Dopaminergic medication alters auditory distractor processing inParkinson's disease

Dejan Georgiev a,b,⁎, Marjan Jahanshahi b,1, Jurij Dreo a,2, Anja Čuš a,3, Zvezdan Pirtošek a,4, Grega Repovš c,5

a Department of Neurology, University Medical Centre, Zaloška cesta 2, 1000 Ljubljana, Sloveniab Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, 33 Queen Square, London WC1N 3BG, United Kingdomc Department of Psychology, Faculty of Arts, Aškerčeva 2, 1000 Ljubljana, Slovenia

a b s t r a c ta r t i c l e i n f o

Article history:Received 30 June 2014Received in revised form 30 January 2015Accepted 3 February 2015Available online xxxx

PsycINFO classification codes:253023402580

Keywords:Parkinson's disease (PD)Event-related potentialsP3Visual and auditory attentionExecutive functionsMovement disorders

Parkinson's disease (PD) patients show signs of cognitive impairment, such as executive dysfunction, workingmemory problems and attentional disturbances, even in the early stages of the disease. Thoughmotor symptomsof the disease are often successfully addressed by dopaminergic medication, it still remains unclear, howdopaminergic therapy affects cognitive function. The main objective of this study was to assess the effect ofdopaminergic medication on visual and auditory attentional processing. 14 PD patients and 13 matched healthycontrols performed a three-stimulus auditory and visual oddball task while their EEGwas recorded. The patientsperformed the task twice, once on- and once off-medication.While the results showed no significant differencesbetween PD patients and controls, they did reveal a significant increase in P3 amplitude on- vs. off-medicationspecific to processing of auditory distractors and no other stimuli. These results indicate significant effect ofdopaminergic therapy on processing of distracting auditory stimuli. With a lack of between group differencesthe effect could reflect either 1) improved recruitment of attentional resources to auditory distractors; 2) reducedability for cognitive inhibition of auditory distractors; 3) increased response to distractor stimuli resulting inimpaired cognitive performance; or 4) hindered ability to discriminate between auditory distractors and targets.Further studies are needed to differentiate between these possibilities.

© 2015 Elsevier B.V. All rights reserved.

1. Introduction

Parkinson's disease (PD) is a chronic, neurodegenerative diseasecharacterized by loss of dopamine-producing cells in the SubstantiaNigra pars compacta (SNpc) (Thenganatt & Jankovic, 2014). In additionto the motor symptoms (resting tremor, bradykinesia, rigidity, and inlater stages, impaired postural reflexes), PDpatients also showcognitive

deficits even in the early stage of the disease (Dirnberger & Jahanshahi,2013; Ryterska, Jahanshahi, & Osmana, 2013). Commonly reportedcognitive difficulties in early stage PDpatients are executive dysfunction(e.g. difficulties in planning, set-shifting, conflict resolution, andreduced ability to perform tasks concurrently) (Dirnberger &Jahanshahi, 2013), deficits in working memory (WM) (Lee, Cowan,Vogel, Fernando, &Hackley, 2010), visuospatial function, and condition-al associative learning (Kehagia, Barker, & Robbins, 2010). In addition tothese, attentional difficulties are also very common in PD. Selective at-tention deficits (Zhou et al., 2012), problemswith involuntary attention(Solis-Vivanco et al., 2011), attention set-shifting and flexibility deficitsand disturbance of auditory attention (Bronnick, Nordby, Larsen, &Aarsland, 2010) have all been reported in PD patients. Therefore, arange of cognitive deficits, including attentional deficits, are common inearly stage PDandhavebeendirectly related to thebasic neuropathologicalchanges in PD— decreased production of dopamine in SNpc, that leads todecreased concentration of dopamine in the striatum and consequentlydisturbed neuronal activity, primarily in the frontostriatal circuits includingthe associative circuit between the caudate and the dorsolateral prefrontalcortex (DLPFC) (Cools, 2006; Gotham, Brown, & Marsden, 1988).

Even though dopaminergic medication undoubtedly improves themotor symptoms of the disease, the effect of dopaminergic medication

Acta Psychologica 156 (2015) 45–56

Abbreviations: BDI, Back Depression Inventory; CON, healthy controls; ICD, ImpulseControl Disorder; MMN, mismatch negativity; MNV, mean normalized value; MoCA,Montreal Cognitive Assessment; PD OFF, PD patients off medication; PD ON, PD patientson medication; PD, Parkinson's disease; RON, reorientation of attention; WM, workingmemory.⁎ Corresponding author at: Department of Neurology, University Medical Centre,

Zaloška cesta 2, 1000 Ljubljana, Slovenia. Tel.: +44 7429 088 621.E-mail addresses: dgeorgiev@ucl.ac.uk, dejan.georgiev@kclj.si (D. Georgiev),

m.jahanshahi@ucl.ac.uk (M. Jahanshahi), jurij.dreo@gmail.com (J. Dreo),anja.cus@gmail.com (A. Čuš), zvezdan.pirtosek@kclj.si (Z. Pirtošek),grega.repovs@psy.ff.uni-lj.si (G. Repovš).

1 Tel.: +44 20 7837 3611.2 Tel.: +386 40 510 956.3 Tel.: +386 40 759 100.4 Tel.: +386 31 303 387.5 Tel.: +386 41 356 512.

http://dx.doi.org/10.1016/j.actpsy.2015.02.0010001-6918/© 2015 Elsevier B.V. All rights reserved.

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on cognition is diverse and often unpredictable. Namely, dopaminergicmedication may either alleviate or deteriorate cognitive function, orhave no effect on cognitive function (Briand, Hening, Poizner, &Sereno, 2001; Bronnick et al., 2010; Cools, 2006, 2011; Cools, Barker,Sahakian, & Robbins, 2001; Gauntlett-Gilbert, Roberts, & Brown, 1999;Gotham et al., 1988; Kiesel, Miller, Jolicoeur, & Brisson, 2008; Sawadaet al., 2012; Solis-Vivanco et al., 2011; Tachibana, Toda, & Sugita, 1992;Tinaz, Courtney, & Stern, 2011; Tombaugh, 2004; Tsuchiya, Yamaguchi,& Kobayashi, 2000). It has been postulated that these contrasting effectsof dopaminergic medication stem from an imbalance of dopamine indistinct regions of the striatum (Gotham et al., 1988).

Research in healthy subjects (Cools & D'Esposito, 2011) has indicat-ed that cognitive function depends on the optimal level of dopamine,which can be disrupted either by lack of or an overabundance ofdopamine, resulting in an inverted-U-shape dependence of cognitiveperformance on dopamine level. In the early stages of PD the dopaminedepletion is restricted to the dorsal striatum, leaving the ventralstriatum relatively spared (Gotham et al., 1988; Kish, Shannak, &Hornykiewicz, 1988). This leads to a specific pattern of cognitivedysfunction dependent on specific neuronal circuits needed for theexecution of the cognitive task tested. Relatedly, when dopaminergicmedication is adjusted to ameliorate the depleted levels of dopaminein the dorsal striatum, it may overdose the ventral striatum, resultingin improvement of those symptoms and functions that depend on thedorsal, and deterioration of those that depend on the ventral striatum(Gotham et al., 1988). In summary, due to the way the dopaminergicsystem is affected in different parts of the striatum in early PD, the effectof dopaminergic medication on cognition in PD patients is complexand depends on many factors, such as the specific nature of the task,the engaged neuronal circuit, and the stage of the disease (Cools,2006; Gotham et al., 1988).

Attention is one of the central concepts in neuropsychology andunderlines most cognitive processes (Bocquillon et al., 2012). Theinvolvement of the basal ganglia and dopamine in attention is complex(Bocquillon et al., 2012; Knight, Grabowecky, & Scabini, 1995). PD,characterized by dopamine depleted basal ganglia circuits, is a goodmodel for studying the relation of attention to dopamine. In the studyof human cognition a P3 cognitive event related potential (ERP) isprobably the most used neural correlate of attention. Elicited whenprocessing low-probability (rare) target stimuli (Polich, 2007), it hasbeen shown to significantly correlate with attentional processes(Bledowski, Prvulovic, Goebel, Zanella, & Linden, 2004). The P3 hasbeen robustly identified when actively or passively paying attentionto rare target stimuli in a single (target only), double (rare targetintermixed with frequent standard stimuli), or three (rare targetintermixedwith frequent standard and rare distractor stimuli) stimulusparadigms, in the auditory, visual, or somatosensory modality (Lugoet al., 2014; Polich, 2007; Wronka, Kaiser, & Coenen, 2008).

Interestingly, rare non-target, distractor stimuli also elicit a P3response, which however, differs from the response to the target stim-ulus in its latency, amplitude and spatial distribution. The P3 responseelicited by target stimuli (P3b) is characterized by a parietal maximumand a longer latency, compared to the P3 response elicited by distractorstimuli (P3a), which is more frontally distributed, has a shorter latency,and somewhat larger amplitude (Daffner, Mesulam, Holcomb, et al.,2000; Daffner, Mesulam, Scinto, et al., 2000). P3a is assumed to reflectattentional reorientation and subsequent reallocation of attention tosalient but irrelevant stimuli, and can be regarded as a marker ofresponse inhibition processes in response to irrelevant stimuli. Incontrast, P3b is thought to reflect components of attentional, WM,or event categorization processes that lead to decision making(Bledowski et al., 2004). Both P3a and P3b are traditionally describedby their amplitude and latency; the former is considered to reflectthe selective attention resources devoted to processing of the stimuli,whereas the latter is assumed to index the time necessary for controlledinformation processing (Kok, 2001).

Empirical data from lesion and fMRI studies suggest differentgenerators of P3a and P3b. For example, lesions of the prefrontal cortexdecrease the response to distracting novel, but not to target stimuli inthe three stimulus oddball paradigms (Knight, 1984; Wascher,Hoffmann, Sanger, & Grosjean, 2009). Similarly, patients with hippo-campal damage can show a reduced response to distracting novel stim-uli (Knight, 1996). In contrast, discrete lesions of the temporoparietaljunction can result in reduced amplitude of both, P3a and P3b (Knight,Scabini, Woods, & Clayworth, 1989; Nieuwenhuis, Aston-Jones, &Cohen, 2005). It seems that the orienting response to rare (target ordistractor) stimuli, which reflects the immediate response to anychange in the environment, activates frontal regions first; this signal isthen transmitted towards the temporoparietal regions of the brain,possibly reflecting memory related processes (Polich, 2007). Indeed,imaging data show that both target and distractor stimuli activate theventrolateral frontoparietal network, indicating a common mechanismfor detection of rare events engaging bottom-up attentional processes(Bledowski et al., 2004). Presence of distractor stimuli further activatesthe dorsolateral frontoparietal network. This network is believed to beengaged in attentional switch from the target/standard discriminationand consequent attention allocation to the salient, rare distractor stim-ulus (Bledowski et al., 2004). In summary, it seems that different neuralmechanisms, possibly regulated by different neurotransmitter systems,are involved in processing of distractor and target stimuli. Indeed,according to the dual-transmitter hypothesis (Polich, 2007; Polich &Criado, 2006), frontally related P3a is likely mediated by dopaminergicactivity, whereas P3b, which is related to parietotemporal brain regions,is probably mediated by noradrenaline activity. Furthermore, dopami-nergic projections to the cortex are most abundant in frontal areas(Goldman-Rakic, 1998), whereas noradrenergic projections from locuscoeruleus, are more diffusely distributed across the cortex, includingthe posterior and parietotemporal parts of the brain (Berridge &Waterhouse, 2003; Nieuwenhuis et al., 2005). Therefore, it could beexpected that different medications have different effects on P3a andP3b, depending on the mechanism of action. Specifically, dopaminergicmedication should affect P3a rather than P3b, as the modulation of P3aseems to be more heavily dependent on the dopaminergic system.

There are several lines of clinical evidence suggestive of the impor-tance dopamine plays in the generation of the P3a/b response. Forexample, patients with restless leg syndrome, a condition marked bydecreased dopaminergic state, show larger reduction of P3a comparedto P3b amplitude (Choi, Ko, Lee, Jung, & Kim, 2012). A study byTakeshita and Ogura (1994) demonstrated that administration of a do-paminergic antagonist results in a differential effect depending on thebaseline P3b amplitude: subjects with low P3b amplitude at baselineexhibited an increase of the amplitude after sulpiride (dopamine antag-onist) administration; whereas conversely, subjects with high P3b atbaseline exhibited an amplitude decrease after sulpiride administration.

Despite important differences in the processes underlying P3a andP3b evoked potentials and their assumed dependence on dopamine,many of the studies of PD focused exclusively on the P3b potentialevoked by the standard two-stimulus oddball paradigm. Some ofthese studies (Elwan et al., 1996; Graham, Yiannikas, Gordon, Coyle, &Morris, 1990; Green et al., 1996; Karayanidis, Andrews, Ward, &Michie, 1995) found no differences between PD patients and healthycontrols, whereas others reported reduced P3b amplitude (Koberskaia,Zenkov, and Iakhno (2003)), or prolonged P3b latency (Stanzioneet al. (1998)) in PD patients compared to healthy controls. Additionally,Bodis-Wollner et al. (1995) have found that the P3b latencies in bothauditory and visual oddball tasks significantly but differentiallycorrelate with scores on cognitive tests. Specifically, P3b latency in theauditory oddball negatively correlated with basic visual perception,whereas P3b latency in the visual oddball task negatively correlatedwith tests of abstract reasoning.

Of the studies that did differentiate between P3a and P3b, Tsuchiyaet al. (2000) reported somewhat smaller P3b amplitudes in PD patients

46 D. Georgiev et al. / Acta Psychologica 156 (2015) 45–56

compared to healthy controls with more pronounced differences in P3aresponse to novel sounds, which was reduced, delayed and of a moreposterior distribution in patients vs. controls. Similarly, in a recentstudy Solis-Vivanco et al. (2011) looked at a number of ERP correlatesof involuntary attention, including mismatch negativity (MMN), P3a,and reorientation negativity (RON) in both medicated and non-medicated early PD patients compared to healthy controls. Whereasno group differences were identified in MMN amplitude, reflectingautomatic detection of stimulus change, both P3a, reflecting distractordetection, andRON, reflecting reorienting towards task-relevant aspectsof stimulation after distraction, were lower in medicated PD patientscompared to non-medicated patients and healthy controls. There wasno difference in latencies between different groups. In an earlier doubleblind placebo controlled study on healthy young participants withthe dopaminergic (D2) antagonist haloperidol, Kahkonen et al. (2002)got similar results — haloperidol decreased the amplitude of P3a andRON, and did not change the amplitude of MMN. The latencies of allthree components were also not affected by haloperidol.

Even though different versions of the oddball task have beenemployed in the study of PD many times, there is, surprisingly, a lackof studies that would directly, in a repeated measures design, assessthe effect of dopaminergic therapy on distractor and target processing,and their related P3a and P3b components in PD patients. This wasthe objective of the current study. Specifically, the study was designedto investigate the effect of dopaminergic medication on ERP measuresof distractor and target processing in PD patients in a counterbalancedrepeated measures study. Additionally, to better understand the natureof the effect in relation to potential restorative vs. overdose effects ofdopaminergic therapy, patients both off and on medication, were alsocompared to an age-matched healthy control group.

Based on previous literature we expected both P3a as well as P3bamplitudes to be reduced and latencies prolonged in PD patients offmedication compared to healthy controls. Due to differences in process-es underlying target and distractor processing, we expected a remedia-tion of P3awithmedication, as P3a, reflecting distractor processing, is toa larger extent dependent on dopamine-modulated prefrontal cortex. Inother words, we expected higher P3a amplitude and shorter P3alatencies on medication compared to off medication in PD patients.Furthermore, we expected P3b, reflecting target processing thatinvolves wider cortical areas modulated by other neurotransmittersystems (e.g. noradrenaline and acetylcholine), which are also affectedin PD (Braak et al., 2003), to be less affected by the dopaminergictherapy. More specifically, we hypothesized that there would be nodifference in either P3b amplitude or P3b latency in PD patients onmedication compared to off medication. Finally, taking into account theassumption that the dopaminergic therapy results primarily inreconstitution of cognitive function related to P3a we expected lowerP3b amplitude and longer P3b latency and no difference in P3a ampli-tude and latency in patients onmedication compared to healthy subjects.

2. Methods

2.1. Participants

Fourteen PD patients (6 females, 10 right handed) and 13 healthyparticipants (6 females, 12 right handed) took part in the study. Thetwo groups were matched in age, education and handedness (Table 1).All participants reported normal or corrected to normal (color) visionand hearing. All participants signed informed consent and received nopayment for participation in the study. The study was reviewed and ap-proved by the medical ethical committee at the University of Ljubljana.

2.2. Study design and procedure

PD patients and healthy controls performed an active three-stimulusoddball task in both the visual andauditorymodality during simultaneous

EEG recording. PD patients performed the task twice, once on medica-tion and once off medication, after medication withdrawal for at least12 h (range: 12–17 h), in a randomized counterbalanced fashion(half of the patients performed the task first off, then on medicationand vice versa). Healthy controls performed the task only once. Duringthe first visit both PD patients and healthy controls were screenedfor cognitive decline (Montreal Cognitive Assessment (MoCA)(Nasreddine et al., 2005)) and depression (Back Depression Inventory(BDI) (Beck, Ward, Mendelson, Mock, & Erbaugh, 1961)). There wasno significant difference in MoCA and BDI score between healthysubjects and PD patients (Table 1). Before performing the task, bothon and off medication, the PD patients were also assessed on themotor part of the Unified Parkinson's Disease Rating Scale (UPDRS-III)(Goetz et al., 2007) and the Hoehn & Yahr rating of disease stage(Hoehn & Yahr, 1967). As expected UPDRS-III was higher in PD patientsoff than on medication (t(13) = 6.51, p b .0001) (Table 1).

2.3. Oddball task

Participants performed four blocks of active visual three-stimulusand four blocks of active auditory three-stimulus oddball task persession. They were instructed to mentally count the number of rare-target stimuli and report them at the end of each block. The order ofthe visual and auditory oddball blocks was randomized across partici-pants. Every session started with either a block of the auditory or visualoddball task, which was then followed by a block from the othermodality. At the beginning of the session participants received 2 minof practice that included 40 trials per modality: 8 rare target, 8 raredistractor, and 24 frequent standard stimuli. The task was programmedand presented using E-Prime® 2.0 Professional software running onWindows PC.

In the auditory blocks (Combs & Polich, 2006) the rare target stimuliwere sinusoid, monochromatic, 1000 Hz sounds, embedded in a seriesof frequent standard, 500 Hz frequency sounds and occasionallyappearing rare distractor sounds in the form of white noise. As in thevisual version of the task, the duration of stimuli was 200 ms with2500ms intertrial interval (Fig. 1, upper panel). Stimuli were presentedvia loudspeaker; sound intensity was set to 60 dB. Participants wereasked to hold their gaze on a red fixation dot presented on a blackbackground on the computer monitor in front of them.

In the visual blocks (Hagen, Gatherwright, Lopez, & Polich, 2006;Polich, 2007) rare target stimuli were big light-blue circles subtending5.72° of the visual field,whereas frequent standard stimuli were smallerlight blue circles subtending 4.36° of the visual filed. Rare distractorstimuli were chessboard patterns (5.72° × 5.72°, one black or whitesquare subtending 0.57° × 0.57° of the visual field). All the stimuliwere presented on a black background for 200 ms with 2500 ms inter-stimulus interval (Fig. 1, lower panel), during which a red fixation dotwas present on display (0.69°). The participants were instructed tokeep their eyes on the red fixation dot throughout the duration of the

Table 1Demographic and clinical data for the Parkinson's disease patients and healthy controls.

MPD SDPD MCON SDCON p

Age 60.39 12.25 57.00 8.58 .57Education 13.42 2.82 14.76 2.28 .19MoCA 27.57 1.60 27.92 1.60 .57BDI 5.21 4.76 5.54 3.45 .84UPDRS III on 28.64 7.66UPDRS III off 40.07 7.66H&Y off 1.78 .42Disease duration 3.53 3.03LEDD 492.29 306.83

MoCA — Montreal Cognitive Assessment, BDI — Beck Depression Inventory, UPDRS-III —Unified Parkinson's Disease rating Scale part III, H&Y — Hoehn & Yahr rating of diseasestage, LEDD — Levodopa Equivalent Daily Dose, PD— Parkinson's disease, CON — healthycontrols.

47D. Georgiev et al. / Acta Psychologica 156 (2015) 45–56

experiment. Stimuli were presented on a 27 inch wide LG monitor(Flatron W2753VC) with a resolution of 1920 × 1080 and a refreshrate of 60 Hz.

In both, the auditory and the visual blocks, standard, target anddistractor stimuli were presented on 70%, 15% and 15% of the trials,respectively, in a pseudorandomized order over 4 blocks of each taskmodality. Overall 387 frequent (98 + 107 + 103 + 89), 85 target(21 + 23 + 22 + 19), and 85 distractor stimuli (21 + 23 + 22 + 19)were presented during a single recording session lasting for about25 min for each task modality.

2.4. EEG data recording and analysis

An elastic cap with a chinstrap was used to record from 32 Ag/AgClactive electrodes (actiCAP, Brain Products, GmbH, Herrsching,Germany). Abrasive gel (NuPrep, D.O. Weaver and Company, Aurora,Colorado) was used to abrade the skin under the ground and the refer-ence electrodes; Super Visc conductive gel (SuperVisc, Brain Products,GmbH, Herrsching, Germany) was used to keep the impedance below10 kΩ. Thirty-two electrodes plus ground and reference (positioned atFCz) electrodes, were positioned according the 10–20 system atstandard positions (Fp1, Fp2, F7, F3, Fz, F4, F8, FC5, FC1, FCz, FC2, FC6,T7, C3, Cz, C4, T8, TP9, CP5, CP1, CP2, CP6, TP10, P7, P3, Pz, P4, P8, PO9,PO10 O1, Oz, O2). EEG was recorded by using 32-electrode BrainAmpamplifier (BrainAmp, Brain Products, GmbH, Herrsching, Germany)with 0.01 Hz analogue high-pass filter. Analogue to digital conversionwas performed at a sampling rate of 512 Hz. On-line horizontaleye movement monitoring was performed by a virtual channel(HEOG), defined as a difference between electrodes F7 and F8. VEOGchannel was calculated from the Fp1 and Fp2 electrodes (VEOG =[Fp1 + Fp2] / 2).

Raw EEG signals were analyzed off-line by using EEG/ERPLABsoftware (Delorme & Makeig, 2004; Lopez-Calderon & Luck, 2014).Data were re-referenced to a linked ear common referenced offline,calculated as the difference between T7 and T8. Epochs with obviousartifacts, such as muscle artifacts, were identified visually and rejectedmanually. Similarly, bad channels were identified, excluded fromindependent component analysis (ICA) decomposition and interpolated

using spherical spline interpolation after removal of independentcomponents capturing noise and artefactual signals. The independentcomponents reflecting eye blinks, eye movements and muscle activitywere identified by visual inspection of the topographical distributionof the components, signal to noise ratio (SNR) and the frequencyspectrum of each independent component. The data were time-lockedto the presentation of target, distractor and standard stimuli. Epochsstarting 500 ms before and ending 2000ms after stimulus presentationwere generated. Baseline correction was performed between−500 msand −0 ms before memory array presentation. DC (Direct Current)trend correction was also performed (Luck, 2005).

Themean P3 amplitude and 50% fractional area latency for distractor(P3a) and target (P3b) stimuli were measured in auditory (timewindow 200 to 700 ms post-stimulus presentation) and visual oddball(time window 300 to 800 ms post-stimulus presentations) tasks. Thestart and end point of the time windows were set based on previousstudies and by observing the time course of distractor and targetwaveforms in both auditory and visual oddball tasks (Ito, Takamatsub,Kitagawaa, & Kimurac, 1995; Polich & Comerchero, 2003; Wronkaet al., 2008).We opted to use themean P3 amplitude and 50% fractionalarea latency because of its advantages over peak amplitude and peaklatency when measuring late, large components such as P3 (Kieselet al., 2008; Kok, 2001; Stanzione et al., 1998). Because P3 is mostpronounced at the electrodes located on the central, mid-sagittal line,data from the midline electrodes (Fz, FCz, Cz and Pz) were exportedand subjected to further analysis.

2.5. Statistical analysis

SPSS version 20.0 was used for statistical analysis of the data. TheShapiro–Wilk test was used to test for normality. Parametric datawere analyzed by Repeated measures ANOVA, Mixed design ANOVAand t-test. If the assumption of sphericity was violated (Mauchly'stest), Greenhouse–Geisser correction was used. χ2-test was used toanalyze non-parametric data. Bonferroni correction was used to controlfor multiple comparisons. Probability value of p = .05 was used as acriterion for statistical significance.

Fig. 1.Auditory and visual oddball tasks used in the study. In the auditory blocks the target stimuli weremonochromatic soundswith a frequency of 1000 Hz, standard stimuli were lowerfrequencymonochromatic sounds (500Hz),whereas distractor stimuliwere noise sweeps. In the visual blocks, the target stimuliwere big blue circles; small blue circles served as standardstimuli, whereas chessboard fields served as distractor stimuli.

48 D. Georgiev et al. / Acta Psychologica 156 (2015) 45–56

3. Results

3.1. Task performance

To compare the performance between groups and conditions, foreach participant and condition the mean normalized values werecalculated as follows: the absolute differences between the reportedand actual number of targets for each block were first normalized bythe actual number of targets in the block and then averaged across allfour blocks of the same modality (Table 2). Mixed design ANOVAscomparing PD patients (on and off medication separately) with healthycontrols, as well as auditory and visual modality of the task revealedno significant effect of group, modality or their interaction (allps N .20). Similarly, repeated measures ANOVA with factors medication(PD patients on vs. off medication) and modality (visual vs. auditory)also yielded no significant difference in response accuracy either dueto medication, modality or their interaction (all ps N .12). In summary,no behavioral differences in task performance were identified eitherbetween the two groups or due to medication status.

3.2. Group differences in P3a/b

To better understand the effect of dopaminergic therapy and inorder to establish the extent to which mean amplitude and fractionallatency of P3a/b might be affected in PD we first compared PD patientsoff medication to healthy controls. To achieve that, we computed twofour-way mixed design ANOVAs with between subject factor group(PD off medication vs. healthy subjects) and within subject factorsstimulus type (distractor vs. target), modality (auditory vs. visual) andelectrode location (Fz, FCz, Cz and Pz) on both amplitude and latency.Though numerically PD patients exhibited lower amplitudes in bothmodalities, and shorter latencies in auditory modality (see Figs. 2 and3) ANOVA revealed no significant main effect of group or its interactionwith other factors on either P3a/b amplitude or latency (all ps N .18).Obtaining no significant differences, we next compared healthy controlswith PD patients on medication. This analysis again revealed no signifi-cant main effect of group or its interaction with other factors on P3a/bamplitude or latency (all ps N .15).

3.3. Effect of medication on P3a/b

Next we focused our analysis directly on the effect of medicationon P3a/b. To compare the P3a/b in PD patients on and off medication,we computed a four-way repeated measures ANOVA with factorsmedication (PD patients on vs. off medication), stimulus type(distractor vs. target), modality (auditory vs. visual) and electrodelocation (Fz, FCz, Cz and Pz). The analysis of P3a/b amplitudes revealedno significant main effect of medication, F(1, 13) = .08, p = .78, buta significant two-way interaction of medication, F(1, 13) = 5.44, p =

Table 2Mean normalized values of the number of target stimuli reported by patients withParkinson's disease patients and healthy controls.

MNVauditory SDauditory MNVvisual SDvisual

PD ON − .002 .089 .033 .047PD OFF − .007 .054 − .002 .052HC − .070 .198 − .068 .270

MNV — mean normalized value, PD ON — Parkinson's disease patients on medication, PDOFF— Parkinson's disease patients off medication.

Fig. 2.Mean P3a (distractor, gray lines) and P3b (target, black lines) amplitude (in μV, y-axis) in timewindow 200–700ms for auditory and 300–800ms for visual oddball for PD patientsoff and on medications and healthy controls for the central electrode sites (Fz, FCz, Cz and Pz).

49D. Georgiev et al. / Acta Psychologica 156 (2015) 45–56

.036, and electrode location, F(3, 39)=2.98,p=.043,with stimulus type,aswell as a significant four-waymedication× stimulus type×modality×electrode location interaction, F(3, 39) = 2.87, p= .049.

In order to disentangle the significant interaction effects weconducted four separate repeated measures ANOVAs with factorsmedication (PD patients on vs. off medication) and electrode location(Fz, FCz, Cz and Pz) for each combination of stimulus type (target anddistractor) and modality (visual and auditory). The analyses revealeda significantly higher amplitude of P3a in patients on medicationcompared to patients off medication in response to auditory distractorstimuli, F(1,13)=4.73, p= .049, and no significant effect of medicationin response to any of the other stimuli (all ps N .13; see Fig. 2, upper leftpanel). Based on significantmedication× electrode location interaction,F(3, 39) = 6.97, p = .001, in the case of auditory distractor stimuli, weconducted a further (Bonferroni corrected) post-hoc analysis of theeffect of medication at different electrode locations. The P3a amplitudewas significantly higher over FCz, t(13) = 2.35, p = .035, Cz, t(13) =2.44, p = .030, and Pz, t(13) = 2.71, p = .018, electrodes but not overthe Fz electrode (p = .52).

To further understand the effect ofmedicationwe repeated the post-hoc two-way repeated measures ANOVAs with factors medication (PDpatients on vs. off medication) and electrode location (Fz, FCz, Cz andPz) separately for low and high responders based on the median splitof differences in UPDRS score on and off medication. The results againrevealed significantly higher P3a amplitude in response to auditorydistractor stimuli on medication, F(1, 6) = 21.92, p = .003, but only inhigh responders (Fig. 4, upper left panel). In the same group, therewas no significant difference on vs. off medicationwhen auditory targetstimuli were presented, F(1, 6)=1.06, p=.344. Similarly, P3 amplitudedid not change significantly on vs. offmedicationwhen visual distractor,

F(1, 6)= .78, p= .790 (Fig. 4, upper right panel) or visual target stimuli,F(1, 6) = .43, p = .538, were presented. The interaction effect medica-tion state × electrode location was significant for the high respondersonly when auditory distractors were presented, F(3, 18) = 9.24, p =.001, indicating higher P3a difference on vs. off medication at the poste-rior electrodes (Pz, Cz) compared to the anterior electrode sides(Fz, FCz) (Fig. 4, left upper panel). The other interaction effects werenot significant (all ps N .25).

Separate ANOVAs onP3a/b latencies revealed no further informationon the effect of dopaminergic medication on distractor and targetprocessing. There was no significant main effect of medication or itsinteraction with other factors (stimulus type, modality, channellocation; all ps N .25). The stimulus type × electrode site interactionwas significant, F(3, 33) = 8.35, p b .0001, reflecting longer latenciesfor target compared to distractor stimuli parietally (Pz), F(1, 11) =15.11, p = .003 (Fig. 3). As expected, the latency in the visual modalitywas longer than in the auditory modality, F(1, 11) = 66.09, p b .0001.The significant modality × electrode site interaction, F(3, 33) = 18.25,p b .0001, indicated that there was an increase in the latency fromfrontal to parietal electrodes in auditory oddball task (Fig. 3, left panels),the longest latency being at Pz, F(1, 11) = 14.72, p b .0001, whereas inthe visual modality the latency was rather stable across differentelectrode sites (Fig. 3, right panels). Detailed time courses and peakP3a/b topographies are provided in Figs. 5 and 6.

4. Discussion

The primary aim of the study was to evaluate the effect ofdopaminergic therapy on distractor and target processing when PDpatients were performing auditory and visual oddball tasks. To better

Fig. 3. P3a (distractor, gray lines) and P3b (target, black lines) fractional area latency (50%) in ms (y-axis) for PD patents (PD ON) on and off (PD OFF) medications and healthy controls(CON) at the central electrode sites (Fz, FCz, Cz, Pz).

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understand the nature of the effects, the PD patients both on and offmedication were also compared to age-matched healthy controls.Based on the literature suggesting that distractor processing dependson the dopamine-mediated frontal mechanisms (Goldman-Rakic,1998; Polich, 2007; Polich & Criado, 2006) to a larger extent than targetprocessing, which depends on awider set of cortical areasmodulated byother neurotransmitters (Berridge & Waterhouse, 2003; Nieuwenhuiset al., 2005), we expected a specific effect of medication on distractorbut not target processing reflected in the P3a and P3b ERP respectively.Based on previous literature showing that both P3a and P3b are affectedin PD patients, and the assumption that the dopaminergic therapyresults primarily in reconstitution of cognitive function related to P3a,we expected lower P3a and P3b amplitudes and longer P3a and P3blatency in both the auditory and visual modality in PD patients offmedication compared to healthy controls, but only lower P3b amplitudeand longer P3b latency in patients on medication compared to healthyparticipants.

4.1. Dopaminergic therapy affects processing of distractors but not targets

The key finding of the study is that dopaminergic medication, asexpected, significantly increases the amplitude of the P3a component,however only in response to auditory but not visual distractor stimuli.Amplitudes of the P3b component in response to both auditory andvisual targets were not affected and similarly P3a or P3b latencieswere not altered.

The difference in the observed effect of dopaminergic therapy on P3avs. P3b in the auditory version of the task provides uswith useful cues asto the processes affected by the dopaminergic therapy. As both targetand distractor processing are assumed to elicit the orienting response

and engage the ventral attentional network (Bledowski et al., 2004), itseems that the ventral attentional network is not significantly affectedby the dopaminergic therapy, as in such a case the effect should bepresent in both P3a and P3b amplitudes. Rather, it seems that thesystems primarily affected by the dopaminergic therapy are those thatare differentially recruited by processing of the distractor stimuli. Onesuch candidate is the dorsal attentional network believed to be specifi-cally engaged in processing of distractor stimuli (Bledowski et al., 2004).

The hypothesis of such differential processing of target vs. distractorstimuli was also supported by a significant interaction betweenstimulus type and electrode location for both P3a/b amplitude andlatency, due to longer latency for target compared to distractor stimuliat Pz, and higher amplitude at Pz for target compared to distractor stim-uli. In line with previous studies (Bennington & Polich, 1999;Comerchero & Polich, 1999; Polich, 2007) the amplitude for distractorstimuli was higher at Fz, FCz and Cz compared to target stimuli.

4.2. The effect of dopaminergic therapy is limited to the auditory modality

The differences in the amplitude of the P3a response to distractorswhen on compared to off medication were observed only in the audito-ry and not the visual modality. The differences between modalities arefurther evident in a significant interaction between modality andelectrode location. Specifically, the P3 amplitude increased from frontalto parietal electrodes in auditory, but not in the visual oddball task,whereas latencies at different electrodes were rather stable acrossgroups and stimulus type. We consider two possible explanations forthis pattern of results. First, different networks can be engaged depend-ing on stimulusmodalities, and second, distractors in the twomodalitiesto different degrees could evoke different processes.

Fig. 4.Mean P3a amplitude (in μV, y-axis) for the distractor condition in timewindow 200–700ms for auditory and 300–800ms for visual oddball for PD patients off (PD OFF) and on (PDON)medications for the central electrode sites (Fz, FCz, Cz and Pz) as divided by themedianvalue (12.50) of thedifference betweenmotorUPDRS score offminus onmedication (ΔUPDRS)into high and low responder subgroups.

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The first possibility is supported by studies showing differentialengagement of brain systems in auditory and visual stimuli detection(Braga, Wilson, Sharp, Wise, & Leech, 2013; Kong et al., 2014; O'Learyet al., 1997; Shinn-Cunningham, 2008). Specifically, Braga et al. (2013)have shown that visuospatial stimuli activated the superior fron-toparietal network, whereas the non-spatial auditory stimuli activatedthe frontotemporal network. Further evidence also suggests (Baueret al., 2012; Stormer, Passow, Biesenack, & Li, 2012) that visual attentionis primarily mediated by the cholinergic system, whereas auditoryattention is mainly regulated by dopamine, which would explain thepresence of a medication effect for the auditory but not visual stimuli.

The second possibility is that the auditory stimuli used in the task,more so than the visual stimuli, engaged inhibitory processes. Whereasvisual distractors introduced a deviant non-target stimulus, auditorydistractors in the form of white noise, as used in our study, can beperceived as unpleasant, eliciting significantly stronger P3a responsesthan deviants, comparable to P3a responses to novel stimuli (Combs &Polich, 2006). The higher salience of auditory compared to visualdistractor stimuli can be glimpsed from the striking difference inresponse to distractor vs. target stimuli evident for the auditory stimuli

that is not present for the visual stimuli, where the responses to targetsand distractors are rather similar (Figs. 2 and 5, Cz electrode). If auditorydistractors indeed elicit stronger inhibitory processes dependent on anintact dopaminergic system, they would present a more sensitiveprobe of the effect of dopaminergic modulation, which we consider inthe following section.

4.3. Mechanisms underlying the effect of dopaminergic therapy on auditorydistractor processing

While providing evidence that dopaminergic medication increasesthe amplitude of the P3a response to auditory distractors, the studycould not unambiguously show that this was due to an improvementof auditory attention to distractors. Therefore, the results of the studycan be accounted for by at least four different possibilities: 1) dopami-nergic medication may selectively restore the attentional response toauditory distractors; 2) dopaminergic medication may selectivelyimpair inhibition of the response to auditory distractors; 3) dopaminer-gic medication may increase the response to distractors, but impaircognitive performance; and 4) dopaminergic medication may hinderdiscrimination between targets and distractors. These possibilities willbe addressed in the following paragraphs.

To differentiate between the restorative vs. disruptive nature of thedopaminergic therapy, we compared ERP correlates of distractor andtarget stimuli processing between patients off and on medication andhealthy controls. If the action of the dopaminergic therapy wasreconstitutive, we would expect significant differences betweenpatients off medication and healthy controls, which would be eliminat-ed with dopaminergic therapy. If, however, the dopaminergic effectswere of a disruptive nature we would expect the differences to beintroduced with dopaminergic medication.

Numerically, when considering auditory distractors, the results areconsistent with the restorative hypothesis. However, when consideringthe auditory and visual targets they are more consistent with thedisruptive hypothesis (Figs. 2 and 4). Such differential effects ofdopaminergic therapy would be plausible given different processesand brain systems being involved in processing of target and distractorstimuli, and related differences in the extent of dopamine depletion indorsal vs. ventral striatum in early stages of the disease (Gotham et al.,1988; Kish et al., 1988). The dopaminergic medication could amelioratethe depleted levels of dopamine and improve cognitive function(and other symptoms) related to the dorsal striatum, but overdose theventral striatum, and deteriorate the related symptoms (Cools, 2006;Gotham et al., 1988).

The relation of dorsal striatum to attentional processes has beenwellestablished. The striatum plays a crucial role in regulating attentionswitching by gating the top-down bias from the prefrontal cortex onthe stimulus-specific posterior cortex (Cools, 2011). It seems that thedorsal striatum plays an especially important role in attention throughits vast connections to the dorsolateral prefrontal cortex through thedorsolateral prefrontal circuit (Alexander, DeLong, & Strick, 1986). Thedopaminergic input to this part of the striatum comes mainly fromthe SNpc. The dopaminergic deficit has already been shown to beimplicated in deficits of attention, impulse control and behavioral flexi-bility (Agnoli, Mainolfi, Invernizzi, & Carli, 2013). Therefore, in ourstudy, dopaminergic medication could have influenced the attentionalprocesses dependent on the dorsal striatum by restoring the deficit ofdopamine, hence increasing the amplitude of the P3a response.

While the results are numerically consistent with this hypothesis,statistical analysis of group differences, probably due to low samplesize and large between subject variability, failed to reach significanceand provide the necessary support, leaving the identified significantwithin subject medication effects open to an alternative explanation,namely, that the observed differences are due to selective impairmentof response inhibition of auditory distractors. For example, Obeso et al.(2011) have shown that in PD response inhibition on a stop signal

Fig. 5. ERP waveforms for auditory and visual distractor and target stimuli at Cz and Pzelectrode sites. x-axis— time inmilliseconds (ms); y-axis— amplitude inmicrovolts (μV).

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task is impaired both on and off dopaminergic medication.Dopaminergic-medication also induces Impulse Control Disorders(ICD) in PD. Indeed, dopaminergic medication can increase impulsivityeven in patients who do not primarily show signs of ICD, due to eitherincreased impulsive drive, decreased inhibitory control or a combina-tion of both (Djamshidian et al., 2012). This can be explained by anoverflow of dopamine in the ventral striatum, which, in addition toboosting cognitive flexibility, can also increase impulsivity in PDpatients (Cools, Barker, Sahakian, & Robbins, 2003). The results fromour study could therefore reflect impaired response inhibition relatedto increased levels of dopamine in PD patients tested on medication.Specifically, as the effect was observed only in P3a amplitude inresponse to auditory distractors, but not in P3b response to targetstimuli, the observed differences could indicate reduced ability toinhibit responses to irrelevant, distracting stimuli in PD patients onmedication. Such possibility is in line with the proposal that P3a canbe considered a marker of response inhibition processes active when adistractor stimulus is presented, and an indicator of the orientingresponse reallocating attention to salient but irrelevant stimuli(Bledowski et al., 2004).

Another possible explanation would be that dopamine increases theresponse to distractors, but impairs global cognitive performance.Indeed, it has been shown that PD patients with ICD, characterized byan enhanced response to dopaminergic therapy, remember distractorseasier than PD patients without ICD in WM tasks (Djamshidian et al.,2012). Even though no difference in the performance on the WM taskwas observed in the study, PD patientsmademore irrational and impul-sive choices on other tasks. Hence, enhanced response to dopaminergicmedication can lead to an increased ability to remember the distractors,but at the same time render PD patients more impulsive and thereforedisrupt their performance. Indeed, WM can be disrupted by externalinterference (Clapp, Rubens, & Gazzaley, 2010). As mentioned beforethe behavioral results of the active, mental counting oddball task usedin our study revealed no evidence of performance impairment. Thebehavioral measure used was, however, crude and we cannot rule outthat more sensitive behavioral performance indices, such as errorrate or reaction time, might reveal more subtle changes in behavioralperformance.

Lastly, one may argue that the observed results stem from observa-tions that the amplitude of P3a depends on the perceptual distinctive-ness of the stimuli (Comerchero & Polich, 1999). Namely, if the

perceptual distinctiveness of distractor and standard stimuli is high,the P3a amplitude depends on the difficulty to discriminate betweentarget and standard stimuli, such that if it is hard to discriminatebetween the target and standard stimuli, the P3a amplitude is high;conversely, if it is easy to discriminate between the target and standardstimuli, the P3a amplitude is low. Our results could therefore beexplained by a decreased ability to discriminate between auditorydistractor and target stimuli when on medication, which would leadto an increase in P3a amplitude to auditory distractors. However, sever-al arguments can be made against this possibility. First, studies showthat dopamine enhances WM performance by increasing the signal tonoise ratio of neurons in the prefrontal cortex, leading to stabilizationof currently goal relevant representations and increment of theirrobustness relative to the distractors (van Schouwenburg, Aarts, &Cools, 2010). Second, no differences were observed in performanceeither in the auditory or the visual versions of the task. Third, theauditory distractors significantly differed from both target andstandards, not only in pitch, but also spectral composition, whichmakes them very salient and difficult to confuse with other stimuli.And last, if reduced discriminability would result from reduced signal-to-noise ratio, we would expect it to affect both auditory as well asvisual distractors, which was not the case.

In conclusion, more than one explanation can account for the resultsfrom our study. Taking into account all the arguments presented above,it seems that the most probable explanation for the observed selectiveincrease in P3a amplitude in response to auditory distractors underdopaminergic medication is a reduced ability to inhibit response toirrelevant, distracting stimuli. Further studies will, however, need toprovide conclusive evidence to differentiate between the discussedpossibilities.

4.4. No differences in P3a/b latency between groups or due to dopaminergicmedication

The results showed no changes in either P3a or P3b latency withdopaminergic medication. While P3a/b amplitude is considered toreflect the amount of selective attention resources to stimuli or theintensity of processing, P3a/b latency is an index of the time necessaryfor controlled information processing (Kok, 2001). Based on this wecan conclude that speed of information processing was not affected bydopaminergic medication.

Fig. 6. Scalp potential map for target (T) and distractor (D) stimuli in PD patients off (PD OFF), on (PD ON) medication and healthy controls (CON) for the auditory (mean amplitude be-tween 200 and 700 ms) and visual oddball (mean amplitude between 300 and 800 ms) tasks. Scale in microvolts (μV).

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Furthermore, no significant group differences in P3a/b latency wereobserved between PD patients and healthy controls. Previous findingsrelated to difference in P3a/b latency between PD patients and healthycontrols are inconsistent. Tsuchiya et al. (2000) for example havefound prolonged latency of P3a, but not of P3b in PD patients, conclud-ing that the orienting response in PD patients was impaired. Prolonga-tion of P3b latency has been found in other studies as well (Katsarou,Bostantjopoulou, Kimiskidis, Rossopoulos, & Kazis, 2004; Raudino,Garavaglia, Beretta, & Pellegrini, 1997; Tachibana, Aragane, Miyata, &Sugita, 1997). In a review of ERPs in different neurological conditions,Verleger (2003) concluded that the P3 latency tends to be prolongedin PD patients, particularly in those with overt cognitive decline. Incontrast, Hozumi, Hirata, Tanaka, and Yamazaki (2000) have foundshortened P3a latency in PD patients compared to controls andinterpreted it as a lack of habituation to novelty in PD patients due todysfunctional frontostriatal circuits. In other studies, however, nodifferences in latencies between PD patients and healthy controlswere reported (Graham et al., 1990; Green et al., 1996; Hansch et al.,1982; Pirtošek, Jahanshahi, Barrett, & Lees, 2001; Raudino et al., 1997).It needs to be noted that the differences in P3 findings across studiescould be a result of differentmethodologies used to record andmeasurethe P3 response.

4.5. Limitations of the study

There are important limitations of the study that need to be noted.First, the small number of participants could have prevented detectionof small effect sizes and consequently to fully identify the effects ofmedication as well as group differences. Lack of differences betweenpatients on or off medication and healthy controls, however, relates togeneral inconsistencies in reported behavioral and ERP findings acrossstudies. To illustrate, while in some studies no differences were foundbetween PD patients off medication and healthy controls (Grahamet al., 1990; Green et al., 1996), in others, PD patients off medicationperformed significantly worse than healthy controls (Stanzione et al.,1998). Similarly, whereas some studies report no difference in PDpatients on medication and healthy controls (Karayanidis et al., 1995),others report of significantly worse performance in PD patients onmedication compared to healthy controls (Tsuchiya et al., 2000). Suchinconsistencies can be due to a number of issues, among themdifferences in the paradigms used and in the medication status of PDpatients participating in the studies, both making the interpretation ofthe findings and their comparison between studies difficult.

Second, whereas PD patients performed the task twice, healthycontrols performed the task only once, preventing the use of a fullfactorial model when analyzing the data, thus making the comparisonsmore complicated and less reliable.

Third, there is an inherent disadvantage to recruiting clinical popula-tions such as PD, since patients differ on the LEDD and the specificdopaminergic drugs prescribed, which makes the population lesshomogenous and the results harder to interpret. This could beaddressed in future replications on a larger sample of de novo, drugnaive PD patients who are administered an equal dose of dopaminergicmedication.

Finally, all electrophysiological research suffers from importantlimitations, such as inherent inter-subject variability, accounted for bythe unique anatomy, physiology and psychology of participants, aswell as motor and cognitive interference during task execution thatcan add to the overall noise of the data andmake the comparison, espe-cially comparison between groups, less reliable and sometimes difficultto reproduce (Horvath, Carter, & Forte, 2014).

5. Conclusions

To our knowledge, this was the first repeated measures study of theeffect of dopaminergic therapy on both P3a and P3b ERP correlates of

cognitive processing in PD. The study revealed a differential effect ofdopaminergic therapy on processing of irrelevant vs. target auditorystimuli and related brain systems. Though the study failed to providemore specific information about the nature of the effect, it revealedimportant specificity in the effect of dopaminergic medication oncognitive processing, underlying the need for further detailed studiesof the effects of dopaminergic therapy on cognition in PD.

Acknowledgments

This research was supported by the Slovenian Research Agency(ARRS), Grant No. 30915, awarded to Dejan Georgiev.

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