National Institutes of Health, Bethesda, Maryland 4 Genomic Imaging Unit, Department of Psychiatry, University of Würzburg, Germany

Transcription

1 Human Bain Mapping 30: (2009) Regional Bain Activation Changes and Abnomal Functional Connectivity of the Ventolateal Pefontal Cotex Duing Woking Memoy Pocessing in Adults With Attention-Deficit/ Hypeactivity Disode Robet C. Wolf, 1 * Michael M. Plichta, 2 Fabio Sambatao, 3 Andeas J. Fallgatte, 2 Chistian Jacob, 2 Klaus-Pete Lesch, 2 Matin J. Hemann, 4 Calos Schönfeldt-Lecuona, 1 Benhad J. Connemann, 1 Geog Gön, 1 and Nenad Vasic 1 1 Depatment of Psychiaty and Psychotheapy III, Univesity of Ulm, Leimgubenweg 12-14, Ulm, Gemany 2 Depatment of Psychiaty, Univesity of Wüzbug, Gemany 3 Clinical Bain Disodes Banch, Genes Cognition and Psychosis Pogam, National Institute of Mental Health, National Institutes of Health, Bethesda, Mayland 4 Genomic Imaging Unit, Depatment of Psychiaty, Univesity of Wüzbug, Gemany Abstact: Pevious studies on woking memoy (WM) function in adults with attention-deficit/hypeactivity disode (ADHD) suggested abeant activation of the pefontal cotex and the ceebellum. Although it has been hypothesized that activation diffeences in these egions most likely eflect abeant fontoceebella cicuits, the functional coupling of these bain netwoks duing cognitive pefomance has not been investigated so fa. In this study, functional magnetic esonance imaging (fmri) and both univaiate and multivaiate analytic techniques wee used to investigate egional activation changes and functional connectivity diffeences duing cognitive pocessing in healthy contols (n 5 12) and ADHD adults (n 5 12). Behavioal pefomance duing a paametic vebal WM paadigm did not significantly diffe between adults with ADHD and healthy contols. Duing the delay peiod of the activation task, howeve, ADHD patients showed significantly less activation in the left ventolateal pefontal cotex (VLPFC), as well as in ceebella and occipital egions compaed with healthy contol subjects. In both goups, independent component analyses evealed a functional netwok compising bilateal lateal pefontal, stiatal, and cingulate egions. ADHD adults had significantly lowe connectivity in the bilateal VLPFC, the anteio cingulate cotex, the supeio paietal lobule, and the ceebellum compaed with healthy contols. Inceased connectivity in ADHD adults was found in ight pefontal egions, the left dosal cingulate cotex and the left cuneus. These findings suggest both egional bain activation deficits and functional connectivity changes of the VLPFC and the ceebellum as well as functional connectivity abnomalities of the anteio cingulate and the paietal cotex in ADHD adults duing WM pocessing. Hum Bain Mapp 30: , VC 2008 Wiley-Liss, Inc. Additional Suppoting Infomation may be found in the online vesion of this aticle. Contact gant sponso: Deutsche Foschungsgemeinschaft; Contact gant numbe: KFO 125/1-1. *Coespondence to: Robet Chistian Wolf, Univesity of Ulm, Depatment of Psychiaty and Psychotheapy III, Leimgubenweg 12-14, Ulm, Gemany. chistian.wolf@uni-ulm.de Received fo publication 29 Mach 2008; Revised 11 August 2008; Accepted 25 August 2008 DOI: /hbm Published online 23 Decembe 2008 in Wiley InteScience (www. intescience.wiley.com). VC 2008 Wiley-Liss, Inc.

2 Pefontal Dysconnectivity in ADHD Adults Key wods: woking memoy; pefontal cotex; ceebellum; independent component analysis; functional connectivity; functional magnetic esonance imaging INTRODUCTION Deficits in executive function, behavioal inhibition, and woking memoy (WM) ae consideed as one of the key neuopsychological featues in childen and adolescents with attention-deficit/hypeactivity disode (ADHD) [Matinussen et al., 2005; Willcutt et al., 2005]. In fact, seveal authos have hypothesized that symptoms of ADHD aise fom a pimay deficit in specific domains of executive function, most notably in those cognitive domains associated with cognitive contol [Ansten and Li, 2005; Bakley, 1997]. Fo instance, impaied esponse inhibition has been epeatedly found in childhood ADHD [Bakley, 1997; Lijfijt et al., 2005] and ADHD adults [Clak et al., 2007; Lijfijt et al., 2005]. On the othe hand, WM function has been widely studied on the behavioal level in childen and adults with ADHD, showing both vebal and spatial WM deficits in affected individuals [Dowson et al., 2004; Lui and Tannock, 2007; Matinussen et al., 2005]. The concept of WM efes to the ability to tansiently stoe and manipulate infomation held online fo futhe behavioal guidance [Baddeley, 2003], and distinct WM subpocesses have been shown to be mediated by fontopaietal, stiatal and ceebella egions [Baddeley, 2003; Owen et al., 2005; Postle and D Esposito, 2000]. It is less clea, howeve, if impaied inhibitoy contol and WM dysfunction epesent distinct deficits in ADHD patients, o if these impaied cognitive domains shae a common neuobiological substate [Castellanos and Tannock, 2002]. Recently, it has been suggested that both esponse inhibition and WM deficits in ADHD may stem fom a common pathologic pocess involving the infeio fontal cotex, athe than being manifestations of a distinct neuopathological mechanism [Clak et al., 2007]. In addition to the infeio fontal cotex, fontopaietal, stiatal, and ceebella activation abnomalities have been fequently epoted duing tasks that tap executive function including esponse inhibition and WM [Castellanos and Tannock, 2002; Clak et al., 2007; Dickstein et al., 2006]. Specifically, bain activation abnomalities of the ventolateal pefontal cotex (VLPFC), the anteio cingulate, and the ceebellum in childen with ADHD have been associated with a deficit in inhibitoy contol [Duston et al., 2006; Schulz et al., 2004; Tausche et al., 2002]. With egad to the VLPFC, functional activation changes of this egion have been associated with ADHD symptom pesistence [Schulz et al., 2005] and genetic vulneability fo ADHD [Duston et al., 2006]. Howeve, functional bain imaging eseach on cognitive pocesses involving spatial o vebal WM function in childen and adolescents with ADHD has been elatively spase compaed with studies conducted on inhibitoy contol [Sheidan et al., 2007; Stevens et al., 2007; Vance et al., 2007]. Moeove, despite the inceased ecognition of ADHD in adults [Faaone et al., 2000], eseach on executive function in adults with ADHD has been less extensive compaed with the extant child and adolescent liteatue [Seidman et al., 2005]. Although WM dysfunction is ecognized as an impotant cognitive coelate of the disode, only a few functional imaging studies have attempted to examine the functional neuoanatomy undelying WM function in ADHD adults [Hale et al., 2007; Schweitze et al., 2000; Valea et al., 2005], yielding ambiguous esults with egad to pefontal and ceebella activation abnomalities: using positon emission tomogaphy (PET) and a paced auditoy seial addition task, Schweitze et al. found that task-elated changes in egional ceebal blood flow (CBF) in men without ADHD wee moe pominent in pefontal and tempoal egions [Schweitze et al., 2000]. In ADHD adults, inceased activation in pefontal aeas associated with language pocessing was found in a ecent functional magnetic esonance imaging (fmri) study using the fowad and backwad digit span [Hale et al., 2007]. In contast, Valea et al. epoted no activation diffeences in an a pioi identified ight pefontal egion and deceased activation in ceebella egions duing n-back task pefomance in a elatively lage sample of ADHD adults [Valea et al., 2005]. Although it has been peviously hypothesized that egional bain activation abnomalities in ADHD adults likely eflect abeant connectivity of a pefontoceebella netwok [Valea et al., 2005], the functional coupling of bain egions associated with cognitive pefomance in ADHD adults has not been investigated so fa. In this study, we used event-elated fmri [Josephs and Henson, 1999] and a peviously validated paametic vebal WM task [Wolf and Walte, 2005; Wolf et al., 2006] to investigate WM-elated bain activation in adults with ADHD compaed with healthy contols. To addess the issues of egional bain activation abnomalities and changes in functional connectivity duing WM pocessing, we used both univaiate and multivaiate statistical appoaches. Regional activation changes between healthy contols and ADHD adults wee investigated within the famewok of the Geneal Linea Model (GLM). Paametic activation effects duing dissociable WM subpocesses [D Esposito et al., 2000; Postle and D Esposito, 2000] wee sepaately analyzed fo thee diffeent task peiods involv- 2253

3 Wolf et al. TABLE I. Demogaphics and ADHD symptom scale scoes Healthy contols (n 5 12) ADHD adults (n 5 12) Mean SD Mean SD P value Age (yeas) Education (yeas) IQ a a Age ange (yeas) Education ange (yeas) IQ ange a a Lateality scoe b Adult Self Repot Scale (ASRS): global scoe Adult Self Repot Scale (ASRS): attention deficit Adult Self Repot Scale (ASRS): hypeactivity Wende Utah Rating Scale (WURS) Baatt Impulsiveness Scale (BIS) Eysenck Impulsiveness Questionnaie (EIQ) a Rated by the suboutine 3 fom the Leistungspuefsystem (Hon, 1983). b Rated by the Edinbugh handedness inventoy (Oldfield, 1971). ing encoding, manipulation/maintenance, and etieval of vebal stimuli. Changes in the functional coupling of the VLPFC wee investigated using a multivaiate statistical appoach, i.e. independent component analysis (ICA). ICA is a statistical technique that maximizes the independence between the output components [Calhoun et al., 2001, 2004], thus identifying a set of spatially nonovelapping and tempoally synchonous bain netwoks. In its application to fmri data, ICA has been demonstated to be a viable method fo evealing functionally elated bain egions in healthy contols and patients with neuopsychiatic disodes [Celone et al., 2006; Gaity et al., 2007; Sambatao et al., 2008]. The combination of both univaiate (GLM) and multivaiate (ICA) statistical methods has been peviously shown to exploe diffeent aspects of bain activity [Esposito et al., 2006], whee GLM-based methods ae thought to be moe sensitive to detect functional specificity, while an ICA appoach is bette suited to define aspects of functional connectivity [Esposito et al., 2006; Sambatao et al., 2008]. We wee paticulaly inteested in egional activation diffeences and the netwok involving the VLPFC and the ceebellum, since a dysfunction of this cicuit has been ecognized to play a pivotal ole in the pathophysiology of ADHD [Ansten and Li, 2005; Bush et al., 2005; Faaone and Biedeman, 1998; Seidman et al., 2006]. As pedicted by neuobiological models of pefontal dysfunction in ADHD [Ansten and Li, 2005; Dickstein et al., 2006; Duston et al., 2006], we hypothesized that compaed with healthy contols, ADHD adults would show lowe activation of the lateal pefontal cotex and the ceebellum duing WM pocessing. Futhemoe, we hypothesized that apat fom egional bain activation changes in the lateal pefontal cotex and the ceebellum, ADHD adults would exhibit an abeant connectivity patten in a functionally elated pefontoceebella netwok. MATERIALS AND METHODS Subjects A total of 13 ight-handed adult males with a diagnosis of ADHD accoding to DSM-IV citeia (combined type, n 5 9; pedominantly inattentive type n 5 2, pedominantly hypeactive-impulsive type, n 5 2) wee ecuited fom among the outpatients teated at the Depatment of Psychiaty at the Univesity of Wüzbug, Gemany. One patient s task fmri pefomance data set was lost due to technical difficulties, thus educing the numbe of patients included in all subsequent analyses to n 5 12 (combined type, n 5 8; pedominantly inattentive type n 5 2, pedominantly hypeactive-impulsive type, n 5 2); see Table I fo details on demogaphics and psychopathology. All patients wee diagnosed by an expeienced consultant in psychiaty (C.J.). The diagnosis of childhood manifestation of ADHD was etospectively assessed with the DSM-IV symptom list fo ADHD (17 items) and by means of the 61-item Wende Utah Rating Scale (WURS) [Wad et al., 1993]. To ensue diagnostic validity, additional infomation was collected fom patnes, elatives, fiends, and fom school epot cetificates. Adult manifestations of ADHD wee assessed with the DSM-IV symptom list fo ADHD. ADHD patients wee excluded fom paticipation if they (1) had a cuent axis-i mood, substance-elated, psychotic, o anxiety disode and/o a concuent axis-ii disode accoding to DSM-IV (following a stuctued clinical inteview (SCID I and II fo DSM-IV) conducted by C.J.), (2) had a histoy of dependence on illicit dugs o alcohol, (3) wee cuently taking any psychotopic medication othe than psychostimulants, and (4) had sensoimoto deficits o othe neuological disodes. Futhe geneal exclusion citeia wee manifest eading disabilities (as indicated by subjective complaints, infomation fom 2254

4 Pefontal Dysconnectivity in ADHD Adults paents, elatives, and by school epots) and an IQ level below 80. All patients had a histoy of methylphenidate (MPH) teatment. At the time of the fmri scanning, six patients wee emoved fom medication fo at least 6 weeks, wheeas the emaining six patients discontinued thei teatment with MPH at least 3 days pio to the scanning pocedue. ADHD psychopathology was ated by means of the Adult Self Repot Scale (ASRS) [Kessle et al., 2005; Reute et al., 2006]. Impulsiveness was assessed by the Baatt Impulsiveness Scale (BIS) [Patton et al., 1995] and the Eysenck Impulsiveness Questionnaie (EIQ) [Goss et al., 1999]. The healthy contol goup was ecuited fom the Univesity of Ulm campus and consisted of 12 ight-handed males matched fo age, education and intelligence. Fluid intelligence in patients and contols was measued using a suboutine fom the Leistungspuefsystem [Hon, 1983]. Contols wee excluded fom paticipation if they (1) had a cuent axis-i and/o a concuent axis-ii disode accoding to DSM-IV (following a stuctued clinical inteview (SCID I and II fo DSM-IV) conducted by R.C.W. and N.V.), (2) had a fist-degee elative with a neuologic o psychiatic disode, (3) had a histoy of dependence on illicit dugs o alcohol, (4) wee cuently taking any psychotopic medication, and (5) had sensoimoto deficits o othe neuological disodes. All paticipants eceived monetay compensation fo thei paticipation. The poject was appoved by the local Institutional Review Boad. Witten infomed consent accoding to the Declaation of Helsinki was obtained fom all subjects following a complete desciption of the puposes and isks of the study. Neuopsychological Tests To povide additional infomation on cognitive function in this patient sample, a neuopsychological test battey assessing vebal and spatial WM, executive function and behavioal inhibition was administeed to each subject. Vebal and spatial WM tests included the digit span [Wechsle, 1981] and the Cosi block [Milne, 1971]. WM maintenance was assessed by fowad testing, and WM manipulation pocesses wee detemined by backwad testing (12 vebal and 9 spatial items, espectively, pesented at 1 Hz). Executive function was measued using a computeized vesion of the Wisconsin Cad Soting Test, WCST [Nelson, 1976]. This WCST vaiant consisted of 48 cads and a maximum of five categoy switches. Inhibition was tested by a computeized vesion of the Stoop Wod- Colo Intefeence Test [Pelstein et al., 1998] based on andomized single tials (20 tials pe colo and condition). Cognitive Activation Task fo fmri The cognitive activation task has been descibed elsewhee in full detail [Wolf and Walte, 2005; Wolf et al., 2006]; see also Figue 1. Fo each single tial, thee capital gay lettes appeaed on a black sceen duing an initial stimulus peiod of 1,500 ms. One, two, o thee of these lettes wee highlighted at the end of the stimulus peiod fo 500 ms. Subjects wee instucted to focus only on those lettes which wee highlighted and to memoize the lette(s) which followed them next in the alphabet (i.e. manipulated set). By emphasizing a shift of memoanda towad othe lettes of the alphabet, a manipulation component duing the delay peiod was intoduced. Low manipulation demand (i.e. WM load level 1) was chaacteized by one lette which had to be identified as the one which followed next in the alphabet and had to be maintained fo 6,000 ms. Intemediate and high manipulation demand wee chaacteized by two and thee lettes, espectively (i.e. load levels 2 and 3). In the pobe peiod of 2,000 ms, subjects had to indicate whethe a lowe-case lette was o was not pat of the manipulated set. The contol condition displayed thee gay X s and equied a steeotype button pess in esponse to the pesentation of a small x duing the pobe peiod, thus foming a moto task without WM equiements. Functional Data Acquisition The functional data wee acquied using a 3T Magnetom ALLEGRA (Siemens, Elangen, Gemany) head MRI system. T2*-weighted images wee obtained using echoplana imaging in an axial oientation (TR 5 2,400 ms, TE 5 40 ms, FoV 192 mm, matix, 28 slices, slice thickness 3 mm, gap 1 mm). Stimuli wee pesented via LCD video goggles (Resonance Technologies, Nothidge, CA) and both eaction times (RT) and accuacy indices wee ecoded. Head movement was minimized using padded ea phones. The fmri potocol was an eventelated design with a pseudoandomized time jitte of TR intetial-inteval (single tial duation 5 10 s s). The stimuli wee pseudoandomized and countebalanced fo the elative fequency of each lette pe WM load, position, and pobe. The appeaance of pobes fom the two immediately peceding tials was avoided in ode to pevent poactive intefeence fom peceding stimuli [Jonides et al., 1998]. All subjects pefomed thee sessions in total, each including 28 tials, compising 164 volumes. The fist eight volumes of each session wee discaded to allow fo equilibation effects. Behavioal data analysis Data Analysis Pefomance measues on the neuopsychological test battey wee ecoded as follows: (1) digit span, fowad and backwad condition: numbe of coectly etieved items; (2) spatial span, fowad and backwad condition: numbe of coectly etieved items; (3) WCST: numbe of peseveative eos and adjusted switch costs [Spitze et al., 2001]; (4) Stoop test: mean RT of coectly identified 2255

5 Wolf et al. Figue 1. Activation paadigm. Duing a stimulus peiod of 1,500 ms, thee capital gay lettes appeaed on a black sceen. One, two, o thee of these lettes would then become highlighted fo 500 ms. Subjects wee instucted that duing a subsequent 6,000 ms delay peiod they wee to focus only on those lettes which wee highlighted and to memoize the lettes which followed them in the alphabet (manipulated set). Low-woking memoy demand was chaacteized by one lette which had to be identified as the one which followed next in the alphabet and had to be maintained fo a shot peiod of time (load level 1). Intemediate and high woking memoy demand was chaacteized by the pocessing of two and thee next lettes, espectively (load levels 2 and 3). In the pobe peiod of 2,000 ms a lowe case lette was pesented, and subjects had to indicate whethe this lette was o was not pat of the manipulated set. The contol condition displayed thee gay X s and equied a button pess (ight middle finge) in esponse to the pesentation of a small x duing the pobe peiod. In this example, the pobe (c) was always pat of the manipulated set. tagets and eo diffeences between the inconguent and conguent conditions. Diffeences between contols and ADHD patients wee assessed by calculating eight sepaate t tests (P < 0.05). In ode to avoid a-eo accumulation, all t tests wee Bonfeoni-coected (P < ). Task pefomance duing fmri was ecoded as pecentage of coect esponses (accuacy) and RT of coectly pefomed tials. Between goup diffeences in task accuacy and RT with inceasing load wee assessed sepaately using epeated-measues analysis of vaiance (ANOVA; P < 0.05) with the factos goup and load fo accuacy and RT. Additionally, we pefomed diected t tests fo RT and accuacy duing all WM conditions (P < 0.05) between contols and patients. Analysis of functional MRI data Data pepocessing. Pepocessing of the functional data was pefomed using SPM5 (Wellcome Depatment of Cognitive Neuology, London) and MATLAB 7.2 (Math- Woks, Natick, MA). The functional images wee coected fo slice timing diffeences and fo motion atifacts, then spatially nomalized to the MNI template with a final voxel esolution of 3 mm 3 3 mm 3 3 mm voxels. All images wee spatially smoothed with a 9 mm full width at half maximum (FWHM) isotopic Gaussian kenel. Goup-level geneal linea model (GLM) analysis. To investigate paametically vaied local changes in bain activation, i.e. linea bain activation esponses with linealy inceasing WM load, single subject analyses and goup compaisons wee pefomed within a GLM famewok [Fiston et al., 1995a] using the canonical-hf function as a pedicto to estimate the hemodynamic esponse function. A paametic design matix was computed fo each subject using SPM5. The stimulus, delay, and taget peiods wee modeled as events occuing at the beginning of the espective phase, lasting 2,000 ms, 6,000 ms, and 2,000 ms, espectively. To assess linea bain activation esponses with linealy inceasing WM load, the stimulus, the delay, and the taget peiod wee sepaately modeled using a linea modulation of the espective egesso. Incoectly pefomed tials and the individual head movement paametes wee used as egessos of no inteest. All images wee enteed into a fixed-effects model fo each subject [Fiston et al., 1995b] and adjusted fo global effects. Low-fequency difts wee emoved via a highpass filte using low-fequency cosine functions with a cutoff of 137 s. Fo each subject egionally specific paametic esponses wee calculated fo the stimulus, the delay, and the pobe peiod using linea contasts. These analyses yielded individual activation maps of linealy inceasing 2256

6 Pefontal Dysconnectivity in ADHD Adults bain activation with linealy inceasing WM pocessing fo the stimulus, the delay, and the pobe phase. To account fo inteindividual vaiance and in ode to genealize infeences, andom-effects analyses wee computed on the 2nd level [Holmes and Fiston, 1998]. Fo within-goup analyses, voxelwise one-sample t tests (P < 0.001, uncoected) wee used to calculate paametic within-goup maps fo each task peiod (stimulus, delay and pobe). Fo between-goup analyses, a two-sample t test, masked by a combination of the main effects maps of both goups fo each task peiod (i.e. the stimulus, delay and taget phase, P < 0.001, uncoected) was used to compae spatial maps between healthy contols and ADHD individuals. Being a pioi diven, the statistical theshold fo this between-goup compaison was set at P < 0.005, and a spatial contiguity citeion of 25 adjacent voxels [Foman et al., 1995]. Independent component analysis (ICA). To investigate the functional coupling of the VLPFC and the ceebellum, a spatial ICA was pefomed using a goup ICA fo fmri toolbox (GIFT; [Coea et al., 2005]. The dimensionality of the functional data fo each subject was educed using thee consecutive steps of a Pincipal Component Analysis altenated with data concatenation, esulting in one aggegate mixing matix fo all subjects. The fmri data wee fist concatenated pe subject and then acoss all subjects. An ICA decomposition using the Infomax algoithm was used to extact 19 independent components (ICs), consisting of goup spatial maps and elated timecouses. The minimum desciption length citeia as implemented in GIFT wee used to estimate the ode selection, i.e. the numbe of ICs [Calhoun et al., 2001] fom the smoothed data sets afte taking into account the spatial and tempoal coelation of the fmri data. Fist, a set of effectively independent and identically distibuted data samples was estimated fo each subject though a subsampling algoithm. Second, the median of these values acoss the whole sample was used fo ode selection. The estimation of the numbe of the ICs pefomed diectly on the data has been poven to effectively educe the occuence of ove/undefitting the data [Li et al., 2007]. Eventually, the estimated ICs wee used fo a back econstuction into individual ICs using the aggegate mixing matix ceated duing the dimensionality data eduction steps. To identify a task-elated pefontoceebella netwok of inteest, the individual ICs consisting of individual spatial independent maps and time-couses wee spatially soted using a mask compising the left VLPFC (BA 47) and the ight ceebellum. Using MasBa 0.41 [Bett et al., 2002], this mask was ceated fom the between-goup diffeences on the 2nd level (healthy contols > ADHD adults, see also GLM analysis: between-goup compaisons section) and thus included the left VLPFC and ight ceebellum as well as the ight insula, the ight middle occipital gyus, and the ight medial fontal gyus. The component of inteest (COI) that showed the highest positive spatial coelation with this mask acoss all thee sessions was chosen fo subsequent 2nd level within- and between-goup analyses. The voxel weights acoss all sessions fo each subject s spatial COI wee used as andom effects vaiables and analyzed on the 2nd level using SPM5. Fo within-goup analyses, voxelwise one-sample t tests against the null hypothesis of zeo magnitude wee used to calculate withingoup maps (P < 0.001, uncoected). Fo between-goup analyses, two-sample t tests wee used to compae spatial maps between healthy contols and ADHD adults. These analyses wee masked by a combination of the main effects maps of both goups fo the espective COI (P < 0.001, uncoected). The statistical theshold fo these compaisons was set at P < 0.05 coected fo multiple compaisons using the false discovey ate (qfdr) [Genovese et al., 2002; Stoey and Tibshiani, 2003]. Fo all analyses, all anatomical egions and denominations ae epoted accoding to the atlases of Talaiach and Tounoux [1988] and Duvenoy [1999]. Coodinates ae maxima in a given cluste accoding to the MNI template. Coelation analyses. Exploatoy coelation analyses (P < 0.05, uncoected fo multiple compaisons) wee calculated in ode to investigate the elationship between bain function, ADHD symptoms, and WM task accuacy duing fmri. A nonpaametic analysis was chosen in ode to minimize potential effects of data outlies and of a non- Gaussian distibution of the data. Speaman coelations wee computed using the appopiate clinical vaiables, the accuacy measues fo all WM load levels (levels 1 3) and the extacted beta paamete at the most significantly activated clustes emeging fom the between-goup analyses (Figs. 2b and 3b). The beta paametes wee extacted fom both the paametic analysis (coesponding to the pecent signal change) and the ICA (coesponding to the mean voxel weights of the COI). All coelation analyses wee pefomed using the Statistica softwae package (Vesion 6.0, StatSoft Inc., Tulsa, OK). RESULTS Behavioal Results Neuopsychological esults (Table II) Compaed with healthy contols, ADHD patients task pefomance was wose duing the digit span (both fowad and backwad testing; P < 0.05, uncoected). Howeve, this diffeence did not suvive the Bonfeoni coection fo multiple compaisons (P < ). No significant diffeences wee found fo vaiables measuing spatial WM, executive function and behavioal inhibition. Task Pefomance Duing fmri (Table III) In both goups, we found inceasing eaction times (RTs) with inceasing WM load (F (3, 66) , P ). A significant goup effect was not found (F (1, 22) 2257

7 Wolf et al. Left: Bain egions in which healthy contols (geen) and ADHD adults (blue) showed a linea incease in bain activation with linealy inceasing WM load duing the delay peiod. Results of the 2nd level within-goup analysis, P < (uncoected at the voxel level, P < 0.05 cluste coected). Right: Bain egions in Figue 2. which healthy contols showed a geate linea incease in bain activation with linealy inceasing WM load duing the delay peiod compaed with ADHD adults. Results of the 2nd level between-goup analysis, P < (uncoected) , P ). Thee was no significant goup-byload inteaction (F (3, 66) , P ). Fo accuacy measues, we obseved a significant linea decline with inceasing WM load in both goups (F (3, 66) , P ). A significant goup effect was not found (F (1, 22) , P ). Thee was no goupby-load inteaction (F (3, 66) , P ). Diected t tests fo RT and accuacy did not show any significant diffeences at any WM load level at the chosen significance theshold of P < Functional Imaging Results GLM analysis: Paametic effects of WM load within-goup Encoding peiod. In healthy contols, linealy inceasing activation with inceasing stimulus load (1 3 highlighted stimuli) was found in the left VLPFC (infeio fontal gyus, BA 47), the ight middle fontal gyus (BA 11), the ight insula, the left middle tempoal gyus (BA 21), the left supeio fontal gyus (BA 9), the left dosal cingulate cotex, and the bilateal infeio paietal lobule (BA 40). A simila paametic activation patten was found in ADHD adults; see also Suppoting Infomation Figue S1a. Delay peiod. Both goups showed a linealy inceasing activation patten with inceasing WM pocessing in bilateal bain egions including the VLPFC (BA 44, 45, 47), the dosolateal pefontal cotex (DLPFC; BA 9, 46, 10), the cingulate gyus (BA 24/32, 31), the pemoto cotex, the supplementay moto aea, the insula, the supeio and infeio paietal lobule (BA 7 and 40), the pecuneus, the middle and infeio tempoal gyus (BA 21 and 22), the middle occipital gyus (BA 18, 19), the fusifom gyus, the stiatum (putamen and caudate), the thalamus, the ceebellum and the bainstem; Figue 2 (left), see Suppoting Infomation Table SI fo detailed steeotaxic coodinates and Z-scoes. Pobe peiod. In healthy contols, linealy inceasing activation with inceasing etieval load was found in the bilateal middle fontal gyus (BA 9), the ight infeio fontal gyus (BA 44), and the bilateal infeio paietal lobule. ADHD adults showed a paametic incease in activation in the ight infeio fontal gyus (BA 9), the ight 2258

8 Pefontal Dysconnectivity in ADHD Adults Left: ICA-deived spatial patten of a component-of-inteest (COI) which was positively coelated with the pefontoceebella mask deived fom the paametic GLM analysis and with the delay egesso of the fmri task design matix in healthy contols (geen) and ADHD adults (blue). Results of the 2nd level within-goup analysis, P < (uncoected at the voxel Figue 3. level, P < 0.05 cluste coected). Right: Bain egions within the ICA-deived positive delay-elated COI showing significant diffeences in functional connectivity between healthy contols and ADHD adults. Results of the 2nd level between-goup analysis, P < 0.05 FDR coected. supeio fontal gyus (BA 8), and the left supeio paietal lobule (BA 7); see also Suppoting Infomation Figue S1b. GLM analysis: Between-goup compaisons Encoding and pobe peiod. No significant esults wee found when computing the contasts (contols > patients) and vice vesa (P < 0.005). Delay peiod. Compaed with healthy contols, ADHD adults showed lowe activation of the left VLPFC (infeio fontal gyus, BA 47), the ight insula, the ight middle occipital gyus (BA 18), the ight medial fontal gyus (BA 6), and the ight ceebellum; Figue 2 (ight), see also Table IV fo detailed steeotaxic coodinates and Z-scoes. The contast (patients > contols) did not yield any activation diffeences. ICA: Within-goup effects In both healthy contols and ADHD adults, one COI was identified that showed the geatest positive spatial coelation with the pefontoceebella mask deived fom the GLM between-goup analysis ( ). The timecouse of this COI also showed a positive tempoal coelation with the delay egesso of the task design matix ( ). The COI evealed a patten of functional connectivity compising the bilateal VLPFC (bilateal infeio fontal gyus 47 and left BA 44), the DLPFC (supeio and middle fontal gyus, BA 9), the fontopola cotex (middle fontal gyus, BA 10), the cingulate cotex (BA 24 and 32), the supeio fontal cotex (BA 6 and 8), the infeio paietal lobule (BA 40), the pecuneus, the stiatum (putamen and caudate), the ight thalamus and the ight middle tempoal gyus (BA 21). Activation of the supeio paietal lobule (BA 7) and the ceebellum was found in healthy contols only; Figue 3 (left), see Suppoting Infomation Table SII fo detailed steeotaxic coodinates and Z-scoes. ICA: Between-goup compaisons Compaed with healthy contols, ADHD adults showed lowe connectivity of the bilateal VLPFC (infeio fontal gyus, BA 47), the left anteio cingulate cotex (BA 32), the supeio medial fontal gyus (BA 10), the bilateal supeio fontal gyus (BA 6), the bilateal supeio paietal 2259

9 Wolf et al. TABLE II. Results of the neuopsychological assessment (two sample t test, P < 0.05) Test Healthy contols (n 5 12) ADHD adults (n 5 12) Analysis Mean SD Mean SD T value lobule (BA 7), and the bilateal ceebellum. Compaed with healthy contols, ADHD adults showed a highe degee of functional connectivity of the left dosal cingulate cotex (BA 24), the ight infeio fontal gyus (BA 44), the ight supeio fontal gyus (BA 6), and the left cuneus (BA 17); Figue 3 (ight), see also Table V fo detailed steeotaxic coodinates and Z-scoes. Coelation of bain function with ADHD symptoms and task accuacy A negative coelation between bain function and ADHD symptoms, as ated by the WURS was found in the ight ceebellum (x 5 6, y 5257, z 5239; , P < 0.05, uncoected). No significant coelations between egional bain activation, functional connectivity measues, and ADHD psychopathology wee found when coelating the ASRS, BIS, and WURS scoes with the VLPFC, the supeio fontal and paietal cotex, the insula and the anteio cingulate cotex. A positive coelation between task pefomance and bain function in the ADHD goup was found between task accuacy at load level 3 and functional connectivity indices in the ight infeio fontal gyus (BA 44, x 5 39, y 5 6, z 5 33; , P < 0.05, uncoected) only. DISCUSSION unco. P value DS-f a DS-b a SS-f SS-b WCST-P WCST-sc 2.0 s s Stoop-RT ms ms Stoop-e DS-f, digit span, fowad condition; DS-b, digit span, backwad condition; SS-f, spatial span, fowad condition; SS-b, spatial span, backwad condition; WCST-P, numbe of peseveative eos; WCST-sc, switch costs; Stoop-RT, Stoop-effect, eaction time; Stoop-E, Stoop-effect, numbe of eos. See also Neuopsychological esults and Neuopsychological tests sections fo a detailed desciption of the cognitive tasks, the statistical analysis and significance levels. a This diffeence did not suvive the Bonfeoni coection fo multiple compaisons (P < ). In this study, we used fmri and a paametic WM activation paadigm to investigate both egional changes in bain activation and functional connectivity diffeences in bain netwoks undelying WM pocessing in adults with ADHD. Ou data evealed thee main findings: fist, although behavioal pefomance did not significantly diffe between healthy contols and ADHD adults, the latte showed lowe paametically modulated activation in distinct cotical and subcotical aeas compaed with healthy subjects. Regional activation diffeences wee confined to the delay peiod of the activation task and wee not detected duing the encoding o duing the pobe phase. As pedicted, lowe activation in ADHD adults was found in the left VLPFC (BA 47) and the ight ceebellum. Second, connectivity abnomalities wee detected by means of ICA within a functionally elated netwok compising bilateal vento- and dosolateal pefontal egions, the anteio cingulate cotex, the bilateal paietal cotex, and the ceebellum. Specifically, ADHD adults showed a deceased functional connectivity patten in cotical and subcotical netwok nodes compising the bilateal VLPFC (BA 47), the left anteio cingulate cotex (BA 32), the bilateal supeio paietal lobule (left BA 7), and the bilateal ceebellum compaed with healthy subjects. Thid, within the same functional netwok, ADHD adults exhibited a patten of inceased connectivity in the ight infeio fontal gyus (BA 44), the left dosal cingulate cotex (BA 24), the ight supeio fontal gyus (BA 6), and the left cuneus (BA 17). Ou functional imaging findings ae consistent with the hypothesis of pefonto-paietal, anteio cingulate, and ceebella dysfunction in ADHD [Bush et al., 2005; Castellanos and Tannock, 2002; Dickstein et al., 2006; Faaone and Biedeman, 1998; Valea et al., 2005] suggesting both egional and functional connectivity deficits in multimodal cotical and subcotical egions associated with WM pocessing, inhibitoy contol and attention. In paticula, paametically modulated egional bain activation changes wee found in the left VLPFC (BA 47) and the ight ceebellum duing the delay peiod of the cognitive activation task, whee manipulation and maintenance of stimuli wee equied. In contast, no egional changes in bain activation wee obseved duing the stimulus and pobe peiod, TABLE III. Task pefomance (means and SD) of healthy subjects and ADHD adults Task condition Healthy contols (n 5 12) Reaction time Accuacy ADHD adults (n 5 12) Reaction time Accuacy Mean SD Mean SD Mean SD Mean SD Contol condition Load level Load level Load level The eaction time (RT) of coectly pefomed tials is given in ms; task accuacy is given in pecent of coect answes. 2260

10 Pefontal Dysconnectivity in ADHD Adults TABLE IV. Bain egions in which healthy contols showed a geate paametic activation esponse with inceasing WM load duing the delay peiod compaed with ADHD adults Anatomical Region x y z Z No. of activated voxels Healthy contols > ADHD adults Left infeio fontal gyus (BA 47) Right insula Right middle occipital gyus (BA 18) Right medial fontal gyus (BA 6) Right ceebellum Results of the 2nd level between-goup analysis, P < (uncoected). in accodance with the notion of impaied vebal stoage and executive pocesses in ADHD patients duing WM pocessing [Matinussen et al., 2005]. Evidence fom functional neuoimaging studies of memoy pocesses in humans have suggested that the implementation of an intended act o plan to ecall o emembe a specific stimulus set may be the lowest common denominato of VLPFC activation [Coutney et al., 1997; Henson et al., 1999; Owen, 2000]. Consistent with this notion, VLPFC activation in healthy subjects has been demonstated to occu duing tasks that equie the active compaison of stimuli held in both WM and long-tem memoy [Owen et al., 2005; Petides, 1994; Wolf et al., 2006], stimulus selection [Rushwoth et al., 1997], and holding online of both spatial and nonspatial infomation [Goldman-Rakic, 1990, 1996]. The finding of lowe ceebella activation duing the delay peiod in ADHD adults, as in ou study, is consistent with functional neuoimaging findings in the child and adolescent liteatue [Bush et al., 2005; Faaone and Biedeman, 1998]. In addition, a ecent fmri study investigating vebal WM in adults with ADHD epoted deceased activity in ceebella egions as one of its majo findings [Valea et al., 2005]. Futhemoe, egional activation changes in both the VLPFC and the ceebellum have been linked to familial vulneability to ADHD [Duston et al., 2006; Mulde et al., 2008]. Ceebella contibutions to cognition have been linked to the epesentation of pecise tempoal elationships and timing pocesses duing sensoy anticipation [Castellanos and Tannock, 2002], and the ole of the ceebellum duing WM has been inceasingly ecognized [Owen et al., 2005]. In conjunction with pevious findings in healthy contols and ADHD patients, the egional activation abnomalities in ADHD adults, as shown by ou GLM-based appoach, suggest that with inceasing demand on manipulation of vebal stimuli duing the delay peiod, impaied ventolateal pefontal and ceebella egions in ADHD might be paticulaly sensitive to cognitive load. Thus, lowe pefontoceebella activation in ADHD adults could mio deficient pocesses of stimulus monitoing and timing as well as deficits duing compaison of to be manipulated stimuli epesenting tansiently elevant infomation (i.e. vebal stimuli pesented pio to manipulation duing the delay peiod). Although we cannot exclude the possibility of impaied encoding and etieval pocesses in ADHD adults, the egionally abnomal patten of bain activation duing the delay phase at least suggests that abnomal activation in ADHD duing WM pocessing is elated to cognitive sub- TABLE V. Bain egions showing significant diffeences in functional connectivity between healthy contols and ADHD adults Anatomical egion x y z Z No. of activated voxels Healthy contols > ADHD adults Left infeio fontal gyus (BA 47) Right infeio fontal gyus (BA 47) Left anteio cingulate (BA 32) Medial fontal gyus (BA 10) Left supeio fontal gyus (BA 6) Right supeio fontal gyus (BA 6) Left supeio paietal lobule (BA 7) Right supeio paietal lobule (BA 7) Left ceebellum Right ceebellum ADHD adults > healthy contols Left dosal cingulate (BA 24) Right infeio fontal gyus (BA 44) Right supeio fontal gyus (BA 6) Left cuneus (BA 17) Results of the 2nd level between-goup analysis, P < 0.05 FDR coected. x, y, and z ae Talaiach coodinates of the most significant cente of activation within an activated cluste. Z, Z-value; BA, Bodmann Aea. 2261

11 Wolf et al. pocesses equied duing the delay peiod to a geate extent than duing the othe two dissociable phases. In addition to egional activation abnomalities, ADHD adults showed a patten of lowe functional connectivity in the bilateal VLPFC (BA 47), the left anteio cingulate cotex (BA 32), the bilateal supeio paietal lobule (left BA 7), and the bilateal ceebellum compaed with healthy subjects. These esults complement the GLM-based findings of lowe activation found in the left VLPFC and the ight ceebellum by showing that connectivity abnomalities in ADHD involve moe widespead lateal and medial pefontal, paietal and ceebella egions, which ae not evident using a GLM-based appoach only. Thee is abundant evidence fom functional neuoimaging studies suggesting that inhibitoy contol is associated with an activation patten including the VLPFC, the anteio cingulate and the paietal cotex, e.g. [Duston et al., 2002, 2006; Konishi et al., 1999; Smith et al., 2006], and that these functionally heteogeneous egions also subseve WM pocesses [Owen et al., 2005; Wolf and Walte, 2005]. Moeove, pevious studies in childen and adults with ADHD have epoted abnomal activation of the VLPFC and the anteio cingulate cotex duing esponse inhibition [Bush et al., 1999; Duston et al., 2006] and WM [Schweitze et al., 2000], as well as hypoactivation of the paietal cotex associated with task switching [Smith et al., 2006]. Indeed, infeio fontal and cingulate cotex hypoactivity in ADHD patients has been shown to be a obust finding consideing the extant functional neuoimaging liteatue [Dickstein et al., 2006]. Ou ICA-deived esults suppot the notion of abeant ventolateal pefontal, cingulate, paietal, and ceebella connectivity in ADHD [Castellanos and Tannock, 2002; Dickstein et al., 2006; Valea et al., 2005], and povide evidence fo a common pathophysiologic mechanism undelying commonly obseved deficits in cognitive and inhibitoy contol in ADHD patients. Specifically, we hypothesize that within a neual netwok subseving WM, attention and inhibition pocesses, distinct netwok nodes might be diffeentially affected with egad to the equiements of a given cognitive activation task, e.g., duing WM o behavioal inhibition. Indeed, a common neual mechanism fo both WM and esponse inhibition deficits in ADHD adults has been suggested peviously given common behavioal deficits duing WM and inhibition pocesses in ADHD adults and patients with damage to the ight infeio pefontal cotex [Clak et al., 2007]. Ou functional connectivity esults suppot this notion by showing that in addition to egional activation abnomalities in the left VLPFC, a functional decoupling of ight hemisphee VLPFC egions is also pesent duing WM pocessing. Howeve, given methodological limitations inheent to an ICA appoach, we cannot pase out the elative contibution of the ight VLPFC, the anteio cingulate, the bilateal paietal cotex and the ceebellum to distinct cognitive subpocesses duing WM. Although the patten of functional connectivity was positively coelated with the delay peiod, diffeential contibutions of these bain aeas could be also linked to seveal task-inheent pocesses othe than WM, e.g., to the allocation of attentional esouces o to monitoing pocesses. Of note, ADHD adults also exhibited a patten of inceased connectivity in the ight infeio fontal gyus (BA 44), the left dosal cingulate (BA 24), the ight supeio fontal gyus (BA 6), and the left cuneus (BA 17). The possibility that neual eoganization o othe compensatoy mechanisms could compensate fo egions deficient duing manipulation and maintenance of memoanda in patients with ADHD has been peviously discussed against the backgound of obsevations of inceased cotical activation [Bush et al., 1999, 2005; Epstein et al., 2007; Hale et al., 2007; Schweitze et al., 2000; Sheidan et al., 2007]. Although less obust and consistent compaed with findings of functional hypoactivation in patients with ADHD, cuently available neuoimaging studies of cognitive function in ADHD povide accumulating evidence fo the notion that neual dysfunction in geneal in ADHD patients might be chaacteized by both deceased and inceased activation [Dickstein et al., 2006]. Fo instance, it has been suggested that individuals with ADHD may be less able to ecuit netwoks engaged in executive pocessing in ode to fulfill the equiements of the inceasing task demand [Fassbende and Schweitze, 2006; Sheidan et al., 2007], i.e. show a less efficient pefontal function [Sheidan et al., 2007]. Altenatively, the possibility of abnomally inceased activation that intefees with bain activation typically elicited by a given task has been poposed [Dickstein et al., 2006]. It has been hypothesized that inceased activation in ADHD could elate to compensatoy bain and behavioal function due to inceased cognitive effot [Fassbende and Schweitze, 2006; Sheidan et al., 2007] o due to symptom emission [Schulz et al., 2005]. Given ou findings of inceased functional connectivity in the infeio fontal and the dosal cingulate cotex, a compensatoy ecuitment of these egions duing WM pocessing seems one plausible explanation. Indeed, measues of task accuacy wee positively coelated with indices of functional connectivity stength in the ight infeio fontal cotex (BA 44), at least suggesting a elationship between inceasing connectivity in this bain egion and task pefomance. Howeve, infeio fontal and cingulate egions have also been associated with attentional pocesses within the so called default-mode netwok [Raichle et al., 2001; Weissman et al., 2006]. Recently, a decoupling between the anteio cingulate and the pecuneus/posteio cingulate cotex duing the bain s esting state has been poposed as a new candidate locus of dysfunction in ADHD adults [Castellanos et al., 2008], complementing a pio epot showing abeant esting-state connectivity in the dosal cingulate cotex in ADHD patients [Tian et al., 2006]. Howeve, since both inceased [Tian et al., 2006, 2008] and deceased [Castellanos et al., 2008; Uddin et al., 2008] esting-state connectivity of posteio cotical egions has been epoted in ADHD patients, it is unclea if a patten of task-elated inceased connectivity as shown in this 2262

12 Pefontal Dysconnectivity in ADHD Adults study actually eflects compensatoy activation elated to cognitive demand o inceased baseline activity. Thus, although ou study may suggest pefomance-elated compensatoy cotical pocesses in ADHD adults, the issue of functional hypeactivation in ADHD clealy necessitates futhe eseach. It is impotant to note that the between-goup activation diffeences found in this study ae unlikely to be a seconday effect of academic achievement, IQ, o impaied cognitive pefomance. The ADHD adults included in this study did not diffe fom healthy contols with egad to IQ, yeas of education, and behavioal pefomance duing a boad ange of cognitive domains, indicating well-peseved cognitive function and academic achievement simila to healthy contols as demonstated by the fact that vebal and spatial WM, cad soting, and inhibition duing the Stoop task wee not significantly impaied in the patient goup compaed with healthy contols. With egad to task pefomance duing fmri, ADHD adults did not significantly diffe fom healthy contols with espect to both RT and accuacy at highe WM load levels, in accodance with pevious behavioal findings in adult ADHD patients duing vebal WM pefomance [Hale et al., 2007; Valea et al., 2005]. Eventually, as we included only coectly pefomed tials in the functional analyses based on the GLM, we sought to minimize the potentially elevant activation bias esulting fom deceased task accuacy in both goups. In addition, although IQ measues did not significantly diffe between ADHD patients and healthy contols (P < 0.31), all 2nd level analyses wee nevetheless ecalculated including the individual IQ values as a nuisance vaiable. These analyses did not significantly alte the functional esults on both the egional and on the functional connectivity level, being in line with the notion that WM impaiment in ADHD is not sufficiently explained by diffeences in oveall intellectual ability [Matinussen et al., 2005; Willcutt et al., 2005]. Howeve, the behavioal esults ae potentially limited by the elatively small sample size included in this study and by the fact that the patient goup consisted of highly motivated ADHD patients, who eceived monetay compensation fo thei paticipation in this poject. As such, we cannot ule out a motivational bias which may have additionally contibuted to negative goup effects in cognitive pefomance. Although the functional data ae consistent with the notion of a disupted cicuity involving the ventolateal pefontal cotex, the anteio cingulate, the paietal cotex, and the ceebellum in ADHD patients [Dickstein et al., 2006; Valea et al., 2005], the functional esults deived fom this study ae nevetheless limited by the elatively small sample size (n 5 12), and, thus, have to be eplicated in a lage patient cohot. Moeove, all ADHD patients included in this study had a histoy of MPH medication. WM dysfunction in both childen and adolescents with ADHD is emediated by MPH teatment [Kempton et al., 1999; Mehta et al., 2004], and the administation of MPH in ADHD patients has been shown to be associated with inceased activation in fonto-stiatal and ceebella egions [Epstein et al., 2007; Vaidya et al., 1998]. Howeve, a substantial popotion of ou main findings, namely egional activation abnomalities of ventolateal pefontal and ceebella aeas and abeant connectivity of the bilateal VLPFC, the anteio cingulate, the paietal cotex, and the ceebellum in ADHD adults indicate coticosubcotical hypoactivation in patients compaed with healthy contols, consistent with models of hypofontality in ADHD [Dickstein et al., 2006]. Moeove, a ecent statistically based metaanalysis of functional neuoimaging studies in ADHD failed to suppot the notion that functional activation changes in this patient population eflect the impact of psychotopic medication as opposed to ADHD pathology [Dickstein et al., 2006]. Nevetheless, although all patients investigated in this study wee emoved fom medication at least thee days pio to scanning, the long-tem effects of medication on bain function ae not yet well known [Langleben et al., 2002], and may have had an impact on ceebal activation and connectivity diffeences obseved in the ADHD goup. Thus, the esults of this study should be cautiously intepeted fom this pespective. Anothe potential limitation of this study is that although patients with manifest subjective eading disability wee excluded fom paticipation, eading disability was not fomally tested in the patient goup. Howeve, we sought to exclude manifest eading disability in the patient sample not only by assessing subjective complaints but also by obtaining independent infomation fom paents, elatives, and school epots and thus additionally minimizing potential inclusion bias. Futhemoe, vebal WM pefomance in childen and adolescents with ADHD has been shown to be independent of comobidity with language leaning disodes [Matinussen et al., 2005], wheeas the impact of comobid language leaning disodes on WM pefomance and WMelated bain function in ADHD adults is yet not clea [Samuelsson et al., 2004] and meits futhe investigation. Keeping these limitations in mind, this study suggests both egional bain activation deficits and functional connectivity changes of ventolateal pefontal and ceebella egions in ADHD adults duing cognitive pocessing. Moeove, functional connectivity analyses povide peliminay evidence fo a disupted coticosubcotical netwok including ventolateal pefontal, anteio cingulate, paietal, and ceebella egions in ADHD adults, suppoting the notion of a common abeant netwok fo attention, inhibitoy contol, and WM dysfunction. Futhe eseach will be conducted in a lage patient population in ode to investigate the association of clinically and genetically chaacteized ADHD subtypes with these pattens of egional bain dysfunction and disupted pefontal connectivity. ACKNOWLEDGMENTS The authos would like to thank Alexande Lin, Califonia Institute of Technology, Pasadena, CA, fo insightful comments on a pevious vesion of this manuscipt. 2263