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Scott T Grafton,1 Andreas B Ralston,2 John D Ralston21Department of Psychological & Brain Sciences, UC Santa Barbara, Santa Barbara, CA 93106-9660, USA; 2Clinical Studies Department, Protxx Inc, Menlo Park, CA, 94025-4317, USAObjective: To assess the utility of a head-mounted wearable inertial motion unit (IMU)-based sensor and 3 proposed measures of postural sway to detect outliers in athletic populations at risk of balance impairments.Methods: Descriptive statistics are used to define a normative reference range of postural sway (eyes open and eyes closed) in a cross-sectional sample of 347 college students using a wireless head-mounted IMU-based sensor. Three measures of postural sway were derived: linear sway power, eyes closed vs eyes open sway power ratio (Ec/Eo ratio), and weight-bearing asymmetry (L-R ratio), and confidence intervals for these measures were calculated. Questionnaires were used to identify potentially confounding state variables. A prospective study of postural sway changes in 47 professional, college, and high school athletes was then carried out in on-field settings to provide estimates of session-to-session variability and the influence of routine physical activity on sway measures. Finally, pre-post-injury changes in sway are measured for a participant who was diagnosed with a concussion.Results: Despite the heterogenous population and sampling environments, well-defined confidence intervals were established for all 3 sway measures. Men demonstrated significantly greater sway than women. Two state variables significantly increased sway: the use of nicotine and prescription medications. In the athletes, session-to-session variability and changes due to routine physical activity remained well within 95% confidence intervals defined by the cross-sectional sample for all 3 sway measures. The increase in sway power following a diagnosed concussion was more than an order of magnitude greater than the increases due to session-to-session variability, physical activity, or other participant state variables.Conclusion: The proposed postural sway measures and head-mounted wearable sensor demonstrate analytic utility for on-field detection of abnormal sway that could be potentially useful when making remove-from-activity and return-to-activity decisions for athletes at risk of impact-induced balance impairments.Keywords: wearable sensor, balance impairments, postural sway, concussion

As evidence mounts that the cardiac-sympathetic nervous system reacts to challenging cognitive settings, we ask if these responses are epiphenomenal companions or if there is evidence suggesting a more intertwined role of this system with cognitive function. Healthy male and female human participants performed an approach-avoidance paradigm, trading off monetary reward for painful electric shock, while we recorded simultaneous electroencephalographic and cardiac-sympathetic signals. Participants were reward sensitive but also experienced approach-avoidance "conflict" when the subjective appeal of the reward was near equivalent to the revulsion of the cost. Drift-diffusion model parameters suggested that participants managed conflict in part by integrating larger volumes of evidence into choices (wider decision boundaries). Late alpha-band (neural) dynamics were consistent with widening decision boundaries serving to combat reward sensitivity and spread attention more fairly to all dimensions of available information. Independently, wider boundaries were also associated with cardiac "contractility" (an index of sympathetically mediated positive inotropy). We also saw evidence of conflict-specific "collaboration" between the neural and cardiac-sympathetic signals. In states of high conflict, the alignment (i.e., product) of alpha dynamics and contractility were associated with a further widening of the boundary, independent of either signal's singular association. Cross-trial coherence analyses provided additional evidence that the autonomic systems controlling cardiac-sympathetics might influence the assessment of information streams during conflict by disrupting or overriding reward processing. We conclude that cardiac-sympathetic control might play a critical role, in collaboration with cognitive processes, during the approach-avoidance conflict in humans., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Objective: The corticospinal tract (CST) is considered the most important motor output pathway comprising fibers from the primary motor cortex (M1) and various premotor areas. Damage to its descending fibers after stroke commonly leads to motor impairment. While premotor areas are thought to critically support motor recovery after stroke, the functional role of their corticospinal output for different aspects of post-stroke motor control remains poorly understood., Methods: We assessed the differential role of CST fibers originating from premotor areas and M1 in the control of basal (single-joint muscle synergies and strength) and complex motor control (involving inter-joint coordination and visuomotor integration) using a novel diffusion imaging approach in chronic stroke patients., Results: While M1 sub-tract anisotropy was positively correlated with basal and complex motor skills, anisotropy of PMd, PMv, and SMA sub-tracts was exclusively associated with complex motor tasks. Interestingly, patients featuring persistent motor deficits showed an additional positive association between premotor sub-tract integrity and basal motor control., Interpretation: While descending M1 output seems to be a prerequisite for any form of upper limb movements, complex motor skills critically depend on output from premotor areas after stroke. The additional involvement of premotor tracts in basal motor control in patients with persistent deficits emphasizes their compensatory capacity in post-stroke motor control. In summary, our findings highlight the pivotal role of descending corticospinal output from premotor areas for motor control after stroke, which thus serve as prime candidates for future interventions to amplify motor recovery., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Psoriatic arthritis (PsA) is an inflammatory joint and entheseal disease associated with significant personal and public health burden. PsA has a prevalence of up to 1%, affecting ~20% of people suffering with psoriasis. PsA is frequently accompanied by metabolic syndrome (MetS), and both conditions are characterised by a chronic pro-inflammatory state, with several key cytokines in PsA (interleukin (IL)-17 and IL-23) also elevated in those with MetS. This narrative review aims to provide an update on MetS in PsA, focusing on its prevalence, pathogenesis, prognosis, treatment interactions and future therapeutic options. MetS is particularly prevalent in PsA compared to other inflammatory arthritides. Cohort studies indicate a higher risk of PsA in individuals with obesity, while Mendelian randomization studies link childhood obesity, insulin resistance, and dyslipidaemia to PsA. Weight loss interventions have been shown to reduce disease activity in PsA. Additionally, MetS negatively impacts the efficacy of tumour necrosis factor inhibitor (TNFi) drugs in treating PsA. Drugs given for PsA may also affect the conditions constituting MetS. Leflunomide has been shown to reduce body weight but also increase blood pressure. TNFi drugs lead to weight gain but reduce cardiovascular risk. Janus kinase inhibitors increase lipid levels and cardiovascular risk among high-risk groups. Anti-IL-17 and anti-IL-12/IL-23 drugs may cause a short-term increase in cardiovascular risk, although the long-term effects have yet to be established. Weight loss represents an unexplored avenue for disease modification in PsA, alongside a plethora of general health benefits. Dietary and exercise modifications are the cornerstone of weight management but vary substantially across individuals. Novel therapies to treat weight loss, such as glucagon-like peptide 1 agonists and sodium-glucose cotransporter 2 inhibitors, may prove useful alongside disease-modifying therapies for those with PsA and MetS and should be investigated as potential therapeutic adjuncts., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Cyclic fluctuations in hypothalamic-pituitary-gonadal axis (HPG-axis) hormones exert powerful behavioral, structural, and functional effects through actions on the mammalian central nervous system. Yet, very little is known about how these fluctuations alter the structural nodes and information highways of the human brain. In a study of 30 naturally cycling women, we employed multidimensional diffusion and T 1 -weighted imaging during three estimated menstrual cycle phases (menses, ovulation, and mid-luteal) to investigate whether HPG-axis hormone concentrations co-fluctuate with alterations in white matter (WM) microstructure, cortical thickness (CT), and brain volume. Across the whole brain, 17β-estradiol and luteinizing hormone (LH) concentrations were directly proportional to diffusion anisotropy (μFA; 17β-estradiol: β 1  = 0.145, highest density interval (HDI) = [0.211, 0.4]; LH: β 1  = 0.111, HDI = [0.157, 0.364]), while follicle-stimulating hormone (FSH) was directly proportional to CT (β 1  = 0 .162, HDI = [0.115, 0.678]). Within several individual regions, FSH and progesterone demonstrated opposing relationships with mean diffusivity (D iso ) and CT. These regions mainly reside within the temporal and occipital lobes, with functional implications for the limbic and visual systems. Finally, progesterone was associated with increased tissue (β 1  = 0.66, HDI = [0.607, 15.845]) and decreased cerebrospinal fluid (CSF; β 1  = -0.749, HDI = [-11.604, -0.903]) volumes, with total brain volume remaining unchanged. These results are the first to report simultaneous brain-wide changes in human WM microstructure and CT coinciding with menstrual cycle-driven hormone rhythms. Effects were observed in both classically known HPG-axis receptor-dense regions (medial temporal lobe, prefrontal cortex) and in other regions located across frontal, occipital, temporal, and parietal lobes. Our results suggest that HPG-axis hormone fluctuations may have significant structural impacts across the entire brain., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Objectives: Sleep disturbance has been associated with chronic widespread pain (CWP), but their causal relationship remains unclear. We aimed to examine the causal relationship and direction between CWP and sleep traits, namely insomnia, sleep duration and chronotype, using Mendelian Randomization., Method: We used genetic association data from ~0.5 million individuals and up to 1.8 million controls from the UK Biobank (UKB). All traits were defined predominantly by self-report. Short sleep duration was defined as average ≤6 hours per 24 hours. Chronotype refers to the inclination to sleep at certain times where some wake and go to bed early ('morning' person), and others wake and go to sleep later ('evening' person). To permit use of the largest available genetic association data, we used the Causal Analysis Using Summary Effect estimates (CAUSE) method, which allows for sample overlap., Results: Insomnia (OR 1.009, 95% credible interval 1.005, 1.014; p = 0.018 that the causal model is a better fit than non-causal model) and short sleep duration (OR 1.060, 95%CrI 1.038, 1.083; p = 0.040) were causally associated with increased risk of CWP, with limited evidence for reverse causation. There was no evidence in support of long sleep duration or chronotype being associated with CWP., Conclusions: This study suggest that insomnia and short sleep duration (≤6 hours) are associated with an increased risk of CWP. Improving short sleep duration and insomnia, rather than chronotype, may be effective in reducing the risk of CWP, although these results should be replicated in epidemiological and interventional studies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: Vascular aging is characterized by vessel stiffening, with increased deposition of extracellular matrix (ECM) proteins including collagens. Oxidative DNA damage occurs in vascular aging, but how it regulates ECM proteins and vascular stiffening is unknown. We sought to determine the relationship between oxidative DNA damage and ECM regulatory proteins in vascular aging., Methods and Results: We examined oxidative DNA damage, the major base excision repair (BER) enzyme 8-Oxoguanine DNA Glycosylase (Ogg1) and its regulators, multiple physiological markers of aging, and ECM proteomics in mice from 22-72w. Vascular aging was associated with increased oxidative DNA damage, and decreased expression of Ogg1, its active acetylated form, its acetylation regulatory proteins P300 and CBP, and the transcription factor Foxo3a. Vascular stiffness was examined in vivo in control, Ogg1-/-, or mice with vascular smooth muscle cell-specific expression of Ogg1+ (Ogg1) or an inactive mutation (Ogg1KR). Ogg1-/- and Ogg1KR mice showed reduced arterial compliance and distensibility, and increased stiffness and pulse pressure, whereas Ogg1 expression normalised all parameters to 72w. ECM proteomics identified major changes in collagens with aging, and downregulation of the ECM regulatory proteins Protein 6-lysyl oxidase (LOX) and WNT1-inducible-signaling pathway protein 2 (WISP2). Ogg1 overexpression upregulated LOX and WISP2 both in vitro and in vivo, and downregulated Transforming growth factor β1 (TGFb1) and Collagen 4α1 in vivo compared with Ogg1KR. Foxo3a activation induced Lox, while Wnt3 induction of Wisp2 also upregulated LOX and Foxo3a, and downregulated TGFβ1 and fibronectin 1. In humans, 8-oxo-G increased with vascular stiffness, while active OGG1 reduced with both age and stiffness., Conclusions: Vascular aging is associated with oxidative DNA damage, downregulation of major BER proteins, and changes in multiple ECM structural and regulatory proteins. Ogg1 protects against vascular aging, associated with changes in ECM regulatory proteins including LOX and WISP2., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Improved screening and treatment have decreased breast cancer mortality, although incidence continues to rise. Women at increased risk of breast cancer can be offered risk reducing treatments, such as tamoxifen, but this has not been shown to reduce breast cancer mortality. New, more efficacious, risk-reducing agents are needed. The identification of novel candidates for prevention is hampered by a lack of good preclinical models. Current patient derived in vitro and in vivo models cannot fully recapitulate the complexities of the human tissue, lacking human extracellular matrix, stroma, and immune cells, all of which are known to influence therapy response. Here we describe a normal breast explant model utilising a tuneable hydrogel which maintains epithelial proliferation, hormone receptor expression, and residency of T cells and macrophages over 7 days. Unlike other organotypic tissue cultures which are often limited by hyper-proliferation, loss of hormone signalling, and short treatment windows (< 48h), our model shows that tissue remains viable over 7 days with none of these early changes. This offers a powerful and unique opportunity to model the normal breast and study changes in response to various risk factors, such as breast density and hormone exposure. Further validation of the model, using samples from patients undergoing preventive therapies, will hopefully confirm this to be a valuable tool, allowing us to test novel agents for breast cancer risk reduction preclinically., (© 2024. The Author(s).)

Diffusion Spectrum Imaging (DSI) using dense Cartesian sampling of q-space has been shown to provide important advantages for modeling complex white matter architecture. However, its adoption has been limited by the lengthy acquisition time required. Sparser sampling of q-space combined with compressed sensing (CS) reconstruction techniques has been proposed as a way to reduce the scan time of DSI acquisitions. However prior studies have mainly evaluated CS-DSI in post-mortem or non-human data. At present, the capacity for CS-DSI to provide accurate and reliable measures of white matter anatomy and microstructure in the living human brain remains unclear. We evaluated the accuracy and inter-scan reliability of 6 different CS-DSI schemes that provided up to 80% reductions in scan time compared to a full DSI scheme. We capitalized on a dataset of 26 participants who were scanned over eight independent sessions using a full DSI scheme. From this full DSI scheme, we subsampled images to create a range of CS-DSI images. This allowed us to compare the accuracy and inter-scan reliability of derived measures of white matter structure (bundle segmentation, voxel-wise scalar maps) produced by the CS-DSI and the full DSI schemes. We found that CS-DSI estimates of both bundle segmentations and voxel-wise scalars were nearly as accurate and reliable as those generated by the full DSI scheme. Moreover, we found that the accuracy and reliability of CS-DSI was higher in white matter bundles that were more reliably segmented by the full DSI scheme. As a final step, we replicated the accuracy of CS-DSI in a prospectively acquired dataset (n = 20, scanned once). Together, these results illustrate the utility of CS-DSI for reliably delineating in vivo white matter architecture in a fraction of the scan time, underscoring its promise for both clinical and research applications., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Active reinforcement learning enables dynamic prediction and control, where one should not only maximize rewards but also minimize costs such as of inference, decisions, actions, and time. For an embodied agent such as a human, decisions are also shaped by physical aspects of actions. Beyond the effects of reward outcomes on learning processes, to what extent can modeling of behavior in a reinforcement-learning task be complicated by other sources of variance in sequential action choices? What of the effects of action bias (for actions per se) and action hysteresis determined by the history of actions chosen previously? The present study addressed these questions with incremental assembly of models for the sequential choice data from a task with hierarchical structure for additional complexity in learning. With systematic comparison and falsification of computational models, human choices were tested for signatures of parallel modules representing not only an enhanced form of generalized reinforcement learning but also action bias and hysteresis. We found evidence for substantial differences in bias and hysteresis across participants-even comparable in magnitude to the individual differences in learning. Individuals who did not learn well revealed the greatest biases, but those who did learn accurately were also significantly biased. The direction of hysteresis varied among individuals as repetition or, more commonly, alternation biases persisting from multiple previous actions. Considering that these actions were button presses with trivial motor demands, the idiosyncratic forces biasing sequences of action choices were robust enough to suggest ubiquity across individuals and across tasks requiring various actions. In light of how bias and hysteresis function as a heuristic for efficient control that adapts to uncertainty or low motivation by minimizing the cost of effort, these phenomena broaden the consilient theory of a mixture of experts to encompass a mixture of expert and nonexpert controllers of behavior., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Colas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

There are known individual differences in both the ability to learn the layout of novel environments and the flexibility of strategies for navigating known environments. However, it is unclear how navigational abilities are impacted by high-stress scenarios. Here we used immersive virtual reality (VR) to develop a novel behavioral paradigm to examine navigation under dynamically changing situations. We recruited 48 participants (24 female; ages 17-32) to navigate a virtual maze (7.5 m × 7.5 m). Participants learned the maze by moving along a fixed path past the maze's landmarks (paintings). Subsequently, participants experienced either a non-stress condition, or a high-stress condition tasking them with navigating the maze. In the high-stress condition, their initial path was blocked, the environment was darkened, threatening music was played, fog obstructed more distal views of the environment, and participants were given a time limit of 20 s with a countdown timer displayed at the top of their screen. On trials where the path was blocked, we found self-reported stress levels and distance traveled increased while trial completion rate decreased (as compared to non-stressed control trials). On unblocked stress trials, participants were less likely to take a shortcut and consequently navigated less efficiently compared to control trials. Participants with more trait spatial anxiety reported more stress and navigated less efficiently. Overall, our results suggest that navigational abilities change considerably under high-stress conditions., (© 2024. The Author(s).)

Head motion correction is particularly challenging in diffusion-weighted MRI (dMRI) scans due to the dramatic changes in image contrast at different gradient strengths and directions. Head motion correction is typically performed using a Gaussian Process model implemented in FSL's Eddy. Recently, the 3dSHORE-based SHORELine method was introduced that does not require shell-based acquisitions, but it has not been previously benchmarked. Here we perform a comprehensive evaluation of both methods on realistic simulations of a software fiber phantom that provides known ground-truth head motion. We demonstrate that both methods perform remarkably well, but that performance can be impacted by sampling scheme and the extent of head motion and the denoising strategy applied before head motion correction. Furthermore, we find Eddy benefits from denoising the data first with MP-PCA. In sum, we provide the most extensive known benchmarking of dMRI head motion correction, together with extensive simulation data and a reproducible workflow. PRACTITIONER POINTS: Both Eddy and SHORELine head motion correction methods performed quite well on a large variety of simulated data. Denoising with MP-PCA can improve head motion correction performance when Eddy is used. SHORELine effectively corrects motion in non-shelled diffusion spectrum imaging data., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

We describe methods and software resources for a bioimpedance measurement technique, 'trans-radial electrical bioimpedance velocimetry' (TREV) that allows for the non-invasive monitoring of relative cardiac contractility and stroke volume. After reviewing the relationship between the measurement and cardiac contractility, we describe the general recording methodology, which requires impedance measurements of the forearm. We provide open-source Jupyter-based software (operable on most computers) for deriving cardiac contractility from the impedance measurements. The software includes tools for removing variance associated with heart rate and respiration. We demonstrate the ability of this bioimpedance measurement for tracking beat-to-beat changes of contractility in a maximal grip force production task. Critically, the results demonstrate both a reactive increase in contractility with force production, and suggest there is a learned increase in contractility prior to grip onset, consistent with anticipatory allostatic autonomic regulation mediated by sympathetic inotropy. The method and software should be of broad utility for investigations of event-related cardiac dynamics in psychophysical studies., (© 2023 The Authors. Psychophysiology published by Wiley Periodicals LLC on behalf of Society for Psychophysiological Research.)

Tractography can generate millions of complex curvilinear fibers (streamlines) in 3D that exhibit the geometry of white matter pathways in the brain. Common approaches to analyzing white matter connectivity are based on adjacency matrices that quantify connection strength but do not account for any topological information. A critical element in neurological and developmental disorders is the topological deterioration and irregularities in streamlines. In this paper, we propose a novel Reeb graph-based method "ReeBundle" that efficiently encodes the topology and geometry of white matter fibers. Given the trajectories of neuronal fiber pathways (neuroanatomical bundle), we re-bundle the streamlines by modeling their spatial evolution to capture geometrically significant events (akin to a fingerprint). ReeBundle parameters control the granularity of the model and handle the presence of improbable streamlines commonly produced by tractography. Further, we propose a new Reeb graph-based distance metric that quantifies topological differences for automated quality control and bundle comparison. We show the practical usage of our method using two datasets: (1) For International Society for Magnetic Resonance in Medicine (ISMRM) dataset, ReeBundle handles the morphology of the white matter tract configurations due to branching and local ambiguities in complicated bundle tracts like anterior and posterior commissures; (2) For the longitudinal repeated measures in the Cognitive Resilience and Sleep History (CRASH) dataset, repeated scans of a given subject acquired weeks apart lead to provably similar Reeb graphs that differ significantly from other subjects, thus highlighting ReeBundle's potential for clinical fingerprinting of brain regions.

Ovarian cancer is amongst the ten most common cancer types in women, and it is one of the leading causes of death. Despite the promising results of targeted therapies, including anti-angiogenic agents and poly (ADP-ribose) polymerase inhibitors (PARPi), the majority of patients will relapse and develop treatment resistance, implying that novel therapeutic strategies are required. Adoptive cell therapy (ACT) refers to the process by which autologous immune cells are used to eliminate cancer. Examples include tumour infiltrating lymphocytes (TILs), T cells genetically engineered with T cell receptors (TCR), or chimeric antigen receptor (CAR)-T cells. Recently, ACT has revealed promising results in the treatment of haematological malignancies, however, its application to solid tumours is still limited due to lack of functionality and persistence of T cells, prevalence of an exhausted phenotype and impaired trafficking towards the tumour microenvironment (TME). In this review we explore the potential of ACT for the treatment of ovarian cancer and strategies to overcome its principal limitations., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CG – no declarations. MK, GK and RH are employees of Instil Bio with stock or stock options. RJE – received honoraria from GSK, & Clovis Inc., (Copyright © 2023. Published by Elsevier Ltd.)

Objective: Although ample evidence highlights that the ipsilesional corticospinal tract (CST) plays a crucial role in motor recovery after stroke, studies on cortico-cortical motor connections remain scarce and provide inconclusive results. Given their unique potential to serve as structural reserve enabling motor network reorganization, the question arises whether cortico-cortical connections may facilitate motor control depending on CST damage., Methods: Diffusion spectrum imaging (DSI) and a novel compartment-wise analysis approach were used to quantify structural connectivity between bilateral cortical core motor regions in chronic stroke patients. Basal and complex motor control were differentially assessed., Results: Both basal and complex motor performance were correlated with structural connectivity between bilateral premotor areas and ipsilesional primary motor cortex (M1) as well as interhemispheric M1 to M1 connectivity. Whereas complex motor skills depended on CST integrity, a strong association between M1 to M1 connectivity and basal motor control was observed independent of CST integrity especially in patients who underwent substantial motor recovery. Harnessing the informational wealth of cortico-cortical connectivity facilitated the explanation of both basal and complex motor control., Interpretation: We demonstrate for the first time that distinct aspects of cortical structural reserve enable basal and complex motor control after stroke. In particular, recovery of basal motor control may be supported via an alternative route through contralesional M1 and non-crossing fibers of the contralesional CST. Our findings help to explain previous conflicting interpretations regarding the functional role of the contralesional M1 and highlight the potential of cortico-cortical structural connectivity as a future biomarker for motor recovery post-stroke. ANN NEUROL 2023;94:785-797., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Aims: We aimed to evaluate the association between metabolic syndrome (MetS) and long-term all-cause mortality., Methods and Results: The LIPIDOGRAM studies were carried out in the primary care in Poland in 2004, 2006, and 2015. MetS was diagnosed based on the National Cholesterol Education Program, Adult Treatment Panel III (NCEP/ATP III), and Joint Interim Statement (JIS) criteria. The cohort was divided into four groups: non-obese patients without MetS, obese patients without MetS, non-obese patients with MetS, and obese patients with MetS. Differences in all-cause mortality were analysed using Kaplan-Meier and Cox regression analyses. A total of 45 615 participants were enrolled (mean age 56.3, standard deviation: 11.8 years; 61.7% female). MetS was diagnosed in 14 202 (31%) by NCEP/ATP III criteria and 17 216 (37.7%) by JIS criteria. Follow-up was available for 44 620 (97.8%, median duration 15.3 years) patients. MetS was associated with increased mortality risk among the obese {hazard ratio, HR: 1.88 [95% confidence interval (CI) 1.79-1.99] and HR: 1.93 [95% CI 1.82-2.04], according to NCEP/ATP III and JIS criteria, respectively} and non-obese individuals [HR: 2.11 (95% CI 1.85-2.40) and 1.7 (95% CI 1.56-1.85) according to NCEP/ATP III and JIS criteria, respectively]. Obese patients without MetS had a higher mortality risk than non-obese patients without MetS [HR: 1.16 (95% CI 1.10-1.23) and HR: 1.22 (95% CI 1.15-1.30), respectively in subgroups with NCEP/ATP III and JIS criteria applied]., Conclusions: MetS is associated with increased all-cause mortality risk in non-obese and obese patients. In patients without MetS, obesity remains significantly associated with mortality. The concept of metabolically healthy obesity should be revised., Competing Interests: Conflict of interest: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: J.J. and M.B. have received an unrestricted educational grant from Valeant and have served as consultants or speakers for Valeant. P.P. owns four shares in AstraZeneca PLC and has received honoraria and/or travel reimbursement for events sponsored by AKCEA, Amgen, AMRYT, Link Medical, Mylan, Napp, and Sanofi. All other authors declare no conflicts of interest concerning the results of this analysis. All authors revised the article critically for important intellectual content. All authors gave final approval of the work, have participated sufficiently in the work, and take public responsibility for appropriate portions of the content., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

As suggested by previous research, sleep health is assumed to be a key determinant of future morbidity and mortality. In line with this, recent studies have found that poor sleep is associated with impaired cognitive function. However, to date, little is known about brain structural abnormalities underlying this association. Although recent findings link sleep health deficits to specific alterations in grey matter volume, evidence remains inconsistent and reliant on small sample sizes. Addressing this problem, the current preregistered study investigated associations between sleep health and grey matter volume (139 imaging-derived phenotypes) in the UK Biobank cohort (33 356 participants). Drawing on a large sample size and consistent data acquisition, sleep duration, insomnia symptoms, daytime sleepiness, chronotype, sleep medication and sleep apnoea were examined. Our main analyses revealed that long sleep duration was systematically associated with larger grey matter volume of basal ganglia substructures. Insomnia symptoms, sleep medication and sleep apnoea were not associated with any of the 139 imaging-derived phenotypes. Short sleep duration, daytime sleepiness as well as late and early chronotype were associated with solitary imaging-derived phenotypes (no recognizable pattern, small effect sizes). To our knowledge, this is the largest study to test associations between sleep health and grey matter volume. Clinical implications of the association between long sleep duration and larger grey matter volume of basal ganglia are discussed. Insomnia symptoms as operationalized in the UK Biobank do not translate into grey matter volume findings., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Network neuroscience provides important insights into brain function by analyzing complex networks constructed from diffusion Magnetic Resonance Imaging (dMRI), functional MRI (fMRI) and Electro/Magnetoencephalography (E/MEG) data. However, in order to ensure that results are reproducible, we need a better understanding of within- and between-subject variability over long periods of time. Here, we analyze a longitudinal, 8 session, multi-modal (dMRI, and simultaneous EEG-fMRI), and multiple task imaging data set. We first confirm that across all modalities, within-subject reproducibility is higher than between-subject reproducibility. We see high variability in the reproducibility of individual connections, but observe that in EEG-derived networks, during both rest and task, alpha-band connectivity is consistently more reproducible than connectivity in other frequency bands. Structural networks show a higher reliability than functional networks across network statistics, but synchronizability and eigenvector centrality are consistently less reliable than other network measures across all modalities. Finally, we find that structural dMRI networks outperform functional networks in their ability to identify individuals using a fingerprinting analysis. Our results highlight that functional networks likely reflect state-dependent variability not present in structural networks, and that the type of analysis should depend on whether or not one wants to take into account state-dependent fluctuations in connectivity., (© 2023. The Author(s).)

Heuristics can inform human decision making in complex environments through a reduction of computational requirements (accuracy-resource trade-off) and a robustness to overparameterisation (less-is-more). However, tasks capturing the efficiency of heuristics typically ignore action proficiency in determining rewards. The requisite movement parameterisation in sensorimotor control questions whether heuristics preserve efficiency when actions are nontrivial. We developed a novel action selection-execution task requiring joint optimisation of action selection and spatio-temporal skillful execution. State-appropriate choices could be determined by a simple spatial heuristic, or by more complex planning. Computational models of action selection parsimoniously distinguished human participants who adopted the heuristic from those using a more complex planning strategy. Broader comparative analyses then revealed that participants using the heuristic showed combined decisional (selection) and skill (execution) advantages, consistent with a less-is-more framework. In addition, the skill advantage of the heuristic group was predominantly in the core spatial features that also shaped their decision policy, evidence that the dimensions of information guiding action selection might be yoked to salient features in skill learning., (© 2023. The Author(s).)

Humans show remarkable habituation to aversive events as reflected by changes of both subjective report and objective measures of stress. Although much experimental human research focuses on the effects of stress, relatively little is known about the cascade of physiological and neural responses that contribute to stress habituation. The cold pressor test (CPT) is a common method for inducing acute stress in human participants in the laboratory; however, there are gaps in our understanding of the global state changes resulting from this stress-induction technique and how these responses change over multiple exposures. Here, we measure the stress response to repeated CPT exposures using an extensive suite of physiologic measures and state-of-the-art analysis techniques. In two separate sessions on different days, participants underwent five 90 s CPT exposures of both feet and five warm water control exposures, while electrocardiography (ECG), impedance cardiography, continuous blood pressure, pupillometry, scalp electroencephalography (EEG), salivary cortisol and self-reported pain assessments were recorded. A diverse array of adaptive responses are reported that vary in their temporal dynamics within each exposure as well as habituation across repeated exposures. During cold-water exposure there was a cascade of changes across several cardiovascular measures (elevated heart rate (HR), cardiac output (CO) and Mean Arterial Pressure (MAP) and reduced left ventricular ejection time (LVET), stroke volume (SV) and high-frequency heart rate variability (HF)). Increased pupil dilation was observed, as was increased power in low-frequency bands (delta and theta) across frontal EEG electrode sites. Several cardiovascular measures also habituated over repeated cold-water exposures (HR, MAP, CO, SV, LVET) as did pupil dilation and alpha frequency activity across the scalp. Anticipation of cold water induced stress effects in the time-period immediately prior to exposure, indexed by increased pupil size and cortical disinhibition in the alpha and beta frequency bands across central scalp sites. These results provide comprehensive insight into the evolution of a diverse array of stress responses to an acute noxious stressor, and how these responses adaptively contribute to stress habituation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bullock, MacLean, Santander, Boone, Babenko, Dundon, Stuber, Jimmons, Raymer, Okafor, Miller, Giesbrecht and Grafton.)

Anisotropy of descending motor pathways has repeatedly been linked to the severity of motor impairment following stroke-related damage to the corticospinal tract. Despite promising findings consistently tying anisotropy of the ipsilesional corticospinal tract to motor outcome, anisotropy is not yet utilized as a biomarker for motor recovery in clinical practice as several methodological constraints hinder a conclusive understanding of degenerative processes in the ipsilesional corticospinal tract and compensatory roles of other descending motor pathways. These constraints include estimating anisotropy in voxels with multiple fibre directions, sampling biases and confounds due to ageing-related atrophy. The present study addressed these issues by combining diffusion spectrum imaging with a novel compartmentwise analysis approach differentiating voxels with one dominant fibre direction (one-directional voxels) from voxels with multiple fibre directions. Compartmentwise anisotropy for bihemispheric corticospinal and extrapyramidal tracts was compared between 25 chronic stroke patients, 22 healthy age-matched controls, and 24 healthy young controls and its associations with motor performance of the upper and lower limbs were assessed. Our results provide direct evidence for Wallerian degeneration along the entire length of the ipsilesional corticospinal tract reflected by decreased anisotropy in descending fibres compared with age-matched controls, while ageing-related atrophy was observed more ubiquitously across compartments. Anisotropy of descending ipsilesional corticospinal tract voxels showed highly robust correlations with various aspects of upper and lower limb motor impairment, highlighting the behavioural relevance of Wallerian degeneration. Moreover, anisotropy measures of two-directional voxels within bihemispheric rubrospinal and reticulospinal tracts were linked to lower limb deficits, while anisotropy of two-directional contralesional rubrospinal voxels explained gross motor performance of the affected hand. Of note, the relevant extrapyramidal structures contained fibres crossing the midline, fibres potentially mitigating output from brain stem nuclei, and fibres transferring signals between the extrapyramidal system and the cerebellum. Thus, specific parts of extrapyramidal pathways seem to compensate for impaired gross arm and leg movements incurred through stroke-related corticospinal tract lesions, while fine motor control of the paretic hand critically relies on ipsilesional corticospinal tract integrity. Importantly, our findings suggest that the extrapyramidal system may serve as a compensatory structural reserve independent of post-stroke reorganization of extrapyramidal tracts. In summary, compartment-specific anisotropy of ipsilesional corticospinal tract and extrapyramidal tracts explained distinct aspects of motor impairment, with both systems representing different pathophysiological mechanisms contributing to motor control post-stroke. Considering both systems in concert may help to develop diffusion imaging biomarkers for specific motor functions after stroke., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The model-free algorithms of "reinforcement learning" (RL) have gained clout across disciplines, but so too have model-based alternatives. The present study emphasizes other dimensions of this model space in consideration of associative or discriminative generalization across states and actions. This "generalized reinforcement learning" (GRL) model, a frugal extension of RL, parsimoniously retains the single reward-prediction error (RPE), but the scope of learning goes beyond the experienced state and action. Instead, the generalized RPE is efficiently relayed for bidirectional counterfactual updating of value estimates for other representations. Aided by structural information but as an implicit rather than explicit cognitive map, GRL provided the most precise account of human behavior and individual differences in a reversal-learning task with hierarchical structure that encouraged inverse generalization across both states and actions. Reflecting inference that could be true, false (i.e., overgeneralization), or absent (i.e., undergeneralization), state generalization distinguished those who learned well more so than action generalization. With high-resolution high-field fMRI targeting the dopaminergic midbrain, the GRL model's RPE signals (alongside value and decision signals) were localized within not only the striatum but also the substantia nigra and the ventral tegmental area, including specific effects of generalization that also extend to the hippocampus. Factoring in generalization as a multidimensional process in value-based learning, these findings shed light on complexities that, while challenging classic RL, can still be resolved within the bounds of its core computations., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Influential theories of skilled action posit that distinct cognitive mechanisms and neuroanatomic substrates support meaningless gesture imitation and tool use pantomiming, and poor performance on these tasks are hallmarks of limb apraxia. Yet prior research has primarily investigated brain-behavior relations at the group level; thus, it is unclear whether we can identify individuals with isolated impairments in meaningless gesture imitation or tool use pantomiming whose performance is associated with a distinct neuroanatomic lesion profile. The goal of this study was to test the hypothesis that individuals with disproportionately worse performance in meaningless gesture imitation would exhibit cortical damage and white matter disconnection in left fronto-parietal brain regions, whereas individuals with disproportionately worse performance in tool use pantomiming would exhibit cortical damage and white matter disconnection in left temporo-parietal brain regions. Fifty-eight participants who experienced a left cerebrovascular accident took part in a meaningless gesture imitation task, a tool use pantomiming task, and a T1 structural MRI. Two participants were identified who had relatively small lesions and disproportionate impairments on one task relative to the other, as well as below-control-level performance on one task and not the other. Using these criteria, one participant was disproportionately impaired at meaningless gesture imitation, and the other participant was disproportionately impaired at pantomiming tool use. Graph theoretic analysis of each participant's structural disconnectome demonstrated that disproportionately worse meaningless gesture imitation performance was associated with disconnection among the left inferior parietal lobule, the left superior parietal lobule, and the left middle and superior frontal gyri, whereas disproportionately worse tool use pantomiming performance was associated with disconnection between left temporal and parietal regions. Our results demonstrate that relatively focal lesions to specific portions of the Tool Use Network can be associated with distinct limb apraxia subtypes., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: To investigate how work participation outcomes in randomized controlled trials are measured internationally and across disciplines., Study Design and Setting: We identified trials that reported on work participation in Medline, Embase, PsycINFO and Cochrane Central published between 2014 and 2019. Screening, selection, and data extraction were done by two authors independently. We grouped outcomes into four categories ("employment status", "absence from work", "at-work productivity loss," and "employability") and created subcategories according to how the outcome was measured., Results: From 10,022 database hits we selected 269 trials reporting on 435 work participation outcomes. Authors used inconsistent outcome terminology to describe the measured constructs. Grouped in four main categories we identified 70 outcomes that reported on "employment status", 196 on "absence from work" and return-to-work, 132 on "at-work productivity loss," and 37 on "employability" outcomes. Variability in measurement methods existed across all categories. Employment status and absenteeism measures consisted mostly of clinimetrically unvalidated tools. "At-work productivity loss" and "employability" were measured by at least 41 different questionnaires., Conclusion: Extensive variability exists among trials in the measurement of outcomes, measurement methods and measurement instruments that focus on work participation. This study is a first step towards the development of a Core Outcome Set for work participation., (Copyright © 2021. Published by Elsevier Inc.)

Background: Improving telephone triage for patients with chest pain has been identified as a national research priority. However, there is a lack of strong evidence to define the life-threatening conditions (LTCs) that telephone triage ought to identify. Therefore, we aimed to build consensus for the LTCs associated with chest pain that ought to be identified during telephone triage for emergency calls., Methods: We conducted a Delphi study in three rounds. Twenty experts in pre-hospital care and emergency medicine experience from the UK were invited to participate. In round I, experts were asked to list all LTCs that would require priority 1, 2, and 4 ambulance responses. Round II was a ranking evaluation, and round III was a consensus round. Consensus level was predefined at > = 70%., Results: A total of 15 participants responded to round one and 10 to rounds two and three. Of 185 conditions initially identified by the experts, 26 reached consensus in the final round. Ten conditions met consensus for requiring priority 1 response: oesophageal perforation/rupture; ST elevation myocardial infarction; non-ST elevation myocardial infarction with clinical compromise (defined, also by consensus, as oxygen saturation < 90%, heart rate < 40/min or systolic blood pressure < 90 mmHg); acute heart failure; cardiac tamponade; life-threatening asthma; cardiac arrest; tension pneumothorax and massive pulmonary embolism. An additional six conditions met consensus for priority 2 response, and three for priority 4 response., Conclusion: Using expert consensus, we have defined the LTCs that may present with chest pain, which ought to receive a high-priority ambulance response. This list of conditions can now form a composite primary outcome for future studies to derive and validate clinical prediction models that will optimise telephone triage for patients with a primary complaint of chest pain., (© 2021. The Author(s).)

Background: Studies have shown that losartan reduces serum uric acid in adults, unlike angiotensin-converting enzyme inhibitors. A previous study demonstrated that losartan and enalapril had comparable effects on proteinuria in children., Methods: We conducted a post hoc analysis of results from a prospective trial in which the proteinuria-reducing effects of losartan and enalapril were compared. We have now evaluated (a) the effects of these medications on SUA in 248 children with proteinuria and (b) the correlation between changes in SUA and eGFR., Results: SUA levels after 36 months were found to be increased when compared to baseline in both losartan and enalapril groups. The mean change in SUA from baseline was significantly different at 12 months between 23 hypertensive patients randomised to losartan (3.69% decrease [95% CI 11.31%, 3.93%]) and 24 randomised to enalapril (12.57% increase [95% CI 3.72%, 21.41%]), p = 0.007. This significant difference remained after 24, 30 and 36 months but was observed in the entire group of 248 patients only at 12 months. There was a statistically significant negative correlation between changes in SUA and changes in eGFR at each time point over 36 months., Conclusions: Losartan may have long-term beneficial effects on SUA and eGFR in children with proteinuria., (© 2021. The Author(s).)

How does the brain change during learning? In functional magnetic resonance imaging (fMRI) studies, both multivariate pattern analysis (MVPA) and repetition suppression (RS) have been used to detect changes in neuronal representations. In the context of motor sequence learning, the two techniques have provided discrepant findings: pattern analysis showed that only premotor and parietal regions, but not primary motor cortex (M1), develop a representation of trained sequences. In contrast, RS suggested trained sequence representations in all these regions. Here, we applied both analysis techniques to a five-week finger sequence training study, in which participants executed each sequence twice before switching to a different sequence. Both RS and pattern analysis indicated learning-related changes for parietal areas, but only RS showed a difference between trained and untrained sequences in M1. A more fine-grained analysis, however, revealed that the RS effect in M1 reflects a fundamentally different process than in parietal areas. On the first execution, M1 represents especially the first finger of each sequence, likely reflecting preparatory processes. This effect dramatically reduces during the second execution. In contrast, parietal areas represent the identity of a sequence, and this representation stays relatively stable on the second execution. These results suggest that the RS effect does not reflect a trained sequence representation in M1, but rather a preparatory signal for movement initiation. More generally, our study demonstrates that across regions RS can reflect different representational changes in the neuronal population code, emphasizing the importance of combining pattern analysis and RS techniques. SIGNIFICANCE STATEMENT Previous studies using pattern analysis have suggested that primary motor cortex (M1) does not represent learnt sequential actions. However, a study using repetition suppression (RS) has reported M1 changes during motor sequence learning. Combining both techniques, we first replicate the discrepancy between them, with learning-related changes in M1 in RS, but not pattern dissimilarities. We further analyzed the representational changes with repetition, and found that the RS effects differ across regions. M1's activity represents the starting finger of the sequence, an effect that vanishes with repetition. In contrast, activity patterns in parietal areas exhibit sequence dependency, which persists with repetition. These results demonstrate the importance of combining RS and pattern analysis to understand the function of brain regions., (Copyright © 2021 the authors.)

Diffusion-weighted magnetic resonance imaging (dMRI) is the primary method for noninvasively studying the organization of white matter in the human brain. Here we introduce QSIPrep, an integrative software platform for the processing of diffusion images that is compatible with nearly all dMRI sampling schemes. Drawing on a diverse set of software suites to capitalize on their complementary strengths, QSIPrep facilitates the implementation of best practices for processing of diffusion images.

Objective . Both artificial and biological controllers experience errors during learning that are probabilistically distributed. We develop a framework for modeling distributions of errors and relating deviations in these distributions to neural activity. Approach . The biological system we consider is a task where human subjects are required to learn to minimize the roll of an inverted T-shaped object with an unbalanced weight (i.e. one side of the object is heavier than the other side) during lift. We also collect BOLD activity during this process. For our experimental setup, we define the state of the system to be the maximum magnitude roll of the object after lift onset and give subjects the goal of achieving the zero state. Main Results . We derive a model for this problem from a variant of Temporal Difference Learning. We then combine this model with Distributional Reinforcement Learning (DRL), a framework that involves defining a value distribution by treating the reward as stochastic. This model transforms the goal of the controller from achieving a target state, to achieving a distribution over distances from the target state. We call it a Distributional Temporal Difference Model (DTDM). The DTDM allows us to model errors in unsuccessfully minimizing object roll using deviations in the value distribution when the center of mass of the unbalanced object is changed. We compute deviations in global neural activity and show that they vary continuously with deviations in the value distribution. Different aspects might contribute to this global shift or signal difference, including a difference in grasp and lift force at lift onset, as well as sensory feedback of error/roll after lift onset. We predict that there exists a coordinated, global response to errors that incorporates all of this information, which is encoding the DTDM objective and used on subsequent trials enabling success. We validate the utility of the DTDM as a model for biological adaptation by using it to engineer a robotic controller to solve a similar problem. Significance . We develop a novel theoretical framework and show that it can be used to model a non-trivial motor learning task. Because this theoretical framework is consistent with state-of-the-art reinforcement learning, we can also use it to program a robot to perform a similar task. These results suggest a way to model the multiple subsystems composing global neural activity in a way that transfers well to engineering artificial intelligence., (© 2021 IOP Publishing Ltd.)

Anxiety is characterized by low confidence in daily decisions, coupled with high levels of phenomenological stress. Ventromedial prefrontal cortex (vmPFC) plays an integral role in maladaptive anxious behaviors via decreased sensitivity to threatening vs. non-threatening stimuli (fear generalization). vmPFC is also a key node in approach-avoidance decision making requiring two-dimensional integration of rewards and costs. More recently, vmPFC has been implicated as a key cortical input to the sympathetic branch of the autonomic nervous system. However, little is known about the role of this brain region in mediating rapid stress responses elicited by changes in confidence during decision making. We used an approach-avoidance task to examine the relationship between sympathetically mediated cardiac stress responses, vmPFC activity and choice behavior over long and short time-scales. To do this, we collected concurrent fMRI, EKG and impedance cardiography recordings of sympathetic drive while participants made approach-avoidance decisions about monetary rewards paired with painful electric shock stimuli. We observe first that increased sympathetic drive (shorter pre-ejection period) in states lasting minutes are associated with choices involving reduced decision ambivalence. Thus, on this slow time scale, sympathetic drive serves as a proxy for "mobilization" whereby participants are more likely to show consistent value-action mapping. In parallel, imaging analyses reveal that on shorter time scales (estimated with a trial-to-trial GLM), increased vmPFC activity, particularly during low-ambivalence decisions, is associated with decreased sympathetic state. Our findings support a role of sympathetic drive in resolving decision ambivalence across long time horizons and suggest a potential role of vmPFC in modulating this response on a moment-to-moment basis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dundon, Shapiro, Babenko, Okafor and Grafton.)

Sex steroid hormones have been shown to alter regional brain activity, but the extent to which they modulate connectivity within and between large-scale functional brain networks over time has yet to be characterized. Here, we applied dynamic community detection techniques to data from a highly sampled female with 30 consecutive days of brain imaging and venipuncture measurements to characterize changes in resting-state community structure across the menstrual cycle. Four stable functional communities were identified, consisting of nodes from visual, default mode, frontal control, and somatomotor networks. Limbic, subcortical, and attention networks exhibited higher than expected levels of nodal flexibility, a hallmark of between-network integration and transient functional reorganization. The most striking reorganization occurred in a default mode subnetwork localized to regions of the prefrontal cortex, coincident with peaks in serum levels of estradiol, luteinizing hormone, and follicle stimulating hormone. Nodes from these regions exhibited strong intranetwork increases in functional connectivity, leading to a split in the stable default mode core community and the transient formation of a new functional community. Probing the spatiotemporal basis of human brain-hormone interactions with dynamic community detection suggests that hormonal changes during the menstrual cycle result in temporary, localized patterns of brain network reorganization., Competing Interests: Competing Interests: The authors have declared that no competing interests exist., (© 2020 Massachusetts Institute of Technology.)

We report the simple synthesis of bismuthene nanosheets (BiNS) by ionic liquid assisted grinding exfoliation, followed by size selection sequential centrifugation steps for the first time. The exfoliation process results in the formation of self-assembled spherule-like superstructures with abundant edge sites, which are able to catalyze the oxygen reduction reaction (ORR) via a two-electron pathway, with a higher efficiency than the bulk Bismuth. We rationalize the enhanced ORR activity of the BiNS to: (i) the presence of 1 dimensional topological edge states, which provide strong conduction channels for electron hopping between the bismuth layers and (ii) the more active role of edge sites in facilitating O 2 adsorption and dissociation of O-O bonds compared to the basal plane. The present study provides a pathway for employing 2D topological insulators as a new class of electrocatalysts for clean energy applications., Competing Interests: The authors have no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

The cerebellum contains the vast majority of neurons in the brain and houses distinct functional networks that constitute at least two homotopic maps of cerebral networks. It is also a major site of sex steroid hormone action. While the functional organization of the human cerebellum has been characterized, the influence of sex steroid hormones on intrinsic cerebellar network dynamics has yet to be established. Here we investigated the extent to which endogenous fluctuations in estradiol and progesterone alter functional cerebellar networks at rest in a woman densely sampled over a complete menstrual cycle (30 consecutive days). Edgewise regression analysis revealed robust negative associations between progesterone and cerebellar coherence. Graph theory metrics probed sex hormones' influence on topological brain states, revealing relationships between sex hormones and within-network integration in Ventral Attention, Dorsal Attention, and SomatoMotor Networks. Together these results suggest that the intrinsic dynamics of the cerebellum are intimately tied to day-by-day changes in sex hormones.

Humans are seamless in their ability to efficiently and reliably generate fingertip forces to gracefully interact with objects. Such interactions rarely end in awkward outcomes like spilling, crushing, or tilting given advanced motor planning. Here we combine multiband imaging with deconvolution- and Bayesian pattern component modeling of functional magnetic resonance imaging data and in-scanner kinematics, revealing compelling evidence that the human brain differentially represents preparatory information for skillful object interactions depending on the saliency of visual cues. Earlier patterned activity was particularly evident in ventral visual processing stream-, but also selectively in dorsal visual processing stream and cerebellum in conditions of heightened uncertainty when an object's superficial shape was incompatible rather than compatible with a key underlying object feature., (© The Author(s) 2020. Published by Oxford University Press.)

The brain is an endocrine organ, sensitive to the rhythmic changes in sex hormone production that occurs in most mammalian species. In rodents and nonhuman primates, estrogen and progesterone's impact on the brain is evident across a range of spatiotemporal scales. Yet, the influence of sex hormones on the functional architecture of the human brain is largely unknown. In this dense-sampling, deep phenotyping study, we examine the extent to which endogenous fluctuations in sex hormones alter intrinsic brain networks at rest in a woman who underwent brain imaging and venipuncture for 30 consecutive days. Standardized regression analyses illustrate estrogen and progesterone's widespread associations with functional connectivity. Time-lagged analyses examined the temporal directionality of these relationships and suggest that cortical network dynamics (particularly in the Default Mode and Dorsal Attention Networks, whose hubs are densely populated with estrogen receptors) are preceded-and perhaps driven-by hormonal fluctuations. A similar pattern of associations was observed in a follow-up study one year later. Together, these results reveal the rhythmic nature in which brain networks reorganize across the human menstrual cycle. Neuroimaging studies that densely sample the individual connectome have begun to transform our understanding of the brain's functional organization. As these results indicate, taking endocrine factors into account is critical for fully understanding the intrinsic dynamics of the human brain., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

The rhythmic production of sex steroid hormones is a central feature of the mammalian endocrine system. In rodents and nonhuman primates, sex hormones are powerful regulators of hippocampal subfield morphology. However, it remains unknown whether intrinsic fluctuations in sex hormones alter hippocampal morphology in the human brain. In a series of dense-sampling studies, we used high-resolution imaging of the medial temporal lobe (MTL) to determine whether endogenous fluctuations (Study 1) and exogenous manipulation (Study 2) of sex hormones alter MTL volume over time. Across the menstrual cycle, intrinsic fluctuations in progesterone were associated with volumetric changes in CA2/3, entorhinal, perirhinal, and parahippocampal cortex. Chronic progesterone suppression abolished these cycle-dependent effects and led to pronounced volumetric changes in entorhinal cortex and CA2/3 relative to freely cycling conditions. No associations with estradiol were observed. These results establish progesterone's ability to rapidly and dynamically shape MTL morphology across the human menstrual cycle., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Appraising sequential offers relative to an unknown future opportunity and a time cost requires an optimization policy that draws on a learned estimate of an environment's richness. Converging evidence points to a learning asymmetry, whereby estimates of this richness update with a bias toward integrating positive information. We replicate this bias in a sequential foraging (prey selection) task and probe associated activation within the sympathetic branch of the autonomic system, using trial-by-trial measures of simultaneously recorded cardiac autonomic physiology. We reveal a unique adaptive role for the sympathetic branch in learning. It was specifically associated with adaptation to a deteriorating environment: it correlated with both the rate of negative information integration in belief estimates and downward changes in moment-to-moment environmental richness, and was predictive of optimal performance on the task. The findings are consistent with a framework whereby autonomic function supports the learning demands of prey selection.

Anticipatory force control is a fundamental means by which humans stave off slipping, spilling, and tilting disasters while manipulating objects. This control must often be adapted due to changes in an object's dynamics (e.g. a lighter than expected mug of coffee) or its relation with involved effectors or digits (e.g. lift a mug with three vs. five digits). The neural processes guiding such anticipatory and adaptive control is understudied but presumably operates along multiple time scales, analogous to what has been identified with adaptation in other motor tasks, such as perturbations during reaching. Learning of anticipatory forces must be ultrafast to minimize tilting a visually symmetric object towards its concealed asymmetric center of mass (CoM), but slower when the CoM is explicitly and systematically switched from side to side. Studying the neural substrates of this latter slower learning process with rapid multiband brain imaging, in-scanner kinematics and Bayesian pattern component modelling, we show that CoM-specific pattern distances increase with repeated CoM switching exposures and improved learning. The cerebellum showed the most prominent effects, fitting with the idea that it forms a stored internal model that is used to build and update anticipatory control. CoM-specific pattern distances were present 24 h later, in line with the presence of consolidation effects.

The ability of humans to reach and grasp objects in their environment has been the mainstay paradigm for characterizing the neural circuitry driving object-centric actions. Although much is known about hand shaping, a persistent question is how the brain orchestrates and integrates the grasp with lift forces of the fingers in a coordinated manner. The objective of the current study was to investigate how the brain represents grasp configuration and lift force during a dexterous object-centric action in a large sample of male and female human subjects. BOLD activity was measured as subjects used a precision-grasp to lift an object with a center of mass (CoM) on the left or right with the goal of minimizing tilting the object. The extent to which grasp configuration and lift force varied between left and right CoM conditions was manipulated by grasping the object collinearly (requiring a non-collinear force distribution) or non-collinearly (requiring more symmetrical forces). Bayesian variational representational similarity analyses on fMRI data assessed the evidence that a set of cortical and cerebellar regions were sensitive to grasp configuration or lift force differences between CoM conditions at differing time points during a grasp to lift action. In doing so, we reveal strong evidence that grasping and lift force are not represented by spatially separate functionally specialized regions, but by the same regions at differing time points. The coordinated grasp to lift effort is shown to be under dorsolateral (PMv and AIP) more than dorsomedial control, and under SPL7, somatosensory PSC, ventral LOC and cerebellar control. SIGNIFICANCE STATEMENT Clumsy disasters such as spilling, dropping, and crushing during our daily interactions with objects are a rarity rather than the norm. These disasters are avoided in part as a result of our orchestrated anticipatory efforts to integrate and coordinate grasping and lifting of object interactions, all before the lift of an object even commences. How the brain orchestrates this integration process has been largely neglected by historical approaches independently and solely focusing on reaching and grasping and the neural principles that guide them. Here, we test the extent to which grasping and lifting are represented in a spatially or temporally distinct manner and identified strong evidence for the consecutive emergence of sensitivity to grasping, then lifting within the same region., (Copyright © 2020 the authors.)

Two fundamental goals of decision making are to select actions that maximize rewards while minimizing costs and to have strong confidence in the accuracy of a judgment. Neural signatures of these two forms of value: the subjective value (SV) of choice alternatives and the value of the judgment (confidence), have both been observed in ventromedial prefrontal cortex (vmPFC). However, the relationship between these dual value signals and their relative time courses are unknown. Twenty-eight men and women underwent fMRI while performing a two-phase approach-avoidance (Ap-Av) task with mixed-outcomes of monetary rewards paired with painful shock stimuli. Neural responses were measured during offer valuation (offer phase) and choice valuation (commit phase) and analyzed with respect to observed decision outcomes, model-estimated SV and confidence. During the offer phase, vmPFC tracked SV and the decision but not confidence. During the commit phase, vmPFC tracked confidence, computed as the quadratic extension of SV, but not the offer valuation nor the decision. In fact, vmPFC responses from the commit phase were selective for confidence even for reject decisions wherein confidence and SV are inversely related. Conversely, activation of the cognitive control network, including within lateral prefrontal cortex (lPFC) and dorsal anterior cingulate cortex (dACC) was associated with ambivalence, during both the offer and commit phases. Taken together, our results reveal complementary representations in vmPFC during value-based decision making that temporally dissociate such that offer valuation (SV) emerges before decision valuation (confidence)., Competing Interests: The authors have declared that no competing interests exist.

Producing a tool use gesture is a complex process drawing upon the integration of stored knowledge of tools and their associated actions with sensory-motor mechanisms supporting the planning and control of hand and arm actions. Understanding how sensory-motor systems in parietal cortex interface with semantic representations of actions and objects in the temporal lobe remains a critical issue and is hypothesized to be a key determinant of the severity of limb apraxia, a deficit in producing skilled action after left hemisphere stroke. We used voxel-based and connectome-based lesion-symptom mapping with data from 57 left hemisphere stroke participants to assess the lesion sites and structural disconnection patterns associated with poor tool use gesturing. We found that structural disconnection among the left inferior parietal lobule, lateral and ventral temporal cortices, and middle and superior frontal gyri predicted the severity of tool use gesturing performance. Control analyses demonstrated that reductions in right-hand grip strength were associated with motor system disconnection, largely bypassing regions supporting tool use gesturing. Our findings provide evidence that limb apraxia may arise, in part, from a disconnection between conceptual representations in the temporal lobe and mechanisms enabling skilled action production in the inferior parietal lobule., (© The Author(s) 2020. Published by Oxford University Press.)

Cartilage engineering with stem cells in 3D scaffolds is a promising future therapy to treat cartilage defects. One challenge in the field is to design carriers to efficaciously deliver biological factors in 3D scaffolds containing stem cells to appropriately guide differentiation of these cells in same scaffolds and promote specific tissue synthesis. Graphene-based 2D nanomaterials have recently attracted extensive interest for their biomedical applications as they can adsorb a plethora of biological molecules, thus offering high potential as delivery carriers. This study utilized graphene oxide (GO) flakes to adsorb transforming growth factor β3 (TGF-β3), which were then incorporated into a collagen hydrogel. Human mesenchymal stem cells (hMSCs) were encapsulated in the same gel and chondrogenic differentiation assessed. The study showed GO flakes adsorbed > 99% TGF-β3 with <1.7% release. Adsorbed TGF-β3 retained a similar conformation to its dissolved counterpart (free protein) but importantly demonstrated greater conformational stability. Smad2 phosphorylation was promoted, and higher chondrogenic gene expression and cartilage-specific extracellular matrix deposition were achieved compared to exogenously delivering TGF-β3 in culture media. Effects were sustained in long-term 28-day culture. The results demonstrate GO flakes as highly-efficient for delivering GFs in 3D to guide cells in the same scaffold and induce tissue formation. The ability of GO flakes to provide sustained local delivery makes this material attractive for tissue engineering strategies, in particular for regionally-specific MSC differentiation (e.g. osteochondral tissue engineering). STATEMENT OF SIGNIFICANCE: Cartilage engineering involving stem cells in 3D scaffolds is a promising future therapy to treat cartilage defects which can lead to debilitating conditions such as osteoarthritis. However, this field faces the challenge to design delivery carriers to efficaciously deliver biological factors inside these 3D cell-containing scaffolds for appropriately-guided cell differentiation. Graphene-based 2D nanomaterials offer high potential as delivery carriers, but to date studies using them to deliver biological factors have been restricted to 2D substrates, non-scaffold cell masses, or acellular 3D scaffolds. Our study for the first time demonstrated simultaneously incorporating both human mesenchymal stem cells (hMSCs) and GO (graphene oxide)-adsorbed growth factor TGFβ3 into a 3D scaffold, where GO-adsorbed TGFβ3 enhanced chondrogenic differentiation of hMSCs and cartilage-tissue synthesis throughout the scaffold without needing to repeatedly supply TGFβ3 exogenously., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)