# Investigation of Locus Coeruleus Function in Sustained Attention

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2023 · $199,358

## Abstract

PROJECT SUMMARY
Attention failures negatively impact goal pursuit and have significant consequences on performance in many
environments. Attentional control of perceptual, motor and cognitive functions are believed to be partly
determined by functioning of the locus coeruleus-norepinephrine (LC-NE) system. The LC, a small brainstem
nucleus that is the primary source for NE in the forebrain, has motivated hypotheses about human cognition,
including mental health disorders with known alterations in attention and cognition (e.g., attention-
deficit/hyperactivity disorder (ADHD), schizophrenia) even though methods for measuring human LC activity
have significant limitations. Existing methods to study LC function in humans rely on pupillometry and fMRI.
Because pupil diameter correlates with LC activity, it has been used as a proxy for LC activity. However, the
anatomical pathway linking the LC to pupil dilation has not been established and pupil diameter also correlates
with activity in other brain areas. Thus, inferring LC activity from pupillometry alone is problematic. fMRI has
also been used to measure activity from the LC, but the imaging methods used to date have relied on
resolutions that are coarse relative to the size and shape of LC. Prior fMRI results have therefore not been
adequate for event-related analyses. The goal of the proposed work is to develop and validate methods for
using fMRI to measure LC activity, specifically event-related responses that will allow for testing of influential
hypotheses of LC function in humans. This goal is appropriate for the R21 mechanism, which is meant to
“encourage exploratory/developmental research by providing support for the early and conceptual stages of
project development” and to test innovative, high-risk, high reward research. This project has two specific aims,
which are both tested with sustained attention tasks. The first aim uses high-resolution fMRI to maximize the
number of measurements within LC combined with neuromelanin-sensitive imaging to localize BOLD
responses to LC. We will measure (a) pre-trial activity (i.e., during inter-trial intervals; this period is thought to
reflect tonic LC activity) and (b) trial response (i.e., phasic LC activity) by estimating the beta weights for each
trial. The second aim uses modafinil administration to modulate LC activity and confirm the location of BOLD
responses measured during the sustained attention tasks to the LC. We will administer modafinil and placebo
to participants in a double-blind, placebo-controlled crossover study. Pupillometry data will also be collected for
both the modafinil and placebo conditions, and we will use the pupillometry data to test for a correlation with
LC BOLD response amplitude. This combination of techniques will demonstrate whether fMRI can be used to
measure LC activity in a targeted fashion. Developing these tools meets Goal 1 (Strategy 1.3D) of the 2020
Strategic Plan of the NIMH by permitting direct measurem...

## Key facts

- **NIH application ID:** 10693968
- **Project number:** 5R21MH130924-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** SAMUEL M MCCLURE
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $199,358
- **Award type:** 5
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10693968

## Citation

> US National Institutes of Health, RePORTER application 10693968, Investigation of Locus Coeruleus Function in Sustained Attention (5R21MH130924-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10693968. Licensed CC0.

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