SPECT of 32 boys with previously untreated ADHD. Kim et al21 found that the presence of reduced right or left, or both, frontal rCBF, which normalized with 8 weeks of stimulant therapy, predicted symptom improvement in 85% of patients. Absence of improvement of reduced frontal rCBF had a 75% negative predictive value for treatment response. (Additionally, hyperperfusion of the somatosensory cortex has been demonstrated in children with ADHD,16,22 suggesting increased responsiveness to extraneous environmental input.)
SPECT of 40 untreated pediatric patients compared with 17 age-matched controls. Using SPECT, Lee et al23 reported rCBF reductions in the orbitofrontal cortex and the medial temporal gyrus of participants; reductions corresponded to areas of motor and impulsivity control. The researchers also demonstrated increased rCBF in the somatosensory area.
After methylphenidate treatment, blood flow to these areas normalized, and rCBF to higher visual and superior prefrontal areas decreased. Substantial clinical improvement occurred in 64% of patients—suggesting methylphenidate treatment of ADHD works by (1) increasing function of areas of the brain that control impulses, motor activity, and attention, and (2) reducing function to sensory areas that lead to distraction by extraneous environmental sensory input.
O-15-labeled water PET of 10 adults with ADHD. Schweitzer et al24 found that participants who demonstrated improvement in behavioral symptoms with chronic stimulant therapy had reduced rCBF in the striata at baseline—again, suggesting that baseline hypometabolism in the striata is associated with ADHD.
PET of regional cerebral glucose metabolism
Cerebral metabolism requires a constant supply of glucose; regional differences in cerebral glucose metabolism can be assessed directly with positron-emitting F-18-fluoro-2-deoxyglucose. Although metabolically inert, this agent is transported intracellularly similar to glucose; once phosphorylated within brain cells, however, it can no longer undergo further metabolism or redistribution.
Studies using PET to assess rCGM were some of the earliest molecular imaging applications in ADHD. Zametkin et al25 reported low global cerebral glucose utilization in adults, but not adolescents,26 with ADHD. However, further study, with normalization of the PET data, confirmed reduced rCGM in the left prefrontal cortex in both adolescents26 and adults,27 indicating hypometabolism of cortical areas associated with impulse control and attention in ADHD. In adolescents, symptom severity was inversely related to rCBF in the left anterior frontal cortex.
Synaptic imaging
Nuclear imaging has been used to study several components of the striatal dopaminergic synapse, including:
• dopamine substrates, using fluorine- 18-labeled dopa or carbon-11-labeled dopa
• dopamine receptors, using carbon- 11-labeled raclopride or iodine-123 iodobenzamide
• the tDaT, using iodine-123 ioflupane, 99m-technetium TRODAT, or carbon-11 cocaine (Figure 3).
All of these synaptic imaging agents were used mainly as research tools until 2011, when the FDA approved the SPECT imaging agent iodine-123 ioflupane (DaTscan) for clinical use in assessment of Parkinson’s disease.28 This commercially available agent has high specificity for the DaT, with little background activity noted on SPECT imaging (Figure 4).
Dopamine transporter imaging
Because the site of action of methylphenidate is the DaT, imaging this component of the striatal dopaminergic synapse has been an area of intense investigation in ADHD. Located almost exclusively in the striata, DaT reduces synaptic concentrations of dopamine by means of reuptake channels in the cell membrane.29 By reversibly binding to, and occupying sites on, the DaT, methylphenidate impedes dopamine reuptake, which results in increased availability of dopamine at the synapse.30
By demonstrating an increase in striatal DaT density in patients with ADHD— first reported by Dougherty et al31 using iodine-123 altropane (a dopaminergic uptake inhibitor) in 6 adults with ADHD—investigators have hypothesized that excessive expression of the DaT protein in the striata, which may result from genetic or environmental factors, is a central causative agent of ADHD.32 Subsequent studies, however, have yielded contradictory findings: Hesse et al,33 using SPECT imaging, and Volkow et al,34 using carbon-11 cocaine PET imaging, found reduced DaT density in, respectively, 9 and 26 patients with ADHD.
To clarify the role of DaT levels in the etiology of ADHD and to explain discrepant results, Fusar-Poli et al35 performed a meta-analysis of 9 published papers that reported the results of DaT imaging in a total of 169 ADHD patients and 129 controls. They noted that these studies included 6 different imaging agents and protocols. Patients were stimulant therapy-naïve (n = 137) or drug-free (refrained from stimulant therapy for a time [n = 32]). The team found that the degree of elevation of the striatal DaT concentration correlated with a history of stimulant exposure, and that the drug-naïve group had a reduced DaT level.
Fusar-Poli’s hypothesis? Elevated DaT levels result from up-regulation in the presence of chronic methylphenidate therapy, which accounts for early reports that demonstrated increased striatal DaT density. Clinically, up-regulation might explain the lack of sustained relief of behavioral symptoms with stimulant therapy in 20% of patients with ADHD who showed clinical improvement initially.36