No abstract

The locus coeruleus-noradrenergic (LC-NA) neuromodulatory system has been implicated in a broad array of cognitive processes, yet scope for investigating this system's function in humans is currently limited by an absence of reliable non-invasive measures of LC activity. Although pupil diameter has been employed as a proxy measure of LC activity in numerous studies, empirical evidence for a relationship between the two is lacking. In the present study, we sought to rigorously probe the relationship between pupil diameter and BOLD activity localized to the human LC. Simultaneous pupillometry and fMRI revealed a relationship between continuous pupil diameter and BOLD activity in a dorsal pontine cluster overlapping with the LC, as localized via neuromelanin-sensitive structural imaging and an LC atlas. This relationship was present both at rest and during performance of a two-stimulus oddball task, with and without spatial smoothing of the fMRI data, and survived retrospective image correction for physiological noise. Furthermore, the spatial extent of this pupil/LC relationship guided a volume-of-interest analysis in which we provide the first demonstration in humans of a fundamental characteristic of animal LC activity: phasic modulation by oddball stimulus relevance. Taken together, these findings highlight the potential for utilizing pupil diameter to achieve a more comprehensive understanding of the role of the LC-NA system in human cognition.

"Attention" is not a unitary brain process. Evidence from adult studies indicates that distinct neuroanatomical networks perform specific attentional operations and that these are vulnerable to selective damage. Accordingly, characterising attentional disorders requires the use of a variety of tasks that differentially challenge these systems. Here we describe a novel battery, the Test of Everyday Attention for Children (TEA-Ch), comprising nine subtests adapted from the adult literature. The performance of 293 healthy children between the ages of 6 and 16 is described together with the relationships to IQ, existing measures of attention, and scholastic attainment. This large normative sample also allows us to test the fit of the adult model of functionally separable attention systems to the observed patterns of variance in children's performance. A Structural Equation Modelling approach supports this view. A three-factor model of sustained and selective attention and higher-level "executive" control formed a good fit to the data, even in the youngest children. A single factor model was rejected. There are behavioural and anatomical grounds to believe that Attention Deficit Disorder (ADD) is particularly associated with poor self-sustained attention and behavioural control. The TEA-Ch performance of 24 boys diagnosed with ADD presented here is consistent with this view. When performance levels on WISC-III subtests were taken into account, specific deficits in sustained attention were apparent while selective attention performance was within the normal range.

The adaptive gain theory highlights the pivotal role of the locus coeruleus-noradrenergic (LC-NE) system in regulating task engagement. In humans, however, LC-NE functional dynamics remain largely unknown. We evaluated the utility of two candidate psychophysiological markers of LC-NE activity: the P3 event-related potential and pupil diameter. Electroencephalogram and pupillometry data were collected from 24 participants who performed a 37-min auditory oddball task. As predicted by the adaptive gain theory, prestimulus pupil diameter exhibited an inverted U-shaped relationship to P3 and task performance such that largest P3 amplitudes and optimal performance occurred at the same intermediate level of pupil diameter. Large phasic pupil dilations, by contrast, were elicited during periods of poor performance and were followed by reengagement in the task and increased P3 amplitudes. These results support recent proposals that pupil diameter and the P3 are sensitive to LC-NE mode.

Two studies assessed the effects of a training procedure (Goal Management Training, GMT), derived from Duncan's theory of goal neglect, on disorganized behavior following TBI. In Study 1, patients with traumatic brain injury (TBI) were randomly assigned to brief trials of GMT or motor skills training. GMT, but not motor skills training, was associated with significant gains on everyday paper-and-pencil tasks designed to mimic tasks that are problematic for patients with goal neglect. In Study 2, GMT was applied in a postencephalitic patient seeking to improve her meal-preparation abilities. Both naturalistic observation and self-report measures revealed improved meal preparation performance following GMT. These studies provide both experimental and clinical support for the efficacy of GMT toward the treatment of executive functioning deficits that compromise independence in patients with brain damage. (JINS, 2000, 6, 299–312.)