CLINICAL FOCUS

Primary Psychiatry. 2009;16(7):47-54

The Neurobiological Basis of Attention-Deficit/Hyperactivity Disorder Amy F.T. Arnsten, PhD, Craig W. Berridge, PhD, and James T. McCracken, MD

ABSTRACT

FOCUS POINTS

Attention-deficit/hyperactivity disorder (ADHD) is a common childhood-

• The prefrontal cortex (PFC) regulates attention and behavior; lesions to the PFC induce a profile of poor sustained attention, distractibility, impulsivity, disorganization, and poor planning. • Functional and structural imaging studies of subjects with attention-deficit/hyperactivity disorder (ADHD) reveal differences in prefrontal cortical circuits and poor performance on PFC tasks. • PFC function is robustly moderated by catecholamines— high or low levels of norepinephrine-engaging postsynaptic α2A adrenoceptors and dopamine-engaging D1 receptors are associated with reduced function. • ADHD is highly heritable. Genetic studies suggest that several genes involved in catecholamine signaling may confer a portion of risk for ADHD, including some genes that have been associated with poor sustained attention and reduced executive functions. • Most pharmacologic treatments for ADHD influence catecholamine neurotransmission. Therapeutic doses of stimulants increase norepinephrine and dopamine in key cortical regions that are presumed to lead to improved PFC function.

onset neuropsychiatric disorder characterized by cardinal features of inattention, locomotor hyperactivity, and poor impulse control. Research indicates that ADHD is associated with alterations in the higher cortical circuits that mediate attention and behavioral control. Given the prominent role of the prefrontal association cortex in regulating cognition and behavior through its extensive connections to sensory and motor cortices as well as subcortical structures, impairments in prefrontal function are believed to underlie many of the behavioral features of ADHD. Prefrontal cortex is sensitively modulated by numerous neurotransmitters including catecholamines, and changes in levels of dopamine-1 and norepinephrine α2A-adrenoceptor stimulation are associated with prominent effects on prefrontal function. Effective treatments for ADHD (including stimulants, atomoxetine, and guanfacine) influence catecholamine signaling in the prefrontal cortex and are believed to ameliorate ADHD symptoms via their effects on improved prefrontal cortical regulation of attention and impulse control.

by inattention, poor impulse control, and hyperactivity. Recent advances in molecular and cognitive neuroscience are beginning to clarify how dysfunction in brain regions regulating higher-order processes may underlie many of the core features of ADHD. These prefrontal association regions regulate atten-

INTRODUCTION Attention-deficit/hyperactivity disorder (ADHD) is a prevalent childhood-onset neuropsychiatric disorder characterized

Dr. Arnsten is professor in the Department of Neurobiology at the Yale University School of Medicine in New Haven, Connecticut. Dr. Berridge is professor in the Department of Psychology at the University of Wisconsin in Madison. Dr. McCracken is professor in the Division of Child and Adolescent Psychiatry, Neuropsychiatric Institute, and David Geffen School of Medicine at the University of California, Los Angeles. Disclosures: Dr. Arnsten has a licensing agreement with Shire Development Inc for the development of guanfacine for the treatment of attention-deficit/hyperactivity disorder. She has received research funding from Shire, as well as performed scientific advisory, consulting, and speaking engagements with Shire. Dr. Berridge receives honoraria from Shire and research/grant support from the National Institutes of Health and the University of Wisconsin Graduate School. Dr. McCracken has served as a consultant to sanofi-aventis and Wyeth, is an expert witness for Novopharm, and receives research support from Eli Lilly. This article was supported by Shire Development, Inc, in Wayne, Pennsylvania. Off-label disclosure: This article includes discussion of the following experimental medications for attention-deficit/hyperactivity disorder: immediate release forms of clonidine and guanfacine. Acknowledgments: Editorial assistance was provided by Jennifer Steeber, PhD, of Health Learning Systems in Parsippany, New Jersey. The authors did not receive financial reimbursement for preparation of this article. This article was prepared by the authors with minimal editorial assistance and all ideas conveyed in this article represent those of the authors. Please direct all correspondence to: Amy F.T. Arnsten, PhD, Yale Medical School, Department of Neurobiology, PO Box 208001, New Haven, CT 06520-8001; Tel: 203-785-4431; Fax: 203-785-5263; E-mail: [email protected].

Primary Psychiatry

© MBL Communications Inc.

47

July 2009

A.F.T. Arnsten, C.W. Berridge J.T. McCracken

tion, impulse control, and cognitive and behavioral responses to various situations and stimuli. In particular, the right prefrontal cortex (PFC), which is essential for inhibiting inappropriate impulses,1 demonstrates structural and functional differences in imaging studies of subjects with ADHD.2 It is well established that prefrontal cortical function is tightly influenced by catecholamines, including norepinephrine (NE) and dopamine (DA),3 with a prominent dose-response relationship. Awareness of the small, but perhaps significant, role of several purported catecholamine genes as risk alleles for ADHD, and initial demonstrations of reduced dopamine release from in vivo studies,3,4 have contributed to continued hypotheses of catecholamine dysfunction in ADHD. Furthermore, the role of catecholamine dysfunction has found additional support from the mechanism of many ADHD treatments, since most medications that effectively treat ADHD affect catecholamine transmission in the PFC.5 These treatments are viewed as enhancing prefrontal cortical regulation of attention and behavior, thereby ameliorating ADHD symptoms.5 Key elements of this increasingly cohesive story are reviewed here.

Temporal Association Cortices The temporal association cortices process visual and auditory information—the inferior regions are devoted to visual processing and the superior regions mediate auditory processing. Extensive research on the visual cortices has shown that the processing of visual stimuli proceeds as a “ventral stream” of information from the primary visual cortex in the occipital lobe through progressive levels of analyses by the inferior temporal cortices. Damage to the inferior temporal cortices in both hemispheres can result in agnosia, an inability to recognize and attach meaning to sensory information.9 Physiologic recordings of neuronal activity in monkeys support the importance of this cortical region in visual recognition, and distinct columns of neurons are devoted to specific stimulus features (eg, a face in profile versus a face in full view).12 Interestingly, repeated exposure to the same visual stimulus leads to gradual attenuation of the physiologic response such as seen with neuronal firing patterns,13 which may relate to the physiologic challenge of sustaining attention under conditions of low novelty or salience. Interference from nearby stimuli in the same visual field also

THE ASSOCIATION CORTICES CONTROL AND COORDINATE DIFFERENT ASPECTS OF ATTENTION

FIGURE 1

THE PREFRONTAL CORTEX EXERTS “TOP-DOWN” REGULATION OF ATTENTION AND BEHAVIOR

Characterizing the nature of impaired attention in ADHD has been a challenging problem for many years, in large part due to the varieties of attentional and cognitive processes impacted in ADHD, a lack of specificity in characterizing ADHD symptoms, and the difficulties inherent in isolating components of attention or cognitive control in experimental paradigms.6,7 The diagnostic term “inattention” can be confusing because it can describe several aspects of impaired attention. In the context of ADHD, inattention usually means inadequate regulation of attention—ADHD patients are easily distracted and find it hard to pay attention for long periods, and their attention is easily disrupted by stimuli that would not be bothersome to people without ADHD. However, inattention may also describe difficulty perceiving items or events that would normally demand attention (such as an oncoming car) even when there are no competing stimuli to draw attention away. This pattern of impairment implies an inability to properly allocate attentional resources. These different aspects of attention are mediated by distinct, but interconnected, regions of the association cortices (Figure 1). The temporal and parietal association cortices are responsible for so-called “bottom-up” attention processes, which are allocated based on the salience of the stimulus, eg, whether it is moving or brightly colored.8 In contrast, the prefrontal association cortices are responsible for so-called “top-down” attention, which is allocated based on relevance to a task at hand and internal goals.9-11 Primary Psychiatry

© MBL Communications Inc.

The prefrontal cortex regulates attention and behavior. The prefrontal cortex inhibits processing of distracting stimuli and enhances processing of relevant stimuli through extensive projections to the sensory cortices. The right inferior prefrontal cortex is especially important for inhibiting inappropriate responses. These inhibitory abilities likely involve projections to the premotor and motor cortices, and subcortical structures such as the striatum and subthalamic nucleus, and cerebellar cortices by way of the pontine nuclei. These extensive projections allow the prefrontal cortex to orchestrate behavior and attention in a thoughtful manner. Arnsten AFT, Berridge CW, McCracken JT. Primary Psychiatry. Vol 16, No 7. 2009.

48

July 2009

The Neurobiological Basis of Attention-Deficit/Hyperactivity Disorder

diminishes processing of visual stimuli, perhaps reflecting the behavioral phenomenon of distraction.10 Although these two suppressive mechanisms arise from intrinsic properties of inferior temporal neurons, they can be overridden by inputs from the PFC via “top-down” projections that allow for directed selective attention of visual feature processing.

and to the cerebellum (by way of the pons).28 In humans, the right inferior PFC is particularly important for behavioral inhibition29; functional imaging studies reveal activity in the right inferior PFC when subjects successfully inhibit or stop movements.30 A fascinating recent study31 in normal subjects showed that weakened cortical function induced by transmagnetic stimulation over the right inferior PFC actually impaired the ability to inhibit prepotent motor responses. Not surprisingly, lesions to this area in humans lead to poor impulse control.29

Parietal Association Cortices A second “dorsal stream” of visual data proceeds from the primary visual cortex up into the parietal cortex, and is responsible for orienting attention in space and time.14 This pathway is devoted to analysis of movement,15 mapping spatial position,16 and allocating and orienting conscious attentional resources.17 In humans, the posterior right hemisphere of the parietal cortex allocates attention to parts of visual space, and lesions to this region result in contralateral neglect: the loss of awareness for the left side of visual space.9 Thus, this cortex contributes to the ability to “pay” attention. Interconnections between the temporal and parietal cortices permit the fusion of visual perceptions regarding position and features of a stimulus, providing a person with a cohesive, conscious experience.18,19 The temporal and parietal cortices also project information about visual features and spatial positions forward to the prefrontal cortices, which are the most highly evolved portions of the human brain.

THE PREFRONTAL CORTEX REQUIRES OPTIMAL LEVELS OF NOREPINEPHRINE AND DOPAMINE FOR PROPER FUNCTION As shown in Figure 2,5,32 NE and DA are important components of arousal systems that arise from the brainstem and project across the entire cortical mantle, including the prefrontal cortices.33 NE acts at α1, α2, and β adrenoceptors, with the highest affinity for α2 adrenoceptors. There are three subtypes of α2 adrenoceptors: α2A, α2B, and α2C.34 The most prominent DA receptors in the prefrontal cortices are the dopamine (D)1 receptor family, which includes D1 and D5 receptors. These receptors are very similar and there are currently no drugs that possess selective D1 versus D5 affinity (thus, in this review, D1 refers to both D1 and D5). A second DA receptor family, the D2 receptor family, includes the D2, D3, and D4 receptors. Importantly, the D4 receptor possesses greater non-specific roles in catecholaminergic neurotransmission, since both NE and DA have high binding affinity for this receptor.

Prefrontal Association Cortices The PFC regulates attention and thought through massive projections back to the temporal and parietal association cortices, ie, “top-down” attention.20 The PFC provides the ability to inhibit distractions and gate sensory inputs based on internal goals21,22; it also facilitates sustained attention (especially over long delays),23 and inhibits interference from irrelevant information.24 Taken together, these critical organizing and modulating functions subserved by the PFC make up what is referred to as “cognitive control.” Patients with prefrontal cortical lesions are easily distracted, have poor concentration and organization, have difficulty dividing or focusing attention, and are more vulnerable to disruption from interference, resembling many facets of the behavioral features of ADHD.25

Optimal Level of Norepinephrine and Dopamine The PFC requires an optimal level of NE and DA for proper function. Either too little (when we are drowsy) or too much (when we are stressed) markedly impairs prefrontal cortical regulation of behavior and thought (the so-called “inverted-U” dose-response relationship).35 Indeed, animal research has found that NE and DA depletion paradigms are associated with deficits of prefrontal cortical cognitive function as pronounced as removing the cortex itself.36 Given the non-linear nature of the NE/DA dose-response functions for the PFC, therapeutic strategies using agents modulating catecholaminergic regulation of cognition have evolved to consider achieving “optimal” NE and/or DA stimulation.

THE PREFRONTAL CORTEX IS KEY FOR BEHAVIORAL INHIBITION The PFC is also essential for regulating behavior; lesions in this region can induce locomotor hyperactivity and impulsive responses (eg, on go/no-go tasks).26,27 As shown schematically in Figure 1, the PFC is able to guide behavioral output via massive projections to the motor cortices, to basal ganglia structures (including the caudate and subthalamic nucleus), Primary Psychiatry

© MBL Communications Inc.

Receptor Actions The beneficial effects of optimal levels of NE and DA release occur primarily through actions at α2A and D1 receptors, respectively. NE has its beneficial actions at α2A

49

July 2009

A.F.T. Arnsten, C.W. Berridge J.T. McCracken

receptors that reside on prefrontal cortical neurons, postsynaptic to NE axons.37 Although previous research has emphasized the important role of presynaptic α2 receptors on NE neurons (which reduce NE cell firing and decrease NE release),38 it is now appreciated that there are massive numbers of postsynaptic α2A receptors as well,39 which are the sites of the enhancing effects of NE on prefrontal cortical function.37 Electron microscopic studies37,40 indicate that α2A and D1 receptors reside on separate dendritic spines on prefrontal cortical pyramidal cells, near synaptic inputs from other cortical cells. Stimulation of these receptors gates synaptic inputs to prefrontal neurons, with α2A adrenoceptor stimulation strengthening appropriate inputs, and D1 receptor stimulation weakening inappropriate inputs.35 Blockade of either the α2A or the D1 receptor dramatically impairs prefrontal cortical function.41,42 Recent studies43 in

humans indicate that catecholamines enable the right inferior PFC to carry out behavioral regulation. Consistent with this observation, blockade of α2 receptors in the monkey PFC induces a profile of locomotor hyperactivity,44 poor impulse control,45 and weakened working memory needed to overcome distractors.42 Thus, insufficient α2A receptor stimulation in PFC mimics the profile of ADHD. In contrast, α2A receptor stimulation with guanfacine enhances prefrontal activity and function.37,46,47 However, excessive release of the catecholamines NE and DA (eg, during stress) markedly impairs prefrontal cortical function.48 High levels of NE release impairs prefrontal function because NE begins to engage lower affinity α1 and β receptors,49,50 while high levels of DA release stimulates abnormally high numbers of D1 receptors.51 Excessive D1 or α1 receptor stimulation suppresses prefrontal cell firing.51,52

FIGURE 2

ADHD IS ASSOCIATED WITH IMPAIRED PREFRONTAL CORTICAL FUNCTION AND STRUCTURE

METHYLPHENIDATE INDUCES SIGNIFICANT INCREASES IN NOREPINEPHRINE AND DOPAMINE ACTIVITY IN THE PREFRONTAL CORTEX5,32

Structure/Function Studies Subjects with ADHD show deficits on tasks that depend on the PFC, including tests of cognitive control, such as working memory, sustained attention, and inhibitory control.29,53 Imaging studies of subjects with ADHD show small (≤5%) but consistently reduced volumes and reduced hemodynamic activation in response to challenges of the PFC2,54,55 that are particularly prominent on the right side, consistent with the important role of the right PFC in the regulation of behavior and attention.29 Reduced size also has been reported in brain regions that are components of prefrontal circuits, including the caudate and cerebellum.56 In addition, recent studies57,58 have reported disorganized white matter tracks emanating from PFC in subjects with ADHD, consistent with weaker prefrontal connectivity. In development, the PFC matures more slowly than less evolved brain regions, and there is preliminary evidence of slower prefrontal development in some subjects with ADHD.59 However clinically, ADHD is a lifelong disorder for many patients, and imaging studies continue to show evidence of atypical prefrontal function and reduced right prefrontal volume in adults with ADHD symptoms.60,61 The data described so far refer to patients with the combined subtype of ADHD, who have symptoms of both inattention and impulsivity/hyperactivity. There is some suggestion that a different neurobiologic basis may underlie the purely inattentive ADHD subtype. Research on the purely inattentive subtype of ADHD is in its early stages and may require evaluation tools that are better able to differentiate the

The prefrontal cortex receives noradrenergic inputs from the locus coeruleus in the pons, and dopaminergic inputs from the substantia nigra/ventral tegmental area complex in the midbrain. Administration of low, therapeutic doses of methylphenidate greatly increase NE and DA efflux in the rat PFC; note that NE release is much greater than DA release at doses that enhance prefrontal cognitive function.5 In contrast, these doses of methylphenidate have more subtle effects on subcortical (Subcort) catecholamine release,5 with only small increases in NE in the medial septal area and in DA in the nucleus accumbens core. The relatively small effects on DA in the nucleus accumbens likely explain why therapeutic doses of stimulants have little drug abuse liability and do not lead to sensitization in rodents.32 NE=norepinephrine; DA=dopamine; PFC=prefrontal cortex; D1=dopamine-1. Berridge CW, Devilbiss DM, Andrzejewski ME, et al. Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function. Biol Psychiatry. 2006;60(10):1111-1120. Adapted with permission from Elsevier. Copyright 2006. Arnsten AFT, Berridge CW, McCracken JT. Primary Psychiatry. Vol 16, No 7. 2009.

Primary Psychiatry

© MBL Communications Inc.

50

July 2009

The Neurobiological Basis of Attention-Deficit/Hyperactivity Disorder

aspects of attention that are mediated by the different association cortices. For example, the inattention rating scale from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,62 primarily assesses aspects of attention regulated by the PFC (distractibility, sustained attention) rather than those regulated by the temporal or parietal cortices. These issues may be very relevant to treatment, as the parietal and temporal association cortices are modulated differently than the prefrontal association cortices (eg, their functions are not improved by α2A-adrenoceptor stimulation).63

Stimulants Amphetamines and methylphenidate are highly effective in treating attentional problems and the hyperactive/impulsive symptoms associated with ADHD.72 Importantly, when administered at low and clinically relevant doses to normal human subjects, these drugs have cognition-enhancing and activity-reducing effects similar to the effects seen in ADHD patients.72,73 Thus, stimulant actions in ADHD are not paradoxical, as frequently presumed. Stimulants block the action of both catecholamine transporters, the NE transporter (NET), and the DA transporter (DAT). In the PFC, where DAT levels are low, the NET clears both NE and DA.74 Early biochemical studies of amphetamine and methylphenidate in rodents employed inappropriately high doses that increase locomotor activity, impair prefrontal cortical function, and have sensitizing effects on pathways involved with drug abuse. More recent studies5,32,75 using substantially lower and clinically relevant doses have demonstrated reduced locomotor activity and improved prefrontal cortical cognitive function in rats, similar to their effects in humans. The action of these therapeutic doses appears to be especially prominent in the PFC, where there is substantially increased NE and DA release. In contrast, the effect on catecholamine release is much less pronounced in subcortical or other cortical regions.5,32 As Figure 2 illustrates, therapeutic doses of stimulants increased NE release more than DA release in the rat PFC; it is therefore inaccurate to refer to these agents as simply dopaminergic.5 Consistent with dual actions on both NE and DA, the cognitive-enhancing effects of these agents in rodents are blocked by either NE α2 or D1 receptor antagonists.75 These data indicate that stimulants have their effects through stimulation of both NE α2 and D1 receptors.76 These results also provide supporting evidence for the assessment of low abuse potential of therapeutic doses of stimulants when properly administered.77 In contrast to the effects of low doses of stimulants, higher doses impair prefrontal cortical function in a way similar to that observed following uncontrollable stress,75 and are probably relevant to the cognitive inflexibility that can occur with excessive doses of stimulant medication.78 High doses of stimulants also increase dopamine levels in the nucleus accumbens, considered a key neurobiologic “pathway” underlying the process of reward and conditioning thought to lead to the potential for drug abuse.5,32 In normal young adult human subjects, imaging studies show that therapeutic doses of stimulants improve prefrontal cortical functions and enhance the efficiency of prefrontal cortical activity73; a similar but more pronounced profile is observed in subjects with ADHD.79-81 Taken together, these animal and human studies indicate that stimulant actions in ADHD are not paradoxical, but are instead more apparent in this patient population because of their impaired attentional processes and higher impulsivity/activity levels at baseline.72,82

Genetic Studies of ADHD ADHD is a highly heritable disorder, with estimates based on family and twin studies suggesting that risk attributable to genes may represent up to 60% to 70% of the overall risk for the disorder. Although many gene variants have been associated with increased risk of ADHD, to date the risk attributed to any one of the putative risk genes represents only a small fraction of the overall genetic liability.3 However, the putative risk genes are of interest with respect to treatment, as most involve genes encoding molecules involved in catecholamine signaling (eg, NE and DA receptors)64-67; NE and DA transporters64,65,68; and dopamine beta hydroxylase (DBH), the enzyme required for NE synthesis.65,69 For example, in one report, gene variants associated with differences in DBH activity are associated with reduced ability to regulate attention70 and with differences in executive functions.71 Such gene variants may be relevant to the mechanism of therapeutic benefit conferred by medications that affect or enhance NE actions at α2A adrenoceptors (see below). Nevertheless, many other putative risk genes involve genes unrelated to catecholamine synthesis and function, including some associations of gene variants of serotoninergic genes with ADHD risk.3 Despite some replications of association studies of ADHD for several risk genes, the contribution of any single gene to the development of ADHD symptoms appears to be small.

TREATMENTS FOR ADHD ENHANCE CATECHOLAMINE TRANSMISSION IN THE PREFRONTAL CORTEX Recent biochemical studies5 have revealed that therapeutic doses of both stimulant and nonstimulant medications potentiate catecholamine neurotransmission in the PFC. Speculation of the mechanisms of therapeutic benefit of these agents in ADHD includes the notion that treatment may optimize catecholamine neurotransmission in patients with genetically mediated differences in NE and DA pathways. Alternatively, they may optimize levels of catecholaminergic neurotransmission in a way that compensates for differences in PFC function not directly related to altered catecholaminergic tone. Primary Psychiatry

© MBL Communications Inc.

51

July 2009

A.F.T. Arnsten, C.W. Berridge J.T. McCracken

with tics.97 Clonidine also has been associated with the problematic side effects of prominent sedation and hypotension.96 Although clonidine and guanfacine have not been directly compared “head to head” in regard to efficacy in treating ADHD symptoms, they have been directly compared in regard to hypotensive and sedative properties. Clonidine is ~10 times more potent in lowering blood pressure than guanfacine, and is much more sedating than guanfacine in both human subjects98 and monkeys.99 Clonidine is less selective than guanfacine. It has high affinity for the α2B- and α2C-adrenoceptor subtypes as well as the α2A adrenoceptor,100 and also has high affinity for imidazoline I1 receptors.101 In addition, clonidine is 10 times more potent than guanfacine with regard to activity at presynaptic α2A adrenoreceptors.88 Since stimulation of α2B- and α2C-adrenoceptor subtypes may contribute to sedation,102,103 the nonselective profile and pronounced presynaptic activity of clonidine probably underlie its powerful sedating effects, while its activity at brainstem imidazoline I1 receptors is thought to contribute to its marked hypotensive actions.101 In summary, the stimulants and atomoxetine appear to have their therapeutic effects through indirect stimulation of prefrontal α2A and D1 receptors, while guanfacine and clonidine likely enhance prefrontal cortical regulation of behavior through direct stimulation of postsynaptic α2A adrenoceptors on prefrontal neurons.

Nonstimulants Atomoxetine selectively blocks the NET. However, it is important to note that the NET transports both NE and DA in the PFC; thus, atomoxetine has been shown to increase the levels of both catecholamines in the rat PFC.83 Preliminary data indicate that moderate doses of atomoxetine, like methylphenidate, improve prefrontal functions based on their activity at both NE α2 and D1 receptors, whereas higher doses can impair prefrontal function in some animals (AFT Arnsten, unpublished data, 2008). In addition, recent studies84 have shown that therapeutic doses of atomoxetine can strengthen performance on measures of response inhibition in normal controls as well as in subjects with ADHD. The therapeutic effect of atomoxetine is consistent with the ability of desipramine, a tricyclic antidepressant with high selectivity for the NET, to reduce ADHD-related symptoms.85 Guanfacine mimics the beneficial effects of NE at postsynaptic α2A adrenoceptors in PFC, strengthening regulation of attention and behavior.37 Animal studies46,86,87 have shown that acute guanfacine administration improves a wide range of prefrontal functions via direct actions within the PFC. Guanfacine strengthens synaptic inputs onto prefrontal neurons and enhances prefrontal network connectivity, thus improving prefrontal cortical regulation of attention and behavior.37 The beneficial effects of systemically administered guanfacine on prefrontal cortical function are independent of the drug’s sedating actions,25 which probably involve all three α2-adrenoceptor subtypes as well as presynaptic α2A adrenoceptors on NE cell bodies and terminals.34 It should be noted that guanfacine has a lower affinity for the presynaptic α2A adrenoceptors than does clonidine,88 and this likely contributes to its reduced liability for sedative side effects. Clinically, guanfacine is currently prescribed off-label to both children and adults with ADHD, and has been shown in one large-scale, double-blind, placebo-controlled clinical trial89 of children with ADHD to improve ratings on an ADHD inattention and hyperactivity/impulsivity scale. Two other smaller, placebo-controlled trials90,91 suggest clinically relevant improvements in ratings of ADHD behaviors in adults with ADHD and in children with ADHD and comorbid chronic tic disorders. Clinical guidelines for ADHD treatment suggest that guanfacine and clonidine may be especially helpful in ADHD patients who cannot tolerate stimulant medications because of tics, or who may have prominent aggressive symptoms or drug abuse liability.90 As with stimulants, guanfacine can improve PFC-dependent behavior in normal subjects,92,93 but it is far more effective in individuals with impaired prefrontal abilities.25,93 In addition, treatment with guanfacine extended release (SPD503; Shire Development, Inc, Wayne, PA) has shown benefits in subjects who showed suboptimal response to stimulants.94,95 Clonidine is a nonselective α2-adrenoceptor agonist that can improve symptoms of ADHD96 and ADHD comorbid Primary Psychiatry

© MBL Communications Inc.

CONCLUSION The PFC plays a crucial role in regulating attention and behavior. Differences in prefrontal cortical structure and function, including altered catecholamine transmission, likely contribute to the etiology of ADHD symptoms. The PFC requires optimal levels of catecholamines for proper function—moderate levels of NE-engaging postsynaptic α2A adrenoceptors and DA-stimulating D1 receptors. Effective treatments for ADHD may optimize catecholamine signaling in PFC; both stimulants and atomoxetine have their effects through indirect stimulation of NE α2 and D1 receptors, while guanfacine mimics NE actions at postsynaptic α2A adrenoceptors in PFC. All of these treatments improve prefrontal cortical regulation of attention and behavior, thus reducing ADHD symptoms. PP

REFERENCES 1. Robbins TW. Shifting and stopping: fronto-striatal substrates, neurochemical modulation and clinical implications. Philos Trans R Soc Lond B Biol Sci. 2007;362(1481):917-932. 2. Rubia K, Overmeyer S, Taylor E, et al. Hypofrontality in attention deficit hyperactivity disorder during higher-order motor control: a study with functional MRI. Am J Psychiatry. 1999;156(6):891-896. 3. Faraone SV, Perlis RH, Doyle AE, et al. Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005;57(11):1313-1323. 4. Volkow ND, Wang GJ, Newcorn J, et al. Depressed dopamine activity in caudate and preliminary evidence of limbic involvement in adults with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 2007;64(8):932-940. 5. Berridge CW, Devilbiss DM, Andrzejewski ME, et al. Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function. Biol Psychiatry. 2006;60(10):1111-1120.

52

July 2009

The Neurobiological Basis of Attention-Deficit/Hyperactivity Disorder

6. Nigg JT. Neuropsychologic theory and findings in attention-deficit/hyperactivity disorder: the state of the field and salient challenges for the coming decade. Biol Psychiatry. 2005;57(11):1424-1435. 7. Posner MI, Petersen SE. The attention system of the human brain. Annu Rev Neurosci. 1990;13:25-42. 8. Knudsen EI. Fundamental components of attention. Annu Rev Neurosci. 2007;30:57-78. 9. Mesulam MM. From sensation to cognition [review]. Brain. 1998;121(Pt 6):1013-1052. 10. Desimone R. Visual attention mediated by biased competition in extrastriate visual cortex. Philos Trans R Soc Lond B Biol Sci. 1998;353(1373):1245-1255. 11. Buschman TJ, Miller EK. Top-down versus bottom-up control of attention in the prefrontal and posterior parietal cortices. Science. 2007;315(5820):1860-1862. 12. Fujita I, Tanaka K, Ito M, Cheng K. Columns for visual features of objects in monkey inferotemporal cortex. Nature. 1992;360(6402):343-346. 13. Desimone R. Neural mechanisms for visual memory and their role in attention. Proc Natl Acad Sci USA. 1996;93(24):13494-13499. 14. Coull JT, Nobre AC. Where and when to pay attention: the neural systems for directing attention to spatial locations and to time intervals as revealed by both PET and fMRI. J Neurosci. 1998;18(18):7426-7435. 15. Rudolph K, Pasternak T. Transient and permanent deficits in motion perception after lesions of cortical areas MT and MST in the macaque monkey. Cereb Cortex. 1999;9(1):90-100. 16. Snyder LH, Grieve KL, Brotchie P, Andersen RA. Separate body- and world-referenced representations of visual space in parietal cortex. Nature. 1998;394(6696):887-891. 17. Crowe DA, Chafee MV, Averbeck BB, Georgopoulos AP. Neural activity in primate parietal area 7a related to spatial analysis of visual mazes. Cereb Cortex. 2004;14(1):23-34. 18. Ungerleider LA. The corticocortical pathways for object recognition and spatial perception. In: Chagas C, Gattass R, Gross C, eds. Pattern Recognition Mechanisms. Rome, Italy: The Pontifical Academy of Sciences; 1985:21-37. 19. Friedman-Hill SR, Robertson LC, Treisman A. Parietal contributions to visual feature binding: evidence from a patient with bilateral lesions. Science. 1995;269(5225):853-855. 20. Gazzaley A, Rissman J, Cooney J, et al. Functional interactions between prefrontal and visual association cortex contribute to top-down modulation of visual processing. Cereb Cortex. 2007;17(suppl 1):i125-i135. 21. Chao LL, Knight RT. Human prefrontal lesions increase distractibility to irrelevant sensory inputs. Neuroreport. 1995;6(12):1605-1610. 22. Moore T, Armstrong KM. Selective gating of visual signals by microstimulation of frontal cortex. Nature. 2003;421(6921):370-373. 23. Wilkins AJ, Shallice T, McCarthy R. Frontal lesions and sustained attention. Neuropsychologia. 1987;25(2):359-365. 24. Bunge SA, Ochsner KN, Desmond JE, Glover GH, Gabrieli JD. Prefrontal regions involved in keeping information in and out of mind. Brain. 2001;124(Pt 10):2074-2086. 25. Arnsten AF, Steere JC, Hunt RD. The contribution of α2-noradrenergic mechanisms to prefrontal cortical cognitive function. Potential significance for attention-deficit hyperactivity disorder. Arch Gen Psychiatry. 1996;53(5):448-455. 26. French GM. Locomotor effects of regional ablations of frontal cortex in rhesus monkeys. J Comp Physiol Psychol. 1959;52(1):18-24. 27. Drewe EA. Go - no go learning after frontal lobe lesions in humans. Cortex. 1975;11(1):8-16. 28. Middleton FA, Strick PL. Basal ganglia and cerebellar loops: motor and cognitive circuits. Brain Res Brain Res Rev. 2000;31(2-3):236-250. 29. Clark L, Blackwell AD, Aron AR, et al. Association between response inhibition and working memory in adult ADHD: a link to right frontal cortex pathology? Biol Psychiatry. 2007;61(12):1395-1401. 30. Aron AR, Robbins TW, Poldrack RA. Inhibition and the right inferior frontal cortex. Trends Cog Sci. 2004;8(4):170-177. 31. Chambers CD, Bellgrove MA, Stokes MG, et al. Executive “brake failure” following deactivation of human frontal lobe. J Cogn Neurosci. 2006;18(3):444-455. 32. Kuczenski R, Segal DS. Exposure of adolescent rats to oral methylphenidate: preferential effects on extracellular norepinephrine and absence of sensitization and cross-sensitization to methamphetamine. J Neurosci. 2002;22(16):7264-7271. 33. Lewis DA. The catecholamine innervation of primate cerebral cortex. In: Solanto MV, Arnsten AF, Castellanos FX, eds. Stimulant Drugs and ADHD: Basic and Clinical Neuroscience. New York, NY: Oxford University Press; 2001:77-103. 34. MacDonald E, Kobilka BK, Scheinin M. Gene targeting-homing in on alpha 2-adrenoceptor-subtype function. Trends Pharmacol Sci. 1997;18(6):211-219. 35. Arnsten AF. Catecholamine and second messenger influences on prefrontal cortical networks of “representational knowledge”: a rational bridge between genetics and the symptoms of mental illness. Cereb Cortex. 2007;17(suppl 1):i6-i15. 36. Brozoski TJ, Brown RM, Rosvold HE, Goldman PS. Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey. Science. 1979;205(4409):929-932. 37. Wang M, Ramos BP, Paspalas CD, et al. α2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell. 2007;129(2):397-410. 38. Cedarbaum JM, Aghajanian GK. Catecholamine receptors on locus coeruleus neurons: pharmacological characterization. Eur J Pharmacol. 1977;44(4):375-385. 39. U’Prichard DC, Bechtel WD, Rouot BM, Snyder SH. Multiple apparent alpha-noradrenergic receptor binding sites in rat brain: effect of 6-hydroxydopamine. Mol Pharmacol. 1979;16(1):47-60. 40. Smiley JF, Williams SM, Szigeti K, Goldman-Rakic PS. Light and electron microscopic characterization of dopamine-immunoreactive axons in human cerebral cortex. J Comp Neurol. 1992;321(3):325-335. 41. Sawaguchi T, Goldman-Rakic PS. D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science. 1991;251(4996):947-950. 42. Li BM, Mei ZT. Delayed-response deficit induced by local injection of the α2-adrenergic antagonist yohimbine into the dorsolateral prefrontal cortex in young adult monkeys. Behav Neural Biol. 1994;62(2):134-139. 43. Chamberlain SR, Muller U, Blackwell AD, Clark L, Robbins TW, Sahakian BJ. Neurochemical modulation of response inhibition and probabilistic learning in humans. Science. 2006;311(5762):861-863. 44. Ma CL, Arnsten AF, Li BM. Locomotor hyperactivity induced by blockade of prefrontal cortical α2-adrenoceptors in monkeys. Biol Psychiatry. 2005;57(2):192-195. 45. Ma CL, Qi XL, Peng JY, Li BM. Selective deficit in no-go performance induced by blockade of prefrontal cortical 2-adrenoceptors in monkeys. Neuroreport. 2003;14(7):1013-1016. 46. Avery RA, Franowicz JS, Studholme C, van Dyck CH, Arnsten AF. The alpha-2A-adrenoceptor agonist, guanfacine, increases regional cerebral blood flow in dorsolateral prefrontal cortex of monkeys performing a spatial working memory task. Neuropsychopharmacology. 2000;23(3):240-249.

Primary Psychiatry

© MBL Communications Inc.

47. O’Neill J, Fitten LJ, Siembieda DW, Ortiz F, Halgren E. Effects of guanfacine on three forms of distraction in the aging macaque. Life Sci. 2000;67(8):877-885. 48. Arnsten AF. The biology of being frazzled. Science. 1998;280(5370):1711-1712. 49. Birnbaum S, Gobeske KT, Auerbach J, Taylor JR, Arnsten AF. A role for norepinephrine in stress-induced cognitive deficits: α−1-adrenoceptor mediation in the prefrontal cortex. Biol Psychiatry. 1999;46(9):1266-1274. 50. Ramos BP, Colgan L, Nou E, Ovadia S, Wilson SR, Arnsten AF. The beta-1 adrenergic antagonist, betaxolol, improves working memory performance in rats and monkeys. Biol Psychiatry. 2005;58(11):894-900. 51. Vijayraghavan S, Wang M, Birnbaum SG, Williams GV, Arnsten AF. Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat Neurosci. 2007;10(3):376-384. 52. Birnbaum SG, Yuan PX, Wang M, et al. Protein kinase C overactivity impairs prefrontal cortical regulation of working memory. Science. 2004;306(5697):882-884. 53. Loo SK, Humphrey LA, Tapio T, et al. Executive functioning among Finnish adolescents with attentiondeficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(12):1594-1604. 54. Bush G, Valera EM, Seidman LJ. Functional neuroimaging of attention-deficit/hyperactivity disorder: a review and suggested future directions. Biol Psychiatry. 2005;57(11):1273-1284. 55. Sheridan MA, Hinshaw S, D’Esposito M. Efficiency of the prefrontal cortex during working memory in attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(10):1357-1366. 56. Castellanos FX, Lee PP, Sharp W, et al. Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder. JAMA. 2002;288(14):1740-1748. 57. Casey BJ, Epstein JN, Buhle J, et al. Frontostriatal connectivity and its role in cognitive control in parentchild dyads with ADHD. Am J Psychiatry. 2007;164(11):1729-1736. 58. Makris N, Buka SL, Biederman J, et al. Attention and executive systems abnormalities in adults with childhood ADHD: A DT-MRI Study of connections. Cereb Cortex. 2008;18(5):11210-11220. 59. Shaw P, Eckstrand K, Sharp W, et al. Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation. Proc Natl Acad Sci U S A. 2007;104(49):19649-19654. 60. Makris N, Biederman J, Valera EM, et al. Cortical thinning of the attention and executive function networks in adults with attention-deficit/hyperactivity disorder. Cereb Cortex. 2007;17(6):1364-1375. 61. Seidman LJ, Valera EM, Makris N, et al. Dorsolateral prefrontal and anterior cingulate cortex volumetric abnormalities in adults with attention-deficit/hyperactivity disorder identified by magnetic resonance imaging. Biol Psychiatry. 2006;60(10):1071-1080. 62. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: Americn Psychiatric Association; 2000. 63. Witte EA, Marrocco RT. Alteration of brain noradrenergic activity in rhesus monkeys affects the alerting component of covert orienting. Psychopharmacology (Berl). 1997;132(4):315-323. 64. Bobb AJ, Addington AM, Sidransky E, et al. Support for association between ADHD and two candidate genes: NET1 and DRD1. Am J Med Genet B Neuropsychiatr Genet. 2005;134(1):67-72. 65. Daly G, Hawi Z, Fitzgerald M, Gill M. Mapping susceptibility loci in attention deficit hyperactivity disorder: preferential transmission of parental alleles at DAT1, DBH and DRD5 to affected children. Mol Psychiatry. 1999;4(2):192-196. 66. Tahir E, Yazgan Y, Cirakoglu B, Ozbay F, Waldman I, Asherson PJ. Association and linkage of DRD4 and DRD5 with attention deficit hyperactivity disorder (ADHD) in a sample of Turkish children. Mol Psychiatry. 2000;5(4):396-404. 67. Kustanovich V, Ishii J, Crawford L, et al. Transmission disequilibrium testing of dopamine-related candidate gene polymorphisms in ADHD: confirmation of association of ADHD with DRD4 and DRD5. Mol Psychiatry. 2004;9(7):711-717. 68. Mill J, Caspi A, Williams BS, et al. Prediction of heterogeneity in intelligence and adult prognosis by genetic polymorphisms in the dopamine system among children with attention-deficit/hyperactivity disorder: evidence from 2 birth cohorts. Arch Gen Psychiatry. 2006;63(4):462-469. 69. Roman T, Schmitz M, Polanczyk GV, Eizirik M, Rohde LA, Hutz MH. Further evidence for the association between attention-deficit/hyperactivity disorder and the dopamine-beta-hydroxylase gene. Am J Med Genet. 2002;114(2):154-158. 70. Bellgrove MA, Hawi Z, Gill M, Robertson IH. The cognitive genetics of attention deficit hyperactivity disorder (ADHD): sustained attention as a candidate phenotype. Cortex. 2006;42(6):838-845. 71. Kieling C, Genro JP, Hutz MH, Rohde LA. The -1021 C/T DBH polymorphism is associated with neuropsychological performance among children and adolescents with ADHD. Am J Med Genet B Neuropsychiatr Genet. 2008;147B(4):485-490. 72. Rapoport JL, Inoff-Germain G. Responses to methylphenidate in attention-deficit/hyperactivity disorder and normal children: update 2002. J Atten Disord. 2002;6(suppl 1):S57-S60. 73. Mehta MA, Owen AM, Sahakian BJ, Mavaddat N, Pickard JD, Robbins TW. Methylphenidate enhances working memory by modulating discrete frontal and parietal lobe regions in the human brain. J Neurosci. 2000;20(6):RC65. 74. Sesack SR, Hawrylak VA, Matus C, Guido MA, Levey AI. Dopamine axon varicosities in the prelimbic division of the rat prefrontal cortex exhibit sparse immunoreactivity for the dopamine transporter. J Neurosci. 1998;18(7):2697-2708. 75. Arnsten AF, Dudley AG. Methylphenidate improves prefrontal cortical cognitive function through α2 adrenoceptor and dopamine D1 receptor actions: relevance to therapeutic effects in attention deficit hyperactivity disorder. Behav Brain Funct. 2005;1(1):2. 76. Arnsten AFT, Castellanos FX. Neurobiology of attention regulation and its disorders. In: Martin A, Scahill L, Charney DS, Leckman JF, eds. Pediatric Psychopharmacology: Principles and Practice. New York, NY: Oxford University Press, Inc.; 2003:99-109. 77. Biederman J, Faraone SV, Milberger S, et al. Is childhood oppositional defiant disorder a precursor to adolescent conduct disorder? Findings from a four-year follow-up study of children with ADHD. J Am Acad Child Adolesc Psychiatry. 1996;35(9):1193-1204. 78. Dyme IZ, Sahakian BJ, Golinko BE, Rabe EF. Perseveration induced by methylphenidate in children: preliminary findings. Prog Neuropsychopharmacol Biol Psychiatry. 1982;6(3):269-273. 79. Aron AR, Dowson JH, Sahakian BJ, Robbins TW. Methylphenidate improves response inhibition in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2003;54(12):1465-1468. 80. Turner DC, Blackwell AD, Dowson JH, McLean A, Sahakian BJ. Neurocognitive effects of methylphenidate in adult attention-deficit/hyperactivity disorder. Psychopharmacology (Berl). 2005;178(2-3):286-295. 81. Bush G, Spencer TJ, Holmes J, et al. Functional magnetic resonance imaging of methylphenidate and placebo in attention-deficit/hyperactivity disorder during the multi-source interference task. Arch Gen Psychiatry. 2008;65(1):102-114. 82. Mehta MA, Sahakian BJ, Robbins TW. Comparative psychopharmacology of methylphenidate and related drugs in human volunteers, patients with ADHD, and experimental animals. In: Solanto MV, Arnsten AFT, Castellanos FX, eds. Stimulant Drugs and ADHD: Basic and Clinical Neuroscience. New York, NY: Oxford University Press; 2001:303-331.

53

July 2009

A.F.T. Arnsten, C.W. Berridge J.T. McCracken

83. Bymaster FP, Katner JS, Nelson DL, et al. Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology. 2002;27(5):699-711. 84. Chamberlain SR, Del Campo N, Dowson J, et al. Atomoxetine improved response inhibition in adults with attention deficit/hyperactivity disorder. Biol Psychiatry. 2007;62(9):977-984. 85. Biederman J, Baldessarini RJ, Wright V, Knee D, Harmatz JS. A double-blind placebo controlled study of desipramine in the treatment of ADD: I. Efficacy. J Am Acad Child Adolesc Psychiatry. 1989;28(5):777-784. 86. Steere JC, Arnsten AF. The alpha-2A noradrenergic receptor agonist guanfacine improves visual object discrimination reversal performance in aged rhesus monkeys. Behav Neurosci. 1997;111(5):883-891. 87. Mao ZM, Arnsten AF, Li BM. Local infusion of an α-1 adrenergic agonist into the prefrontal cortex impairs spatial working memory performance in monkeys. Biol Psychiatry. 1999;46(9):1259-1265. 88. Engberg G, Eriksson E. Effects of α2-adrenoceptor agonists on locus coeruleus firing rate and brain noradrenaline turnover in N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ)-treated rats. Naunyn Schmiedebergs Arch Pharmacol. 1991;343(5):472-477. 89. Biederman J, Melmed RD, Patel A, et al, for the SPD503 Study Group. A randomized, double-blind, placebocontrolled study of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder. Pediatrics. 2008;121(1):e73-e84. 90. Scahill L, Chappell PB, Kim YS, et al. A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder. Am J Psychiatry. 2001;158(7):1067-1074. 91. Taylor FB, Russo J. Comparing guanfacine and dextroamphetamine for the treatment of adult attentiondeficit/hyperactivity disorder. J Clin Psychopharmacol. 2001;21(2):223-228. 92. Franowicz JS, Arnsten AF. The alpha-2a noradrenergic agonist, guanfacine, improves delayed response performance in young adult rhesus monkeys. Psychopharmacology (Berl). 1998;136(1):8-14. 93. Jakala P, Riekkinen M, Sirvio J, et al. Guanfacine, but not clonidine, improves planning and working memory performance in humans. Neuropsychopharmacology. 1999;20(5):460-470.

Primary Psychiatry

© MBL Communications Inc.

94. Spencer T, Greenbaum M, Ginsberg LD, Murphy WR, Farrand K. Open-Label Coadministration of Guanfacine Extended Release and Stimulants in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder. Poster presented at: The 161st Annual Meeting of the American Psychiatric Association; May 3-8, 2008; Washington, DC. 95. Sallee FR, McGough JJ, Wigal T, Sea D, Lyne A, Biederman J. Long-term safety and efficacy of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder. Poster presented at: The 63rd Annual Meeting of the Society of Biological Psychiatry; May 1-3, 2008; Washington, DC. 96. Hunt RD, Minderaa RB, Cohen DJ. Clonidine benefits children with attention deficit disorder and hyperactivity: report of a double-blind placebo-crossover therapeutic trial. J. Am Acad Child Psychiatry. 1985;24(5):617-629. 97. The Tourette’s Syndrome Study Group. Treatment of ADHD in children with tics: a randomized controlled trial. Neurology. 2002;58(4):527-536. 98. Sorkin EM, Heel RC. Guanfacine: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of hypertension. Drugs. 1986;31(4):301-336. 99. Arnsten AF, Cai J, Goldman-Rakic PS. The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects. J Neurosci. 1988;8(11):4287-4298. 100. Uhlen S, Porter AC, Neubig RR. The novel alpha-2 adrenergic radioligand [3H]-MK912 is alpha-2C selective among human alpha-2A, alpha-2B and alpha-2C adrenoceptors. J Pharmacol Exp Ther. 1994;271(3):1558-1565. 101. van Zwieten PA, Chalmers JP. Different types of centrally acting antihypertensives and their targets in the central nervous system. Cardiovasc Drugs Ther. 1994;8(6):787-799. 102. Scahill L, Barloon L, Farkas L. Alpha-2 agonists in the treatment of attention deficit hyperactivity disorder. J Child Adolesc Psychiatr Nurs. 1999;12(4):168-173. 103. Arnsten AF. Catecholamine regulation of the prefrontal cortex. J Psychopharmacol. 1997;11(2):151-162.

54

July 2009