Neuroscience Letters

Multiple lines of evidence point to the volume regulated anion channel (VRAC) as being instrumental for cellular volume regulation in many cell types, including astrocytes. VRAC are thought to open during periods of astrocyte swelling, releasing anions and osmolytes to drive water out of the cell, allowing it to return to baseline volume even under sustained osmotic or ionic challenge, a process called regulatory volume decrease, or RVD. However, the occurrence of RVD and VRACs role in this process has remained controversial, with clear evidence in cultured cells but mixed reports from work in intact brain tissue. In the present study, we aimed to address this gap by generating a transgenic mouse line in which VRAC is conditionally ablated in astrocytes (VRAC cKO) and recording the volume responses of astrocytes in VRAC cKO and control tissue using real-time volume imaging. We found that the effect of VRAC cKO on astrocyte swelling was dependent on whether swelling was evoked by elevated extracellular potassium, or by reduced extracellular osmolarity. We also found that both VRAC and the presence of sufficient intracellular taurine concentration were required to elicit RVD in astrocytes, but only in hypoosmolar conditions. Our findings provide new information on the conditions needed to elicit RVD in intact brain tissue, and that VRAC is required for RVD to occur. Our findings further suggest that reduction of intracellular ion concentration is essential for VRAC to be activated, rather than simply membrane expansion. Future experiments will examine the solute release aspect of VRAC activation upon astrocyte swelling, as well as the contributions of VRAC to pathological volume dysregulation.

In human dorsal root ganglia (DRG), and trigeminal (TG) neurons, the various voltage-gated sodium channel (Nav) isoforms play critical roles in the firing of action potentials, which drive electrical impulses that encode somatosensations including, itch, and pain. The SCN11A gene encodes the tetrodotoxin (TTX)-resistant voltage-gated sodium channel Nav1.9, characterized by unique gating properties. Unlike other isoforms, the Nav1.9 channel activates and inactivates slowly and has a hyperpolarized voltage-dependence of activation and depolarized voltage-dependence of inactivation. This leads to a large window current that has been suggested to function as a regulator of the resting membrane potential of neurons. Mutations in Nav1.9 channels lead to congenital insensitivity to pain (gain-of-function) or familial episodic pain syndrome (loss-of-function) suggesting the channel is a critical mediator of pain. Despite its relevance in pain pathophysiology, most existing data relies on rodent models or heterologous expression systems, leaving the specific pharmacology and biophysical behavior of these channels in human primary neurons largely unknown. In this study, we pharmacologically isolated and characterized native Nav1.9 channel currents in human DRG and TG neurons to compare their biophysical profiles. Our findings reveal significant kinetic and voltage-dependent differences between the two populations. Specifically, Nav1.9 channels in TG neurons exhibit a right-shifted steady-state inactivation curve, a larger window current, and faster activation kinetics compared to those in DRG neurons. In addition, conditions that simulate inflammatory states in-vivo greatly potentiates the Nav1.9 currents consistent with similar observations in rodent models. By detailing these distinct biophysical properties, this research offers crucial insights into Nav1.9 channel function relevant for drug discovery efforts aimed at developing analgesics for both acute and chronic pain.

Every known life form senses and reacts to mechanical forces. These mechanical stimuli can be converted into electrical signals by mechanically gated ion channels, a transduction cascade pivotal to numerous physiological functions including touch, hearing, mechanical pain, circulation, gastrointestinal function, and mechanical loading in various tissues. Despite continuous efforts, numerous mechanically gated ion channels with the mechanotransduction process underlying these physiological functions remain unidentified. Here, we focused on the transmembrane channel-like (TMC) protein family expressed in the cultured cells to identify those with potential mechanosensitive activity. Remarkably, in contrast to human TMC1/2 (HsTMC1/2), human TMC3-8 (HsTMC3-8) proteins are localized to the plasma membrane when heterologously expressed in the cultured cells. Further experiments revealed that mechanical poking stimuli can effectively activate HsTMC3-8. In addition, HsTMC3-8 induced stretch-activated currents and elicited well-resolved single-channel activities in response to negative pressure stimulation. The mutants near the putative pore region altered reversal potentials (Erev) of HsTMC3-8, suggesting that TMC3-8 are likely pore-forming subunits of ion channels. In summary, we proposed that TMC proteins are the largest mammalian mechanically gated ion channel family.

Intergroup conflict is one of the most significant issues in human society. In the 1950s, Sherif et al. reported that intergroup conflict could be artificially induced in boys through intergroup competition with tug-of-war and ball games. Since this iconic study, researchers have developed various experimental methods to replicate intergroup competition and/or conflicts. However, although intergroup conflicts in wild animals are often reported, it has been difficult to establish a situation of intergroup conflict in laboratory rodents that is discriminable from aggressive behavior individually. In this study, we established a novel experimental paradigm for intergroup competition in mice in which the members of each group shared objectives and tasks. Adult male ICR/Jcl mice were housed in groups of six, divided into two teams of three and repeatedly performed a competitive Tsunahiki task (tsunahiki means tug-of-war in Japanese). The competitive Tsunahiki task was conducted in an open field divided into two experimental fields, with three ropes stuck to a wall separating the fields. The mice were required to pull two ropes out faster than their opponent team to win, and only the winners could proceed to the reward area separated by a guillotine door. We demonstrated that the experience of the competitive Tsunahiki task induced attack bites selectively toward members of the other team (out-group members). Our findings suggest that intergroup competition induces intergroup conflict in mice, providing a technical breakthrough in elucidating the detailed neuroscientific mechanisms underlying intergroup conflict.

Metastability is a fundamental dynamical property of large-scale brain networks and reflects the capacity of the brain to flexibly reorganize transient coordination patterns. In this study, we investigated whether metastable properties of resting-state electroencephalographic (EEG) phase synchronization networks are associated with individual differences in autistic traits. Resting-state EEG data from 88 neurotypical adults were analyzed using two complementary metrics: synchrony coalition entropy (SCE), which quantifies the diversity of transient phase synchronization patterns, and the metastability index (MSI), which quantifies temporal variance in global phase synchronization. SCE showed frequency-specific associations with the Autism-Spectrum Quotient (AQ) attention-switching subscore at 18-24 Hz and the communication subscore at 4-8 Hz, suggesting that frequency- and network-specific patterns of metastable synchronization are associated with distinct aspects of autistic traits. In contrast, MSI showed a modest association with the social-skill subscore in the lower-beta range, but this effect did not survive a cluster-based permutation test. This exploratory observation suggests that global synchronization variability may capture a weaker, complementary aspect of trait-related metastable dynamics. These findings suggest that, within a neurotypical population, individual differences in autistic traits may be more sensitively captured by the repertoire of transient phase synchronization patterns, as indexed by SCE, than by global phase synchronization variability, as indexed by MSI. Moreover, the associations of distinct AQ subscores with SCE in different frequency ranges suggest that different dimensions of autistic traits may be related to metastable network dynamics operating at different temporal scales. Author SummaryThe brain constantly coordinates activity across many regions, and this coordination changes over time rather than remaining constant. Understanding these dynamic patterns is important for explaining individual differences in cognition and behavior. In this study, we focused on a dynamical property called "metastability," which describes how brain activity flexibly shifts between different patterns of coordination. Instead of remaining in a stable state, the brain repeatedly forms and dissolves coordinated activity across regions. We analyzed brain signals recorded with resting-state electroencephalography (EEG) and examined whether these dynamic patterns were related to individual differences in autistic traits. We found that different aspects of time-varying coordination were linked to different dimensions of autistic traits in a neurotypical population. These findings suggest that examining how brain activity changes over time, rather than relying only on time-averaged measures, can reveal neural features associated with individual differences in autistic traits. Our study highlights metastability as a useful concept for understanding the flexible and dynamic nature of human brain function.

The ventral motor and the centromedian (CM) nuclei receive prominent GABAergic inputs from the basal ganglia, massive glutamatergic projections from motor cortices and significant GABAergic afferents from the reticular thalamic nucleus. There is strong evidence that disrupted processing of information through these connections may contribute to the pathophysiology of the basal ganglia-thalamocortical loop in Parkinson's disease (PD). To further assess potential ultrastructural changes in synaptic connectivity and mitochondrial integrity that may contribute to these network dysfunctions, we used a 3D electron microscopic approach to determine whether the pattern of synaptic innervation and morphological integrity of dendritic mitochondria are altered in the basal ganglia-receiving parvocellular ventral anterior nucleus (VApc) and CM neurons of MPTP-treated parkinsonian monkeys. Three main conclusions can be drawn from our findings: (1) Although the overall pattern of synaptic innervation of VApc and CM neurons is not altered in parkinsonian monkeys, the volume of putative corticothalamic terminals is significantly increased in both nuclei, (2) the prevalence of corticothalamic terminals in contact with distal dendrites is several orders of magnitude higher in VApc than CM in both control and parkinsonian monkeys, (3) the complexity and ultrastructural integrity of dendritic mitochondria is altered in CM, but not in the VApc, of parkinsonian monkeys. These findings lay the foundation for future studies of changes in cortical neuromodulation of VApc and CM neurons in parkinsonism and suggest that mitochondrial defects may contribute to the degeneration of CM neurons in PD.

Theft, including shoplifting, extorts a pervasive societal and economic burden. However, the neurobehavioral mechanisms underlying recurrent theft remain sparsely understood. In this study, we investigated social cognition deficits in theft recidivists with kleptomania (TR+K) and instrumental theft recidivists without kleptomania (TR-K) compared to control subjects without criminal records (CT), for which the Social Norms Questionnaire (SNQ-22) to assess explicit moral knowledge, alongside the Dictator Game (DG) and Hawk-Dove Game (HDG) to evaluate discretionary and competitive resource allocation with others, respectively, were administered. Bayesian statistical analyses revealed that all groups demonstrated comparable social norm recognition in SNQ-22 and prosociality in the DG. However, distinct behavioral profiles emerged in specific contexts, such that TR+K exhibited more unfairness than CT and TR-K at discretionary resource allocations in the DG, whereas in the HDG, TR-K demonstrated more aggressive, resource-monopolizing responses, particularly when against an aggressive opponent, than CT and TR+K. These results suggest that theft recidivism may stem from contextual failures rather than general deficits in moral knowledge, which are distinct between TR+K rooted in the internal factor, such as heightened loss aversion, and TR-K characterized by impulsivity over the external factor, such as social conflicts with others.

Dietary iron deficiency in the absence of anemia (IDNA) affects numerous people worldwide, with a wide range of negative effects on brain functioning and cognition. Although studies employing electroencephalography (EEG) have revealed a number of negative effects of IDNA in both the time- and frequency domains, to date there have been no attempts to characterize the effects of IDNA on the temporal dynamics of whole brain interactions. To address this issue, we applied multiscale entropy (MSE) analysis to resting-state EEG data collected from IDNA (n = 21) and iron sufficient (IS, n = 21) women. The MSE analysis on this data revealed that entropy was higher overall for the IS than the IDNA group, with significant differences appearing primarily at longer time scales and under right frontal and left and right parietal electrodes. These results suggest that IDNA may negatively affect long-distance interactions among brain regions and that this could conceivably be a source of diminished cognitive function and neural resilience in IDNA.

Chronic pain is frequently accompanied by negative affect and motivational deficits due to dysregulated mesocorticolimbic dopamine and kappa opioid receptor (KOR) signalling. Although intracranial KOR antagonism prevents pain-induced negative affect in preclinical models, systemic KOR antagonists can produce adverse off-target effects in the periphery, thereby limiting its clinical utility. Consistent with this, we found that systemic administration of KOR antagonist norbinaltorphimine (NorBNI), exacerbated motivational deficits in rats with persistent inflammatory pain. We hypothesized that maximizing central and minimizing peripheral KOR antagonism could overcome these limitations. To test this, we engineered an intranasal liposomal NorBNI formulation incorporated into an in-situ forming mucoadhesive hydrogel to enable selective nose-to-brain delivery (Nor-BNILV-HG). We characterized its physicochemical properties and functional efficacy in rats with inflammatory pain produced by Complete Freund's Adjuvant (CFA). NorBNI-loaded liposomes exhibited high drug entrapment efficiency, nanometric size, and suitable surface charge for intranasal administration. The selected thermosensitive hydrogel demonstrated appropriate gelation properties and sustained drug release. Intranasal administration of NorBNI-LV-HG produced negligible systemic NorBNI levels compared with intraperitoneal delivery. In vivo microdialysis showed that NorBNI-LV-HG prevented KOR agonist-induced reductions in nucleus accumbens (NAc) dopamine release, confirming functional central KOR blockade. Behaviourally, intranasal NorBNI-LV-HG attenuated pain-induced impairments in sucrose motivation. Importantly, unlike systemic NorBNI, repeated intranasal NorBNI-LV-HG did not alter mechanical nociceptive thresholds in pain-naive animals, suggesting this strategy mitigates unwanted peripheral nociceptive effects. Together, these findings demonstrate that intranasal NorBNI-LV-HG achieves functional brain KOR antagonism while minimizing systemic exposure and off-target effects. Selective nose-to-brain delivery of KOR antagonists therefore represents a promising therapeutic strategy to prevent and potentially reverse the affective and motivational consequences of pain and may overcome key translational barriers associated with systemic KOR treatments.

Understanding the complex network that regulates pain is fundamental to develop strategies to combat its growing prevalence and increase useful therapeutics. Although extensive literature identifies the importance of cannabinoid receptors and endocannabinoids in controlling pain, their efficacy and loci of action remain debated. To directly test the actions of peripherally restricted cannabinoids and elucidate the minimal circuitry capable of producing cannabinoid-mediated analgesia, we utilized a novel genetic approach that allows for cell-specific reactivation of cannabinoid receptor 1 (CB1R) selectively in peripheral sensory neurons using newly developed CB1R floxed-stop-floxed mice (CB1RLOXTB) crossed with Nav1.8-cre mice (Nav1.8+/-:CB1RLOXTB). Ex vivo and in vivo experiments confirmed successful knockout and reactivation of CB1R. Wildtype littermate controls, but neither Nav1.8+/-:CB1RLOXTB nor CB1RLOXTB animals, exhibited robust analgesia after systemic WIN55,212-2 (WIN) treatment in the tail flick assay. Furthermore, the presence of CB1R on Nav1.8 neurons was not associated with either a difference in the development of inflammatory pain or the response to WIN. However, after neuropathic injury, CB1RLOXTB animals displayed an earlier onset of both mechanical and thermal hypersensitivity than their Nav1.8+/-:CB1RLOXTB or wildtype counterparts, suggesting a dual role for CB1R in inflammatory and neuropathic pain. These studies represent an important approach to further improve our mechanistic understanding of cannabinoid modulation of pain in the nervous system and begins to settle long-standing controversies in cannabinoid literature. Table of ContentsPeripherally restricted cannabinoids show strong preclinical analgesic efficacy but have not translated clinically. Using a genetic model restricting CB1R to Nav1.8-expressing sensory neurons, we show peripheral neuronal endocannabinoid signaling is required for chronic, but not acute pain modulation. This dissociation suggests clinical failures may reflect testing peripheral cannabinoids in acute rather than chronic pain paradigms, informing future translational strategies.

Emerging evidence suggests that cortical activity is organized in traveling waves that coordinate neural activity across space and time. How anesthesia alters these waves remains underexplored. We recently showed that cortical activity undergoes spontaneous state transitions at steady-state anesthetic concentrations including a paradoxical state exhibiting awake-like spectral properties during deep anesthesia. Here, we investigated traveling wave dynamics across spontaneous cortical states using hemispheric electrocorticography in rats anesthetized with desflurane at inhaled concentrations of 6, 4, 2, and 0%. Compared with the awake state, delta-band traveling waves in cortical states predominantly associated with 4-6% desflurane were more frequent and exhibited more stereotyped propagation patterns, characterized by a greater prevalence of planar waves and a corresponding reduction in source/sink wave patterns. The occurrence rate and pattern complexity of theta- and gamma-band waves remained largely unchanged, whereas the propagation direction of planar waves became more variable. Feedforward-feedback organization was also altered: compared with the awake state, the feedback-dominance of theta-band diminished, and the feed-forward dominance of gamma-band was attenuated. Despite occurring predominantly in deep anesthesia associated with behavioral unresponsiveness, traveling-wave dynamics of the paradoxical state exhibited partial, frequency-dependent shifts toward those observed in the awake state. These findings demonstrate that spontaneous cortical states under anesthesia are associated with frequency-dependent reorganization of cortical traveling waves and identify the paradoxical state as a distinct dynamical regime of deep anesthesia. Significance StatementAnesthesia is commonly thought to alter cortical dynamics progressively with increasing anesthetic depth, yet cortical activity can transition spontaneously between distinct states even at constant anesthetic concentrations. Here, we show that cortical states spectrally derived from the electrocorticogram of rats are associated with distinct frequency-specific organization of cortical traveling waves, revealing spatiotemporal dynamics beyond conventional spectral measures. Notably, a paradoxical state, occurred predominantly in deep anesthesia associated with behavioral unresponsiveness, exhibited traveling-wave dynamics that approached those observed during wakefulness. These findings demonstrate that cortical traveling-wave organization changes dynamically with brain state rather than anesthetic concentration alone. They suggest that structured cortical dynamics can emerge during deep anesthesia, providing new insights into large-scale cortical dynamics associated with anesthetic modulation of consciousness.

RationaleNeurogenic inflammation is recognised as an important contributor to the pathophysiology of Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS). Substance P (Sub P), a neuropeptide released from sensory nerves, is a potent inducer of mast cell degranulation through the Mas-related G protein-coupled receptor member X2 (MRGPRX2), resulting in the release of pro-inflammatory mediators that perpetuate chronic bladder inflammation. Medihoney, a medical-grade M[a]nuka honey, possesses well-established antimicrobial and anti-inflammatory properties, and we have recently demonstrated its ability to stabilise mast cells through inhibition of histamine release. However, its effects on Sub P-induced mast cell activation and MRGPRX2-mediated neurogenic inflammation have not previously been investigated. Aim of the studyWe aimed to investigate the inhibitory effects of Medihoney and a sugar-free M[a]nuka honey extract on Substance P-induced mast cell degranulation and MRGPRX2 activation as potential therapeutic approaches for chronic neurogenic inflammation associated with IC/BPS. In addition, we examined the expression of MRGPRX2 in bladder biopsies from patients with IC/BPS. Materials and methodsHuman LAD2 mast cells were stimulated with Substance P (1 M) for 40 minutes following 20-minute pre-incubation with Medihoney or a sugar-free M[a]nuka honey extract. Mast cell degranulation was quantified by measuring {beta}-hexosaminidase release. MRGPRX2 activation was assessed by intracellular calcium imaging using Fluo-4 in MRGPRX2-expressing HEK-293 cells. Bladder biopsies obtained from patients with IC/BPS and healthy controls were immunostained for mast cell tryptase, chymase and MRGPRX2. ResultsMedihoney at 2% and 4% markedly inhibited Substance P-induced mast cell degranulation in LAD2 cells by approximately 90%, an effect that was similarly observed with the sugar-free M[a]nuka honey extract. Both preparations produced a dose-dependent inhibition of Substance P-induced intracellular signalling in MRGPRX2-expressing HEK-293 cells, demonstrating suppression of MRGPRX2 activation. Furthermore, immunohistochemical analysis of bladder biopsies revealed that approximately 66% of tryptase-positive mast cells expressed MRGPRX2 in patients with IC/BPS, which was significantly higher than that observed in healthy control tissues (25%). ConclusionThe present study demonstrates that mast cells within IC/BPS bladder tissue express increased levels of MRGPRX2, suggesting enhanced responsiveness to Substance P and supporting a role for neurogenic inflammation in the pathophysiology of IC/BPS. Medihoney and the sugar-free M[a]nuka honey extract significantly inhibit Substance P-induced mast cell degranulation through modulation of MRGPRX2-mediated intracellular signalling, highlighting their potential as novel therapeutic agents for reducing neurogenic bladder inflammation associated with IC/BPS. ImpactThis study provides evidence that MRGPRX2-mediated neurogenic mast cell activation is enhanced in IC/BPS and demonstrates, for the first time, that Medihoney and a sugar-free M[a]nuka honey extract effectively inhibit Substance P-induced mast cell degranulation through modulation of MRGPRX2 signalling. These findings provide new mechanistic insight into the anti-inflammatory actions of M[a]nuka honey-derived preparations and identify MRGPRX2 as a potential therapeutic target in IC/BPS. The observed inhibition of neurogenic mast cell activation suggests that these naturally derived preparations may offer a novel strategy for limiting chronic bladder inflammation. Overall, this work provides a foundation for future preclinical and clinical studies evaluating the safety and therapeutic efficacy of Medihoney and M[a]nuka honey-derived compounds in patients with IC/BPS.

BackgroundThe integration of virtual reality (VR) and non-invasive brain stimulation (NIBS), particularly transcranial magnetic stimulation (TMS), represents a promising approach for closed-loop neuromodulation. Yet the concurrent application remains limited, partly due to insufficient characterization of hardware compatibility of head-mounted displays with standard TMS coil placement protocols. ObjectiveTo systematically quantify the coil-to-scalp distance constraints imposed by VR headsets across cortical targets and coil orientations and to determine feasible intensity compensation ranges based on stimulator output parameters. MethodsNeuronavigated coil positioning was performed on five anatomically realistic 3D-printed head models across 26 scalp positions in eight coil orientations based on the 10-10 EEG system and dorsolateral prefrontal cortex (DLPFC) using two VR headsets of notably different form factors (Meta Quest 2 and Bigscreen Beyond). The deviations of coil positions from intended targets were registered and quantified as coil-to-scalp distance displacement. Individual electric field (E-field) simulations were conducted in SimNIBS at the F3 position across 4-40 mm coil-to-scalp distance to characterize field decay and assess the limits of intensity compensation. ResultsBoth in the directed DLPFC targeting and in systematic scalp positions evaluation, the Meta Quest 2 headset substantially increased coil-to-scalp distance over prefrontal regions, exceeding the compensable range across all metrics. The Bigscreen Beyond headset produced significantly smaller coil-to-scalp distance displacement in prefrontal regions, remaining within feasible E-field intensity compensation limits. Single-pulse and iTBS protocols did not induce functional interference with the hardware under realistic targeting conditions. ConclusionVR headset geometry is the primary determinant of concurrent VR-TMS feasibility. The findings define practical quantitative hardware design requirements and boundaries for future integrated VR-TMS systems and provide a practical framework for optimizing existing VR-TMS protocols.

The sodium leak channel NALCN regulates resting membrane potential and spontaneous firing in neurons and can be modulated by G-protein coupled receptors (GPCRs). Whether metabotropic glutamate receptors (mGluRs) modulate NALCN is unknown and would represent a novel mechanism through which glutamate could affect neuronal excitability. Here we examine NALCN function and modulation by mGluRs in cerebellar unipolar brush cells (UBCs) in mouse brain slices. Activation of group II mGluRs inhibited the NALCN current through a G protein-dependent mechanism, as the effect was abolished by intracellular GDP-{beta}-S and by NALCN deletion. The OFF UBC subtype that is inhibited by glutamate had a larger NALCN current than the ON UBC subtype that is excited by glutamate. OFF UBCs also had a tonic NALCN current that was absent in ON UBCs. Genetic deletion of NALCN converted the regular spontaneous firing pattern of OFF UBCs, to an irregular pattern similar to that of ON UBCs, suggesting that a tonic NALCN current may be a general mechanism to promote regular firing. Additionally, we identify the presence of group III mGluRs in OFF UBCs and GABA-B receptors in ON UBCs and show that neither inhibit NALCN, demonstrating that different GPCRs engage distinct downstream ion channels. These findings identify a previously unrecognized form of glutamatergic synaptic inhibition that is selectively initiated by group II mGluRs, but not other Gi/o-coupled GPCRs, within the same neurons.

Background: The primary neuroanatomical site of Huntington-s disease (HD) pathology resides in the striatum and its atrophy identifies important disease progression from HD-ISS Stage 0 to Stage 1. Immune-associated proteins may capture variation in HD that is incompletely represented by markers of neuroaxonal injury. Objectives: To determine whether cerebrospinal-fluid myeloperoxidase contributes information about striatal volume loss beyond genetic disease burden and neurofilament light. Methods: Cross-sectional data from 88 persons with HD were analyzed. Cerebrospinal-fluid myeloperoxidase and neurofilament light were measured with a nucleic acid-linked immunosandwich assay. Normalized putamen volume was derived from structural magnetic resonance imaging. Linear regression adjusted for genetic disease burden and sex. Results: Higher neurofilament light was associated with smaller normalized putamen volume (standardized {beta} = -0.322, (P=.0066)). Higher myeloperoxidase was associated with larger normalized putamen volume after adjustment for genetic disease burden, sex, and neurofilament light (standardized {beta} = 0.183, (P=.0386)). Adding myeloperoxidase increased explained variance in striatal loss. Conclusions: Cerebrospinal fluid myeloperoxidase contributed modest incremental information about striatal volume in this cross-sectional sample. Independent longitudinal studies are needed to determine its biological source, temporal behavior, and potential biomarker value. Findings advance efforts to characterize multicomponent biological markers of HD.

Physiological mirror activity (pMA) is the increase in involuntary muscle activity observed on the contralateral side during unilateral voluntary movement in neurologically healthy participants. This cross-sectional study aimed to explore the relationship between pMA and corticomuscular coherence (CMC) during finger dexterity tasks in young and older adults. Thirty-one right-handed young adults and 24 older adults performed a left-hand finger dexterity task. Electroencephalogram (EEG) signals were recorded from C3 and C4, and electromyogram (EMG) signals were collected from bilateral finger flexors and extensors. pMA was quantified as the change in right-hand EMG from rest to task. Gamma-band CMC was calculated from task-related EEG-EMG pairs, and its association with pMA was analyzed. In young adults, greater pMA was associated with lower CMC (C3- and C4-right flexors), whereas in older adults, greater pMA was associated with higher CMC (C3-left flexor). Young adults may suppress pMA emergence by appropriately monitoring and inhibiting activity, in the hand not performing the task. Conversely, in older adults, the mobilization of the ipsilateral motor cortex may have contributed to pMA emergence. This study suggests that the neuromuscular mechanisms involved in pMA during finger dexterity tasks differ between young and older adults.

Cueing paradigms are commonly used to study the neural mechanisms of visual spatial attention control. In these paradigms, each trial starts with an external cue, which instructs the subject to pay covert attention to a spatial location in anticipation of an impending stimulus (instructed attention). Recent work has introduced a new type of cue which prompts the subject to spontaneously decide which spatial location to attend (willed attention). We studied the neural mechanisms of willed attention control by analyzing fMRI and EEG data recorded at two institutions (UF and UC Davis) using the same willed attention paradigm. The findings include: (1) both instructional cues and the choice cue activated the DAN, (2) the choice cue additionally activated a frontoparietal decision network consisting of dorsal anterior cingulate cortex (dACC), anterior insula (AI), anterior prefrontal cortex (APFC), dorsal lateral prefrontal cortex (DLPFC), and inferior parietal lobule (IPL), (3) the decision about where to attend can be decoded in frontoparietal decision network in choice trials but not in instructional trials, and (4) EEG alpha oscillation patterns immediately preceding the choice cue, but not the instructional cues, predicted the postcue direction of attention and the frontoparietal decision network activity. Based on these findings we proposed a model of willed attention control suggesting how the direction of visual spatial attention was decided upon in the absence of external instructions.

Background: Brain banks usually provide small tissue blocks fixed by immersion in neutral-buffered formalin (NBF). While still underexploited for research, gross anatomy laboratories could provide full brains fixed by perfusion with solutions better suited for gross anatomy dissection. However, the chemicals in these solutions might have a different impact on histology protocols for cell quantification than in NBF-fixed brains. The main goal of this study is to compare the effects on the number and size of labeled neurons of the primary motor cortex (PMC) of mouse brains fixed with three different solutions: (1) NBF, typical of brain banks, (2) a saturated salt solution (SSS), and (3) an alcohol-formaldehyde solution (AFS), both used in human anatomy laboratories. Methods: 27 C57BL/6J mouse brains were perfused with the NBF (N=9), SSS (N=9) or AFS (N=9), then cut in 40-m slices and processed with immunohistochemistry to target neurons. Various quantitative variables were assessed manually and automatically on photomicrographs of 3 regions of interest (ROIs) of the PMC per specimen, namely the total and individual neuronal profile areas, number and diameters. The effects of the three fixatives on these variables were compared using ANOVA or Kruskal-Wallis, depending on the distribution. For measures on individual cells, a generalized linear mixed model was applied. Dice coefficients and correlations were applied to evaluate the agreement of the manual and automatic methods. Results: There was no significant difference between the brains fixed by the three fixatives for the total and individual cell areas, the total cell count and the cell diameters. The values obtained from manual and automatic measures had an overall good agreement (Dice coefficients > 0.79). Conclusion: It was found that the SSS and AFS had similar impacts on the quantitative variables in the tissue as the NBF. These results are promising for neuroscientists interested in using brains from anatomy laboratories for quantitative research on neurons from the PMC.

Recognizing others emotions is central to social interaction. Traditional biological psychology infers emotional responding via laboratory measures, whereas contemporary computer vision algorithms claim to identify emotions unobtrusively from facial video. However, the validity of such algorithms for classifying spontaneous emotional responses occurring without explicit communicative intent remains debated. We compared established psychophysiological measures (EEG, facial EMG, EDA activity) with the open-source facial behavior toolkit OpenFace for classifying participants spontaneous responses during free viewing of happiness-inducing, disgust-inducing, and neutral pictures. Participants provided valence and arousal ratings and later selected the basic emotion that best matched their reaction which served as the classification criterion. Using within-participants single-trial support vector machine (SVM) classification, EEG achieved the highest accuracy (40%), followed by facial EMG (37%); OpenFace reached 36%. All methods except EDA exceeded chance performance (33.3%) and were lower compared to human raters (48%). Predictions declined slightly for across-participants SVMs, being at chance for OpenFace and EDA. The results indicate that in principle both, psychophysiological measures and video-derived facial action units, can capture diagnostically relevant aspects of emotional responding during picture viewing, but that their performance is limited when expressions are spontaneous and not produced for communicative purposes. Inter-individual variability in expressivity and physiological responding likely contributes to these limitations and should be considered when deploying automatic emotion recognition in research or applied settings.

Past studies using transcranial magnetic stimulation have shown larger motor-evoked potentials when people observe someone lifting a heavy object than when they observe someone lifting a light one. This means that observers may engage their own motor system in proportion to the perceived effort. However, the different responses during the observation of light and heavy objects may have been influenced by predictable trial sequences within blocked presentation, making it unclear whether corticospinal excitability reflects online processing of kinematics or is affected by top-down expectations. In this Registered Report, 57 right-handed participants passively observed videos of a precision grip and lift of heavy and light objects while receiving a single-pulse TMS to the left primary motor cortex during the lift phase of the movement. Motor-evoked potentials were recorded from the right first dorsal interosseous muscle. The study compared two main observation contexts: a predictable trial sequence in which repeated videos of the same lifts were presented in a blocked order, and an unpredictable one in which videos were presented semi-randomly and participants could rely only on kinematic cues to perceive the weight of the lifted object. In both conditions, the same videos of lifts of equivalent-looking heavy and light objects were used and only the order of presentation differed. Contrary to our predictions, in the blocked (predictable) condition, there was no significant difference in MEPs elicited by light and heavy lifts. In the unpredictable condition, participants showed greater corticospinal excitability during the observation of the light lifts compared to the heavy lifts. This suggests that in the absence of predictable information, the corticospinal system was sensitive to the observed kinematics, but contrary to previous findings, its excitability varied inversely with the object weight.