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Kaneko, N.

Publications and source records attributed to Kaneko, N..

18 recordsLinked to original sources

Nonhuman primates exhibit error type-dependent post-error slowing across modalities

Mistakes make up our daily lives. Once a mistake has been committed, it is common to pause before you continue. This slowing is called post-error slowing (PES). Although several theories have been proposed to account for PES in humans, findings across cognitive tasks show variation in how PES occurs, and it is unclear how this phenomenon may translate across modalities to a key model organism of human cognition, macaque monkeys. To determine whether monkeys exhibit PES, we tested three rhesus macaque monkeys in components of cognitive sequential decision-making tasks that used either eye tracking or touch screens to report responses. Here we show that monkeys exhibit non-adaptive, error type-dependent PES across modalities. Task structure and context also modulated PES in the eye tracking task, and no modality improved task performance following PES. These results suggest that monkey PES is a combination of cognitive and non-cognitive related responses to error that are modulated by task structures such as error type and task context. Overall, the flexibility in monkey PES is comparable to that of humans, further supporting the importance of monkeys as a translational model in investigating the mechanisms of PES.

neuroscience↗

Height-induced postural threat selectively facilitates spinal reflex in the tibialis anterior muscle during quiet standing

Long-latency stretch reflex and corticospinal excitability in the tibialis anterior muscle (TA) are facilitated when balance is threatened, even without background TA activity, suggesting supraspinal modulation as preparatory tuning for ankle stabilization. However, it remains unclear whether such tuning is evident at the spinal level and specific to the TA among lower-limb muscles. We therefore examined the effects of height-induced postural threat on multi-segmental monosynaptic spinal reflexes (MMR) in lower-limb muscles during quiet standing. Seventeen healthy young males performed 90-s standing tasks under three postural threat conditions, created by combining real and virtual reality (VR) heights: (1) Low-threat (real ground & VR ground), (2) Medium-threat (real table & VR ground), and (3) High-threat (real table & VR bridge). During each condition, transcutaneous spinal cord stimulation (tSCS) was applied to the lumbar spine to elicit MMR in lower-limb muscles. Electromyograms (EMG) were recorded from six muscles of the right leg: vastus medialis (VM), biceps femoris (BF), TA, soleus (SOL), medial (MG), and lateral gastrocnemius (LG). MMR excitability was quantified as peak-to-peak EMG amplitude. Fear ratings and electrodermal activity were higher in High-threat than Low-threat (all p < 0.05), confirming successful threat induction. Peak-to-peak EMG amplitude in the TA was significantly higher in High-threat than Low-threat (17.1% increase, p = 0.0393), whereas background TA activity remained absent across conditions. These results indicate that TA has unique function to facilitate spinal excitability as a preparatory tuning for ankle stabilization. Key pointsO_LIPrevious studies have shown the supraspinal facilitation of the tibialis anterior muscle without background muscle activation as a preparatory tuning for ankle stabilization. C_LIO_LITo test the hypothesis that such tuning is also evident at the spinal level and specific to the tibialis anterior muscle, this study examined whether height-induced postural threat modulates multi-segmental monosynaptic reflex excitability in lower-limb muscles using transcutaneous spinal cord stimulation. C_LIO_LIElectrodermal activity and fear ratings increased under height-induced postural threat, confirming the successful induction of postural threat. C_LIO_LIUnder height-induced postural threat, the multi-segmental monosynaptic reflex was selectively facilitated in the tibialis anterior muscle, while its background activity remained absent. C_LIO_LIOur findings demonstrate selective facilitation of spinal excitability in the tibialis anterior muscle, which may serve as preparatory tuning for ankle stabilization under threat to balance. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/742625v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@19fde78org.highwire.dtl.DTLVardef@c6aa8dorg.highwire.dtl.DTLVardef@e73a76org.highwire.dtl.DTLVardef@af393d_HPS_FORMAT_FIGEXP M_FIG C_FIG Abstract figure legendWhen balance is threatened, corticospinal excitability and long-latency stretch reflex in the tibialis anterior muscle (TA) are facilitated even in the absence of background TA activity, suggesting supraspinal preparatory tuning for ankle stabilization. This study tested the hypothesis that such facilitation is also expressed at the spinal level and is specific to the TA. Participants completed 90-s quiet standing trials under three different height-induced postural threat conditions. During each trial, transcutaneous spinal cord stimulation was delivered over the lumbar spine to elicit multi-segmental monosynaptic reflexes (MMR) in multiple lower-limb muscles. High-threat condition increased fear ratings and electrodermal activity, indicating successful threat induction. Moreover, MMR excitability was selectively increased in the TA under High-threat condition despite the absence of background TA activity. These findings suggest that spinal facilitation is selectively expressed in the TA and may reflect preparatory tuning for ankle stabilization under threat to balance.

neuroscience↗

Modeling interregional propagation of α-synuclein in human striatal-midbrain assembloids

Parkinsons disease is characterized by the progressive degeneration of dopaminergic (DA) neurons in the substantia nigra that project to the striatum. Postmortem studies have found that -synuclein pathology spreads across brain regions in a prion-like manner. Human three-dimensional neural tissues provide experimentally tractable platforms for clarifying the molecular pathology of synucleinopathy that overcome the limitations of postmortem brain studies. In this study, we established a human striatal-midbrain assembloid model enabling spatially and temporally controlled -synuclein induction after formation of the nigrostriatal pathway within hStrMAs. Human induced pluripotent stem cells (hiPSCs) were differentiated into striatal spheroids and midbrain spheroids, which were fused to reconstruct the nigrostriatal pathway in vitro. Histological, electrophysiological, and single-cell RNA sequencing analyses confirmed the generation of region-specific neuronal populations, including striatal GABAergic neurons and midbrain DA neurons, and demonstrated that distinct forebrain and ventral midbrain identities were preserved within assembloids. To model synucleinopathy, we generated a doxycycline-inducible -synuclein hiPSC line, permitting selective induction of -synuclein expression in the striatal region after assembloid formation. Spatially restricted -synuclein induction resulted in the progressive accumulation of phosphorylated and fibrillar -synuclein in midbrain DA neurons, indicating interregional propagation through established neural circuits. Transcriptomic analysis of the midbrain region revealed significant downregulation of DA identity and synaptic function genes, suggesting functional impairment of DA neurons following -synuclein propagation. These findings demonstrate that the human neural circuit architecture contributes to the interregional propagation of -synuclein pathology. Our controllable human assembloid platform provides a powerful experimental framework for dissecting the mechanisms of pathological protein spread and developing therapeutic strategies targeting molecular pathology in neurodegenerative diseases. Significance statementOne pathological feature of Parkinsons disease is the progressive spread of -synuclein pathology across brain regions. However, the molecular mechanisms underlying this process remain poorly understood. In this study, we established a human striatal-midbrain assembloid model in which -synuclein expression can be spatially restricted and temporally induced after the nigrostriatal pathway is formed, thus enabling the experimental dissection of interregional -synuclein propagation across brain regions. We demonstrated that -synuclein pathology initiated in the striatal region propagated to midbrain dopaminergic neurons, leading to disease-relevant molecular and transcriptional alterations. These findings provide direct evidence that human neural circuits contribute to the spread of synucleinopathy and offer a controllable human model for studying disease progression and therapeutic strategies.

neuroscience↗

Cortical and spinal contributions to remote interlimb facilitation in humans

Voluntary contraction in one limb can facilitate motor output in a distant limb, a phenomenon commonly referred to as the remote effect. However, the neural mechanisms underlying this remote interlimb facilitation remain unclear. This study investigated cortical and spinal contributions to the remote effect in able-bodied participants. Transcranial magnetic stimulation (TMS) was applied over the hand area of the primary motor cortex using posterior-anterior (PA) and anterior-posterior (AP) current directions, which are sensitive to different cortical inputs. Cortical excitability was assessed using single- and paired-pulse paradigms to measure short-interval intracortical inhibition (SICI), short-interval intracortical facilitation (SICF), and short-latency afferent inhibition (SAI). Spinal motoneuron excitability was assessed from F-waves elicited by peripheral nerve stimulation. During voluntary lower-limb contractions, single-pulse TMS elicited larger motor evoked potentials in hand muscles across current directions, indicating a broad increase in net corticospinal output. However, only AP-sensitive paired-pulse measures showed reduced SICI and enhanced SICF during contraction, whereas PA-sensitive SICI and SICF were not significantly altered, suggesting that cortical modulation during the remote effect is expressed more clearly in AP-sensitive measures. SAI with PA stimulation was less consistently expressed during contraction, suggesting that afferent-related inhibitory modulation may also be influenced during the remote effect. In parallel, F-wave amplitude and persistence increased, consistent with enhanced spinal motoneuron excitability. Together, these results provide converging evidence that the remote effect in humans involves broad corticospinal and spinal facilitation, accompanied by current direction-dependent modulation of cortical excitability measures. KEY POINTS SUMMARYO_LIVoluntary contraction in one limb can facilitate motor output in a distant limb, but the mechanisms underlying this remote interlimb facilitation remain unclear. C_LIO_LIWe tested whether remote lower-limb contraction modulates corticospinal output, intracortical excitability, and spinal motoneuron excitability in a resting hand muscle. C_LIO_LISingle-pulse transcranial magnetic stimulation showed that motor evoked potentials in the hand were facilitated during remote lower-limb contraction across multiple current directions, indicating a broad increase in net corticospinal output. C_LIO_LIPaired-pulse measures were modulated preferentially with anterior-posterior stimulation, with reduced short-interval intracortical inhibition and increased short-interval intracortical facilitation, suggesting current direction-dependent modulation of cortical excitability measures. C_LIO_LIF-wave amplitude and persistence were also enhanced during remote lower-limb contraction, indicating increased spinal motoneuron excitability. These findings provide converging evidence that the remote effect involves both cortical and spinal contributions. C_LI

neuroscience↗

Distinct neural input strategies to motor units in the soleus and medial gastrocnemius during quiet standing

Standing posture control critically depends on the activation of the soleus (SOL) and medial gastrocnemius (MG), which serve distinct functional roles. Identifying underlying neural mechanisms has been challenging, as conventional invasive techniques sample only limited motor units (MUs). Recent advances in high-density surface electromyography (HDsEMG) have enabled analysis of MU activity and estimation of common synaptic inputs to spinal motoneurons. Therefore, we aimed to elucidate the common synaptic inputs underlying the distinct MU behaviors of SOL and MG during standing. We recorded HDsEMG from the SOL and MG, alongside electroencephalography, from 20 male participants during standing and isometric voluntary contractions. EMG signals were decomposed into individual MU activity, with common synaptic inputs estimated through intramuscular and corticomuscular coherence analyses (IMC and CMC). Compared to SOL, the MG exhibited significantly higher delta-, alpha-, and beta-band IMC during standing. In task comparisons, alpha-band IMC increased during standing specifically in the MG. Furthermore, although beta-band CMC decreased in both muscles while standing, IMC was preserved in the MG but markedly reduced in SOL. This dissociation suggests that the common neural drive to the MG during standing is likely derived from subcortical rather than cortical pathways. These results demonstrate that the SOL and MG are governed by distinct neural control strategies, which likely underlie their functional roles. Given the low CMC, the MG relies on strong common synaptic input from subcortical pathways (e.g., vestibulospinal and reticulospinal) to produce rapid corrective torque, whereas the SOL functions with lower neural synchrony to ensure steady ankle stiffness. Key pointsO_LIThe soleus and medial gastrocnemius play distinct roles in standing control, however, due to technical limitations, it has been difficult to identify the underlying neural mechanisms responsible for these differences. C_LIO_LIUsing high-density surface electromyography, we examined motor unit activity and neural inputs to these muscles during standing. C_LIO_LIThe medial gastrocnemius shows greater common synaptic input, potentially facilitating rapid ankle plantarflexion torque generation to correct postural sway. C_LIO_LIThe soleus exhibits lower motor unit synchrony, enabling stable and continuous ankle plantarflexion torque generation for body weight support. C_LIO_LIThis study demonstrates that the soleus and medial gastrocnemius are governed by distinct neural control strategies, which likely underlie their distinct functional roles. C_LI Abstract figure legend O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/698550v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@be53aorg.highwire.dtl.DTLVardef@f6793aorg.highwire.dtl.DTLVardef@190e8f9org.highwire.dtl.DTLVardef@af5e4b_HPS_FORMAT_FIGEXP M_FIG C_FIG Motor unit spike trains were decomposed from high-density surface electromyograms recorded from the medial gastrocnemius (MG; left; red) muscle and soleus (SOL; right; blue). To compare the neural input to the spinal motor neurons between them, we quantified the intramuscular coherence (IMC) of motor unit spike trains within the delta, alpha, and beta bands. MG exhibited greater IMC than SOL during standing, indicating stronger common synaptic input, likely mediated by vestibulospinal and reticulospinal pathways. In contrast, SOL showed lower IMC, suggesting a greater contribution of independent synaptic input. As a consequence, high motor-unit synchrony in the MG supports rapid, phasic torque generation for postural sway attenuation, whereas low synchrony in the SOL enables smooth, steady torque production for weight bearing during standing.

physiology↗

Facilitating the Supplementary Motor Area Activity Reduces Variability of Ball Arrival Position in Accurate Ball Throwing Performance

Maintaining high accuracy during rapid, dynamic movements is a significant challenge for the central nervous system. The supplementary motor area (SMA) is a key cortical region for orchestrating motor commands and regulating movement variability, yet its causal role in maintaining precision during high-speed tasks remains to be fully elucidated. We investigated the impact of modulating SMA excitability on throwing performance in fourteen healthy adults with no competitive throwing experience. Participants performed maximal and submaximal (50% effort) throwing tasks before and after receiving intermittent (facilitatory) or continuous (inhibitory) theta burst stimulation (TBS) over the SMA. Outcome measures included ball speed, variability of pitch location--quantified as variable error (95% confidence ellipse area) and absolute error (Euclidean distance from the ellipse center to the target)--and introspective ratings of performance via visual analog scales (VAS). Results showed that intermittent TBS (iTBS) significantly reduced the variable error of pitch location during maximal-effort throwing--where neural noise is theoretically elevated--without compromising ball speed. In contrast, no significant changes in performance were observed following continuous TBS or during the submaximal throwing task. Notably, objective precision gains under iTBS were dissociated from subjective ratings of accuracy, which increased globally over time independent of stimulation type. These findings demonstrate that the SMA plays a critical causal role in stabilizing motor output under high motor drive. This study suggests that SMA-mediated stabilization operates as a subconscious process, offering new insights for optimizing complex motor skills. HighlightsO_LIiTBS over the SMA significantly reduces throwing variable error in novices. C_LIO_LIImproved precision occurs without compromising maximal ball throwing speed. C_LIO_LIThe SMA causally stabilizes motor output during high-speed movements. C_LIO_LIObjective precision gains are dissociated from subjective performance ratings. C_LIO_LISMA-mediated stabilization operates as a subconscious motor process. C_LI

neuroscience↗

Musicianship and active musical engagement predict facilitation of auditory-motor plasticity: evidence from auditory-motor paired associative stimulation

Background and AimAuditory-motor paired associative stimulation (PAS) probes experience-dependent plasticity in auditory-motor circuits. We tested whether musical experience and musical sophistication modulate PAS-induced facilitation when instrument tones are paired with transcranial magnetic stimulation (TMS) over the left primary motor cortex. MethodSixteen musicians and thirteen non-musicians completed two sessions. Session 1 estimated an individualized inter-stimulus interval (ISI) by testing seven tone-TMS delays (25-300 ms). Session 2 applied PAS at the optimal ISI. Corticospinal excitability was assessed by motor-evoked potentials (MEPs) from right first dorsal interosseus at baseline and post-intervention. Group comparisons and a stepwise multiple regression with Goldsmiths Musical Sophistication Index (Gold-MSI) subscales evaluated predictors of the PAS effect. ResultsA stepwise multiple regression model selected "Group" and "Active Engagement" (Gold-MSI Factor 1) as independent predictors (F (2,26) = 4.59, p = 0.020, adjusted R2 = 0.204), without interaction: musicians exhibited smaller facilitation than non-musicians, and higher Active Engagement predicted greater facilitation across groups. DiscussionThe lack of facilitation in musicians contrasts with somatosensory PAS reports of enhanced plasticity in experts. A modality-specific ceiling effect may contribute, whereby long-term training optimizes auditory-motor transmission, reducing headroom for facilitation. The association with Active Engagement suggests motivational/reward mechanisms--potentially dopaminergic-- gate responsiveness to auditory-motor PAS. ConclusionUnder this protocol, auditory-motor PAS with instrument tones facilitated corticospinal excitability in non-musicians but not in musicians. Individual differences in Active Engagement predicted facilitation, indicating that both group membership and active musical engagement shape susceptibility to auditory-motor associative plasticity.

neuroscience↗

Developmental Reorganization of Whole-Body Muscle Synergies During Overarm Throwing in Children

Overarm throwing is a uniquely human skill that requires precise whole-body coordination. Although throwing behavior emerges early in childhood, the neuromuscular mechanisms that support its development remain poorly characterized. Here, we provide novel evidence for the developmental reorganization of whole-body muscle synergies during maximum-effort throwing in preschool-aged (PS) and school-aged (SA) children. Electromyography was recorded from 16 muscles, and non-negative matrix factorization was applied to extract low-dimensional coordination modules (muscle synergies). We compared ball speed, number of synergies, synergy structure, and temporal consistency between groups. Ball speed was significantly higher in SA than PS (33.6 {+/-} 10.2 vs. 21.4 {+/-} 6.2 km/h, p < 0.05), reflecting improved performance. Yet, the number of synergies did not differ (PS: 6.0 {+/-} 1.1; SA: 6.4 {+/-} 1.3, p > 0.05), suggesting that the dimensionality of coordination is largely established by the preschool years. Instead, developmental improvements were driven by structural and temporal reorganization: trunk- and upper-limb synergies merged into a single module in SA, reflecting improved postural integration, while a bilateral soleus-dominant synergy fractionated into lateralized modules, reflecting increased lower-limb specialization. Moreover, the temporal variability of synergy activation was reduced in SA (p < 0.01), indicating that movement sequences became more precise and stable with development. These findings reveal that early gains in throwing arise not from expanding synergy number but from reorganizing their structure and sharpening temporal coordination, offering mechanistic insight into how complex whole-body skills are refined during childhood. Significance StatementThrowing is a hallmark of human motor behavior, requiring precise sequencing of whole-body muscle activity. Yet how children develop this ability has remained unclear. By applying muscle synergy analysis to electromyographic recordings of preschool and school-aged children performing maximum-effort throws, we found that improvements in performance were not due to an increase in synergy number but rather to structural reorganization and greater temporal precision. Specifically, trunk and upper-limb modules merged, lower-limb modules fractionated, and activation timing became more consistent. These results identify merging and fractionation as complementary mechanisms supporting developmental refinement of motor skills. More broadly, they provide a mechanistic framework for understanding how complex whole-body actions are acquired and offer markers for pediatric training and rehabilitation strategies.

neuroscience↗

Loss of B cell tolerance at the T2/T3a B cell transition is a convergent pathogenic mechanism in common variable immunodeficiency

Many patients with common variable immunodeficiency (CVID), including those with CTLA4 deficiency, NFKB1 variants and activated PI3K-delta syndrome (APDS), develop autoimmunity that is refractory to treatment. Despite this shared clinical phenotype, a unifying mechanism for the breakdown of B cell tolerance across monogenic forms of CVID has not been established. Here, we demonstrate that patients with loss-of-function NFKB1 variants, like those with CTLA4 variants and APDS, exhibit dysregulated CD4+ T cell expansion, accumulation of transitional B cells, and a relative lack of follicular B cells. In patients with monogenic CVID and clinical autoimmunity, we observed a relative expansion of transitional and activated naive (aN: CD21loCD11chi) B cells in peripheral blood accompanied by a marked increase in the frequency of VH4-34 expressing autoreactive 9G4+ B cells, which expanded between T2 and T3a transitional B cell stages. Single-cell transcriptomic and B cell receptor analysis further revealed a marked expansion of activated T1/2, T3 and extrafollicular activated naive and double negative (DN: IgD-CD27-) B cell subsets in APDS patients. Notably, one B cell subset appeared exclusively in the APDS disease state, characterized by high oxidative phosphorylation in transitional B cells, specifically. In APDS patients, we also observed a clonal expansion of specific extrafollicular class-switched DN B cells, which were clonally derived from activated transitional B cells. DN B cells were also identified in APDS lung tissue, consistent with the contribution of activated, extrafollicularly-derived B cells to tissue inflammation. Together, these findings suggest that in many patients with CVID and autoimmune features, premature activation of autoreactive transitional T2 and T3a B cells induces the survival and expansion, rather than the tolerization and elimination, of self-reactive B cells. This process leads to extrafollicular expansion of autoreactive B cells capable of tissue infiltration. One Sentence SummaryLoss of transitional B cell tolerance and extrafollicular expansion of autoreactive B cells drive autoimmunity in monogenic causes of CVID.

immunology↗

Modulation of cortico-muscular coupling associated with split-belt locomotor adaptation

Humans can adjust their walking patterns according to the demands of their internal and external environments, referred to as locomotor adaptation. Although significant functional coupling (i.e. cortico-muscular coherence [CMC]) has been shown between cortical and lower-limb muscle activity during steady-state walking, little is known about CMC in locomotor adaptation. Therefore, we investigated the adaptation-dependent modulation of the CMC between the sensorimotor region and the tibialis anterior muscle using a split-belt locomotor adaptation paradigm that can impose an asymmetric perturbation. We hypothesized that the CMC would temporarily decrease after exposure to the asymmetric perturbation and removal of the perturbation because of a mismatch between the predicted and actual sensory feedback. We also hypothesized that the CMC would increase as adaptation and de-adaptation to perturbation progressed because the motor system could become able to predict sensory feedback. Our findings revealed that the CMC temporarily decreased after exposure to and removal of the perturbation. Moreover, the CMC increased with adaptation and de-adaptation to perturbation. Although these results depend on the leg, frequency bands, and gait phases, they partially support our hypothesis. These findings suggest that flexible updating of cortico-muscular coupling in the motor system is a key mechanism underlying locomotor adaptation in humans. The results from our study on healthy young individuals contribute to the understanding of neuromuscular control of gait and provide valuable insight for optimising gait rehabilitation. Key pointsO_LILocomotor adaptation plays a crucial role in our daily activities and gait rehabilitation. C_LIO_LIAlthough knowledge regarding the brain and muscle activities associated with locomotor adaptation has been accumulated, little is known about the functional coupling of the brain and muscle activities. C_LIO_LIUsing high-density EEG and lower limb EMG, we demonstrated the modulation of cortico-muscular coherence between the sensorimotor region and the tibialis anterior muscle with adaptation and de-adaptation during a split-belt treadmill walking paradigm. C_LIO_LIOur findings suggest that flexible updating of cortico-muscular coupling in the motor system underlies locomotor adaptation in humans. C_LIO_LIUnderstanding the human brains control of muscles during split-belt locomotor adaptation will deepen our knowledge of neuromuscular control of gait and provide valuable insights for gait rehabilitation. C_LI

neuroscience↗

Spatial Clustering Analysis with Spectral Imaging-based Single-Step Multiplex Immunofluorescence (SISS-mIF)

Precision medicine, based on spatial biology, is crucial for accurately diagnosing cancer and predicting drug responses. Here, we introduce the Spectral Imaging-based Single-Step Multiplex Immunofluorescence (SISS-mIF) technique, utilizing hyperspectral imaging to capture fluorescence spectra simultaneously. This approach optimizes tissue autofluorescence spectra for each image automatically, allowing the use of fluorescent direct-labeled antibodies for multicolor staining in a single step. Unlike conventional methods, the images are generated as standardized intensity independent of capture conditions, enabling consistent comparisons under different imaging conditions. This technique allows the detection of CD3, CD5, and CD7 in T-cell lymphoma on a single slide. The use of fluorescent direct-labeled antibodies enables triple staining of CD3, CD5, and CD7 without cross-reactivity, maintaining the same intensity as single stains. Furthermore, we developed a joint Non-Negative Matrix Factorization-based Spatial Clustering Analysis (jNMF-SCA) with a modified spectral unmixing system, highlighting its potential as a supportive diagnostic tool for T-cell lymphoma.

pathology↗

Accurate localization of cortical and subcortical sources of M/EEG signals by a convolutional neural network with a realistic head conductivity model: Validation with M/EEG simulation, evoked potentials, and invasive recordings

While electroencephalography (EEG) and magnetoencephalography (MEG) are well-established non-invasive methods in neuroscience and clinical medicine, they suffer from low spatial resolution. Particularly challenging is the accurate localization of subcortical sources of M/EEG, which remains a subject of debate. To address this issue, we propose a four-layered convolutional neural network (4LCNN) designed to precisely locate both cortical and subcortical source activity underlying M/EEG signals. The 4LCNN was trained using a vast dataset generated by forward M/EEG simulations based on a realistic head volume conductor model. The 4LCNN implicitly learns the characteristics of M/EEG and their sources from the training data without need for explicitly formulating and fine-tuning optimal priors, a common challenge in conventional M/EEG source imaging techniques. We evaluated the efficacy of the 4LCNN model on a validation dataset comprising forward M/EEG simulations and two types of real experimental data from humans: 1) somatosensory evoked potentials recorded by EEG, and 2) simultaneous recordings from invasive electrodes implanted in the brain and MEG signals. Our results demonstrate that the 4LCNN provides robust and superior estimation accuracy compared to conventional M/EEG source imaging methods, aligning well with established neuroscience knowledge. Notably, the accuracy of the subcortical regions was as accurate as that of the cortical regions. The 4LCNN method, as a data-driven approach, enables accurate source localization of M/EEG signals, including in subcortical regions, suggesting future contributions to various research endeavors such as contributions to the clinical diagnosis, understanding of the pathophysiology of various neuronal diseases and basic brain functions.

neuroscience↗

Congenital T cell activation impairs transitional to follicular B cell maturation in humans

CTLA4-deficient patients exhibit profound humoral immune dysfunction, yet the basis for the B cell defect is not known. We observed a marked reduction in transitional to follicular B cell development in CTLA4-deficient patients, correlating with decreased CTLA4 function in regulatory T cells and increased mTORC1 signaling in transitional B cells. Treatment of transitional B cells with CD40L was sufficient to induce mTORC1 signaling and inhibit follicular B cell maturation in vitro. Frequent cell-cell contacts between CD40L+ T cells and naive IgD+CD27- B cells were observed in patient lymph nodes. Follicular B cell maturation in CTLA-deficient patients was partially rescued following CTLA4 replacement therapy in vivo. We conclude that functional regulatory T cells and the containment of excessive T cell activation are required for follicular B cells to mature and attain metabolic quiescence and thus acquire a state of immunological self-tolerance. One Sentence SummaryCongenital T cell activation in CTLA4-deficient patients impairs transitional to follicular B cell maturation and can be rescued by CTLA4 replacement therapy in vivo.

immunology↗

ADAMTS2 regulates radial neuronal migration by activating TGF-β signaling at the subplate layer of the developing neocortex

During the development of the mammalian brain, neocortical structures are formed by the sequential radial migration of newborn excitatory neurons. The early migrating neurons exhibit a multipolar shape, but they undergo a multipolar-to-bipolar transition at the subplate (SP) layer, where extracellular matrix (ECM) components are abundantly expressed. In this study, we revealed that the TGF-{beta} signaling-related ECM proteins, such as latent TGF-{beta}-binding protein 1 (LTBP1) and fibrillin 2, and TGF-{beta} receptor II (TGF-{beta}RII) and its downstream effector, p-smad2/3, are selectively expressed at the SP layer, suggesting that TGF-{beta} is sequestered in a latent form by forming complexes with these ECM components and then its signaling is activated by ECM remodeling. We found that the migrating multipolar neurons transiently express a disintegrin and metalloproteinase with thrombospondin motif 2 (ADAMTS2), an ECM metalloproteinase, just below the SP layer. Knockdown and knockout of Adamts2 suppressed the multipolar-to-bipolar transition of migrating neurons, and therefore, disturbed radial migration. Similar phenotypes were observed by the perturbation of TGF-{beta} signaling in the migrating neurons. Time-lapse luminescence imaging of TGF-{beta} signaling indicated that ADAMTS2 activates this signaling pathway in the migrating neurons during the multipolar-to-bipolar transition at the SP layer. These results suggest that the ADAMTS2 secreted by the migrating multipolar neurons activates TGF-{beta} signaling by ECM remodeling of the SP layer, leading to the multipolar-to-bipolar transition. We propose that the SP layer plays an essential role in the radial neuronal migration as a signaling center of the developing neocortex. SIGNIFICANCEThe neocortex is formed by the sequential radial migration of newborn neurons, which undergo a multipolar-to-bipolar transition at the subplate (SP) layer. The extracellular matrix (ECM) is abundantly expressed in the SP layer. However, the roles of the ECM in the SP layer have been unclear. We found that migrating neurons transiently express a disintegrin and a metalloproteinase with thrombospondin motif 2 (ADAMTS2), an ECM metalloproteinase, just below the SP layer. We show that ADAMTS2 secreted by multipolar migrating neurons activates TGF-{beta} signaling through remodeling of the ECM in the SP layer, leading to the multipolar-to-bipolar transition. Thus, the SP layer plays an essential role in radial migration as a signaling center of the developing neocortex

neuroscience↗

Firing behavior of single motor neurons of the tibialis anterior in human walking as non-invasively revealed by HDsEMG decomposition

Investigation of the firing behavior of spinal motor neurons (MNs) provides essential neuromuscular control information because MNs form the "final common pathway" in motor control. The MNs activated during human infants leg movements and rodent locomotion, mainly controlled by the spinal central pattern generator (CPG), show highly synchronous firing. In addition to spinal CPGs, the cerebral cortex is involved in neuromuscular control during walking in human adults. Thus, MN firing behavior during adult walking is expected to be similar to that of infants and rodents and has some unique features. Recent technical advances allow non-invasive investigation of MN firing by high-density surface electromyogram (HDsEMG) decomposition. Therefore, we investigated the MN firing behavior of the tibialis anterior muscle during walking by HDsEMG decomposition. We found motor unit recruitment modulation compared with steady isometric contractions, doublet firings, and gait phase-specific firings during walking. We also found high MN synchronization during walking over a wide range of frequencies, probably including cortical and spinal CPG-related components. The amount of MN synchronization was modulated between the gait phases and motor tasks. These results suggest that the central nervous system, including the spinal CPG and cerebral cortex, flexibly controls MN firing to generate appropriate muscle force during human walking. In addition to revealing the neural control mechanisms of walking, our data demonstrate the feasibility of non-invasive investigation of MNs during walking, which will open new frontiers for the study of neuromuscular function in medical and exercise sciences.

neuroscience↗

Neural decoding of gait phase information during motor imagery and improvement of the decoding accuracy by concurrent action observation

Brain decoding of motor imagery (MI) is crucial for the control of neuroprosthesis, and it provides insights into the underlying neural mechanisms. Walking consists of stance and swing phases, which are associated with different biomechanical and neural control features. However, previous studies on the decoding of the MI of walking focused on the classification of more simple information (e.g., walk and rest). Here, we investigated the feasibility of electroencephalogram (EEG) decoding of the two gait phases during the MI of walking and whether the combined use of MI and action observation (AO) would improve decoding accuracy. We demonstrated that the stance and swing phases could be decoded from EEGs during AO or MI alone. Additionally, the combined use of MI and AO improved decoding accuracy. The decoding models indicated that the improved decoding accuracy following the combined use of MI and AO was facilitated by the additional information resulting from the concurrent cortical activations by multiple regions associated with MI and AO. This study is the first to show that decoding the stance versus swing phases during MI is feasible. The current findings provide fundamental knowledge for neuroprosthetic design and gait rehabilitation, and they expand our understanding of the neural activity underlying AO, MI, and AO+MI of walking. Significance StatementBrain decoding of detailed gait-related information during motor imagery (MI) is important for brain-computer interfaces (BCIs) for gait rehabilitation. However, previous knowledge on decoding the motor imagery of gait is limited to simple information (e.g., the classification of "walking" and "rest"). Here, we demonstrated the feasibility of EEG decoding of the two gait phases during MI. We also demonstrated that the combined use of MI and action observation (AO) improves decoding accuracy, which is facilitated by the concurrent and synergistic involvement of the cortical activations by multiple regions for MI and AO. These findings extend the current understanding of neural activity and the combined effects of AO and MI and provide a basis for developing effective techniques for walking rehabilitation.

neuroscience↗

Detecting task-dependent modulation of spatiotemporal module via tensor decomposition: application to kinematics and EMG data for walking and running at various speed

How the central nervous system (CNS) controls many joints and muscles is a fundamental question in motor neuroscience and related research areas. An attractive hypothesis is the module hypothesis: the CNS controls groups of joints or muscles (i.e., spatial modules) while providing time-varying motor commands (i.e., temporal modules) to the spatial modules rather than controlling each joint or muscle separately. Another fundamental question is how the CNS generates numerous repertories of movement patterns. One hypothesis is that the CNS modulates the spatial and/or temporal modules depending on the required tasks. It is thus essential to quantify the spatial module, the temporal module, and the task-dependent modulation of those modules. Although previous methods attempted to quantify these aspects, they considered the modulation in only the spatial or temporal module. These limitations were possibly due to the constraints inherent to conventional methods for quantifying the spatial and temporal modules. Here, we demonstrate the effectiveness of tensor decomposition in quantifying the spatial module, the temporal module, and the task-dependent modulation of these modules without such limitations. We further demonstrate that the tensor decomposition provides a new perspective on the task-dependent modulation of spatiotemporal modules: in switching from walking to running, the CNS modulates the peak timing in the temporal module while recruiting proximal muscles in the corresponding spatial module.\n\nAuthor summaryThere are at least two fundamental questions in motor neuroscience and related research areas: 1) how does the central nervous system (CNS) control many joints and muscles and 2) how does the CNS generate numerous repertories of movement patterns. One possible answer to question 1) is that the CNS controls groups of joints or muscles (i.e., spatial modules) while providing time-varying motor commands (i.e., temporal modules) to the spatial modules rather than controlling each joint or muscle separately. One possible answer to question 2) is that the CNS modulates the spatial and/or temporal module depending on the required tasks. It is thus essential to quantify the spatial module, the temporal module, and the task-dependent modulation of those modules. Here, we demonstrate the effectiveness of tensor decomposition in quantifying the modules and those task-dependent modulations while overcoming the shortcomings inherent to previous methods. We further show that the tensor decomposition provides a new perspective on how the CNS switches between walking and running. The CNS modulated the peak timing in the temporal module while recruiting proximal muscles in the corresponding spatial module.

neuroscience↗

Cortical control of locomotor muscle activity through muscle synergies in humans: a neural decoding study

Walking movements are orchestrated by the activation of a large number of muscles. The control of numerous muscles during walking is believed to be simplified by flexible activation of groups of muscles called muscle synergies. Although significant corticomuscular connectivity during walking has been reported, the level at which the cortex controls locomotor muscle activity (i.e., muscle synergy or individual muscle level) remains unclear. Here, we examined cortical involvement in muscle control during walking by brain decoding of the activation of muscle synergies and individual muscles from electroencephalographic (EEG) signals using linear decoder models. First, we demonstrated that activation of locomotor muscle synergies was decoded from slow cortical waves with significant accuracy. In addition, we found that decoding accuracy for muscle synergy activation was greater than that for individual muscle activation and that decoding of individual muscle activation was based on muscle synergy-related cortical information. Taken together, these results provide indirect evidence that the cerebral cortex hierarchically controls multiple muscles through a few muscle synergies during walking. Our findings extend the current understanding of the role of the cortex in muscular control during walking and could accelerate the development of effective brain-machine interfaces for people with locomotor disabilities.

neuroscience↗