# Defining Neuronal Circuits and Cellular Processes Underlying Resting fMRI Signals

> **NIH NIH R01** · NATHAN S. KLINE INSTITUTE FOR PSYCH RES · 2020 · $99,150

## Abstract

Intrinsic ‘functional connectivity’ (iFC), a measure of correlation between spontaneous fluctuations in the blood
oxygen level dependent (BOLD) signal, reliably distinguish networks of cortical and subcortical areas during
both rest and active task performance. iFC methods can map the functional architecture of the human brain in
both healthy and pathological conditions, in high detail using as little as 5 minutes of data. Striking
reproducibility and test-retest reliability of findings across centers have fueled a widespread application of iFC
measures in clinical neuroscience, biomarker discovery, and human connectomics. However, the neural
circuits and cellular processes underlying BOLD-iFC remain poorly specified. BOLD amplitude itself appears
related to neural activity in the high gamma (HG) range (~70-200 Hz), and thus to an extent, with neuronal
firing. However, BOLD’s relationship to the lower frequencies is controversial. This is a critical disconnect, as
oscillatory activities below 40Hz reflect ongoing cell-circuit excitability fluctuations that control neuronal firing;
i.e., the amplitude of neural population firing is “coupled” to oscillatory phase. In this, the simplest form of such
phase-amplitude coupling (PAC), amplitude variations in higher frequency activity (e.g., firing or HG) are
coupled to the phase of a lower frequency (e.g., theta). PAC operates both pairwise and recursively over the
spectrum, from the range of neuronal firing down to the slow/infraslow (<1Hz) range where BOLD amplitude
fluctuations are observed using resting state fMRI (R-fMRI). Thus PAC may provide a key to connecting resting
BOLD fluctuations to activity cycles in the underlying cell circuits. In our framework: 1) At a microscopic,
cortical cell-circuit level, a complex of excitatory and inhibitory interactions between neurons generate rhythmic
excitability fluctuations (oscillations). 2) PAC organizes slow (0.5-12) Hz and mid-range (13-40Hz) oscillations
hierarchically, ultimately controlling temporal patterns of neuronal firing. 3) Infraslow (0.01-0.1 Hz) neural
activity fluctuations synchronize to form the macroscale intrinsic connectivity networks (ICN) indexed by R-
fMRI, and use PAC to orchestrate faster activity within a network. Our broad goal is to use integrated human
and monkey studies to investigate the relationship between macroscale BOLD-derived iFC patterns, and their
underlying mechanisms at the microscale cell-circuit level. We will study the sensorimotor network, as its
“nodal” organization and other properties are well understood, and it shows good human-simian
correspondence. Focusing on key nodes in this network (e.g., face and hand areas), we will recapitulate prior
work tying R-FMRI iFC to macroscale scalp EEG and mesoscale stereotactic (S)-EEG, and will use innovative
laminar multielectrode methods to establish novel links to the cell circuit level. Established modeling and
computational methods will help to construct a comprehe...

## Key facts

- **NIH application ID:** 10071735
- **Project number:** 3R01MH111439-05S1
- **Recipient organization:** NATHAN S. KLINE INSTITUTE FOR PSYCH RES
- **Principal Investigator:** Michael Peter Milham
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $99,150
- **Award type:** 3
- **Project period:** 2016-09-22 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071735

## Citation

> US National Institutes of Health, RePORTER application 10071735, Defining Neuronal Circuits and Cellular Processes Underlying Resting fMRI Signals (3R01MH111439-05S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10071735. Licensed CC0.

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