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Human postural sway during quiet standing has been characterized as a proportional-integral-derivative controller with intermittent activation. In the model, patterns of sway result from both instantaneous, passive, mechanical resistance and delayed, intermittent resistance signaled by the central nervous system. A Kalman-Filter framework was designed to directly estimate from experimental data the parameters of the model's stochastic delay differential equations with discrete dynamic switching conditions. Simulations showed that all parameters could be estimated over a variety of possible data-generating configurations with varying degrees of bias and variance depending on their empirical identification. Applications to experimental data reveal distributions of each parameter that correspond well to previous findings, suggesting that many useful, physiological measures may be extracted from sway data. Individuals varied in degree and type of deviation from theoretical expectations, ranging from harmonic oscillation to non-equilibrium Langevin dynamics.

For many phenotypes, individual scores are obtained as the parameter estimates of person-level models fit to intensive repeated measures from physiological sensors or experience sampling studies. Biometrical genetic analysis of such phenotypes is often done in a 2-step sequence: first the phenotypic parameters are estimated for each individual, then classical twin modeling is used to partition their variance. This study demonstrates deficiencies in accuracy and statistical power of the two-step approach to estimate genetic signals and advocates for the use of hierarchical models to overcome both problems. Simulations are used to demonstrate the benefits to accuracy and statistical power from a hierarchical modeling approach. A model of heart rate fluctuations was applied to experimental data from twin pairs recorded in independent trials. Results of the data application reveal moderate but uncorrelated heritabilities for two parameters of heart rate: oscillation frequency and damping ratio. By merging biometrical genetic analysis with process models, hierarchical mixed-effects modeling has potential to assist with discovery and extraction of novel phenotypes from within-person data and to validate theoretical models of within-person processes.

Genetic studies of complex traits often show disparities in estimated heritability depending on the method used, whether by genomic associations or twin and family studies. We present a simulation of individual genomes with dynamic environmental conditions to consider how linear and nonlinear effects, gene-by-environment interactions, and gene-by-environment correlations may work together to govern the long-term development of complex traits and affect estimates of heritability from common methods. Our simulation studies demonstrate that the genetic effects estimated by genome wide association studies in unrelated individuals are inadequate to characterize gene-by-environment interaction, while including related individuals in genome-wide complex trait analysis (GCTA) allows gene-by-environment interactions to be recovered in the heritability. These theoretical findings provide an explanation for the “missing heritability” problem and bridge the conceptual gap between the most common findings of GCTA and twin studies. Future studies may use the simulation model to test hypotheses about phenotypic complexity either in an exploratory way or by replicating well-established observations of specific phenotypes.

Social distancing and public policy have been crucial for minimizing the spread of SARS-CoV-2 in the United States. Publicly available, county-level time series data on mobility are derived from individual devices with global positioning systems, providing a variety of indices of social distancing behavior per day. Such indices allow a fine-grained approach to modeling public behavior during the pandemic. Previous studies of social distancing and policy have not accounted for the occurrence of pre-policy social distancing and other dynamics reflected in the long-term trajectories of public mobility data. We propose a differential equation state-space model of county-level social distancing that accounts for distancing behavior leading up to the first official policies, equilibrium dynamics reflected in the long-term trajectories of mobility, and the specific impacts of four kinds of policy. The model is fit to each US county individually, producing a nationwide data set of novel estimated mobility indices. A differential equation model was fit to three indicators of mobility for each of 3054 counties, with T=100 occasions per county of the following: distance traveled, visitations to key sites, and the log number of interpersonal encounters. The indicators were highly correlated and assumed to share common underlying latent trajectory, dynamics, and responses to policy. Maximum likelihood estimation with the Kalman-Bucy filter was used to estimate the model parameters. Bivariate distributional plots and descriptive statistics were used to examine the resulting county-level parameter estimates. The association of chronology with policy impact was also considered. Mobility dynamics show moderate correlations with two census covariates: population density (Spearman r ranging from 0.11 to 0.31) and median household income (Spearman r ranging from -0.03 to 0.39). Stay-at-home order effects were negatively correlated with both (r=-0.37 and r=-0.38, respectively), while the effects of the ban on all gatherings were positively correlated with both (r=0.51, r=0.39). Chronological ordering of policies was a moderate to strong determinant of their effect per county (Spearman r ranging from -0.12 to -0.56), with earlier policies accounting for most of the change in mobility, and later policies having little or no additional effect. Chronological ordering, population density, and median household income were all associated with policy impact. The stay-at-home order and the ban on gatherings had the largest impacts on mobility on average. The model is implemented in a graphical online app for exploring county-level statistics and running counterfactual simulations. Future studies can incorporate the model-derived indices of social distancing and policy impacts as important social determinants of COVID-19 health outcomes.

Many tasks require flexibly modifying perception and behavior based on current goals. Humans can retrieve episodic memories from days to years ago, using them to contextualize and generalize behaviors across novel but structurally related situations. The brain's ability to control episodic memories based on task demands is often attributed to interactions between the prefrontal cortex (PFC) and hippocampus (HPC). We propose a reinforcement learning model that incorporates a PFC-HPC interaction mechanism for goal-directed generalization. In our model, the PFC learns to generate query-key representations to encode and retrieve goal-relevant episodic memories, modulating HPC memories top-down based on current task demands. Moreover, the PFC adapts its encoding and retrieval strategies dynamically when faced with multiple goals presented in a blocked, rather than interleaved, manner. Our results show that: (1) combining working memory with selectively retrieved episodic memory allows transfer of decisions among similar environments or situations, (2) top-down control from PFC over HPC improves learning of arbitrary structural associations between events for generalization to novel environments compared to a bottom-up sensory-driven approach, and (3) the PFC encodes generalizable representations during both encoding and retrieval of goal-relevant memories, whereas the HPC exhibits event-specific representations. Together, these findings highlight the importance of goal-directed prefrontal control over hippocampal episodic memory for decision-making in novel situations and suggest a computational mechanism by which PFC-HPC interactions enable flexible behavior.

How to enable human-like long-term memory in large language models (LLMs) has been a central question for unlocking more general capabilities such as few-shot generalization. Existing memory frameworks and benchmarks focus on finding the optimal memory compression algorithm for higher performance in tasks that require recollection and sometimes further reasoning. However, such efforts have ended up building more human bias into the compression algorithm, through the search for the best prompts and memory architectures that suit specific benchmarks, rather than finding a general solution that would work on other data distributions. On the other hand, goal-directed search on uncompressed information could potentially exhibit superior performance because compression is lossy, and a predefined compression algorithm will not fit all raw data distributions. Here we present SUMER (Search in Uncompressed Memory via Experience Replay), an end-to-end reinforcement learning agent with verifiable reward (RLVR) that learns to use search tools to gather information and answer a target question. On the LoCoMo dataset for long-context conversation understanding, SUMER with Qwen2.5-7B-Instruct learned to use search tools and outperformed all other biased memory compression approaches and also the full-context baseline, reaching SOTA performance (43% gain over the prior best). We demonstrate that a simple search method applied to raw data outperforms goal-agnostic and biased compression algorithms in current long-context memory tasks, arguing for new paradigms and benchmarks that are more dynamic and autonomously scalable. Code for SUMER and all implemented baselines is publicly available at https://github.com/zycyc/SUMER.

The Bayesian brain hypothesis postulates that the brain accurately operates on statistical distributions according to Bayes' theorem. The random failure of presynaptic vesicles to release neurotransmitters may allow the brain to sample from posterior distributions of network parameters, interpreted as epistemic uncertainty. It has not been shown previously how random failures might allow networks to sample from observed distributions, also known as aleatoric or residual uncertainty. Sampling from both distributions enables probabilistic inference, efficient search, and creative or generative problem solving. We demonstrate that under a population-code based interpretation of neural activity, both types of distribution can be represented and sampled with synaptic failure alone. We first define a biologically constrained neural network and sampling scheme based on synaptic failure and lateral inhibition. Within this framework, we derive drop-out based epistemic uncertainty, then prove an analytic mapping from synaptic efficacy to release probability that allows networks to sample from arbitrary, learned distributions represented by a receiving layer. Second, our result leads to a local learning rule by which synapses adapt their release probabilities. Our result demonstrates complete Bayesian inference, related to the variational learning method of dropout, in a biologically constrained network using only locally-learned synaptic failure rates.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder linked to repetitive traumatic brain injury (TBI) and characterized by deposition of hyperphosphorylated tau at the depths of sulci. We sought to determine the presence of CTE pathology in a brain bank for neurodegenerative disorders for individuals with and without a history of contact sports participation. Available medical records of 1721 men were reviewed for evidence of past history of injury or participation in contact sports. Subsequently, cerebral cortical samples were processed for tau immunohistochemistry in cases with a documented history of sports exposure as well as age- and disease-matched men and women without such exposure. For cases with available frozen tissue, genetic analysis was performed for variants in APOE , MAPT , and TMEM106B . Immunohistochemistry revealed 21 of 66 former athletes had cortical tau pathology consistent with CTE. CTE pathology was not detected in 198 individuals without exposure to contact sports, including 33 individuals with documented single-incident TBI sustained from falls, motor vehicle accidents, domestic violence, or assaults. Among those exposed to contact sports, those with CTE pathology did not differ from those without CTE pathology with respect to noted clinicopathologic features. There were no significant differences in genetic variants for those with CTE pathology, but we observed a slight increase in MAPT H1 haplotype, and there tended to be fewer homozygous carriers of the protective TMEM106B rs3173615 minor allele in those with sports exposure and CTE pathology compared to those without CTE pathology. In conclusion, this study has identified a small, yet significant, subset of individuals with neurodegenerative disorders and concomitant CTE pathology. CTE pathology was only detected in individuals with documented participation in contact sports. Exposure to contact sports was the greatest risk factor for CTE pathology. Future studies addressing clinical correlates of CTE pathology are needed.

Background Being an informal carer of a person with dementia (PwD) can have a negative effect on the carer’s health and quality of life, and spouse carers have been found to be especially vulnerable. Yet relatively little is known about the care provided and support received by spouse carers. This study compares spouse carers to other informal carers of PwDs regarding their care provision, the support received and the psychosocial impact of care. Methods The study was a cross-sectional questionnaire-based survey of a stratified random sample of the Swedish population aged 18 or over. The questionnaire explored how much care the respondent provided, the support received, and the psychosocial impact of providing care. Of 30,009 people sampled, 11,168 (37.7 %) responded, of whom 330 (2.95 %) were informal carers of a PwD. Results In comparison to non-spouse carers, spouse carers provided more care more frequently, did so with less support from family or the local authority, while more frequently experiencing negative impacts on their social life and psychological and physical health. Spouse carers also received more carer support and more frequently experienced a closeness in their relationship with the care-recipient. Conclusions Spouse carers of PwD differed from non-spouse carers on virtually all aspects of their care situation. Policy and practice must be more sensitive to how the carer-care-recipient relationship shapes the experience of care, so that support is based on an understanding of the individual carer’s actual needs and preferences rather than on preconceptions drawn from a generalised support model.

Abstract Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder associated with exposure to head trauma. In 2015, a panel of neuropathologists funded by the NINDS/NIBIB defined preliminary consensus neuropathological criteria for CTE, including the pathognomonic lesion of CTE as “an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern,” based on review of 25 tauopathy cases. In 2016, the consensus panel met again to review and refine the preliminary criteria, with consideration around the minimum threshold for diagnosis and the reproducibility of a proposed pathological staging scheme. Eight neuropathologists evaluated 27 cases of tauopathies (17 CTE cases), blinded to clinical and demographic information. Generalized estimating equation analyses showed a statistically significant association between the raters and CTE diagnosis for both the blinded (OR = 72.11, 95% CI = 19.5–267.0) and unblinded rounds (OR = 256.91, 95% CI = 63.6–1558.6). Based on the challenges in assigning CTE stage, the panel proposed a working protocol including a minimum threshold for CTE diagnosis and an algorithm for the assessment of CTE severity as “Low CTE” or “High CTE” for use in future clinical, pathological, and molecular studies.