# Longitudinal Sub-thalamic Structure and Functional Alterations in Mild Traumatic Brain Injury

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $386,250

## Abstract

ABSTRACT/PROJECT SUMMARY
Several preclinical & clinical studies have implicated that acceleration/deceleration forces to the brain
beyond a certain threshold can lead to disruption of both axonal microtubules and vascular
endothelium. The consequences of such injury include diffuse axonal injury and transitory blood
flow impairment at the acute stage and the accumulation of toxic protein species such as
phosphorylated tau over time, a key factor in the development of vascular cognitive impairment
and dementia. In addition, it is thought that the AD-related tau cytoskeletal pathology in the thalamus
most likely contributes substantially to the neuropsychiatric symptoms, attention deficits, sleep
disturbances, oculomotor dysfunctions and altered pain perception. A brain wide “glymphatic system”,
driven by arterial pulsatility, comprised of paravascular pathways and meningeal lymphatic channels is
now recognized as a major pathway of clearance of these proteins from the brain. This pathway, tightly
temporally correlated to sleep, has recently shown to be affected by TBI. The thalamus plays a well-
known role in sleep regulation. We therefore posit that a likely “vicious cycle” exists wherein glymphatic
pathways disrupted by TBI fail to clear toxic protein species from the thalamus, affecting its structure
and function, resulting in sleep dysregulation and thereby, impaired glymphatic efflux. As a supplement
to the parent grant which is focused on examining the longitudinal changes in the structural and
functional connectivity of the thalamus after TBI, we wish to examine, using advanced MRI techniques,
whether symptoms of TBI arise from an interplay between thalamic injury and impaired glymphatic
efflux. We hypothesize that vascular impairments following TBI include not only endothelial damage
but also extend to glymphatic disruption and meningeal lymphatic injury and that such disruption will
differentially affect thalamic structural and functional connectivity. Using advanced imaging techniques,
we propose to address this using the following two aims: (1) we wish to examine in vivo, using MRI,
differences in the structure and function of the human glymphatic system spanning the perivascular
space to the meningeal lymphatics between patients with mild TBI and age and gender matched control
subjects both at the early (~6mo) and late stages of injury (~5y after initial injury). In Aim 2 we will
assess the influence of glymphatic dysfunction upon global thalamic and individual thalamic nuclear
structure and thalamocortical structural and functional connectivity and upon performance on
neuropsychological assessments. The results from this study will provide a unified framework to
understand mechanisms that lead to not only TBI related dementia, vascular cognitive
impairment and Alzheimer’s disease but also those that arise from toxic protein accumulation
such as Frontotemporal dementia and Lewy Body Disease among others.

## Key facts

- **NIH application ID:** 10287719
- **Project number:** 3R01NS105503-04S1
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Neeraj Badjatia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $386,250
- **Award type:** 3
- **Project period:** 2018-07-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10287719

## Citation

> US National Institutes of Health, RePORTER application 10287719, Longitudinal Sub-thalamic Structure and Functional Alterations in Mild Traumatic Brain Injury (3R01NS105503-04S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10287719. Licensed CC0.

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