body parts after the amputation (phantom limbs). Phantom limb pain (PLP) is intense pain that is felt in the phantom limb. The mechanism of PLP is still unclear, but the major hypothesis is that it is derived from dysfunction of the brain. There are a few neurorehabilitation techniques using a mirror or virtual reality (VR) that present the visual image of a phantom limb to the patients, and this produce the movement perception of their phantom limb. Here, we developed a multimodal (visual, auditory, and tactile) VR system to obtain the perception of voluntary phantom limb movements. We applied this system to five PLP patients for three tactile feedback conditions as a pilot study. In conclusion, four of the five patients reported pain amelioration, up to 86% decrease in the tactile feedback condition. In addition, our results demonstrated that the best suited condition of feedback-sense modalities depends on the patient. These results suggest that this system can be applied to a rehabilitation platform to offer flexible neurorehabilitation regimens for each patient.

Somatosensory Feedback to the Cheek During Virtual Visual Feedback Therapy Enhances Pain Alleviation for Phantom Arms

Background. Patients who suffer from phantom limb pain can perceive tactile stimuli applied to the cheek on their affected side as if it were coming from their phantom limb, a phenomenon called “referred sensation.” Objectives. To investigate the analgesic effect produced by tactile feedback provided to the cheek during neurorehabilitation using visual feedback. Methods. Nine participants with phantom upper limb pain performed virtual reality neurorehabilitation exercises in which they repeatedly touched a target object with a virtual representation of their affected limb. We applied tactile feedback to their cheek when their virtual affected limb touched a virtual object (Cheek Condition). We also included 2 control conditions where tactile feedback was either applied to their intact hand (Intact Hand Condition) or not applied at all (No Stimulus Condition). We evaluated pain intensity on an 11-point rating scale and pain quality using the short-form McGill Pain Questionnaire before and after each rehabilitation condition. Results. The median pain-reduction rate in the Cheek Condition (33.3 ± 24.4%) was significantly higher than in the Intact Hand Condition (16.7 ± 12.3%) and the No Stimulus Condition (12.5 ± 13.5%; P < .05). Even patients who did not feel referred sensations reported significant pain reduction after the Cheek Condition. Conclusions. The analgesic effect of neurorehabilitative visual feedback during phantom limb movement is significantly improved by applying somatosensory feedback to the cheek on the affected side. Further studies are needed to extend these findings to objective pain measures and to elucidate the neural mechanisms that underlie the analgesic effect.

Neurodevelopmental Hypothesis about the Etiology of Autism Spectrum Disorders

Previous models or hypotheses of autism spectral disorder (ASD) failed to take into full consideration the chronological and causal developmental trajectory, leading to the emergence of diverse phenotypes through a complex interaction between individual etiologies and environmental factors. Those phenotypes include persistent deficits in social communication and social interaction (criteria A in DSM-5), and restricted, repetitive patterns of behavior, interests, or activities (criteria B in DSM-5). In this article, we proposed a domain-general model that can explain criteria in DSM-5 based on the assumption that the same etiological mechanism would trigger the various phenotypes observed in different individuals with ASD. In the model, we assumed the following joint causes as the etiology of autism: (1) Hypoplasia of the pons in the brainstem, occurring immediately following neural tube closure; and (2) Deficiency in the GABA (γ-aminobutyric acid) developmental switch during the perinatal period. Microstructural abnormalities of the pons directly affect both the structural and functional development of the brain areas strongly connected to it, especially amygdala. The impairment of GABA switch could not only lead to the deterioration of inhibitory processing in the neural network, but could also cause abnormal cytoarchitecture. We introduced a perspective that atypical development in both brain structure and function can give full explanation of diverse phenotypes and pathogenetic mechanism of ASD. Finally, we discussed about neural mechanisms underlying the phenotypic characteristics of ASD that are not described in DSM-5 but should be considered as important foundation: sleep, global precedence, categorical perception, intelligence, interoception and motor control.

Reliability of phantom pain relief in neurorehabilitation using a multimodal virtual reality system

The objective of this study is to demonstrate the reliability of relief from phantom limb pain in neurore-habilitation using a multimodal virtual reality system. We have developed a virtual reality rehabilitation system with multimodal sensory feedback and applied it to six patients with brachial plexus avulsion or arm amputation. In an experiment, patients executed a reaching task using a virtual phantom limb displayed in a three-dimensional computer graphic environment manipulated by their real intact limb. The intensity of the phantom limb pain was evaluated through a short-form McGill pain questionnaire. The experiments were conducted twice on different days at more than four-week intervals for each patient. The reliability of our tasks ability to relieve pain was demonstrated by the test-retest method, which checks the degree of the relative similarity between the pain reduction rates in two experiments using Fishers intraclass correlation coefficient (ICC). The ICC was 0.737, indicating sufficient reproducibility of our task. The average of the reduction rates across participants was 50.2%, and it was significantly different from 0 (p <; 0:001). Overall, our findings indicate that neurorehabilitation using our multimodal virtual reality system reduces the phantom limb pain with sufficient reliability.

Atypical delayed auditory feedback effect and Lombard effect on speech production in high-functioning adults with autism spectrum disorder.

Individuals with autism spectrum disorder (ASD) show impaired social interaction and communication, which may be related to their difficulties in speech production. To investigate the mechanisms of atypical speech production in this population, we examined feedback control by delaying the auditory feedback of their own speech, which degraded speech fluency. We also examined feedforward control by adding loud pink noise to the auditory feedback, which led to increased vocal effort in producing speech. The results of Japanese speakers show that, compared with neurotypical (NT) individuals, high-functioning adults with ASD (including Asperger’s disorder, autistic disorder, and pervasive developmental disorder not otherwise specified) were more affected by delayed auditory feedback but less affected by external noise. These findings indicate that, in contrast to NT individuals, those with ASD relied more on feedback control than on feedforward control in speech production, which is consistent with the hypothesis that this population exhibits attenuated Bayesian priors.

Brief Report: Body Image in Autism: Evidence from Body Size Estimation

Individuals with autism spectrum disorder (ASD) have difficulties with social interaction and communication. First-hand accounts written by individuals with ASD have shown the existence of other atypical characteristics such as difficulties with body awareness. However, few studies have examined whether such atypicalities are found more generally among individuals with ASD. We examined body image (i.e., self-body awareness) by asking individuals with ASD and typically developing (TD) individuals to estimate their own body size (shoulder width). Results show that TD individuals estimated their shoulder width more accurately than individuals with ASD. This study suggests that individuals with ASD often experience misperceptions in their body size.