Biology subjects

Harris, N. G.

Publications and source records attributed to Harris, N. G..

9 recordsLinked to original sources

bioRxiv2026

Persistent Hypersensitivity after Repeat Concussion is Associated with Chronic Cognitive Dysfunction

Persistent sensory hypersensitivity is a common but under-recognized feature of post-concussion syndrome (PCS) following mild traumatic brain injury (mTBI), and may contribute to chronic cognitive complaints. However, the mechanistic relationship between long-term sensory dysregulation and cognitive dysfunction after repeat concussion remains poorly understood. Here, we used an experimental repeated closed-head injury (rCHI-5x), in young adult mouse model targeting the frontal cortex at 8-weeks of age to test whether chronic sensory processing abnormalities contribute to cognitive impairment under increased sensory load chronically at 8-10 weeks post-injury (4-months old). rCHI mice exhibited significant sensory dysfunction across multiple modalities, including increased tactile sensitivity, tactile avoidance, and impaired habituation to auditory startle, despite the absence of gross structural brain damage and preserved learning and memory under low-demand conditions. While spatial learning and working memory in the Barnes maze were intact, rCHI mice displayed increased perseveration and reduced cognitive flexibility. However, these cognitive deficits emerged only when auditory and tactile sensory distractors were introduced during testing, unmasking impairments that were not evident under baseline conditions. Within-animal statistical analyses found strong associations between the severity of sensory hypersensitivity, impaired sensory habituation, and deficits in cognitive flexibility in rCHI mice, but not in sham controls. These findings indicate that chronic sensory dysregulation following repeat mild concussion is not merely a secondary symptom, but a primary contributor to cognitive impairment under conditions of increased sensory load. Together, this work identifies persistent sensory processing and gating dysfunction as a key driver of PCS-related cognitive deficits and reveals that targeting sensory circuitry for therapeutic neuromodulation may offer functional rescue across multiple domains, extending beyond sensory symptoms to improve higher-order cognitive performance.

neuroscience↗

bioRxiv2025

Improved Injury Detection Through Harmonizing Multi-Site Neuroimaging Data after Experimental TBI: A Translational Outcomes Project in NeuroTrauma (TOP-NT) Consortium Study

Multi-site neuroimaging studies have become increasingly common in order to generate larger samples of reproducible data to answer questions associated with smaller effect sizes. The data harmonization model NeuroCombat has been shown to remove site effects introduced by differences in site-related technical variance while maintaining group differences, yet its effect on improving statistical power in pre-clinical models of CNS disease is unclear. The present study examined fractional anisotropy data computed from diffusion weighted imaging data at 3 and 30 days post-controlled cortical impact injury from 184 adult rats across four sites as part of the Translational-Outcome-Project-in-Neurotrauma (TOP-NT) Consortium. Findings confirmed prior clinical reports that NeuroCombat fails to remove site effects in data containing a high proportion-of-outliers (>5%) and skewness, which introduced significant variation in non-outlier sites. After removal of one outlier site and harmonization using a global sham population, harmonization displayed an increase in effect size in data that displayed group level effects (p<0.01) in both univariate and voxel-level volumes of pathology. This was characterized by movement toward similar distributions in voxel measurements (Kolmogorov-Smirnov p<<0.001 to >0.01) and statistical power increases within the ipsilateral cortex. Harmonization improved statistical power and frequency of significant differences in areas with existing group differences, thus improving the ability to detect regions affected by injury rather than by other confounds. These findings indicate the utility of NeuroCombat in reproducible data collection, where biological differences can be accurately revealed to allow for greater reliability in multi-site neuroimaging studies. Significance StatementThis project demonstrates the utility of NeuroCombat in reducing site effects in multi-site rodent imaging. We also demonstrate that harmonization improves the ability to distinguish between sham and injured rats at the voxel level and increase statistical power and effect size in areas of injury. Multi-center studies are becoming more common to allow for increased efficiency in data collection, and with conservative approaches and analysis into the datasets, NeuroCombat can be utilized to improve study reliability and reproducibility.

neuroscience↗

bioRxiv2025

Unbiased Population-Based Statistics to Obtain Pathologic Burden of Injury after Experimental TBI

Reproducibility of scientific data is a current concern throughout the neuroscience field. There are multiple on-going efforts to help resolve this problem. Within the preclinical neuroimaging field, the continued use of a region-of interest (ROI) type approaches combined with the well-known spatial heterogeneity of traumatic brain injury pathology is a barrier to the replicability and repeatability of data. Here we propose the conjoint use of an unbiased analysis of the whole brain after injury together with a population-based statistical analysis of sham-control brains as one approach that has been used in clinical research to help resolve this issue. The approach produces two volumes of pathology that are outside the normal range of sham brains, and can be interpreted as whole brain burden of injury. Using diffusion weighted imaging derived scalars from a tensor analysis of data acquired from adult, male rats at 2, 9 days, 1 and 5 months after lateral fluid percussion injury (LFPI) and in shams (n=73 and 12, respectively), we compared a data-driven, z-score mapping method to a whole brain and white matter-specific analysis, as well as an ROI-based analysis with brain regions preselected by virtue of their large group effect sizes. We show that the data-driven approach is statistically robust, providing the advantage of a large group effect size typical of a ROI analysis of mean scalar values derived from the tensor in regions of gross injury, but without the large multi-region statistical correction required for interrogating multiple brain areas, and without the potential bias inherent with using preselected ROIs. We show that the technique correctly captures the expected longitudinal time-course of the diffusion scalar volumes based on the spatial extent of the pathology and the known temporal changes in scalar values in the LFPI model.

neuroscience↗

bioRxiv2024

Mouse Brain Extractor: Brain segmentation of mouse MRI using global positional encoding and SwinUNETR

In spite of the great progress that has been made towards automating brain extraction in human magnetic resonance imaging (MRI), challenges remain in the automation of this task for mouse models of brain disorders. Researchers often resort to editing brain segmentation results manually when automated methods fail to produce accurate delineations. However, manual corrections can be labor-intensive and introduce interrater variability. This motivated our development of a new deep-learning-based method for brain segmentation of mouse MRI, which we call Mouse Brain Extractor. We adapted the existing SwinUNETR architecture (Hatamizadeh et al., 2021) with the goal of making it more robust to scale variance. Our approach is to supply the network model with supplementary spatial information in the form of absolute positional encoding. We use a new scheme for positional encoding, which we call Global Positional Encoding (GPE). GPE is based on a shared coordinate frame that is relative to the entire input image. This differs from the positional encoding used in SwinUNETR, which solely employs relative pairwise image patch positions. GPE also differs from the conventional absolute positional encoding approach, which encodes position relative to a subimage rather than the entire image. We trained and tested our method on a heterogeneous dataset of N=223 mouse MRI, for which we generated a corresponding set of manually-edited brain masks. These data were acquired previously in other studies using several different scanners and imaging protocols and included in vivo and ex vivo images of mice with heterogeneous brain structure due to different genotypes, strains, diseases, ages, and sexes. We evaluated our methods results against those of seven existing rodent brain extraction methods and two state-of-the art deep-learning approaches, nnU-Net (Isensee et al., 2018) and SwinUNETR. Overall, our proposed method achieved average Dice scores on the order of 0.98 and average HD95 measures on the order of 100 {micro}m when compared to the manually-labeled brain masks. In statistical analyses, our method significantly outperformed the conventional approaches and performed as well as or significantly better than the nnU-Net and SwinUNETR methods. These results suggest that Global Positional Encoding provides additional contextual information that enables our Mouse Brain Extractor to perform competitively on datasets containing multiple resolutions.

neuroscience↗

bioRxiv2024

Constraint Induced Movement Therapy Confers only a Transient Behavioral Benefit but Enduring Functional Circuit-Level Changes after Experimental TBI.

Although the behavioral outcome of Constraint-Induced Movement Therapy (CIMT) is well known, and that a combination of CIMT and arm use training potentiates the effect, there has been limited study of the brain circuits involved that respond to therapy. An understanding of CIMT from a brain network level would be useful for guiding the duration of effective therapy, the type of training regime to potentiate the outcome, as well as brain regional targets that might be amenable for direct neuromodulation. Here we investigated the effect of CIMT therapy alone unconfounded by additional rehabilitation training in order to determine the impact of intervention at the circuit level. Adult rats were injured by controlled cortical impact injury and studied before and then after 2wks of CIMT or noCIMT at 1-3wks post-injury using a combination of forelimb behavioral tasks and task-based and resting state functional magnetic resonance imaging at 3 and 7wks post-injury and compared to sham rats. There was no difference in behavior or functional imaging between CIMT and noCIMT after injury before intervention so that data are unlikely to be confounded by differences in injury severity. CIMT produced only a transient reduction in limb deficits compared to noCIMT immediately after the intervention, but no difference thereafter. However, CIMT resulted in a persistent reduction in contralesional limb-evoked activation and a corresponding ipsilesional cortical plasticity compared to noCIMT that endured 4wks after intervention. This was associated with a significant amelioration of intra and inter-hemispheric connectivity present in the noCIMT group at 7wks post-injury.

neuroscience↗

bioRxiv2024

Acute rapamycin treatment reveals novel mechanisms of behavioral, physiological, and functional dysfunction in a maternal inflammation mouse model of autism and sensory over-responsivity

Maternal inflammatory response (MIR) during early gestation in mice induces a cascade of physiological and behavioral changes that have been associated with autism spectrum disorder (ASD). In a prior study and the current one, we find that mild MIR results in chronic systemic and brain inflammation, mTOR pathway activation, mild brain overgrowth followed by regionally specific volumetric changes, sensory processing dysregulation, and social and repetitive behavior abnormalities. Prior studies of rapamycin treatment in autism models have focused on chronic treatments that alter or prevent physical brain changes. Here, we have focused on the acute effects of rapamycin to uncover novel mechanisms of dysfunction related to mTOR pathway signaling. We find that within 2 hours, rapamycin treatment could rapidly rescue neuronal hyper-excitability, seizure susceptibility, functional network connectivity and brain community structure, repetitive behaviors, and sensory over-responsivity in adult offspring with persistent mild brain overgrowth. These CNS-mediated effects are also associated with alteration of the expression of several ASD-, ion channel-, and epilepsy-associated genes in the same time frame. Reduction of microglia with CSF1R inhibitors or inhibition of NADPH oxidase in young animals reduces the development of some of the behavioral phenotypes, but neither is as effective as acute mTOR inhibition. Our findings indicate that mTOR dysregulation in MIR offspring is a key contributor to various levels of brain dysfunction. However, we demonstrate that the adult MIR brain is also amenable to rapid normalization of these functional changes which results in the rescue of both core and comorbid ASD-like behaviors in adult animals without requiring long-term physical alterations to the brain. Restoring excitatory/inhibitory imbalance and sensory functional network modularity may therefore be important targets for therapeutically addressing both primary sensory and compensatory repetitive behavior phenotypes.

neuroscience↗

bioRxiv2024

The Surgical Method of Craniectomy Differentially Affects Acute Seizures, Brain Deformation and Behavior in a TBI Animal Model

Traumatic brain injury (TBI) is the leading cause of morbidity and mortality worldwide. Multiple injury models have been developed to study this neurological disorder. One such model is the lateral fluid-percussion injury (LFPI) rodent model. The LFPI model can be generated with different surgical procedures that could affect the injury and be reflected in neurobehavioral dysfunction and acute EEG changes. A craniectomy was performed either with a trephine hand drill or with a trephine electric drill that was centered over the left hemisphere of adult, male Sprague Dawley rats. Sham craniectomy groups were assessed by hand-drilled (ShamHMRI) and electric-drilled (ShamEMRI) to evaluate by MRI. Then, TBI was induced in separate groups (TBIH) and (TBIE) using a fluid-percussion device. Sham-injured rats (ShamH/ShamE) underwent the same surgical procedures as the TBI rats. During the same surgery session, rats were implanted with screw and microwire electrodes positioned in the neocortex and hippocampus and the EEG activity was recorded 24 hours for the first 7 days after TBI for assessing the acute EEG seizure and Gamma Event Coupling (GEC). The electric drilling craniectomy induced greater tissue damage and sensorimotor deficits compared to the hand drill. Analysis of the EEG revealed acute seizures in at least one animal from each group after the procedure. Both TBI and Sham rats from the electric drill groups had a significant greater total number of seizures than the animals that were craniectomized manually (p<0.05). Similarly, EEG functional connectivity was lower in ShamE compared to ShamH rats. These results suggest that electrical versus hand drilling craniectomies produce cortical injury in addition to the LFPI which increases the likelihood for acute post-traumatic seizures. Differences in the surgical approach could be one reason for the variability in the injury that makes it difficult to replicate results between preclinical TBI studies.

neuroscience↗

bioRxiv2024

Different Trajectories of Functional Connectivity Captured with Gamma-Event Coupling and Broadband Measures of EEG in the Rat Fluid Percussion Injury Model.

Functional connectivity (FC) after TBI is affected by an altered excitatory-inhibitory balance due to neuronal dysfunction, and the mechanistic changes observed could be reflected differently by contrasting methods. Local gamma event coupling FC (GEC-FC) is believed to represent multiunit fluctuations due to inhibitory dysfunction, and we hypothesized that FC derived from widespread, broadband amplitude signal (BBA-FC) would be different, reflecting broader mechanisms of functional disconnection. We tested this during sleep and active periods defined by high delta and theta EEG activity, respectively, at 1,7 and 28d after rat fluid-percussion-injury (FPI) or sham injury (n=6/group) using 10 indwelling, bilateral cortical and hippocampal electrodes. We also measured seizure and high-frequency oscillatory activity (HFOs) as markers of electrophysiological burden. BBA-FC analysis showed early hyperconnectivity constrained to ipsilateral sensory-cortex-to-CA1-hippocampus that transformed to mainly ipsilateral FC deficits by 28d compared to shams. These changes were conserved over active epochs, except at 28d when there were no differences to shams. In comparison, GEC-FC analysis showed large regions of hyperconnectivity early after injury within similar ipsilateral and intrahemispheric networks. GEC-FC weakened with time, but hyperconnectivity persisted at 28d compared to sham. Edge- and global connectivity measures revealed injury-related differences across time in GEC-FC as compared to BBA-FC, demonstrating greater sensitivity to FC changes post-injury. There was no significant association between sleep fragmentation, HFOs, or seizures with FC changes. The within-animal, spatial-temporal differences in BBA-FC and GEC-FC after injury may represent different mechanisms driving FC changes as a result of primary disconnection and interneuron loss. Significance statementThe present study adds to the understanding of functional connectivity changes in preclinical models of traumatic brain injury. In previously reported literature, there is heterogeneity in the directionality of connectivity changes after injury, resulting from factors such as severity of injury, frequency band studied, and methodology used to calculate FC. This study aims to further clarify differential mechanisms that result in altered network topography after injury, by using Broadband Amplitude-Derived FC and Gamma Event Coupling-Derived FC in EEG. We found post-injury changes that differ in complexity and directionality between measures at and across timepoints. In conjunction with known results and future studies identifying different neural drivers underlying these changes, measures derived from this study could provide useful means from which to minimally-invasively study temporally-evolving pathology after TBI.

neuroscience↗

bioRxiv2020

Spatial distribution of neuropathology and neuroinflammation elucidate the biomechanics of fluid percussion injury

Diffuse brain injury is better described as multi-focal, where pathology can be found adjacent to seemingly uninjured neural tissue. In experimental diffuse brain injury, pathology and pathophysiology have been reported far more lateral than predicted by the impact site. Finite element biomechanical models of diffuse brain injury predict regions of maximum stress and strain. However, the application of a skull with uniform thickness may mask the pathophysiology due to varying thickness of human and animal skulls. Force applied to the intact skull would diffuse the forces, whereas forces applied through an open skull are distributed along paths of least resistance within and then exiting the skull. We hypothesized that the local thickening of the rodent skull at the temporal ridges serves to focus the intracranial mechanical forces experienced during brain injury and generate predictable pathology in underlying cortical tissue. We demonstrated local thickening of the skull at the temporal ridges using contour analysis of coronal skull sections and oblique sectioning on MRI. After diffuse brain injury induced by midline fluid percussion injury (mFPI), pathological foci along the anterior-posterior length of cortex under the temporal ridges were evident acutely (1, 2, 7 days) and chronically (28 days) post-injury by deposition of argyophilic reaction product. Area CA3 of the hippocampus and lateral nuclei of the thalamus showed pathological change, suggesting that mechanical forces to or from the temporal ridges shear subcortical regions. A proposed model of mFPI biomechanics suggests that injury force vectors reflect off the skull base and radiate toward the temporal ridge due to the material properties of the skull based on thickness, thereby injuring ventral thalamus, dorsolateral hippocampus, and sensorimotor cortex. Surgically thinning the temporal ridge prior to injury reduced the injury-induced inflammation in sensorimotor cortex. These data build evidence for the temporal ridges of the rodent skull to contribute to the observed pathology, whether by focusing extracranial forces to enter the cranium or intracranial forces to escape the cranium. Pre-clinical investigations can take advantage of the predicted pathology to explore injury mechanisms and treatment efficacy. HighlightsO_LIThe temporal ridge is 75% thicker than the adjacent skull of the rodent C_LIO_LIExperimental diffuse TBI neuropathology occurs beneath the length of the temporal ridge C_LIO_LINeuropathology encompasses sensorimotor cortex, somatosensory thalamus, and dorsolateral hippocampus C_LIO_LIProposed mechanism of biomechanical injury forces include the temporal ridge C_LI

neuroscience↗