Granulocyte macrophage colony-stimulating factor-induced macrophages of individuals with autism spectrum disorder adversely affect neuronal dendrites through the secretion of pro-inflammatory cytokines.

BACKGROUND: A growing body of evidence suggests that immune dysfunction and inflammation in the peripheral tissues as well as the central nervous system are associated with the neurodevelopmental deficits observed in autism spectrum disorder (ASD). Elevated expression of pro-inflammatory cytokines in the plasma, serum, and peripheral blood mononuclear cells of ASD has been reported. These cytokine expression levels are associated with the severity of behavioral impairments and symptoms in ASD. In a prior study, our group reported that tumor necrosis factor-α (TNF-α) expression in granulocyte-macrophage colony-stimulating factor-induced macrophages (GM-CSF MΦ) and the TNF-α expression ratio in GM-CSF MΦ/M-CSF MΦ (macrophage colony-stimulating factor-induced macrophages) was markedly higher in individuals with ASD than in typically developed (TD) individuals. However, the mechanisms of how the macrophages and the highly expressed cytokines affect neurons remain to be addressed. METHODS: To elucidate the effect of macrophages on human neurons, we used a co-culture system of control human-induced pluripotent stem cell-derived neurons and differentiated macrophages obtained from the peripheral blood mononuclear cells of five TD individuals and five individuals with ASD. All participants were male and ethnically Japanese. RESULTS: Our results of co-culture experiments showed that GM-CSF MΦ affect the dendritic outgrowth of neurons through the secretion of pro-inflammatory cytokines, interleukin-1α and TNF-α. Macrophages derived from individuals with ASD exerted more severe effects than those derived from TD individuals. LIMITATIONS: The main limitations of our study were the small sample size with a gender bias toward males, the use of artificially polarized macrophages, and the inability to directly observe the interaction between neurons and macrophages from the same individuals. CONCLUSIONS: Our co-culture system revealed the non-cell autonomous adverse effects of GM-CSF MΦ in individuals with ASD on neurons, mediated by interleukin-1α and TNF-α. These results may support the immune dysfunction hypothesis of ASD, providing new insights into its pathology.

Brain-derived neurotrophic factor from microglia regulates neuronal development in the medial prefrontal cortex and its associated social behavior.

Microglia and brain-derived neurotrophic factor (BDNF) are essential for the neuroplasticity that characterizes critical developmental periods. The experience-dependent development of social behaviors-associated with the medial prefrontal cortex (mPFC)-has a critical period during the juvenile period in mice. However, whether microglia and BDNF affect social development remains unclear. Herein, we aimed to elucidate the effects of microglia-derived BDNF on social behaviors and mPFC development. Mice that underwent social isolation during p21-p35 had increased Bdnf in the microglia accompanied by reduced adulthood sociability. Additionally, transgenic mice overexpressing microglial Bdnf-regulated using doxycycline at different time points-underwent behavioral, electrophysiological, and gene expression analyses. In these mice, long-term overexpression of microglial BDNF impaired sociability and excessive mPFC inhibitory neuronal circuit activity. However, administering doxycycline to normalize BDNF from p21 normalized sociability and electrophysiological function in the mPFC, whereas normalizing BDNF from later ages (p45-p50) did not normalize electrophysiological abnormalities in the mPFC, despite the improved sociability. To evaluate the possible role of BDNF in human sociability, we analyzed the relationship between adverse childhood experiences and BDNF expression in human macrophages, a possible proxy for microglia. Results show that adverse childhood experiences positively correlated with BDNF expression in M2 but not M1 macrophages. In summary, our study demonstrated the influence of microglial BDNF on the development of experience-dependent social behaviors in mice, emphasizing its specific impact on the maturation of mPFC function, particularly during the juvenile period. Furthermore, our results propose a translational implication by suggesting a potential link between BDNF secretion from macrophages and childhood experiences in humans.

I am not the cause of this pain: An experimental study of the cognitive processes underlying causal attribution in the unpredictable situation whether negative outcomes.

OBJECTIVES: Pain causal attribution is the attribution of pain causes to self or others, which may depend on one's choice of actions. The study aimed to examine how the cognitive processes of pain causal attribution as one aspect of the sense of agency change in healthy individuals based on free or forced choice, using a temporal binding (TB) experimental task. METHODS: Participants pressed keys (action) in a combined TB task, with one key having a high probability of delivering pain (with tone). In fact, only the bias between the free-choice and the forced choice conditions was manipulated. Participants estimated the time between their action and tone, with shorter intervals indicating internal attribution. RESULTS: Interval estimation was significantly longer in the forced-choice condition than in the free-choice condition when a pain stimulus was delivered. CONCLUSIONS: Explicit complaints of pain being caused by others may be represented in implicit cognitive processes.

Unveiling the Impact of Outpatient Physiotherapy on Specific Motor Symptoms in Parkinson's Disease: A Prospective Cohort Study.

Understanding how outpatient physiotherapy impacts on specific motor symptoms in Parkinson's disease (PD) is important for multidisciplinary care, but these points have not been clarified. We investigated the impact of outpatient physiotherapy on individual motor symptoms in PD patients. Fifty-five PD patients participated in the prospective cohort study, which examined the changes in motor symptoms after 90 min of outpatient physiotherapy program (1×/week for 10 weeks) and at 3 months follow-up. Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor score and tremor, rigidity, bradykinesia, and axial scores were assessed and compared pre-intervention, post-intervention, and at follow-up. Significant level was set at 0.05. Their MDS-UPDRS motor score and axial score significantly decreased post-intervention and at the follow-up. In the analysis differentiating effects based on the severity of motor symptoms according to the MDS-UPDRS motor score, only the moderate-severe group showed significant decreases in their MDS-UPDRS motor score, bradykinesia, and axial scores post-intervention, as well as in their MDS-UPDRS motor score, rigidity, bradykinesia, and axial scores at the follow-up. These findings suggest the outpatient physiotherapy might provide benefits, particularly in managing axial symptoms and bradykinesia, for community dwelling PD patients with moderate-severe motor symptoms within a multidisciplinary care framework.

Brain-derived neurotrophic factor from microglia regulates neuronal development in the medial prefrontal cortex and its associated social behavior.

Microglia and brain-derived neurotrophic factor (BDNF) are essential for the neuroplasticity that characterizes critical developmental periods. The experience-dependent development of social behaviors-associated with the medial prefrontal cortex (mPFC)-has a critical period during the juvenile period in mice. However, whether microglia and BDNF affect social development remains unclear. Herein, we aimed to elucidate the effects of microglia-derived BDNF on social behaviors and mPFC development. Mice that underwent social isolation during p21-p35 had increased Bdnf in the microglia accompanied by reduced adulthood sociability. Additionally, transgenic mice overexpressing microglia Bdnf-regulated using doxycycline at different time points-underwent behavioral, electrophysiological, and gene expression analyses. In these mice, long-term overexpression of microglia BDNF impaired sociability and excessive mPFC inhibitory neuronal circuit activity. However, administration of doxycycline to normalize BDNF from p21 normalized sociability and electrophysiological functions; this was not observed when BDNF was normalized from a later age (p45-p50). To evaluate the possible role of BDNF in human sociability, we analyzed the relationship between adverse childhood experiences and BDNF expression in human macrophages, a possible substitute for microglia. Results show that adverse childhood experiences positively correlated with BDNF expression in M2 but not M1 macrophages. Thus, microglia BDNF might regulate sociability and mPFC maturation in mice during the juvenile period. Furthermore, childhood experiences in humans may be related to BDNF secretion from macrophages.

Characteristics of uneven surface walking in stroke patients: Modification in biomechanical parameters and muscle activity.

BACKGROUND: Stroke patients have difficulty walking in outdoor environments, including uneven surfaces, reducing their opportunities for social participation. Changes in stroke patients' gait while walking on even surfaces have been reported; however, gait alterations on uneven surfaces remain unclear. RESEARCH QUESTION: To what extent do biomechanical parameters and muscle activity during even and uneven surface walking differ between stroke patients and healthy people? METHODS: Twenty stroke patients and 20 age-matched healthy people walked on a 6 m even and uneven surfaces. Data on gait speed, root mean square (RMS) of trunk acceleration as a measure of gait stability, maximum joint angle, average muscle activity, and muscle activity time were quantified using accelerometers attached to the trunk, video camera images, and electromyography of lower extremities. A two-factor mixed-model analysis of variance was used to test the effects of group, surface, and group × surface interactions. RESULTS: Gait speed decreased (p < 0.001) on the uneven surface in stroke patients and healthy people. RMS showed an interaction (p < 0.001), and the post-hoc test revealed an increase in stroke patients in the mediolateral direction during the swing phase on the uneven surface. The hip extension angle during the stance phase showed an interaction (p = 0.023), and the post-hoc test revealed a decrease in stroke patients on the uneven surface. The soleus muscle activity time showed an interaction during the swing phase (p = 0.041), and the post-hoc test revealed an increase in stroke patients compared to healthy people only on the uneven surface. SIGNIFICANCE: While walking on an uneven surface, stroke patients showed decreased gait stability, decreased hip extension angle during stance phase, and increased ankle plantar flexor activity time during swing phase. These changes may result from impaired motor control and compensatory strategies used by stroke patients on uneven surfaces.

Influence of vibrotactile random noise on the smoothness of the grasp movement in patients with chemotherapy-induced peripheral neuropathy.

Patients with chemotherapy-induced peripheral neuropathy (CIPN) often suffer from sensorimotor dysfunction of the distal portion of the extremities (e.g., loss of somatosensory sensation, numbness/tingling, difficulty typing on a keyboard, or difficulty buttoning/unbuttoning a shirt). The present study aimed to reveal the effects of subthreshold vibrotactile random noise stimulation on sensorimotor dysfunction in CIPN patients without exacerbating symptoms. Twenty-five patients with CIPN and 28 age-matched healthy adults participated in this study. To reveal the effects of subthreshold vibrotactile random noise stimulation on sensorimotor function, participants were asked to perform a tactile detection task and a grasp movement task during random noise stimulation delivered to the volar and dorsal wrist. We set three intensity conditions of the vibrotactile random noise: 0, 60, and 120% of the sensory threshold (Noise 0%, Noise 60%, and Noise 120% conditions). In the tactile detection task, a Semmes-Weinstein monofilament was applied to the volar surface of the tip of the index finger using standard testing measures. In the grasp movement task, the distance between the thumb and index finger was recorded while the participant attempted to grasp a target object, and the smoothness of the grasp movement was quantified by calculating normalized jerk in each experimental condition. The experimental data were compared using two-way repeated-measures analyses of variance with two factors: experimental condition (Noise 0, 60, 120%) × group (Healthy controls, CIPN patients). The tactile detection threshold and the smoothness of the grasp movement were only improved in the Noise 60% condition without exacerbating numbness/tingling in CIPN patients and healthy controls. The current study suggested that the development of treatment devices using stochastic resonance can improve sensorimotor function for CIPN patients.

Anticipatory postural adjustments mediate the changes in fear-related behaviors in individuals with chronic low back pain.

OBJECTIVES: The role(s) of anticipatory postural adjustments (APAs) in changes in subsequent motor and postural controls in response to movement perturbations are unclear in individuals with chronic low back pain (CLBP). This study aimed to clarify the relationships among kinesiophobia, APAs, lumbar kinematic output, and postural control associated with lumbar movement in individuals with CLBP. METHODS: CLBP participants (n=48) and healthy controls (HCs) without CLBP (n=22) performed a bend-forward task using their lumbar region on a force platform and returned upright. Each participant's lumbar movements were recorded using an electrogoniometer. We calculated the APA duration, the duration of lumbar direction changes from forward to backward, and the center of pressure (COP) position after lumbar movement tasks completion. RESULTS: Compared with the HCs, the duration of direction changes in lumbar movement and the APA duration in CLBP participants were prolonged, and the COP position was shifted forward. The mediation analysis revealed that the duration of lumbar direction changes in the CLBP group was subjected to a significant indirect effect of APAs and a direct effect of kinesiophobia, and the COP position was subjected to a significant indirect effect of kinesiophobia through APAs. CONCLUSIONS: APAs partially mediate the relationship between kinesiophobia and changes in lumbar motor control and mediate the relationship between kinesiophobia and postural control in response to movement perturbations. These findings expand our understanding of APAs in altered subsequent movement and postural controls due to kinesiophobia in individuals with CLBP.

A novel form of transcutaneous electrical nerve stimulation for the reduction of dysesthesias caused by spinal nerve dysfunction: A case series.

Background: Current therapeutic interventions for dysesthesias caused by spinal cord dysfunctions are ineffective. We propose a novel intervention using transcutaneous electrical nerve stimulation (TENS) for dysesthesias, and we present an in-depth case series. Patients and methods: Conventional high-frequency TENS and the novel dysesthesia-matched TENS (DM-TENS) were applied to 16 hands of nine patients with spinal cord dysfunction. The dysesthesia-matched TENS' stimulus intensity and frequency matched the intensity and somatosensory profile of the patients' dysesthesias. The Short-Form McGill Pain Questionnaire version-2 (SF-MPQ2) and quantitative sensory testing (QST) were applied during electrical stimulation/no stimulation. We determined intraclass correlation coefficients (ICCs) to evaluate the reliability of the setting and the effects on the dysesthesias and the change in subjective dysesthesia between each patient's baseline without TENS and DM-TENS. Results: We were able to apply electrical stimulation matching the patients' subjective dysesthesia for 14 hands (eight patients). TENS could not be applied for the remaining patient due to severe sensory deficits. Compared to the patients' baseline and high-frequency TENS, the DM-TENS provided significant decreases in tingling/pins-and-needles and numbness on the SF-MPQ2, and it significantly improved the dynamic and static mechanical detection on QST. Regarding the reliability of the dysesthesia-matched TENS settings, the ICCs (1,5) were intensity, 0.95; frequency, 1.00; and effect on dysesthesia, 0.98. Conclusion: DM-TENS improved the dysesthesias and mechanical hypoesthesia caused by spinal cord dysfunction. The effectiveness of DM-TENS particularly for tingling and numbness was clearly higher and was reliable within the patients. These results may suggest an effective treatment of dysesthesias in patients with spinal cord dysfunction. Clinical trial registration: [https://rctportal.niph.go.jp/s/detail/um?trial_id=UMIN000045332], identifier [UMIN000045332].

The Pain Intensity/Quality and Pain Site Association with Muscle Activity and Muscle Activity Distribution in Patients with Chronic Low Back Pain: Using a Generalized Linear Mixed Model Analysis.

Background: Pain can alter muscle activity, although it is not clear how pain intensity and site location affect muscle activity. This study aimed to reveal the complex associations among the pain site, pain intensity/quality, muscle activity, and muscle activity distribution. Methods: Electromyographic signals were recorded from above a bilateral lumbar erector spinae muscle with a four-channel electrode in 23 patients with chronic low back pain while they performed a lumbar bending and returning task. We calculated the average value of muscle activity during the extension phase (agonist activity) and the centroid of muscle activity, as well as the distance between the centroid of muscle activity and pain site. We also assessed the pain site and pain intensity/quality by the interview and questionnaire method. A generalized linear mixed model analysis was performed to determine the relationships among pain intensity/quality, pain site, and muscle activity. Results: The results showed that muscle activity during the extension phase was significantly negatively associated with neuropathic pain and "pain caused by light touch." In addition, the distance between the centroid of muscle activity and pain site during the extension phase was significantly positively associated with intermittent pain, "throbbing pain," "splitting pain," "punishing-cruel," and "pain caused by light touch." Conclusions: Our findings suggest the existence of a motor adaptation that suppresses muscle activity near the painful area as the pain intensity increases. Furthermore, the present study indicates that the presence or absence of this motor adaptation depended on the pain quality.

Association Between Temporal Asymmetry and Muscle Synergy During Walking With Rhythmic Auditory Cueing in Survivors of Stroke Living With Impairments.

Objective: To examine the relationship between temporal asymmetry and complexity of muscle synergy during walking using rhythmic auditory cueing (RAC) and the factors related to changes in muscle synergy during walking with RAC in survivors of stroke. Design: Cross-sectional study. Setting: Wards at 2 medical corporation hospitals. Participants: Forty survivors of stroke (N=40; mean age, 70.4±10.3 years; time since stroke, 72.2±32.3 days) who could walk without physical assistance. Interventions: Not applicable. Main Outcome Measures: The participants were assessed in a random block design under 2 conditions: comfortable walking speed (CWS) and walking with RAC. Single-leg support time, kinematics, and electromyograms were measured. Factors related to the complexity of muscle synergy (variance accounted for by 1 synergy [VAF1]) between the walking conditions were examined using hierarchical multiple regression analysis. Results: In the RAC condition, lower limb flexion and knee flexion angles, single-leg support time on the paretic side, and the symmetry index of single-leg support time were increased compared with those in the CWS condition. VAF1 was decreased in the RAC condition (73.9±0.15) compared with that in the CWS condition (76.9±0.13, P=.002). Hierarchical multiple regression analysis revealed that the change in VAF1 was explained by change in single-leg support time (R 2=0.43, P=.002). Conclusions: The RAC condition demonstrated a more complex representation of muscle synergy than the CWS condition; the change in single-leg support time on the paretic side related to the changes in muscle synergy more than changes in lower limb angle. These findings can help in the walking-training concept to improve muscle synergy deficits in survivors of stroke.

Spatial Instability during Precision Grip-Lift in Children with Poor Manual Dexterity.

Although children with developmental coordination disorder (DCD) show impaired precision grip control due to a sensory-motor integration deficit, their spatial instability (such as changes in force direction and object roll during a precision grip task) is unclear. Herein, we investigated the spatial instability in the precision grip force control of children with poor manual dexterity. We divided 66 school-aged children who performed a precision gripping and lifting of heavy- or lightweight objects into those with low manual dexterity (n = 11) and those with high manual dexterity (n = 55) as revealed by the Movement Assessment Battery for Children (2nd edition). The group and weight effects were then determined. The results revealed that the total trajectory lengths of the center of pressure (COP) were longer in the lightweight object data of the children in the low-manual-dexterity group and were related to the children's grip force. The low-manual-dexterity group also showed a shifted COP position from the center of the object in the medial-lateral direction and in the object roll regardless of the object's weight; these were closely related in both weights' tests. These results demonstrated that children with poor manual dexterity show spatial instability and different adaptations to the weight of objects during a precision grip task. Further studies are needed to determine whether these findings would be replicated in children with a diagnosis of DCD.

Merged swing-muscle synergies and their relation to walking characteristics in subacute post-stroke patients: An observational study.

In post-stroke patients, muscle synergy (the coordination of motor modules during walking) is impaired. In some patients, the muscle synergy termed module 1 (hip/knee extensors) is merged with module 2 (ankle plantar flexors), and in other cases, module 1 is merged with module 4 (knee flexors). However, post-stroke individuals with a merging pattern of module 3 (hip flexor and ankle dorsiflexor) and module 4, which is the swing-muscle synergy, have not been reported. This study aimed to determine the muscle-synergy merging subtypes of post-stroke during comfortable walking speed (cws). We also examined the effect of experimental lower-limb angle modulation on the muscle synergy patterns of walking in each subtype. Forty-one participants were assessed under three conditions: cws, long stepping on the paretic side (p-long), and long stepping on the non-paretic side (np-long). Lower-limb flexion and extension angles and the electromyogram were measured during walking. Subtype classification was based on the merging pattern of the muscle synergies, and we examined the effect of different lower-limb angles on the muscle synergies. We identified three merging subtypes: module 1 with module 2 (subtype 1), module 1 with module 4 (subtype 2), and module 3 with module 4 (subtype 3). In the cws condition, the lower-limb flexion angle was reduced in subtype 3, and the lower-limb extension angle was decreased in subtype 1. A more complex muscle synergy was observed only in subtype 3 in the p-long condition versus cws (p = 0.036). This subtype classification of walking impairments based on the merging pattern of the muscle synergies could be useful for the selection of a rehabilitation strategy according to the individual's particular neurological condition. Rehabilitation with increased lower-limb flexion may be effective for the training of patients with merging of modules 3 and 4 in comfortable walking.

Changes in Trunk Variability and Stability of Gait in Patients with Chronic Low Back Pain: Impact of Laboratory versus Daily-Living Environments.

BACKGROUND: Individuals with chronic low back pain (CLBP) experience changes in gait control due to pain and/or fear. Although CLBP patients' gait has been performed in laboratory environments, changes in gait control as an adaptation to unstructured daily living environments may be more pronounced than the corresponding changes in laboratory environments. We investigated the impacts of the environment and pathology on the trunk variability and stability of gait in CLBP patients. METHODS: CLBP patients (n=20) and healthy controls with no low-back pain history (n=20) were tasked with walking in a laboratory or daily-living environment while wearing an accelerometer on the low back. We calculated the stride-to-stride standard deviation and multiscale sample entropy as indices of "gait variability" and the maximum Lyapunov exponent as an index of "gait stability" in both the anterior-posterior and medial-lateral directions. The participants were assessed on the numerical rating scale for pain intensity, the Tampa Scale for Kinesiophobia, and the Roland-Morris Disability Questionnaire for quality of life (QOL). RESULTS: In a repeated-measures ANOVA, the standard deviation was affected by environment in the anterior-posterior direction and by group and environment in the medial-lateral direction. Multiscale sample entropy showed no effect in the anterior-posterior direction and showed both effects in the medial-lateral direction. Maximum Lyapunov exponents showed both effects in the anterior-posterior direction, but none in the medial-lateral direction. These changes of trunk motor control by CLBP patients were found to be related to pain intensity, fear of movement, and/or QOL in the daily-living environment but not in the laboratory environment. CONCLUSION: These results revealed that CLBP patients exhibit changes in trunk variability and stability of gait depending on the environment, and they demonstrated that these changes are related to pain, fear, and QOL. We propose useful accelerometer-based assessments of qualitative gait in CLBP patients' daily lives, as it would provide information not available in a general practice setting.

Relationship between iliopsoas muscle thickness and hip angle during squats in different pelvic positions.

[Purpose] This study aimed to investigate the relationships among the changes in iliopsoas muscle thickness, hip angle, and lower limb joint moment during squatting in different pelvic positions to help in performing hip-dominant squatting exercises. [Participants and Methods] The participants were seven healthy adult males. The measurement task consisted of squatting with 60 degrees of knee flexion in three positions: the anterior, neutral, and posterior pelvic tilt positions. The iliopsoas muscle thickness was measured in the center of the inguinal region using ultrasonography. A three-dimensional motion analysis system was used to measure the joint angles and joint moments. [Results] There were no significant differences in pelvic angles between the pelvic positions. The hip angle differences were significantly higher in the anterior and neutral pelvic tilt positions compared to those in the posterior tilt position. Only the anterior pelvic tilt position had a significantly positive correlation with iliopsoas muscle thickness and hip angle differences. [Conclusion] Squatting in the neutral or posterior pelvic tilt position was not associated with hip angle and iliopsoas muscle thickness changes, whereas squatting in an anterior pelvic tilt position was associated with changes in the iliopsoas muscle thickness and hip flexion angle. Our findings suggest that activation of the iliopsoas muscle might be necessary to promote hip-dominant squatting.

Fear of movement-related pain disturbs cortical preparatory activity after becoming aware of motor intention.

Fear of movement-related pain is known to disturb the process of motor preparation in patients with chronic pain. In the present study, we aimed to clarify the neural mechanisms underlying the influence of fear movement-related pain on motor preparatory brain activity using Libet's clock and electroencephalography (EEG). Healthy participants were asked to press a button while watching a rotating Libet's clock-hand, and report the number on the clock ("W time") when they made the "decision" to press the button with their right index finger. Immediately after pressing the button, a painful electrical stimulus was delivered to the dorsum of the left hand, causing participants to feel fear of movement (button press-related pain). We found that fear of movement-related pain caused the W time to be early, and that the amplitudes of readiness potentials (RPs) increased after awareness of motor intention emerged. In addition, fear of movement-related pain caused over-activation of the medial frontal cortex, supplementary motor area, cingulate motor area, and primary motor cortex after participants became aware of their motor intention. Such over-activation might result from conflict between the unrealized desire to escape from a painful experience and motivation to perform a required motor task.

Kinematic changes in goal-directed movements in a fear-conditioning paradigm.

In individuals with a musculoskeletal disorder, goal-directed reaching movements of the hand are distorted. Here, we investigated a pain-related fear-conditioning effect on motor control. Twenty healthy participants (11 women and 9 men, 21.7 ± 2.7 years) performed a hand-reaching movement task. In the acquisition phase, a painful electrocutaneous stimulus was applied on the reaching hand simultaneous with the completion of reaching. In the subsequent extinction phase, the task context was the same but the painful stimulus was omitted. We divided the kinematic data of the hand-reaching movements into acceleration and deceleration periods based on the movement-velocity characteristics, and the duration of each period indicated the degree of impairment in the feedforward and feedback motor controls. We assessed the wavelet coherence between electromyograms of the triceps and biceps brachii muscles. In the acquisition phase, the durations of painful movements were significantly longer in both the acceleration and deceleration periods. In the extinction phase, painful movements were longer only in the acceleration period and higher pain expectation and fear were maintained. Similarly, the wavelet coherence of muscles in both periods were decreased in both the acquisition and extinction phases. These results indicate that negative emotional modulations might explain the altered motor functions observed in pain patients.

Aeration mitigates endoplasmic reticulum stress in Saccharomyces cerevisiae even without mitochondrial respiration.

Saccharomyces cerevisiae is a facultative anaerobic organism that grows well under both aerobic and hypoxic conditions in media containing abundant fermentable nutrients such as glucose. In order to deeply understand the physiological dependence of S. cerevisiae on aeration, we checked endoplasmic reticulum (ER)-stress status by monitoring the splicing of HAC1 mRNA, which is promoted by the ER stress-sensor protein, Ire1. HAC1-mRNA splicing that was caused by conventional ER-stressing agents, including low concentrations of dithiothreitol (DTT), was more potent in hypoxic cultures than in aerated cultures. Moreover, growth retardation was observed by adding low-dose DTT into hypoxic cultures of ire1Δ cells. Unexpectedly, aeration mitigated ER stress and DTT-induced impairment of ER oxidative protein folding even when mitochondrial respiration was halted by the ρo mutation. An ER-located protein Ero1 is known to directly consume molecular oxygen to initiate the ER protein oxidation cascade, which promotes oxidative protein folding of ER client proteins. Our further study using ero1-mutant strains suggested that, in addition to mitochondrial respiration, this Ero1-medaited reaction contributes to mitigation of ER stress by molecular oxygen. Taken together, here we demonstrate a scenario in which aeration acts beneficially on S. cerevisiae cells even under fermentative conditions.

Electrical stimulation of referred sensation area alleviates phantom limb pain.

BACKGROUND: Patients with brachial plexus avulsion (BPA) usually experience phantom sensations and phantom limb pain (PLP) in the deafferented limb. It has been suggested that evoking the sensation of touch in the deafferented limb by stimulating referred sensation areas (RSAs) on the cheek or shoulder might alleviate PLP. However, feasible rehabilitation techniques using this approach have not been reported. OBJECTIVE: The present study sought to examine the analgesic effects of simple electrical stimulation of RSAs in BPA patients with PLP. METHODS: Study 1: Electrical stimulation of RSAs for 60 minutes was conducted for six BPA patients suffering from PLP to examine short-term analgesic effects. Study 2: A single case design experiment was conducted with two BPA patients to investigate whether electrical stimulation of RSAs was more effective for alleviating PLP than control electrical stimulation (electrical stimulation of sites on side opposite to the RSAs), and to elucidate the long-term effects of electrical stimulation of RSAs. RESULTS: Study 1: Electrical stimulation of RSAs evoked phantom touch sensations in the deafferented limb, and significantly alleviated PLP (p < 0.05). Study 2: PLP was alleviated more after electrical stimulation on RSAs compared with control electrical stimulation (p < 0.05). However, the analgesic effects of electrical stimulation on RSAs were observed only in the short term, not in the long term (p > 0.05). CONCLUSIONS: Electrical stimulation of RSAs not only evoked phantom touch sensation but also alleviated PLP in the short term. The results indicate that electrical stimulation of RSAs may provide a useful practical rehabilitation technique for PLP. Future studies will be required to clarify the mechanisms underlying immediate PLP alleviation via electrical stimulation of RSAs.

Goal sharing with others modulates the sense of agency and motor accuracy in social contexts.

Sense of agency (SoA), the feeling of control over one's own actions and their effects, is fundamental to goal-directed actions at the individual level and may constitute a cornerstone of everyday life, including cooperative behavior (i.e., goal sharing). Previous studies have demonstrated that goal sharing can activate the motor prediction of both agent's action and partner's action in joint-action tasks. Moreover, given that from an SoA perspective, predictive processes are an essential basis, there is a possibility that goal sharing may modulate SoA. However, the possibility for goal sharing to modulate SoA remains unclear. This study aimed to investigate whether goal sharing modulates the intentional binding (IB) effect (a method that can quantitatively measure SoA) of self-generated and observed partner's actions and improves motor accuracy. Participants were required to stop a circular horizontal moving object by pressing a key when the object reaches the center of a target in a social situation. This task measured IB by having participants estimate the time interval between action and effect in several 100 milliseconds, with shorter time interval estimations indicating enhancement of SoA. Participants were randomly divided into 13 Cooperative groups (goal sharing) and 13 Independent groups (non-goal sharing). Cooperative groups were instructed to perform the task together, while Independent groups did so individually. Participants estimated the time interval between them by pressing the key and hearing the corresponding sound (Self-generated action) and the other person pressing the key and hearing the sound (Observed action). Our results indicated that goal sharing improved motor accuracy and enhanced both the IB of Self-generated and Observed actions compared to non-goal sharing. We suggest that SoA can be modulated by goal sharing in specific social contexts.