Uncontrolled Manifold (UCM) analysis separates the variability of multi-joint motion into a part that affects the task goal (task-relevant) and a part that does not (task-irrelevant), using the geometric relationship-the task Jacobian-between joint motion and task outcome. The resulting partition has been interpreted as evidence of neural control strategies that stabilize task goals while permitting flexibility in execution. UCM is conventionally reported as time-averaged variance indices, and this time-averaging step discards the temporal structure of movement variability. Using a three-joint planar reaching model, we generate variability with three temporal structures (periodic oscillation, white noise, and pink noise) matched in spatial covariance, and find that the time-averaged geometric indices-the ratio [Formula: see text] and the [Formula: see text]-transformed synergy index [Formula: see text]-remain statistically indistinguishable for white and pink noise, whereas temporal indices computed on the same trials (lag-1 autocorrelation, detrended-fluctuation scaling, spectral slope) show large effect sizes. This double dissociation confirms that time-averaged summaries remain blind to temporal correlations. The projection operation retains temporal information in the single-trial and time-resolved components, yet the meaning of that information for motor control remains open: the mapping from a temporal property of a projected series to a specific control process is itself unestablished, so applying time-series methods to the projections opens a fresh interpretive problem. UCM therefore identifies whether coordination is structured by task constraints while leaving the generating processes undetermined. Establishing this boundary is the contribution of the present work: geometric partitioning yields a spatial account of coordination whose temporal origins lie beyond the method and call for a dedicated dynamical theory.

We used the concept of performance-stabilizing synergies to test predictions of two hypotheses on the organization of reach-to-grasp movements, one assuming separate control of the transport and aperture, and the other assuming that such actions represent pointing movements by the opposing digits. Healthy participants performed series of reach-to-grasp movements to a cylindrical object with and without targets on the object surface with the dominant and non-dominant hands. Joint motion was captured by a motion analysis system. Inter-trial variance in the joint configuration space was analyzed within the framework of the uncontrolled manifold (UCM) hypothesis, and synergy indices were computed for the thumb and index finger tips, hand, and aperture trajectories. The synergy index was higher for both digit-tip trajectories and the hand compared to the synergy index for the aperture during the first half of the movement. Analysis of the variance components showed that, compared to the values computed for the aperture, there was lower variance affecting the trajectories of each of the two digits (orthogonal to the UCM), while variance that did not affect those trajectories (within the UCM) was higher for the index finger and lower for the thumb. We interpret these findings as supporting the two-digit pointing hypothesis. They illustrate the power of the UCM-based method to distinguish between competing motor control hypotheses.

White matter injury (WMI) is a critical pathological feature of various neurological disorders. Microglial pyroptosis, a form of inflammatory cell death mediated by the NLRP3/caspase-1 inflammasome, exacerbates neuroinflammation and contributes to WMI progression. This study investigated the therapeutic potential of rosiglitazone (ROSI), a peroxisome proliferator-activated receptor γ (PPAR-γ) agonist, in alleviating WMI by targeting microglial pyroptosis. In vitro, LPS/ATP-stimulated HMC3 cells exhibited elevated pyroptosis markers (NLRP3, caspase-1, GSDMD, ASC) and inflammatory cytokines (IL-1β, IL-18), which were significantly suppressed by ROSI. ROSI also reduced LPS/ATP-induced injury in co-cultured MO3.13 oligodendrocyte precursor cells (OPCs), improving cell viability and reducing apoptosis. In direct-treatment experiments, ROSI did not significantly affect MO3.13 cell viability, supporting an indirect protective effect on OPCs. Mechanistically, ROSI downregulated KLF4, a transcription factor critical for NLRP3 activation, and this effect was confirmed using KLF4-overexpressing HMC3 cells, where ROSI's anti-pyroptotic effects were abolished. Supplementary GW9662 experiments further suggested that the inhibitory effects of ROSI were not obviously reversed by PPAR-γ antagonism. In vivo, ROSI treatment in a rat model of WMI improved cognitive function, attenuated white matter pathology, and suppressed microglial pyroptosis by reducing NLRP3/caspase-1 activation and inflammatory cytokine release. Notably, ROSI downregulated KLF4 in microglia isolated from WMI rats, further supporting its role in inhibiting pyroptosis. Collectively, these findings demonstrated that ROSI alleviated WMI by inhibiting NLRP3/caspase-1-mediated microglial pyroptosis through downregulation of KLF4, highlighting its potential as a therapeutic strategy for WMI.

Inhibition of Return (IOR) is the phenomenon of being slower to re-attend to previously attended locations, and is thought to improve the efficiency of attention. Previous studies of dopaminergic disorders indicate that excessive or insufficient dopamine signaling in the striatum of the brain reduces IOR magnitude. However, there have been no studies of the direct effects of dopamine depletion on IOR in healthy individuals, or that have compared the effect of dopamine increases and decreases within the same population. Therefore, in the present study, we administered a selective dopamine-2 receptor (D2R) agonist and antagonist to the same healthy participants (cabergoline and amisulpride, respectively) and measured IOR. We further investigated the effects of dopamine manipulation on the underlying cognitive processes of IOR using event-related potentials. Both manipulations reduced the IOR effect relative to placebo, consistent with a non-linear relationship between dopamine and IOR. Given the D2R selectivity of both drugs and the accompanying changes in eye-blink rate, these effects are likely driven by primarily striatal dopamine, potentially reflecting frontostriatal modulation of the balance between attentional flexibility and stability.

High-intensity interval training (HIIT) has emerged as a promising non-pharmacological strategy for neuroprotection, although its molecular effects in Alzheimer's disease (AD) remain unclear. This study investigated the effects of HIIT on gene expression (FNDC5, PPARGC1A, APP), protein expression, cognitive performance, and neuronal apoptosis in a β-amyloid-induced rat model of AD. Sixty male Wistar rats were divided into four groups: sham sedentary (SS), sham trained (ST), Alzheimer sedentary (AS), and Alzheimer trained (AT). AD-like pathology was induced by intrahippocampal infusion of β-amyloid (Aβ1-42). Animals underwent an 8-week HIIT protocol. Gene expression was assessed by qPCR using the ΔCt method, and statistical analyses were performed using two-way ANOVA or mixed-design ANOVA followed by Tukey's post hoc test. HIIT significantly increased PPARGC1A expression (p < 0.05), while FNDC5 gene expression remained unchanged (p > 0.05). However, FNDC5 protein expression was increased in trained groups. APP gene expression was significantly reduced at the transcriptional level (p < 0.05), whereas APP protein abundance differed among experimental conditions without a uniform training-related reduction. HIIT improved physical performance (p < 0.0001) and reduced hippocampal neuronal apoptosis (p < 0.05). In the Morris water maze, improvement was observed only within the Alzheimer-trained group, with no significant differences between groups. HIIT was associated with molecular and cellular adaptations consistent with a neuroprotective response in this β-amyloid-induced model, including metabolic-pathway modulation, reduced APP transcription, and attenuated neuronal apoptosis. These effects were not accompanied by robust between-group cognitive improvement.

Peripersonal space (PPS) refers to the multisensory space surrounding the body and plays an important role in interactions with external objects and the preparation of defensive responses. Recent studies suggest that PPS varies as a function of spatial direction. Since PPS is shaped by bodily action capabilities in nearby space, age-related declines in bodily and motor functions may alter PPS representation in older adults. However, whether older adults maintain front-rear anisotropy in PPS similar to that in younger adults, and such spatial characteristics are related to sensorimotor function remains unclear. Older adults performed an audio-tactile PPS task in the front and rear spaces; their performance was compared with data from younger adults. A vibrotactile stimulus was presented while a task-irrelevant sound approached the participant, and participants responded to the tactile stimulus. The Timed Up and Go (TUG) test was used to examine older adults' functional mobility. Auditory-facilitation effect was greater in the rear space than in the front space even in older adults, suggesting front-rear differences in PPS-related auditory facilitation. Importantly, this age-related change was direction-specific: no age-group difference was observed in the front space; conversely, the auditory-facilitation effect in the rear space was significantly greater in older adults. In addition, higher TUG scores were associated with a larger front-rear difference in facilitation, indicating relatively greater rear space facilitation in older adults with lower functional mobility. Thus, age-related changes in PPS-related auditory facilitation were particularly evident in the rear space, and functional mobility may be linked to front-rear asymmetry in this facilitation effect.

The primary motor cortex (M1) of the brain is responsible for learning and executing motor skills. Previous studies have reported that performing a complex unilateral motor task activates both the contralateral and ipsilateral M1 (ipsi-M1) regions. Corticospinal excitability in ipsi-M1 has been shown to decrease as motor skills are acquired. However, the temporal changes in this excitability throughout the motor learning process remain unclear. Therefore, this study aimed to clarify how corticospinal excitability in ipsi-M1 changes over time during motor learning of a unilateral complex task. Fifteen right-handed healthy adults were enrolled in the study and asked to perform a ball rotation (BR) task. In this motor task, the participants rotated two balls with their right hand. Corticospinal excitability was assessed at rest, followed immediately by the first assessment during movement (T1). Subsequently, the first BR practice and performance evaluation (P1) was conducted. Thereafter, corticospinal excitability assessments (T2-T10) and performance evaluations (P2-P10) were alternated for up to 10 sets. The results showed that motor performance significantly improved from P1 to P6. The motor-evoked potential (MEP) amplitude significantly increased at T1 compared to rest and significantly decreased at T5-T6 and T8-T10 compared to T1. These findings demonstrate that ipsi-M1 excitability increases during the early stages of learning but decreases even before motor learning reaches a plateau. In summary, these findings demonstrate the temporal changes in ipsi-M1 excitability associated with motor learning and may facilitate future investigations on the role of the ipsi-M1 in neurorehabilitation contexts.

Normative goal-directed hand and finger movements often follow invariant kinematics, characterized by approximate straight-line trajectories. A fundamental unresolved issue is whether movement trajectories are planned or whether they are a consequence of trajectory-free online control. We addressed this question using Spearman's rank correlation, zero-crossings rate, and z-scores, and analyzed the time evolution of kinematic variability during the presence or absence of a task in finger and whole-arm reaching movements. We found that the central nervous system (CNS) implements control that is consistent with task-dependent trajectory regulation, where task-relevant movements showed enhanced control toward an average trajectory. Further, we found behavioral signatures of rapid kinematic control that might operate on these planned trajectories as early as ~ 60 ms in finger movements and ~ 70 ms in whole-arm reaching movements. Such early signatures of control in behavior suggest that the system could exploit a trajectory plan along with fast feedback to implement meaningful corrections during simple voluntary unperturbed movements. The analysis also revealed that the control peaked distinctly during the early (20%) and late (80-90%) phases, among both finger and arm movements, implying that the extent of trajectory control was not constant during the execution of movement.

Redox stress is a significant contributor to the molecular dysfunction associated with traumatic brain injury (TBI). Each of the canonical molecular biomarkers of TBI, including GFAP and UCHL1, demonstrate a clear relationship with redox stress via protein oxidation and enzymatic inhibition. Additionally, several markers of redox stress have demonstrated utility in assessing preclinical and clinical TBI, including F2-isoprostanes, generated from the oxidation of arachidonic acid. Thus, we investigated the role of urinary 8-isoprostane as a biomarker for delineating between sham and impacted mice. In this study, male and female mice (n = 19) subjected to five daily impacts using a repeated impact acceleration (rIA) model were evaluated against sham mice for neurological deficits. Impacted mice exhibited behavioral deficits, with increases in righting reflex (RR) times (p < 0.0001), and time-course increases in modified neurological severity scores (mNSS) (p < 0.01). Urine collected immediately following (day 5) and 72 h post-rIA (day 8) revealed time-course increases in 8-isoprostane levels (p < 0.05). Tissue-based protein expression for several markers of molecular dysfunction was assessed using immunoblotting in a two stage discovery based strategy, for which GFAP expression significantly differed with respect to treatment (p < 0.0001) and sex (p < 0.01). Pooled, unadjusted analysis identified a significant relationship between GFAP and urinary 8-isoprostane levels at day 8 (R[2] = 0.75; p < 0.0001) with a non-significant, attenuated within-group relationship (R[2] = 0.08; p > 0.05). Overall, these results suggest repeated impacts using a preclinical TBI mouse model induce acute neurobehavioral deficits, assessed via RR and mNSS, and molecular deficits, including increases in GFAP and urinary 8-isoprostane.

We report super-additive impairment in participants using a joystick to stay upright and avoid crashing while riding in a motion simulator programmed to topple as an inverted pendulum away from an upright direction of balance about two axes (2D) relative to 1D. The 2D test configuration provided participants with full vestibular/somatosensory cues about tilt relative to gravity. The 2D impairment was a) only marginally mitigated by vision relative to blindfolded conditions, and b) worse than a 1D decrement in a 0-g analog condition which precluded gravitational tilt cues by having participants balance in the horizontal roll plane where they were always 90 degrees from the vertical. With practice in the upright 2D balance task over two test days, the deficit declined nearly to the upright 1D level of proficiency. The outsized effect of expanding self-balancing from 1D to 2D and the surprisingly insubstantial visual recovery justify reconsideration of prevailing servo-like models and methods for assessing risk and preventing loss of life from aircraft mishaps, falls, and other tasks involving guidance of an unstable plant. As an alternative explanation, we expand a serial motor decision-making model originally developed for 1D balancing.

As one of the most critical experiential attributes of cosmetics, tactile sensation directly shapes the perception of cosmetic value. To investigate its neural underpinnings, a task was designed to investigate the relationship between electroencephalographic (EEG) signal activity elicited during sunscreen application and willingness to pay (WTP). A total of 25 participants applied 6 sunscreens in a randomized order on the dorsum of the hand. EEG signals were recorded synchronously during application, and WTP was collected afterward. Linear mixed-effects models (LMM) were used to examine the association between multiple EEG features-including emotional valence, arousal, and principal components extracted from spectral power in the alpha (8-12 Hz), beta (12-27 Hz) and gamma (27-40 Hz) bands-on log-transformed WTP. Only the second principal component of alpha power during the application phase (APPLY_α_PC2) showed a significant positive association with WTP (t = 4.000, p < 0.001). This component exhibited a distinct oscillatory topography characterized by alpha synchronization over prefrontal and parietal regions and alpha desynchronization over temporoparietal areas, suggesting a neural pattern that may reflect task-relevant cortical engagement during tactile experience. The specific neural state indexed by prefrontal-parietal alpha synchronization is more directly associated with WTP than conventional emotional indicators. This neural pattern could serve as a candidate objective marker for evaluating cosmetic application experiences in product development and sensory testing.

Somatosensory feedback provides ongoing representation of the body's movements and interaction with the environment that is important for postural control. Altered somatosensory feedback may require compensation to maintain balance, which could include greater attentional resources or increased reliance on other sensory modalities to maintain posture through sensory reweighting. The prefrontal cortex (PFC) has been implicated in allocating attentional resources to maintain postural control, which may be associated with reweighting among sensory modalities. It is unknown whether increased PFC activity will compensate for altered sensory feedback and will be associated with sensory reweighting, demonstrated by changes in visual and somatosensory cortical activity. Therefore, the purpose of this study was to evaluate the contribution of attentional resources and sensory reweighting to postural control, assessed by changes in cortical activity and body sway under conditions of altered sensory feedback during standing. Fifteen healthy, neurotypical participants (ages 21-58) completed somatosensory testing and the Modified Clinical Test of Sensory Interaction in Balance whilst activity in the PFC, somatosensory, visual and motor cortices was measured using functional near-infrared spectroscopy, and an inertial sensor tracked postural sway. Increased postural sway and PFC activity were evident with vision occluded and unstable surface. Somatosensory, visual and motor cortices demonstrated chromophore and side-specific differences that may reflect the range of age and somatosensory function among the sample cohort and suggest that a threshold of sensory challenge may be necessary to evoke cortical changes. However, increased PFC activity supports increased reliance on attentional resources to maintain balance in response to sensory challenge.

We explored the relations between unintentional finger force production (enslaving) and multi-finger force-stabilizing synergies using the framework of the uncontrolled manifold (UCM) hypothesis. In particular, we formulated three mutually exclusive hypotheses on the relations between the synergy indices for the force produced by the instructed finger, enslaved fingers, and all the fingers. The subjects performed accurate force production task with two fingers of a hand (index and ring) while the visual feedback showed the force produced by all the fingers (unknown to the subjects). Synergy index reflecting inter-trial variance analysis confirmed strongest synergies stabilizing the total force and weakest synergies stabilizing the force by the enslaved fingers. Analysis of 60-s trials with and without continuous visual feedback on total force demonstrated an increase in the enslaving index. Analysis of the diffusion plots (Hurst index) confirmed larger stability along the UCM for the enslaved finger force. Overall, our results show that the traditional view on enslaving as a robust phenomenon ensuring linear relations between the intended and unintended finger forces is likely wrong: Enslaving increases with time as reflected in the smaller indices of force-stabilizing synergies. These findings also suggest that enslaving is defined predominantly by neural factors.

Hypoxic-ischemic brain injury (HIBI) is characterized by complex pathological processes that contribute to acute neuronal damage. Photobiomodulation (PBM) and hydrogen inhalation have each demonstrated neuroprotective effects in ischemic and hypoxic models; however, the effects of their combined application in acute HIBI have not been directly evaluated. In this study, HIBI was induced in mice, followed by treatment with PBM alone, hydrogen inhalation alone, or their combination. Behavioral performance, physiological parameters, and molecular markers of neuronal survival, glial activation, neuroinflammation, apoptosis, and hypoxia signaling were evaluated at 24 h after injury. While PBM or hydrogen alone partially attenuated HIBI-induced alterations, combined treatment more effectively preserved locomotor activity, stabilized physiological parameters, and reduced neuronal loss. These effects were accompanied by decreased glial activation and inflammatory signaling, suppression of apoptotic pathways, and improved regulation of hypoxia-related signaling. Collectively, these findings demonstrate that combined PBM and hydrogen inhalation confers enhanced neuroprotection compared with monotherapies by modulating multiple pathological mechanisms in acute HIBI.