Neural correlates of inhibitory control in adult attention deficit/hyperactivity disorder: Evidence from the Milwaukee longitudinal sample

Abstract

Only a few studies have investigated the neural substrate of response inhibition in adult attention deficit hyperactivity disorder (ADHD) using Stop-Signal and Go/No-Go tasks. Inconsistencies and methodological limitations in the existing literature have resulted in limited conclusions regarding underlying pathophysiology. We examined the neural basis of response inhibition in a group of adults diagnosed with ADHD in childhood and who continue to meet criteria for ADHD. Adults with ADHD (n = 12) and controls (n = 12) were recruited from an ongoing longitudinal study and were matched for age, IQ, and education. Individuals with comorbid conditions were excluded. Functional magnetic resonance imaging (fMRI) was used to identify and compare the brain activation patterns during correct trials of a response-inhibition task (Go/No-Go). Our results showed that the control group recruited a more extensive network of brain regions than the ADHD group during correct inhibition trials. Adults with ADHD showed reduced brain activation in the right frontal eye field, pre-supplementary motor area, left precentral gyrus, and the inferior parietal lobe bilaterally. During successful inhibition of an inappropriate response, adults with ADHD display reduced activation in fronto-parietal networks previously implicated in working memory, goal-oriented attention, and response selection. This profile of brain activation may be specifically associated with ADHD in adulthood.

Introduction

Attention deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder characterized by developmentally inappropriate levels of inattention, hyperactivity, and impulsivity (American Psychiatric Association, 1994). ADHD is often considered a childhood disorder, as it occurs in 1–5% of children (Faraone and Biederman, 2005). However, ADHD also occurs in 1–7% of adults (Simon et al., 2009), and prospective longitudinal follow-up studies show that rather than normalizing with increasing age, ADHD persists into adulthood in 4–66% of individuals diagnosed in childhood (Weiss et al., 1985, Mannuzza et al., 1998, Rasmussen and Gillberg, 2000, Barkley et al., 2002).

Psychological theories have proposed that ADHD symptoms follow from a primary deficit in inhibitory control (Barkley, 1997, Quay, 1997). Functional neuroimaging studies suggest that a network of fronto-parietal brain regions is implicated in motor response inhibition as assessed by Stop-Signal and Go/No-Go tasks. Brain regions implicated include inferior prefrontal, medial prefrontal (including the pre-supplementary motor area), and inferior parietal areas (for review see Chambers et al., 2009). Lesion and transcranial magnetic stimulation (TMS) studies suggest that two subregions of prefrontal cortex, the right inferior frontal gyrus (IFG) and the pre-supplementary motor area (pre-SMA), are critically involved in inhibitory control, as patients with lesions to these regions and healthy participants undergoing TMS to these regions perform “Stop” and “No-Go” trials of the Stop-Signal and Go/No-Go tasks more slowly and less accurately than healthy controls (Aron et al., 2003, Chambers et al., 2006, Floden and Stuss, 2006, Picton et al., 2007, Chen et al., 2009). Taken together, these studies provide compelling evidence that the frontal lobes play a critical role in response inhibition, and that the pre-SMA and the right IFG represent subregions of the frontal lobes that are critically related to inhibitory control.

The theory that individuals with ADHD have deficits in response inhibition that follow from dysfunction of the frontal lobes is consistent with several different lines of research. Individuals with ADHD demonstrate behavioral impairments relative to healthy control participants on “Stop” and “No-Go” trials of the Stop-Signal and Go/No-Go paradigms. Differences in performance have been observed in samples of ADHD children (Trommer et al., 1988, Tamm et al., 2004, Lijffijt et al., 2005) and in samples of ADHD adults (Bekker et al., 2005, O'Connell et al., 2009, Burden et al., 2010). Functional neuroimaging studies have shown that when children with ADHD perform “Stop” and “No-Go” trials on the Stop-Signal and Go/No-Go paradigms they display reduced activation in the frontal lobes compared to matched healthy control participants (Dickstein et al., 2006, Rubia et al., 2008, Suskauer et al., 2008, Passarotti et al., 2010). Clinical reports and longitudinal data have also shown that adults with ADHD exhibit a pervasive pattern of disinhibition in several major life activities including money management, excessive substance abuse, and gambling (Barkley et al., 2008). Taken together, these data suggests that the neural correlates of inhibitory control are dysfunctional in adults with ADHD.

Functional neuroimaging studies have only very recently begun to investigate the neural correlates of response inhibition in adults with ADHD using Stop-Signal and Go/No-Go tasks. Five functional magnetic resonance imaging (fMRI) studies that compared groups of adults diagnosed with ADHD to matched controls while each group performed the same Stop-Signal or Go/No-Go task have yielded inconsistent findings (Epstein et al., 2007, Dibbets et al., 2009, Cubillo et al., 2010, Dillo et al., 2010, Kooistra et al., 2010). Three of the studies reported that adults with ADHD demonstrate increased prefrontal activation while inhibiting a motor response (Epstein et al., 2007, Dibbets et al., 2009, Kooistra et al., 2010). This is consistent with a recently proposed hypothesis suggesting that adults with ADHD may rely on the frontal lobes to compensate for primary dysfunction in other brain regions (Halperin and Schulz, 2006). However, two studies have reported that adults with ADHD demonstrate reduced activation of frontal brain regions while inhibiting a motor response (Epstein et al., 2007, Cubillo et al., 2010). This supports the alternative claim that dysfunction of the frontal lobes is directly related to deficits in response inhibition in individuals with ADHD (Rubia et al., 1999, Booth et al., 2005).

There may be several reasons for the inconsistent findings. First, prospective longitudinal follow-up studies suggest that retrospective self-report of ADHD symptoms may be inaccurate (Barkley et al., 2002, Mannuzza et al., 2002), calling into question whether the participants in the three studies that used retrospective diagnosis of ADHD (Epstein et al., 2007, Dibbets et al., 2009, Dillo et al., 2010) were assigned to the appropriate experimental group.

Secondly, the potential influence of comorbid psychiatric disorders on the outcome of functional neuroimaging studies should also be considered. Although four of the studies reported that they excluded comorbid conditions, two studies excluded participants based on report of psychiatric disorder rather than on the results of structured psychiatric interviews (Dibbets et al., 2009, Kooistra et al., 2010). Furthermore, two studies did not exclude comorbidities that are commonly present in adults with ADHD including learning disabilities and current use of substances (Epstein et al., 2007, Cubillo et al., 2010). These approaches raise questions as to whether the functional neuroimaging patterns described in these studies were specifically related to ADHD (Adler et al., 2005, Leibenluft et al., 2007, Paloyelis et al., 2007, Cubillo and Rubia, 2010).

Thirdly, methodological issues may have contributed to the inconsistent findings. Four of the studies used an event-related design, while one study utilized a block design. Interestingly, the four that used event-related designs examined activation associated with correct trials only and found that ADHD and control participants activated the prefrontal cortex to a different degree during inhibition of a prepotent motor response (Epstein et al., 2007, Dibbets et al., 2009, Cubillo et al., 2010, Kooistra et al., 2010), while the study that used a block design did not find activation differences in the frontal lobes (Dillo et al., 2010). Several authors have noted that block designs may be more susceptible to a variety of functional neuroimaging confounds, including effects of task difficulty, response preparation, habituation, different stimuli, maintenance of stimulus–response associations, changes in set, stimulus analysis, processing of conflict and error, novelty processing, mixed event types, and frequency of motor events (Garavan et al., 2002, Tamm et al., 2004, Paloyelis et al., 2007, Simmonds et al., 2008). Additionally, it is not possible to examine brain activation associated with correct trials within the context of a block design.

Finally, a recent meta-analysis that examined the neural correlates of response inhibition in healthy samples noted that another possible factor that could contribute to variable functional neuroimaging findings when using the Go/No-Go task is contrast of “Go” and “No-Go” trials (Simmonds et al., 2008). The meta-analysis examined the results of 11 event-related fMRI studies that administered the Go/No-Go task to healthy individuals, and suggested that although the contrast of “No-Go” and “Go” trials would reveal areas of the brain that were uniquely involved in response inhibition and selection, this type of contrast would also fail to associate any brain region that contributed to both cognitive processes, such as the pre-SMA. Interestingly, none of the five studies that examined the neural correlates of response inhibition in adults with ADHD contrasted brain activation patterns associated with “No-Go” trials against implicit task baseline, and this may be the reason why none of these studies found activation differences between ADHD and control participants that were located in the pre-SMA despite this region's critical role in response inhibition.

The five previous studies in adults with ADHD provided inconsistent results and may have been confounded by issues that were related to sample assessment, functional neuroimaging design and analysis. For this reason, the aim of the current study was to examine the neural correlates of response inhibition in adults with ADHD while addressing these previous limitations. To ensure that adults in our sample had symptoms of ADHD in childhood as well as in adulthood and were therefore assigned to the correct experimental group, we examine an adult ADHD sample that was recruited from an ongoing longitudinal study (Barkley et al., 2008). To confirm that resulting brain activation patterns were specifically associated with ADHD, we exclude individuals with current psychiatric or neurological comorbidities. To avoid potential confounds associated with fMRI block designs and to be able to compare our neuroimaging findings with those of other studies that have used the same task, we administer an event-related version of the Go/No-Go task that has been studied within samples of healthy participants (Garavan et al., 1999, Garavan et al., 2002, Garavan et al., 2003, Hester et al., 2004a, Kelly et al., 2004). To reveal activation in a network of brain regions associated with the act of inhibiting a prepotent response without eliminating brain regions that may play an important role in both response selection and inhibition, we contrast activation associated with “No-Go” trials against an implicit task baseline. We perform this contrast prior to testing whether ADHD and control participants demonstrate differences in mean hemodynamic response during the correct performance of “No-Go” trials , and hypotheses related to differential activation are only tested within the boundaries of functionally defined brain regions of interest that are identified through the contrast of “No-Go” trials with implicit task baseline. These procedures allow us to examine differences in activation that are correlated with the act of inhibiting a prepotent response.

In keeping with the theory that dysfunction of the frontal lobes is associated with deficits in response inhibition in individuals with ADHD, we hypothesized that our sample of adults with ADHD would demonstrate less accurate performance and less prefrontal activation than controls during “No-Go” trials. More specifically, we predicted that our group of adults with ADHD would demonstrate reduced activation in subregions of prefrontal cortex thought to play a critical role in response inhibition, such as the right IFG and the pre-SMA.