# Investigating the neurophysiological basis of circuit-specific laminar rs-fMRI

> **NIH NIH RF1** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $2,141,175

## Abstract

Resting-state fMRI has emerged as a potential method to identify diagnostic bio-imaging markers of a broad
spectrum of neurological disorders by measuring the low-frequency fluctuation (LFF) correlation features of
diseased brains. Due to the fMRI signal’s indirect coupling to neuronal activity, a fundamental challenge of rs-
fMRI mapping is how to extract the true “functional connectivity” feature across cortices with circuit specificity.
Both direct corticocortical connections, e.g. callosal projections, and subcortical neuromodulatory projections
can modulate rs-fMRI connectivity with converging effects on neuro-glio-vascular (NGV) interactions. Also, au-
tonomic regulation on gliovascular dynamics further confounds rs-fMRI LFF when interpreting the brain dam-
age with vascular impairment in various cerebrovascular diseases. We propose to implement line-scanning
and single-vessel fMRI methods in a multi-modal platform to dissect laminar and vascular-specific rs-fMRI LFF
and decipher NGV signaling underlying rs-fMRI LFF. Here, we will focus on elucidating the transcallosal circuit-
based interhemispheric rs-fMRI LFF correlation in the normal and diseased mouse model with hypoperfusion-
induced cerebrovascular white matter injury in the corpus callosum. Three aims will be addressed: 1). We will
investigate the causal linkage between laminar-specific bilateral LFF and transcallosal projection. Two hypoth-
eses will be tested: i). Layer-specific transcallosal projections determine bilateral LFF laminar correlation pat-
terns, and ii). Callosal-driven laminar LFF holds distinct oscillation features from brain state-dependent global
LFF. 2). We will differentiate the NGV signaling of callosal-specific and global vascular LFF using multi-modal
fMRI. Also, we will test two hypotheses: i). Callosal projection neuron-specific oscillation mediates circuit-spe-
cific bilateral LFF, and ii). Distinct astrocytic Ca2+ signals coupled to either callosal projection neuronal activity
or global neuromodulation contribute to different forms of LFF correlation. 3). We will specify callosal-specific
and global vascular LFF in the hypoperfusion-induced white matter injury mouse model. We will test if hy-
poperfusion-induced cerebral flow changes alter global vascular LFF and hypoperfusion-induced injury in the
corpus callosum leads to altered bilateral rs-fMRI connectivity. This proposal aims to reveal the mechanistic
NGV regulation of circuit-specific rs-fMRI LFF and apply novel rs-fMRI methods in the diseased mouse model
to set the foundation to translate specific LFF correlation patterns as potential biomarkers of circuit dysfunction
or vascular impairment in pathological brains.

## Key facts

- **NIH application ID:** 10518479
- **Project number:** 1RF1NS124778-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** EMERY N BROWN
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,141,175
- **Award type:** 1
- **Project period:** 2022-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10518479

## Citation

> US National Institutes of Health, RePORTER application 10518479, Investigating the neurophysiological basis of circuit-specific laminar rs-fMRI (1RF1NS124778-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10518479. Licensed CC0.

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