# Energetics of Neuronal Populations by fMRI

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $384,054

## Abstract

Resting-state fMRI (R-fMRI) is a major method for studying human brain networks. It relies on correlations
in spontaneous fluctuations of BOLD signal. However BOLD signal fluctuations are poorly understood, leading
to ambiguity in interpretation of R-fMRI derived networks. For task fMRI (T-fMRI) we, and others, have shown a
direct relationship between BOLD signal changes of glutamatergic neuronal signaling and oxidative demand.
The evoked changes in oxidative demand (CMRO2), measured by calibrated T-fMRI combines measurements
of BOLD signal, blood flow (CBF), blood volume (CBV), and subject-specific biophysical constants. However a
similar level of metabolic understanding for R-fMRI has been elusive.
 In the past cycle, using calibrated T-fMRI with 1H[13C] MRS and extracellular recordings, we developed and
validated transfer functions of BOLD, CBF, CBV, and CMRO2 signals that related them directly to extracellular
recordings of multi-unit activity (MUA) and local field potentials (LFP). Inverse of the transfer functions allowed
calibrated T-fMRI maps to be converted into neuronal activity maps. However this approach has limitations
when applied to calibrated R-fMRI, in particular the small spatial scale of MUA/LFP recordings is not suitable
for correlating with large regions involved in correlated network fluctuations and lack of a stimulus trigger in
resting-state to allow recordings in and out of scanner to be time synchronized.
 We will overcome these limitations by simultaneous calibrated R-fMRI and calcium (Ca2+) imaging
in Snap25-GCaMP6 mice, which contain genetically encoded fluorescent Ca2+ reporters. Since Ca2+
imaging directly measures neuronal activity in these transgenic mice, we will improve the biomarker
potential of R-fMRI derived functional connectivity density (FCD) differences in health and disease.
 Preliminary data show that the spatiotemporal structure of R-fMRI and resting Ca2+ (R-Ca2+) networks quite
similarly, and long-term mitochondrial health (e.g., aging) can also perturb R-fMRI network patterns. Since we,
and others, have shown that the resting-state fluctuations depend on the total activity, an independent and
absolute measure of total activity (by high-resolution 1H[13C] spectroscopic imaging) is critical, so that we can
bridge the gap between BOLD signal and underlying activities of neuronal populations (by electrophysiology).
We build on these preliminary results and propose: In Aim 1 we will develop technologies for simultaneous
calibrated R-fMRI and R-Ca2+ imaging. In Aim 2 we will measure and validate state-dependent neurovascular
and neurometabolic transfer functions. In Aim 3 we will apply calibrated R-fMRI and R-Ca2+ imaging in aging,
with and without calorie restriction,to validate that the methods can accurately track how neuronal resting-state
fluctuations are altered and sensitivity to an intervention. Given that network changes as revealed by fMRI-
derived FCD is a feature of brain disorders (e.g., autis...

## Key facts

- **NIH application ID:** 10084927
- **Project number:** 5R01MH067528-15
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Dewan Syed Fahmeed Hyder
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $384,054
- **Award type:** 5
- **Project period:** 2002-08-16 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10084927

## Citation

> US National Institutes of Health, RePORTER application 10084927, Energetics of Neuronal Populations by fMRI (5R01MH067528-15). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10084927. Licensed CC0.

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