Brain function and structure in adults with attention-deficit/hyperactivity disorder

Brain function and structure in adults withattention-deficit/hyperactivity disorderLarry J. Seidman, PhDa–f,*, Eve M. Valera, PhDa,b,

George Bush, MD, MSa,baPediatric Psychopharmacology Unit, Massachusetts General Hospital,

15 Parkman Street, WAAC 725, Boston, MA 02114, USAbPsychiatric Neuroscience Program, Massachusetts General Hospital, CNY 2603,

Building 149, Charlestown, MA 02129, USAcCommonwealth Research Center, Harvard Medical School Department of Psychiatry

at Massachusetts Mental Health Center,180 Morton Street, Boston, MA 02130, USA

dLaboratory of Neuropsychology, Harvard Medical School Department of Psychiatry,25 Shattuck Street, Boston, MA 02115, USA

eLaboratory of Psychiatric Epidemiology and Genetics,Harvard Medical School Department of Psychiatry, 25 Shattuck Street,

Boston, MA 02115, USAfMassachusetts Mental Health Center, Harvard Medical School Department of Psychiatry,

25 Shattuck Street, Boston, MA 02115, USA

Although most knowledge about attention-deficit/hyperactivity disorder(ADHD) developed from clinical observations and research with children,understanding of the disorder in adults is growing rapidly. Researchers arediscovering that adults and children with ADHD share similar clinicalfeatures, comorbidities, neuropsychological deficits, and failures in majorlife domains (eg, academics and work) [1–5]. It has become clear that to gaina full understanding of brain function and structure in ADHD, one muststudy the disorder from a lifespan perspective, integrating what is knownabout how it a!ects both adults and children [6].

This work was supported by grants from the National Institute of Mental Health (NIMH)(MH62152) and the March of Dimes Foundation to Larry J. Seidman, PhD, a NationalResearch Service Award (NIH, 1F32, MH065040) to Eve M. Valera, PhD, and by grants fromNIMH (Scientist Development Award 01611), National Science Foundation, The MINDInstitute, National Association for Research in Schizophrenia and Depression (NARSAD) andthe Forrest C. Lattner Foundation, and Eli Lilly to George Bush, MD, MS.

* Corresponding author.E-mail address: [email protected] (L.J. Seidman).

0193-953X/04/$ - see front matter ! 2004 Elsevier Inc. All rights reserved.doi:10.1016/j.psc.2004.01.002

Psychiatr Clin N Am27 (2004) 323–347

mailto:[email protected]

Cross-sectional data suggest that brain dysfunctions are a centralcomponent of the childhood syndrome [7,8], and a growing literature issuggesting the same for adults [9]. This article reviews the current state ofthe literature pertaining to the structural and functional brain abnormalitiesthat are found in adults with ADHD. Because the literature on ADHD inchildren is more extensive than that reported heretofore in ADHD in adults,the authors include brief summaries of the child literature to help informthat found in adults.

Historical background for hypotheses of brain dysfunctionsin attention-deficit/hyperactivity disorder

Development of the concept of attention–executive dysfunction in ADHD

Formerly called hyperactivity, hyperkinesis disorder of childhood, orminimal brain dysfunction, ADHD first was described 100 years ago as achildhood disorder found mainly in boys [10]. Revisions in the diagnosticconstruct have been made a number of times over the past century [11]. Themost important shift occurred in the 1970s, when the concept of attentiondysfunction was introduced as the central defining feature [12], and thedisorder was renamed accordingly. The key symptoms needed for thediagnosis were behavioral descriptions of motor and attentional problems,however, rather than direct cognitive measures of inattention. Nevertheless,the renaming of the disorder and the subsequent focus on attention ledto a range of neurological, neuropsychological, and neurobiological hy-potheses regarding the etiology and pathophysiology of ADHD [13,14].Moreover, these hypotheses were linked to advances in understanding theneurological bases of attention [15–17].

The current diagnosis of ADHD is made on the basis of developmentallyinappropriate symptoms of inattention, impulsivity, and motor restlessness[18]. Three subtypes are recognized: inattentive, hyperactive–impulsive, andcombined (reflecting a combination of the other two types). Symptomsmust be: observed early in life (before age 7), pervasive across situations,and chronic. The similarities between this clinical presentation and thoseof neurological patients have suggested that ADHD is a brain disordersubstantially a!ecting the prefrontal cortex [14], and current theoriesemphasize the central role of attentional and executive dysfunctions anddisinhibition in ADHD [19].

It is important to recognize that behavioral studies of normal persons andof brain-injured and psychiatric patients have emphasized that attentionalfunctions are not unitary processes [15–17]. Attention refers to a complex setof mental operations that includes focusing on or engaging a target,sustaining the focus over time using vigilance, encoding stimulus properties,and disengaging and shifting the focus. Executive functions regulatebehavioral output; typically, they involve inhibition and impulse control,

324 L.J. Seidman et al / Psychiatr Clin N Am 27 (2004) 323–347

working memory, cognitive flexibility, and planning and organization [20].Working memory, a key function linked to the dorsolateral prefrontalcortex (DLPFC) has been defined as the temporary maintenance, manip-ulation, and storage of information for use in other cognitive operationssuch as reasoning [21]. It is analogous to a mental clipboard that holdsinformation on line for short periods of time.

These attention and executive functions have become the focus of currenttheories concerning the neuropsychological basis of ADHD. Unlike 10 yearsago, when cognitive neuropsychological research in ADHD concentratedonly on attention deficit (eg, vigilance), today’s studies examine dysfunc-tions in the executive processes that control subordinate cognitive processes[22]. Although there is a lack of consensus about a taxonomy of executiveprocesses, there is some agreement that these processes include attention andinhibition, task management, planning, monitoring, and decoding [13].

One particular executive process, inhibition, has been implicated as apotential locus of a core deficit in ADHD [19,13]. Executive inhibition (ascontrasted with motivational inhibition) comes into play in situations thatrequire withholding or suddenly interrupting an ongoing action or thought(suppression of a primary response, as on the Stop Signal task). It alsooccurs with the suppression of information that one wishes to ignore,such as an interfering or conflicting stimulus, as on the Stroop test [23].According to this model, deficient inhibitory control impairs the ability ofADHD children (and adults) to engage other executive control strategies tooptimize behavior. Fuster [24], in particular, has argued that the proficiencyof a related executive function, working memory, is dependent on responseinhibition and interference control. Deficient inhibitory control can intrudeinto working memory capacity, leading to disruption of working memoryand interference with planning and organized behavior.

Neuropsychological studies in children and adolescents with ADHD

The neuropsychological functioning of children with ADHD has beenstudied extensively since the early 1970s, beginning with the pioneeringwork by Douglas [12] on vigilance deficits. Numerous clinical studies havecompared groups of children with ADHD under age 12 with normalcontrols. These studies generally have indicated that children with ADHDexhibit subaverage or relatively weak performance on various tasks ofvigilance, verbal learning (particularly encoding), working memory, andexecutive functions such as set shifting, planning and organization, complexproblem solving, and response inhibition [19,25–30]. The literature is farfrom definitive, however, and the specificity, severity, and consistency ofneuropsychological impairments in ADHD still are debated [31].

There is evidence that these abnormalities are independent ofpsychiatric comorbidities [28–30,32] and persist into adolescence [25,29].The authors’ group has shown that these attention and executive functions

325L.J. Seidman et al / Psychiatr Clin N Am 27 (2004) 323–347

are especially impaired in ADHD children with comorbid learning disabilities[33], and these impairments are of equal severity in girls with the disorder [34].Deficits on the Stroop color–word task appear to be among the mostsignificant neuropsychological impairments [26]. This task, requiring sup-pression of interference arising from conflictual information (responseinhibition), has been shown to be abnormal in large samples of boys andgirls with ADHD (Seidman, et al, unpublished data).

Paralleling the large number of clinical neuropsychological studies,paradigms from experimental psychology and cognitive neurosciencehave been put to use. For example, experimental investigations of responseinhibition or interference control [35] have demonstrated excessive sen-sitivity to processing irrelevant information in Stroop paradigms [36].Asymmetrical performance deficits on a covert orienting task implicatingabnormal right hemisphere processing [37] also have been observed.

Neuropsychological studies in adults with ADHD

Over the past decade, research on clinical neuropsychological dysfunc-tions in adult ADHD has intensified, and the evidence for such deficits inadults with ADHD is mounting. Vigilance deficits have been demonstratedby di!erent versions of the continuous performance test (CPT) [38–44].Perceptual motor slowing has been demonstrated by the digit symbol codingtest [38,39,41,43,45]. Working memory has been examined using digit spanbackward testing [41,42]. The California Verbal Learning Test has been usedto show verbal learning deficits, especially in semantic clustering [41,43,44],and the Stroop test has been used to measure response inhibition [46,47].In a recent meta-analysis of adult studies, results suggested that neuro-psychological deficits are expressed in adults across many domains offunctioning, with prominent deficits in attention, memory, and behavioralinhibition [48]. Thus, the neuropsychological di"culties found in adults withADHD (at least in persons up to age 50) appear to be qualitatively similar tothose seen in children and teenagers with the disorder; thus, they support thenotion of syndromic continuity (please see article by Seidman, et al in thisissue).

Structural and functional brain imaging in children and teenagers withattention-deficit/hyperactivity disorder

Hypothesized brain regions of interest and empirical findings

As investigators began to consider that the attentional symptomsassociated with ADHD reflected brain dysfunction, they observedphenotypic similarities with frontal lobe injured patients [14]. Thus, theyhypothesized that the syndrome was based largely on frontal lobedysfunction. Some investigators [49] proposed that these symptoms were


caused by fronto–limbic dysfunction, suggesting that insu"cient frontalcortical inhibitory control was an underlying mechanism. They felt thatsupport for this model came from the success of stimulant medications, andfrom animal models implicating dopamine pathways [50], which havea strong predilection for prefrontal cortex.

The models have become more complex and di!erentiated. A body ofevidence now suggests that a widespread network of inter-related brainareas contributes selectively to the specific attentional–executive processesdescribed and to behavioral self-regulation, and that dysfunction in variouscomponents of this network can be associated with ADHD [20]. TheDLPFC supports planning and executive control, including shifts ofattentional focus and working memory [15–17,51]. The basal gangliaparticipate in a number of discrete, somatotopically distributed circuits thatare considered essential for many executive functions. The cingulate cortexplays a role in motivational aspects of attention and in response selectionand inhibition [15,52]. The lateral prefrontal and parietal cortices areactivated during sustained and directed attention (such as in vigilance tasks)across sensory modalities [53–56]. The parietal lobule and superior temporalsulcus are polymodal sensory convergence areas that provide a representa-tion of extrapersonal space. They play an important role in focusing onand selecting a target stimulus [57,58]. The brain stem reticular activat-ing system—the reticular thalamic nuclei and the pulvinar nucleus of thethalamus—regulate attentional tone and filter interference, respectively[16,55,59]. Thus, many brain regions are candidates for impaired atten-tional–executive functioning in ADHD.

A relatively consistent literature of structural MRI studies in children(ages 6 to 19 years) supports the notion that circuitry involving the lateralprefrontal cortex, cingulate cortex, striatum, cerebellum, and corpuscallosum is altered in children with ADHD [8]. Despite a growing literatureon brain structure in children with ADHD (we found 23 published reports),however, scant attention has been paid to structural brain imaging in adultswith the disorder. In fact, in a Medline search through 2002, the authorsfound only one publication on structural brain abnormalities in adults withADHD [60]. The following section reviews the brain regions of interest(ROIs) studied in children and teenagers thus far.

Total and lateralized cerebral volume

Six studies [61–66] have shown that in children with ADHD through age19, the cerebrum, particularly the right hemisphere, is smaller by about 3%to 5%. These data support hypotheses based on observations of patientswith neglect to the left side of visual space [16,67] that brain abnormalities inADHD would be found predominantly in the right hemisphere. Neuro-psychological studies also have demonstrated significant right hemispheredysfunctions in children with AHDD [37,68].


Prefrontal cortex

The frontal cortex can be divided into five major subdivisions: theprefrontal (orbital, dorsolateral, and mesial), premotor, and motor regions.There is abundant evidence that it is not unitary in its functions [24]. Orbital(OF) lesions are associated with social disinhibition and impulse controldisorders; DLPFC lesions are associated with organizational, planning,working memory, and attentional dysfunctions, and mesial lesions arelinked with dysfluency and the slowing of spontaneous behaviors. Motorand premotor cortices are involved in elemental and sequential motormovements, respectively. Prefrontal hypotheses in ADHD primarily haveinvolved DLPFC and OF. Some investigators [51] hypothesize that theability to maintain context (a form of working memory) relies ondopaminergic tone in DLPFC, a putative neuromodulator disturbance inADHD. Others [13] have suggested that behavioral (or response) inhibitionmay be associated with OF dysfunction in ADHD. Six ROI MRI studies ofchildren with ADHD [61,62,65,66,69,70] have identified smaller prefrontalvolumes in areas corresponding to the DLPFC, either in the right or lefthemisphere. Overmeyer et al [71], using voxel-based morphometry (VBM)showed a reduction in right superior frontal gyrus volume.

Dorsal anterior cingulate cortex

The dorsal anterior cingulate cortex (dACC), lying on the medial surfaceof the frontal lobe, has strong connections to the DLPFC. The dACCis believed to play a critical role in complex and e!ortful cognitive process-ing [72], particularly target detection, response selection, error detection,online monitoring of performance, and reward-based decision-making [73].Functional neuroimaging studies on normal volunteers have shown thedACC to be activated by numerous cognitive tasks, including Stroop andStroop-like cognitive interference tasks, divided attention tasks, workingmemory tasks, and response selection tasks [35,74,75]. Based on theseconvergent findings, it has been hypothesized that the dACC plays a primaryrole in stimulus selection when faced with competing streams of input, orresponse selection, by means of the facilitation of correct responses and theinhibition of incorrect actions.

The only study reporting cingulate abnormalities in brain structure inchildren with ADHD used a VBM method that showed a reduction in rightposterior cingulate gyrus volume [71].

Corpus callosum

The corpus callosum (CC), composed of myelinated and unmyelinatedaxons, connects homotypic regions of the two cerebral hemispheres. Sizevariations in the CC presumably reflect di!erences in the number of axonsor the size of axons (relating to the extent of myelination) that connect these


regions. Changes also may reflect di!erences in the number of corticalneurons within homologous regions. Abnormalities of the CC may influencecommunication between the two cerebral hemispheres negatively [15].

Abnormalities of the CC have been reported in several morphometricstudies of children with ADHD [66,76–80]. Di!erent morphometricmeasures were used (some studies used five subdivisions, and others usedthe seven subdivisions in Witelson’s approach [81]), so the results cannot becompared easily. Nevertheless, fairly consistent evidence indicates thatabnormalities in children with ADHD are found in the anterior regions,mainly linked to prefrontal and premotor cortices; the genu [76]; therostrum and rostral body [77,79], and the posterior regions linked totemporal and parietal cortices, the splenium [76,78] and isthmus [80]. Inaddition, Hill et al [66] report smaller total volumes of the CC.

Basal ganglia (striatum)

The caudate, putamen, and globus pallidus (ie, the pallidum) are partof a number of discrete, somatotopically distributed circuits essential forexecutive functions. These circuits include prefrontal-basal ganglia-thalamicloops [82]. It has been suggested that the di"culty with inhibition in ADHDis caused by a deficit in the indirect caudate–pallidum route to thalamicoutput neurons [8]. Damage to the striatum is associated plausibly with theetiology of ADHD [83]. First, because it is located at a border zone ofarterial supply and is exposed to circulatory compromise, the striatum isvulnerable to perinatal hypoxic complications (which occur at higher thannormal rates in ADHD) [84]. Second, experimental lesions in the striatum ofanimals produce hyperactivity and poor performance in working memoryand go–no go (response inhibition) tasks [82]. Third, the striatum is oneof the richest sources of dopaminergic synapses [85], and dopamine is im-portant in the regulation of striatal functions. Finally, stimulant medi-cations, commonly used to treat ADHD, have been shown to have e!ects onstriatum [86,87].

A growing body of brain imaging evidence supports a role for thebasal ganglia inhibitory circuits in ADHD. Several studies have shownabnormalities of the caudate, including a significantly smaller size on eitherthe left or right side [61,62,79,88–91], although no di!erences were reportedin one study [66]. The pallidum has been shown to be smaller on the right[61,71] and on the left [90]. Early studies demonstrated that regional cerebralblood flow (rCBF) was reduced in the caudate bilaterally in children 8 to 15years of age with ADHD and comorbid conditions, and in the right caudatealone in children with ADHD without comorbidity [92,93]. With stimulanttreatment, perfusion in the caudate was increased. There have been concernsabout the methods used in these early studies (small samples, high rates ofcomorbid learning disabilities (LDs), and early imaging technology with lessrefined spatial resolution), and inconsistent results in adolescents have cast


some doubt on the robustness of these findings [94]. In addition, animportant finding was reported by Castellanos et al [64], who demonstratedthat significant di!erences between children with ADHD and controls incaudate volume diminished by the oldest age studied (19 years). Thissuggests that adult studies are necessary to determine the persistence andstability of di!erent ROIs across the lifespan.

Nucleus accumbens

Although the nucleus accumbens (NA) has not been studied previouslyin ADHD, it may be important because of its essential role in rewardmechanisms [95]. Alterations in reward behavior have been considered bysome to be critically abnormal in ADHD [11,95]. Functionally, the NAappears to lie at the junction between the limbic and motor systems. The NAhas been shown to receive substantial inputs from the amygdala andhippocampus, and also from the ACC. Through outputs to the substantianigra and the ventral pallidum, the NA gains access to the motor system andbecomes a crucial part of a ventral–striatal loop [96]. This anatomicalposition has led to the suggestion that the NA may be important for theassociation of motivationally and emotionally salient stimuli with motorresponses and that it also may be involved in behavioral switching orcognitive flexibility. Further, reward mechanisms, and the genetic abnor-malities associated with them, such as the DRD4 dopamine gene [95], havebeen linked to ADHD. Thus, the study of the NA is important in furtherunderstanding the pathophysiology of ADHD.

Thalamus

The thalamus is one of the key subcortical structures involved inthe modulation of attentional processing [97]. Thalamus activation alsohas been reported in subspan and supraspan tasks of long-term verbalmemory [98] and verbal working memory [99]. Three nuclei of the thalamus(ie, medial nuclear, intralaminar, and lateral nuclear groups) have beenimplicated in cognitive aspects of working memory tasks. The medial dorsalnucleus is involved in verbal long-term memory [100]; the intralaminarthalamic nuclei have been shown to regulate attentional tone and to beinvolved in vigilance [101], and the pulvinar is considered to play a crucialrole in filtering of interference (filtering out irrelevancies) [15]. The thalamus,particularly the pulvinar and medial dorsal nuclei, is interconnected withmany regions considered to be part of the human attentional network (ie,prefrontal and posterior parietal cortices, cerebellum, and basal ganglia).Moreover, the thalamus is thought to play an important role in behavioralinhibition. Thus, the thalamus may prove to be an important part of thewidespread networks underlying executive and attentional deficits inADHD.


Cerebellum

Recently, clinical observations and brain imaging studies of normalsubjects have suggested a significant role of the cerebellum in cognitiveprocessing over and above that of its established role in the coordination ofmovement [102]. The cerebellar contribution to cognition is presumablydependent on cerebellar–cortical pathways involving the pons andthalamus. These consist of a feedforward, or a!erent limb, and a feedback,or e!erent limb. The feedforward limb is comprised of the corticopontineand pontocerebellar mossy fiber projections. The feedback limb consists ofthe cerebellothalamic and thalamocortical pathways. Cortical links includeposterior parietal and prefrontal areas.

Various hypotheses link di!erent parts of the cerebellum to di!erentbehavioral and cognitive functions. The archicerebellum, vermis, andfastigial nucleus are thought to be especially involved in a!ective andautonomic regulation and emotionally relevant memory. The cerebellarhemispheres and dentate nucleus likely are more concerned with executive,visual–spatial, language, and memory functions [102].

Three groups of researchers have shown structural abnormalities of thecerebellum [64–66,103]. One group found significantly less volume of thevermis in 46 right-handed boys with ADHD, compared with matchedcontrols [103]. This reduction involved mainly the posterior–inferior lobe(lobules VIII to X), but not the posterior–superior lobe (lobules VI to VII).The second group, using a smaller all-male sample, found similar results[104] in children with ADHD. They reported a significant decrease in thesize of the posterior vermis, but only the inferior posterior lobe (lobules VIIIto X) was a!ected, not the superior lobe (lobules VI to VII). Researchersalso have found similar abnormalities in girls with ADHD [63]. Theconsistency of these three reports and a subsequent study with anincrementally larger sample suggests that smaller cerebellar volumes arean important part of the ADHD syndrome [64].

Are brain abnormalities in childhood attention-deficit/hyperactivitydisorder accounted for by confounds?

Psychiatric comorbidity

Children and adults with ADHD frequently have comorbid antisocial,substance abuse, mood, anxiety, or learning disorders [105]. Althoughspurious comorbidity can occur because of referral and screening artifacts,a review suggested that these artifacts cannot explain the high levels ofpsychiatric comorbidity [106]. Family studies of comorbidity also disputethe notion that artifacts cause comorbidity; rather, they show a causal role toetiological relationships among the disorders [107–109]. In addition, studiesin children [28–30,32] and adults [5,44] showed that neuropsychological


deficits in ADHD remained robust after statistically adjusting for thepresence of psychiatric comorbidities. A challenge to the field, however,remains in that the specificity of neuropsychological deficits acrossvarious diagnoses (eg, ADHD, conduct disorder, autism) has not beenestablished [31].

Most of the morphometric MRI studies of children with ADHD didnot address psychiatric, cognitive comorbidity, or medication status. Theoutcomes of several studies [61,62,78,90] dealing with these potentialconfounds, however, provide support for the notion that the predictedstructural abnormalities will be found in children and adults with ADHD.When the authors’ group studied children with ADHD without comorbid-ity, significant volume reductions in the anterior frontal lobes, the cau-date, and the corpus callosum were found [62,78]. In the largest andmost comprehensive studies of childhood ADHD [64,77,89], reducedvolumes remained significant after adjusting statistically for comorbiditiesand removing the subjects who had learning disabilities. Importantly,Castellanos et al [64] studied a large number of subjects with ADHD whowere medication-naı̈ve, providing strong evidence that morphometricfindings could not be ascribed to medication exposure. Thus, the existingdata suggest that at least some brain abnormalities in ADHD appearto be independent of psychiatric comorbidity and medication.

Learning disabilities

There is much research indicating that subjects with ADHD often havecomorbid LDs; estimates are approximately 30%, depending on how LDis defined [110]. Because LDs such as dyslexia involve brain abnormalities,it is necessary to know which abnormalities are caused by ADHD, andwhich are caused by LDs. This issue has been addressed in only one small-sample, early generation MRI study [69], which found that both dyslexicand ADHD children had smaller right anterior width measurements thandid controls. The dyslexic children had a bilaterally smaller insular regionand a significantly smaller left planum temporale than the controls.The research literature [111] suggests that dyslexia manifests itself withsymmetry of the plana (compared with the typical larger left asymmetryfound in normal subjects), a larger corpus callosum, especially in theposterior third [112], and left hemisphere structural and functional ab-normalities [113,114]. Thus, the fronto–striatal brain anomalies attributedto ADHD (especially in the right hemisphere), cerebellar abnormalities,and smaller corpus callosum volumes appear to be distinct from theabnormalities in dyslexia.

Mood disorders

In MRI studies of adults with bipolar disorders, brain anatomicabnormalities have been documented in the ventricles, thalamus, temporal


lobe, cerebellar volumes, and in the subcortical deep white matter andperiventricular region, with an increased number of white matter hyper-intensities [115–126]. Adults with unipolar depression have been reported tohave a smaller frontal lobe, cerebellum, caudate, and putamen [118,123]. Incontrast to MRI findings in ADHD, MRI studies of mood disorderedpatients have not found abnormalities in the corpus callosum or globalvolume reductions consistently [118,122]. Nevertheless, further research isneeded to address the role of psychiatric comorbidity, particularly mooddisorders, on brain abnormalities in ADHD.

Relating brain structure, function, and neuropsychological dysfunctions

The analysis of attention and executive functions into subcompo-nents—and the mapping of attentional functions onto di!erent brainregions—support the proposition that response inhibition and otherexecutive deficits in ADHD will be associated with structural and functionalbrain abnormalities in specific regions. There is limited ADHD research inthis area, however. In children, Casey et al [127] found that performance onthree response inhibition tasks correlated only with those anatomicalmeasures of fronto–striatal circuitry observed to be abnormal in ADHD (ie,the prefrontal cortex, caudate, and globus pallidus, but not the putamen).The significant correlations between task performance and anatomicalmeasures of the prefrontal cortex and caudate nuclei were predominantly inthe right hemisphere, supporting the role of right fronto–striatal circuitry inresponse inhibition and ADHD. Semrud-Clikeman et al [128], also studyingchildren, found a significant relationship between reversed caudate asym-metry and measures of inhibition (as measured by the Stroop test) andexternalizing behavior.

There is some limited evidence from studies of children with ADHDthat executive dysfunctions associated with ADHD are correlated withbrain volume abnormalities. Poorer performance on sustained attentiontasks was related to smaller volume of the right hemispheric white matter[128]. Castellanos et al [61] found that full-scale IQ score correlatedsignificantly with total brain volume and with left and right prefrontalregions. Using the same sample, researchers found in a di!erent reportthat full-scale IQ correlated with cerebellar volumes in ADHD [103]. Thearea of the rostral body of the corpus callosum was correlatedsignificantly with scores on the impulsivity/hyperactivity scale of theConners’ questionnaire [77]. These studies were conducted on boys withADHD. The only study of girls demonstrated that the pallidum, caudate,and prefrontal brain volumes correlated significantly with ratings ofADHD severity and cognitive performance [63]. The extant data, whilelimited, suggest that impairments on neuropsychological measures ofexecutive dysfunction are associated with abnormal brain structures inADHD.


Heterogeneity of attention-deficit/hyperactivity disorderand brain abnormalities

Attention-deficit/hyperactivity disorder is known to be a heterogeneousdisorder with substantial psychiatric and cognitive comorbidity, and it isimportant to understand this heterogeneity by clarifying the relationship ofstructural and functional abnormalities to subgroups of patients. Thereappear to be at least three heuristically meaningful subgroups: those definedby presence or absence of family history, comorbid LD, and neuropsy-chological deficits [129]. Studies [130] indicate that as many as 57% of adultswith ADHD have a family history of ADHD (ie, at least one first-degreerelative with ADHD). There is preliminary evidence that these individualsare more neuropsychologically impaired than those without a family history[32]. The most robust functional brain abnormalities in adults with ADHDwere acquired on samples of adults with familial, childhood-onset ADHD[131,132]. In addition, a structural MRI study of ADHD in childhood isbased on a similarly acquired sample of familial ADHD [62,78]. These dataprovide some support for the idea that the familial subgroup may bea distinct, homogeneous entity and may have more demonstrable brainabnormalities. Alternatively, they may lie on a more impaired end ofa continuum of severity.

Another important form of heterogeneity is based on the frequentpresence of associated LDs. The authors and other research groups haveshown that ADHD and LDs are transmitted independently in families [133]and that executive dysfunctions are more severe in subjects with bothADHD and LD, suggesting that LDs contribute additional features toADHD [33]. It is therefore important to examine ADHD subjects withcomorbid LD (eg, reading disability) to investigate whether they demon-strate brain abnormalities (such as in the insula and planum temporale)associated with the additional condition.

As noted previously, a substantial subgroup of persons with ADHDappears to have neuropsychological dysfunctions. Clarifying the still un-known relationship between these neuropsychological deficits and brainabnormalities will be important for putting the ADHD brain behaviorrelationship on solid, empirical grounds.

Assessing the e!ects of gender on brain abnormalitiesin attention-deficit/hyperactivity disorder

Health issues have been understudied in females, especially for disordersthat are more prevalent in males [134]. Because family disruption and severebehavioral disturbances are observed less frequently among girls withADHD, they may be less likely to come to the attention of health careproviders [135]. Depending on the sampling source, ADHD is two to ninetimes more prevalent among boys than girls [136]. In adults, however, theratio is closer to 1.5 (males):1.0 (females) [6].


Although it is increasingly recognized that ADHD a!ects both genders,most of the research literature is limited to males [134,137]. A review [134]indicated that few studies have included a su"cient number of females towarrant gender-based conclusions regarding ADHD. Recent work by theauthors’ group has helped remedy this situation. Based on the largest dataset on girls with ADHD thus far, the authors identified more similaritiesthan di!erences in the core features of ADHD. There were a few notableexceptions. Girls were somewhat more likely than boys to have thepredominantly inattentive type of ADHD (although the combined type ledin both genders), less likely to have a learning disability, less likely tomanifest problems in school or in their spare time, and at lower risk forcomorbid conduct disorder and oppositional–defiant disorder [138,139].The authors also documented that ADHD is highly familial in girls [140].From this sample, they also conducted a study of neuropsychological func-tion in girls and boys with ADHD versus sex-matched controls [34]. Theauthors found that girls with ADHD have significant impairments inexecutive functions. Neuropsychological measures of these functions wereimpaired equally in girls compared with boys with ADHD. The authorsconcluded that executive dysfunctions are correlates of ADHD, regardlessof gender. These data tend to suggest largely comparable abnormalities ingirls and boys with ADHD.

The problem of samples with few girls with ADHD is also present inMRI studies. In the published literature up to 2001, the authors reviewedpapers reporting MRI abnormalities in children with ADHD in studiesinvolving approximately 200 boys and only 15 girls. A recently publishedstudy using a substantial sample size, however, compared morphometricanalyses of girls with ADHD to normal girls [63]. The investigators studied50 girls with ADHD and 50 matched healthy controls, ages 5 to 16 years,using the same protocol they had employed in previous studies of boys[77,89]. Like boys with ADHD, girls with ADHD di!ered from controlsin total cerebral volume (TCV). Analysis of covariance (using TCV)demonstrated significantly smaller volumes in posterior–inferior cerebellarvermis regions and the left caudate. Nonsignificant trends were noted insmaller left frontal and right caudate volumes. These findings were con-firmed with an extended sample of boys and girls [64]. Thus, it appears thatbrain regions are reduced in girls with ADHD, as they are in boys.

The idea that there might be gender di!erences in brain structure inADHD is appealing, because of the number of sexually dimorphic areas ofthe brain relevant to attention and executive functions, including the corpuscallosum, basal ganglia, and prefrontal cortex. Recent MRI studies [141]found significant sex di!erences in normal adults in cortical and subcorticalregions, including the DLPFC [142]. Additionally, using positron emissiontomography (PET), Ernst et al [143] found, that, relative to control femalesand ADHD males, ADHD females showed lower global cerebral me-tabolism compared with controls, suggesting less brain activity. Thus, future


studies should address the possibility of sex di!erences in brain function andstructure by matching male and female controls with both genders inADHD.

Structural and functional brain imaging in adults withattention-deficit/hyperactivity disorder

In contrast to most psychiatric disorders, there are very few neuro-imaging studies in adult ADHD. Though the child ADHD literature hasa fair number of structural neuroimaging papers, there appears to be onlyone structural imaging paper in adults [60]. This section reviews the adultfunctional and structural imaging studies.

Prefrontal cortex

Only one structural MRI study has been reported on adults with ADHD[60]. Researchers found that there was a significant reduction of the volumeof the left orbital–frontal cortex in eight men with ADHD compared with 17healthy male controls.

Prefrontal dysfunction in ADHD was first demonstrated by Zametkinet al [131], who used PET and an auditory CPT to study a large sample ofadults with childhood onset-familial ADHD. In the context of a globaldecrease in metabolism, the largest decreases were seen in the superiorfrontal and premotor cortices. When cerebral metabolism was normalizedto control for the influence of individual di!erences in global cerebralmetabolic rate of glucose (CMRglu) on regional CMRglc, four regions,medial frontal (anterior cingulate cognitive division (personal communica-tion), left anterior frontal, left posterior frontal, and Rolandic, remainedsignificant.

A recent study also showed prefrontal reduction in blood flow. In a briefreport, Schweitzer et al [144] used a working memory task, the PacedAuditory Serial Addition Test (PASAT), with PET to examine performancerelated blood flow changes in six men with ADHD and six age- and IQ-matched controls. As predicted, the men with ADHD performed morepoorly on the task than did controls, and the two groups showed di!erentpatterns of neural activation. Although the groups were not compareddirectly, the controls primarily activated frontal and temporal regionsconsistent with working memory circuitry. The pattern of activation for menwith ADHD, however, was more widespread and located in occipital(precuneus and left inferior parietal/angular gyrus) regions.

Dorsal anterior cingulate cortex

There are no structural MRI studies of the dACC in adults with ADHD.This is unfortunate, as such studies would be very valuable, given the


functional imaging results in adults with ADHD [131,132] and the structuralstudy by Casey et al in 26 normal children that showed attention taskperformance was correlated with right ACC volume [145].

The two functional neuroimaging studies of adults with childhood onsetand familial ADHD implicate the dACC [131,132]. In the first [131], whileglobal cerebral glucose metabolism was 8.1% lower in the never medicatedADHD group than in controls, anterior cingulate cortex was one of onlyfour regions evaluated (out of 60) that showed regional hypoactivity afterglobal normalization. Later, Bush et al [132] used the Counting Stroop,a cognitive interference task developed for functional magnetic resonanceimaging (fMRI), to demonstrate that adults with ADHD failed to activatethe dACC compared with healthy adults. This study involved a homoge-neous group of ADHD adults with stringent exclusion criteria (nocomorbidities) and a close matching procedure. Similar to the Zametkinet al [131] study, there were no significant behavioral di!erences inperformance on the task. Nonetheless, while the control group predictablyactivated the dACC (cognitive division), the ADHD group did not. Directcomparison of fMRI signal between ADHD and controls confirmed thatthe controls displayed significantly higher dACC activity. Also, whenexamined individually, the two groups activated di!erent neural networks.Whereas the controls activated the dACC, middle frontal, parietal, andoccipital regions, the ADHD group activated a di!erent fronto–striatalinsular network, including inferior frontal, insula, caudate, putamen,thalamus, and pulvinar regions. Both of these studies of adults withADHD [131,132] demonstrated functional deficits in the ACC when eitheronly subjects with no comorbidities were included [132], or after subjectswith LDs were excluded [131]. Finally, the findings of dACC dysfunctionfrom these adult studies are supported by similar findings of dACChypofunction in children [146,147] and adults [148] with ADHD.

Basal ganglia (striatum)

Alterations in dopamine transporter density have been shown in adultswith ADHD. Three out of four adult studies [85,149–151] and the lone studyin children [152] have reported that striatal dopamine transporter density iselevated by as much as 70% in patients with ADHD compared with healthyage-matched controls. Researchers in studies using PET cognitive activationparadigms [131] also have found decreased caudate metabolism in adultswith ADHD, as did Vaidya et al [153] and Durston et al [147] in fMRIstudies using response inhibition tasks in children.

Other subcortical and cortical regions

Given the relatively small number of imaging studies, which have useddi!erent modalities and tasks in di!erent age groups, it is di"cult to drawany firm conclusions about the integrity of brain regions that have not been


identified as an ROI in an a priori manner. One theme that is starting toemerge, however, which goes along with initial work by Zametkin et al [130],is that in addition to patients with ADHD displaying focal dysfunction inareas such as dACC, dorsolateral prefrontal cortex and striatum, patientswith ADHD also tend to display less activation and di!erent activationpatterns than do healthy controls [132,144,146–148,153].

This relative dearth of functional neuroimaging studies underscores thenecessity for more well-designed and well-controlled studies with largersample sizes. Similarly, the presence of only one adult morphometric MRIstudy draws attention to the need to carefully study brain structure inadults with ADHD. A wider range of structures needs to be considered inunderstanding ADHD, particularly the cerebellum, because it has beenshown to be altered structurally in a number of studies of children up to age19. Finally, longitudinal neuroimaging studies need to be conducted toassess changes over the lifespan.

Future directions for research

Although there is growing information that identifies neurobiologicabnormalities in childhood and teenage years, there is still relatively littlesystematic neurobiological information on ADHD in adulthood. Theselacunae in our understanding of ADHD and the brain suggest severaldirections for future research regarding the pathophysiology of ADHD.First, it would be useful to conduct studies that use identical measuresto assess neurobiological syndromic continuity in both a child andadult sample, with the adults and children coming from the same family.Such a design would enable an evaluation of the association of brainabnormalities in two generations of persons with ADHD. By collectingstructural and functional imaging and neuropsychological data in bothadults and children, one will be able to determine if adults with ADHDshare abnormalities found in children with the disorder. Second, it would beimportant to evaluate a child sample longitudinally to determine whetherthe brain abnormalities change throughout the life cycle.

There is only one study that has begun to conduct longitudinal studiesof brain structure in ADHD [64], and more research is needed. Third,combining neuropsychological, structural, and functional MRI measureswill allow an evaluation of structure–function relationships in ADHD.Fourth, studying both males and females with ADHD would provide a testof gender di!erences or similarities in the expression of brain abnormalitiesin ADHD. Fifth, there is a need for studies to evaluate the increasingevidence of genetic anomalies with measures of brain dysfunction. Althoughit is premature to identify an association between gene variants and brainabnormalities in ADHD, the authors believe that when ADHD suscepti-bility genes have been discovered and confirmed, DNA-imaging resources


will provide a useful means of testing hypotheses about gene–brainassociations. This work could include genes such as the 7-repeat allele ofthe DRD4 gene and the 480 allele of the DAT gene, which already havebeen implicated in ADHD by several studies [154–162], although there aresome discrepant results [157,163–165]. These dopamine genes may haveparticular relevance to certain brain regions altered in ADHD that are richin dopamine [85], such as the caudate.

Finally, it is essential to stress that there is a critical distinction to bemade between group-averaged structural and functional imaging studies(which can be used for elucidating pathophysiology but are not clinicallymeaningful) and studies that focus on individual subjects. As discussed inBush et al [166], novel imaging techniques that produce robust and reliableresults at the level of the individual patient must be developed and refined toprovide clinically useful information for patients. Although the potential useof noninvasive neuroimaging techniques as a diagnostic tool for ADHD iso! in the future, it remains a laudable goal.

In summary, many investigators hypothesize that a key brain abnormal-ity in ADHD involves frontal–striatal circuitry [9,68,164], reflected inneurocognitive deficits in attention and executive functions (especiallyworking memory and inhibition) [13,19], and in structural abnormalities inbrain regions hypothesized to underlie these functions. These include lateralprefrontal cortex, dorsal ACC, basal ganglia (especially caudate), corpuscallosum, and cerebellum. The identification of neuropsychological,neuroanatomical, and functional abnormalities in ADHD, and the in-terrelationship among these abnormalities, is crucial for understanding theneurobiological mechanisms involved in ADHD.

Further, although this article focused primarily on how brain structureand function might relate to cognitive abnormalities in ADHD, informationon brain structure and function is also critical for increasing understandingof a!ective abnormalities in ADHD. Clinical understanding of the ADHDbrain will facilitate knowledge of the relationship between cognitive anda!ective di"culties and provide a greater opportunity for improved andmore integrated treatment approaches. It also will direct the development ofbetter assessment protocols that might provide a greater rate of bothsensitivity and specificity in diagnosing ADHD. This greater knowledgeof the ADHD brain is necessary to help clarify the neurodevelopmentalevolution of the disorder, treatment response, and the meaning of the dis-order to patients, families, and treating clinicians.

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Brain function and structure in adults with attention-deficit/hyperactivity disorder

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