Understanding the effects of stimulant medications on cognition in individuals with attention-deficit hyperactivity disorder: a decade of progress

Abstract

The use of stimulant drugs for the treatment of children with attention-deficit hyperactivity disorder (ADHD) is one of the most widespread pharmacological interventions in child psychiatry and behavioral pediatrics. This treatment is well grounded on controlled studies showing efficacy of low oral doses of methylphenidate and amphetamine in reducing the behavioral symptoms of the disorder as reported by parents and teachers, both for the cognitive (inattention and impulsivity) and non-cognitive (hyperactivity) domains. Our main aim is to review the objectively measured cognitive effects that accompany the subjectively assessed clinical responses to stimulant medications. Recently, methods from the cognitive neurosciences have been used to provide information about brain processes that underlie the cognitive deficits of ADHD and the cognitive effects of stimulant medications. We will review some key findings from the recent literature, and then offer interpretations of the progress that has been made over the past decade in understanding the cognitive effects of stimulant medication on individuals with ADHD.

Figure 1

Anticorrelated brain activity in a component of the task-positive network related to externally cued attention. (a) The intraparietal sulcus (IPS), frontal eye field (FEF) and middle temporal (MT) areas are the positive nodes (shown in warm colors) and are significantly correlated with seed regions involved in focused attention and working memory (task-positive seeds). The task-positive seeds are significantly anticorrelated with seed regions that are routinely de-activated during attention-demanding cognitive tasks (task-negative seeds shown in cool colors) and located in the posterior cingulate cortex (PCC)/precuneus, lateral parietal cortex (LP), and medial prefrontal cortex (MPF). (b) The bottom actograms represent the time course for a single run based on the seed region (PCC, in yellow), a region positively correlated with this seed region in the MPF (orange), and a region negatively correlated with the seed region in the IPS (blue). Modified with permission from Fox and Raichle (2007) and Fox et al (2005).

Figure 2

The pattern of negative correlation between blood oxygen level-dependent (BOLD) activity in the default mode network (DMN) (equivalent to RSN-2) and the task-positive network for a component of the attentional network task (ANT) task. (a) Z-score threshold maps of the spontaneously active (task-independent) DMN (purple/pink) and its negatively correlated task mode network (TMN) (red/orange). (b) An individual example of a nearly perfect negative correlation (r=−0.97) between DMN and TMN antiphase time series. Reprinted with permission from Kelly et al (2008).

Figure 3

Differences in task activation between placebo (PL) and methylphenidate (MP). Statistical Parametric Mapping (SPM) results showing the areas (in yellow) that had greater increases in metabolism when the cognitive task was given with placebo vs when it was given with MP. Comparisons correspond to paired t-tests (p<0.005 uncorrected >100 pixels). None of the brain regions had higher metabolism for the cognitive task when given with MP than with placebo. Reprinted with permission from Volkow et al (2008).

Figure 4

U-shaped curve relating activity on the prefrontal cortex (PFC) to levels of catecholamine release. As noted by Arnsten (2009), the PFC is very sensitive to catecholamine levels, with which it is suffused as a function of the arousal state. As proposed, PFC function is impaired whenever too little or too much catecholamine is released. In this schematic representation, moderate levels of noradrenaline (NA) and dopamine (DA) improve PFC function by optimally engaging their cognate receptors. Reprinted with permission from Arnsten (2009).