Contents

1 Human imaging contributions

The literature on positron emission tomography (PET) imaging supports the dopamine (DA) hypothesis of attention-deficit/hyperactivity disorder (ADHD), but the specific details are not yet clear. Some studies support the dopamine transporter (DAT) excess hypothesis, which results in a DA deficit owing to increased reuptake of synaptic DA, whereas others suggest this is just DAT plasticity that resets density based on levels of synaptic DA, which may be low in stimulant-naïve individuals, but high in treated individuals taking methylphenidate (MPH), as a result of adaptation to treatment rather than the presence of the disorder [5].

On the basis of imaging studies, it has been hypothesized that stimulant medications may act by facilitating the engagement of a dorsal task-positive attention network and the deactivation of the ventral resting state network [6]. This may reflect in part improved filtering out of task-irrelevant stimuli by way of stimulant-mediated DA and norepinephrine (NE) release in the prefrontal cortex and anterior cingulate gyrus [1]. Recent findings from PET brain imaging studies have documented that the DA deficits in ADHD were most prominent in the ventral striatum (a crucial brain region for modulating reward and motivation) and in the midbrain (where most DA neurons are located), which highlights the relevance of the reward/motivational circuit in this disorder [7]. As a result of their ability to increase DA, stimulants appear to enhance the motivational saliency of cognitive tasks. MPH-induced DA increases modulate the perception of how interesting and engaging a task is, which may explain why stimulants improve performance of a boring task in normal healthy individuals as well as in ADHD individuals [3, 4] and why unmedicated children with ADHD are able to perform properly when the task is salient to them [2].

Acronyms

ADHD

attention-deficit/hyperactivity disorder

DAT

dopamine transporter

DA

dopamine

MPH

methylphenidate

NE

norepinephrine

PET

positron emission tomography

References

Contents

1 Positron Emission Tomography Studies

The positron emission tomography (PET) imaging method has been very popular for studying the effects of methylphenidate (MPH) in the human brain, examining the amount of drug in the brain, its distribution, its binding to the dopamine transporter (DAT) and different dopamine (DA) receptors using various radioactive ligands, depending on the study. PET imaging limits the collection of data between 30 s and 60 s intervals, far slower than the rapid millisecond time-course of nerve-impulse-associated release of DA. Therefore, the PET image reflects the time-averaged result of the competition between endogenous DA and the [¹¹C]ligand [4]. Thus, the PET data represent the average net effect of elevated extracellular DA arising from an increase in the resting level of DA as well as in the pulsatile release of DA.

Surprisingly, it is still debated whether DA activity is enhanced or depressed in individuals with attention-deficit/hyperactivity disorder (ADHD). Many of biological theories of ADHD suggest that the disorder is associated with abnormally high levels of DAT density, prompted by studies evaluating small samples of ADHD adults [2, 3]. These studies suggested the hypothesis that high DAT density would accelerate reuptake of synaptic DA and create a DA deficit. In one of the largest studies so far, Spencer [5] evaluated unmedicated ADHD adults and reported striatal binding potential was 2 SD above the mean for the control group, indicating high endogenous expression of DAT.

Some studies, however, suggest the reverse. In a series of PET studies using the radioligands [¹¹C]raclopride and [¹¹C]cocaine, Volkow et al. [12] assessed the density of DAT and DA D2/D3 receptors in the striatum of stimulant-naïve adults with ADHD. Individual differences in MPH-induced increases in synaptic DA were not related to individual differences in DAT density [11], suggesting that variability in DA release rather than the DA reuptake may be a primary factor contributing to a DA deficit in the ADHD brain and the manifestations of deficits in attention. Volkow et al. [13] found lower DAT and D2/D3 receptor density in the nucleus accumbens (NAcc) as well as the caudate nucleus. In a long-term treatment study of MPH [14], DAT density was assessed in a set of ADHD patients before and after 1 year of MPH treatment, with a 24 h washout to avoid the confusion of DAT density with DAT occupancy by MPH. A formerly decreased DAT density at study start was now increased in the same individuals, suggesting that neuroplasticity may operate in a homeostatic way to maintain DA levels in a narrow range: in response to high synaptic DA that results from blockade of DAT by clinical oral doses of MPH [9, 11], DAT density may increase and be a consequence of the DA agonist effect of MPH. This may contribute to acute tolerance [6, 8, 10, 11] and possibly long-term tolerance [1, 7] to clinical doses of stimulant medications.

Acronyms

ADHD

attention-deficit/hyperactivity disorder

DAT

dopamine transporter

DA

dopamine

MPH

methylphenidate

NAcc

nucleus accumbens

PET

positron emission tomography

References

Contents

1 MRI and fMRI Studies

A single dose of methylphenidate (MPH) in attention-deficit/hyperactivity disorder (ADHD) subjects upregulates and normalizes the underfunctioning of the dorsomedial frontal cortex, left inferior frontal cortex, posterior cingulate, and parietal regions that in concert play an important role in error processing [1]. In a cognitive task, during error trials, ADHD boys treated with placebo compared with healthy control subjects showed significant underactivation in this error processing and performance monitoring network [1]. However, with MPH treatment, brain activation differences between control subjects and ADHD patients were no longer observed [1]. The normalization of ADHD dysfunction in these key regions of performance monitoring reinforce the association between dopaminergic neurotransmission abnormalities, ADHD, and poor performance monitoring and may underlie the behavioral effects of improving attention and school performance in boys with ADHD [1].

Regularly prescribed, clinically effective stimulant medications alter ADHD brain activity during a working memory fMRI task by increasing the magnitude of some frontoparietal networks’ activity and changing regional functional connectivity across the brain [3]. Insofar as increased connectivity reflects enhanced interregional communication, this indicates that the net effect of psychostimulants is to facilitate neurotransmission through long-distance connections between widespread brain regions [3].

For two different cognitive tasks, studying verbal working memory and verbal attention, MPH increased brain activation in ‘dorsal attention network’ areas, and increased deactivation of some ‘default mode network’ areas. Overall, the MPH treated group had increased activation and increased deactivation in brain regions that were moderately activated/deactivated in controls, suggesting that MPH enhanced the BOLD responses similarly for the verbal working memory and verbal attention tasks over control subjects. However, there were no differences in performance accuracy between the control and MPH group [2].

Acronyms

ADHD

attention-deficit/hyperactivity disorder

MPH

methylphenidate

References

Contents

1 How minimal?

Historically, when the term Minimal Brain Damage was in use, it meant brain damage that could not at that time be detected on current scanning technology, nor even in post-mortem gross anatomy examination. Modern brain imaging studies now detect the presence of abnormalities in structure (smaller size) and function (hypoactivation) of critical brain regions related to dopamine (DA) in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD) [13].

2 Specific Deficits

Lou [8] and Volpe [14] suggest an excitotoxicity hypothesis to explain how ‘minimal brain damage’ may not be detected by earlier brain imaging techniques: the damage might preferentially affect late-developing granular cells and other interneurons and pathologically reduce the population of neurons that will later differentiate into specific brain structures. Thus, the morphology of the structure and overall brain will be normal, but smaller. The striatum was specifically highlighted because it is rich in dopaminergic synapses, is vulnerable to perinatal hypoxic complications, and if damaged, produces hyperactivity and poor inhibitory control [8].

This hypothesis has gained further support with modern structural and functional neuroimaging studies showing ADHD subjects to have small volume reductions in frontal–subcortical regions [5, 11]. This is consistent with studies of brain anatomy of children with ADHD, which reported a 5 % reduction in overall cerebral volume [3].

Jin et al. [6] used neuroimaging in medication-naïve ADHD children, and suggests that 20 % to 25 % of neurons in the globus pallidus had died or were severely dysfunctional, and reported a mild hyperactivity of the cholinergic system in the striatum. Other reports implicate reductions in specific areas of the prefrontal cortex, basal ganglia, cerebellum, and corpus callosum [9, 11, 12], some of which are outside the frontal–subcortical circuits, but are involved in coordinating activities of multiple brain regions.

3 Mild Abnormalities of Anatomy and Activity

This hypothesis also fits a curious pattern observed in follow-up studies of premature infants by Krägeloh-Mann et al. [7]: A 5 year follow up of a cohort of babies born prematurely and had MRI performed at time of birth found a correlation between later incidence of ADHD-like symptoms and more mild abnormalities in the neonate MRI. Damage to a frontal–subcortical network important for coordinating motivation and cognition in decision-making processes, like learning from mistakes and delaying gratification to maximize short- and long-term benefits of choices [1] may lead ADHD sufferers to have dysfunctional responses to reward and punishment [2], including severe delay aversion [10].

Functional MRI studies have found frontal hypoactivity affecting the anterior cingulate, dorsolateral, and inferior prefrontal cortex, portions of parietal cortex, basal ganglia, and thalamus [4]. Recent studies have shown disruptions in ADHD affect not only the activity in these brain regions, but also the way in which they connect with one another to form networks [11].

Acronyms

ADHD

attention-deficit/hyperactivity disorder

DA

dopamine

References