Clinical Neurophysiology

Genetic deletion or pharmacological blockade of P2X7 receptors (Rs) counteract status epilepticus (SE) in animal models of epilepsy. It is, however, unclear whether P2X7Rs are localized at astrocytes or neurons, and the reason for astrocytic atrophy arising in consequence of SE is also ambiguous. We conducted a combined morphological/electrophysiological study in order to investigate these issues. It has been shown that kainic acid (KA)-induced SE in mice led to the atrophy of hippocampal astrocytes and at the same time to the decrease of ezrin immunoreactivity and its co-expression with mCherry, whose synthesis has been initiated by the injection of a virus complex. mCherry expression in astrocytes enabled us to study changes in cell somata and processes brought about by KA-injection. Ezrin is a plasmalemmal-cytoskeleton linker; its grade of expression indicates changes in the existence/function of small peripheral astrocytic processes. Pretreatment of mice with the blood-brain barrier-permeable P2X7R antagonist JNJ-47965567 prevented the SE-induced damage of astrocytes. KA caused a potentiation of dibenzoyl-ATP (Bz-ATP) currents in astrocytes but not neurons of the hippocampus. This effect was also abolished by pre-treatment of mice with JNJ-47965567 before applying KA, although no similar changes occurred in hippocampal CA1 neurons. The measurement of spontaneous postsynaptic currents (sPSCs) and spontaneous excitatory postsynaptic currents (sEPSCs) indicated a presynaptic facilitation of neurotransmitter release by Bz-ATP. In conclusion, we suggest that astrocytic P2X7Rs are the primary target of ATP release from damaged CNS cells in the hippocampus which simultaneously causes damage to astrocytic somata and processes.

Short-interval intracortical inhibition (SICI) is the most widely used neurophysiological index of GABAergic inhibition in the human cortex. However, it is an indirect measure, inferring synaptic inhibition from suppression of peripherally recorded motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS). In the standard protocol, a subthreshold conditioning pulse suppresses the MEP evoked by a suprathreshold test pulse delivered 1-5 ms later. Interpretation is further complicated by temporal overlap with short-interval intracortical facilitation (SICF), reflecting excitatory interactions at interstimulus intervals of [~]1.5 and 2.7 ms. To overcome these limitations, we recorded immediate TMS-evoked EEG potentials (iTEPs; 1-10 ms post-stimulus) as a more direct measure of motor cortical activity in 16 healthy volunteers (20-35 years; 7 male). The conventional SICI protocol suppressed only later components of the iTEP, likely corresponding to late corticospinal volleys previously identified in epidural spinal recordings after suprathreshold TMS, while the earliest iTEP component was unaffected. Importantly, later iTEPs were suppressed to a similar extent whether conditioning-test intervals coincided with SICF peaks or troughs, and the magnitude of iTEP suppression correlated with concurrently recorded paired-pulse MEP suppression. SICI also reduced an early TEP component (N15; 10-20 ms), but paired-pulse N15 suppression showed a different dependence on stimulus intensity and did not correlate with MEP suppression. These findings demonstrate that SICI measured via MEPs does not reflect a global index of cortical GABAergic motor cortical inhibition but instead reflects inhibition within specific cortical circuits that can be investigated directly with iTEPs.

BackgroundDistinguishing epilepsy from functional/dissociative seizures (FDS) is an ongoing diagnostic challenge. Misdiagnosis delays appropriate treatment and puts patients at significant risk. Quantitative analyses of clinical EEG offer a potential avenue for developing decision-support tools in the diagnosis of seizure disorders. Recent work using univariate features demonstrated that reliably identifying diagnostic traits in the presence of confounding factors remains challenging. However, diagnostic information might be available in multivariate features such as network-based measures. Using a well-controlled dataset, we run the first diagnostic accuracy study assessing the potential of multivariate resting-state EEG markers to directly discriminate between a diagnosis of epilepsy and one of FDS at the time when a diagnosis is suspected and prior to treatment initiation. MethodsThe dataset, previously examined in a published study, includes 148 age- and sex-matched individuals with suspected seizure disorders who were later diagnosed with non-lesional epilepsy (n=75) or FDS (n=73). Eyes-closed, resting-state EEG data used for the analyses were normal on visual inspection, and acquired while participants were medication-free. Functional network measures in the 6-9 Hz range were extracted and machine learning implemented to assess their predictive potential; different model configurations (including varying model types, dimensionality reduction methods, and approaches to enhance feature stability) were tested to identify the most promising approach for future translational implementations. ResultsNetwork measures derived from resting-state EEG discriminate between conditions at levels significantly above chance (maximum balanced accuracy: 67.5%). Their sensitivity to epilepsy (81.8%) is consistently higher than their sensitivity to FDS (53.3%). A systematic assessment of model choices indicates that improving the temporal stability of network features through epoch-wise averaging improves classification accuracy (62.6% to 67.5%). Multiple nonlinear model types succeed on the classification problem, with the three-best performing assigning a consistent diagnostic label to 77.5% of the individuals; however, model choice remains a strong determinant of overall classification accuracy. Dimensionality reduction did not provide a significant advantage in our models. ConclusionWe establish evidence for the clinical validity of selected network-based markers to discriminate between a diagnosis of non-lesional epilepsy and FDS prior to treatment initiation, highlighting the measures potential to support post-test probability estimation in the clinic. Our models, configured to optimise balanced accuracy, classified people with epilepsy more accurately than people with FDS, indicating that these measures are specific to epilepsy and should not be interpreted as markers of a positive diagnosis of FDS.

Objective: Electrical brain stimulations (EBS) are central to epileptic network identification and functional mapping during stereo-electroencephalography (SEEG), yet stimulation frequencies remain empirical, and standardized across patients and brain regions, producing false negatives and false positives, and potentially compromising surgical outcome. We investigated theta-range EBS (7 Hz) in the temporal lobe, a prominent physiological frequency band in this region, and compared it with conventional 1-Hz and 50-Hz protocols. Methods: We analyzed 1,408 temporal EBS in 25 patients with drug-resistant epilepsy. Epileptic responses (afterdischarges, seizures) and clinical signs were assessed across the epileptic network and temporal structures (amygdala, hippocampus, neocortex, parahippocampal gyrus, white matter), and analyzed according to stimulation parameters (frequency, intensity, duration, total charge). Results: At matched intensity and duration, 7-Hz EBS were associated with a higher occurrence of afterdischarges and clinical signs than 1-Hz EBS in several temporal structures (e.g., parahippocampal epileptogenic zone: p=0.014). Effects on usual seizure induction were less consistent. Comparisons with 50 Hz showed no systematic significant differences, with responses observed at one or both frequencies depending on structure and outcome. When controlling for total charge, frequency-related differences were attenuated. Some effects were sporadically observed at both intermediate frequency and charge quantity. No adverse events occured. Significance: Theta-range stimulation modulates electrophysiological and clinical responses during SEEG mapping and may provide complementary information to conventional frequencies. These findings support exploring a broader range of stimulation frequencies, rather than relying solely on standard protocols.

BackgroundAccumulating results suggest that reticulospinal tract (RST) excitability increases after stroke. While animal studies suggest this hyperexcitability may compensate for corticospinal tract (CST) damage, its role in motor function in people with stroke (PwS) remains debated. This study aimed to: (1) replicate findings of RST hyperexcitability in PwS using the StartReact paradigm, measuring acceleration of motor response to a startling auditory stimulus; (2) examine the relationship between RST hyperexcitability and motor impairments after stroke; and (3) explore whether RST hyperexcitability provides functional benefits in severely impaired PwS. MethodsForty-six PwS completed the StartReact paradigm and motor assessments (Fugl-Meyer, ARAT, grip strength, Modified Ashworth Scale). PwS were categorized into high StartReact effect and typical StartReact effect subgroups based on comparisons with a healthy control group (n=37). Severe impairment was defined as ARAT [≤]10. ResultsPwS exhibited significantly greater StartReact effects than controls. The high StartReact effect subgroup showed worse motor function, weaker grip strength, and higher spasticity. Among severely impaired PwS, high StartReact effect was not associated with improved grip strength. ConclusionsThese findings confirm the existence of RST hyperexcitability after stroke and suggest it is associated with poorer motor outcomes, likely due to reduced cortical input to the brainstem. The absence of functional benefit in severely impaired individuals supports the interpretation that RST hyperexcitability is a maladaptive rather than a compensatory reaction to brain damage. These findings provide insight into the neurophysiological mechanisms underlying motor impairments after stroke and do no imply direct clinical or therapeutic applications.

BackgroundRespiration is a key central nervous system rhythm that modulates sensorimotor function in healthy individuals, but the neurophysiological mechanisms of volitional breathing-mediated sensorimotor modulation and its preservation in stroke patients remain unclear. This study aimed to characterize the effects of volitional fast inspiration on sensorimotor pathway excitability in healthy and stroke populations, and provide a mechanistic basis for respiratory-integrated post-stroke rehabilitation. MethodsA multimodal case-control neurophysiology study was conducted in 52 healthy volunteers (26 {+/-} 3 years, 30 males) and 44 first-ever subacute stroke patients (66 {+/-} 10 years, 30 males). Three complementary experiments assessed transcranial magnetic stimulation-induced motor-evoked potentials (MEPs), peripheral nerve stimulation-induced somatosensory-evoked potentials (SEPs), and functional electrical stimulation -evoked muscle force under three breathing conditions: volitional fast inspiration (IN), fast expiration (EX), and spontaneous breathing (CON). Two-way and one-way repeated measures ANOVA with Bonferroni post hoc tests were used for statistical analysis. ResultsVolitional fast inspiration significantly enhanced sensorimotor pathway excitability and muscle force generation in both groups. Volitional fast inspiration increased MEP amplitudes relative to spontaneous breathing and fast expiration (p {inverted exclamation} 0.05), with further amplification during active muscle contraction (p {inverted exclamation} 0.05). It also elevated SEP amplitudes in healthy parietal/frontal cortical regions and the stroke parietal cortex (p {inverted exclamation} 0.05). Synchronizing volitional fast inspiration with voluntary finger contraction increased muscle force evoked by functional electrical stimulation by 16-18% relative to spontaneous breathing (p {inverted exclamation} 0.05), with non-significant force gains at rest. ConclusionsVolitional fast inspiration bidirectionally enhances corticospinal transmission, somatosensory integration, and functional force generation in both healthy individuals and stroke patients, with preserved respiratory modulation in stroke-damaged neuropathways. By demonstrating preserved respiratory modulation in stroke-damaged neuropathways, our results provide mechanistic support for integrating controlled breathing into low-cost, non-invasive post-stroke rehabilitation paradigms.

Structured AbstractO_ST_ABSBackgroundC_ST_ABSAtrial fibrillation (AF) is maintained by complex dynamics, clinically characterised by bursting periods of organization and disorganization in intracardiac electrograms. We have previously postulated that cardiac conduction behaves like a critical system, where phase shift from organised rhythm to AF is a phase transition at the critical point. We thus hypothesized that using multifractal analysis of AF electrograms could potentially quantify non-stationary fluctuations, revealing novel mechanistic insights into the cardiac critical system and examine potential clinically relevant markers of AF dynamics, phenotype and treatment response. ObjectivesTo determine whether multifractal analysis of AF electrograms can (i) Distinguish paroxysmal (PAF0 and non-paroxysmal AF (NPAF), (ii) predict response to pharmacologic modulation, and (iii) identify imminent spontaneous termination, thereby acting as marker of proximity to criticality along complex system phase spectrum. MethodsWe analysed >1.4 million seconds of high-density bipolar electrograms from 106 patients (paroxysmal n{approx}52, non-paroxysmal n{approx}54) undergoing left atrial mapping with a 24-bipole HD-Grid catheter at standardized sites (RENEWAL AF-ANZCTR ACTRN12619001172190)). Multifractal analysis using the Wavelet Transform Modulus Maxima Method (WTMM) was applied to a burst-energy observable to derive log-normal multifractal parameters c (support dimension), c (spectrum location), and c2 (fluctuations). Hierarchical mixed-effects models accounted for channels nested within locations within patients. A flecainide sub-study (n=15) provided paired pre-/post-infusion recordings, and 27 spontaneous termination events in 15 patients were analysed using 60-s pre-termination windows. Spatial texture of c2 was quantified by variogram-derived correlation length and sill. ResultsAF electrograms exhibited robust multifractality confirming multifractal fluctuations as an intrinsic property of AF. Non-paroxysmal AF showed significantly reduced fluctuations versus paroxysmal AF (c2: {beta}=-0.01, p=0.001), indicating a paradoxical loss of fluctuations with disease progression. Flecainide selectively increased fluctuations in paroxysmal AF ({Delta}c2 = +0.04, p<0.01; {Delta}c = +0.06, p<0.01) but had no significant effect on fluctuations (c2) in non-paroxysmal AF, revealing phenotype-dependent drug response. Immediately prior to spontaneous AF termination, fluctuations increased significantly compared with sustained AF (c2: 0.198 vs 0.181, p=0.024). Spatial variogram analysis revealed heterogenous patterns in paroxysmal AF, whereas non-paroxysmal AF displayed a homogenised, flattened fluctuations landscape. ConclusionsAtrial fibrillation exhibits robust multifractal dynamics rather than random electrical activity. Reduced fluctuations characterizes non-paroxysmal AF, whereas higher fluctuations is observed in paroxysmal AF, during flecainide modulation, and immediately prior to spontaneous termination. These findings suggest that multifractal fluctuations (c2) reflects the dynamical state of AF and may serve as a quantitative biomarker of disease progression, pharmacologic responsiveness, and proximity to termination. CONDENSED ABSTRACTTAtrial fibrillation (AF) exhibits multifractal electrogram fluctuations that vary with disease stage, pharmacologic responsiveness, and proximity to spontaneous termination. In this study, multifractal fluctuations (c2) was higher in paroxysmal than non-paroxysmal AF, increased selectively with flecainide in paroxysmal AF, and rose immediately before spontaneous termination. These findings identify c2 as a quantitative marker of AF progression, and imminent reorganization. Clinically, multifractal analysis may enhance intra-procedural assessment of AF phenotype, guide drug selection, and improve recognition of transitions toward sinus rhythm, and connects AF with concepts of criticality and phase transitions.

Background: Spinal cord injury (SCI) is associated with widespread reorganisation of cortical sensorimotor circuits. Persistent complications such as spasticity and neuropathic pain suggest that homeostatic plasticity, which normally helps stabilise and constrain activity-dependent changes in sensorimotor circuits, may be disrupted after SCI. Homeostatic plasticity can be probed using repeated blocks of transcranial direct current stimulation (tDCS); in healthy individuals, two closely spaced excitatory blocks typically leads to an inhibitory response, reflected as a reduction in corticomotor excitability. Objective: To determine whether individuals with SCI show reduced homeostatic suppression of corticospinal excitability in response to repeated anodal tDCS, compared with healthy controls. Methods: Twenty adults with thoracic or below SCI and 20 healthy controls completed three counterbalanced sessions. Each session comprised two 10-minute blocks of 2 mA tDCS separated by 5 minutes, with the second block always being anodal tDCS over left primary motor cortex. The first block was either anodal, cathodal, or sham tDCS, yielding 3 condition types: anodal-anodal, cathodal-anodal, and sham-anodal. To assess corticomotor excitability, transcranial magnetic stimulation-evoked motor evoked potentials (MEPs) were elicited at baseline, after priming, and every 5 minutes for 60 minutes after the second block. The primary outcome was percent change in MEP amplitude from baseline. Results: In the anodal-anodal condition, the SCI group showed greater facilitation than controls over 0-30 minutes (estimate = 83.09, 95% CI 49.75 to 116.43, p < 0.001), suggestive of a weaker homeostatic response. The cathodal-anodal condition led to a significant overall facilitatory effect with no between-group difference, while the sham-anodal condition showed no change in MEP amplitude relative to baseline. Within the SCI group, exploratory subgroup analysis suggests that those with neuropathic pain and a traumatic injury showed greater facilitation in the anodal-anodal condition than those without these features, indicative of a weaker homeostatic response. Conclusions: SCI is associated with impairment in the homeostatic regulation of corticomotor excitability following repeated excitatory brain stimulation. Disrupted plasticity stabilisation may be relevant to persistent symptoms such as neuropathic pain.

Parkinson's Disease (PD) is a complex neurodegenerative disorder that manifests through systemic, large-scale physiological reorganizations. While research often focuses on region-specific neural changes, there is a growing need for multidomain approaches to capture the complexity of the disease and its clinical heterogeneity. This study proposes an analytical pipeline to evaluate Brain-Heart Interplay (BHI) as a novel systemic biomarker for neurodegeneration and healthy ageing. In this study we assessed BHI across three open-source datasets (EEG and ECG signals). We compared Healthy Young, Healthy Elderly, and PD patients in resting state to investigate the effects of ageing and cognitive performance. Additionally, we studied BHI trends in PD patients in the moment of freezing of gait (FOG). Methodologically, brain network organization was quantified using coherence-based EEG connectivity and graph theory, while heart activity was analyzed through Poincare plot-derived measures of cardiac autonomic activity. The coupling between these two systems was measured using the Maximal Information Coefficient to capture linear and non-linear dependencies between global cortical organization and cardiac autonomic outflow. The results demonstrate that BHI is a sensitive biomarker for detecting early multisystem dysfunction in both neurodegeneration and ageing. Furthermore, the identification of specific BHI trends during FOG onset suggests new opportunities for understanding the physiological mechanisms driving motor complications in PD. Our proposed pipeline provides a guiding tool for large-scale physiological assessment in clinical research.

1.PurposeSYNGAP1-related developmental and epileptic encephalopathy (SYNGAP1-DEE) is characterized by high rates of both epilepsy and autism spectrum disorder (ASD). While the clinical spectrum is well-documented, the link between specific seizure semiologies and caregiver-reported autistic behaviors is not well understood. This study analyzed the correlation between ten distinct seizure types, their frequencies, and a caregiver-reported autistic behavior score. MethodClinical data were extracted from the PATRE (PATient-based phenotyping and evaluation of therapy for Rare Epilepsies) Registry for SYNGAP1, in the framework of the EURAS project (Grant No. 101080580, Horizon Europe). This study employed a retrospective cross-sectional analysis of caregiver-reported registry data. Analysis was restricted to an analytic cohort of N=337 participants with complete data for both the epilepsy questionnaire (including epilepsy status, seizure semiology, and peak seizure frequency items) and the behavior questionnaire (from a total N=522 registry participants). Caregiver-reported autistic behaviors were quantified using a standardized caregiver-reported scale (Likert 1-5). Statistical associations were evaluated using the Wilcoxon rank-sum test to compare caregiver-reported autistic behavior scores across different seizure semiologies and Spearmans rank correlation to assess the impact of seizure frequency (9-point scale). ResultsWithin the analytic cohort (N=337), epilepsy was reported in 259 patients. Eyelid myoclonia was the most prevalent semiology, affecting 64.9% (n=168) of the epilepsy-positive group. Atypical absences (n=77) demonstrated the most profound and statistically robust association with higher caregiver-reported autistic behavior scores (FDR-adjusted p = 0.001). Significant associations were also observed for typical absences (n=70, FDR-adjusted p = 0.018), eyelid myoclonia (FDR-adjusted p = 0.018), myoclonic-atonic seizures (n=40, FDR-adjusted p = 0.019), and atonic seizures (n=72, FDR-adjusted p = 0.025). Focal and tonic-clonic seizures showed weaker associations (FDR-adjusted p = 0.026 and p = 0.047, respectively). Crucially, quantitative analysis revealed no significant correlation between ordinal caregiver-reported peak seizure frequency ratings and caregiver-reported autistic behavior scores across all semiologies (e.g., Eyelid Myoclonia: p=0.096; Atypical Absences: p=0.744), indicating no detectable association between peak-frequency ratings and caregiver-reported autistic behavior scores. ConclusionHigher caregiver-reported autistic behavior scores in SYNGAP1-DEE were most strongly associated with the presence of atypical absences, representing a generalized, thalamocortical seizure network dysfunction. In contrast, no detectable association was observed between caregiver-reported autistic behavior scores and the ordinal caregiver-reported peak seizure frequency metric. Atypical absences and related semiologies may serve as clinical "red flags" for increased neurodevelopmental comorbidity severity, regardless of reported peak seizure frequency. Abstract SummaryThis study investigates the relationship between ten seizure semiologies, seizure frequency, and severity of caregiver-reported autistic behaviors in a large-scale international cohort of N=337 patients with SYNGAP1-DEE. We identify a robust association between elevated caregiverreported autistic behavior scores and specific thalamocortical seizure patterns, most prominently atypical absences. Notably, our analysis reveals that this association is independent of seizure frequency, demonstrating no detectable association between this ordinal, caregiver-reported seizure frequency metric and caregiver-reported autistic behaviors.

Both episodic memory and word retrieval have been linked to power decreases in the alpha and beta oscillatory bands, but these patterns have rarely been related to each other, partly due to a lack of methodological approaches available. In this explorative study, we investigate the similarities and dissimilarities in the oscillatory fingerprints of the retrieval of words and episodes by directly comparing the activity patterns across time, frequency, and space. We acquired electroencephalography (EEG) data of participants performing a language and an episodic memory task based on the same stimulus material. With a newly developed approach, we directly compared the source-reconstructed oscillatory activity using mutual information and a feature-impact analysis. While left temporal and frontal regions showed dissimilarities between the tasks, right-hemispheric parietal regions exhibited similarities. We speculate that this could indicate a homologous function of these regions, potentially sharing less-specific representations between the tasks. We further uncovered a dissociation of the alpha and beta bands regarding the similarity across tasks. While the beta band was dissimilar between word and episodic memory retrieval, the alpha band seemed to contribute to the similarity we observed in right parietal regions. Whether this points to a task-unspecific function of the alpha band or a functional role in the retrieval process of the presumed representations, remains to be determined. In summary, we present an approach to study similarity across tasks using the temporal, spectral, and spatial dimensions of EEG data, and present results of exploring the shared oscillatory fingerprints between episodic memory and word retrieval.

BackgroundTourette Syndrome (TS) is a neurodevelopmental movement disorder involving involuntary motor and vocal tics believed to be characterised by disordered neural inhibition. Cortical representations have previously been manipulated by disruptions in the inhibitory neurotransmitter {gamma}-aminobutyric acid (GABA). However, while facial tics are the most reported motor tic, it is unclear if facial sensorimotor representations differ in TS. MethodsSixteen individuals with Tourette Syndrome (TS) or chronic tic disorder and twenty typically developing (TD) control participants underwent 3-Tesla functional magnetic resonance imaging (fMRI). Blood-oxygenation level-dependent (BOLD) responses were measured during a block-design task comprising cued facial movements of common facial tics (blinking, grimacing and jaw clenching). Activations in bilateral pre- and post-central cortices and supplementary motor areas (SMA) were examined. Conjunction analyses identified voxels commonly and uniquely activated across movements within each group. ResultsBoth groups showed significant activations in the bilateral sensorimotor cortices and SMA in response to blink, grimace and jaw clench movements, with no significant between-group differences. Between-group similarities were lowest for unique blink maps. Common voxel maps also revealed low between-group similarity, with reduced sensorimotor activation and no shared SMA activation across movements in the TS group. ConclusionVoluntary facial sensorimotor representations do not differ between groups. However, low similarities between group unique blink maps may reflect greater prevalence of blinking tics in TS. Additionally, reduced overlap in sensorimotor activation and absent common SMA engagement across cued movements in the TS group may indicate altered motor integration or action initiation.

Atypical sensory experiences are highly prevalent in autistic children and include both hyper- and hypo-responsivity, often accompanied by sensory overload. Alpha oscillations (7-13 Hz), which dynamically regulate cortical excitability, represent a plausible neural mechanism underlying these phenomena: reduced alpha activity is associated with enhanced sensory responsiveness, whereas increased alpha supports suppression of external input. Although decreased alpha power has been repeatedly reported in autism, it remains unclear whether this reduction reflects lower oscillatory amplitude or reduced temporal stability of alpha rhythms, two mechanisms with distinct neurophysiological implications. To better characterize alpha activity in autism, we examined resting-state alpha dynamics in non-autistic children (NA; n = 39), autistic children (AU; n = 52), and siblings of autistic children (SIB; n = 26), aged 8-14 years. We combined traditional broadband measures of relative alpha power, parametric separation of periodic and aperiodic activity, and single-event analyses that quantify the temporal structure of alpha oscillations. Both broadband relative alpha power and periodic alpha power were reduced in autism over parietal regions, replicating prior findings. Importantly, ordinal analyses revealed an intermediate profile in siblings, supporting a liability-related gradient of alpha alterations. However, single-event analyses demonstrated that the average amplitude of individual alpha bursts did not differ between groups. Instead, autistic children showed significantly shorter alpha burst duration and reduced alpha abundance (i.e., proportion of time occupied by rhythmic alpha episodes), with siblings again exhibiting intermediate values. Linear regression analyses confirmed that reductions in relative and periodic alpha power were primarily driven by decreased alpha abundance rather than diminished burst amplitude. These findings indicate that altered alpha activity in autism reflects reduced temporal stability and density of alpha events rather than weaker oscillatory amplitude per se. Reduced persistence of alpha rhythms may therefore represent a neural marker of altered cortical excitability and sensory regulation in autism. Lay summaryAutistic children often experience the world differently at the sensory level, including being more easily overwhelmed by sounds, lights, or other stimuli. In this study, we looked at a type of brain activity called alpha rhythms, which help regulate how strongly the brain responds to incoming information. We found that, in autistic children, these alpha rhythms were not weaker when they occurred, but they lasted for a shorter time and happened less often. Siblings of autistic children showed an intermediate pattern. These results suggest that sensory differences in autism may be linked to less stable brain rhythms that normally help control sensory input. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=158 SRC="FIGDIR/small/716324v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1be733dorg.highwire.dtl.DTLVardef@7fea49org.highwire.dtl.DTLVardef@1ee9124org.highwire.dtl.DTLVardef@17af139_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundTranscranial Magnetic Stimulation (TMS) studies identify the Resting Motor Threshold (RMT) to calibrate stimulation intensity. However, this procedure is time-consuming and subject to variability. We developed an automated procedure to improve the efficiency and standardization of RMT determination. New methodWe developed an algorithm that measures MEP amplitudes and automatically adjusts stimulation intensity to determine the RMT. Experiment 1 compared this automated method with the manual procedure in terms of reliability and equivalence. Experiment 2 developed a "Fast" automated process, assessing it against both the manual and initial automated procedures. ResultsAcross both experiments the automated approach demonstrated excellent test-retest reliability and strong agreement with the manual method (Intraclass Correlation Coefficients [&ge;]0.95), giving estimates of RMT statistically equivalent to those of manual measurements within {+/-}3% MSO, with the majority of comparisons within {+/-}2% MSO. Experiment 2 optimized the procedure, allowing empirical determination of the RMT in an average of <3 minutes with only 33-34 pulses. Comparison with existing methods RMT-Finder provides a reliable and time-efficient alternative to manual approaches. To the best of our knowledge RMT-Finder presents the first closed-loop feedback approach to identify the RMT without manual intervention. This procedure can improve standardization and reproducibility in TMS studies. ConclusionsAutomating RMT assessment allows rapid and highly reproducible assessment of this standard TMS measurement, making it viable for inclusion in routine clinical applications that require standardized procedures.

ImportanceEpilepsy is one of the most common neurological disorders globally. A significant proportion of patients fail to achieve effective seizure control with medication and ultimately develop drug-resistant epilepsy, particularly mesial temporal lobe epilepsy (MTLE). While surgical resection and laser interstitial thermal therapy (LITT) are effective treatments for drug-resistant MTLE, these procedures may be associated with severe adverse events. In contrast, allogeneic induced pluripotent stem cell (iPSC)-based therapy is expected to offer a novel, potentially safer therapeutic approach with fewer side effects for patients with drug-resistant MTLE. ObjectiveTo evaluate the safety and preliminary efficacy of a single intracranial injection of ALC05 (iPSC-derived GABAergic interneurons) in patients with unilateral MTLE, and to assess the therapeutic effects of different dosage levels. Design, Setting, and ParticipantsThis single-center, randomized, double-blind, Phase 1 clinical trial will enroll 12 subjects with unilateral MTLE. All subjects will be randomly assigned to either the low-dose or high-dose group in a 1:1 ratio. To minimize risks at each dose level, the first subject in each dose group will be monitored for safety for at least 3 months following ALC05 injection and must demonstrate acceptable safety and tolerability before the remaining subjects are enrolled. The primary outcome will be the incidence and severity of adverse events (AEs) and serious adverse events (SAEs). Secondary outcomes include cell engraftment and survival, responder rate, and seizure frequency. The follow-up period for this study is 1 year. After completing the follow-up period within this study, subjects will enter a 15-year long-term safety follow-up. DiscussionMTLE remains a significant challenge in neurology. The results of this study will provide critical data regarding the feasibility and preliminary efficacy of ALC05 in treating MTLE and may offer a transformative therapeutic option for this condition.

Non-invasive brain stimulation (NiBS) studies frequently report exploratory correlations between individual-level changes in neurophysiological and behavioural measures. However, these analyses are typically underpowered and rely on ratio-based change scores with known statistical limitations. We addressed these limitations by pooling individual data from three independent studies (total N = 69), providing adequate power to detect small-to-medium effects. All studies applied 20 Hz transcranial alternating current stimulation (tACS) targeting the pre-supplementary motor area (preSMA) and right inferior frontal gyrus (rIFG), regions central to inhibitory control. Changes in preSMA-rIFG connectivity measured with EEG imaginary coherence (ImCoh) and response inhibition (stop-signal reaction time, SSRT) were quantified using reliable change indices (RCI), which were z-standardised within studies to enable pooled mixed-effects regression. No meaningful association was found between tACS-induced ImCoh change and SSRT change (r = .013, marginal R{superscript 2} = .004), with project-wise correlations that were small, non-significant, and inconsistent in direction. Sensitivity analysis using ratio-based change scores converged on the same null result (r = .014), though ratio scores showed severe distributional violations relative to the approximately normal RCI distributions, supporting the methodological case for RCI on statistical grounds. These results provide no support for a systematic individual-level brain-behaviour coupling between preSMA-rIFG connectivity and response inhibition following 20 Hz tACS, and suggest that any true effect is likely to be small. The present work offers a methodological benchmark for quantifying individual-level brain-behaviour coupling in NiBS research, and highlights the need for more sensitive neural markers and adequately powered design.

BackgroundGlobal cerebral anoxia is a leading cause of death and resuscitated patients often remained persistently affected by neurological deficits. While previous studies suggest that brain-heart electrophysiological interactions may predict severity and prognosis after hypoxic brain injury coma, little is known about the brain-heart dynamics at near-death. Gaining insight into these mechanisms is crucial for developing targeted interventions in critical conditions. ResultsUsing a rodent model of reversible systemic anoxia (n=29, male and female rats), we investigated whether brain-heart interactions during the asphyxia onset could predict the return of brain electrical activities after resuscitation. Electrophysiological recordings confirmed that cerebral activity declines following asphyxia, coinciding with increased heart rate variability. Notably, the strong coupling between cardiac parasympathetic activity and high-frequency brain activity in the somatosensory cortex and hippocampus serves as a key predictor of a favorable outcome. ConclusionOur study underscores the involvement of the brain-heart axis mechanisms in the physiology of dying and the potential prognostic significance of these mechanisms, paving the way for translational research into critical care, based on new characterizations of cardiac reflexes and brain-heart interactions.

BackgroundBalance instability is a major contributor to disability and falls in people with Parkinsons disease (PwP) and is often insufficiently explained by motor impairment alone. Altered awareness of motor control has been suggested to contribute to sensorimotor dysfunction in PwP, but its relationship with balance performance is poorly understood. ObjectiveTo determine whether awareness of balance control, assessed using a control detection task (CDT), differs between healthy controls (HC) and PwP, and whether CDT performance is associated with balance-related measures. MethodsHealthy older adults (n=20) and PwP (n=22) performed a standing version of the CDT based on center-of-pressure (COP) control, using a force plate. CDT accuracy was used as the primary outcome measure. Static balance during quiet standing was assessed using the COP trajectory length and rectangular area. Dynamic standing balance was assessed using the Index of Postural Stability (IPS). Group differences were examined by independent-samples t-tests. Correlations between CDT accuracy and balance measures were analyzed. ResultsThe PwP group showed significantly lower CDT accuracy. Higher CDT accuracy was associated with better static balance in the HC group and the combined sample, and with higher IPS primarily in the PwP group. ConclusionsMotor awareness during postural tasks is altered in PwP and is associated with balance control. These findings suggest that balance instability in Parkinsons disease may involve altered balance-related action-outcome monitoring in addition to motor dysfunction.

Background: Peri-lead edema (PLE) occurs in up to 15% of Deep Brain Stimulation (DBS) cases, can cause morbidity, and its etiology remains unknown. We hypothesized that PLE represents a secondary brain injury modulated by hypoxemia, and that patients with obstructive sleep apnea (OSA) are at elevated risk. Methods: We conducted a retrospective case-control study of 121 Parkinson's disease (PD) patients undergoing DBS at a single center (2019-2024). PLE severity was quantified by CT volumetric segmentation and Hounsfield unit (HU) measures. Perioperative SpO2 and PaO2 were recorded. Polysomnography (PSG) was available in 26 patients; and the REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) was administered retrospectively. Results: Symptomatic PLE occurred in 12 patients (9.9%), with onset at 3.5 (2-9) days postoperatively. PLE patients had higher body mass index (p = 0.022) and higher OSA prevalence (75% vs. 30%; p = 0.002). Perioperative SpO2 was lower in the PLE group in both the operating room and post-anesthesia care unit (PACU; p < 0.05); PaO2 was lower in the PACU (p = 0.037). In the PSG subgroup, REM Sleep Behavior Disorder (RBD) incidence was lower in PLE patients (20% vs. 60%; unadjusted p = 0.048), and PLE severity correlated significantly with sleep-related hypoxemia and respiratory indices. RBDSQ scores were positively associated with edema density (normalized HU: rho = 0.86, p = 0.024). Conclusions: OSA and perioperative hypoxemia are associated with symptomatic PLE following DBS, while RBD appears protective. Preoperative sleep evaluation and optimized perioperative airway management warrant prospective investigation as PLE prevention strategies.

Although many individuals with chronic aphasia respond to language therapy, there remains a need for adjunctive interventions that can enhance treatment response. Approaches targeting multiple modalities, such as gesture cueing, and neuromodulation techniques, such as transcranial magnetic stimulation, have shown promise for supporting language recovery. The present pilot study investigated whether enhancing activation of the action semantic network could facilitate verb production in individuals with chronic aphasia. Participants were recruited as a convenience sample and completed a within-subject design in which all individuals received each condition. Two non-linguistic methods of activating the action semantic network were evaluated: (1) pantomimed gesture cues to prime action concepts and (2) intermittent theta-burst stimulation to the left posterior middle temporal gyrus (pMTG), an intact action-semantic network node in our participants. We examined individual and combined effects of gesture priming and stimulation to test whether a combined approach would yield additive or interactive benefits. Using a Bayesian generalized linear mixed-effects model, we observed a moderate interaction between gesture priming and stimulation site. Contrary to predictions, combining gesture priming with pMTG stimulation did not produce additional benefits over either intervention alone. Instead, pMTG stimulation attenuated the priming advantage observed under vertex stimulation, and gesture priming attenuated the advantage observed with pMTG stimulation alone. Posterior estimates provided substantial preliminary evidence for this interaction in our pilot sample size. These findings suggest that combined activation of the action semantic network through gesture and neuromodulation approaches may not benefit verb retrieval above and beyond each approach alone.