Investigation of Locus Coeruleus Function in Sustained Attention

NCT ID: NCT06041048

Last Updated: 2025-12-12

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-10-01
• Study Completion Date: 2025-12-30

Brief Summary

The norepinephrine-producing locus coeruleus (LC) is thought to be central to a wide array of cognitive functions, like attention and goal pursuit, and has been implicated in dysfunctions including attention deficit hyperactivity disorder and schizophrenia. The goal of this proposal is to develop methods that permit measurement of activity in the human LC. Because the LC is small and located in the pons, the Investigators will use high resolution magnetic resonance imaging techniques tailored to the brainstem environment, including neuromelanin-sensitive images shown to delineate the LC, combined with pharmacological manipulation to confirm the location of functional activity.

Detailed Description

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., attentiondeficit/ 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. The Investigators 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. The Investigators 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 the Investigators 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 measurement of a brain structure central in attentional control.

Conditions

Attention - no Condition is Being Assessed - Healthy Adults

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: TRIPLE

Study Groups

Modafinil

Single oral dose (200 mg) of medication versus placebo given to healthy control subjects

Group Type: ACTIVE_COMPARATOR

Modafinil

Intervention Type: DRUG

Single dose (200 mg) of medication versus placebo given to healthy control subjects

Placebo

Oral placebo

Group Type: PLACEBO_COMPARATOR

Modafinil

Intervention Type: DRUG

Single dose (200 mg) of medication versus placebo given to healthy control subjects

Interventions

Modafinil

Single dose (200 mg) of medication versus placebo given to healthy control subjects

Intervention Type: DRUG

Other Intervention Names

Provigil

Eligibility Criteria

Inclusion Criteria

• Between the ages of 18 - 60 years of age,
• Typically developing, healthy adult

Exclusion Criteria

• History of schizophrenia, other forms of psychosis,
• Specific or focal neurological disorder or severe alcohol or drug use disorder within the past 5 years
• History of left ventricular hypertrophy or in patients with mitral valve prolapse who have experienced the mitral valve prolapse syndrome when previously receiving CNS stimulants, or who have had recent history of myocardial infarction or unstable angina.
• Volunteers with known hypersensitivity to modafinil or armodafinil or its inactive ingredients
• Known allergy/sensitivity or any hypersensitivity to components of modafinil or its formulation
• Inability to swallow tablets or tolerate oral medication;
• Pregnant or nursing (participants will be required to have a negative pregnancy test)
• Contraindication for MRI scanning (metal implants, pacemakers, metal foreign bodies, or pregnancy)
• Use of psychotropic medication within the past week
• Claustrophobic and not comfortable being in a small space may also not want to participate

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of California, Davis

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

University of California, Davis

Sacramento, California, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Julie Schweitzer, PhD

Role: CONTACT

jschweitzer@ucdavis.edu

9167030450

Jared Borden, MA

Role: CONTACT

Jborden@ucdavis.edu

9167030294

Facility Contacts

Jared Borden

Role: primary

jborden@ucdavis.edu

Other Identifiers

1939774

Identifier Type: -

Identifier Source: org_study_id