Neurobiology of Learning and Memory

Homeostatic mechanisms adjust synaptic strengths to regulate neuronal activity across wake-sleep cycles. Although sleep supports memory consolidation, limited research has explored how sleep-induced homeostatic changes influence memory outcomes in humans. The EEG-derived aperiodic slope (1/f) could be a candidate measure of homeostatic memory processes through its reflection of neural excitation-inhibition balance. In this study, 27 participants learned object-word pairs, and completed an immediate recognition test before either a nap or equivalent wakeful period. Resting-state EEG was recorded, both before and after learning and the interval, to derive changes in aperiodic slope values. A delayed recognition test then assessed whether changes in the aperiodic slope (i.e., homeostatic activity) across learning and the interval predicted memory accuracy and N400 amplitude, an index of stimulus expectancy and recognition. Our study found evidence to suggest homeostatic renormalisation, for the nap condition only, indicated by a shift towards inhibition across sleep which was inversely related to the slope change across learning. Although the aperiodic slope change across the nap and wake intervals did not predict delayed memory accuracy, a shift towards inhibition during learning was beneficial for memory accuracy, only in the nap condition. Similarly, a shift towards inhibition across learning, followed by a shift towards excitation in the nap condition, predicted reduced N400 amplitudes. This suggests that homeostatic renormalisation across the nap influenced model updating and stimulus expectancy. This study provides evidence for a link between synaptic homeostatic processes and memory consolidation, emphasising the importance of encoding-related aperiodic activity in this relationship.

Hippocampal place cells encode spatial information within a theta-organized temporal framework paced by the medial septum (MS). Lesions or inactivation of the MS impair spatial learning and disrupt hippocampal theta rhythmicity, long-term potentiation, and plasticity-related gene expression, while often sparing spatially selective firing of CA1 neurons (but not CA3 neurons). Although many rodent studies argue against classical systems consolidation by showing persistent hippocampal dependence of spatial memories, other work has suggested that training structure, spaced vs. massed trials, can influence this dependence. To investigate this possibility, we used DREADD-based, reversible, inhibition of MS GABAergic neurons, some of which are known to project to hippocampus. DREADD activation reduced hippocampal theta power and spatial information encoded by hippocampal neurons while largely preserving overall neuronal firing. We then examined the effect of inhibition of medial septal GABAergic neurons on learning the correct goal arm in an 8-arm maze when the correct arm was randomly changed each day. On each day, the mice were given two forced-choice trials indicating the correct arm and then 5 free-choice trials (without correction) and were always started from an opaque cylinder in the maze center, in a random orientation, to eliminate possible use of a simple response strategy. When the correct goal arm varied randomly daily, MS cell inhibition severely and repeatedly impaired acquisition. In contrast, when the correct goal arm was subsequently fixed across days, performance was initially impaired but became resistant to DREADD activation over time. Once performance reached asymptote, the goal arm was switched to a new (random) position. In this case, learning was no longer impaired by DREADD activation. This generalization suggests that repeated fixed-goal training in the same environment induces a broader reorganization of the neural systems supporting spatial behaviour. One possibility is that mice develop a septal-independent task-solving strategy that supports both retrieval of established goal locations and acquisition of new ones within a stable environment. This transition could reflect the gradual adoption of a non-spatial strategy such as visual pattern recognition, or the use of a directional cue. Moving the most salient distal cue in the environment (a single room light) produced a substantial change in the visual configurations seen from the arm entry points, and disrupted performance; however, it did not produce a consistent directional shift relative to the cue, suggesting that the light contributed to an integrated visuo-spatial representation rather than serving as the reference frame origin. We conclude that the mice switched from a hippocampus/MS-dependent spatial strategy to a non-hippocampus-dependent visual pattern matching solution.

It is estimated that approximately fifty percent of the population will encounter at least one traumatic event during their lifetime; however, only six percent develop Posttraumatic Stress Disorder (PTSD), a trauma-related disorder characterized by persistent alterations in affect and cognition, including an exaggerated fear response. It is well established that females (9.7%) are more than twice as likely as males (3.6%) to be diagnosed with PTSD. Nevertheless, a significant challenge remains in understanding how the severity of traumas experienced in childhood versus adulthood influences PTSD development across sexes. To address this challenge effectively, the adoption of preclinical animal models that accurately reflect these key characteristics is crucial. The Stress Enhanced Fear Learning (SEFL) paradigm in rodents encapsulates some of these complexities associated with PTSD, such as persistent fear sensitization following exposure to acute trauma. This study investigates how stress severity and developmental timing affect the long-term maintenance of SEFL in male and female rats. Juvenile and adult rats were initially subjected to no stress (control, context only), low stress (1 footshock), moderate stress (3 footshocks), or high stress (15 footshocks), followed by an extinction session either one day (recent) or sixty days (remote) later. Subsequently, to evaluate SEFL in a new context, all subjects received a single footshock and were tested the following day. Shortly after stress induction, all groups displayed SEFL. Although the effects persisted for sixty days in adult males and juvenile females, even at the lowest stress level, they were significantly reduced in juvenile males and adult females. These findings offer novel insights into sex-related differences in the persistence of SEFL and introduce new considerations regarding how the timing of developmental stressors influences future threat encoding and fear responses.

Objectives: Opioids disrupt sleep, but how repeated exposure reorganizes thalamocortical networks is unknown. We asked whether morphine alters sleep architecture, regional oscillations, and phase synchronization, and how exposure history modifies these effects. Methods: From mice, we analyzed cortical electroencephalogram (EEG), central medial thalamic (CMT) local field potentials (LFP), and electromyography (EMG) for 24h after the first and fourth injections of morphine and in abstinence, and quantified vigilance-state occupancy, spectral power, state-power correlations, and the weighted phase-lag index (wPLI), which minimizes volume conduction. Results: Morphine produced hyperlocomotion, wake promotion persisting with repeated exposure, non-rapid eye movement (NREM) sleep suppression, complete rapid eye movement (REM) sleep loss, and rebound sleep. Cortex and thalamus dissociated: in NREM sleep after the first injection, cortical delta and low-gamma power increased, while CMT delta, theta, alpha, and beta power decreased. NREM occupancy coupled more strongly to CMT delta and theta power after both injections, whereas cortical wake correlations in theta, alpha, and beta fell and reversed during abstinence. Overall synchronization was altered only in theta and alpha: corticocortical alpha synchronization decreased acutely, and repeated exposure reduced thalamocortical theta synchronization in wake and NREM sleep. During abstinence, sleep architecture and synchronization largely normalized while spectral and state-power abnormalities persisted alongside mechanical hypersensitivity. Conclusions: We found that morphine does not merely reduce sleep; it reorganizes it: cortex and CMT move in opposite directions, thalamocortical phase synchronization is redistributed, and the resulting spectral and state-power abnormalities outlast the recovery of sleep architecture itself rather than producing tolerance.

Animals and humans often forgo sleep in response to other physiological needs. Prolonged wakefulness leads to a compensatory homeostatic sleep response involving enhanced amounts of sleep and electroencephalographic delta (0.5-4 Hz) power, yet how the type of preceding wakefulness and brain activity affects this response is poorly understood. Here we compared the pattern of brain activity and the homeostatic sleep response following sustained wakefulness induced by either gentle handling (GH), a widely used form of sleep deprivation in rodents; or optogenetic stimulation of neurons involved in avoidance/defensive responses, basal forebrain (BF) vesicular glutamatergic transporter type 2 (vGluT2) neurons. Local infusion of ionotropic glutamate receptor antagonists partially attenuated the wake-inducing effect of vGluT2-stimulation, but not that of GH, suggesting mediation by other non-glutamatergic BF subtypes. These antagonists also tended to produce more NREM sleep and a shorter NREM latency in the recovery period following vGluT2-stimulation. Both manipulations increased high theta (7-9 Hz) during wakefulness, an effect partially blocked by local infusion of the glutamate antagonist cocktail. Enhanced NREM sleep time and NREM delta power in the recovery period were more pronounced following GH than following vGluT2 stimulation. Whole-brain cFos immunohistochemistry revealed stronger neuronal activity in brain regions involved in stress and avoidance/defensive behaviors with vGluT2 stimulation, compared to GH. Our results demonstrate that activation of a brain system involved in defensive behavior (BF vGluT2) elicits a distinct and diminished homeostatic sleep response compared to GH, potentially an evolutionary sleep adaptation which would maintain vigilance in the face of an ongoing threat.

Older adults typically exhibit reduced episodic memory precision, while maintaining relatively preserved retrieval success. However, little is known about whether these age-related differences are influenced by internal biological factors (e.g., chronotype) or external testing conditions (e.g., experiment format, time of day). To address this question, younger and older adults completed an object-location memory task online, either in the morning or evening, and either with or without video-based supervision. Memory performance was assessed using mean absolute error and Bayesian hierarchical mixture modelling, which dissociated memory precision ({kappa}) from the probability of memory-based responding ({theta}). Immediate memory performance was high across age groups, irrespective of time of day. Greater encoding error predicted greater retrieval error, and participants tested in the video condition exhibited lower recall error and higher recognition performance than those tested without supervision. Consistent with prior studies, older adults exhibited reduced memory precision relative to younger adults, whereas retrieval success remained largely intact. However, Bayesian Hierarchical Modelling provided no evidence that time of day, experiment format, or their interactions with age influenced either memory precision or retrieval probability. Older adults reported stronger morning preferences than younger adults, and participants generally selected testing times that aligned with their chronotype. Nevertheless, alignment between chronotype and testing time did not modulate memory performance. The results indicate that age-related differences in episodic memory precision are robust across variations in testing context, including time of day, experiment format, and individual differences in chronotype. More broadly, the results support the feasibility of remote and unsupervised testing for memory precision research and suggest that chronotype and testing time are unlikely to be major sources of variability in immediate object-location memory performance.

Hippocampal sharp-wave ripple (SWR) events occur during post-experience rest and sleep and play a significant role in memory consolidation. Recent ex vivo studies have found orexin-driven neuromodulatory effects on SWR parameters and proposed that they can influence memory consolidation. Additionally, behavioral studies demonstrate contradictory results regarding orexinergic effects on memory acquisition depending on task structure and intervention time. This inconsistency, along with the diffuse spread of orexin receptors (OXR) in the CA1 and CA3 hippocampus, challenges theoretical interpretation of orexinergic effects on memory. To reconcile this problem, we propose a rate-based model linking orexinergic tone-dependent SWR statistics to memory performance. The model combines an encoding module whose gain scales with the global orexinergic tone with a consolidation module driven by OX2R-specific replay dynamics. The model is based on a plasticity rule that considers SWR events as the unit of induction. Therefore, weight change requires sufficient replay content and depolarizing drive. We observed that, depending on the task structure, encoding-dominant learning benefits discrimination as the orexin drive increases. Consolidation-dominant learning shows a non-monotonic relationship with an internal optimum level of orexinergic tone. This interaction highlights that stronger truncation at higher receptor engagement shortens memory replay and reduces the efficacy of the consolidation process. The model predicts that the optimal regime depends on task complexity reflected in sequence length. Together, these results demonstrate how task demands determine whether increased orexinergic drive enhances or impairs effective consolidation and SWR-dependent replay in the hippocampus.

Flexible decision making depends on internal representations that capture the latent structure of a task, allowing prior knowledge to be applied in novel circumstances. Spatial navigation provides a useful model for studying flexible choice behavior, because spatial location is itself a latent variable that must be inferred rather than directly perceived. Here, we trained rats on a navigation task that required them to reach the same goal via two distinct paths from different starting locations, and then return to one of the two starting locations before beginning the next trial. Some rats were trained to rely on distal visual landmarks, allowing task states to be identified from current sensory information, whereas others were trained to rely on path integration, requiring task states to be inferred from self-motion information accumulated over the preceding trajectory. Rats trained to rely on path integration acquired the task similarly to rats trained to rely on distal visual landmarks. However, reliance on path integration enhanced rats' ability to generalize their learning to novel situations, including finding the goal from an untrained starting location and adapting to a relocated goal that reversed learned choice sequences. These findings suggest that reliance on path integration promotes the acquisition and use of mental representations that capture the latent spatial structure of navigational tasks, thereby favoring flexible navigational decisions over rigid retrieval of reinforced responses. More broadly, our findings demonstrate how information available during training can shape representations learned from experience and thereby constrain the flexibility of decision making during inference.

Extensive work has established that exposure to a single acute stressor can have profound impacts on future reactivity to new stressors, including enhanced acquisition of new fear. The impact of stressor type on development of stress sensitization, however, remains unclear. We investigated whether fundamentally different acute stressors (shock, social defeat, or restraint stress) differ in ability to sensitize acquisition of a new, contextually distinct fear memory in adult male mice two weeks following stress exposure. Stressor subtype differentially sensitized new fear learning; specifically, shock and social defeat - but not restraint stress - led to enhanced recall of a new shock-paired fear memory. We also compared how stressor subtypes differentially engage the brain-periphery interactions that regulate stress responsivity. Notably, restraint stress, which did not lead to fear sensitization to foot shock, drove similar or even greater corticosterone release than other stressors, suggesting that the neuroendocrine response to the original stressor is dissociable from development of a behavioural fear sensitization response. Using the immediate-early gene FOS as a marker of neural activity, all conditions - including the context-only control condition - activated a similar number of neurons in the basolateral amygdala. In contrast, only stressful conditions activated the paraventricular nucleus of the hypothalamus, and restraint stress selectively spared activation of the dorsal hippocampus. These data collectively suggest that future responses to stress depend critically on the identity of previously experienced stressors, rather than simply on prior exposure to stress, establishing a powerful comparative model for investigating the specific mechanisms underlying stress-enhanced fear learning.

Naming pictures from the same semantic category can interfere with subsequent word retrieval. Although the left inferior frontal gyrus (LIFG) has been implicated in resolving this semantic interference, its causal role in this process remains unclear. Across three experiments, we investigated the contribution of the LIFG to interference resolution during blocked-cyclic naming. Experiment 1 tested whether continuous theta-burst stimulation over the LIFG increased semantic interference relative to vertex stimulation. Although the overall interference effect did not differ significantly between stimulation sites, exploratory analyses revealed an unexpected pattern based on the initial context (related vs. unrelated) with which items were named, suggesting that LIFG disruption affected retrieval of previously related items even when they were subsequently named in unrelated contexts. This observation motivated two further experiments examining the consequences of prior naming context more directly. Experiment 2 established that, without stimulation, interference observed in related blocks was no longer evident after the items were redistributed into unrelated blocks. Experiment 3 combined this design with cathodal or sham transcranial direct current stimulation (tDCS) over the LIFG. Planned comparisons showed that cathodal stimulation slowed naming of initially related items both within related blocks and after redistribution into unrelated blocks; corresponding comparisons for items named consistently in unrelated blocks were not significant. The similar patterns across two stimulation methods suggest that LIFG-mediated control may influence both selection under current competition and subsequent retrieval of previously competing words. These findings could be accommodated within a hybrid account in which working memory supports context-guided selection and selection-related control helps recalibrate lexical accessibility, limiting the carryover of interference into subsequent naming.

Childhood absence epilepsy (CAE), the most common childhood epilepsy syndrome, is associated with bursts of generalized thalamocortical spike-wave discharges and cognitive impairment, yet the physiological mechanisms linking disease activity, treatment, and cognition remain unclear. Sleep spindles, generated by thalamocortical circuits, are associated with cognitive function and may be disrupted by epileptic activity. Here, we retrospectively studied 87 EEGs from 53 children with active and resolved CAE and 87 age- and sex-matched controls to evaluate sleep spindle activity across disease states and its association with antiseizure medication (ASM) exposure. We found that children with active CAE had reduced spindle rates across all cortical regions compared to those with resolved CAE and controls, with the largest reduction in the frontal region, where epileptic spike activity was also most prominent. Spindle rate was inversely correlated with epileptic spike rate, consistent with a shared thalamocortical circuitry. The association between ASM exposure and spindle rate varied by disease state. In active CAE, treated children had higher spindle rates than untreated children. In resolved CAE, treated children had lower spindle rates than untreated children. In contrast, ASM-related differences in spike rate were more limited, although a medication-specific reduction was observed in active CAE. These findings support sleep spindle rate as a candidate physiological marker of disease state and ASM exposure in children with CAE. Given the established role of sleep spindles in memory consolidation, these findings support testing of whether spindle disruption provides a mechanistic link between epileptic thalamocortical activity and cognitive vulnerability in CAE.

Memory faces a fundamental challenge. It has to become flexible enough to be accessed by novel cues without losing the specific information that defines each individual episode. Whether memory transformation solves this problem by sacrificing details or by adaptively expanding retrieval while preserving them is unclear. We tested this by manipulating the match between a memory and its retrieval cue. Participants retrieved object associations after 6, 24 and 48 hours using either the original encoded image or novel exemplars that were more typical or more distinctive of the same object category. Retrieval initially benefited from the originally encoded image, but this advantage was reduced across delay. By 48 hours, a never-seen, more typical exemplar triggered retrieval as effectively as the original one, while the same convergence was not evident for less-typical exemplars. Crucially, such cue expansion was not accompanied by a loss of perceptual specificity. Participants retained access to the originally encoded exemplar across delays, while errors increasingly favoured more typical alternatives. At the item level, stronger episodic memories predicted better access to perceptual detail, but did not predict the tendency of errors for category-like information, which instead increased with delay. This dissociation suggests that memory generalisation and the continued accessibility of visual detail reflect partly separable transformations rather than opposite ends of a single continuum.

Study Objectives: Sleep disturbances are common in youth with anxiety disorders, yet most prior work relies on subjective measures and does not capture underlying neural processes. We examined whether alterations in non-rapid eye movement (NREM) sleep oscillations are present in children with anxiety disorders and whether these features relate to internalizing symptoms and emotional functioning. Methods: Children aged 9-13 years with diagnosed anxiety disorders (ANX; n = 17) and typically developing non-psychiatric comparison participants (NC; n = 26) completed overnight polysomnography. Slow oscillations (SO) and slow and fast sleep spindles were characterized using validated automated detection algorithms. Participants also completed a pre-sleep emotional processing task, and parents provided standardized measures of youth mental health. Group differences and dimensional associations between NREM oscillations, internalizing symptoms, and behavioral indices of emotional processing were examined. Results: Sleep architecture did not differ between groups. Slow spindle duration was shorter in the ANX group. Across the full sample, shorter slow spindle duration was associated with greater internalizing symptoms, whereas higher SO density was positively associated with internalizing symptoms. Children in the ANX group exhibited greater facial emotional arousal and more frequent look-away behavior during the emotional processing task. Across participants, greater emotional arousal and look-away behavior were associated with shorter spindle duration during subsequent sleep. Conclusions: Specific features of NREM microarchitecture were associated with individual differences in internalizing symptoms and emotional functioning during early adolescence. These findings highlight the potential relevance of NREM oscillations for understanding developmental links between sleep and youth psychopathology.

Background: ADHD is characterized by inattention and impulsivity. Stimulants such as amphetamine are the first line treatments for ADHD. Amphetamine (AMPH) works by increasing extracellular levels of dopamine and noradrenaline. Such stimulants are used to test predictive validity of animal tasks, where it has been reported that amphetamine improves rat 5-CSRTT accuracy when the session length is increased to 250 trials. This improvement in accuracy was observed later in the session as control performance declined. Proving that amphetamine can improve 5C-CPT task performance adds to the predictive validity of the task. No previous works has demonstrated the pro-attentional effects of amphetamine on sustained attention in rat 5C-CPT. We have previously shown that pharmacological manipulations of dopaminergic system improve waiting impulsivity in a rate dependent manner and the importance of analysing the data using Oldham method. The present study extends this work to investigate the effect of amphetamine on attentional processes. Objective: to investigate effects of amphetamine on attentional processes as measured by 5C-CPT task using correlational analysis and group performance. Methods: Trained female Lister hooded rats were tested with AMPH (0.1, 0.2 and 0.4 mg/kg) under reduced stimulus duration schedule (0.25,0.5,1,1.5 and 2s SD) over normal length session (120 trials). Correlational analysis (Oldham method) was used to understand the relationship between baseline performance measures and the change following administration of AMPH. Results: The highest dose of AMPH impaired attentional performance in the 5C-CPT under reduced SD challenge (0.5s,1s,1.5s and 2s). This impairment was due to increase in FAR. Previous studies in 5-CSRTT suggest that reducing the SD increases attentional demand in the form of reducing accuracy without affecting waiting impulsivity. However, the 5-CSRTT does not include non-target trials, therefore, it cannot be used to measure sustained attention (SI) and responsivity index. The 5C-CPT requires greater attentional resources than the 5-CSRTT.This study is the first to report that reducing the SD changes responsivity index (bias) rather than measures of sustained attention (sensitivity index) in the 5C-CPT. Control sensitivity index did not change until the SD was reduced to less than 0.5s and this change was due to a change in baseline responsivity index (bias). Performance under each reduced SD revealed that the highest dose of AMPH (0.4 mg/kg) showed a tendency toward reducing sensitivity index at 0.5, 1.0 and 1.5s SDs. Under 1.0s SD, the highest dose of AMPH changed sustained attention (SI, HR and FAR) and omission in a rate-dependent manner without changing responsivity index. Performance across the session revealed that the impairment in sustained attention was observed at the beginning of the session. In the third trial block, Oldham method revealed an inverse relationship between baseline accuracy and the change following administration of 0.2 mg/kg AMPH, indicative of a rate-dependent effect. Conclusions: This study successfully demonstrates rate-dependent effects of AMPH on measures of attentional performance in the 5C-CPT. This experiment also demonstrates that responsivity index is sensitive to reduced SD challenge. To our knowledge this is the first study to report the presence of a direct relationship between baseline sustained attention and magnitude of improvement following administration of 0.4 mg/kg AMPH and an inverse relationship between baseline accuracy and the change following administration of 0.2 mg/kg AMPH in 5C-CPT task. Future studies should test lower doses of amphetamine (0.05 and 0.1 mg/kg) over extended session length (250 trials) to reveal the pro-attentional effects of this drug on 5C-CPT performance measures.

Following cocaine self-administration, male and female rats received daily semaglutide during a 30-day abstinence period before cue- and cocaine-induced reinstatement tests. Semaglutide attenuated cue-induced reinstatement and cocaine-induced stereotypy, although operant responding was elevated following cocaine priming. These findings support further investigation of semaglutide as a treatment for cocaine use disorder.

There are known alterations in decision-making attributed to Parkinson's disease. Yet little is known about how those alterations affect decisions in social contexts. We aimed to assess social decision-making in healthy human volunteers as well as people with Parkinson's disease treated with deep brain stimulation of the subthalamic nucleus. Twenty healthy controls and twenty-two people with Parkinson's in both the stimulation ON and OFF conditions took part in a social discounting task that measured the degree of generosity toward others as a function of social-emotional distance. Using a computational approach, we modelled mechanisms of social discounting across three different models that differed in how they mapped choice valuation onto observed decisions. People with Parkinson's less often made generous choices than controls. Across all analyses, we found converging evidence that this effect was attributable to increased static and dynamic decision noise, i.e. inhibitory and attentional processes, but not changes in prosocial valuation. While stimulation sped up decisions, there was no effect of deep brain stimulation on social decision-making. Present results indicate that people with Parkinson's are more prone to random processes such as increased impulsivity and attentional lapses during choices in social situations. Such changes attributed to the disease appear to evade clinical care with dopaminergic compensation and deep brain stimulation.

Deletion of the microtubule-associated protein, tau reduces seizure burden in rodent models of genetic epilepsies and suppresses evoked seizures. In the intrahippocampal kainate (IHK) model of acquired temporal lobe epilepsy (TLE), mice lacking tau expression develop spontaneous seizures, but at a lower rate than controls. Mechanisms by which tau deletion modifies the development of acquired TLE are not well understood, but a modification of the synaptic reorganization that accompanies epileptogenesis may contribute to modified seizure expression. Increased inhibitory synaptic input to dorsal dentate granule cells (DGCs) contralateral to the focal kainate injection results after development of TLE in tau-/- mice, but inhibitory synaptic reorganization distal to the kainate lesion is undefined in this model. We therefore investigated how development of TLE modifies excitability and synaptic transmission in DGCs of the ventral dentate gyrus, distant from the kainate lesion. Our results show that development of TLE increases evoked action potential firing of ventral DGCs (vDGCs) in mice that develop TLE, demonstrating an effect of TLE development on excitability of DGCs distant from the focal injury. After development of TLE, DGCs from tau-/- mice received increased inhibitory synaptic input bilaterally, suggesting that tau expression suppresses inhibitory synaptic reorganization in DGCs. Optogenetic stimulation of interneurons in tau-/- mice revealed increased inhibitory synaptic input to vDGCs and an increase in inhibitory convergence onto vDGCs once epileptogenesis occurred. Therefore, tau deletion modifies spontaneous seizure expression after epileptogenesis in mice, potentially involving increased synaptic inhibition of DGCs throughout the dentate gyrus.

Study objectives: Aging is associated with increased sleep complaints and changes in sleep architecture, microstructure and rest-activity rhythms. Meditation-based interventions have shown benefits on subjective sleep quality, but their effects on objective sleep parameters remain largely underexplored. This study investigated the effects of an 18-month meditation intervention on sleep combining subjective (questionnaires) and objective (polysomnography and actigraphy) measures in older adults. Methods: A total of 120 cognitively unimpaired older adults ([≥]65 y) with minimal sleep complaint completed questionnaires, one week of actigraphy and in-home polysomnography at baseline, and again 18 months later. Following the baseline visit, participants were randomly assigned to one of 3 groups: meditation training, non-native language training (active control), or passive control. Group-by-visit interactions were examined using mixed-effects models for sleep questionnaires, actigraphy-derived metrics, sleep architecture and microstructure, including slow waves, spindles, and spectral power. Results: Compared to the passive control group only, meditation training was associated with greater ease of morning awakening (p=0.04). No significant intervention effects were observed for any other sleep parameter, including actigraphy- and polysomnography-derived measures. These findings remained unchanged after adjustment for depressive symptoms and trait anxiety. Conclusion: In cognitively unimpaired older adults, this 18-month meditation intervention yielded only limited improvements in subjective sleep assessment. Meditation may therefore have subtle effects on self-reported sleep quality in this healthy older population, although no effects on objective sleep measures were detected. Future studies should examine whether adapting the content, intensity, or timing of meditation practice and enrolling populations with clinically meaningful sleep disturbances or psychoaffective symptoms may yield greater benefits.

Background: Cognitive impairment in Parkinson disease (PD) significantly affects patients ability to perform instrumental activities of daily living (IADLs). However, neuropsychiatric symptoms, which are highly prevalent in PD, may also contribute to functional impairments. In this study, we investigated the independent contributions of cognitive and neuropsychiatric symptoms to functional impairments and tested whether mood mediates cognition-function associations. Methods: We examined 104 patients from the Quebec Parkinson Network and replicated analyses in a sample of 144 patients from an independent online cohort. Participants completed the Penn Parkinsons Daily Activities Questionnaire (PDAQ), a validated patient-reported measure designed to capture cognition-dependent IADLs, standard cognitive tests (executive function, attention, working memory), and neuropsychiatric questionnaires (apathy, depression, impulsivity, and anhedonia). Regression models tested the independent and combined effects of cognition and neuropsychiatric symptoms on PDAQ; mediation analyses explored mechanistic pathways. Results: Both cognitive performance and neuropsychiatric symptoms were independently associated with PDAQ scores and the proportion of variance explained by neuropsychiatric symptoms was comparable to that explained by cognitive performance. Furthermore, depression and impulsivity partially confounded the relationship between cognitive performance and PDAQ and impulsivity partially mediated this relationship. The independent associations between neuropsychiatric symptoms and PDAQ were replicated in the replication sample. Conclusion: These results indicate that impairments in cognitive IADLs reflect contributions of both cognition and neuropsychiatric changes and suggest that trials using measures of IADLs as an outcome measure should also carefully assess and control for neuropsychiatric symptoms.

Rhythmic visual stimulation offers a non-invasive means of modulating oscillatory brain activity, but conventional flicker may induce considerable visual discomfort. We developed an individualized Gabor flicker stimulation designed to balance neural entrainment and tolerability. In Experiment 1, thirty-four participants passively viewed Plain and Gabor flickers presented at their individual alpha frequency (IAF), IAF - 2 Hz, or IAF + 2 Hz, and at threshold-adjusted or full intensity. Steady-state visual evoked potential signal-to-noise ratio (SNR) was highest at IAF and increased with intensity. Plain and Gabor flickers produced comparable overall SNR, but Gabor flicker was rated as substantially more comfortable and less mentally fatiguing, with stimulation at IAF providing the most favorable balance between neural entrainment and tolerability. In Experiment 2, the optimized stimulation parameters were applied during a retro-cue working memory task using individualized theta and alpha frequency flickers. Stimulation increased SNR and inter-trial phase coherence relative to a non rhythmic Natural condition. No behavioral benefit was observed in the full sample. However, an exploratory subgroup analysis indicated higher accuracy with theta stimulation of cued representations and alpha stimulation of uncued representations than in the Natural condition among participants who showed limited baseline retro-cue benefits. These findings show that individualized Gabor flicker can provide robust and well-tolerated neural entrainment during passive viewing and working memory retention, although its behavioral effects may vary across individuals according to their cognitive performance.