Psychophysiology

The proliferation of gambling advertising has intensified concerns regarding its influence on vulnerable populations, yet the neural mechanisms underlying cue-reactivity to these stimuli remain underexplored in ecologically valid settings. This study protocol proposes a novel methodological framework to investigate prefrontal cortical responses to gambling advertisements in individuals with varying degrees of gambling experience. Materials and methods: This cross-sectional study will recruit 44 participants, divided into a clinical group (individuals with high-frequency gambling or gambling disorder) and a matched control group. Neural activity will be recorded using fNIRS while participants view gambling-related, neutral, violent, and sexual stimuli. Secondary measures include validated scales for gambling severity (SOGS), impulsivity, sensation seeking, and alexithymia. Data analysis will primarily utilize inter-subject correlation (ISC) to quantify neural synchronization and multiband frequency decomposition to capture dynamic affective processing. Advanced preprocessing, including short-channel regression, will be applied to ensure signal robustness. Discussion: By combining portable neuroimaging with a data-driven ISC approach, this study aims to identify objective neural markers of gambling vulnerability. The findings will provide novel insights into the idiosyncratic processing of commercial stimuli, potentially informing public health policies and the development of more effective evidence-based regulations for gambling marketing.

Although the associations between cerebrovascular dysfunctions and Alzheimer's disease are increasingly appreciated, the relationship of cerebral blood flow and white matter hyperintensities with tau and amyloid-{beta} pathology remains unclear, particularly in the longitudinal context. This study investigated cross-sectional and longitudinal associations of cerebral blood flow and white matter hyperintensities with tau and amyloid-{beta} pathology using multimodal imaging and blood biomarkers in 179 participants from the ADNI3 cohort. Participants underwent structural (T1-weighted, T2-weighted FLAIR) and arterial spin labelling perfusion MRI, tau and amyloid-{beta} PET, and plasma assay tests for amyloid-{beta} 42, amyloid-{beta} 40, and phosphorylated tau-217. Tau from PET was negatively associated with cerebral blood flow both cross-sectionally and longitudinally in the posterior brain, independent of amyloid-{beta} quantified from PET. Higher white matter hyperintensities volumes were associated with higher levels of tau and amyloid-{beta} at baseline, but the associations were significantly attenuated after further adjusting for amyloid-{beta} and tau, respectively. Plasma amyloid-{beta} 42/40 ratio was negatively associated with white matter hyperintensity volumes both cross-sectionally and longitudinally. In conclusion, tau pathology showed spatially specific associations with cerebral hypoperfusion, independent of amyloid-{beta}, particularly in posterior regions. The attenuation of associations of white matter hyperintensities with amyloid-{beta} and tau after adjustment may reflect shared disease-related variance rather than distinct independent effects. Keywords: Alzheimer's disease, Cerebral blood flow, White matter hyperintensities, Tau pathology, Amyloid-{beta}.

Background: Conventional psychiatric screening instruments summarize symptoms within individual scales and prioritize cases with high single-instrument additive score severity. This design treats items as independent within instruments and ignores cross-instrument covariance structure, making it insensitive to respondents whose responses are distributed across multiple domains in unusual combinations that remain below threshold on every individual scale. Methods: We analyzed two cohorts spanning older and younger adults. Item prompts from depression, stress, anxiety, and sleep instruments were embedded into a shared semantic space using a pretrained sentence encoder. Principal component analysis of the item-prompt embeddings alone---with no use of respondent data at this stage---was used to construct a low-dimensional subspace retaining 80\% of variance in the item embedding matrix. Normalized participant responses were then projected into this subspace, with Jaccard-based stability analysis used as a check on dimensional robustness. Multivariate deviation from the cohort norm was quantified with Mahalanobis distance using Ledoit-Wolf covariance regularization. Candidate outliers were defined by the empirical 95th percentile of the cohort-specific distance distribution. To isolate response configurations not already captured by conventional single-instrument extreme-value logic, we excluded all outlier respondents who had endorsed any individual item at the maximum value of its Likert scale on any instrument. For the remaining outliers, anomalous components were backtracked to their original item loadings for interpretation. Results: In the older-adult Health and Retirement Study (HRS) cohort, principal component analysis of 27 item-prompt embeddings showed that a 10-dimensional subspace provided a stable representation of cross-instrument semantic structure. In the younger-adult Xinxiang cohort the corresponding stable solution was 16-dimensional. In each cohort, seven respondents remained as multivariate outliers despite falling below every single-instrument extreme-value threshold. These cases were not characterized by uniformly severe symptom scores but by unusual cross-domain response configurations that became visible only in the shared semantic covariance subspace. The response structure of the retained configurations differed across cohorts: older-adult cases more often involved weak endorsement of mood-labeled items alongside nonzero body- and sleep-related responses, whereas younger-adult cases more often involved incomplete response configurations spanning mood, sleep, stress, and self-harm-related items. Conclusions: A semantically aligned, auditable covariance subspace provides a practical tool for flagging unusual multivariate response configurations that single-instrument additive screening may not flag. The method is interpretable at the level of original item contributions. It should be understood as a hypothesis-generating screen for unusual response configurations requiring further clinical assessment, not as a diagnostic instrument. Outcome validity remains to be established by prospective study.

Objective: To determine whether absolute ictal energy on intracranial EEG identifies brain regions whose epileptogenic involvement is attenuated under existing baseline-normalized, dynamic-systems, and event-based frameworks. Approach: Intracranial EEG from 56 patients (five centers; 21 SEEG, 35 ECoG) was analyzed using the Teager-Kaiser Energy Operator computed as z-scored and raw envelopes; energy-dominant network regions (EDNRs) were defined as electrodes whose raw-energy rank exceeded their z-score rank by at least 2 positions. Hilbert decomposition characterized instantaneous amplitude and frequency. Main results: EDNRs were identified in 51 of 56 patients (91%; mean 3.4). Hilbert decomposition revealed elevated baseline amplitude in EDNRs relative to both non-involved regions (p < 0.001) and potential seizure onset zones (PSOZs, the top-ranked electrodes under both metrics; p = 0.029), with EDNRs participating in seizure-frequency dynamics comparable to PSOZs (mean ictal frequency shift +3.7 versus +4.1 Hz). EDNR detectability correlated directly with electrode count (Spearman r = 0.899, p < 0.001) without plateau. Significance: Absolute ictal energy identifies an epileptogenic network component with elevated baseline amplitude attenuated under baseline-normalized metrics. The dual-metric framework defines a complementary energy-based axis and establishes the second layer of a two-layer approach with seizure onset and propagation mapping as the first layer. EDNR detectability scales with electrode count, directly relevant to SEEG implantation strategy and to network-level inferences from heterogeneously covered cohorts.

Background: Individuals with body dysmorphic disorder misperceive defects of their physical appearance. Current evidence suggests that visual processing abnormalities may underlie this core symptom. Separate pre-clinical studies testing perceptual and attentional interventions and non-invasive neuromodulation suggest that these visual processing abnormalities may be modifiable, but their combined effects on neural connectivity and perceptual processing remain unclear. Methods: Thirty-nine unmedicated men and women with body dysmorphic disorder or subclinical body dysmorphic disorder received intermittent theta burst stimulation and continuous theta burst stimulation targeting the lateral parietal cortex combined with a visual attention modification paradigm during functional magnetic resonance imaging, in a crossover design. Dynamic effective connectivity within dorsal and ventral visual stream pathways was calculated, and global visual processing biases were assessed using the face inversion effect before and after stimulation plus attention modification. Results: Intermittent theta burst stimulation resulted in increased connectivity in higher-level dorsal visual stream pathways during naturalistic viewing following attention modification, whereas continuous theta burst stimulation was associated with reduced connectivity in lower-level dorsal pathways and increased connectivity in ventral stream pathways. These changes were accompanied by differential effects on global visual processing, with stimulation type modulating the magnitude of the face inversion effect. Conclusions: Combined neuromodulation and visual attention modification modulate visual system connectivity and perceptual processing in individuals with body dysmorphic disorder symptoms. These findings support a mechanistic link between dorsal-ventral stream dynamics and perceptual biases. Integrating neuromodulation with perceptual retraining may represent a viable approach for targeting core symptoms of distorted appearance perception.

INTRODUCTION: Cognitive trajectories may clarify how type 2 diabetes (T2D) and impaired fasting glucose (IFG) relate to dementia risk, but longitudinal associations remain unclear, particularly in the context of stroke. METHODS: Data from 5,631 dementia- and stroke-free older adults (mean age 75 years) from 7 international population-based cohorts were analyzed. Linear mixed-effects models estimated cognitive trajectories during stroke-free and post-stroke follow-up. Glucose status was defined by fasting glucose and prior T2D diagnosis. RESULTS: Over 6.6 years of follow-up (4.5% with incident stroke), T2D was associated with lower baseline cognitive performance compared with normal fasting glucose (-0.14 SD, 95% CI -0.21 to -0.07), but not with faster cognitive decline during stroke-free or post-stroke follow-up. IFG was not associated with lower cognitive performance or faster decline. DISCUSSION: In older adults, T2D was associated with persistently lower cognitive performance but not faster decline, suggesting adverse cognitive effects may be established before late life.

Objective: Cognitive impairment is common among older adults with epilepsy, although efficient screening tools suitable for routine use are lacking. Here we examine, for the first time, the utility of the Alzheimers Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) as a screening tool to identify cognitive impairment in older adults with epilepsy. Methods: Participants included 83 adults (ages over 55) with epilepsy from the Brain, Aging, and Cognition in Epilepsy (BrACE) study and 83 age-, sex-, and education-matched cognitively healthy controls from the Alzheimers Disease Neuroimaging Initiative (ADNI-3). All completed the ADAS-Cog and a comprehensive neuropsychological battery to identify cognitive phenotypes (intact vs impaired). Performance on individual ADAS-Cog items and the total score was assessed, and diagnostic efficiency statistics were determined. Results: Epilepsy participants (mean age=66.4 years) performed significantly worse across the ADAS-Cog total score and 8 of the 13 individual test items compared to controls. The largest effect sizes were observed on verbal learning and memory tasks, particularly word recall (d=0.87) and delayed word recall (d=1.06). An ADAS-Cog total score of at or exceeding 15 yielded optimal diagnostic efficiency (67.5% accuracy, 68.8% sensitivity, 66.7% specificity) for identifying cognitive impairment. Significance: The ADAS-Cog is sensitive to detecting cognitive impairment in older adults with epilepsy and may represent a scalable screening option in this population. Additional comparative studies in older epilepsy populations are needed to determine the sensitivity of this measure to longitudinal change, cross-cultural applicability, and availability across languages. Plain language summary: Cognitive decline is common among older adults with epilepsy, although sufficient evidence supporting the use of screening tools to identify cognitive impairment in this population is lacking. The ADAS-Cog may be a useful screening option in epilepsy research and clinical care, although additional studies are needed to compare it with other cognitive screening tests and to confirm its applicability for clinical care and across cultures and healthcare settings.

AIM: STXBP1-related disorder (STXBP1-RD) is a severe developmental and epileptic encephalopathy characterized by early-onset seizures and persistent cognitive and motor impairments. With disease-modifying trials emerging, a disorder-specific severity scale is needed. To address this, we adapted a validated clinician-reported measure from CDKL5 Deficiency Disorder to develop the STXBP1 Clinical Severity Assessment (S-CSA) and evaluated its psychometric properties. METHOD: The S-CSA was adapted from the CDKL5 Clinical Severity Assessment through expert consensus sessions with STXBP1 clinicians. Revisions addressed gaps in motor and vision domains, adding tremor and vision items. The measure was administered to 123 individuals with STXBP1-RD. Psychometric evaluation included confirmatory factor analysis, internal consistency, composite reliability, average variance extracted, and distinctiveness, compared with recommended thresholds. RESULTS: Analyses supported a three-domain structure (motor, communication, vision) with factor loadings >0.5 and strong internal consistency (Cronbachs alpha >0.7; composite reliability >0.88). Model fit and variance metrics met recommended standards, and domains demonstrated distinctiveness. No ceiling or floor effects were observed. Minimal skew was seen in motor (0.34) and communication (0.16) domains; positive skew in vision (2.2) was seen, identifying patients with and without cortical visual impairment. INTERPRETATION: The S-CSA demonstrates strong validity and reliability in STXBP1-RD and may show utility in clinical trials for STXBP1-RD and potentially other severe DEEs. Key Words: STXBP1-Related Disorder, Developmental and Epileptic Encephalopathies, Clinical Outcome Assessments

Abstract Background Prediction of long-term neurodevelopmental outcomes remains challenging after perinatal asphyxia. Here, we studied whether computational metrics of brain function derived from neonatal EEG are associated with long-term neurodevelopment in infants with perinatal asphyxia. Methods Total of 36 term-born infants with perinatal asphyxia with or without hypoxic-ischemic encephalopathy were studied with neonatal multichannel electroencephalography (EEG). We computed local EEG amplitudes and phase-amplitude coupling (PAC), as well as large-scale functional cortical networks estimated using amplitude-amplitude correlations (AAC) and phase-phase correlations (PPC). These EEG-derived markers were tested for associations with neurodevelopmental outcomes at two years, assessed using the Griffiths Scales of Child Development, 3rd edition (GMDS-III). Results EEG amplitudes showed positive associations with GMDS-III Foundations of Learning and General Development scores across most electrodes during quiet sleep, with the strongest effects observed at frontal and central regions (r = 0.44-0.66). PAC showed negative associations with the same scores mainly over parietal and temporal regions (r = -0.45 to -0.55). Cortical AAC networks demonstrated the most robust and widespread negative associations in all frequency bands during quiet sleep (r = -0.47 to -0.54), with 70-72% of connections significant in high delta frequency. In turn, PPC networks showed frequency-selective and more spatially constrained negative associations during quiet sleep (r = -0.48 to -0.53), involving 5-12% of the network. Conclusions Both local and network-based metrics in the newborn brain show significant association with neurodevelopmental outcome at 2 years after perinatal asphyxia.

Background and Objectives In ADHD, a heterogeneous neurodevelopmental condition, behavioral and motor manifestations may reflect multiple inefficient or perturbed inhibitory systems. To evaluate Transcranial Magnetic Stimulation (TMS) evoked cortical silent period (CSP) duration, an indicator of GABA(B) receptor-mediated inhibition in motor cortex, as a potential biomarker of Attention-Deficit/Hyperactivity Disorder (ADHD) in children. Method We retrospectively analyzed TMS data, obtained using both round and figure-of-8 coils, from three cross-sectional studies conducted in 8- to 12-year-old children with ADHD (n=79; 10.7 +/- 1.5 years old) and age-and-sex-matched typically developing controls (n=96; 10.5 +/- 1.4 years old). Results Median CSP was 32% shorter in ADHD (p=0.02). Regression analysis demonstrated a relationship between shorter CSP and both lower active motor thresholds (p < 0.0001) and more severe hyperactivity symptom rating (p = 0.026). Test-retest CSP measures in 83 children showed moderate reliability (intraclass correlation 0.77 [ADHD], 0.75 [controls]). Conclusion TMS-evoked CSP may be a useful biomarker in future investigations of ADHD subtypes, domains of impaired function, or treatment outcomes.

Background: Sleep debt and irregular sleep patterns are highly prevalent amongst adolescents. However, whether the absence of these sleep behaviours protects against subsequent depression remains unclear. Here, we examined the association of sleep debt, weekend catch-up sleep (WCS), and social jetlag (SJL) in adolescence with depression in young adulthood and identified underlying biopsychosocial mechanisms. Methods: Secondary data analyses were conducted using the Avon Longitudinal Study of Parents and Children. Bedtimes and wake-up times on school days and weekends (i.e., sleep duration) and sleep need were self-reported at 15 years. This was used to generate sleep debt (sleep need minus school day sleep duration), WCS (weekend sleep duration minus school day sleep duration), and SJL (absolute difference in the midpoint of sleep times between school days and weekends). Depression was assessed at 24 years with the Clinical Interview Schedule-Revised. Common mental health symptoms, biological, and school-related factors at 17 years were the mediators. Results: Logistic regression analyses revealed that greater WCS (adjusted odds ratio [AOR]=0.90; 95% CI=0.84-0.97; p=0.004) and lower sleep debt (AOR=1.10; 95% confidence interval [CI]=1.03-1.18; p=0.005) at age 15 reduced the likelihood of depression at 24 years. Irritability at 17 years partially mediated the relationship between sleep debt and depression (bias-corrected estimate=0.003; 95% CI=0.002-0.004; p<0.001). Conclusions: Adolescents who experience less sleep debt (i.e., less discrepancies between their actual sleep and their perceived sleep need) and those who extend their sleep duration on weekends are at reduced risk for depression in young adulthood. These findings underscore the need for greater opportunities for adolescents to obtain more hours of sleep to protect them against later poor mental health outcomes, such as depression. Keywords: Sleep; longitudinal studies; depression; ALSPAC

Objective Memory impairment is a frequent comorbidity of focal epilepsy, incompletely explained by seizure frequency or structural pathology. Ictal and postictal hippocampal dysfunction disrupt memory processes, but their cumulative impact remains poorly quantified. This study introduces cumulative hippocampal seizure-related burden metrics and examines their association with long-term memory consolidation. Methods Twenty consecutive patients undergoing stereo-EEG in Marseille (2016-2018) were prospectively included. Continuous stereo-EEG recordings between two memory assessments (30 minutes and one week post-encoding) were analysed. Hippocampal ictal involvement and durations were assessed using epileptogenicity markers and visual stereo-EEG analysis. The postictal period was quantified using permutation entropy. Cumulative hippocampal seizure-related burden metrics (ictal, postictal and combined: c-HipSZB) were computed across hippocampus-involving ictal events. Verbal and visual memory were assessed using standardized recall and recognition tasks. Associations were examined using univariate and multivariate analyses. Results Higher dominant-hemisphere hippocampal burden was associated with poorer one-week verbal memory (performance and retention), independently of most covariates. Higher c-HipSZB was associated with lower total recall performance (RT; free + cued) and RT retention ({beta} = -25.04 and -23.88; R2 = 0.57 and 0.53; p < 0.05) and accounted for the greatest variance in both outcomes (adjusted R2= 0.59 and 0.53; {beta} = -25.45 and -24.27; p < 0.01), particularly when adjusting for epilepsy duration. No robust associations were observed between non-dominant-hemisphere hippocampal seizure-related burden metrics and visual memory. Effects predominantly involved recall. Interpretation Cumulative ictal-postictal hippocampal dysfunction is a major determinant of impaired long-term verbal memory consolidation in focal epilepsy.

Background: Thalamic low-intensity transcranial focused ultrasound (tFUS) has shown promise for increasing behavioral responsiveness in disorders of consciousness (DOC), but no study has examined whether it can causally modulate the well-validated behavioral, electrophysiological, and metabolic biomarkers of DOC impairment. Methods: Sixteen adult patients (44% Female; Age, M=37.81, SD=15.97) with a chronic DOC (Time Since Injury, M=3.39, SD=1.94 years) secondary to severe brain injury (TBI 44%, non-TBI 56%) underwent a 10-day inpatient, longitudinal, single-arm, open-label protocol. tFUS was delivered in a single session targeting the left central thalamus. Well-known behavioral (CRS-R), electrophysiological (EEG {delta}/{beta} ratio), metabolic (18F-FDG PET), and polysomnographic outcomes were assessed at baseline and after sonication. Results: The maximum CRS-R total score increased significantly following tFUS compared to baseline (M=13.27 vs. M=10.33; t(14)=7.407, p<0.001, d=1.913), as did the global EEG {delta}/{beta} ratio (N=14; W=17, p=0.025, r=0.68), with the degree of frontal slowing positively predicting behavioral gains ({tau}b=0.51, p=0.016). Glucose metabolism decreased bilaterally in thalamus and frontal, temporal, and parietal cortices at both post-tFUS timepoints compared to baseline. Finally, N2 sleep increased by 33% following tFUS (N=11; t(10)=2.386, p=0.038, d=0.72), though this did not survive correction. No severe adverse events were observed. Conclusion: Thalamic tFUS can causally modulate well-validated behavioral, electrophysiological, and metabolic biomarkers of DOC. The convergent inhibitory signature across these measures suggests a thalamocortical reset mechanism, complementing existing excitatory neuromodulation approaches and providing the mechanistic foundation for a large, randomized sham-controlled trial.

INTRODUCTION: MethylCog is a 29-CpG blood DNA methylation (DNAm) proxy for general cognitive ability (g). Its incremental association with blood biomarkers of Alzheimer's disease and related dementias (ADRD) and prospective cognitive ability remains unclear. METHODS: In the held-out test set from the original MethylCog study, we tested whether MethylCog explained baseline g beyond four ADRD blood biomarkers, and whether it predicted six-year follow-up g beyond baseline g and biomarkers. RESULTS: MethylCog showed a stronger age-adjusted association with baseline g than individual biomarkers (r=.368 vs absolute r=.083-.162). MethylCog added 10.0% variance beyond all four biomarkers cross-sectionally (p<.001) and predicted six-year follow-up g in the biomarker-adjusted model (beta=.108, p=.002). No individual ADRD biomarker independently predicted follow-up g. DISCUSSION: MethylCog may provide cognition-related DNAm information complementary to blood-based ADRD biomarkers.

Background: Patients in socioeconomically disadvantaged neighborhoods face barriers to care. Missing BP documentation may signal gaps in risk-factor management, a crucial component of primary and secondary prevention of intracerebral hemorrhage (ICH). We tested whether neighborhood deprivation was associated with absent electronic health record (EHR) blood pressure (BP) documentation surrounding ICH and whether absent documentation predicted subsequent uncontrolled BP. Methods: We conducted a case-only study within the NIH All of Us Research Program. We included ICH survivors (ICD-10 I61.x, surviving >=1 year) with available ZIP3-based Deprivation Index. Deprivation was categorized as Privileged, Intermediate, or Deprived using cohort-based tertiles. We excluded BP measurements collected by All of Us. Outcomes were (1) absent EHR-derived BP documentation and (2) uncontrolled BP (mean systolic BP >=140 mmHg) during three windows: 1-365 days before ICH; 30-365 days and 1-5 years after ICH. Multivariable logistic regression tested associations adjusting for age, sex, and race/ethnicity. Results: 1,474 ICH survivors were included (mean age 60.1, 50.4% female). Compared to privileged neighborhoods, those living in deprived neighborhoods had higher odds of absent EHR BP documentation in the year prior to ICH (OR 2.10, 95% CI 1.60-2.76; p<0.001), 30-365 days post-ICH (OR 2.82, 95% CI 2.14-3.73; p<0.001) and 1-5 years post-ICH (OR 2.81, 95% CI 2.13-3.71; p<0.001). Absence of EHR BP documentation in the year before ICH predicted uncontrolled BP 30-365 days (OR 1.97, 95% CI 1.36-2.85; p<0.001; N=888) and 1-5 years (OR 1.83, 95% CI 1.24-2.69; p=0.002; N=814) after ICH. Absence of BP documentation 30-365 days post-ICH also predicted uncontrolled BP 1-5 years post-ICH (OR 1.66, 95% CI 1.10-2.50; p=0.017; N=814). Conclusions: Neighborhood deprivation is associated with persistent gaps in EHR BP documentation surrounding ICH, and absent documentation before or soon after ICH predicts subsequent uncontrolled BP. These findings highlight the need for community-level strategies that ensure equitable BP monitoring for socioeconomically disadvantaged populations.

Introduction: Menstrual cycle phase has been proposed as a source of intra-individual variability in resting energy expenditure and the thermic effect of food in premenopausal females, yet studies examining the thermic effect of food across menstrual cycle phases report conflicting findings. Methods: This protocol describes a secondary analysis of prespecified outcomes from a non-randomized, two-period crossover trial primarily designed to assess postprandial plasma triglyceride concentrations across menstrual cycle phases (ClinicalTrials.gov: NCT07459465) in 12 premenopausal females aged 18-30 years, free of chronic disease and hormonal contraceptive use, recruited in Ottawa, Canada. Participants complete two experimental sessions: one in the early follicular phase and one in the mid-luteal phase, each involving consumption of a high-fat meal. Eleven secondary outcomes will be reported: fasting resting energy expenditure, thermic effect of food, respiratory exchange ratio, carbohydrate oxidation rate, lipid oxidation rate, desire to eat, hunger, fullness, prospective food consumption, serum beta-estradiol, and serum progesterone. Masked outcome analyses are performed using linear mixed-effects models. Results: Recruitment began on 26 March 2026; results will be reported in the Stage 2 manuscript. Discussion: Findings from this trial may help clarify whether menstrual cycle phase constitutes a meaningful source of intra-individual variability in energy metabolism, with implications for the design of metabolic research in premenopausal females.

Importance: Little is known about the impact of returning Alzheimer disease (AD) biomarkers to cognitively unimpaired (CU) research participants. Objective: Does return of research results (RoRR) negatively impact longitudinal symptoms of depression and cognition. Design: Randomized, noninferiority, delayed-start clinical trial, 2021-2025 Setting: AD biomarker research results offered to CU participants in a longitudinal study of aging Participants: CU participants age 65+ were offered research AD biomarker results (APOE genotype and either plasma AB42/40 or amyloid PET and MRI hippocampal volume) with an estimated 5-year risk of symptomatic AD. Intervention(s) (for clinical trials) or Exposure(s) (for observational studies): 147 participants were randomized to receive results either soon after consent (RoRR arm, N=73) or one year later (delayed-start arm, N=74). Main Outcome(s) and Measure(s): Longitudinal change in Geriatric Depression Scale (GDS), Clinical Dementia Rating sum of boxes (CDR-SB), and global cognitive composite. Outcomes were measured at annual assessments for a longitudinal study of aging. Results: 187 participants received results: 70 in RoRR arm (average age 75, 60% female), 66 in delayed-start arm (average age 73, 53% female). The observed changes in annual measures did not differ between arms in both those with elevated amyloid (AB+) and in those without elevated amyloid (AB-) for GDS (AB+ difference 0.7, 95% CI 0.0-1.3; AB- difference -0.1, 95% CI -0.7-0.5; clinically significant decline >4.0), CDR-SB (AB+ difference 0.0, 95% CI -0.1-0.1; AB difference 0.0, 95% CI 0.0-0.1; clinically significant decline >0.5), and cognitive composite (AB+ difference -0.10, 95% CI -0.25-0.06; AB- difference -0.05, 95% CI -0.17-0.07; clinically significant decline < -0.26). Secondary analyses found no evidence of association between RoRR and proximity to follow-up testing. Conclusions and Relevance: In the first randomized, delayed-start clinical trial of returning AD research results to CU older-adult participants, no effect was seen on longitudinal changes in symptoms of depression or cognition. This supports evidence that there are no harms to returning AD research results, although the results may not apply to more diverse populations not included in this study. Trial Registration: NCT04699786

ABSTRACT INTRODUCTION: Microscopic fractional anisotropy ({micro}FA), an emerging diffusion MRI metric, may be more sensitive than conventional metrics to gray matter microstructural changes in neurodegeneration. This pilot study compared {micro}FA, mean diffusivity (MD), and volume between genetic frontotemporal dementia (FTD) variant carriers and non-carriers in the insula, frontal pole, and medial orbitofrontal cortex (mOFC). METHODS: Carriers and familial non-carriers of FTD variants in C9orf72, GRN, or MAPT were scanned between October 2024-December 2025. Non-parametric aligned rank transform ANCOVAs were computed to analyze between-group differences in {micro}FA, MD, and volume while controlling for age. RESULTS: Carriers (n=12) exhibited lower insula {micro}FA than non-carriers (n=8): F(1,19)=5.89, 95% CI [-10.7,-0.75], p=0.027, 2p=0.26. No group-differences were observed in other metrics, including MD and volume. DISCUSSION: Reduced {micro}FA in the insula, a region vulnerable to early atrophy in FTD, may be more sensitive to early microstructural changes in genetic FTD than traditional diffusivity measures.

Objectives. Despite the body of literature on genetic risk factors for dementia, little is known on protective genetic factors associated with favourable cognitive ageing in the oldest population. In Europe, Italy has a leading position with a swelling population of centenarians, and the urban area of Genoa in the Liguria region has one of the highest prevalence of centenarians. The COOL study is a not-for-profit, multicentric study involving a cohort of centenarians (aged >99) living in the Genoa area. The ultimate aim is the identification of genomic biomarkers associated with cognition in the oldest old population. Results. Participants underwent a semi-structured interview on personal, disease and family history, and a neuropsychological assessment of the main cognitive domains. As of July 2025, we enrolled 88 centenarians (age range: 99-108, median 100.56) with and without cognitive impairment; 32 subjects were followed up. All participants were of Italian ancestry, 81% were female. The cognitive profile in assessed subjects showed a wide range of cognitive health measures (CDR 0-5; MMSE 3-30, median 24). Whole peripheral blood and DNA samples from 67 participants were stored. Conclusions. We demonstrated that the protocol is feasible, and acceptable by participants and their families. A comprehensive phenotype dataset was established, and DNA samples were stored. Centenarians exhibited a broad spectrum of cognitive profiles, from preserved cognition to severe dementia. These findings will eventually allow to interpret the profiles of genomic variants as associated with variability of cognitive performance in centenarians. The molecular underpinnings of healthy cognitive ageing could inform health policy strategies in the general population.

Objective: Interictal spikes have been proposed as a biomarker for both localizing seizure onset zones (SOZ) and tracking changes in seizure risk with neurostimulation in patients with drug-resistant epilepsy. Electrical stimulation can modulate spike rates acutely, and it has been proposed that measuring this modulation can help localize the SOZ. However, it is unclear whether stimulation-induced spike rate changes reflect epilepsy-specific pathology in the stimulated network or simply intrinsic regional excitability, which limits our understanding of their utility in epilepsy surgery planning. Methods: We analyzed low-frequency stimulation (LFS; 1 Hz) applied during a clinical seizure-induction protocol systematically targeting multiple brain regions in 43 patients with drug-resistant epilepsy undergoing intracranial EEG monitoring. A validated, automated spike detector was used to quantify pre-, during-, and post-stimulation spike rates. We tested whether the stimulation-evoked spike rate response (i) tracks the expected change in seizure risk from a seizure induction protocol, (ii) varies with anatomical stimulation site and epilepsy localization, (iii) localizes the SOZ beyond baseline spike rate, and (iv) is accompanied by changes in spike morphology. Results: Nearby LFS acutely increased spike rates in high-spiking channels (inter-stimulation median 2.25 vs. during-stimulation 4.25 spikes/min; p < 0.001), with effects attenuating with distance and resolving within approximately 30 seconds of stimulation offset. Mesial temporal lobe stimulation produced the largest increase in nearby spike rates relative to temporal neocortex and other cortex (Kruskal-Wallis p = 0.003), but this effect did not differ between patients with and without mesial temporal lobe epilepsy. A random forest classifier incorporating stimulation-evoked modulation features achieved an AUC of 0.787, comparable to a resting-state spike model (AUC 0.747; DeLong p = 0.81), indicating that stimulation-evoked spike changes do not add localizing information beyond resting-state spike rates. Stimulation produced a small but significant shift in spike morphology toward broader, higher-amplitude discharges (PERMANOVA p < 0.001), consistent with recruitment of a broader neuronal population. Significance: LFS-evoked increases in interictal spike rates reflect intrinsic regional excitability, greatest in the mesial temporal lobe, rather than epilepsy-specific pathology, and do not improve SOZ localization over resting-state spike rates. These results argue against using the change in spikes with stimulation to localize the SOZ. On the other hand, the transient spike rate increase induced by a pro-epileptic protocol supports the acute change in spike rate as a biomarker of the effect of stimulation on seizure risk, with potential to guide parameter selection for epilepsy neuromodulation.