What does molecular imaging reveal about the causes of ADHD and the potential for better management?

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common pediatric psychiatric dis­orders, occurring in approximately 5% of children.¹ The disorder persists into adulthood in about one-half of those who are affected in childhood.² In adults and children, diagnosis continues to be based on the examiner’s subjec­tive assessment. (Box 1^3-9 describes how ADHD presents a compli­cated, moving target for the diagnostician.)

Patients who have ADHD are rarely studied with imag­ing; there are no established imaging findings associated with an ADHD diagnosis. Over the past 20 years, however, significant research has shown that molecular alterations along the dopaminergic−frontostriatal pathways occur in association with the behavioral constellation of ADHD symptoms—suggesting a pathophysiologic mechanism for this disorder.

In this article, we describe molecular findings from nuclear medicine imaging in ADHD. We also summarize imaging evidence for dysfunction of the dopaminergic-frontostriatal neural circuits as central in the pathophysiol­ogy of ADHD, with special focus on the dopamine reuptake transporter (DaT). Box 2^10,11 reviews our key observations and looks at the future of imaging in the management of ADHD.

Dopaminergic theory of ADHD
The executive functions that are disordered in ADHD (impulse control, judgment, main­taining attention) are thought to be centered in the infraorbital, dorsolateral, and medial frontal lobes. Neurotransmitters that have been implicated in the pathophysiology of ADHD include norepinephrine¹² and dopa­mine¹³; medications that selectively block reuptake of these neurotransmitters are used to treat ADHD.^14,15 Only the dopamine system has been extensively evaluated with molecular imaging techniques.

Because methylphenidate, a potent selec­tive dopamine reuptake inhibitor, has been shown to reduce disordered executive func­tional behaviors in ADHD, considerable imaging research has focused on the dopa­minergic neural circuits in the frontostriatal regions of the brain. The dopaminergic the­ory of ADHD is based on the hypothesis that alterations in the density or function of these circuits are responsible for behaviors that constitute ADHD.

Despite decades of efforts to delineate the underlying pathophysiology and neu­rochemistry of ADHD, no single unifying theory accounts for all imaging findings in all patients. This might be in part because of imprecision inherent in psychiatric diag­noses that are based on subjective observa­tions. The behavioral criteria for ADHD can manifest in several disorders. For example, anxiety-related symptoms seen in post­traumatic stress disorder, social anxiety disorder, and panic disorder also present as behaviors similar to those in ADHD diag­nostic criteria.

Molecular imaging might provide a window into the underlying pathophysiol­ogy of ADHD and, by identifying objective findings, (1) allow for patient stratification based on underlying physiologic subtypes, (2) refine diagnostic criteria, and (3) predict treatment response.

Nuclear medicine findings
In general, nuclear medicine investiga­tions of ADHD can be divided into studies of changes in regional cerebral blood flow (rCBF) or glucose metabolism (rCGM) and those that have assessed the concentration of synaptic structures, using highly specific radiolabeled ligands. Both kinds of studies provide limited anatomic resolution, unless co-registered with MRI or CT scans and either single photon emission computed tomography (SPECT) or positron emission tomography (PET).

Synaptic imaging using radiolabeled ligands with high biologic specificity for synaptic structures has high molecular resolution—that is, radiolabeled ligands used for selective imaging of the dopamine transporter or receptor do not identify sero­tonin transporters or receptors, and vice versa. (Details of SPECT and PET tech­niques are beyond the scope of this article but can be found in standard nuclear medi­cine textbooks.)

SPECT and PET of rCBF
Early investigations of rCBF in ADHD were performed using inhaled radioactive xenon-133 gas.¹⁶ Later, rCBF was assessed using fat-soluble radiolabeled ligands that rapidly distribute in the brain in proportion to blood flow by crossing the blood−brain barrier. Labeled with radioactive 99m-technetium, these ligands cross rapidly into brain cells after IV injection. Once intracellular, cova­lent bonds within the ligands cleave into 2 charged particles that do not easily recross the cell membrane. There is little redistribu­tion of tracer after initial uptake.

The imaging data set that results can be reconstructed as (1) surface images, on which defects indicate areas of reduced rCBF, or (2) tomographic slices on which color scales indicate relative rCBF values (Figure 1). Because of the minimal redistribution of the tracer, SPECT images obtained 1 or 2 hours after injection provide a snapshot of rCBF at the time tracer is injected. Patients can be injected under various conditions, such as at rest with eyes and ears open in a dimly lit, quiet room, and then under cognitive stress (Figure 2), such as performing a computer-based attention and impulse con­trol task, or during stimulant treatment.

Numerous investigators have found reduced frontal or striatal rCBF, or both, in patients with ADHD, unilaterally on the right¹⁷ or left,^18,19 or bilaterally.²⁰ Additionally, with stimulant therapy, normalization of striatal and frontal rCBF has been demon­strated^14,19—changes that correlate with reso­lution of behavioral symptoms of ADHD with stimulant treatment.²¹

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

Only limited conclusions can be drawn about the role of DaT levels in ADHD, given the small number of patients studied in pub­lished reports. In addition, the Fusar-Poli meta-analysis has come under strong criti­cism because of methodological errors with improper patient inclusion and characteriza­tion of treatment status,³⁷ calling into question the investigators’ conclusions.

Does the DaT level hold promise for practice? Despite a lack of clarity about the significance of DaT level in the etiology of ADHD, knowledge of a patient’s level might prove useful in predicting which patients will respond to methylphenidate. Namely, several researchers have found that:
   • an elevated baseline level of DaT (before stimulant therapy) correlates with robust clinical response
   • absence of an elevated baseline DaT level suggests that symptomatic improvement with stimulant therapy in unlikely.^38-40

Dresel et al³⁸ evaluated 17 drug-naïve adults, newly diagnosed with ADHD, using 99m-technetium TRODAT SPECT before and after methylphenidate therapy. They found a 15% increase in specific DaT binding in patients with ADHD, compared with con­trols, at baseline. After treatment, the research­ers observed a 28% reduction in specific DaT binding—a significant change from baseline that correlated with behavioral response.

Study: SPECT in 18 adults with ADHD given methylphenidate. Krause³⁹ used the same SPECT agent to study 18 adults before they received methylphenidate and 10 weeks after treatment. Participants were categorized as responders or nonresponders based on clinical assessment of ADHD symptoms after those 10 weeks. All 12 responders had an elevated striatal DaT concentration at baseline. Of the 6 nonresponders, 5 had a normal level of striatal DaT compared with age-matched controls.

Study: 22 Adult ADHD patients evalu­ated with 99m-technetium TRODAT SPECT. The same group of investigators⁴⁰ presented imaging findings in 22 additional adult patients. Seventeen had an elevated striatal DaT level, 16 of whom responded to stimulant therapy. The remaining 5 patients had reduced striatal DaT at base­line; none had a good clinical response to methylphenidate.

The positive clinical response to methylphenidate in 67%³⁷ and 77%⁴⁰ of patients is in good agreement with results from larger studies, which reported that approximately 75% of patients with ADHD show prompt clinical improvement with stimulants.⁴¹ Improvement might be related to an increase in functioning of the frontostriatal dopami­nergic circuit that is seen with stimulant therapy. Increased availability of dopamine at the synapse, resulting from stimulant blockade of the dopamine reuptake trans­porter, produces increased dopamine neu­rotransmission and increased activation of frontostriatal circuits.

In another study, rCBF in frontostriatal circuits was determined to be inversely proportional to DaT density; rCBF normalized with stimulant therapy.⁴²

Will imaging pave the way for therapeu­tic stratification? Baseline determinations of striatal DaT concentration with SPECT imaging might make it possible to stratify patients with ADHD symptoms into those likely to show significant behavioral symp­tom response to methylphenidate and those who are not likely to respond. There might be an objective imaging finding—striatal DaT density—that allows clinicians to dis­tinguish stimulant-responsive ADHD from stimulant-unresponsive ADHD.

Dopamine substrate imaging
Radiolabeled dopa (carbon-11 or fluorine-18) is transported into presynaptic dopaminer­gic neurons in the striatum, where it is decar­boxylated, converted to radio-dopamine, and stored within vesicles until released in response to neuronal excitation. Semi-quantitative assessment is achieved with calculation of specific (striatal) to nonspecific (background) uptake ratios. Increased val­ues are thought to indicate increased density of dopaminergic neurons.⁴³

Ernst et al⁴⁴ reported a 50% decrease in specific fluorine-18 dopa uptake in the left prefrontal cortex in 17 drug-naïve adults with ADHD, compared with 23 controls. The same team reported increased midbrain fluorine-18 dopa levels in 10 adolescents with ADHD—48% higher, overall, than what was seen in 10 controls.⁴³ They hypoth­esized that these opposite results were the results of a reduction in the dopaminergic neuronal density in adults, which might be part of the natural history of ADHD, or a normal age-related reduction in neuronal density, or both. Increased dopa levels in the team’s adolescent group were hypothesized to reflect up-regulation in dopamine syn­thesis due to low synaptic dopamine con­centrations that might result from increased dopamine reuptake.

Dopamine-receptor imaging
The 5 distinct dopamine receptors (D1, D2, D3, D4, and D5) can be grouped into 2 subtypes, based on their coupling with G proteins. D1 and D5 constitute a group; D2, D3, and D4, a second group.

The D1 receptor is the most common dopamine receptor in the brain and is widely distributed in the striatum and pre­frontal cerebral cortex. D1 receptor knock­out mice demonstrate hyperactivity and poorer performance on learning tasks and are used as an animal model for ADHD.⁴⁵ D1 has been imaged using C-11 SCH 23390 PET⁴⁶ in rats, but its role in ADHD has yet to be evaluated. D5 is the most recently cloned and most widely distributed of the known dopamine receptors; however, there are no imaging studies of the D5 receptor.¹³

D2 receptors are present in presynaptic and postsynaptic neurons⁴⁷ in the neocor­tex, substantia nigra, nucleus accumbens, and olfactory tubercle, as well as in other structures.⁴⁸ Presynaptic D2 receptors act as autoregulators, inhibiting dopaminergic synthesis, firing rate, and release.⁴⁹

Using C-11 raclopride PET imaging, Lou et al⁵⁰ reported high D2/3 receptor availabil­ity in adolescents who had a history of peri­natal cerebral ischemia. They found that this availability is associated with an increase in the severity of ADHD symptoms. They pro­posed that the increase in “empty” receptor density might have been caused by perinatal ischemia-induced presynaptic dopaminer­gic neuronal loss or an increase in presynap­tic dopamine reuptake (Figure 5⁵⁰). Either mechanism could result in up-regulation in postsynaptic D2/3 receptors.

Volkow et al⁵¹ reported that D2 receptor density correlated with methylphenidate-induced changes in rCBF in frontal and tem­poral lobes in humans. They postulated that the variable therapeutic effects of methyl­phenidate seen in ADHD patients might be related to variations in baseline D2 receptor availability.

Lou et al⁵⁰ reported elevated D2 recep­tor density, demonstrated using carbon-11 raclopride, in children with ADHD, com­pared with normal adults.

Further support for a relationship between D2-receptor density and symptom­atic improvement with methylphenidate in ADHD was presented by Ilgin et al⁵² using iodine-123 iodobenzamide SPECT. They found elevated D2 receptor levels in 9 drug-naïve children with ADHD, which is 20% to 60% above what is seen in unaffected chil­dren. They noted that these patients showed improvement in hyperactivity when treated with methylphenidate.

In a similar study of 20 drug-naïve adults, Volkow et al⁵³ found that durable symptom­atic improvement with methylphenidate therapy was associated with increased D2 receptor availability.

Summing up
Striatal DaT is the most likely synaptic tar­get for stratifying patients with ADHD, now that a dopamine transporter imaging agent is available commercially. Stratification might allow for refinement in the diagnostic categorization of ADHD, with introduction of stimulant-responsive and stimulant-unresponsive subtypes that are based on DaT imaging findings.

Bottom Line
Given recent advances showing molecular alterations in the dopaminergic-frontostriatal pathway as central to attention-deficit/hyperactivity disorder, molecular imaging might be useful as an objective study for diagnosis.

Related Resources
• Schweitzer JB, Lee DO, Hanford RB, et al. A positron emis­sion tomography study of methylphenidate in adults with ADHD: alterations in resting blood flow and predict­ing treatment response. Neuropsychopharmacology. 2003;28(5):967-973.
• Raz A. Brain imaging data of ADHD. Psychiatric Times. http://www.psychiatrictimes.com/adhd/brain-imaging-data-adhd.

Drug Brand Names
Iodine-123 ioflupane • Methylphenidate • Ritalin DaTscan

Acknowledgment
Kylee M. L. Unsdorfer, a medical student at Northeast Ohio Medical University, helped prepare the manuscript of this article.

Disclosures
Dr. Thacker reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Binkovitz received 4 doses of ioflupane I123I (DaTscan) from General Electric for investigator-initiated research, used for animal imaging in 2012.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common pediatric psychiatric dis­orders, occurring in approximately 5% of children.¹ The disorder persists into adulthood in about one-half of those who are affected in childhood.² In adults and children, diagnosis continues to be based on the examiner’s subjec­tive assessment. (Box 1^3-9 describes how ADHD presents a compli­cated, moving target for the diagnostician.)

Patients who have ADHD are rarely studied with imag­ing; there are no established imaging findings associated with an ADHD diagnosis. Over the past 20 years, however, significant research has shown that molecular alterations along the dopaminergic−frontostriatal pathways occur in association with the behavioral constellation of ADHD symptoms—suggesting a pathophysiologic mechanism for this disorder.

In this article, we describe molecular findings from nuclear medicine imaging in ADHD. We also summarize imaging evidence for dysfunction of the dopaminergic-frontostriatal neural circuits as central in the pathophysiol­ogy of ADHD, with special focus on the dopamine reuptake transporter (DaT). Box 2^10,11 reviews our key observations and looks at the future of imaging in the management of ADHD.

Dopaminergic theory of ADHD
The executive functions that are disordered in ADHD (impulse control, judgment, main­taining attention) are thought to be centered in the infraorbital, dorsolateral, and medial frontal lobes. Neurotransmitters that have been implicated in the pathophysiology of ADHD include norepinephrine¹² and dopa­mine¹³; medications that selectively block reuptake of these neurotransmitters are used to treat ADHD.^14,15 Only the dopamine system has been extensively evaluated with molecular imaging techniques.

Because methylphenidate, a potent selec­tive dopamine reuptake inhibitor, has been shown to reduce disordered executive func­tional behaviors in ADHD, considerable imaging research has focused on the dopa­minergic neural circuits in the frontostriatal regions of the brain. The dopaminergic the­ory of ADHD is based on the hypothesis that alterations in the density or function of these circuits are responsible for behaviors that constitute ADHD.

Despite decades of efforts to delineate the underlying pathophysiology and neu­rochemistry of ADHD, no single unifying theory accounts for all imaging findings in all patients. This might be in part because of imprecision inherent in psychiatric diag­noses that are based on subjective observa­tions. The behavioral criteria for ADHD can manifest in several disorders. For example, anxiety-related symptoms seen in post­traumatic stress disorder, social anxiety disorder, and panic disorder also present as behaviors similar to those in ADHD diag­nostic criteria.

Molecular imaging might provide a window into the underlying pathophysiol­ogy of ADHD and, by identifying objective findings, (1) allow for patient stratification based on underlying physiologic subtypes, (2) refine diagnostic criteria, and (3) predict treatment response.

Nuclear medicine findings
In general, nuclear medicine investiga­tions of ADHD can be divided into studies of changes in regional cerebral blood flow (rCBF) or glucose metabolism (rCGM) and those that have assessed the concentration of synaptic structures, using highly specific radiolabeled ligands. Both kinds of studies provide limited anatomic resolution, unless co-registered with MRI or CT scans and either single photon emission computed tomography (SPECT) or positron emission tomography (PET).

Synaptic imaging using radiolabeled ligands with high biologic specificity for synaptic structures has high molecular resolution—that is, radiolabeled ligands used for selective imaging of the dopamine transporter or receptor do not identify sero­tonin transporters or receptors, and vice versa. (Details of SPECT and PET tech­niques are beyond the scope of this article but can be found in standard nuclear medi­cine textbooks.)

SPECT and PET of rCBF
Early investigations of rCBF in ADHD were performed using inhaled radioactive xenon-133 gas.¹⁶ Later, rCBF was assessed using fat-soluble radiolabeled ligands that rapidly distribute in the brain in proportion to blood flow by crossing the blood−brain barrier. Labeled with radioactive 99m-technetium, these ligands cross rapidly into brain cells after IV injection. Once intracellular, cova­lent bonds within the ligands cleave into 2 charged particles that do not easily recross the cell membrane. There is little redistribu­tion of tracer after initial uptake.

The imaging data set that results can be reconstructed as (1) surface images, on which defects indicate areas of reduced rCBF, or (2) tomographic slices on which color scales indicate relative rCBF values (Figure 1). Because of the minimal redistribution of the tracer, SPECT images obtained 1 or 2 hours after injection provide a snapshot of rCBF at the time tracer is injected. Patients can be injected under various conditions, such as at rest with eyes and ears open in a dimly lit, quiet room, and then under cognitive stress (Figure 2), such as performing a computer-based attention and impulse con­trol task, or during stimulant treatment.

Numerous investigators have found reduced frontal or striatal rCBF, or both, in patients with ADHD, unilaterally on the right¹⁷ or left,^18,19 or bilaterally.²⁰ Additionally, with stimulant therapy, normalization of striatal and frontal rCBF has been demon­strated^14,19—changes that correlate with reso­lution of behavioral symptoms of ADHD with stimulant treatment.²¹

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

Only limited conclusions can be drawn about the role of DaT levels in ADHD, given the small number of patients studied in pub­lished reports. In addition, the Fusar-Poli meta-analysis has come under strong criti­cism because of methodological errors with improper patient inclusion and characteriza­tion of treatment status,³⁷ calling into question the investigators’ conclusions.

Does the DaT level hold promise for practice? Despite a lack of clarity about the significance of DaT level in the etiology of ADHD, knowledge of a patient’s level might prove useful in predicting which patients will respond to methylphenidate. Namely, several researchers have found that:
   • an elevated baseline level of DaT (before stimulant therapy) correlates with robust clinical response
   • absence of an elevated baseline DaT level suggests that symptomatic improvement with stimulant therapy in unlikely.^38-40

Dresel et al³⁸ evaluated 17 drug-naïve adults, newly diagnosed with ADHD, using 99m-technetium TRODAT SPECT before and after methylphenidate therapy. They found a 15% increase in specific DaT binding in patients with ADHD, compared with con­trols, at baseline. After treatment, the research­ers observed a 28% reduction in specific DaT binding—a significant change from baseline that correlated with behavioral response.

Study: SPECT in 18 adults with ADHD given methylphenidate. Krause³⁹ used the same SPECT agent to study 18 adults before they received methylphenidate and 10 weeks after treatment. Participants were categorized as responders or nonresponders based on clinical assessment of ADHD symptoms after those 10 weeks. All 12 responders had an elevated striatal DaT concentration at baseline. Of the 6 nonresponders, 5 had a normal level of striatal DaT compared with age-matched controls.

Study: 22 Adult ADHD patients evalu­ated with 99m-technetium TRODAT SPECT. The same group of investigators⁴⁰ presented imaging findings in 22 additional adult patients. Seventeen had an elevated striatal DaT level, 16 of whom responded to stimulant therapy. The remaining 5 patients had reduced striatal DaT at base­line; none had a good clinical response to methylphenidate.

The positive clinical response to methylphenidate in 67%³⁷ and 77%⁴⁰ of patients is in good agreement with results from larger studies, which reported that approximately 75% of patients with ADHD show prompt clinical improvement with stimulants.⁴¹ Improvement might be related to an increase in functioning of the frontostriatal dopami­nergic circuit that is seen with stimulant therapy. Increased availability of dopamine at the synapse, resulting from stimulant blockade of the dopamine reuptake trans­porter, produces increased dopamine neu­rotransmission and increased activation of frontostriatal circuits.

In another study, rCBF in frontostriatal circuits was determined to be inversely proportional to DaT density; rCBF normalized with stimulant therapy.⁴²

Will imaging pave the way for therapeu­tic stratification? Baseline determinations of striatal DaT concentration with SPECT imaging might make it possible to stratify patients with ADHD symptoms into those likely to show significant behavioral symp­tom response to methylphenidate and those who are not likely to respond. There might be an objective imaging finding—striatal DaT density—that allows clinicians to dis­tinguish stimulant-responsive ADHD from stimulant-unresponsive ADHD.

Dopamine substrate imaging
Radiolabeled dopa (carbon-11 or fluorine-18) is transported into presynaptic dopaminer­gic neurons in the striatum, where it is decar­boxylated, converted to radio-dopamine, and stored within vesicles until released in response to neuronal excitation. Semi-quantitative assessment is achieved with calculation of specific (striatal) to nonspecific (background) uptake ratios. Increased val­ues are thought to indicate increased density of dopaminergic neurons.⁴³

Ernst et al⁴⁴ reported a 50% decrease in specific fluorine-18 dopa uptake in the left prefrontal cortex in 17 drug-naïve adults with ADHD, compared with 23 controls. The same team reported increased midbrain fluorine-18 dopa levels in 10 adolescents with ADHD—48% higher, overall, than what was seen in 10 controls.⁴³ They hypoth­esized that these opposite results were the results of a reduction in the dopaminergic neuronal density in adults, which might be part of the natural history of ADHD, or a normal age-related reduction in neuronal density, or both. Increased dopa levels in the team’s adolescent group were hypothesized to reflect up-regulation in dopamine syn­thesis due to low synaptic dopamine con­centrations that might result from increased dopamine reuptake.

Dopamine-receptor imaging
The 5 distinct dopamine receptors (D1, D2, D3, D4, and D5) can be grouped into 2 subtypes, based on their coupling with G proteins. D1 and D5 constitute a group; D2, D3, and D4, a second group.

The D1 receptor is the most common dopamine receptor in the brain and is widely distributed in the striatum and pre­frontal cerebral cortex. D1 receptor knock­out mice demonstrate hyperactivity and poorer performance on learning tasks and are used as an animal model for ADHD.⁴⁵ D1 has been imaged using C-11 SCH 23390 PET⁴⁶ in rats, but its role in ADHD has yet to be evaluated. D5 is the most recently cloned and most widely distributed of the known dopamine receptors; however, there are no imaging studies of the D5 receptor.¹³

D2 receptors are present in presynaptic and postsynaptic neurons⁴⁷ in the neocor­tex, substantia nigra, nucleus accumbens, and olfactory tubercle, as well as in other structures.⁴⁸ Presynaptic D2 receptors act as autoregulators, inhibiting dopaminergic synthesis, firing rate, and release.⁴⁹

Using C-11 raclopride PET imaging, Lou et al⁵⁰ reported high D2/3 receptor availabil­ity in adolescents who had a history of peri­natal cerebral ischemia. They found that this availability is associated with an increase in the severity of ADHD symptoms. They pro­posed that the increase in “empty” receptor density might have been caused by perinatal ischemia-induced presynaptic dopaminer­gic neuronal loss or an increase in presynap­tic dopamine reuptake (Figure 5⁵⁰). Either mechanism could result in up-regulation in postsynaptic D2/3 receptors.

Volkow et al⁵¹ reported that D2 receptor density correlated with methylphenidate-induced changes in rCBF in frontal and tem­poral lobes in humans. They postulated that the variable therapeutic effects of methyl­phenidate seen in ADHD patients might be related to variations in baseline D2 receptor availability.

Lou et al⁵⁰ reported elevated D2 recep­tor density, demonstrated using carbon-11 raclopride, in children with ADHD, com­pared with normal adults.

Further support for a relationship between D2-receptor density and symptom­atic improvement with methylphenidate in ADHD was presented by Ilgin et al⁵² using iodine-123 iodobenzamide SPECT. They found elevated D2 receptor levels in 9 drug-naïve children with ADHD, which is 20% to 60% above what is seen in unaffected chil­dren. They noted that these patients showed improvement in hyperactivity when treated with methylphenidate.

In a similar study of 20 drug-naïve adults, Volkow et al⁵³ found that durable symptom­atic improvement with methylphenidate therapy was associated with increased D2 receptor availability.

Summing up
Striatal DaT is the most likely synaptic tar­get for stratifying patients with ADHD, now that a dopamine transporter imaging agent is available commercially. Stratification might allow for refinement in the diagnostic categorization of ADHD, with introduction of stimulant-responsive and stimulant-unresponsive subtypes that are based on DaT imaging findings.

Bottom Line
Given recent advances showing molecular alterations in the dopaminergic-frontostriatal pathway as central to attention-deficit/hyperactivity disorder, molecular imaging might be useful as an objective study for diagnosis.

Related Resources
• Schweitzer JB, Lee DO, Hanford RB, et al. A positron emis­sion tomography study of methylphenidate in adults with ADHD: alterations in resting blood flow and predict­ing treatment response. Neuropsychopharmacology. 2003;28(5):967-973.
• Raz A. Brain imaging data of ADHD. Psychiatric Times. http://www.psychiatrictimes.com/adhd/brain-imaging-data-adhd.

Drug Brand Names
Iodine-123 ioflupane • Methylphenidate • Ritalin DaTscan

Acknowledgment
Kylee M. L. Unsdorfer, a medical student at Northeast Ohio Medical University, helped prepare the manuscript of this article.

Disclosures
Dr. Thacker reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Binkovitz received 4 doses of ioflupane I123I (DaTscan) from General Electric for investigator-initiated research, used for animal imaging in 2012.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common pediatric psychiatric dis­orders, occurring in approximately 5% of children.¹ The disorder persists into adulthood in about one-half of those who are affected in childhood.² In adults and children, diagnosis continues to be based on the examiner’s subjec­tive assessment. (Box 1^3-9 describes how ADHD presents a compli­cated, moving target for the diagnostician.)

Patients who have ADHD are rarely studied with imag­ing; there are no established imaging findings associated with an ADHD diagnosis. Over the past 20 years, however, significant research has shown that molecular alterations along the dopaminergic−frontostriatal pathways occur in association with the behavioral constellation of ADHD symptoms—suggesting a pathophysiologic mechanism for this disorder.

In this article, we describe molecular findings from nuclear medicine imaging in ADHD. We also summarize imaging evidence for dysfunction of the dopaminergic-frontostriatal neural circuits as central in the pathophysiol­ogy of ADHD, with special focus on the dopamine reuptake transporter (DaT). Box 2^10,11 reviews our key observations and looks at the future of imaging in the management of ADHD.

Dopaminergic theory of ADHD
The executive functions that are disordered in ADHD (impulse control, judgment, main­taining attention) are thought to be centered in the infraorbital, dorsolateral, and medial frontal lobes. Neurotransmitters that have been implicated in the pathophysiology of ADHD include norepinephrine¹² and dopa­mine¹³; medications that selectively block reuptake of these neurotransmitters are used to treat ADHD.^14,15 Only the dopamine system has been extensively evaluated with molecular imaging techniques.

Because methylphenidate, a potent selec­tive dopamine reuptake inhibitor, has been shown to reduce disordered executive func­tional behaviors in ADHD, considerable imaging research has focused on the dopa­minergic neural circuits in the frontostriatal regions of the brain. The dopaminergic the­ory of ADHD is based on the hypothesis that alterations in the density or function of these circuits are responsible for behaviors that constitute ADHD.

Despite decades of efforts to delineate the underlying pathophysiology and neu­rochemistry of ADHD, no single unifying theory accounts for all imaging findings in all patients. This might be in part because of imprecision inherent in psychiatric diag­noses that are based on subjective observa­tions. The behavioral criteria for ADHD can manifest in several disorders. For example, anxiety-related symptoms seen in post­traumatic stress disorder, social anxiety disorder, and panic disorder also present as behaviors similar to those in ADHD diag­nostic criteria.

Molecular imaging might provide a window into the underlying pathophysiol­ogy of ADHD and, by identifying objective findings, (1) allow for patient stratification based on underlying physiologic subtypes, (2) refine diagnostic criteria, and (3) predict treatment response.

Nuclear medicine findings
In general, nuclear medicine investiga­tions of ADHD can be divided into studies of changes in regional cerebral blood flow (rCBF) or glucose metabolism (rCGM) and those that have assessed the concentration of synaptic structures, using highly specific radiolabeled ligands. Both kinds of studies provide limited anatomic resolution, unless co-registered with MRI or CT scans and either single photon emission computed tomography (SPECT) or positron emission tomography (PET).

Synaptic imaging using radiolabeled ligands with high biologic specificity for synaptic structures has high molecular resolution—that is, radiolabeled ligands used for selective imaging of the dopamine transporter or receptor do not identify sero­tonin transporters or receptors, and vice versa. (Details of SPECT and PET tech­niques are beyond the scope of this article but can be found in standard nuclear medi­cine textbooks.)

SPECT and PET of rCBF
Early investigations of rCBF in ADHD were performed using inhaled radioactive xenon-133 gas.¹⁶ Later, rCBF was assessed using fat-soluble radiolabeled ligands that rapidly distribute in the brain in proportion to blood flow by crossing the blood−brain barrier. Labeled with radioactive 99m-technetium, these ligands cross rapidly into brain cells after IV injection. Once intracellular, cova­lent bonds within the ligands cleave into 2 charged particles that do not easily recross the cell membrane. There is little redistribu­tion of tracer after initial uptake.

The imaging data set that results can be reconstructed as (1) surface images, on which defects indicate areas of reduced rCBF, or (2) tomographic slices on which color scales indicate relative rCBF values (Figure 1). Because of the minimal redistribution of the tracer, SPECT images obtained 1 or 2 hours after injection provide a snapshot of rCBF at the time tracer is injected. Patients can be injected under various conditions, such as at rest with eyes and ears open in a dimly lit, quiet room, and then under cognitive stress (Figure 2), such as performing a computer-based attention and impulse con­trol task, or during stimulant treatment.

Numerous investigators have found reduced frontal or striatal rCBF, or both, in patients with ADHD, unilaterally on the right¹⁷ or left,^18,19 or bilaterally.²⁰ Additionally, with stimulant therapy, normalization of striatal and frontal rCBF has been demon­strated^14,19—changes that correlate with reso­lution of behavioral symptoms of ADHD with stimulant treatment.²¹

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

Only limited conclusions can be drawn about the role of DaT levels in ADHD, given the small number of patients studied in pub­lished reports. In addition, the Fusar-Poli meta-analysis has come under strong criti­cism because of methodological errors with improper patient inclusion and characteriza­tion of treatment status,³⁷ calling into question the investigators’ conclusions.

Does the DaT level hold promise for practice? Despite a lack of clarity about the significance of DaT level in the etiology of ADHD, knowledge of a patient’s level might prove useful in predicting which patients will respond to methylphenidate. Namely, several researchers have found that:
   • an elevated baseline level of DaT (before stimulant therapy) correlates with robust clinical response
   • absence of an elevated baseline DaT level suggests that symptomatic improvement with stimulant therapy in unlikely.^38-40

Dresel et al³⁸ evaluated 17 drug-naïve adults, newly diagnosed with ADHD, using 99m-technetium TRODAT SPECT before and after methylphenidate therapy. They found a 15% increase in specific DaT binding in patients with ADHD, compared with con­trols, at baseline. After treatment, the research­ers observed a 28% reduction in specific DaT binding—a significant change from baseline that correlated with behavioral response.

Study: SPECT in 18 adults with ADHD given methylphenidate. Krause³⁹ used the same SPECT agent to study 18 adults before they received methylphenidate and 10 weeks after treatment. Participants were categorized as responders or nonresponders based on clinical assessment of ADHD symptoms after those 10 weeks. All 12 responders had an elevated striatal DaT concentration at baseline. Of the 6 nonresponders, 5 had a normal level of striatal DaT compared with age-matched controls.

Study: 22 Adult ADHD patients evalu­ated with 99m-technetium TRODAT SPECT. The same group of investigators⁴⁰ presented imaging findings in 22 additional adult patients. Seventeen had an elevated striatal DaT level, 16 of whom responded to stimulant therapy. The remaining 5 patients had reduced striatal DaT at base­line; none had a good clinical response to methylphenidate.

The positive clinical response to methylphenidate in 67%³⁷ and 77%⁴⁰ of patients is in good agreement with results from larger studies, which reported that approximately 75% of patients with ADHD show prompt clinical improvement with stimulants.⁴¹ Improvement might be related to an increase in functioning of the frontostriatal dopami­nergic circuit that is seen with stimulant therapy. Increased availability of dopamine at the synapse, resulting from stimulant blockade of the dopamine reuptake trans­porter, produces increased dopamine neu­rotransmission and increased activation of frontostriatal circuits.

In another study, rCBF in frontostriatal circuits was determined to be inversely proportional to DaT density; rCBF normalized with stimulant therapy.⁴²

Will imaging pave the way for therapeu­tic stratification? Baseline determinations of striatal DaT concentration with SPECT imaging might make it possible to stratify patients with ADHD symptoms into those likely to show significant behavioral symp­tom response to methylphenidate and those who are not likely to respond. There might be an objective imaging finding—striatal DaT density—that allows clinicians to dis­tinguish stimulant-responsive ADHD from stimulant-unresponsive ADHD.

Dopamine substrate imaging
Radiolabeled dopa (carbon-11 or fluorine-18) is transported into presynaptic dopaminer­gic neurons in the striatum, where it is decar­boxylated, converted to radio-dopamine, and stored within vesicles until released in response to neuronal excitation. Semi-quantitative assessment is achieved with calculation of specific (striatal) to nonspecific (background) uptake ratios. Increased val­ues are thought to indicate increased density of dopaminergic neurons.⁴³

Ernst et al⁴⁴ reported a 50% decrease in specific fluorine-18 dopa uptake in the left prefrontal cortex in 17 drug-naïve adults with ADHD, compared with 23 controls. The same team reported increased midbrain fluorine-18 dopa levels in 10 adolescents with ADHD—48% higher, overall, than what was seen in 10 controls.⁴³ They hypoth­esized that these opposite results were the results of a reduction in the dopaminergic neuronal density in adults, which might be part of the natural history of ADHD, or a normal age-related reduction in neuronal density, or both. Increased dopa levels in the team’s adolescent group were hypothesized to reflect up-regulation in dopamine syn­thesis due to low synaptic dopamine con­centrations that might result from increased dopamine reuptake.

Dopamine-receptor imaging
The 5 distinct dopamine receptors (D1, D2, D3, D4, and D5) can be grouped into 2 subtypes, based on their coupling with G proteins. D1 and D5 constitute a group; D2, D3, and D4, a second group.

The D1 receptor is the most common dopamine receptor in the brain and is widely distributed in the striatum and pre­frontal cerebral cortex. D1 receptor knock­out mice demonstrate hyperactivity and poorer performance on learning tasks and are used as an animal model for ADHD.⁴⁵ D1 has been imaged using C-11 SCH 23390 PET⁴⁶ in rats, but its role in ADHD has yet to be evaluated. D5 is the most recently cloned and most widely distributed of the known dopamine receptors; however, there are no imaging studies of the D5 receptor.¹³

D2 receptors are present in presynaptic and postsynaptic neurons⁴⁷ in the neocor­tex, substantia nigra, nucleus accumbens, and olfactory tubercle, as well as in other structures.⁴⁸ Presynaptic D2 receptors act as autoregulators, inhibiting dopaminergic synthesis, firing rate, and release.⁴⁹

Using C-11 raclopride PET imaging, Lou et al⁵⁰ reported high D2/3 receptor availabil­ity in adolescents who had a history of peri­natal cerebral ischemia. They found that this availability is associated with an increase in the severity of ADHD symptoms. They pro­posed that the increase in “empty” receptor density might have been caused by perinatal ischemia-induced presynaptic dopaminer­gic neuronal loss or an increase in presynap­tic dopamine reuptake (Figure 5⁵⁰). Either mechanism could result in up-regulation in postsynaptic D2/3 receptors.

Volkow et al⁵¹ reported that D2 receptor density correlated with methylphenidate-induced changes in rCBF in frontal and tem­poral lobes in humans. They postulated that the variable therapeutic effects of methyl­phenidate seen in ADHD patients might be related to variations in baseline D2 receptor availability.

Lou et al⁵⁰ reported elevated D2 recep­tor density, demonstrated using carbon-11 raclopride, in children with ADHD, com­pared with normal adults.

Further support for a relationship between D2-receptor density and symptom­atic improvement with methylphenidate in ADHD was presented by Ilgin et al⁵² using iodine-123 iodobenzamide SPECT. They found elevated D2 receptor levels in 9 drug-naïve children with ADHD, which is 20% to 60% above what is seen in unaffected chil­dren. They noted that these patients showed improvement in hyperactivity when treated with methylphenidate.

In a similar study of 20 drug-naïve adults, Volkow et al⁵³ found that durable symptom­atic improvement with methylphenidate therapy was associated with increased D2 receptor availability.

Summing up
Striatal DaT is the most likely synaptic tar­get for stratifying patients with ADHD, now that a dopamine transporter imaging agent is available commercially. Stratification might allow for refinement in the diagnostic categorization of ADHD, with introduction of stimulant-responsive and stimulant-unresponsive subtypes that are based on DaT imaging findings.

Bottom Line
Given recent advances showing molecular alterations in the dopaminergic-frontostriatal pathway as central to attention-deficit/hyperactivity disorder, molecular imaging might be useful as an objective study for diagnosis.

Related Resources
• Schweitzer JB, Lee DO, Hanford RB, et al. A positron emis­sion tomography study of methylphenidate in adults with ADHD: alterations in resting blood flow and predict­ing treatment response. Neuropsychopharmacology. 2003;28(5):967-973.
• Raz A. Brain imaging data of ADHD. Psychiatric Times. http://www.psychiatrictimes.com/adhd/brain-imaging-data-adhd.

Drug Brand Names
Iodine-123 ioflupane • Methylphenidate • Ritalin DaTscan

Acknowledgment
Kylee M. L. Unsdorfer, a medical student at Northeast Ohio Medical University, helped prepare the manuscript of this article.

Disclosures
Dr. Thacker reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Binkovitz received 4 doses of ioflupane I123I (DaTscan) from General Electric for investigator-initiated research, used for animal imaging in 2012.