Neurobiology of Learning and Memory

Anxiety-related traits (ARTs) have been linked to altered fear learning, but previous studies have typically examined different experimental phases and response systems, limiting the comparability of findings and the accumulation of consistent evidence. Here, we comprehensively examined associations between ARTs and fear conditioning across acquisition, extinction and renewal and across subjective, physiological and neural response systems in a well-powered sample (N = 267) using a two-day differential conditioning paradigm. ARTs were operationalized as a composite of trait anxiety, neuroticism, and intolerance of uncertainty and conditioned responding was assessed using skin conductance responses, fear-potentiated startle, US expectancy ratings, fear ratings, and functional magnetic resonance imaging. Higher ARTs were consistently associated with elevated subjective fear and US expectancy to both threat and safety cues during extinction and renewal, without corresponding elevations in physiological responding. At the same time, ARTs were not associated with threat-safety discrimination in subjective or physiological measures across phases, while neural associations were limited to reduced dorsal anterior cingulate cortex discrimination during early renewal. These findings suggest that ARTs are characterized by a CS unspecific cognitive bias toward heightened threat expectancy and evaluation rather than altered associative fear learning, highlighting the importance of distinguishing conditioned discrimination from general levels of responding across response systems.

Abstract: Objective: Post-traumatic epilepsy (PTE) is a common sequela of traumatic brain injury (TBI). Research indicates that individuals with PTE tend to experience greater cognitive difficulties compared to those with TBI alone. However, it is plausible that a distinct cognitive profile exists that distinguishes between TBI cases with and without PTE. We aimed to identify longitudinal changes in cognitive measures among TBI patients to better assess the changes associated with developing PTE. Setting: Outpatient. Participants: Prospective subjects who had suffered TBI within 6 months post-injury (TBI-6M, n=32), retrospective subjects with pre-existing PTE diagnoses (PTE, n=20), and healthy control subjects (HC, n=41). Design: We examined cognitive performance for TBI patients within 6 months post-injury, then again within 12 months (TBI-12M, n=26), and within 18-months (TBI-18M, n=25), and compared this with cognitive performance among HC and PTE. Main Measures: Cognitive tests administered yielded 15 test components for analysis. We utilized linear mixed effects modeling to examine cohort-level differences cognitive function. Results: 11/15 tests showed a significant performance deficit in the PTE subjects compared to HC. TBI-6M was not significantly different from the PTE subjects; with time, 9/15 tests showed some degree of recovery in TBI subjects. Tests for information processing speed/working memory and executive function showed strong recovery (TBI-6M vs. TBI-18M, SDMT written: p<0.0001, SDMT oral and COWAT: p<0.001). Tests for visual attention/working memory also showed a smaller but significant recovery (TBI-18M vs. PTE, p<0.05). By contrast, tests for verbal memory [HVLT-R Delayed Recall] showed chronic impairment in TBI (TBI-18M vs HC, p<0.0001). TBI subjects generally trend towards recovery in cognitive performance post-TBI. Conclusions: Information processing speed/working memory are strong indicators for TBI recovery, while auditory learning/memory shows chronic impairment. The stagnation of recovery in cognitive domains typically characterized by robust recovery may correlate with an elevated risk of developing PTE.

Working memory is capacity-limited, but interactions with episodic memory may offset this constraint. We tested moment-by-moment contributions of episodic representations to working memory by combining the N-back and Mnemonic Similarity tasks. Thirty-one participants, undergoing eye-tracking, first encoded items in a one-back task, classifying them as "same" or "similar" to their predecessor. In a subsequent two-back task, mnemonic discrimination showed a graded, item-specific benefit of prior experience: performance was best for previously compared items, whereas recognition of identical repeats was unaffected. Successful discrimination of previously compared items was accompanied by greater pupil dilation, gradually emerging gaze patterns resembling those elicited by their similar pair-mate, and higher gaze-similarity between one-back and two-back target viewing. Diverging gaze patterns between pair-mates during one-back further predicted two-back discrimination. These findings challenge working memory's characterization as an isolated system, demonstrating how it recruits episodic computations - encoding distinct traces, predicting upcoming content, and reinstating it at retrieval.

BACKGROUND: An individual's adaptation to threatening environments under uncertainty is reflected in stress responses. Predictability (the ability to anticipate events) and controllability (the ability to control outcomes) are central to how one adapts, yet their joint influence on aversive learning remains unclear. METHODS: Thirty healthy adults completed a probabilistic aversive learning task in which cue-outcome contingencies varied across levels of predictability and controllability, i.e. whether shock intensity depended on prediction accuracy. Prediction accuracy, reaction time, subjective stress ratings, and skin conductance responses were recorded throughout. Trial-wise learning dynamics were estimated using the Volatile Kalman Filter. RESULTS: Prediction accuracy reduced as environments became less predictable and negatively associated with higher learning rates across predictability levels, with the strongest relationship observed in highly predictable blocks. Skin conductance responses showed that moderately predictable environments elicited responses like those in highly predictable environments when accurate predictions reduced shock intensity, but resembled responses in unpredictable environments when shock intensity was uncontrollable. Model comparison revealed a double dissociation between subjective stress ratings and skin conductance responses. Subjective ratings were best explained by model-derived volatility when prediction accuracy determined shock intensity and by belief uncertainty when it was independent of prediction accuracy, whereas skin conductance responses showed the reverse pattern. Reaction times were best explained by belief uncertainty when predictions influenced shock intensity. Higher anxiety was associated with elevated learning rates in highly and moderately predictable blocks when predictions did not control shock intensity.

Objective: Cognitive impairment is a common comorbidity among people with epilepsy (PWE) and is associated with disability and reduced quality of life. We characterized the burden of cognitive impairment and identified factors associated with cognitive performance in a large, population-based cohort of PWE living in Northern Peru, a region highly endemic for Taenia solium where neurocysticercosis (NCC) is a common cause of acquired epilepsy. Methods: PWE enrolled in a population-based cohort in Northern Peru between 2007 and 2020 completed the Mini-Mental State Examination (MMSE) at enrollment. Cognitive impairment was defined as an MMSE score <24. Demographic and clinical data, including epilepsy characteristics and NCC status, were collected. Negative binomial regression was used to identify factors associated with the number of MMSE errors. Results: Among 764 participants, the mean MMSE score was 26.4 (SD 4.2), and 16.4% met criteria for cognitive impairment. Memory and attention were the most affected domains. In multivariable analysis, older age and lower educational attainment were independently associated with poorer cognitive performance. Conclusion: In this large, community-based cohort from Northern Peru, approximately 1 in 6 PWE had abnormal global cognition on the MMSE, with memory and attention most affected. These findings underscore the importance of incorporating cognitive evaluation and management into comprehensive epilepsy care, particularly in resource-limited settings where cognitive morbidity may be underrecognized. Given the potential for cognitive difficulties to compound disability and adversely affect quality of life, identifying and addressing cognitive morbidity may be especially important in populations already facing substantial barriers to epilepsy care.

Objective: To determine whether paradoxical relief, feeling unusually better after a seizure compared to before it, is more common after functional/dissociative seizures (FDS) than epileptic seizures (ES), quantify its diagnostic accuracy, and explore its relationship with preictal symptoms. Methods: Consecutive patients admitted to a tertiary epilepsy unit for prolonged inpatient EEG monitoring underwent a structured clinical interview on admission, before final multidisciplinary diagnostic classification. Preictal dissociative and autonomic/somatic symptom burden was assessed using items adapted from established questionnaires. Diagnostic classification incorporated clinical history, seizure semiology, video electroencephalography findings, and collateral information. Patients with dual or indeterminate diagnoses were excluded. Associations with paradoxical relief were examined using logistic regression, followed by an exploratory mediation analysis. Results: Of 176 patients assessed, 66 with FDS and 65 with ES were included. Paradoxical relief was reported by 46/66 patients with FDS (69.7%) and 10/65 with ES (15.4%; unadjusted odds ratio [OR] 12.65, 95% confidence interval [CI] 5.57 to 31.09). As a diagnostic signal for FDS, paradoxical relief had 69.7% sensitivity (95% CI 57.1 to 80.4), 84.6% specificity (95% CI 73.5 to 92.4), a positive likelihood ratio of 4.53 (2.51 to 8.19), and a negative likelihood ratio of 0.36 (0.24 to 0.52). FDS diagnosis remained independently associated with paradoxical relief after adjustment (OR 10.59, 95% CI 3.42 to 38.06). In a parallel mediation analysis, dissociative symptom burden showed a significant indirect effect, accounting for 19.5% of the association between diagnostic group and relief, whereas the indirect effect through somatic/autonomic symptom burden was not significant. Significance: Paradoxical relief is substantially more common after FDS than ES and may provide a simple, clinically useful diagnostic signal. Its absence does not exclude FDS, and the finding requires external validation. The association with dissociative symptoms is exploratory and supports prospective investigation of whether relief reflects transient resolution of a disturbed, disembodied preictal state.

Objective: Whether a scheduled antiseizure medication (ASM) continues on schedule across the ICU-to-floor transfer has not been characterized. We quantified ASM administration-gap frequency across this transfer and compared it with gap frequency during matched non-transfer intervals in the same patient and drug. Methods: In this retrospective MIMIC-IV (version 3.1) cohort study, we identified epilepsy and status-epilepticus admissions with an ICU stay followed by floor transfer and a scheduled ASM order active at ICU departure. A gap was defined as an interval exceeding 1.5 times the expected dosing interval between the last ICU dose and first floor dose, or no further dose before discharge, and compared with a matched non-transfer control interval in the same patient and drug (paired McNemar test). A multivariable model evaluated six prespecified clinical predictors; sociodemographic variables were summarized descriptively. Results: Among 2,469 ASM transition-by-drug observations (1,583 admissions, 1,335 patients), an administration gap occurred in 251 (10.2%; 95% CI, 8.7%-11.7%). Gap frequency across the transfer exceeded frequency during matched non-transfer control intervals in the same patient and drug: a paired rate difference of 5.8 percentage points (95% CI, 4.4-7.1; 7.5% vs 1.7%; P = 7.3 x 10^-22) before the transfer and 6.4 percentage points (95% CI, 4.9-7.9; 8.9% vs 2.5%; P = 1.9 x 10^-23) after. Gap rates were similar for intravenous-available (9.9%) and oral-only (11.4%) drugs (rate difference, 1.5 percentage points; 95% CI, -1.6 to 4.5; P = .34). None of six prespecified predictors reached significance after correction. Significance: An antiseizure medication administration gap occurred in approximately 1 of every 10 drug-transition observations at the ICU-to-floor transfer, exceeding matched non-transfer gap rates by 5.8 to 6.4 percentage points. This transfer-associated excess, rather than any single medication or patient characteristic, supports a structured medication-continuity check.

Excitatory synaptic plasticity within the nucleus accumbens (NAc) drives motivated behaviors, and dysregulation is implicated in several psychiatric disorders marked by impaired reward processing. The NAc integrates glutamatergic input, which conveys information about reward, context, and behavioral goals, with local GABAergic signaling that regulates excitatory transmission and medium spiny neuron (MSNs) output. However, little is known regarding GABA-dependent modulation of activity-dependent excitatory synaptic plasticity. Here, we investigated GABAB receptor (GABABR) regulation of plasticity at hippocampus (Hipp)-NAc synapses, at which plasticity is a key mediator of reward-related behaviors. Using whole-cell electrophysiological recordings in mouse brain slices, we found that pharmacological inhibition of GABABRs converts long-term potentiation (LTP) into long-term depression (LTD) selectively in females, identifying a sex-specific role for GABABRs in modulating long-term plasticity of Hipp-MSN synapses. This LTD required mGluR5 activation and estrogen receptor alpha (ER) in both D1- and D2-expressing MSN subtypes, while only D1-MSNs suggested that LTD was expressed presynaptically through a CB1 receptor-dependent mechanism. Notably, GABABR inhibition did not alter basal synaptic transmission, indicating a specific role for these receptors in gating plasticity beyond regulation of basal excitatory drive. Together, these findings identify a novel, sex-specific mechanism by which GABABRs control the direction of synaptic plasticity.

Opioid addiction treatment is often hampered by the severe dysphoria of opioid withdrawal, but withdrawal treatments are limited by incomplete understanding of brain mechanisms involved. One area frequently implicated in withdrawal symptoms is the central amygdala, whose capsular portion (CeC) is particularly strongly activated during withdrawal. Additionally, a ventral posterior striatal region that resides near CeC, the interstitial nucleus of the posterior limb of the anterior commissure (IPACc), is also activated as strikingly as CeC. However, it is still unknown how these regions are activated, nor whether their activation explains the high intensity of withdrawal dysphoria. Using RNAscope, we found that c-fos expression is induced in the parabrachial nucleus (PB), a key glutamatergic afferent of CeC, after precipitated morphine withdrawal. Chemogenetic inhibition of PB glutamatergic neurons (VG2PB) nearly eliminated withdrawal-induced CeC c-Fos, without affecting IPACc c-Fos, indicating these two nuclei are activated by distinct sources. Furthermore, VG2PB inhibition markedly reduced somatic (jumping) and modestly reduced affective (place avoidance) withdrawal behavior. On the other hand, inhibition of CeC-projecting PB neuronal subtypes expressing calcitonin gene-related peptide (CGRP) or mu opioid receptor (MOR) reduced place avoidance without affecting jumping, indicating their specific role in withdrawal aversion. Strikingly, simultaneous inhibition of VG2PB and posterior striatal region containing IPACc robustly reduced withdrawal-induced place avoidance much more than the modest effects of either inhibition alone, suggesting their cooperative action in driving aversion. Our data suggests that PB-CeC circuit and posterior striatal area constitute a cooperative system driving opioid withdrawal aversion.

Background: Stress research in nursing education has largely focused on distress, stressors, and negative outcomes, although challenging experiences may also support motivation, confidence, learning, and growth when appraised positively. Objective: To develop and evaluate the psychometric properties of the Nursing Student Positive Stress Scale (NSPSS). Design: A methodological instrument development and psychometric evaluation study. Methods: The NSPSS was developed using a deductive, theory-driven approach informed by the transactional theory of stress and coping and positive psychology perspectives. Content validity was assessed by an international nursing expert panel. Psychometric evaluation used national survey data from nursing students in New Zealand. Of 539 responses, 507 were analysed. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were conducted using separate subsamples. Internal consistency was assessed using Cronbach's alpha and McDonald's omega, and convergent validity through correlation with Perceived Stress Scale-10 scores. Results: Content validity was strong (I-CVI = .88-1.00; S-CVI/Ave = .975; S-CVI/UA = .800). EFA identified a dominant factor explaining 41.38% of variance (loadings = .528-.735). CFA supported a two-context Academic and Clinical Positive Stress model with correlated residuals between five parallel item pairs, chi-square(29) = 60.49, CFI = .970, TLI = .954, RMSEA = .063, SRMR = .065. Internal consistency was good (alpha = .839; omega = .843). NSPSS scores correlated negatively with PSS-10 scores (r = -.298, p < .001). Conclusion: The NSPSS demonstrated strong content validity, preliminary evidence of structural and convergent validity, and good internal consistency reliability for assessing positive stress appraisal among nursing students. Further validation in independent samples is warranted.

Background: Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system marked by demyelination and neurodegeneration. Beyond physical symptoms, MS is often linked to clinically relevant sleep disturbances. The variability and unpredictability of symptoms and disease progression can also fuel fear of relapse (FoR), undermining well-being and potentially increasing morbidity through inflammatory processes. Understanding biopsychosocial risk factors, including childhood maltreatment (CM) and sleep, in relation to FoR remains an important gap in MS management and research. Methods: Data from N = 48 participants were collected via an online survey. We used the Pittsburgh Sleep Quality Index (PSQI), the Fear-of-Relapse Scale (FoR), and the Childhood Trauma Questionnaire (CTQ) to assess the variables of interest. In addition, time points of exposure to different CM subtypes were assessed. Linear regression analyses were conducted to examine associations within the proposed negative triad. Results: A significant negative association between overall sleep quality and FoR was observed. In the total cohort, the interaction between CM and sleep was not a significant predictor of FoR. However, exploratory analysis revealed a significant interaction between CM and sleep among male participants, whereas the same interaction was not significant among female participants. Conclusion: A history of CM and impaired sleep quality introduce new stressors in managing one's own illness that have received little attention to date. However, the present study found that these factors were at least partly influential on the FoR. The results underscore the translational need for additional support services to enhance prevention and personalized care.

Despite its strong link to neuropsychiatric conditions, frustration remains critically understudied in humans and animals alike. Therefore, there is an urgent need to develop tools to understand and therapeutically target frustration-related functions. Interestingly, humans and rats respond similarly during frustrative nonreward by increasing barpress durations. We previously validated barpress duration in rat operant tasks as a reliable measure of frustration-related behavior; however, it is wellknown that in addition to duration of responding, emotional states such as frustration alter other aspects of responding such as force of pressing. One-dimensional, static measures such as maximum force could miss rich information contained within operant data. Thus, the objective of this study is to apply machine learning (ML) to force/time profiles to discriminate frustration-related barpresses from non-frustration-related barpresses. Results showed an AUROC for FR1 (i.e., non-frustrated) vs. extinction (frustrated condition) for individual barpresses of 0.65 that improved to 0.84 with a chunk size of 10. The model generalized well to progressive ratio responding, a different kind of frustration procedure. We conclude that force/time profiling does provide utility beyond one dimensional measures of duration or force separately, meaning that we can indeed infer the internal state of frustration from behavior using ML techniques. Importantly, this project will also serve as proof-of-concept for applying ML to predict other internal states from barpress data.

Background: On-call clinicians frequently report the anecdotal impression of 'theme shifts' during which specific acute neurological diagnoses appear to cluster. Whether such clustering reflects a statistically true and reproducible phenomenon has not been systematically investigated; the present paper examines seasonality and temporal clustering within six different acute neurological conditions. Methods: In this retrospective, single-center cohort study, we identified all patients admitted to a tertiary neurological department between July 2016 and June 2026 with acute unilateral vestibulopathy, cerebral artery dissection, generalized epileptic seizures, primary intracerebral hemorrhage, peripheral facial nerve palsy, or transient global amnesia (TGA) (n = 2,140). Monthly and seasonal distributions were assessed using chi-squared goodness-of-fit and cosinor analysis. Short-term temporal clustering was tested by Monte Carlo permutation across time windows from 24 hours to 90 days, and endogenous cluster dynamics were characterized using Hawkes self-exciting point process modeling. Results: Admissions for generalized epileptic seizures showed a statistically significant deviation from a uniform monthly distribution with a winter distribution (p<0.001 and q = 0.002), and a significant temporal clustering across time windows from 72 hours to 90 days (all q < 0.05). Peripheral facial nerve palsy presented significant clustering at the 90-day window (q = 0.029) and TGA at 60-day time window (q = 0.041) without seasonality; the diagnostic groups of acute unilateral vestibulopathy, cerebral artery dissection and primary intracerebral hemorrhage showed neither seasonality nor clustering after correction for multiple comparison. No diagnostic group showed clustering within a 24-hour window, statistically significant self-excitation in Hawkes process modelling, or a significant linear trend in monthly case counts over the study period. Conclusion: The anecdotal impression of diagnostic 'theme shifts' among on-call neurologists appears to have a measurable basis, although clustering is confined to specific conditions and rather on a time scale of weeks to months. Generalized epileptic seizures were the only diagnostic group that uniquely combined seasonality with temporal clustering, suggesting a shared trigger, while facial palsy and TGA showed episodic, yet non-seasonal clustering.

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

Background: Storage symptoms after stroke-isolated urgency, urgency with frequency, and isolated frequency are common but traditionally attributed to a single overactive bladder mechanism via suprapontine disinhibition. However, clinical heterogeneity in symptom presentation suggests distinct underlying mechanisms. We aimed to characterize the neural substrates of three storage symptom subtypes after stroke using comprehensive lesion-symptom mapping. Methods: We prospectively evaluated 1,498 consecutive subacute stroke patients admitted for inpatient rehabilitation (1,105 men, 73.8%; median age 61 years). Storage symptoms were classified into three subtypes: isolated urgency (n=109), urgency with frequency (n=32), and isolated frequency (n=19). Multivariable logistic regression models with Bonferroni correction identified independent predictors across demographic, clinical, white matter hyperintensity (WMH), brain atrophy, and lesion location variables. Results: The three subtypes demonstrated largely distinct sets of independent predictors. The left genu of the corpus callosum (aOR=20.06, 95% CI 7.78-51.74, P<0.001) and the inferior frontal gyrus (aOR=3.48, 95% CI 1.81-6.67, P<0.001) were independently associated with isolated urgency and survived Bonferroni correction, together with a right IFG-insula synergistic effect (OR=21.46, 95% CI 10.49-43.88, P<0.001). Urgency with frequency was associated with a broad fronto-cingulate network-the IFG (aOR=11.45, 95% CI 3.10-42.33, P<0.001, surviving Bonferroni correction) and the ACC (aOR=11.53, 95% CI 2.40-55.49, P=0.002) with diffuse right-hemisphere dominance, older age and brain atrophy. Isolated frequency was associated with anterior corona radiata involvement (aOR=5.46, 95% CI 1.92-15.54, P=0.002) and male sex (aOR=10.62, 95% CI 1.36-82.98, P=0.024), though none reached the strict Bonferroni threshold. Conclusions: These findings identify three mechanistically distinct post-stroke storage symptom subtypes with separable neural substrates, lateralization profiles, and clinical determinants. The triple dissociation across subtypes supports a discrete pathway model over the traditional unitary OAB framework, providing a neuroanatomically grounded basis for subtype-stratified treatment Keywords: storage symptoms; subacute stroke; hemispheric lateralization; structural synergy; lesion-syndrome mapping

The olfactory and intranasal trigeminal systems interact closely, influencing chemosensory perception, yet the mechanisms underlying their interaction remain poorly understood and have been studied mainly in young adults. We aimed to characterize olfactory-trigeminal interactions in aging by comparing electrophysiological and behavioral responses under ipsilateral and contralateral olfactory-trigeminal co-stimulation, to determine the relative contributions of peripheral and central mechanisms. Using chemosensory event-related potentials and a localization task, 44 healthy older adults (66.3 {+/-} 4.6 years; 29 women) were tested under four conditions: pure trigeminal (carbon dioxide; CO2), pure olfactory (2-phenylethanol; PEA), ipsilateral co-stimulation (PEA+CO2 in the same nostril), and contralateral co-stimulation (PEA+CO2 in opposite nostrils). Ipsilateral, but not contralateral olfactory-trigeminal co-stimulation, improved trigeminal localization performance and induced larger late positive component amplitudes. Together, these findings suggest that olfactory-trigeminal interactions are driven primarily by peripheral rather than central mechanisms. This study also provides normative CSERP data for healthy older adults.

Background: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic risk factor for Parkinson's disease (PD). G2019S, the most common pathogenic variant, has been linked to milder motor symptoms, but the effects of other LRRK2 variants on disease trajectory remain incompletely characterized. R1441G, the second most common pathogenic variant, co-occurs with the PD risk variant M1646T on a shared haplotype. Whether this haplotype confers a distinct rate of motor progression has not been established. Methods: We analyzed up to 12 years of longitudinal data from 603 participants in the Parkinson's Progression Markers Initiative (PPMI) with PD and available whole-genome sequencing data: 394 sporadic PD, 169 G2019S carriers, 20 R1441G+M1646T carriers, and 20 M1646T carriers. Motor symptom progression (MDS-UPDRS III) was assessed using linear mixed-effects models with genotype-by-time interactions, adjusted for age at onset, disease duration at baseline, sex, race, baseline score, and levodopa equivalent daily dose. Results: R1441G+M1646T carriers exhibited 76% slower progression in OFF-state MDS-UPDRS III than sporadic PD (0.50 vs. 2.04 points/year; {beta}=-1.54 [95% CI: -2.48, -0.60]; p=0.001). G2019S carriers exhibited 26% slower progression (1.52 points/year; {beta}=-0.52 [-0.99, -0.06]; p=0.03). M1646T carriers did not differ from sporadic PD (p=0.60). Slower progression in R1441G+M1646T carriers was characterized by attenuated bradykinesia (64% slower; p=0.008), axial decline (76% slower; p=0.002), and a lack of orofacial symptom progression (p<0.001). R1441G+M1646T carriers also exhibited 55% slower self-reported motor decline (MDS-UPDRS II; p=0.04) Conclusions: R1441G+M1646T carriers exhibit substantially slower motor progression than sporadic PD while M1646T carriers do not.

BackgroundLocomotor adaptation is essential for adjusting walking patterns to complex environments. This study investigated locomotor adaptation deficits in people with Parkinsons disease (PD) and examined oscillatory activity in the globus pallidus internus (GPi) during walking adaptation. We hypothesized that elevated beta-band activity in the GPi is associated with reduced locomotor adaptability in PD. MethodsTwelve PD patients with GPi deep brain stimulation (DBS) (eleven bilateral and one unilateral) were included. Local field potentials (LFPs) were recorded from DBS electrodes during split-belt treadmill walking. Patients were tested in the medication-off, DBS-off state. Locomotor adaptation was measured as the change in step length asymmetry during split-belt walking, with smaller changes indicating greater adaptation deficits. ResultsWe found that GPi high beta (20-30 Hz) and low gamma (30-60 Hz) oscillations were modulated during split-belt walking. Compared to adapters, non-adapters showed decreased movement-related beta suppression during walking. Across participants, beta activity in the GPi contralateral to the fast leg was negatively associated with adaptation magnitude (Spearmans {rho} = -0.65 to -0.75). ConclusionsGPi oscillations are dynamically modulated during locomotor adaptation in PD. Increased beta activity may underlie impaired sensorimotor adaptation during walking. These findings provide novel insight into basal ganglia mechanisms of gait adaptation in PD and suggest that elevated GPi beta activity may serve as a marker of locomotor adaptation deficits.

During wakefulness, we are used to perceive the environment through our senses, act on it and take these inputs to update our experiences and build the perceptions. When the inputs are not longer accurate or structured, people would sometimes have hallucinatory experiences. Whether such experiences are associated with distinct patterns of thought, and how they relate to large scale brain dynamics, remains unclear. To address these questions, we combined experience sampling protocol with EEG recording during multimodal Ganzfeld, where participants were exposed to unstructured, uniform visual and auditory stimulation. Participants repeatedly reported the complexity of their visual experiences together with ongoing thoughts related to perceptual belief, prediction perception mismatch, active updating, and prior mentation. EEG microstates were extracted to characterize the temporal dynamics of large-scale brain networks. We found that visual complexity was related to all four dimensions, but partly distinct in simple and complex visual experiences. These phenomenological changes were accompanied by distinct, and often nonlinear, dynamics of large-scale brain networks involved in visual processing, salience detection, and internally directed cognition. It also indicates that this paradigm might be a valuable model for investigating the mechanisms underlying hallucinatory experiences in psychosis.

Background Alcohol use disorder (AUD) is highly prevalent in schizophrenia, yet the neurobiological basis of this vulnerability remains poorly understood. Neurodevelopmental models suggest that pre-existing brain dysconnectivity may increase vulnerability to AUD. We therefore tested whether schizophrenia-like neurodevelopmental pathology alters how alcohol-related experience is incorporated into large-scale brain networks. Methods Resting-state functional connectivity was assessed in male Sprague-Dawley rats (n = 18-21/group) with neonatal ventral hippocampal lesions (NVHL), a neurodevelopmental model of schizophrenia, and sham-operated controls, with or without voluntary adolescent alcohol exposure. Functional connectivity was assessed using seed-to-voxel and seed-to-seed analyses within a cortico-striato-limbic network. We additionally examined whether individual alcohol intake during adolescence predicted adult functional connectivity according to neurodevelopmental status. Results NVHL and adolescent alcohol exposure independently produced predominantly hypoconnected cortico-striato-limbic networks. However, alcohol exposure did not exacerbate NVHL-associated dysconnectivity but instead induced a distinct network reorganization characterized by functional hyperconnectivity. Although alcohol intake was comparable between groups, dose-dependent relationships between adolescent alcohol consumption and adult functional connectivity were observed in sham animals but were absent or markedly attenuated in NVHL rats. These effects were primarily centered on prelimbic cortex connectivity with the amygdala, hippocampus, and dorsal striatum, highlighting this circuitry as a major locus of altered experience-dependent remodeling. Conclusions These findings suggest that vulnerability to AUD associated with schizophrenia-like neurodevelopment may arise less from additive network dysfunction than from an altered capacity of large-scale brain networks for experience-dependent functional remodeling. Schizophrenia-like neurodevelopmental pathology may therefore change how alcohol-related experience is translated into persistent brain network organization.