# Neural mechanisms underlying the connection between Neurotrauma and REM Sleep Behavior Disorder

> **NIH VA I01** · PORTLAND VA MEDICAL CENTER · 2024 · —

## Abstract

Neurotrauma, including traumatic brain injury (TBI) and/or posttraumatic stress disorder (PTSD), is highly
prevalent among US Veterans returning from military deployment, approximating upwards of 10-20% from
recent conflicts in the Middle East. In addition to a myriad of disabling daytime symptoms, we and others have
shown that neurotrauma is strongly associated with persistent and profound sleep disruption, in some cases
lasting for decades. In particular, emerging evidence suggests that neurotrauma may disrupt normal inhibition
of muscle tone during sleep. During rapid eye movement (REM) sleep, widespread paralysis of skeletal
muscles normally occurs – a process that is dysregulated in REM sleep behavior disorder (RBD),
characterized by violent dream enactment during REM sleep. We recently reported that RBD is increased by
over two-fold in Veterans with comorbid TBI+PTSD, compared to Veterans without neurotrauma. The
abnormal REM Sleep Without Atonia (RSWA) seen in patients with RBD is widely regarded as one of the
earliest clinical manifestations of synucleinopathy, since 50-70% of patients with RBD eventually phenoconvert
to Parkinson's Disease (PD) or related disorder. Emerging evidence from several epidemiological studies,
including our own, have suggested that both TBI and PTSD synergize to increase risk of later development of
PD. However, major gaps in our understanding remain. We still need to better understand the predictors and
neural pathways by which neurotrauma leads to RBD and synucleinopathy among susceptible individuals, and
we need to identify candidate therapies and windows for potential neuroprotective interventions in order to
prevent phenoconversion. These gaps will be addressed in 3 aims. Aim 1 will determine the behavioral
correlates of RSWA using a mouse model of combined TBI+PTSD. Using our previously established model of
combined TBI+PTSD, mice will undergo controlled cortical impact and single prolonged stress procedures,
followed by gait analysis, fear conditioning, and sleep electroencephalographic (EEG)/ electromyographic
(EMG) recordings to quantify RSWA. Mice will then be segregated into 3 groups on the basis of trauma
exposure and behavioral severity: Neurotrauma (NT), Trauma-Exposed (TE - behaviorally normal), and
Controls (not exposed to trauma). In Aim 1, we hypothesize that mice in the NT group will show increased
RSWA compared to TE and Controls, and the severity of behavioral symptoms will predict the degree of
RSWA within the NT group. In Aim 2, we will determine brain functional connectivity underlying RSWA and
behavioral deficits in mice with TBI+PTSD by using an innovative new method to image cerebral blood flow in
live animals with functional ultrafast ultrasound (fUS). We hypothesize that mice in the NT group will show
increased functional connectivity within the amygdala that will correlate with readouts of both behavior and
RSWA. In Aim 3, we will determine how neurotrauma contributes to RSWA and s...

## Key facts

- **NIH application ID:** 10838359
- **Project number:** 5I01BX006155-02
- **Recipient organization:** PORTLAND VA MEDICAL CENTER
- **Principal Investigator:** Miranda M Lim
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2023-04-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10838359

## Citation

> US National Institutes of Health, RePORTER application 10838359, Neural mechanisms underlying the connection between Neurotrauma and REM Sleep Behavior Disorder (5I01BX006155-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10838359. Licensed CC0.

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