Cortex

ObjectiveTo evaluate central and peripheral correlates of motor control using functional magnetic resonance imaging (fMRI) and surface electromyography (EMG), with a focus on the added value of EMG-informed analysis during movement of the lower limb in healthy controls. MethodsTwenty participants performed dorsi-/plantarflexion of the ankle (Ankle) and gait imagery (GI) in a block design during fMRI. Accelerometry (Acc) and surface EMG from tibialis anterior (TA) activity were recorded and included as regressors in five analysis models, either with or without temporal derivative (TD) to account for time shift in the task regressor. Voxel-wise analyses complemented by post-hoc region-of-interest (ROI) analyses were performed to compare the amount of variability explained by the models. ResultsInclusion of either Acc or EMG on top of the task regressor explained robustly fMRI signal variability in the primary sensorimotor cortices. On top of Acc, EMG additionally explained activation variability mainly in the contralateral thalamus and the secondary somatosensory cortex (S2). This effect was, however, mainly driven by spontaneous signal fluctuations at rest and during imagery. Comparisons between models with and without TD revealed consistent differences in the cerebellum and thalamus across tested models, suggesting that subcortical structures may involve transient signal changes when switching between movement and rest. ConclusionIncluding EMG in fMRI analysis enhances specificity in detecting motor-related brain activity and enables differentiation of spontaneous or unpredicted motor behavior. TD improved signal detection in the primary sensorimotor cortices, but may have a detrimental effect on signal detection in other, mostly subcortical regions, likely reflecting their different temporal signal dynamics.

Semantic cognition allows us to represent, process and manipulate verbal and nonverbal knowledge about the surrounding environment. Semantic cognition plays a critical role in language, communication and many nonverbal behaviours and can be disrupted by several neurological diseases, including stroke and dementias. Therefore for clinical practice, it is essential to evaluate semantic cognition and to do so using culturally-appropriate assessments (given that some facets of semantic knowledge and associations are culturally-specific). Here, we developed and standardized a new verbal and nonverbal semantic assessment, called semantic knowledge test (SKT), for Korean-speaking populations. The SKT was developed and standardized on a large and demographically diverse sample of 325 healthy adults, confirming its high reliability and validity. To explore its clinical utility and added value, we collected data from 101 post-stroke patients alongside the Western Aphasia Battery (WAB). We run a principal component analysis (PCA) using SKT and WAB scores and Voxel-based lesion-symptom mapping (VLSM) using the factor loadings that yielded from the PCA. The principal component analysis (PCA) of behavioural test scores produced two distinctive factors, one with the WAB scores and the other with the SKT scores. VLSM revealed that the neuroanatomical correlates of the WAB factor covered the peri-Sylvian areas, while that of SKT was in the left superior anterior temporal lobe (ATL) and posterior middle temporal gyrus (pMTG). These findings underscore the utility of the SKT in uncovering both behavioural and neuroanatomical facets of semantic cognition that are not captured by the traditional language batteries such as the WAB and emphasize the importance of independent assessment of semantic deficits in clinical populations.

There is a predicted increase in older adults presenting with mild to severe cognitive impairment. Screening tools with high sensitivity are the first frontier in identifying a cognitive pathology; however, to ensure that they are measuring the intended concept or criterion, thorough psychometric procedures should be followed. In this study, convergent criterion validity of Riga Cognitive Screening Task was measured, using cortical thickness of regions of interest as the criterion. 106 older adults (Mage = 70.49, SD =8.08, 35.8% male) with varying levels of cognitive functioning were involved in the study. All participants underwent cognitive assessment with the screening task and a 3T MRI. Cortical thickness of selected temporal and parietal regions was used as a brain measure. Behavioural Partial Least Squares Correlation was conducted and one latent variable was extracted. The results confirmed that Riga Cognitive Screening Task shows good criterion validity, suggesting successful use for screening.

ObjectivesA Script Generation Task (SGT), requiring participants to verbally describe the steps of everyday activities, was investigated as an efficient tool to detect mild functional difficulties and mild cognitive impairment (MCI). Methods83 participants (n=57 HC; n=26 MCI) completed a SGT, performance-based test of everyday function, cognitive tests, and questionnaires. SGT responses were transcribed and scored by human raters and automated text analysis. ResultsParticipants with MCI generated fewer SGT steps in a shorter amount of time and more pronouns relative to nouns, reflecting less specificity. Performance on the SGT was associated with cognitive tests of episodic memory, performance-based tests of everyday function, and questionnaires regarding everyday functioning. Conclusions The SGT holds promise as a highly efficient measure of mild cognitive and functional difficulties in older adults.

ObjectiveDemographic corrections (e.g., sex, education, race, ethnicity) are often applied when assessing cognition in adults; however, these corrections have significant limitations (e.g., using years of education does not capture the quality of, or access to, education). It is therefore critical to develop novel assessment options that are less susceptible to demographic factors. This study compared demographic effects on a verbal memory test and a performance-based test of cognition and daily functioning in older adults. Based on prior work, we hypothesized the performance-based tests would be less susceptible to demographic factors than paired associates learning. MethodData from 1326 participants (mean{+/-}SD age=61.9{+/-}10.9 yrs; Female = 1066, 80%) were collected through the MindCrowd electronic cohort, with 79 (6%) non-White, 109 (8.2%) identifying as Hispanic/Latino ethnicity, and 327 (25%) reporting education as less than a college degree. Paired associates learning is a well-established measure of medial temporal lobe-dependent learning and memory through recall of word-pairs, scored as the number of correct word pairs entered out of 36 possible. The performance-based test involved functional upper-extremity movement, specifically transporting beans to target cups in a repeating sequence (a task also shown to be dependent on the medial temporal lobe), scored as the intraindividual variability (standard deviation) in trial time across four consecutive trials. ResultsAs hypothesized, linear regression analysis showed that PAL was significantly affected by sex, education, race (particularly Black/African American), and ethnicity, whereas the performance-based test was affected only by sex and with a much smaller effect size than that of PAL. ConclusionsPerformance-based assessments may be an equitable approach to evaluating cognition without requiring score corrections, particularly for diverse populations.

BackgroundRecent work has delineated the semantic behavioral variant of frontotemporal dementia (sbvFTD; or right temporal variant of FTD, which is thought to preferentially impair semantic knowledge for emotional concepts. However, this proposed core feature has not yet been empirically validated, and no clinical tool exists to assess it. Establishing reliable markers is essential to clinically differentiate sbvFTD from behavioral variant FTD (bvFTD), which is critical given their overlapping behavioral symptoms but divergent underlying pathologies. Furthermore, contrasting sbvFTD with semantic variant primary progressive aphasia (svPPA) can advance our understanding of semantic memory, revealing how the right and left anterior temporal lobes (ATLs) support emotion- versus tool-related knowledge, highlighting the graded, lateralized organization of the semantic system. MethodsWe studied 15 patients with sbvFTD, 15 with svPPA, 18 with bvFTD, and 37 healthy controls. A novel multimodal semantic battery, the Fear and Spider Test (FST), which assesses tool- and emotion-related concepts across word-based semantic associations, picture-based semantic associations, and sound-to-picture matching, was administered. Stimuli were matched on psycholinguistic and perceptual features, and emotional items were drawn from multicultural facial expressions validated with the Facial Action Coding System. Neural correlates of semantic performance were investigated using voxel-based morphometry. ResultsAs expected, patients with both sbvFTD and svPPA showed greater deficits in all semantic tasks compared to controls and bvFTD, and bilateral anterior temporal lobe (ATL) volumes were broadly associated with performance across all semantic tasks. Interactions between modality and categories were necessary for the emergence of differences between sbvFTD and svPPA and right and left ATL atrophy: performance on the Words-Tools condition was more impaired in svPPA and correlated with left ATL volume, while performance on the Pictures-Emotions condition was more impaired in sbvFTD and correlated with right ATL volume. ConclusionThe FST provides the first clear dissociation of sbvFTD from bvFTD, a distinction of critical clinical importance given their divergent pathological substrates and the absence of frontotemporal lobar degeneration specific biomarkers. The study also refines our understanding of semantic memory: contrasting sbvFTD with svPPA reveals complementary roles of the right and left ATLs in supporting emotion and tool knowledge, underscoring the graded, lateralized organization of the semantic system.

BackgroundAlzheimers disease (AD) patients are characterized by an early decline of episodic memory due to hippocampal damage. Nonetheless, besides the classical negative symptoms related to episodic memory deficits, i.e. failure to retrieve information, it has been shown that AD patients can also suffer from positives symptoms, i.e. confabulations. Some theoretical accounts have been proposed to explain the cognitive mechanisms underlying confabulation. Yet, even if most of these models have lead to some research trying to validate cognitive deficits in some cognitive domains, in particular executive functions, to our knowledge, none has yet tried to determine the specific cognitive profile of confabulatory patients. In the present study the main aim is to characterize the specific cognitive profile of confabulatory patients. Thus, given that AD patients cognitive profile is well known and documented, we compare mild to moderate AD patients with and without confabulations. Methods37 healthy control (HC) and 35 individuals with mild to moderate AD were recruited at the Pitie Salpetriere University Hospital. All participants were evaluated on Dalla Barbas Confabulation Battery to determine their tendency to produce provoked confabulations. Thus, among AD patients, we distinguish between those who produced confabulations in episodic memory questions, and those who did not. Accordingly 27 AD patients were considered free of confabulations (ADC-), and 8 as confabulators (ADC+) (none HC met the criteria). All participants were assessed on a comprehensive neuropsychological battery. ResultsStatistical analyses showed a significant difference between HC participants and the two groups of AD patients, in almost all cognitive domains assessed. However, when comparing the two AD groups, they did not show distinct profiles. Moreover, regarding the type of confabulations, ADC+ produced significantly more confabulations to the Episodic questions (both concerning past and future). ConclusionsBy not demonstrating cognitive differences between patients with and without confabulations, our results cast doubts on some confabulation models, which assume a unique and sufficient cognitive (e.g. executive) deficit underlying the onset of confabulations. HighlightsO_LIAlzheimers disease patients with or without confabulations do not have otherwise distinct cognitive profiles. C_LIO_LIThe emergence of a confabulatory syndrome does not seem to be the result of a necessary and sufficient executive deficit C_LIO_LIAlzheimers disease patients mainly produce episodic memory confabulations, which involve both the past and the future dimension. C_LI

Williams Syndrome (WS) is a rare neurodevelopmental disorder associated with intellectual disability and increased vulnerability to traits such as anxiety, perseveration, and belief inflexibility. In the general population, these traits are linked to self-reported thought disturbances such as paranoia and delusions. However, little is known about how such disturbances present in WS, largely due to concerns regarding the validity of self-report in this population. To address this gap, we collected self- and caregiver-reported measures characterizing thought disturbances and related cognitive traits in adults with WS, assessing inter-rater reliability and correlations among measures. Total scores were similar across reporters, except for delusional ideation, which participants endorsed more strongly than caregivers. Several participants also reported clinically significant levels of paranoia, delusions, and worry that were not captured by caregiver report. These findings suggest that self-report is a valid method for accurately characterizing the severity and nature of thought disturbances in WS.

BACKGROUNDEpisodic memory declines early with aging, reflecting reduced neural resources and diminished memory specificity. However, few studies have created a cognitive challenge with multiple levels of task demand to investigate this early subtle decline. Furthermore, it is unclear whether the genetic Alzheimers disease risk factor APOE4 and early Alzheimers pathology constrain the neural resources required to cope with increasing task demands. METHODSIn this preregistered behavioral study named EMCOMP (Episodic Memory & COMPensation), we conducted a semantic episodic memory retrieval task using a sentence-based task demand manipulation with five demand levels at recognition (novel foils, "old" target sentences, and three lure levels) and two demand levels at free and cued recall (gist and details). We collected data from 100 cognitively unimpaired adults (37 young (mean age 24 years), 63 older (mean age 72 years)) with additional neuropsychological testing and blood-based measures available for the older group. First, we investigated differences in EMCOMP episodic memory retrieval accuracy and confidence between young and older adults in linear mixed-effects models. Second, we investigated differences associated with the APOE4 genotype and plasma-derived Alzheimers pathology. Third, we assessed correlations between EMCOMP recognition and recall and established cognitive tests. RESULTSYoung adults showed higher recognition accuracy and confidence as well as a higher recall score and a lower recall error rate compared to older adults. As recognition-task demand increased there was a steeper decline in recognition accuracy and a steeper increase in high-confidence errors in older compared to younger adults and in older APOE4 carriers compared to older non-carriers. However, we found no associations with Alzheimers pathology. EMCOMP performance was positively correlated with established cognitive tests. CONCLUSIONOur study demonstrates age- and APOE4-related differences in episodic memory retrieval under increasing task demands - differences that may not be detectable in paradigms with only one or two levels of task demand. By manipulating semantic retrieval specificity, we provide a novel approach to detect subtle cognitive deficits and potential functional compensation in cognitively unimpaired older adults with risk factors or early Alzheimers pathology. Future research should extend this work to more diverse samples and combine behavioral assessment with fMRI to examine underlying brain activation patterns and functional connectivity.

BackgroundArtificial Intelligence (AI) based approaches to speech analysis have the potential to assist with objective speech error analysis in aphasia but off-the shelf tools often fail to detect speech errors due to prioritizing "fluent transcription." Speech production errors (dysfluencies) are hallmark diagnostic features of the nonfluent (nfvPPA) and logopenic (lvPPA) variants of primary progressive aphasia, yet they can be challenging to detect and characterize even by expert clinicians. This study aimed to evaluate whether the novel automated lightweight Scalable Speech Dysfluency Modeling system (SSDM-L), specifically designed to detect dysfluencies, could accurately distinguish PPA variants using voice recordings of individuals reading a brief passage. MethodParticipants included a total of 104 individuals, 40 with nfvPPA, 40 with lvPPA (matched on disease severity), and 24 healthy controls who read aloud the Grandfather Passage as part of a widely used motor speech evaluation (MSE). We automatically extracted ten speech error (dysfluency) variables using SSDM-L, including insertions, replacements, and deletions at both phoneme- and word-levels, and phoneme-level prolongations and repetitions. Group differences were assessed via ANCOVAs controlling for age, education, and disease severity (MMSE, CDR sum-of-boxes). To test clinical relevance, we performed correlation analyses with MSE ratings provided by experienced speech-language pathologists (i.e., gold standard) within the nfvPPA group. Classification performance was assessed by training random forest and XGBoost machine-learning models including 5-fold cross-validation. ResultsAll individuals read the entire passage in less than five minutes. SSDM-L detected eight of the ten predefined dysfluency features at sufficient frequency to include them in subsequent analyses. All eight features distinguished PPA from controls (p<.006). Individuals with nfvPPA made more errors than the lvPPA group on every feature (all p<.023). Each feature showed a moderate positive correlation with a global MSE apraxia/dysarthria score (r=.31-.56; p<.001-.053). Together, the eight features were able to classify nfvPPA versus lvPPA at AUC=.806 (random forest) and AUC=.776 (XGBoost). DiscussionAI-based automated speech error analysis accurately distinguished nfvPPA and lvPPA variants using a brief reading task. This quick error-sensitive scalable AI system has the potential of providing a practical tool to aid diagnosis in aphasia and motor speech disorders.

Comprehending how forces are applied to an object during manipulation can help provide important insights into the quality of behavior in daily tasks. We have developed the Bead Maze Hand Function test to objectively measure the quality of hand function in children. This test aims to measure how well an individual performs the activity by integrating measures of time and force control. The main objective of this study was to examine associations between a common clinical measure, the Box and Block Score (BBS), and variables on the Bead Maze Hand Function test that were either time-based or force-based. The sample was composed of neurotypical developing adolescent participants (N=23). We found that the time (duration) on the double curve wire (most complex) was the best predictor of BBT. Furthermore, we found that force-based variables were weak predictors of the clinical, time-based BBS. These findings support the integration of time and force-based metrics to holistically quantify the quality of motor behavior. Linking these metrics into a unified score may serve as a better way to analyze adolescent motor behavior and predict future motor or neurodegenerative conditions.

Structured AbstractO_ST_ABSObjectiveC_ST_ABSGeneral cognitive ability (g), a latent variable derived from cognitive data, can predict life outcomes (e.g., educational attainment and occupational success) among neurologically healthy individuals. The value of g for predicting post-stroke functional outcomes is unknown. We addressed this gap here. MethodWe derived g using exploratory structural equation modeling of 15 neuropsychological tests administered to 112 patients with stroke, 69 of whom also had functional outcome data (42 men; mean age = 53.23 years (SD = 10.54)). We used logistic regressions to compare g and individual tests in terms of their ability to predict the Functional Assessment Measure (FAM) and the Functional Independence Measure (FIM; motor and cognitive subscales) at 12 months post-stroke. Resultsg was a statistically significant predictor of FAM (X2 = 6.86, p = 0.013) and the cognitive (X2 = 11.48, p = 0.002) but not motor FIM subscale (X2 = 0.93, p = 0.154). Individual tests varied widely in terms of predictive utility (X2 range: 0.07-21.03), with the most robust predictors being measures of visuospatial functions. ConclusionsAcute measures of cognition, including g, can predict functional independence 12 months after stroke. g and visuospatial ability measures were the most robust predictors. Statement of Research SignificanceO_ST_ABSResearch QuestionC_ST_ABSGeneral cognitive ability (or, g) is composite score based on scores on performance-based tests of cognition. In neurologically healthy people, g can predict long-term life outcomes. The value of g measured acutely after stroke for predicting functional outcomes one year later is unknown. We evaluated the utility of g for predicting post-stroke functional outcomes. Main FindingsA g factor based on neuropsychological test data collected from acute stroke patients was a statistically significant predictor of cognitive and psychosocial functional outcomes one year later. Lower g after stroke was linked to higher chance of needing functional assistance. Study ContributionsWhen neuropsychological test data are collected in the acute post-stroke period, it may be possible to derive a g factor score based on those data. Our findings suggest that this g factor score could help clinicians tailor treatment strategies to a patients expected long-term functional outcomes.

The neural signature of rhythm and tempo remains difficult to study in both humans and non-human primates. Here we recorded from the motor cortex of human participants implanted with intracortical microelectrode arrays while they performed a series of rhythmic tapping tasks. We found that rhythmic tapping elicited low-dimensional rotational neural dynamics whose radii varied in a tempo-dependent manner and axes related to kinematic properties. Moreover, we observed a spectrum of kinematic and neural behavior as participants shifted from low tempo punctuated taps to high tempo smoother, continuous taps. Surprisingly, we observed that tactile feedback strengthened the rotational dynamics despite reduced kinematic range. Moreover, while tempo preparation did not produce dynamics of their own, motor cortex encoded it in an orthogonal dimension. Finally, we found that switching tempos was achieved with smooth neural transitions that could only be separated in higher dimensions. These results show that motor cortex directly encodes a multitude of rhythm related features.

As implantable brain-computer interfaces (iBCIs) for communication and movement transition from cutting-edge research to clinical practice, a standardized approach will be required to reliably plan neurosurgeries involving complex microelectrode arrays and other neural sensors. Here, through our BrainGate study experiences, we present a replicable methodology, using open-source tools, to create interactive, personalized, 3-dimensional, virtual and physical, functional mapping models to guide iBCI surgical planning and provide intra-operative imaging displays.

Children with cerebral visual impairment (CVI) presenting an atelic profile constitute a population that is largely excluded from neurovisual research, primarily due to the absence of reliable behavioural responses to standard assessment or intervention paradigms. This exclusion often leads to the assumption that a lack of observable response reflects an absence of visual processing, despite converging evidence from neuroscience indicating that neural processing may persist in the absence of overt behavioural expression. This protocol describes a clinical feasibility study designed to evaluate the feasibility, tolerability, and measurement reliability of a passive visual mirror exposure paradigm in children with CVI and an atelic profile. The visual mirror is defined as the repeated presentation of a highly predictable, coherent visual experience, intended to reduce perceptual instability and cognitive load associated with typical visual environments, without aiming to restore or train visual function. The paradigm relies on passive visual exposure delivered via a large screen, or, where appropriate and tolerated, a virtual reality headset configured in a strictly non-interactive mode, without requiring effort, task engagement, or voluntary responses from the child. The study is embedded within a precautionary ethical framework specifically adapted to behaviourally non-responsive paediatric populations, defined here as children presenting absent voluntary behavioural responses to sensory or task-based instructions. Feasibility and tolerability are assessed using predefined safety criteria and non-verbal physiological indicators, including heart rate and autonomic markers, rather than behavioural performance. This feasibility study is designed to characterise the ethical acceptability, implementability, and physiological tolerability of the protocol in this vulnerable population, and to inform future research considerations without implying any obligation or commitment to subsequent studies.

BackgroundEpisodic memory complaints are frequently reported by people with epilepsy (PWE), and often contrast with normal performance on standard neuropsychological assessment using short retention intervals (20-30 minutes). This discrepancy is consistent with the concept of accelerated long-term forgetting (ALF). However, the objective assessment of ALF remains challenging in clinical practice, and the underlying mechanisms, whether related to encoding, early or late consolidation, are still debated. This study aimed to evaluate a specifically designed associative memory task to detect episodic memory impairment and ALF in PWE who show normal performance on standard neuropsychological assessment. MethodsIn a prospective non-randomised controlled study, 40 PWE and 40 healthy controls (HC) completed an associative memory task comprising the encoding of 56 abstract word-naturalistic scene pairs, followed by retrieval at 30min and 72h. At each delay, both recollection and recognition were assessed on complementary halves of the encoded material. During encoding, participants had to provide for each pair a subjective judgement about the congruence between the word and the scene. The primary endpoint was recollection-based memory loss 72h after encoding in PWE compared to HC, analysed using a logistic mixed-effects model. ResultsMemory significantly declined 72h after encoding, with a lower recollection score at 72h than at 30min in both groups (PWE: OR [95%CI]: 0.31 [0.26;0.38]; HC: OR [95%CI]: 0.21 [0.17;0.26]). At 30-min recollection, PWE were less likely to perform correctly than HC (OR [95%CI]: 0.49 [0.38;0.63]) and despite a smaller memory loss over time, PWE continued to perform significantly worse than HC at 72h (OR [95%CI]: 0.73 [0.58;0.91]. No association was found between memory performance and epilepsy-related clinical features. A three-way interaction was observed between the congruence judgement, group and time (p=0.03), with PWE recovering normal recollection performance at 30 min for pairs judged as highly congruent during encoding. DiscussionThe results suggest that ALF in epilepsy may reflect disruption occurring early in the consolidation process, potentially during encoding itself and underline the importance of associative, multimodal episodic memory tasks to better characterise memory impairment in PWE.

IntroductionSleep spindles are electroencephalographic elements characteristic of non-rapid eye movement sleep generated by thalamo-cortical interactions. Spindles have been linked to some of the cognitive benefits afforded by sleep and high spindle activity is associated with increased arousal threshold (deeper sleep). Here, we demonstrate that targeting the thalamus with Transcranial Electrical Stimulation with Temporal Interference (TES-TI) can enhance spindle activity. Methods24 participants (25.5 {+/-} 9.5 years; 69.6% F) underwent thalamic TES-TI stimulation during daytime naps. Three stimulation protocols were tested during stage 2 of non-rapid eye movement sleep (N2): fixed difference frequency of 10 Hz (TES15kHz-TI10Hz), difference frequency matched to individual spindle peak (TES15kHz-TIPeak), and carrier frequency only (TES15kHz). Spectral power in the spindle (sigma) band and integrated spindle activity (ISA) were compared before and during the stimulation, and across stimulation protocols. ResultsTES15kHz-TI10Hz stimulation was associated with a significant increase in sigma band power ({Delta}[x]STIM-PRE = 0.49 log10{micro}V2, p = 0.021) and ISA ({Delta}[x]STIM-PRE = 7.48 {micro}V/s, p = 0.042). Cluster-based analysis localized the increase in sigma power over the frontal and centro-parietal areas (p = 0.022). Linear mixed effects models showed that both sigma band power and ISA during stimulation increased significantly in TES15kHz-TI10Hz compared to the TES15kHz protocol ({beta} = 0.67 log10{micro}V2, p = 0.018; {beta} = 14.70 {micro}V/s, p = 0.0077), while the TES15kHz-TIPeak did not show the same effect. ConclusionsThis study provides evidence supporting the successful use of TES-TI targeting the thalamus to enhance sleep spindle activity. Stimulation at a fixed difference frequency of 10 Hz increased sigma band power and ISA, whereas neither stimulation matched to individual sigma band peak nor TES alone produced comparable effects. These promising results warrant further investigations into the cognitive and clinical impact of TES-TI, a non-invasive neuromodulation tool that can reach deep brain regions. Statement of significanceThis study provides evidence that thalamo-cortical networks, which are central to many physiological and pathological brain activities, can be modulated non-invasively in humans. More specifically, the findings show that transcranial electrical stimulation with temporal interference targeting the thalamus can selectively enhance sleep spindle activity. This work introduces a new strategy for precisely targeting sleep-generating mechanisms regulated by deep brain circuits without surgery or medication. Key next steps include determining how this increase in spindle activity can positively impact cognition and assessing the translational potential of this approach for clinical populations.

Sleep loss is a major contributor to traffic accidents, yet the differential effects of acute versus cumulative 8-hour sleep loss on vehicle control remain poorly quantified. This study leveraged tightly controlled sleep manipulation together with highly immersive driving simulation to directly compare sleep-loss modes under naturalistic driving conditions. To evaluate subjective sleepiness, driving performance and vigilance, healthy male participants completed a randomized within-subject crossover sleep design, comprising normal sleep, cumulative sleep restriction (four nights with 2 h reduced sleep per night), and acute total sleep deprivation (one night without sleep), each followed by a simulated nighttime-to-early-morning driving protocol segmented into modules. Linear mixed-effects models evaluated condition effects and time-on-task dynamics. Acute total sleep deprivation produced pronounced impairments in vehicle control. Most prominently, lateral control deteriorated rapidly under acute deprivation, with effect magnitudes comparable to those reported at high blood alcohol concentrations. Steering instability and integrated driving performance showed convergent deterioration. In contrast, cumulative sleep restriction resulted in smaller and less consistent changes, while vigilance task performance and speed variability were comparatively preserved across all conditions. Despite increased subjective sleepiness, cumulative sleep loss provoked relatively small changes in driving performance, whereas acute sleep deprivation produced a disproportionate risk to driving safety by selectively and rapidly degrading operational vehicle control. These findings, obtained under ecologically relevant sleep and driving conditions, underscore functional and potentially underlying physiological differences between acute and cumulative sleep loss and, practically, highlight the importance of distinguishing between them when considering sleep-loss-related driving impairment and safety risk. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/26343648v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@e136c3org.highwire.dtl.DTLVardef@1d241c9org.highwire.dtl.DTLVardef@dd17f5org.highwire.dtl.DTLVardef@14ff50a_HPS_FORMAT_FIGEXP M_FIG C_FIG Clinical Trials - name, URL and registrationO_ST_ABSClinical Trial nameC_ST_ABSStudy of Identification of Metabolomics-based Sleepiness Markers for Risk Prevention and Traffic Safety - ClinicalTrials.gov Identifier NCT05585515, released on 18.10.2022, https://clinicaltrials.gov/study/NCT05585515; Swiss National Clinical Trial Portal SNCTP000005089, registered on 12.08.2022, https://www.humanforschung-schweiz.ch/de/studiensuche/studien-detail/58930 IRB StatementThis study was approved by the local ethics committee (Kantonale Ethikkommission Zurich, reference number 2022-01273). No identifying images or other personal or clinical details of participants are presented here or will be presented in reports of the trial results. Informed consent materials are available from the corresponding author on request. We confirm all methods were performed in accordance to the Declaration of Helsinki and its later amendments. Statement of significanceSleep loss is common, but not all forms of sleep loss affect driving in the same way. This study shows that a single night without sleep and several nights of restricted sleep have fundamentally different consequences for vehicle control, despite producing significant feelings of sleepiness. By combining controlled sleep manipulation with immersive, ecologically relevant driving assessment, the work reveals that acute sleep deprivation uniquely disrupts the ability to maintain stable control of a vehicle, whereas cumulative sleep loss produces more limited performance changes. These findings challenge assumptions based solely on subjective sleepiness and highlight the need to distinguish between sleep-loss patterns when evaluating driving safety. Future work should address how drivers recognize and respond to these distinct forms of impairment.

Neurodevelopmental disorders (NDDs) influence lifespan neurocognitive trajectories and can be conceptualized as falling on a continuum. However, transdiagnostic neurodevelopmental investigations in cognitive aging are rare. This preliminary, cross-sectional study aimed at exploring lifespan manifestations of neurodevelopmental vulnerabilities (DVs) in cognitive aging, while adopting a dimensional approach to NDDs. The objectives, covered from childhood to adulthood, were: 1) to describe NDDs-related domains of vulnerability; 2) to estimate DVs frequency; 3) to evaluate the persistence of DVs symptoms from childhood to adulthood; 4) to explore the link between DVs, demographics and neuropsychological performance. Cognitively healthy participants underwent a neuropsychological assessment and answered a retrospective questionnaire on NDDs symptoms in childhood and in adulthood. Using a k-means clustering based on questionnaire answers, participants were assigned to a DV+ (with DV) or a DV- (without) cluster. The final sample consisted in 84 participants [age: 69 (8); years of education: 14 (3); 57% females]. In childhood, self-management, reading and writing, school performance, and visuospatial difficulties were reported. In adulthood, difficulties were mainly in self-management. Clustering revealed a DV in 15% of individuals during childhood, and in 21% during adulthood. Throughout life, 86% of participants had a consistent cluster assignation, while 13% changed clusters between childhood and adulthood. Childhood self-management and scholar difficulties significantly predicted self-management difficulties in adulthood. Nevertheless, no link was found between DVs, demographics and neuropsychological performance. Results highlight the relevance of lifespan, dimensional investigations of NDDs; and are discussed in terms of cognitive reserve, compensation processes, heterotypic continuity and psychopathological progression. Public Significance StatementThis preliminary study suggests that developmental vulnerabilities can be detected in cognitively healthy aging individuals. Difficulties in their childhood may relate to self-management, reading and writing, school performance, and visuospatial skills; and may predict self-management difficulties in adulthood. HighlightsO_LILifespan neurodevelopmental vulnerabilities (DVs) were screened using a retrospective questionnaire in 84 cognitively healthy older adults. C_LIO_LIA data-driven dimensional analysis identified DVs in 15% of participants during childhood and 18% during adulthood. C_LIO_LIIn childhood, reported difficulties included self-management, reading and writing, school performance, and visuospatial skills. In adulthood, difficulties were mainly in self-management. C_LIO_LIChildhood self-management and scholar difficulties significantly predicted self-management difficulties in adulthood. C_LI

Predictive processing has been proposed as an explanatory framework for symptom development in both autism (ASD) and schizophrenia (SSD) spectrum disorders, with ASD being associated with an overweighting of (low-level) sensory evidence whereas SSD is characterized by an overweighting of (high-level) prior beliefs. The goal of the present study was to investigate these hypotheses in subclinical expressions of ASD and SSD in the domain of language processing. To test this, we used an auditory comprehension task designed to directly manipulate the precision of high-level semantic prior beliefs and low-level sensory evidence. We applied hierarchical Bayesian belief updating modeling to quantify this effect and used EEG to examine whether an imbalance in the weighting of prior beliefs and sensory evidence would be characterized by altered processing of semantic precision-weighted prediction errors as indexed by alterations in mean N400 amplitudes. Computational modeling revealed that increasing schizotypal traits were associated with a significant overweighting of prior beliefs, while autistic traits did not show a significant shift. Linear mixed models on the mean N400 amplitudes further indicated that this schizotypy-related overweighting of semantic prior beliefs was reflected in a reduced semantic prediction error signal, indexed by smaller N400 differences between low entropy sentences and both high and low-mismatch sentences. A similar pattern emerged for increasing autistic traits, though the effect was weaker and less distinct, pointing to a subtle overweighting of semantic prior beliefs, only. Overall, our findings provide converging computational and electrophysiological support for an overweighting of semantic prior beliefs with increasing subclinical schizotypy, consistent with predictive processing accounts of SSD, whereas we did not find evidence for an overweighting of sensory evidence with increasing autistic traits, with electrophysiological results instead pointing toward subtle alterations in the weighting of semantic prior beliefs.