Contents

1 Neuropsychological Theories of ADHD

No single neuropsychological theory can explain all attention-deficit/hyperactivity disorder (ADHD) features, neuropsychological impairments may be heterogeneous, which probably corresponds to causal heterogeneity [15, 30]. There is considerable clinical and neuropsychological heterogeneity among individuals who meet the criteria for ADHD [4]. Rather than attempting to identify a single neurpsychological weakness that is necessary and sufficient to cause ADHD, more recent theoretical models explicitly hypothesize that complex disorders are heterogeneous conditions that arise from the combined effects of weaknesses in multiple cognitive domains [16, 17, 30].

1.1 Executive dysfunction

A prominent neuropsychological theory of ADHD suggests that ADHD symptoms arise from a primary deficit in executive functions: the cognitive processes that perform appropriate problem-solving in order to attain a future goal [18]. Every day, we continuously evaluate potential actions and select the options that are most appropriate for the current, specific set of circumstances. This task is extremely complex because some potential choices can be directed toward achieving a positive outcome in the future, whereas alternative actions may maximize initial gains but eliminate the chance for larger long-term benefits. Executive functions my be more accurately described as a collection of related but separable abilities: the ability to inhibit maladaptive behaviors (“response inhibition/inhibitory control”); hold and manipulate information in memory (“working memory”); shift back and forth between two simultaneous tasks (“set shifting”); and suppress attention to extraneous information in the environment to increase focus on a target (“interference control”) [4].

Candidates for core neuropsychological deficits in executive function that might cause both ADHD symptoms and the constellation of neuropsychological impairments that accompany ADHD include failure of inhibitory control [2], dysregulation of brain systems mediating reward and response cost [11, 29], and deficits in arousal, activation, and effortful control [23–25]. Deficits in arousal and effort lead to state-dependent cognitive deficits, and therefore, ADHD may cause problems in regulating cognitive functions in general. This pattern of neuropsychological deficit in ADHD patients has been interpreted as being caused by dysregulation of frontal–subcortical circuits [5]. Frontal–subcortical circuits control executive functions, including inhibition, working memory, set-shifting, interference control, planning, and sustained attention [7, 39]. One problem with these overarching theories is that executive dysfunction is common, but not universal in ADHD patients [22, 28].

1.2 Dysfunctional reward sensitivity

Motivation and reward may represent another core deficit of ADHD [31, 36]. Explanations of ADHD related to reward sensitivity suggest that ADHD is attributable to a dysfunctional response to reward and punishment contingencies. Johansen et al. [11] and Sonuga-Barke [28] propose theories that ADHD children have a steeper than normal delay-of-reinforcement gradient, and aversion to delay of reinforcement. Delay aversion is a special variant of the dysfunctional reward sensitivity model that suggests that children with ADHD have a motivational style that leads them to find delay extremely aversive [27, 29]. Tripp and Wickens [35] also proposed the dopamine (DA) transfer deficit theory and suggested that children with ADHD have diminished cellular responses of DA cells to cues that precede reinforcement.

A neural circuit that includes ventromedial prefrontal cortex, the amygdala, and other limbic structures plays an essential role in coordinating the interface between motivation and cognition during decision-making processes [3, 20]. Damage to this network often leads to difficulty learning from mistakes, delaying gratification, and monitoring subtle shifts in reward and punishment probabilities to maximize the short-and long-term benefits of a choice.

1.3 Intelligence and academic achievement

More global cognitive aspects like intelligence, academic achievement, and social cognition are of particular importance to the clinical impact of ADHD, and these broad domains are likely impacted by the individual cognitive processes described above [4]. Individual differences in intelligence and academic achievement may correlate better with neuropsychological deficits associated with ADHD rather than categorical placement [13], however, ADHD symptoms may directly cause an individual to perform poorly on standardized tests of intelligence or reading [2]. Also, while patients with ADHD suffer from a range of social and interpersonal problems, it is unclear whether these difficulties arise from true deficits in social cognition or can be better explained by the behavioral symptoms like lapses in attention and impulsivity [4].

2 Laboratory experiments attempt to capture and quantify ADHD

Spatial working memory tasks show the largest performance difference between children with ADHD and those without [16]. Key domains in which deficits are manifested across cases are vigilance/attention, cognitive control, response suppression, working memory, and motivation. These key domains (cognitive control and motivation) highlight principles of DA reinforcement (as discussed in the Dopamine in the Dentate Gyrus section) and its disruption in this disorder [32]. Historically, the core feature of ADHD has been characterized as one of an attention deficit, but increasing evidence suggests that a reward and motivation deficit may be of equal importance [6, 19, 29, 35–37].

2.1 Response variability

The reaction times of children, adolescents, and adults with ADHD are significantly more variable than the reaction times of individuals without ADHD across a wide range of cognitive tasks [8]. Response variability is one of the ubiquitous findings in ADHD research across a variety of speeded-reaction-time tasks, laboratories, and cultures [7]. Increased response variability seems to be due to a relatively small number of trials with extremely long response times rather than systematically greater response variability across all trials [9]. These slow trials may reflect attentional lapses due to chronic underarousal, or inconsistent regulation of arousal during lengthy tasks. These attentional lapses may be caused by problems in the functional connectivity between anterior cingulate and precuneal regions of the brain [6]. Another theory suggests that greater response variability could result from dysfunction in short-duration timing mechanisms mediated by cerebellar circuits [7, 33].

2.2 Processing speed

Although no neuropsychological theoretical models of ADHD explicitly propose slow cognitive processing speed as the primary neuropsychological weakness in ADHD, deficits in processing speed are among the most robust predictors of ADHD symptoms [4, 21, 39]. Slow processing speed has been reported in groups with ADHD on a range of measures that require both verbal and nonverbal responses [26], and is a consistant finding in studies of both children and adults with ADHD [40]. The neurophysiology of slow processing speed is not well understood, but generalized low cortical arousal provides one potential explanation [4].

3 Effects of stimulant medications

Other, non-stimulant medications used to treat ADHD¹ test superior to placebo, but most head-to-head trials compared to stimulant medications (methylphenidate (MPH) and amphetamine (AMPH)) show greater efficacy for stimulant medications [4].

Across well-controlled studies of individuals with ADHD, stimulant-related cognitive enhancements were more prominent on tasks without an executive function component than on tasks with an executive function component [31]. Dose-response studies of stimulant medications suggest that the optimal dose varies across individuals and depends somewhat on the domain of function, with high doses tending to produce greater enhancement on some (e.g. attention, vigilance, memory, and working memory) but not others (e.g. planning, cognitive flexibility, inhibitory control, naming, and motor speed) [4, 31].

In terms of academic achievement, evidence suggests that stimulants improve acute academic performance of children with ADHD, but that long-term effects have not been supported. For example, the The Multimodal Treatment Study of Children with ADHD Cooperative Group demonstrated that treatment with stimulant medications over the 14-month trial resulted in significant improvement of achievement scores in math and reading on the Wechsler Individual Achievement Test (WIAT) immediately post-treatment. However, these improvements were no longer significant at the 3-year follow up assessment, suggesting that any relative cognitive enhancement may not be sustained [10].

Extensive work examining the effects of stimulants on attentional and executive processes has not found consistent evidence that stimulants enhance or ameliorate these ADHD-related deficits. Although reaction times are significantly reduced, performance on tasks with increased attentional or executive demands is not consistently improved by stimulants [4]. Further, while short-term improvements in academic achievement scores have been demonstrated with stimulant treatment, stimulant medications do not completely normalize academic achievement in children with ADHD.

In contrast to the extensive work on the effects of stimulants on attention, executive function, and achievement, the potential influence of stimulants on other types of cognition implicated in ADHD (e.g. social cognition and reward sensitivity) is comparably unknown. In one study by Williams [41], several abnormalities during emotional processing could be observed prior to treatment, which were ameliorated with methylphenidate. In addition, medication significantly improved baseline deficits in the recognition of anger- and fear-related facial expressions. However, the performance of ADHD patients remained impaired relative to healthy controls. Thus, although methylphenidate normalized neural activity, it was associated with only minimal improvement on emotion recognition. This finding is in line with studies that suggest medication results in improvements of inattention and disruptive behavior in children with ADHD, whereas positive social behavior and peer status remain unchanged [38].

3.1 Non-pharmacological interventions to improve cognition in ADHD

Computer-based working memory training has demonstrated improvements on trained and untrained measures of working memory, and also showed improved response inhibition and reductions in parent-rated inattentive symptoms of ADHD that were durable at follow-up assessments [12]. This training protocol was shown to produce increases in brain activation and changes in the density of prefrontal and parietal dopamine D1 receptor binding potential, indicating neural plasticity that arises as a result of the training [14].

A number of studies have been published examining the effects of neurofeedback on a range of outcome measures in individuals with ADHD. These studies have, in general, produced large effects on parent and teacher-rated ADHD symptoms [34]. However, neurofeedback has shown more variable effects with respect to cognitive outcomes.

4 Relevance of cognition-related endpoints in clinical syndrome of ADHD

In one early review of the literature, Barkley [1] concluded that the ecological validity of laboratory tasks to measure clinically relevant feature of inattention, impulsivity, and overactivity was low to moderate. Other studies have shown that performance on laboratory tasks was not predictive of the clinical response in ADHD patients to different medications. To the extent that specific cognitive endpoints are strongly associated with the clinical features that define the disorder (e.g. link between inhibitory control and DSM-IV impulsivity symptoms), assessing the effects of interventions on these endpoints may be useful. However, as many studies have shown, the acute effects of a range of interventions on cognitive endpoints that are less strongly correlated with ADHD clinical features may be less meaningful from a clinical perspective.

Acronyms

ADHD

attention-deficit/hyperactivity disorder

AMPH

amphetamine

DAT

dopamine transporter

DA

dopamine

MPH

methylphenidate

MTA

The Multimodal Treatment Study of Children with ADHD Cooperative Group

NE

norepinephrine

WIAT

Wechsler Individual Achievement Test

References