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.
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.
