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Recordings were carried out in 4-8 week old C57/Bl6 mice. SERT-Cre::Rosa-TdTomato and SOM-Cre::Rosa-TdTomatotransgenic lines were used to fluorescently label DRN 5-HT and SOM GABA neurons, respectively. All experiments were carried out in accordance with procedures approved by the University of Ottawa Animal Care and Veterinary Services. Experiments were carried out at room temperature using a potassium-gluconate-based internal solution, except for synaptic physiology experiments for which a cesium-based solution was used. In all cases, the external solution consisted of standard artificial cerebrospinal fluid. Detailed information is available in our related publication. The data is laid out as shown below, with recordings from DRN 5-HT, DRN GABA, and L5 mPFC pyramidal neurons stored in the corresponding directories. . ├── 5HT │ ├── current_steps │ ├── GABA_synapses │ ├── gating │ ├── heated_gating │ ├── heated_pharmacology │ ├── long_curr_steps │ ├── membrane_parameters │ ├── OU_noise │ ├── OU_noise_heated │ ├── pharmacology │ └── spk_time ├── GABA │ ├── current_steps │ ├── DRN393_firing_vsteps │ ├── DRN398_firing_vsteps │ ├── long_curr_steps │ ├── matched_I_V_steps │ ├── membrane_parameters │ ├── OU_noise │ ├── spk_time │ └── unmatched_V_steps └── mPFC ├── current_steps ├── gating └── OU_noise The names of subdirectories mainly reflect the different types of experiments carried out in each cell type: current_steps: Short (~1s) steps of current applied in current clamp. long_curr_steps: 20-30s current steps. spk_time: A 1s hyperpolarizing current step of variable amplitude followed by a short depolarizing step to evoke spiking. This protocol has been used in the past to investigate an effect of inactivating potassium currents (eg IA) on spike timing. OU_noise: Frozen Ornstein-Uhlenbeck noise with various timescale and amplitude characteristics applied in current clamp. This protocol provides a rich dataset for training spiking neuron models (see Related works). Each experiment is divided into training and test portions which we recommend using for training and testing models, respectively. gating: Voltage clamp protocol designed to characterize the voltage-dependence of ionic currents that activate near spike threshold. Consists of a hyperpolarizing pulse followed by depolarizing steps of varying amplitude. These experiments were carried out in the presence of tetrodotoxin (TTX) to block voltage-gated sodium channels. In the GABA dataset, these experiments are split across the unmatched_V_steps, matched_V_steps, and DRN39X_firing_vsteps directories because in some cases we were able to carry out spk_time and gating experiments in the same cells. In the case of DRN39X_firing_vsteps, we carried out the spk_timing protocol, applied TTX, then carried out the gating protocol. In the case of matched_I_V_steps, both protocols were carried out in the presence of TTX. pharmacology: Voltage clamp protocol designed to activate voltage-dependent ionic currents. 18411010.abf was recorded under baseline conditions, 18411013.abf was recorded in the presence of TEA, and 18411015.abf was recorded in the presence of TEA + 4AP. All three recordings were carried out in the same cell. membrane_parameters: Passive membrane parameters (resistance and capacitance) of DRN neurons. Most of the data files included in this package are electrophysiological recordings stored in Axon binary format (ABF) which can be opened in Python using neo or ez-ephys (which itself uses neo internally). Recordings are named according to the following convention: <experimenter_prefix><YYMDD><id>.abf where <experimenter_prefix> is an optional prefix with the initials of the person who collected the data, <YYMDD> is the date the experiment was carried out (M is either a number representing a month between January and September, or one of the letters o, n, or d for the remaining months), and <id> is a three digit number. For example, JF19121013.abf was collected by Jean-François Boucher on January 21, 2019. Metadata is included in files named index.csv. These tables include a unique ID for each neuron recorded (this can be used to determine which recordings were carried out in the same neuron), the passive membrane resistance in MOhm (R), membrane capacitance in pF (C), and the holding current at -70 mV or -60 mV in pA (I_hold). checksums.txt includes SHA256 checksums that can be used to verify data integrity. This dataset contains whole-cell electrophysiological recordings (patch-clamp recordings) from three cell types in mice: serotonin (5-HT) neurons, somatostatin (SOM)-expressing GABA interneurons, and layer 5 pyramidal neurons. 5-HT and GABA neurons were recorded in the dorsal raphe nucleus (DRN), which is the main source of serotonergic input to the forebrain. Together, they make up the majority of the neurons found in the DRN. This dataset can be used to investigate the intrinsic electrophysiological properties of these two types of DRN neurons and contrast them with another abundant and well-studied cell type, the L5 pyramidal neuron. This data was used in our paper describing a spiking neural network model of the dorsal raphe nucleus: Emerson F. Harkin, Michael B. Lynn, Alexandre Payeur, Jean-François Boucher, Léa Caya-Bissonnette, Dominic Cyr, Chloe Stewart, André Longtin, Richard Naud, and Jean-Claude Béïque. Temporal derivative computation in the dorsal raphe network revealed by an experimentally-driven augmented integrate-and-fire modeling framework. eLife, 2023. doi: 10.7554/eLife.72951 See the included README.md for detailed information about the dataset.

The persistence of back pain following acute back “sprains” is a serious public health problem with poorly understood pathophysiology. The recent finding that human subjects with chronic low back pain (LBP) have increased thickness and decreased mobility of the thoracolumbar fascia measured with ultrasound suggest that the fasciae of the back may be involved in LBP pathophysiology. This study used a porcine model to test the hypothesis that similar ultrasound findings can be produced experimentally in a porcine model by combining a local injury of fascia with movement restriction using a “hobble” device linking one foot to a chest harness for 8 weeks. Ultrasound measurements of thoracolumbar fascia thickness and shear plane mobility (shear strain) during passive hip flexion were made at the 8 week time point on the non-intervention side (injury and/or hobble). Injury alone caused both an increase in fascia thickness (p = .007) and a decrease in fascia shear strain on the non-injured side (p = .027). Movement restriction alone did not change fascia thickness but did decrease shear strain on the non-hobble side (p = .024). The combination of injury plus movement restriction had additive effects on reducing fascia mobility with a 52% reduction in shear strain compared with controls and a 28% reduction compared to movement restriction alone. These results suggest that a back injury involving fascia, even when healed, can affect the relative mobility of fascia layers away from the injured area, especially when movement is also restricted. pigpaper_thicknessUltrasound Thickness measurementspigpaper_SSUltrasound shear strain measurementspigpaper_wtPig Weightspigpaper_gait_dataGait measurementspigpaper_cgrp_dataSpinal cord substance P and CGRP measurementspigpaper_cortisolSalivary cortisol measurements

Hypertrophic cardiomyopathy (HCM) causes sudden cardiac death (SCD) due to ventricular arrhythmias (VA) manifesting from myocardial fibrosis proliferation. Current clinical risk stratification criteria inadequately identify at-risk patients in need of primary prevention of VA. Here, we use mechanistic computational modeling of the heart to analyze how HCM-specific remodeling of the heart promotes arrhythmogenesis and to develop a personalized strategy to forecast risk of VAs in these patients. We combine contrast-enhanced cardiac magnetic-resonance (CMR) imaging and T1 mapping data to construct digital replicas of HCM patient hearts that represent the patient-specific distribution of focal and diffuse fibrosis and evaluate the substrate propensity to VA. Our analysis indicates that the presence of diffuse fibrosis, which is rarely assessed in these patients, increases arrhythmogenic propensity. In forecasting future VA events in HCM patients, the imaging-based computational heart approach achieved 84.6%, 76.9%, and 80.1% sensitivity, specificity, and accuracy, respectively, and significantly outperformed current clinical risk predictors. This novel VA risk assessment may have the potential to prevent SCD and help deploy primary prevention appropriately in HCM patients. Left ventricular (LV) volumes from short-axis LGE-CMR scans and post-contrast T1 maps were segmented using CardioViz3D (http://www-sop.inria.fr/asclepios/software/CardioViz3D/). LV segmentations (metaimage files) were semi-automatically generated for each patient included in this dataset. The segmented MRI images of the LV can be used to generate the finite element meshes used in this study. LGE LV Tag = 1; T1 LV Tag = 255.

Objective: To generate a national multiple sclerosis (MS) prevalence estimate for the United States by applying a validated algorithm to multiple administrative health claims (AHC) datasets. Methods: A validated algorithm was applied to private, military, and public AHC datasets to identify adult cases of MS between 2008 and 2010. In each dataset, we determined the 3-year cumulative prevalence overall and stratified by age, sex, and census region. We applied insurance-specific and stratum-specific estimates to the 2010 US Census data and pooled the findings to calculate the 2010 prevalence of MS in the United States cumulated over 3 years. We also estimated the 2010 prevalence cumulated over 10 years using 2 models and extrapolated our estimate to 2017. Results: The estimated 2010 prevalence of MS in the US adult population cumulated over 10 years was 309.2 per 100,000 (95% confidence interval [CI] 308.1–310.1), representing 727,344 cases. During the same time period, the MS prevalence was 450.1 per 100,000 (95% CI 448.1–451.6) for women and 159.7 (95% CI 158.7–160.6) for men (female:male ratio 2.8). The estimated 2010 prevalence of MS was highest in the 55- to 64-year age group. A US north-south decreasing prevalence gradient was identified. The estimated MS prevalence is also presented for 2017. Conclusion: The estimated US national MS prevalence for 2010 is the highest reported to date and provides evidence that the north-south gradient persists. Our rigorous algorithm-based approach to estimating prevalence is efficient and has the potential to be used for other chronic neurologic conditions. Prev of MS in the US-E-Appendix-Feb-19-2018

Male, C57BL/6J mice (Jackson Laboratory, Bar Harbor, ME, USA; 000664) were seven-weeks old at the start of all studies. CD-1 retired male breeders (Charles Rivers, age 3 to 6 months upon arrival) were used as aggressors. All mice were singly housed on shaved, pine bedding upon arrival, maintained on a 12:12 L:D lighting cycle for the remainder of the study and randomly assigned to treatment groups. Food and water were available ad libitum. All procedures involving animals received prior approval from the Morehouse School of Medicine Institutional Animal Care and Use Committee (approved protocol 21-02). Surgery: EEG and LFP electrodes. Electroencephalography (EEG): EEG and Electromyography (EMG) electrodes were implanted in isoflurane (1.5–3%) anesthetized mice. Carprofen was given post operatively for two days. A prefabricated head mount (Pinnacle Technology Inc., Lawrence, KS) was used to position three stainless-steel epidural screw electrodes. The first electrode (frontal—located over the frontal cortex) was placed 1.5 mm anterior to bregma and 1.5 mm lateral to the central suture, whereas the second two electrodes (interparietal—located over the visual cortex and common reference) were placed 2.5 mm posterior to bregma and 1.5 mm on either side of the central suture. The resulting two leads (frontal–interparietal and interparietal–interparietal) were referenced contralaterally. A fourth screw served as a ground. Electrical continuity between the screw electrode and head mount was aided by silver epoxy. EMG activity was monitored using stainless-steel Teflon-coated wires that were inserted bilaterally into the nuchal muscle. The head mount (integrated 2 × 3 pin socket array) was secured to the skull with dental acrylic. Mice were allowed to recover for at least 14 days before sleep recording. Resilience, the ability to overcome stressful conditions, is found in most mammals and varies significantly among individuals. A lack of resilience can lead to the development of neuropsychiatric and sleep disorders, often within the same individual. Despite extensive research into the brain mechanisms causing maladaptive behavioral-responses to stress, it is not clear why some individuals exhibit resilience. To examine if sleep has a determinative role in maladaptive behavioral-response to social stress, we investigated individual variations in resilience using a social-defeat model for male mice. Our results reveal a direct, causal relationship between sleep amount and resilience—demonstrating that sleep increases after social-defeat stress only occur in resilient mice. Further, we found that within the prefrontal cortex, a regulator of maladaptive responses to stress, pre-existing differences in sleep regulation predict resilience. Overall, these results demonstrate that increased NREM sleep, mediated cortically, is an active response to social-defeat stress that is both necessary and sufficient for promoting resilience. They also show that differences in resilience are strongly correlated with inter-individual variability in sleep regulation.

Disease epidemiology during ageing shows a transition from cancer to degenerative chronic disorders as dominant contributors to mortality in the old. Nevertheless, it has remained unclear to what extent molecular signatures of ageing reflect this phenomenon. Here we report on the identification of a conserved transcriptomic signature of ageing based on gene expression data from four vertebrate species across four tissues. We find that ageing-associated transcriptomic changes follow trajectories similar to the transcriptional alterations observed in degenerative ageing diseases but are in opposite direction to the transcriptomic alterations observed in cancer. We confirm the existence of a similar antagonism on the genomic level, where a majority of shared risk alleles that increase the risk of cancer decrease the risk of chronic degenerative disorders and vice versa. These results reveal a fundamental trade-off between cancer and degenerative ageing diseases that sheds light on the pronounced shift in their epidemiology during ageing. Code and data for Aramillo Irizar et al. (2017)Source code and data for reproducing the analyses reported in the paper.Aramillo_Irizar_2017_Code_and_Data.zip

Objective: To assess the feasibility, safety, and efficacy of intracoronary allogeneic cardiosphere-derived cells (CAP-1002) in patients with Duchenne muscular dystrophy (DMD). Methods: The Halt Cardiomyopathy Progression (HOPE)-Duchenne trial is a phase I/II, randomized, controlled, open-label trial (NCT02485938). Patients with DMD >12 years old, with substantial myocardial fibrosis, were randomized (1:1) to usual care (control) or global intracoronary infusion of CAP-1002 (75 million cells). Participants were enrolled at 3 US medical centers between January and August 2016 and followed for 12 months. An independent Data and Safety Monitoring Board provided safety oversight. Cardiac function and structure were assessed by MRI, and analyzed by a blinded core laboratory. Skeletal muscle function was assessed by performance of the upper limb (PUL). Results: Twenty-five eligible patients (mean age 17.8 years; 68% wheelchair-dependent) were randomized to CAP-1002 (n = 13) or control (n = 12). Incidence of treatment-emergent adverse events was similar between groups. Compared to baseline, MRI at 12 months revealed significant scar size reduction and improvement in inferior wall systolic thickening in CAP-1002 but not control patients. Mid-distal PUL improved at 12 months in 8 of 9 lower functioning CAP-1002 patients, and no controls (p = 0.007). Conclusions: Intracoronary CAP-1002 in DMD appears safe and demonstrates signals of efficacy on both cardiac and upper limb function for up to 12 months. Thus, future clinical research on CAP-1002 treatment of DMD cardiac and skeletal myopathies is warranted. Classification of evidence: This phase I/II study provides Class II evidence that for patients with DMD, intracoronary CAP-1002 is feasible and appears safe and potentially effective. Supplemental Data HOPE Trail_ DryadSupplemental Tables for the HOPE Trail Manuscript

Objective: Examine the relationship between scalp EEG biomarkers of hyperexcitability in Alzheimer’s disease (AD) and determine how these electrical biomarkers relate to the clinical expression of seizures in AD. Methods: In this cross-sectional study, we performed 24-hour ambulatory scalp EEGs on 43 cognitively normal elderly healthy controls (HC), 41 early-stage AD participants with no history or risk factors for epilepsy (AD-NoEp), and 15 early-stage AD participants with late-onset epilepsy related to AD (AD-Ep). Two epileptologists, blinded to diagnosis, visually reviewed all EEGs and annotated all potential epileptiform abnormalities. A panel of 9 epileptologists, blinded to diagnosis, was then surveyed to generate a consensus interpretation of epileptiform abnormalities in each EEG. Results: Epileptiform abnormalities were seen in 53% of AD-Ep, 22% of AD-NoEp, and 4.7% of HC participants. Specific features of epileptiform discharges, including high frequency, robust morphology, right temporal location, and occurrence during wakefulness and REM, were associated with clinical seizures in AD. Multiple electrical biomarkers concordantly demonstrated a pattern of left temporal lobe hyperexcitability in early stages of AD, whereas clinical seizures in AD were often associated with bi-temporal hyperexcitability. Frequent small sharp spikes were specifically associated with epileptiform EEGs and thus identified as a potential biomarker of hyperexcitability in AD. Conclusion: Epileptiform abnormalities are common in AD, but not all equivalent. Specific features of epileptiform discharges are associated with clinical seizures in AD. Given the difficulty recognizing clinical seizures in AD, these EEG features could provide guidance on which AD patients are at high risk for clinical seizures. This file contains Supplementary Data for the manuscript "Distinct epileptiform abnormalities are associated with clinical seizures in Alzheimer's disease." Included are: - Figure e-1: Recruitment flow chart for this study - Table e-1: Comparison of epileptiform discharge morphological features - Table e-2: Summary of Alzheimer's disease biomarkers for study participants

Primate cognition requires interaction processing. Interactions can reveal otherwise hidden properties of intentional agents, such as thoughts and feelings, and of inanimate objects, such as mass and material. Where and how interaction analyses are implemented in the brain is unknown. Using whole-brain functional magnetic resonance imaging in macaque monkeys, we discovered a network centered in the medial and ventrolateral prefrontal cortex that is exclusively engaged in social interaction analysis. Exclusivity of specialization was found for no other function anywhere in the brain. Two additional networks, a parieto-premotor and a temporal one, exhibited both social and physical interaction preference, which, in the temporal lobe, mapped onto a fine-grain pattern of object, body, and face selectivity. Extent and location of a dedicated system for social interaction analysis suggest that this function is an evolutionary forerunner of human mind-reading capabilities. Social_Networks_mapsStatistical maps for the Agents, Action, Social Interaction, Exclusive Social Interaction Network (ESIN) and Physical Interaction contrasts, on the monkey F99 cortical model of the right hemisphere, from the volume-based FFX group analysis. These metric files were generated using the freely available Caret software developed in the Van Essen Laboratory at the Washington University School of Medicine in Saint Louis, Missouri, USA, available at . The metric files can be opened with this program and overlaid on the monkey F99 cortical model of the right hemisphere. Enhanced activation is show as negative values (i.e in blue), due to the use of contrast agent for functional magnetic resonance imaging scanning.