Priority CommunicationsAnterior cingulate cortex dysfunction in attention-deficit/hyperactivity disorder revealed by fMRI and the counting stroop
Introduction
Attention-deficit/hyperactivity disorder is characterized by developmentally inappropriate symptoms of inattention, impulsivity, and motor restlessness. ADHD affects approximately 5% of school-age children, and persists to a lesser degree into adulthood (see Biederman 1998, Spencer et al 1998). Given the great morbidity associated with the disorder, including persistent neuropsychological impairments (Seidman et al 1998), determining the underlying neurobiology of ADHD is of great importance.
Recent reviews of data from neuroimaging, neuropsychological, genetic, and neurochemical studies have generally implicated frontostriatal network abnormalities as the likely cause of ADHD Castellanos 1997, Ernst 1998, Ernst et al 1998, Lou 1996, Seidman et al 1998, Shaywitz et al 1997, Solanto 1998, Swanson et al 1998, Tannock 1998, Zametkin and Liotta 1998. Of particular interest, while Zametkin and colleagues’ 1990 positron emission tomography (PET) study showed that global cerebral glucose metabolism was 8.1% lower in the ADHD group than in the control subjects, cingulate cortex was one of only four (out of a total of sixty) regions interrogated that still showed regional hypoactivity after global normalization. The current fMRI study was undertaken to specifically examine the hypothesis that dysfunction of the anterior cingulate cognitive division (ACcd), a region vitally important to the proper and efficient functioning of frontostriatal attentional networks, might contribute to producing the core deficits of ADHD.
The ACcd (cytoarchitectural areas 24b′/24c′/32′) is a functional subdivision of the anterior cingulate cortex that plays a critical role in complex cognitive/attentional processing Badgaiyan and Posner 1998, Bush et al 1998, Casey et al 1997b, Devinsky et al 1995, Mayberg 1997, Mega et al 1997, Paus et al 1998, Posner and Petersen 1990, Vogt et al 1992, Vogt et al 1995. The functional neuroimaging literature on normal volunteers has shown the ACcd to be activated by numerous cognitive/attentional tasks, including Stroop and Stroop-like cognitive interference tasks, divided attention tasks, working memory tasks, and response selection/generation tasks (see Figure 5). Based on these convergent findings, the ACcd has been hypothesized to play a primary role in 1) stimulus selection when faced with competing streams of input; and/or 2) response selection via the facilitation of correct responses and/or the inhibition of incorrect actions. Impairments of these functions could produce the core clinical features of ADHD, namely 1) impaired attention; and 2) impulsivity (i.e., defective inhibition of inappropriate responses). Thus, we hypothesized that a dysfunction in the ACcd might lead to inattention/impulsivity, and therefore contribute to the pathophysiology of ADHD.
Given that the ACcd has been repeatedly activated by Stroop and Stroop-like tasks known to activate the ACcd (see Figure 5), a review of the literature pertaining to the performance of ADHD subjects on the traditional Color Stroop task strengthened our suspicion that the ACcd might be impaired, as a number of researchers have reported deficits on the performance of the Color Stroop in ADHD Barkley et al 1992, Carter et al 1995, Carter et al 1995, Seidman et al 1997.
The Counting Stroop (Bush et al 1998) was developed as a cognitive activation paradigm for probing ACcd function. The Counting Stroop is a Stroop variant MacLeod 1991, Stroop 1935 that allows on-line response time measurements without requiring speech. Stroop and Stroop-like tasks produce cognitive interference by pitting two competing information processing operations against one another. During the Counting Stroop, reading and counting processes compete, as subjects are instructed to report via button-press the number of words (1 to 4) on the screen, regardless of word meaning. Neutral trials contain common animals (e.g., “dog” written three times, answer, “three”), while interference trials contain number words that are incongruent with the correct response (e.g., “two” written three times, answer, “three”). The Counting Stroop was created because speaking produces head movements that can exceed those tolerated by fMRI, preventing the collection of vital performance data. In a validation study, the Counting Stroop activated the ACcd in a group of nine normal volunteers, and the degree of ACcd activation paralleled the amount of cognitive interference, as measured by reaction time data (Bush et al 1998). Similar in concept to a cardiac stress test, we predicted that it would tax the ACcd, and thereby, reveal ACcd dysfunction in ADHD that might not otherwise be detectable.
In the present study, the Counting Stroop task and fMRI were used to test the functional integrity of the ACcd in ADHD. Since the persistence of ADHD symptoms into adulthood and a positive family history of ADHD are potential indicators of a more neurobiologically mediated form of the disorder Biederman 1998, Seidman et al 1995, we chose to limit our patient sample to adults with ADHD who had at least one first-degree relative with ADHD. To further maximize the chance of finding group differences in this pilot study, we attempted to improve sample homogeneity by excluding subjects with learning disabilities or other (non-ADHD) Axis I diagnoses. We hypothesized that dysfunction in the ACcd contributes to the attentional deficits observed in ADHD by impairing the ability to select relevant stimuli when processing multiple competing streams of information and/or by influencing response selection. Accordingly, we specifically predicted that: 1) the ADHD group would show a greater interference effect on the Counting Stroop compared to the matched control group, as measured by longer reaction times and/or decreased accuracy; and 2) the ACcd would show greater fMRI activation during the Counting Stroop in normal adults than in the group with ADHD.
Section snippets
Subjects
The study sample (n = 16) consisted of two groups: 8 adults with ADHD (5 men and 3 women), and 8 matched normal control subjects. The subjects ranged in age between 22 to 47 years. Group matching was based on age, gender, socioeconomic status, and education. Informed consent was obtained per Massachusetts General Hospital Subcommittee on Human Subjects guidelines.
Inclusion criteria for all subjects were: 1) age 18 to 55 years; 2) right-handedness (per the Edinburgh Handedness Inventory,
Behavioral data
Analysis of reaction time (RT) data (Figure 2) revealed that within groups, both control subjects and ADHD subjects displayed interference effects (i.e., showed longer RTs during interference trials as compared to neutral trials). Control subjects showed an overall increase in RT during interference blocks (720 msec ± SD 51 msec) as compared to neutral blocks (mean 691 msec ± 42 msec), and a repeated measures condition (interference versus neutral) by scan (scan one versus scan two) ANOVA
Discussion
The Counting Stroop was used in conjunction with fMRI to examine the functional integrity of the cognitive division of the anterior cingulate cortex in adults with ADHD. While both the ADHD group and the control group showed an interference effect, the Counting Stroop fMRI data revealed a relative hypofunctionality of the ACcd in ADHD. The control group showed significant fMRI activation in the ACcd, while the ADHD group did not. In two direct comparisons, the controls showed greater activation
Acknowledgements
Support for this work was provided by NIMH [Grants MH01611 (GB), MH01215 (SLR), MH41314 (JB)], a National Alliance for Research on Schizophrenia and Depression Young Investigator Award (GB), a Lilly Research Award (JAF), the David Judah Fund (MAJ, GB), and the Stanley Foundation (LJS). Dr. Bush also received support as a fellow in the Harvard/MIT Division of Health Sciences and Technology, Beth Israel Deaconess Medical Center Clinical Investigator Training Program, in collaboration with Pfizer,
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