Neural correlates of inhibitory control in adult attention deficit/hyperactivity disorder: Evidence from the Milwaukee longitudinal sample
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.
Section snippets
Participants
Participants were recruited from a long-term, prospective, longitudinal study of “hyperactive” and IQ-matched control children (n = 158) (Barkley et al., 1985, Barkley et al., 2002, Barkley et al., 2008). ADHD participants were originally recruited from consecutive clinic referrals, and continue to meet criteria for combined type ADHD. Individuals in the longitudinal control group (n = 81) were originally recruited using a “snowball” technique in which parents of the hyperactive children provided
Results
Mean accuracy (± S.D.) on “Go” trials was 94% (± 3%) for the control group and 94% (± 3%) for the ADHD group. Mean accuracy (± S.D.) on “No-Go” trials was 89% (± 8%) for the control group and 79% (± 25%) for the ADHD group. There was no significant difference between the ADHD and control groups' performance on “Go” [t (1, 21) = 0.08, p = 0.94, d = 0.03] or “No-Go” trials [t (1, 13) = 1.31, p = 0.21, d = − 0.53].
Direct contrast of peak activation associated with “Go” and “No-Go” trials failed to reveal any
Discussion
The current study examined a well-characterized sample of adults with ADHD from an ongoing longitudinal study that did not include individuals with comorbid conditions. As such, the observed differences in brain activation between individuals with ADHD and controls are unlikely to be due to factors that may be related to inaccurate retrospective assessment of ADHD symptoms or due to disorders that are often comorbid with ADHD. Consistent with the hypothesis that dysfunction of the frontal lobes
Acknowledgments
We acknowledge Blythe Janowiak, Jill Dorflinger, Rebecca Thompson, and Sally Durgerian for personal and technical assistance. This project was supported by NIH-NIMH (R01 MH057836 to SMR, R01 MH057836-03S1 for RCM).
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Cited by (42)
Fronto-parietal engagement in response inhibition is inversely scaled with attention-deficit/hyperactivity disorder symptom severity
2020, NeuroImage: ClinicalCitation Excerpt :However, in studies of adults with ADHD, results are much more inconsistent, and the nature of neural disruption is unclear. As summarized by Congdon and colleagues (Congdon et al., 2014), some studies report hypoactivation in ADHD relative to neurotypicals (Cubillo et al., 2010; Montojo et al., 2015; Mulligan et al., 2011; Sebastian et al., 2012), while other report hyperactivation in ADHD (Dillo et al., 2010; Karch et al., 2010), or no difference between patients and neurotypicals (Carmona et al., 2012; Congdon et al., 2014). The problem is exacerbated by the tendency of studies to report an extensive (and sometimes varied) network of regions associated with inhibition, including inferior frontal cortex, the insula, pre-supplementary motor area, medial-superior frontal gyrus, cingulate cortex, the striatum and thalamus.
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2016, Biological PsychiatryCitation Excerpt :As the meta-analysis of ADHD-related hyperactivated regions would have been underpowered (24), we did not run it. Excluding two studies (39,42) reporting no significant contrasts between adults with ADHD and controls, we found a total of 12 papers including tasks exploring inhibition (10–13,35,40,41,45,47,48,50,52) (reporting, overall, 10 contrasts of controls > ADHD and six contrasts of ADHD > controls), six including working memory tasks (37,46,51,54,56,57), six focusing on attention tests (40,41,47–50), five assessing reward processes (35,36,43,49,53), one using the instructed fear test (38), and one based on the paced or unpaced finger tapping test (55). Therefore, we did not perform planned subgroup analyses on the basis of task type because the number of contrasts was substantially less than 15 (24).
- 1
Present institution: Washington University in St. Louis, Department of Psychiatry.
- 2
Affiliated during data collection.