Boston Massachusetts 3 Department of Psychology, University of Arizona, Tucson, Arizona

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1 Human Bain Mapping 30: (2009) Single Dose of a Dopamine Agonist Impais Reinfocement Leaning in Humans: Evidence Fom Event-Related Potentials and Computational Modeling of Stiatal-Cotical Function Diane L. Santesso, 1 A. Eden Evins, 2 Michael J. Fank, 3 Eika C. Schette, 1 Ryan Bogdan, 1 and Diego A. Pizzagalli 1 * 1 Depatment of Psychology, Havad Univesity, Cambidge, Massachusetts 2 Depatment of Psychiaty, Massachusetts Geneal Hospital and Havad Medical School, Boston Massachusetts 3 Depatment of Psychology, Univesity of Aizona, Tucson, Aizona Abstact: Animal findings have highlighted the modulatoy ole of phasic dopamine (DA) signaling in incentive leaning, paticulaly in the acquisition of ewad-elated behavio. In humans, these pocesses emain lagely unknown. In a ecent study, we demonstated that a single low dose of a D2/D3 agonist (pamipexole) assumed to activate DA autoeceptos and thus educe phasic DA busts impaied ewad leaning in healthy subjects pefoming a pobabilistic ewad task. The pupose of this study was to extend these behavioal findings using event-elated potentials and computational modeling. Compaed with the placebo goup, paticipants eceiving pamipexole showed inceased feedback-elated negativity to pobabilistic ewads and deceased activation in dosal anteio cingulate egions peviously implicated in integating einfocement histoy ove time. Additionally, findings of blunted ewad leaning in paticipants eceiving pamipexole wee simulated by educed pesynaptic DA signaling in esponse to ewad in a neual netwok model of stiatal-cotical function. These peliminay findings offe impotant insights on the ole of phasic DA signals on einfocement leaning in humans and povide initial evidence egading the spatiotempoal dynamics of bain mechanisms undelying these pocesses. Hum Bain Mapp 30: , VC 2008 Wiley-Liss, Inc. Key wods: dopamine agonist; feedback-elated negativity; souce localization; einfocement leaning; anteio cingulate cotex D. Pizzagalli has eceived eseach suppot fom GlaxoSmithKline and Meck & Co., Inc. fo pojects unelated to the pesent study. D. Evins has eceived eseach gant suppot fom Janssen Phamaceutica, Sanofi-Aventis, Asta Zeneca; eseach mateials fom GSK and Pfize, and honoaia fom Pimedia, Inc. Moeove, D. Evins is an investigato in a NIDA-funded collaboative study with GSK. D. Santesso, D. Fank, Ms. Schette, and M. Bogdan epot no competing inteests. Contact gant sponso: NIMH; Contact gant numbe: R01 MH68376; Contact gant sponso: National Institute on Dug Abuse; Contact gant numbe: DA022630; Contact gant sponso: Havad College Reseach Pogam. *Coespondence to: Diego A. Pizzagalli, Ph.D., Depatment of Psychology, Havad Univesity, 1220 William James Hall, 33 Kikland Steet, Cambidge, MA 02138, USA. dap@wjh.havad.edu Received fo publication 16 Octobe 2007; Revised 19 May 2008; Accepted 23 June 2008 DOI: /hbm Published online 22 August 2008 in Wiley InteScience (www. intescience.wiley.com). VC 2008 Wiley-Liss, Inc.

2 Santesso et al. INTRODUCTION In ecent yeas, the ole of dopamine (DA) in einfocement leaning has been stongly emphasized. In paticula, electophysiological studies in nonhuman pimates have shown that midbain DA neuons code ewad-elated pediction eos: unpedicted ewads elicit phasic inceases in DA neuons as well as phasic DA elease (positive-pediction eo), wheeas omission of a pedicted ewad elicits phasic DA deceases (negative-pediction eo) [Fioillo et al., 2003; Schultz, 2007]. These phasic DA esponses have been assumed to eflect a teaching signal fo egions implicated in ewad-elated leaning, including the anteio cingulate cotex (ACC) and basal ganglia [Holoyd and Coles, 2002]. Accodingly, when a positivepediction eo occus, leaning about the consequences of the behavio that led to ewad takes place; when a negative pediction eo occus, behavios that led to lack of ewad is extinguished ([Baye and Glimache, 2005; Gais et al., 1999; Montague et al., 1996; Schultz et al., 1997]; fo findings highlighting the ole of DA signaling in instumental leaning, see Cheng and Feensta [2006], Reynolds et al. [2001], Robinson et al. [2007], and Schwabe and Koch [2007].) Based on these findings, disuption of phasic DA esponses is expected to negatively impact pediction eo and, thus, educe einfocement leaning [Montague et al., 1996; Schultz, 2002]. Evidence fom the animal liteatue indicates that single low doses of D2 agonists suppess DA cell fiing ates though autoecepto stimulation [Fulle et al., 1982; Mates et al., 1977; Piecey et al., 1996; Sumnes et al., 1981; Tissai et al., 1983]. In humans, Fank and O Reilly [2006] epoted that low doses of the D2 agonist cabegoline impaied the ability to optimize esponding based on pobabilistic ewad values, without affecting negative feedback leaning. Moe ecently, Pizzagalli et al. [2008] epoted that administation of a single dose (0.5 mg) of a D2/D3 agonist (pamipexole) to healthy subjects blunted einfocement leaning duing a pobabilistic signal detection task in which coect esponses to two stimuli wee diffeentially ewaded. The goal of this study was twofold. Fist, we aimed to extend ou ecent behavioal findings [Pizzagalli et al., 2008] by examining the effects of a single dose of pamipexole on electophysiological coelates of ewad leaning in a subgoup of these paticipants with eliable event-elated potential (ERP) data. To this end, the feedback-elated negativity (FRN) and cuent souce density undelying the FRN wee used as indices of leaning fom positive feedback. The second goal was to apply a computational modeling of stiatal-cotical function [Fank, 2005] on the behavioal findings descibed by Pizzagalli et al. [2008] and evaluate whethe blunted ewad leaning could be explained by eduction of pesynaptic DA busts (i.e., educed positive pediction eo), as oiginally postulated. Emeging evidence implicates vaious pefontal cotex (PFC) egions in adaptive ewad-elated decision making and also highlights impotant functional dissociations. In functional neuoimaging studies, medial PFC egions spanning into the ostal ACC (i.e., Bodmann aeas 10/32) have been implicated in esponse to immediate, but not delayed, ewad [Knutson et al., 2003; McClue et al., 2004] and has been found to tack the value of ewad [Daw et al., 2006; Mash et al., 2007]. The dosal ACC (dacc), on the othe hand, has been implicated in expeimental tasks equiing epesentation of both gains and losses and in integating einfocement histoy acoss seveal tials [Akitsuki et al., 2003; Enst et al., 2004; Roges et al., 2004]. Simila findings have emeged fom animal studies. Hadland et al. [2003], fo example, found that ACC lesions impaied monkeys ability to select actions based on pio einfoces, but did not impai stimulus-ewad associations. In a citical extension, Kenneley et al. [2006] showed that lesions of the ACC impaied pefomance on a task equiing integation of einfocement histoy ove seveal tials. Thus, wheeas animals with ACC lesions esponded similaly to contol animals on single eo tials, they failed to integate einfocement histoy ove time and wee thus unable to lean which esponse was moe advantageous. Similaly, Amiez et al. [2006] found that activity in macaque ACC neuons encoded the weighted pobabilistic value of available ewads. Collectively, these findings emphasize a ole of the dacc in epesenting the einfocement histoy and integating action outcome pattens ove time to guide goaldiected behavio [Rushwoth et al., 2007]. Although hemodynamic neuoimaging appoaches povide valuable infomation about bain cicuities implicated in ewad-based decision making, thei limited tempoal esolution pecludes investigation of the tempoal unfolding of undelying bain mechanisms. High tempoal esolution is paticulaly impotant when consideing that phasic activation of DA opeate on a time couse of tens of milliseconds [Schultz, 2002]. The FRN a negative ERP deflection peaking ms following feedback with a fontocental scalp distibution offes a noninvasive index of activity in the medial PFC implicated in ewad leaning. The geneato of the FRN has been localized to the ACC: ealy dipole localization studies implicate the dacc [Miltne et al., 1997; Gehing and Willoughby, 2002], wheeas moe ecent ERP/fMRI studies implicate medial PFC egions [Mulle et al., 2005; Nieuwenhuis et al., 2005; Van Veen et al., 2004]. The functional significance of the FRN is unclea. Initial obsevations that the FRN is inceased by negative feedback o when outcomes ae wose than expected led to the assumption that the FRN eflects a ewad pediction eo signal [Gehing and Willoughby, 2002; Holoyd and Coles, 2002; Miltne et al., 1997]. Recent findings fom pobabilistic selection [Hajcak et al., 2005; Mulle et al., 2005], gambling [Yeung and Sanfey, 2004; Donkes et al., 2005], and time estimation [Nieuwenhuis et al., 2005] tasks indicate, howeve, that the FRN is also modulated by positive feedback o expeimental settings in which outcomes ae bette than expected. 1964

3 Dopamine Agonist and Reinfocement Leaning Impotantly, ecent evidence suggests that the key vaiable may not be the valence of the feedback but athe its pedictability. Using an anticipating timing task, Oliveia et al. [2007], fo example, demonstated that the FRN was elicited by unexpected positive as well as negative feedback. Citically, a lage FRN emeged only when the feedback did not match paticipants estimation of task pefomance, including when paticipants eceived positive feedback afte having estimated thei pefomance to be incoect. Along simila lines, Mulle et al. [2005] epoted that equivocal (unexpected) feedback elicited a lage (i.e., moe negative) FRN compaed with negative feedback (27.5 vs lv). On the basis of these findings, Mulle et al. agued that the FRN might eflect the apid evaluation of behavio fom extenal cues (whethe it is positive, negative, o uninfomative feedback), and that the FRN is enhanced unde conditions in which feedback seves to guide pefomance on stimulus-esponse mapping tasks. Of inteest, souce localization analyses of the FRN finding evealed that a numbe of egions in the mpfc/acc wee involved in pocessing the infomation conveyed by feedback stimuli thoughout leaning [Mulle et al., 2005]. Finally, Holoyd and Coles [2008] ecently showed that the FRN can be modulated by positive pediction eos. Specifically, the authos used a two-choice esponse task in which the coect esponse was not clealy defined paticipants had to infe the optimal esponse stategy by tial and eo. When paticipants who had adopted a disadvantageous stategy occasionally choose the bette option and thus eaned moe ewad, a moe positive FRN was obseved. Accoding to these authos, positive and negative pediction eos can decease and incease, espectively, the size of the FRN. Taken togethe, esults fom ecent ERP studies indicate that positive pediction eos can affect the FRN (specifically, educe its negativity); moe geneally, these findings ae consistent with the account that unpedicted ewads, suppoted by phasic DA inceases [Fioillo et al., 2003; Schultz, 2007], also seve as teaching signal fo ACC and basal ganglia to optimize goal-diected behavios [Holoyd and Coles, 2008]. The FRN has been compaed to anothe ACC-geneated negativity the eo-elated negativity (ERN), which occus afte eo commission and is thought to eflect intenally diven eo detection, conflict monitoing, and affective eactions to eos [Luu et al., 2000; Yeung et al., 2004]. In a ecent study, Zinheld et al. [2004] assessed the effect of the D2/D3 ecepto antagonist halopeidol on ERN amplitude and obseved that halopeidol impaied leaning and diminished the ERN on a time estimation task; these findings wee late eplicated by De Buijn et al. [2004] using a flanke task. These authos suggested that halopeidol impaied DA signaling such that the phasic DA dip following negative outcomes (i.e., eos) was educed. Collectively, these studies suggest that ewad pedictions eos fom both intenal (eos) and extenal (feedback) cues may be similaly sensitive to DA manipulation. The fist goal of this study was to extend these ERP findings by investigating the effects of a single dose of pamipexole on the FRN. As in ecent studies in nonhuman pimates [Amiez et al., 2006; Kenneley et al., 2006], paticipants in this study wee confonted with a choice between two esponses associated with diffeent pobabilities of ewad. Owing to the pobabilistic natue of this task, subjects wee not able to infe which stimulus was moe advantageous based on the outcome of single tials but needed to conside the einfocement histoy to optimize thei behavioal choices. As mentioned ealie, we ecently demonstated that a single dose of pamipexole led to blunted ewad leaning and educed win-stay stategy (i.e., a educed popensity to select a moe advantageous stimulus afte it had been ewaded in the peceding tial) [Pizzagalli et al., 2008]. On the basis of pio animal [Fulle et al., 1982; Mates et al., 1977; Piecey et al., 1996; Sumnes et al., 1981; Tissai et al., 1983] and limited human findings [Fank and O Reilly, 2006], we postulated that these impaiments wee due to deceased phasic DA busts to unpedicted ewad (i.e., educed positive pediction eos) leading to educed ability to lean about the consequences of the behavio leading to the positive outcome [Schultz, 2007]. The second goal of this study was to test this hypothesis by investigating whethe blunted ewad leaning in paticipants eceiving pamipexole could be simulated by educed pesynaptic DA signaling in esponse to ewad in a neual netwok model of stiatal-cotical function [Fank, 2005]. On the basis of pio findings, we hypothesized that, compaed with subjects eceiving placebo, those eceiving pamipexole will display lage (i.e., moe negative) FRNs due to (1) blunted ewad leaning esulting in geate ewad expectancy violations [Oliveia et al., 2007]; (2) educed positive pediction eo [Holoyd and Coles, 2008]; and/o (3) ove eliance of feedback infomation to guide pefomance [Mulle et al., 2005]. Moeove, paticipants eceiving pamipexole wee expected to show deceased activation in bain egions that integate einfocement histoies and action outcome pattens acoss time, paticulaly the dacc [Akitsuki et al., 2003; Amiez et al., 2006; Enst et al., 2004; Holoyd and Coles, 2008; Kenneley et al., 2006; Roges et al., 2004]. Finally, we expected that blunted ewad leaning afte pamipexole administation could be modeled though educed phasic DA busts in esponse to ewad. METHOD Paticipants Thity-two paticipants wee ecuited fom the community fo a lage study investigating the effects of a D2 agonist on ewad, moto, and attentional pocesses as well as mood [Pizzagalli et al., 2008]. Afte an initial phone sceening, subjects wee invited to the laboatoy fo a Stuctued Clinical Inteview fo the DSM-IV (SCID) [Fist et al., 2002], which was conducted by a eseach psychiatist o 1965

4 Santesso et al. maste-level inteviewe. Subjects meeting the following exclusionay citeia wee excluded: cuent unstable medical illness; pamipexole containdications; any past o cuent Axis I psychiatic disodes; pesence of any neuological disode o dopaminegic abnomality; pegnancy o beast feeding; use of pesciption o ove-the-counte medications in the past week that may inteact with the metabolism of pamipexole; use of DA antagonists in the past month; use of any CNS depessant in the past 24 h that might affect ewad esponsiveness, including antihistamines and alcohol; and histoy in fist-degee elatives of psychological disodes involving dopaminegic abnomalities (schizophenia, psychosis, schizotypal pesonality disode, bipola disode, majo depession, substance dependence). To minimize side effects, a body mass index (BMI) of at least 20 was used. In light of potential changes in dopaminegic sensitivity duing the menstual cycle, all female paticipants pefomed the expeimental session duing days 1 14 of thei menstual cycle [Myes et al., 2003]. Fom the 32 enolled paticipants, 20 had usable ERP data (13 men; mean age , SD ); data fom emaining paticipants wee lost due to insufficient numbe of atifact-fee ERP data, equipment failue, and/o emegence of advese dug effects (see [Pizzagalli et al., 2008] fo moe detail). Among these 20 paticipants, 13 eceived placebo and 7 eceived pamipexole. All paticipants wee ight-handed [Chapman and Chapman, 1987]. The placebo and pamipexole goups did not diffe with espect to gende atio (8 males/5 females vs. 5 males/2 females; Fishe s Exact test: P > 0.30), age ( vs yeas; t , P > 0.52, two-tailed). In addition, the placebo and pamipexole goups did not diffe on self-epoted depessive symptoms ( vs , P > 0.29) o tait anxiety ( vs , P > 0.06), as assessed by the Beck Depession Inventoy-II [Beck et al., 1996] and the tait fom of the Spielbege State-Tait Anxiety Inventoy [Spielbege et al., 1970], espectively. Paticipants eceived $10/h fo the SCID session, $40 fo the expeimental session, and $24.60 in eanings in the pobabilistic ewad task. All paticipants povided witten infomed consent afte a psychiatist fully explained the expeimental potocol, which had been appoved by the Committee on the Use of Human Subjects at Havad Univesity as well as the Patnes-Massachusetts Geneal Hospital Intenal Review Boad. Phamacological Manipulation Pamipexole dihydochloide and placebo wee administeed in a andomized, double-blind design. Paticipants in the pamipexole goup wee administeed 0.5-mg pamipexole in capsule fom, wheeas those in the placebo goup wee administeed an identical capsule. ERP ecoding was conducted 2 h afte dug administation when pamipexole eaches peak concentation [Wight et al., 1997]. Data Collection and Reduction Pobabilistic ewad task Paticipants completed a task [Pizzagalli et al., 2005] that consisted of 300 tials, divided into thee blocks of 100 tials, sepaated by 30-s beaks. Each tial stated with the pesentation of a fixation point fo 1,450 ms in the middle of the sceen. A mouthless catoon face was pesented fo 500 ms followed by the pesentation of this face with eithe a shot mouth o a long mouth fo 100 ms. Paticipants wee asked to identify whethe a shot o long mouth was pesented by pessing eithe the z key o the / key on the keyboad (countebalanced acoss paticipants). In each block, an equal numbe of shot and long months wee pesented within a pseudoandomized sequence. Fo each block, only 40 coect esponses wee followed by positive feedback ( Coect! You won 20 cents ). To induce a esponse bias, an asymmetical einfoce atio was used: coect esponses fo one stimulus ( ich stimulus ) wee ewaded thee times (30:10) moe fequently than coect esponses fo the othe stimulus ( lean stimulus ). Positive feedback was pesented fo 1,500 ms followed by a blank sceen fo 250 ms, and paticipants wee instucted that not all coect esponses would eceive ewad feedback. Tials without feedback wee timed identically (i.e., mouth onset to the next tials fixation) to those with feedback. Following pio studies [Davison and Tustin, 1978; Pizzagalli et al., 2005], esponse bias (log b) and disciminability (log d) wee computed as: log b ¼ 1 2 log Rich coect 3 Lean incoect Rich incoect 3 Lean coect log d ¼ 1 2 log Rich coect 3 Lean coect Rich incoect 3 Lean incoect As evident fom the fomula, esponse bias incopoates esponses to both the ich and lean stimulus, and inceases if paticipants tend to (1) coectly identify the ich stimulus, and/o (2) misclassify the lean stimulus as the ich stimulus. Scalp event-elated potentials EEG was ecoded continuously using a 128-channel Electical Geodesics system (EGI, Eugene, OR) at 250 Hz with Hz analog filteing efeenced to the vetex. Impedance of all channels was kept below 50 kx. Data wee segmented and eefeenced off-line to an aveage efeence. EEG epochs wee extacted beginning 200 ms befoe and ending 800 ms afte feedback pesentation on coect tials duing Blocks 2 and 3 fo the midline sites 1966

5 Dopamine Agonist and Reinfocement Leaning Fz, FCz, Cz, Pz (sensos 11, 6, 129, 62). Only ERP data fom Blocks 2 and 3 wee used to allow paticipants to be exposed to the diffeential einfocement schedule. Data wee pocessed using Bain Vision Analyze (Bain Poducts GmbH, Gemany). Each tial was visually inspected fo movement atifacts and automatically emoved with a 675 lv citeion. Eye-movement atifacts wee coected by Independent Component Analysis. The amplitude of the ERP was deived fom each individual s aveage wavefom and filteed at 1 30 Hz. The FRN was scoed manually fo each subject at each site using a pestimulus baseline between 2200 and 0 ms and a base-to-peak appoach (see e.g., [Hajcak et al., 2007]). The FRN was defined as the most negative peak ms afte feedback pesentation. In addition, to evaluate potential goup diffeences in othe stages of the infomation pocessing flow, EEG epochs beginning 200 ms befoe and ending 800 ms afte stimulus pesentation (shot o long mouth) wee extacted fom Blocks 2 and 3. N1 amplitude was defined as the most negative peak ms afte stimulus onset and P3 amplitude was defined as the most positive peak ms afte stimulus onset. A pestimulus baseline between 2200 and 0 ms was used. Souce localization analyses Low Resolution Electomagnetic Tomogaphy (LORETA; [Pascual-Maqui et al., 1999]) was used to estimate intaceebal cuent density undelying the FRN. The LORETA algoithm is a fom of Laplacian weighted minimal nom solution that solves the invese poblem by assuming that: (1) neighboing neuons ae synchonously activated and display only gadually changing oientations; and (2) the scalp-ecoded signal oiginates mostly fom cotical gay matte. Unlike othe souce localization techniques (e.g., dipole modeling), the LORETA algoithm does not assume an a pioi numbe of undelying souces to solve the invese poblem. Independent validation fo the algoithm has been deived fom studies combining LORETA with fmri [Mulet et al., 2004; Vitacco et al., 2002], PET ([Pizzagalli et al., 2004]; but see Gamma et al. [2004]) and intacanial ecodings [Zumsteg et al., 2005]. In two ecent studies, LORETA localizations wee, on aveage, 16 mm [Mulet et al., 2004] and 14.5 mm [Vitacco et al., 2002] fom fmri activation loci, a discepancy within the ange of the LORETAs estimated spatial esolution (1 2 cm). Fo this study, a thee-shell spheical head model egisteed to the Talaiach bain atlas (available as digitized MRI fom the Bain Imaging Cente, Monteal Neuological Institute) and EEG electode coodinates deived fom cossegistations between spheical and ealistic head geomety [Towle et al., 1993] wee used. The solution space (2,394 voxels; voxel esolution: 7 mm 3 ) was constained to cotical gay matte and hippocampi, which wee defined accoding to a digitized pobability atlas povided by the MNI (i.e., coodinates epoted in main text ae in MNI space). Based on this pobability atlas, a voxel was labeled as gay matte if its pobability of being gay matte was highe than 33% and highe than the pobability of being white matte o ceebospinal fluid. Afte conveting MNI coodinates into Talaiach space [Bett et al., 2002], the Stuctue-Pobability Maps atlas [Lancaste et al., 1997] was used to identify gyi and Bodmann aea(s). In this analyses, cuent density was computed within a ms postfeedback time window, which captued the mean peak latency of the FRN at Cz (232 ms) on coect tials. At each voxel, cuent density was computed as the linea, weighted sum of the scalp electic potentials (units ae scaled to ampees pe squae mete, A/m 2 ). Fo each subject, LORETA values wee nomalized to a total powe of 1 and then log-tansfomed befoe statistical analyses. Physical advese effects Thoughout the session, paticipants wee asked to indicate the extent to which they expeienced 12 physical symptoms using a five-point Liket scale. The symptoms assessed wee headache, cold o chilled, hot o flushed, dizziness, sleepiness, sweating, blued vision, nausea, fast heatbeat, dy mouth, abdominal pain, and diahea. A total advese effect scoe was obtained by subtacting the peadministation scoe fom the maximal advese effect scoe (see [Pizzagalli et al., 2008] fo moe detail). Statistical Analyses The FRN data wee analyzed using a mixed ANOVA with Goup as between-subject facto and Site (Fz, FCz, Cz) as epeated measue. When applicable, the Geenhouse-Geisse coection was used. Follow-up independent t-tests (two-tailed) wee pefomed to decompose significant effects. Peason coelations wee pefomed among the vaiables. Fo the LORETA data, the goups wee contasted on a voxel-wise basis using unpaied t-tests. Based on pio studies using pemutation pocedues to detemine an expeiment-wide alpha level potecting against Type I eo, statistical maps wee thesholded at P < and displayed on a standad MRI template [Pizzagalli et al., 2001]. Contol analyses Sepaate multiple egession analyses wee conducted to ensue that physical advese effects wee not contibuting to significant findings. Total advese effect scoe was enteed in the fist step followed by goup (dummy-coded) in the second step in analyses pedicting FRN o LORETA data. Finally, to evaluate whethe the two goups diffeed in othe steps of infomation pocessing, sepaate ANOVAs with Site (Fz, FCz, Cz, Pz) and Goup (2) as factos wee conducted on the stimulus-locked N1 and P3 data. 1967

6 Santesso et al. Computational Modeling A computational neual netwok model of stiato-cotical function [Fank, 2005] was used to simulate the behavioal esults epoted in ou ecent study [Pizzagalli et al., 2008]. The model, which includes Go and NoGo stiatal populations fo leaning to facilitate ewading esponses and suppess othes (see Fig. 1), has been applied to seveal othe tasks and has been cooboated by empiical and phamacological data [Fank and O Reilly, 2006; Fank et al., 2004]. The coe netwok paametes wee left unchanged to maintain consistency with pio wok, but simulations wee conducted with a moe ecent model that includes the subthalamic nucleus [Fank, 2006]. The cuently implemented model included explicit inhibitoy inteneuons to egulate oveall stiatal activity, instead of the k winnes take all mathematical appoximation to inhibitoy effects. Simulating the pobabilistic signal detection task Netwoks wee tained on an analogous ewad esponsiveness task as the one used in humans. These new simulations involved pesenting two ovelapping stimuli, labeled ich and lean, espectively, to the input laye. Each input stimulus consisted of 5 units and the two stimuli ovelapped by 4 out of 5 units, so that each stimulus had just one unique unit of activation. The pupose of this ovelap was to appoximate the visual similaity of the ich and lean stimuli. Futhe, human subjects come in to the task with the ability to peceptually disciminate these stimuli and ae povided with explicit task instuctions fo selecting ich and lean pio to leaning. Because the computational model does not simulate the peceptual/object ecognition system and is pimaily focused with ewad leaning and espond selection, we simulated this petask peceptual knowledge and discimination ability by setting the weights fom the unique identifying input unit coesponding to the ich and lean stimulus to the appopiate pemoto output unit (R1 fo ich, R2 fo lean). These peset cotico-cotical weights cause the model to be moe likely at the outset to activate the ich esponse fo the ich stimulus and the lean esponse fo the lean stimulus. But note that these input to pemoto weights do not guaantee that the model selects the appopiate esponses in each tial, because: (i) the input stimuli ae still highly ovelapping, and the ovelapping units begin with andom weights to moto and stiatal units; (ii) both pemoto and stiatal unit activity is noisy; and (iii) the input to pemoto connections only affect the degee to which one o the othe esponse is initially moe biased in pemoto cotex a given esponse is not eliably executed unless it also eceives facilitation fom stiatal Go signals. The weights fom the input laye to the stiatum ae all andomly initialized and ae modified by subsequent phasic changes in DA [Fank, 2005]. Figue 1. Neual netwok model of cotico-stiatal cicuity (squaes epesent units, with height and colo eflecting neual activity; yellow, most active; ed, less active; gay, not active). The model includes the diect (Go) and indiect (NoGo) pathways of the basal ganglia [Fank, 2005, 2006]. The Go cells disinhibit the thalamus via the intenal segment of globus pallidus (GPi) and theeby facilitate the execution of an action epesented in cotex. The NoGo cells have an opposing effect by inceasing inhibition of the thalamus, which suppesses actions and theeby keeps them fom being executed. Dopamine fom the substantia niga pas compacta (SNc) pojects to the dosal stiatum. A tonic level of dopamine is shown in SNc; a bust o dip ensues in a subsequent eo feedback phase, causing coesponding changes in Go/NoGo unit activations, which dive leaning, via simulated D1 and D2 eceptos. Pamipexole was simulated by educing the size of DA busts duing ewads to simulate pesynaptic autoecepto effects induced by the low dose. [Colo figue can be viewed in the online issue, which is available at Taining As in the behavioal expeiments, thee Blocks of 100 tials wee un in the model. Mimicking the behavioal study, netwoks wee ewaded (given a DA bust), on 30 ich and 10 lean tials out of evey 50 tials fo each type. Duing these DA busts, which involve maximal DA unit fiing in intact netwoks, the Go units that paticipated in selecting the associated esponse become tansiently moe active, wheeas thei NoGo countepats become less active. These tansient changes in Go/NoGo activity ae accompanied by changes in synaptic plasticity using contastive Hebbian leaning [Fank, 2005], such that Go epesentations become stonge fo esponses that ae ewaded moe fequently as taining pogesses. Because 1968

7 Dopamine Agonist and Reinfocement Leaning ewaded tials ae vey infequent in this task, a highe leaning ate was applied to ewaded tials (0.003; thee times that of nonewaded tials), enabling weights to change by a geate degee in these tials, and to simulate DA effects on synaptic plasticity. Futhemoe, the infequent pesentation of ewads was assumed to poduce a low ewad expectation, and theefoe it was assumed that DA dips do not occu duing ewad omissions. Howeve, synaptic plasticity is not tuned off duing ewad omissions, and model neuons continue to adjust thei connection weights afte each expeience. Because the coticostiatal pojections and plasticity ae somewhat stonge in stength fom cotex to the NoGo pathway, as suppoted by seveal physiological findings [Beetta et al., 1997, 1999; Keitze and Malenka, 2007; Lei et al., 2004], a nonewad still leads to a small degee of NoGo leaning by default (even without an explicit DA dip). This mechanism effectively allows the model to lean that lean esponses ae moe often associated with NoGo than ich esponses and is not diffeent between intact and pamipexole simulations. Simulating pesynaptic effects of pamipexole As discussed ealie, we posited that the mechanism by which low doses of pamipexole educed esponse bias in this task is by stimulating pesynaptic D2 autoeceptos and educing phasic DA fiing and elease. We theefoe simulated pamipexole effects in the model by educing the magnitude of DA busts such that fiing in DA cells eached only 60% maximal activation, compaed with 100% in the intact case. Accodingly, these pesynaptic simulations diffe fom pevious simulations of educed DA in Pakinson s disease [Fank et al., 2004; Fank, 2005], in which a popotion of DA units wee emoved altogethe fom pocessing to simulate DA cell damage. Thus, pamipexole netwoks had a full set of intact DA units, but fiing duing ewads was simply educed. The abovedescibed incease in leaning ate duing ewaded tials in intact netwoks was also maintained in pamipexole simulations, because it is assumed that inceases in DA (and othe neuomodulatoy signals) duing ewaded tials would still enhance leaning, allowing us to specifically investigate the effects solely due to weakened effects of Go/NoGo modulation duing ewads. (Note that if we also educed the leaning ate in pamipexole netwoks, the esulting esponse bias effects would be even stonge, as netwoks with lowe leaning ates necessaily lean slowe. Thus the cuent implementation shows that the pesynaptic simulation accounts fo the impaied esponse bias effects even without educing the leaning ate and is theefoe a moe fai test of the poposed mechanism.) Finally, tonic levels emained unaffected by pesynaptic simulations, in keeping with suggestions that only phasic DA is modulated by pesynaptic autoecepto stimulation [Gace, 1995]. RESULTS Behavioal Data Findings concening behavioal pefomance in the pobabilistic ewad task have been epoted in detail in Pizzagalli et al. [2008]. Biefly, esponse bias was used to measue the systematic pefeence fo the esponse associated with moe fequent ewaded (ich) stimulus and thus to assess the extent to which behavio was modulated by einfocement histoy. Rewad leaning was calculated by subtacting the esponse bias fo Block 1 fom Block 3. Disciminability povided a measue of the paticipants ability to distinguish between the two stimuli. As shown in the left panel of Figue 2, compaed with the placebo goup, paticipants eceiving pamipexole showed significantly (1) educed esponse bias in Block 2 and Block 3 and oveall educed ewad leaning acoss blocks; (2) lowe accuacy fo ich stimuli in Block 3 and highe accuacy fo lean stimuli in Blocks 2 and 3; and (3) educed pobability of choosing ich following a ewaded ich stimulus (i.e., win-stay stategy). No significant effects emeged fo disciminability, suggesting that the two goups did not diffe in task difficulty. Significantly educed esponse bias and accuacy fo the ich stimulus wee eplicated in the educed sample size used in this study (all Ps < 0.03). Scalp ERP Data As hypothesized, a main effect fo Goup emeged, due to lage FRN fo the pamipexole goup than placebo goup acoss sites (F 1, , P ) (Fig. 3a,b). Follow-up t-tests indicated that the pamipexole goup had lage (i.e., moe negative) FRNs compaed with the placebo goup at Fz (t , P ) and FCz (t , P ) only (see Table I). Souce Localization Data LORETA was used to estimate intaceebal cuent density undelying the FRN. As hypothesized, the pamipexole goup showed elatively lowe activity to the ewad feedback stimulus than the placebo goup in the dacc (BA 24), a egion peviously implicated in epesenting einfocement histoies and integating action outcome pattens [Amiez et al., 2006; Kenneley et al., 2006] (see Table II, Fig. 3c). In diect contast, the pamipexole goup showed elatively highe activity in mpfc egions (BA 10/ 11/32) peviously implicated in esponding to single einfocements. Contol Analyses Hieachical egession analyses confimed that the behavioal, FRN, and LORETA esults emained afte adjusting fo advese dug side effects (all DR 2 s > 0.39, all DFs > 11.49, all Ps <.003). Moeove, no significant diffeences 1969

8 Santesso et al. Left panel: Summay of (a) esponse bias; (b) disciminability; (c) accuacy fo the moe fequently ewaded (ich) stimulus; and (d) accuacy fo the less fequently ewaded (lean) stimulus. Figues modified fom Pizzagalli et al. [2008] with pemission. Right panel: Figue 2. Coesponding vaiables fo the intact neual netwok of coticostiatal cicuity ( placebo goups ) and the neual netwok simulating educed pesynaptic DA busts in esponse to ewads ( pamipexole goup ). Eo bas efe to standad eos. 1970

9 Dopamine Agonist and Reinfocement Leaning (a) Aveaged ERP wavefoms fom 200 ms befoe to 600 ms afte the pesentation of coect feedback duing the pobabilistic ewad task fo the pamipexole (heavy line) and placebo (light line) goup aveaged acoss Fz, FCz, and Cz; (b) Topogaphic map of the FRN diffeence wave between the pamipexole and placebo goup (pamipexole minus placebo); and (c) Figue 3. Results of voxel-by-voxel independent t-tests contasting cuent density fo the placebo and pamipexole goup in esponse to ewad feedback. Red: elatively highe activity fo placebo subjects. Blue: elatively highe activity fo pamipexole subjects. Statistical map is thesholded at P < and displayed on the MNI template. 1971

10 Santesso et al. TABLE I. Means (SD) fo FRN time-locked to feedback pesentation and the N1 and P3 time-locked to stimulus pesentation fo the placebo (n 5 13) and pamipexole (n 5 7) goup Fz FCz Cz Pz Placebo FRN 2.51 (2.07) 2.92 (2.66) 1.19 (3.42) N (1.12) (1.05) (1.51) (1.29) P (2.27) 2.64 (2.23) 3.38 (2.17) 3.27 (1.81) Pamipexole FRN (2.22) 0.15 (2.78) (2.50) N (0.49) (0.53) (0.90) (1.64) P (0.75) 1.79 (0.86) 3.44 (1.77) 4.13 (2.13) asymmetic phasic DA bust pobabilities fo the ich and lean stimuli. This bias was pimaily associated with inceased accuacy to the ich stimulus, but also with elatively deceased accuacy to the lean stimulus, as taining pogessed (Fig. 2c,d). In contast, netwoks with simulated eductions in pesynaptic DA busts duing ewads showed oveall educed esponse bias, and the simulated esponse bias in Blocks 1 and 2 mioed pefomance in the pamipexole goup. In sum, the cuent simulations eveal that an a pioi model of coticostiatal function can captue DA-dependent ewad leaning biases in the signal detection task, theeby poviding an explicit account fo ewad blunting induced by pamipexole. DISCUSSION between goups wee found fo the N1 and P3 time-locked to the pesentation of the stimulus (all Fs > 2.19, all Ps > 0.16; see Table I). These esults povide suppot that thee was no geneal effect of sedation and stimulus infomation pocessing and categoization. Computational Modeling The ight panel of Figue 2 shows the esults of the neual netwok simulating pefomance in the pobabilistic ewad task in an intact model of stiato-cotical function ( placebo goup ) and a model incopoating educed pesynaptic DA signals in esponse to ewads ( pamipexole goup ). To geneate these data, we fist appoximated the netwok s disciminability to those of the paticipants descibed in Pizzagalli et al. [2008] by tuning the weights fom sensoy input epesentations to the coesponding cotical esponse units (see modeling methods). Specifically, the weight fom the unique unit epesenting ich o lean stimulus to the coesponding cotical esponse unit was initialized to This poduced disciminability esults that oughly matched those of human subjects (Fig. 2b). Next, we examined coesponding esponse bias effects in these netwoks. Intact netwoks developed apid inceases in esponse bias even in the vey fist block (Fig. 2b), which continued to incease acoss blocks due to A lage body of animal data has emphasized the modulatoy ole of ewad-elated DA signaling in incentive leaning, paticulaly in the acquisition of ewad-elated behavio [Gais et al., 1999; Reynolds et al., 2001] and expectation of ewad [Fioillo et al., 2003]. Using a pobabilistic ewad task in conjunction with a phamacological challenge, we peviously showed that a single, low dose of a D2/3 agonist led to diminished ewad esponsiveness towad a moe fequently einfoced stimulus [Pizzagalli et al., 2008]. On the basis of the obsevations that (1) pesynaptic D2 eceptos have highe affinity fo DA than postsynaptic eceptos [Coope et al., 2003]; (2) low doses of D2 agonists stimulate autoeceptos and thus educe phasic DA eleases [Fulle et al., 1982; Mates et al., 1977; Tissai et al., 1983]; and (3) low doses of D2 agonists suppess DA cell fiing ates in the vental tegmental aea [Piecy et al., 1996], we oiginally suggested that blunted ewad leaning in the pamipexole goup might have been due to educed phasic signaling to the positive feedback ([Pizzagalli et al., 2008]; see also [Fank and O Reilly, 2006]). This intepetation was suppoted by the pesent simulations deived fom an a pioi computational modeling of stiatal-cotical function [Fank, 2005], which showed that diminished DA bust in the Go leaning pathway impaied the ability to lean fom positive feedback. In addition, high-density ERPs evealed that blunted ewad leaning was associated with disupted activation TABLE II. Summay of significant esults emeging fom whole-bain LORETA analyses contasting the placebo (n 5 13) and pamipexole (n 5 7) goup Region MNI coodinates x y z Bodmann s aea Voxels t-value P-value Dosal anteio cingulate cotex Medial pefontal cotex The anatomical egions, MNI coodinates, and BAs of exteme t-values ae listed. Positive t-values ae indicative of stonge cuent density fo the placebo than pamipexole goup, and vice vesa fo negative t-values. The numbes of voxels exceeding the statistical theshold ae also epoted (P < 0.005). Coodinates in mm (MNI space), oigin at anteio commissue; (x), left (2) to ight (1); (y), posteio (2) to anteio (1); (z), infeio (2) to supeio (1). 1972

11 Dopamine Agonist and Reinfocement Leaning within fontocingulate pathways implicated in integating einfocement histoy ove time. Impotantly, sedative effects cannot explain the effect of pamipexole on esponse bias because no goup diffeences emeged fo esponse time [Pizzagalli et al., 2008] and goup diffeences emained when contolling fo advese effects. In addition, modulation of the FRN did not eflect global DA-induced attenuation in bain activity because the N1 and P3 amplitudes wee not affected by pamipexole. Rathe, the FRN an ERP component assumed to geneate fom DA-mediated pediction eo [Holoyd and Coles, 2002, 2008] was uniquely affected. Consistent with the behavioal findings of impaied ewad leaning, the pamipexole goup displayed lage (i.e., moe negative) FRNs compaed to the placebo goup. Although the FRN is typically epoted following eos and poo pefomance, the FRN can be elicited by positive (paticulaly unexpected) feedback [Hajcak et al., 2005; Holoyd and Coles, 2008; Mulle et al., 2005; Nieuwenhuis et al., 2005; Oliveia et al., 2007; Yeung et al., 2004]. Thee ae a few possible explanations fo these FRN esults. Fist, Mulle et al. [2005] epoted that the size of the FRN deceased ove time as paticipants leaned a stimulusesponse association. They intepeted thei finding as suggesting that, as leaning pogessed, extenally diven feedback was no longe needed to guide pefomance. Because leaning was impaied fo paticipants eceiving pamipexole, pehaps they continued to ely on extenal feedback as indexed by lage (i.e., moe negative) FRNs. Unfotunately, thee wee too few tials to examine the amplitude of the FRN acoss blocks to test this explanation. Second, pamipexole-induced blunted ewad leaning might have impaied the paticipants ability to pedict positive feedback, esulting in geate expectancy violations, and consequently inceased FRN. As Oliveia et al. [2007] suggested, the FRN may eflect activity of a geneal pefomance monitoing system that detects violations in feedback expectancies, whethe good o bad. Thid, accoding to Nieuwenhuis et al. [2005], activity fom egions associated with positive and negative feedback ceate a baseline negativity (o ERP deflection). Activity fom distinct aeas associated with positive feedback (e.g., mpfc and ostal ACC egions) push the baseline negativity in a positive diection, yielding a less negative FRN. In this sense, blunted phasic inceases in DA induced by pamipexole might have inhibited this positive push, leading to a moe negative FRN in the pamipexole goup. This latte intepetation is consistent with ecent ERP and modeling data showing that positive pediction eos can educe the FRN (i.e., diminish its negativity) [Holoyd and Coles, 2008]. In the pamipexole goup, blunted positive pediction eos to ewads could have contibuted to a elatively moe negative FRN compaed to placebo. Futue studies will be equied to evaluate the elative contibutions of these accounts to the pesent findings. A substantial body of wok deived fom human functional neuoimaging and single unit ecodings in animals has emphasized the ole of vaious pefontal egions in einfocement-guided decision making. Recent evidence indicates, howeve, that the dacc and othe mpfc egions may make distinct contibutions to einfocementguided decision making. Although the dacc has been implicated in integating action outcome pattens ove time and in mediating the link between pevious actioneinfocement histoies and the upcoming behavioal choices, mpfc egions (including the OFC) have been shown to be citically involved in the epesentation of ewad values [Rushwoth et al., 2007]. Inteestingly, in this study, a low dose of a D2/3 agonist was associated with elatively educed activation in the dacc but elatively inceased activation in moe ostal mpfc egions (BA 10,11,32). Of note, in a ecent study in a lage sample of healthy adults tested with the same pobabilistic ewad task, we found that paticipants failing to develop a esponse bias had significantly lowe dacc activation to ewad feedback compaed to those developing a bias towad the moe fequently ewaded stimulus [Santesso et al., 2008]. Moeove, a positive coelation between dacc activation to ewad feedback and the ability to develop a esponse bias emeged. In this study, exploatoy analyses confimed a positive coelation between dacc activity and ewad leaning fo the pamipexole ( , P , one-tailed) but not placebo ( , P , one-tailed) goup. Collectively, findings fom these two independent studies ae consistent with the hypotheses that (1) the dacc plays an impotant ole in epesenting einfocement histoies to guide adaptive behavio [Amiez et al., 2006; Holoyd and Coles, 2008; Kenneley et al., 2006], and (2) phasic DA busts act as teaching signals that einfoce ewad-elated behavios behavios [Baye and Glimache, 2005; Gais et al., 1999]. Futhemoe, the cuent findings extend ecent evidence suggesting that acute DA pecuso depletion impaied the ability to pefeentially espond to stimuli pedicting ewad in healthy subjects, a finding that was evesed by L-DOPA administation [Leyton et al., 2007]. Additional studies with lage sample sizes using a DA manipulation ae needed to confim a key ole of the dacc in infeing which stimulus is moe advantageous based on the einfocement histoy [Rushwoth et al., 2007]. Seveal limitations of this study should be acknowledged. Fist, a negative feedback condition was not included in the pesent task. The FRN deflection is lage following negative vesus positive feedback and might be geneated by distinct aeas in the mpfc/acc [Nieuwenhuis et al., 2005]. Unfotunately, the design of the pesent signal detection task pecludes the examination of ERP diffeence waves and/o souce localization duing positive vesus negative feedback pocessing. Additionally, although the pesent computational modeling indicated that blunted ewad leaning was epoduced by educed DA bust in the Go leaning pathway disupting the ability to lean fom positive feedback, empiical and modeling data have also emphasized the ole of the NoGo pathway 1973

12 Santesso et al. in einfocement leaning [Fank et al., 2004; Fank and O Reilly, 2006; Sumnes et al., 1981]. Along simila lines, the computational model postulated that low doses of pamipexole suppessed DA cell fiing ates though D2 autoecepto stimulation. Although this mechanism successfully modeled behavioal pefomance and was consistent with pio finding of educed ewad leaning afte administation of cabegoline, which is moe selective fo D2 eceptos than pamipexole, it is impotant to emphasize that pamipexole has both D2 and D3 effects; accodingly, it is cuently unclea whethe D3 eceptos may play a ole in the effects epoted in this study. Second, although the methodology used in this study allowed us to investigate the spatio-tempoal dynamics of bain mechanisms undelying einfocement leaning with millisecond time esolution, it pevented us fom examining bain activation in subcotical egions (e.g., midbain) as well as inteactions between midbain and cingulate egions. An integation of electophysiological and hemodynamic neuoimaging techniques will be equied fo a definite test of tempoal unfolding of bain mechanisms undelying einfocement leaning in humans, paticulaly because animal studies have shown that cingulate neuons can modulate activity in the stiatum and midbain and vice vesa [Eblen and Gaybiel, 1995; Onn and Wang, 2005]. Inteestingly, in humans, DA synthesis capacity in the vental stiatum has been found to positively coelate with BOLD signal in the dacc in esponse to positive, but not negative, pictues [Sissmeie et al., 2006]. Thid, although the LORETA algoithm has eceived impotant cossmodal validation, the coase spatial esolution of this souce localization technique (1 2 cm) as well as the use of a spheical head model (as opposed to ealistic head models deived fom individual subjects MRI) epesent futhe limitations of this study. We note, howeve, that the pesent findings of elatively deceased dacc activation and elatively inceased mpfc activation in the pamipexole goup ae consistent with ecent hemodynamic findings showing that (1) administation of a DA antagonist deceased BOLD signal in the dacc duing the anticipation of a potential ewad [Able et al., 2007] and inceased mpfc activation compaed with both amphetamine and placebo administation [Menon et al., 2007]; and (2) administation of DA-enhancing dugs (amphetamine, cocaine) inceased ceebal blood flow [Jenkins et al., 2004], glucose metabolism [Vollenweide et al., 1998] and BOLD signal [Beite et al., 1997] in the dacc. Finally, the sample size of this study was small due, in pat, to paticipant withdawal fom the side effects of pamipexole. Consequently, these esults should be intepeted with caution and eplicated with a lage sample size. Finally, it will be impotant to eplicate these findings using a cossove design (see e.g., [de Buijn et al., 2004]) to contol fo potential goup diffeences on demogaphic o mood vaiables not consideed hee. In sum, this study povides conveging behavioal, electophysiological, and computational modeling evidence highlighting the citical ole of phasic DA signaling and dacc egions in einfocement leaning in humans. These peliminay esults suggest that leaned esponse outcome associations elies on the dacc, which because of its contibution to contol of moto behavio and use of DA-einfocement signals might guide adaptive behavio by integating einfocement histoy and selecting the optimal stimulus. These findings do not only povide initial infomation about the spatio-tempoal dynamics of bain mechanisms undelying einfocement leaning in humans but offe an useful famewok fo testing the ole of dysfunctional DA pathways in vaious foms of psychopathology, including substance abuse, schizophenia, and depession. ACKNOWLEDGMENTS The authos thank D. Catheine Fulleton, Melissa Culhane, and Avam Holmes fo thei assistance with subject ecuitment and clinical inteviews, as well as Peta Pajtas and Kyle Ratne fo thei skilled assistance with the poject. REFERENCES Able B, Ek S, Walte H (2007): Human ewad system activation is modulated by a single dose of olanzapine in healthy subjects in an event-elated, double-blind, placebo-contolled fmri study. Psychophamacology (Bel) 191: Akitsuki Y, Sugiua M, Watanabe J, Yamashita K, Sassa Y, Awata S, Matsuoka H, Maeda Y, Matsue Y, Fukuda H, Kawashima R (2003): Context-dependent cotical activation in esponse to financial ewad and penalty: An event-elated fmri study. Neuoimage 19: Amiez C, Joseph JP, Pocyk E (2006): Rewad encoding in the monkey anteio cingulate cotex. Ceeb Cotex 16: Baye HM, Glimche PW (2005): Midbain dopamine neuons encode a quantitative ewad pediction eo signal. Neuon 47: Beck AT, Stee RA, Bown GK (1996): Beck Depession Inventoy Manual, 2nd ed. San Antonio, TX: The Psychological Copoation. Beetta S, Pathasaathy HB, Gaybiel AM (1997): Local elease of GABAegic inhibition in the moto cotex induces immediateealy gene expession in indiect pathway neuons of the stiatum. J Neuosci 17: Beetta S, Sachs Z, Gaybiel AM (1999): Cotically diven Fos induction in the stiatum is amplified by local dopamine D2- class ecepto blockade. Eu J Neuosci 11: Beite HC, Gollub RL, Wiesskoff RM, Kennedy DN, Makis N, Beke JD, Goodman JM, Kanto HL, Gastfiend DR, Rioden JP, Mathew RT, Rosen BR, Hyman SE (1997): Acute effects of cocaine on human bain activity and emotion. Neuon 19: Chapman LJ, Chapman JP (1987): The measuement of handedness. Bain Cogn 6: Cheng J, Feensta MG (2006): Individual diffeences in dopamine efflux in nucleus accumbens shell and coe duing instumental leaning. Lean Mem 13: Coope JR, Bloom FE, Roth RH (2003): The biochemical basis of neuophamacology, 8th Ed. Oxfod: Oxfod Univesity Pess. 1974