# Noradrenergic modulations of fMRI signal

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $427,153

## Abstract

PROJECT SUMMARY/ABSTRACT
Functional magnetic resonance imaging (fMRI) with blood oxygenation level-dependent (BOLD) contrast
indirectly measures neuronal activity by way of their localized hemodynamic responses. BOLD responses
typically show sustained increases above their baseline (i.e., positive BOLD responses, PBR), but sometimes
show sustained decreases below their baseline (i.e., negative BOLD responses, NBR). While the PBR is well
associated with increased neuronal activity, the NBR has been associated with decreased neuronal activity or
is thought to have non-neuronal origins, such as “blood stealing”, whereby blood is diverted from lesser active
regions to more active regions due to local pressure changes independent of local neuronal activity. Therefore,
the physiological origin of the NBR remains elusive. Our long-term goal is to determine how properties of
neurovascular coupling change with varying locus coeruleus (LC) activity, and the associated changes in
noradrenaline (NA) release, in behaving animals. The overall objective in this application is to determine and
characterize the involvement of LC activity in the generation of the NBR in the rodent somatosensory cortex.
Our central hypothesis is that modulations of LC activity evoked by sensory stimulation directly alters both
vascular tone and neuronal activity, which affect the NBR as well as the PBR. The rationale for this project is
that determining how LC activity is involved in fMRI signals in normal physiological conditions will facilitate a
deeper understanding of how functional alterations of LC activity in diseased states, such as with
schizophrenia and Alzheimer's disease, may contribute to noninvasive fMRI signal changes. The central
hypothesis will be tested by pursuing the specific aim to identify the effects of direct LC modulations on the
NBR and, specifically, the effect of NA on the NBR. Under this aim, LC-NA activity will be enhanced by
electrical stimulation of LC and, in different experiments, suppressed by optogenetic inhibition of LC to
evaluate how it modulates the NBR. In addition, NBRs evoked by sensory stimulation in the somatosensory
cortex will be suppressed by blocking presynaptic release of NA to evaluate if NA modulates the NBR. The
research proposed in this application is innovative because it focuses on the direct and transient modulations
of LC activity to test their effects on the NBR and examines the actions of LC on modality-specific brain
regions, which is a departure from the status quo. The proposed research is significant because it will integrate
the dual vascular and neuronal origins of the NBR by demonstrating a sensory-stimulation driven role of the
LC-NA system on neuromodulation and hemodynamic responses. Without such information, the neural
interpretation of fMRI maps will likely remain limited, especially inferences from resting-state fMRI studies and
hemodynamic responses of different LC-dependent cortical states.

## Key facts

- **NIH application ID:** 10373198
- **Project number:** 1R21NS121838-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** MITSUHIRO FUKUDA
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $427,153
- **Award type:** 1
- **Project period:** 2021-09-29 → 2024-03-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10373198

## Citation

> US National Institutes of Health, RePORTER application 10373198, Noradrenergic modulations of fMRI signal (1R21NS121838-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10373198. Licensed CC0.

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