Fixed Time-Point Analysis Reveals Repetitive Mild Traumatic Brain Injury Effects on Resting State Functional Magnetic Resonance Imaging Connectivity and Neuro-Spatial Protein Profiles

Abstract

Repetitive mild traumatic brain injuries (rmTBIs) are serious trauma events responsible for the development of numerous neurodegenerative disorders. A major challenge in developing diagnostics and treatments for the consequences of rmTBI is the fundamental knowledge gaps of the molecular mechanisms responsible for neurodegeneration. It is both critical and urgent to understand the neuropathological and functional consequences of rmTBI to develop effective therapeutic strategies. Using the Closed-Head Impact Model of Engineered Rotational Acceleration, or CHIMERA, we measured neural changes following injury, including brain volume, diffusion tensor imaging, and resting-state functional magnetic resonance imaging coupled with graph theory and functional connectivity analyses. We determined the effect of rmTBI on markers of gliosis and used NanoString-GeoMx to add a digital-spatial protein profiling analysis of neurodegenerative disease-associated proteins in gray and white matter regions. Our analyses revealed aberrant connectivity changes in the thalamus, independent of microstructural damage or neuroinflammation. We also identified distinct changes in the levels of proteins linked to various neurodegenerative processes including total and phospho-tau species and cell proliferation markers. Together, our data show that rmTBI significantly alters brain functional connectivity and causes distinct protein changes in morphologically intact brain areas.

Age dictates brain functional connectivity and axonal integrity following repetitive mild traumatic brain injuries

“…This study only includes tissue examination in the aged group. Immunohistochemistry results for gliosis and other disease-like markers in young mice were reported previously 17 .…”

“…Images were converted from Bruker to nifty format. All rsfMRI images underwent a comprehensive pre-processing pipeline using Analysis of Functional NeuroImages (AFNI) 23 , Functional MRI of the Brain Library (FSL) 24 , Advanced Normalization Tools (ANTs) software as outlined previously 17 . Pre-processing involved distortion and phase correction using FSL’s TOPUP, removal of time series spikes and slow temporal variations, noise decomposition applying the independent component analysis (ICA), removal of skull using three-dimensional pulsed coupled neural networks (PCNN3D) in MATLAB ( Figure 1B ).…”

“…Resting-state functional magnetic resonance imaging (rsfMRI) and diffusion tensor imaging (DTI) are valuable non-invasive tools used to define imaging biomarkers of brain damage after injury 11–17 . rsfMRI enables the evaluation of functional connectivity, whereas DTI captures structural alterations in the white matter fiber tracks.…”

Targeted brain-specific tauopathy compromises peripheral skeletal muscle integrity and function

“…Hemibrains were embedded in paraffin and serial sections (10µm) were cut from the midline. Immunohistochemistry (IHC) was performed as previously described (Sakthivel et al, 2023), using the HT7 primary antibody (Thermo Fisher Scientific MN1000; 1:1000) and the corresponding Goat Anti-Mouse IgG (H+L) biotinylated secondary antibody (Vector Laboratories; 1:1000) to detect injected human derived tau with DAB labeling. The slides were imaged with the Aperio slide scanner (20x objective lens, Scan Scope TM XT, Aperio Technologies, Inc. Vista, CA).…”

Functional connectivity, tissue microstructure and T2 at 11.1 Tesla distinguishes neuroadaptive differences in two traumatic brain injury models in rats: A Translational Outcomes Project in NeuroTrauma (TOP-NT) UG3 phase study

“…Whether or not such changes are specifically restricted to cognitive, motor, sensory, or association cortices over time remains unclear. Animal studies recapitulating mild concussive injuries caused by sports injuries or automobile accidents are necessary to model prevalent forms of TBI in humans 12,13 . Like clinical TBI, however, these produce diffuse and heterogenous pathology that, while invaluable to determining construct validity of preclinical TBI models, have so far shown limited ability to reveal fundamental mechanisms involved in cortical reorganization observed with contusions and penetrating cortical injuries.…”