Understanding Disorders of Attention

Amphetamine-Induced Dopamine Release and Neurocognitive Function in Treatment-Naive Adults With ADHD

Cherkasova MV, Faridi N, Casey KF, et al
Neuropsychopharmacology. 2013 Dec 30. [Epub ahead of print]

Attentional Disorders

Disorders of attention can be conceptualized as disorders of ineffective frontal lobe processing of incoming stimuli.^[1] Parts of the frontal-subcortical circuits involved in executive function, reward, and motivation have been targeted in functional MRI studies of attentional disorders, yielding consistent patterns of abnormal frontal-striatal activation.^[2]

The dopaminergic system in particular has been consistently linked to attentional and cognitive processing abnormalities.^[3] In many cases, impulsivity is strongly associated with impaired attention and attention-deficit/hyperactivity disorder (ADHD) traits.^[4]

In psychiatry, strict use of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), in making a diagnosis leads more often than not to the inclusion of different diagnoses under axis IV that may share common symptoms. If the DSM symptom criteria are strictly followed, the triad of inattention, impulsivity, and cognitive impairment can certainly be observed in disorders as phenomenologically separate as major depression, schizophrenia, bipolar disorder, and substance dependence.^[5]

Brief Study Description

This commentary is based on a double-blind randomized study of 2 matched groups: 15 male patients with ADHD and 18 healthy male controls. Standard DSM-IV criteria were used to diagnose ADHD. The 2 main design points of the study involved use of 2 PET scans and administration of neuropsychological tests to both groups. PET was done with [¹¹C]raclopride, a radiolabeled synthetic compound that antagonizes the dopamine receptor, in the study groups before and after lactate infusion and amphetamine administration.

The main goal of this study was to further elucidate the neurochemical and structural abnormalities within the basal ganglia (the corpus striatum in particular) of the dopamine system indirectly, via measurement of binding to dopamine 2 and 3 (D2/D3) receptors. The investigators quantified the D2/D3 binding potential by measuring the difference in binding of raclopride vs dopamine; dopamine levels are expected to increase after amphetamine infusion. They included within their regions of interest the following areas of functional striatum: ventral striatum (called "limbic striatum" in the article), caudate (associative striatum [AST]), and putamen (sensorimotor striatum [SMST]).

Dopamine dysfunction -- in this case, less of it -- should in theory lead to greater availability of empty receptor space. This can be measured indirectly by receptor binding competition between [¹¹C]raclopride and dopamine, the latter of which is increased or stimulated by amphetamines.

The investigators also administered 2 neuropsychological tests commonly used for ADHD patients: the antisaccade task and the stop-signal reaction-time task. In general, the more errors made on these tests, the more impulsivity is understood to exist.

The investigators found the following:

• The percent elevation in antisaccade errors was associated with increased binding potential in the AST and SMST of patients in the ADHD group

• The percent elevation in anticipatory saccades was associated with increased binding potential in the AST and SMST in patients with ADHD.

• The stop-signal reaction time was elevated in the ADHD group vs the control group, in association with increased binding potential in the AST and SMST.

The investigators describe their results as the ADHD group having a more robust d-amphetamine-induced decrease in striatal [¹¹C]raclopride binding, which was accompanied by poorer performance on inhibition tests. On the basis of their results, they conclude that the ADHD group with poor inhibition has greater availability of dopaminergic receptor binding sites (in this case, the D2/D3 receptors). They also speculate that the change in receptor binding potential might be related to an increase in phasic (cyclic vs tonic, or more constant dopamine release) striatal dopamine transmission.

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