Irritability

Neuropsychologia 48 (2010) 549557

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Neuropsychologia

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Irritability in pre-clinical Huntingtons disease

Stefan Kl roviOliver T S.J.a Department o try, Frb Wellcome Truc Division of Add Department oe MRC Cognitiof Department of Neurology, Neurozentrum, Freiburg Brain Imaging, University Clinic Freiburg, Freiburg, Germanyg Academic Unit of Medical Genetics and Regional Genetic Service, St Marys Hospital, Manchester, UKh Department of Clinical Neurology, Institute of Neurology, UCL, London, UKi Service de neurologie, Centre hospitalier universitaire vaudois et Universit de Lausanne, Switzerlandj Laboratory of Neuroimaging, IRCCS Santa Lucia, Roma, Italy

a r t i c l

Article history:Received 7 MaReceived in reAccepted 20 OAvailable onlin

Keywords:Huntingtons dIrritabilityfMRIAmygdalaOrbitofrontal c

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a b s t r a c t

Irritability, together with depression and anxiety, form three salient clinical features of pre-symptomaticHuntingtons disease (HD). To date, the understanding of irritability in HD suffers from a paucity ofexperimental data and is largely based on questionnaires or clinical anecdotes. Factor analysis suggeststhat irritability is related to impulsivity and aggression and is likely to engage the same neuronal circuitsas these behaviours, including areas such as medial orbitofrontal cortex (OFC) and amygdala.

16pre-symptomatic genecarriers (PSCs) and15of their companionswereasked to indicate the largeroftwo squares consecutively shown on a screen while undergoing functional magnetic resonance imaging(fMRI). Despite correct identication of the larger square, participants were often told that they or theirpartner had given the wrong answer. Size differences were subtle to make negative feedback crediblebut detectable.

Although task performance, baseline irritability, and reported task-induced irritationwere the same forboth groups, fMRI revealed distinct neuronal processing in those who will later develop HD. In controlsbut not PSCs, task-induced irritation correlated positively with amygdala activation and negatively withOFC activation. Repetitive negative feedback induced greater amygdala activations in controls than PSCs.In addition, the inverse functional coupling between amygdala and OFC was signicantly weaker in PSCscompared to controls.

Our results argue that normal emotion processing circuits are disrupted in PSCs via attenuated modu-lation of emotional status by external or internal indicators. At later stages, this dysfunction may increasethe risk for developing recognised, HD-associated, psychiatric symptoms such as irritability.

2009 Elsevier Ltd. All rights reserved.

ction

tons disease (HD) is an inherited neurodegenerativeused by an expanded number of triplet repeats of thebases cytosine, adenine and guanine (CAG) in the geneeproteinhuntingtin (HDCollaborativeResearchGroup,ability, together with depression and anxiety, form ae psychiatric features of pre-symptomatic HD. Irrita-

ding author at: Department of Psychiatry and Psychotherapy, Uni-reiburg, Hauptstrasse 5, 79104 Freiburg, Germany.70 5234; fax: +49 761 270 5416.ress: [email protected] (S. Klppel).

tion is dened as a temporary psychological state characterised byimpatience, intolerance, and poorly controlled anger. It includeselements of anger, aggression and reduced impulse control andcan occur independently of depression (Snaith, Constantopoulos,Jardine, & McGufn, 1978).

To date, studies of irritability in patients with HD have relied onquestionnaires. A recent study found increased levels of irritabilityin around 20% of pre-symptomatic gene carriers (PSCs) with lessthan 10 years to estimated diagnostic onset who were unawareof their gene status (Julien et al., 2007). Irritability causes greatdistress to those close toHDpatients and often determines if some-body can be managed in the community or needs to be admittedto a nursing home (Folstein, Chase, Wahl, McDonnell, & Folstein,1987; Hamilton et al., 2003; Wheelock et al., 2003).

see front matter 2009 Elsevier Ltd. All rights reserved.neuropsychologia.2009.10.016ppela,b,, Cynthia M. Stonningtonb,c, Predrag Petscher f, David Craufurdg, Sarah J. Tabrizih, Richardf Psychiatry and Psychotherapy, Section of Gerontopsychiatry, Section of Neuropsychiast Centre for Neuroimaging, Institute of Neurology, UCL, London, UKult Psychiatry, Mayo Clinic, Scottsdale, AZ, USAf Clinical Neuroscience, Karolinska Hospital, Stockholm, Swedenn and Brain Sciences Unit, Cambridge, UKte /neuropsychologia

cb,d, Dean Mobbsb,e,Frackowiakb,i,j

eiburg Brain Imaging, University Clinic Freiburg, Freiburg, Germany

550 S. Klppel et al. / Neuropsychologia 48 (2010) 549557

Factor analysis suggests that irritability in HD is related toimpulsivity and aggression (Craufurd, Thompson, & Snowden,2001). The amygdala and medial orbitofrontal cortex (OFC) are keycircuits involved in impulsive aggression (Blair, 2007; Davidson,Putnam, &in studiesDamasio, TLemieux, Thropsycholo& Coccaro,Doughertyinverse corDougherty eing an inhibdirect anato

Neuropainvolvemenaggression,Oliver, & Snand prefronthere is littleast in earlanism is noin impulsiv1997). Theinhibitors cMarchi, Dan1996) as anGiladi, 2002

Our studassociatedFirstly, weirritation insuch a taskgross impaperformedtial dexteriUnmatchedof differencin PSC havedifferences2004; Wolf2007). In linprocessingtation, evenAs outlinedimpulsive aon previouder (Coccaraggression,elicit increaamygdala-Oby others (SHD genemuWe therefoPSCs lost ato trials los

2. Material a

2.1. Participan

16 PSCs asame-generatimentioned, wdiseasewho thinclusion of cotion which wa

PSCs comprised a wide range of estimated years to clinical diagnosis, based onageand thenumberof CAGrepeats (Langbehn, Brinkman, Falush, Paulsen,&Hayden,2004). With the exception of the one relative, companions did not undergo genetictesting but none had a family history of HD or showed clinical signs. Other thanone control subject who had isolated seizures under the age of 12, there were no

co-morbidities. Two PSCs had previously taken antidepressant medicationthan a year (one took citalopram30mg; the other could not recall the namebstance or dosage), but none were actively using antidepressants at study.was taking 10g creatine daily. No one else had a history of neurological orric disorder and none had used centrally acting medication. A neurologistced in HD examined all PSCs. One control failed to undergo scanning andxcluded from all analyses. The remaining subjects were matched for age,National Adult Reading Test (NART) score (Nelson & Willison, 1991) andeducation (Table 1). The local Ethics Committee approved the study and allants gavewritten informed consent according to theDeclaration of Helsinki.

erimental procedure

task was designed to study two factors. Firstly, we sought to study neuronalng with false allegations of ones own performance errors. We expected theirritation to build up with repetition of these false allegations. The secondnder study was the identity of the second player. Based on clinical expe-e expected a stronger emotional response when a round was lost by a

ionsmegrateipantals pepilot pidentid thaobjectudy.followby th

s betwable pwswitwhenfoundions sd getty descng.

eedbachypoth

madore,

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entityects wr whonswefor evand toa comand

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t CAG

SquarLarson, 2000; Siever, 2008). This notion was suggestedfocusing on structural changes (Anderson, Bechara,ranel, & Damasio, 1999; Tebartz van Elst, Woermann,ompson, & Trimble, 2000) and later conrmed by neu-

gical and functional imaging studies (Best, Williams,2002; Coccaro, McCloskey, Fitzgerald, & Phan, 2007;et al., 2004). A growing body of evidence suggests anrelation between these two areas (Coccaro et al., 2007;t al., 2004; Urry et al., 2006)with themedial OFC exert-itory inuence on the amygdala, most likely throughmical connections (Rempel-Clower, 2007).thological as well as imaging studies indicate ant in HD of structures implicated in the regulation ofincluding the amygdala (Douaud et al., 2006; Mann,owden, 1993; Pavese et al., 2003; Rosas et al., 2003)tal cortex (Pavese et al., 2003; Rosas et al., 2002) butle indication of a specic involvement of the OFC, atier stages of the disease. Although the neuronal mech-t fully understood, a role for the serotonergic systeme aggression has been suggested (Coccaro & Kavoussi,very limited available data indicate serotonin reuptakeould be useful for the treatment of irritability in HD (Deiele, & Ragone, 2001; Ranen, Lipsey, Treisman, & Ross,alternative to atypical neuroleptics (Paleacu, Anca, &; Squitieri et al., 2001).y therefore aimed to examine the emotional circuitrywith induced irritation with a focus on the amygdala.intended to develop a task capable of reliably causingparticipants and to study the neuronal correlates of

with functional MRI (fMRI). Although PSC do not showirments we sought to design a task that can easily bein an fMRI environment and does not require substan-ty or rely heavily on working memory performance.task performance could have made the interpretationes in neuronal processing difcult. A number of studiesshown altered neuronal processing in the absence of

in task performance (Kloppel et al., 2009; Reading et al.,, Vasic, Schonfeldt-Lecuona, Landwehrmeyer, & Ecker,e with these studies, we expected changes in neuronalassociated with an experimental task that induces irri-in those PSCs without clinically increased irritability.above, we assumed irritability in HD to be related toggression and inuenced by social interaction. Baseds work in subjects with intermittent explosive disor-o et al., 2007), a disease characterized by impulsivewe hypothesized that our experimental task wouldsed amygdala activations in PSCs and a disruption ofFC coupling. Our clinical experience, and that reportednowden et al., 2003), indicates that individualswith thetation get particularly irritatedwith close companions.re expected greater activations of the amygdala whenround due to a mistake by their companion comparedt by mistakes from a computer.

nd methods

ts

nd their close companions (14 partners, one close friend and oneon relative) were included. PSCs were aware of their gene status. Ase decided to include companions who are indirectly affected by theereforedonot represent thegeneral population.Wereasoned that thempanions would illicit the strongest levels of irritability. An assump-s based on our clinical experience as outlined in the introduction.

medicalformoreof the suOne PSCpsychiatexperienso was egender,years inparticip

2.2. Exp

Theprocessiinducedfactor urience, wcompanwere intto particof 50 tri

In atask weWe founthe rstfor the sand wasfolloweddistancecomfortinterviecredibleber wasinstructtasks anthe studprocessi

2.2.1. FWe

they hadFurthermallegatioicting fpanel). Ttwo con

2.2.2. IdSubj

computehad to aaccountparisonform ofa human

Table 1Demogrmean an

NGendeAgeCAGYearsYearsUHDRNART

a Exacment.

b Chi-istake than thatmadeby anon-human (i.e., a computer). Both factorsd into the same task in which two squares were shown consecutively

s who were asked to identify the larger (see Fig. 1 for details). A totalr run were performed.hase with healthy participants performing different versions of theed a difculty level that resulted in correct answers on most trials.t it is much harder to correctly compare the size of two objects whent shown is larger. We therefore ended up with three different squaresIf a smaller square was shown rst, it measured 2.8 cm edge lengthed by a larger square of 2.9 cm. A square of 3.1 cm edge length wase square of 2.8 cm edge length. Slight differences of the combinedeen screen and mirror and mirror and eye were tolerated to ensure

ositioning of subjects and an unblocked view of the screen. Based onhparticipants of thepilot studywedetermined that the task remained28% of correct answerswere followed by error as feedback. This num-through trial and error in runs limited to exactly 50 trials. Written

tated that the study examines how the brain responds when doinging feedback. We deliberately avoided any mention of irritability inription, as that might have altered emotional responses and neural

k on own performanceesised that subjectswould experience irritation after being informede a mistake in a task they were sure they had performed correctly.we expected the induced irritation to build up with repetition of falseerroneous performance. We therefore varied the percentage of con-ck responses over the course of the 50 trials as shown in Fig. 2 (leftriation was constrained by avoiding presentations with more thanve trials comprising incorrect negative feedback.

of the second playerere led to believe that their computer was linked to their partnerswas playing simultaneously in another room and that both players

r correctly to win a round. Three pounds were added to a playersery round won and deducted again when a round was lost. For com-allow full balancing of the design, an additional second player in theputer was introduced which would try to simulate the behaviour ofcould therefore make mistakes. Playing with a computer was found

and basic cognitive details of participants. Results are reported withdard deviation.

PSC Controls p-Values

16 15 NA)b 8/8 8/7 0.8

39.37.9 40.490.4 0.7342.142.2a NA NA

mated onset 16.88.8 NA NAcation 14.92.9 15.63.1 0.57or 2.31.5 NA NA

104.210.2 108.99.0 0.18length missing from two subjects measured with different equip-

e test for gender.

S. Klppel et al. / Neuropsychologia 48 (2010) 549557 551

Fig. 1. Overvisequentially. Trst and seconboth players arandomised (j

less emotionalSanfey, Aronso

After a brieruns of 50 trialperformed inusing a standaand whether Pstudy.

2.2.3. RatingsAfter train

ranging from they and theirsubjects wereAfter the expescale (Snaith eMock, & Erbauand Spielbergmight be relucof Chatterjee,crepancies betHopkins irritaquestionnairetionnaire as th

study by Chatterjee et al. (2005). In addition, they completed a questionnaire ofhow they felt when receiving feedback. We assumed that each subject would havea different understanding of irritation. We therefore asked them to rate three neg-ative emotions (irritation, anger, tension) ranging from zero (emotion not felt) tothree (emotion strongly felt). Similarly, subjects were asked to report, using thesame scale, their positive emotions (happy and relieved) on receiving positive feed-back. We tested for a positive correlation of negative emotions (composite scoreof irritability, anger, and tension) induced by the task, with Snaiths score and theirritability subscore (summation of inward and outward irritability sub-scores) toidentify a relation of the task to our concept of irritability. Similarly, since irritabilityis closely connected to problemswith impulse control (Craufurd et al., 2001) scoringon the BIS-11 and task-induced negative emotions were also expected to be posi-tively correlated. Signicancewas testedwithnon-parametric testswhensignicantKolmogorovSmirnov tests indicated a violation of assumptions for parametric test-ing.

Before detailed debrieng, all participants took part in a semi-structured inter-view, one purpose of which was to verify that they had believed in the integrity ofthe task, the link with the other player and the correctness of feedback.

2.3. MRI-scanning

Weused an echo planar imaging sequence optimised for sensitivity in amygdala(Deichmann, Gottfried, Hutton, & Turner, 2003) scanned on a 1.5 Tesla MRISonatludedfactot 30 .to the02). Tngonbauervaluat, 200

ge da

proces(ww

olumtempin thristonigh-pt eachregrealysis, for t

Fig. 2. Left: ThBilaterally thesquare.ew of task. Subjects had to identify the larger of two squares shownhis was followed by feedback on the correctness of the answer of thed player. A separate screen indicated if the round was won (whennswered correctly) or lost. Timing intervals between screens wereittered) where indicated.

ly involving in our pilot study which mirrors results of others (Rilling,n, Nystrom, & Cohen, 2004).f training period with correct feedback, each subject performed fours. Two runs (one with a partner and the other with a computer) werethe MRI scanner. The other two were performed in a testing roomrd PC. Participants swapped rooms after two runs. The order of runsSCs or controls started in the MRI scanner was randomised over the

and questionnaires

and OFCsystem (eters incdistanceangled adala dueet al., 20dependiSchwarzand to e& Friston

2.4. Ima

Pre-softwarekernel, vimagingincludedmodel (FA 128 s hmated aseparatemary anfeedbacking, subjects were asked to indicate on a visual analogue scale (VAS),100 (indicatingworst performance) to +100, howwell they expectedpartnerwould do. Using a similar VAS after every twoor three rounds,asked how condent they were with their performance in the task.riment, subjects completed the Snaith irritability self-assessmentt al., 1978), Beck Depression Inventory (BDI; Beck, Ward, Mendelson,gh, 1961), Barratts Impulsivity Scale (BIS-11; Barratt & Patton, 1983)er State-Trait Anxiety Inventory (STAI; Spielberger, 1988). As PSCtant to admit their true level of irritability we adopted the approachAnderson, Moskowitz, Hauser, and Marder (2005) by evaluating dis-ween PSCs self rating and that of their companions using the Johnsbility questionnaire. Results between the two groups on the 14 itemwere compared using two-tailed paired t-tests. We refer to this ques-e Johns Hopkins irritability questionnaire. All items are listen in the

blocks with a lSince we wereseparate paramoften subjectsin Fig. 2 the mwas receivedthree returnedages as includitask less belietors assignedlow and for awith 14 trialsillustration ofthe parametri

e graph displays the changing percentage of positive feedback in the last three trials for eamygdala showed signicantly greater activations in controls compared to PSCswhen suba; Siemens, Erlangen, Germany) at a single centre. Scanning param-: repetition time 3600ms; echo time 50ms; eld of view 192mm;r 50%; ip angle 90 . We used 40 slices with a thickness of 3mmWe sought to measure the individual distortions in OFC and amyg-close proximity of air-lled cavities by acquiring eld maps (Hutton

otal scanning time for the fMRI task was around 30min per subjectspeedof responses. An additional T1-weighted sequence (Deichmann,, & Turner, 2004) was acquired to exclude structural abnormalitiese structural differences using voxel-based morphometry (Ashburner0) (see supplementary material).

ta analysis

sing and statistical analysis of fMRI data were carried out using SPM5w.l.ion.ucl.ac.uk/spm/). Before smoothing with an 8mm Gaussianes were realigned and spatially normalised to a standard echo planarlate in Montreal Neurological Institute (MNI) space. Field maps weree realignment step. A rst-level analysis based on the general linear, Frith, Turner, & Frackowiak, 1995) was performed for each subject.ass lter was applied. Task-related changes in fMRI signal were esti-voxel by modelling the onsets and length of each event type as a

ssor convolved with a haemodynamic response function. For our pri-, we used four regressors to model the onset of positive and negativehe rst and second player respectively. They were modelled as mini-ength of 35 s, depending on the onset of the next screen (see Fig. 1).interested in the effect of repeated negative feedback, we entered aetric modulator to both regressors of negative feedback, coding how

had received negative feedback in the last three trials. As illustratedodulator thus contains values of either 100 when positive feedbackfor all three previous trials 66 or 33 when only one trials of the lastpositive feedback.We did not aim to evenly distribute these percent-ng too many trials with false negative feedback would have made thevable. All four feedback conditions had separate parametric modula-to model linear effects of time (e.g., due to fatigue). Error rates weresubject not making a real mistake 36 correct trials were contrastedin which false allegations of erroneous performance was reported. Anthe design matrix is provided as supplementary material. As shown,c modulator coding past negative feedback is assigned to the nega-

ach run given that a subjects true answer was always correct. Right:jectswere repeatedly given feedback that they had chosen thewrong


Table 2Details of task performance and questionnaires completed after the experiment. Results are reported with mean and standard deviation unless stated otherwise.

PSC Controls p-Values

BIS total 62.011.8 63.38.9 0.71STAI (state) 2.6STAI (trait) 0.4BDISnaith total .4Snaith irritaNegative em )Positive emoCorrect resp .9Expected pe 0.0Expected pe 5.0Condence i 5.8

a Reported w

tive feedbackpresses, the distep to accounthree axes). Tranalysis. We rthose where nmistakes, partsecond case iseach contrast

2.5. Group-lev

2.5.1. FeedbacParameter

feedback enteparticipants inmates from thin the last threthat emotionscorrect perform

2.5.2. CorrelatWe expec

reported in qunegative feedparameter imafrom the paramthree trials wisor. As before,diagnostic dise

2.5.3. RegionsThe prima

was the amygtissue analysisvoxelswith atwas the mediacreated a sphemedial OFC frx, y, z= 6, 52comparisons wrate (FDR) as iOutside our reperformed acr

2.5.4. Time seAs in a rela

to test for a difand medial OF(andnoton theactivity in abraregions depenanalysis descriand not just daamygdala wer(Eickhoff et al.in MNI space).The resulting pdescribed abo

entityperforSC anand copair

F-testn previnterortexn waexplo

nicanion of

ults

havi

partitiveetw

ing thn marly, nands irr6.3;ailab

betwthat2). Fndicannaoneabilitns wimp

or apscorwe34.0134.215.75.913.26

bility subscore 5.63.3otion with loosing (max=9)a 2.0 (09tion with winning (max=6) 3.51.5onses [%] 93.84rformance of self (min=100, max=+100) 17.43rformance of 2nd player (min=100, max=+100) 57.62n answer (min=100, max=+100) 29.42ith median and range; MannWhitney test for between-group comparison.

condition only. Additional regressors were included to model buttonfferent screens as well as six regressors obtained at the realignmentt for movements (translations in three planes and rotations alongials when a player made a real mistake were excluded from furthereasoned that cognitive processing of such trials would differ fromegative feedback followed correct performance. In the case of trueicipants might doubt their answers while negative feedback in thelikely to be more unexpected. The resulting set of voxel values for

entered a second level analysis.

el random effects analysis

k on own performanceimages of the differential effect of negative compared to positive

red a 2-sample t-test with 28 degrees of freedom resulting from 30two groups. A similar design was employed to study parameter esti-e parametric modulator coding the percentage of negative feedbacke trials (Fig. 2). As explained above, this analysis tests the hypothesisbuild up when subjects repeatedly receive negative feedback, despiteance.

ional analysisted that subjects with a higher level of task-induced irritabilityestionnaires would show greater activations in the amygdala whenback was compared to positive feedback. We also correlated theges from the comparison of negative and positive feedback and thoseetric modulation of the percentage of negative feedback in the last

th the estimated years to onset and included age as a separate regres-we expected increased activations of the amygdala with approachingase onset and a higher frequency of erroneous negative feedback.

of interestry focus of the feedback and correlational analyses described abovedala, dened using the anatomy toolbox, based on post-mortem(Eickhoff et al., 2005). We created a region of interest including all

least a 50% probability of belonging to the amygdala. The second focusl OFC for which no such template is currently available. We thereforere with a radius of one cm around the most activated voxel in the

om the control group of a recent study on impulsive aggression (at, 20 in MNI space) (Coccaro et al., 2007). Correction for multipleithin each of the regions was performed using the false discovery

mplemented in SPM5 at a critical p-value of 0.05 at the voxel level.gions of interest voxels are reported if they survived FDR correctionoss the whole brain.

2.5.5. IdWe

levels: Ppartnereach of asequentBased o2004) onfrontal ccorrectioa stronglobe siginteract

3. Res

3.1. Be

Alla negaences bincludrelatioSimilaratingsHopkin11.6data avencesexcept(p=0.0toms iquestioall butof irritrelatioBIS-11trend fity subequallyries analysisted study (Coccaro et al., 2007), we performed an additional analysisference in the strength of the negative correlation between amygdalaC that depends on gene status. Based solely on the fMRI time seriesparameter imagesused inother analyses), this analysis testswhetherin region (i.e., the amygdala) correlates differentiallywithother brain

ding on gene status. This analysis is complementary to the group-levelbed above as it takes the fMRI time series from the whole experimentta from one specic condition. The time-courses in the left and righte extracted from the centre of the probabilistic atlas of the amygdala, 2005) (centro-lateral segment) (x, y, z=25, 9, 18 and 29, 8, 19The time series was used as a single regressor in subsequent analysis.arametric images entered a second level 2-sample t-test analysis as

ve.

(Table 2). Tworse thantionnaires wInterviewscorrectness

3.2. Image

No signwhen negathe scannecombined.31.78.9 0.5738.010.8 0.326.96.1 0.5913.35.5 0.955.52.9 0.962.0 (07) 0.223.71.5 0.5593.84.9 0.9936.733.1 0.149.025.5 0.3538.732.6 0.33

of the second playermed an exploratory three-way ANOVA with the factor GROUP (twod controls) and two repeated-measures factors, PLAYER (two levels:mputer) and CONDITION (four levels: positive/negative feedback on

of players). Of primary interest to our research question was the sub-that identied regions showing an interaction of GROUP by PLAYER.ious studies (Gallagher, Jack, Roepstorff, & Frith, 2002; Rilling et al.,action of humans with computers we expected the dorso-medial pre-(dmPFC) to show increased activity if the partner was human. FDR

s performed in the same regions of interest as above. This analysis hadratory component and we thus report all regions within the frontalt at p0.5, paired t-test;le from 15 pairs only). There were no signicant differ-een PSCs close to and far from estimated clinical onsetthose far fromonset had a lower number of CAG repeatsour PSCs and three controls had mild depressive symp-ted by a BDI over 10. The rating on Snaiths irritabilityire was within the normal range (Snaith et al., 1978) inPSC. Task-induced negative emotions (composite scorey, anger and tension) showed a signicant positive cor-ith both Snaiths score (rSpearman =0.31; p=0.048) andulsivity score (rSpearman =0.46; p=0.005). Similarly, aositive correlationwas foundwith the Snaiths irritabil-e (rSpearman =0.28; p=0.064). Both groups performedll and were equally condent about their decisions

here was a tendency that PSCs expected to performcontrols (p=0.1). No correlations of scores in ques-ith the estimated years to clinical onset were found.

and debrieng conrmed that subjects believed in theof feedback and the link between cooperating players.

data analysis

icant activations in amygdala or OFC were observedtive and positive feedback was compared for players inr either separately for each group or for both groupsThere was also no signicant effect when testing for an


Fig. 3. Areas showing a stronger negative correlation between right amygdala activity (white circle) in the control group compared to PSCs. The seed region in the amygdala isenlarged for visualisation purposes. The plots on the left display the strength and direction of coupling. Bars report the strength of correlation in arbitrary units (a.u.) with 90%condence intervals. Imaging results are overlaid on the mean brain from all subjects in MNI space at a threshold, for visualisation purposes only, of p


Fig. 5. Effect o increato a computer ive inin both areas w e). In bcompanion. Er 1 (uncortex; dmPFC

4. Discussi

4.1. Behavi

We founand controlSnaith irritaically overtthan 10 ye(Julien et alless than 10of increasedmore stresPSC self ratfound whic(2005). Thesive symptoemotional bwell as PSC

Equal leated with deither comtability quebetween gring research

4.2. Feedba

Our fMRing task-indactivationswas compaferential ac

ondd co

threef identity of the second player. The top left panel depicts areas where controls show. The lower left panel indicates that this effect is weaker in PSCs, resulting in a posithen partner and computer conditions are compared (co-ordinates are in MNI spacror bars indicate 90% condence intervals. Results are displayed at a level of p10) in both groups, potentially reecting theurden of pre-symptomatic HD on close companions ass.vels of self-reported task-induced irritation associ-ifferential group specic neural responses suggest thatpensatory mechanisms are in place or that the irri-stionnaires lacks sensitivity to detect subtle differencesoups. Their improvement is an important part of ongo-.

ck on own performance

I analysis leads us to reject our rst hypothesis regard-uced amygdala activations. PSC did not show greaterin the amygdala than controls when negative feedbackred to positive feedback. We found no indication for dif-tivations in the OFC/amygdala axis with the identity of

PSCs were mneous respoirritation) tcated eithenegative feeareas of theor absent inamygdala/mpsychiatric

4.3. Time se

A disrupin recent wand also in(Doughertyrelated paththe basis oflevels of exings to aggaggressiveropsycholoaforementitoms (Coccanormal leveet al., 1978)

Reducedrelate to th2003). At lsed activations when the second player is a human partner comparedteraction in both areas. The two right panels depict the signal changeoth areas, PSCs have reduced activations when the second player is a

corrected) for visualisation purposes. dACC: dorsal anterior cingulate

player. We can, however conrm the hypothesis of aupling between amygdala and medial OFC in the PSC

imaging analyses indicate that neuronal responses in

odulated less by external (i.e., the proportion of erro-

nses) and internal factors (i.e., the level of task-inducedhan in controls. Increasing false negative feedback (indi-r by subject-specic ratings or a higher frequency ofdback) resulted in increased activations in overlappingamygdala in controls, whereas this effect was reducedPSCs. We argue that the inappropriate responses of theedial OFC axis make PSCs prone to the development of

symptoms such as irritation.

ries analysis

tion of the amygdala/medial OFC axis has been foundork on impulsive aggression (Coccaro et al., 2007)subjects suffering from depression with anger attackset al., 2004). Early involvement of the amygdala in HD-ology (Douaud et al., 2006; Rosas et al., 2003) could bethe reduced coupling and responsiveness to reportedperienced negative emotions. The similarity of nd-ressive disorders lends support to the presence of anelement in HD, which has also been suggested by neu-gical factor analysis (Craufurd et al., 2001). While theoned studies included patients with psychiatric symp-ro et al., 2007; Dougherty et al., 2004) our PSCs showedls of irritability as measured by the Snaith scale (Snaith.functional coupling could limit the ability of PSCs toe strength and value of an emotion (Anderson et al.,east for the emotion of fear, it has previously been


reported that under conditions of diminished conscious emotionalawareness there is a decrease of connectivity between amygdalaand cortical association areas (Williams et al., 2006). PSCs could befailing to recognise their own emotional state or might be denyingit, a notionings betweeHoth et al.,

4.4. Effect o

Based oity in PSCsclose compaby interviewtheir partnthe case forelement ofies (Rillingdepended odepend on tof the secon

Thedorscated in sowere indeerather thanThis ndingperspectivetered moredmPFC area2006). Impaself (e.g., asone more pever, thesestemfromalittle to diff

Althoughcorrect answand controlthan a collasensitivityespecially iexperiencedness of feepick up this

4.5. Limitat

A numbDespite a tring in the tasimilar levedence in thehelped to enot a sourcdifferencesease proceswere awareenced themwidespreadto represening with irrin these cirrisk subjectsubjects haand signic

tory counselling, could themselves modify clinical presentationsof HD-related irritability.

As pointed out in the introduction, there is some evidencefor structural changes affecting the amygdala. Although the anal-

themened ws unefferelaasedeticaive a1), ognitialuatve ato rager an th

ires it of id annnain thcicalectein q

sioncordnducility.quesize tour atrospnna

s queare nort tC arecess

clus

onclrespock inell psuchxpreYounat dy

ear008n prility.

ting

e

g

s wortothat is supported by a study comparing symptom rat-n HD patients and collaterals (Chatterjee et al., 2005;2007).

f second player

n clinical experience, we hypothesised that irritabil-is particularly pronounced in their interactions withnions.No clear indication for this hypothesiswas found. Both groups consistently reported that playing with

er was more emotionally involving but that this wasboth positive and negative feedback. The interactive

our task was far less pronounced than in other stud-et al., 2004); although the outcome of a given roundn both players, the response of one player did nothat of the other. This is likely to have reduced the effectd players identity.al anterior cingulate cortexanddmPFChavebeen impli-cial interaction (Amodio & Frith, 2006). These regionsd activated by controls when playing with a partnera computer, whereas this effect was absent in PSCs.could represent a reduction in the ability to take theof others, so that the identity of a second player mat-to controls than to PSCs. A complimentary view is thats represent others views of the self (Amodio & Frith,irment in assessingwhat other people think about one-when the self gets false negative feedback) could makerone to aggressive and disinhibited behaviour. How-ndings should be interpreted cautiously since theynexploratoryanalysis and the interviewresultsprovideerentiate between the two possible explanations.

instructions stated that both players needed to giveers in order to win a round and the money, three PSCs

s perceived the task as a friendly competition ratherborative effort. Such heterogeneity is likely to reducefor detection of differences between the two groups,n amygdala. We conrmed our pilot study as subjects

irritation with the task and believed in the correct-dback and the link between computers, but did notambiguity.

ions

er of aspects of the current study should be noted.end for PSCs expecting to performworse prior to engag-sk, both groups actually performed equally well, withls of induced positive and negative emotions and con-ir decisions. A taskwith low levels of cognitive demandnsure that subtle cognitive impairments in PSCs weree of between-group differences, making the observedin neuronal activations more likely to reect the dis-s and compensation for it. Notably, PSC in our studyof their genetic status which is likely to have inu-at the behavioural and neuronal levels. Given theavailability of genetic testing, this situation is likely

t the standard situation in a clinical setting when deal-itability and the study aimed to understand processingcumstances. More to the point, most studies with at-s ignorant of their genetic status were performed afterd decided to undergo genetic testing. The uncertaintyance of the testing procedure, that includes manda-

ysis ofsuppleidentichangeremote

Theor disehypothimpulsal., 200and conot evmay haaskedity, anbetweetionnaconcepsion anquestiomatrixity spepre-sesimilardepresThe reskin coirritab

AllminimbehaviThis requestioSnaithreportWe repand OFthe pro

5. Con

In cronalfeedbamay wstates,facial e(Gray,and thtions inet al., 2emotioirritab

Compe

Non

Fundin

Thi2/04/2structural data acquired for the current study (seetarymaterial) failed to identify changes in the structuresith functional imaging, it is possible that structuralderlie some of the functional differences found viacts.tive absence of studies on irritability in either healthypopulations made it necessary to base this study onl assumptions. While the relationship of irritability toggression is supported by a factor analysis (Craufurd etther clinical presentations of HD, including poor sleepve dysfunction, may play an important role and wereed. As mentioned in the Methods section, each subjectdifferent concept of irritability. Subjects were thereforete the intensity of three negative emotions (irritabil-nd tension). The signicant positive correlation foundese emotions and the impulsivity and irritability ques-llustrates that the task is at least related to thepresentedrritability. Given that irritability co-occurswith depres-xiety and HD and that the results from the respectiveires were correlated with each other (see correlatione supplement)wecannot claimtobe lookingat irritabil-lly and exclusively. Futurework could focus on subjectsd for increased levels of irritability to see if results areuality and if the effect of contributing factors such aspoor sleep and cognitive dysfunction can be isolated.ing of additional physiological data, e.g., heart rate ortance could also prove useful to nd effects related to

tionnaires were completed after the experiment tohe effect of reecting on emotions from inuencingnd cognitive processing as the experiment progressed.ective nature could have inated correlations betweenires that were or were not related to the task (e.g.,stionnaire). Finally, a number of the imaging resultsweot signicant after correction formultiple comparisons.hemdescriptively to illustrate that ndings in amygdalavery probably bilateral and to generate hypothesis of

ing of the second players identity.

ion

usion, our results indicate a poor dependency of neu-nses on reported emotions or the quality of recentPSC. The disruption of emotion processing circuits

redispose to the development of recognised psychiatricas irritability. There is evidence that the processing ofssions of negative emotions is affected already in PSCg, Barker, Curtis, & Gibson, 1997; Johnson et al., 2007)sphoria inducing pictures elicit differential brain activa-ly affected HD patients compared to controls (Paradiso). Future research could clarify if these impairments ofocessing predispose one to the clinical manifestation of

interests

k was supported by the Wellcome Trust (grant 075696R.S.J.F., and S.J.T.) and the Bundesministerium fr


Forschung und Gesundheit (BMBF grant 01GW0730 to O.T.). Whilewriting the manuscript S.K. was funded by the MedizinischeFakultt of the University of Freiburg. P.P. is supported by a grantfrom Vetenskaps rdet and Hjrnfonden, Sweden.

Acknowled

WewouRachel Taylrecruitmenof the NARTChristoph Kmanuscript

Appendix A

Supplemthe online v

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Irritability in pre-clinical Huntingtons diseaseIntroductionMaterial and methodsParticipantsExperimental procedureFeedback on own performanceIdentity of the second playerRatings and questionnaires

MRI-scanningImage data analysisGroup-level random effects analysisFeedback on own performanceCorrelational analysisRegions of interestTime series analysisIdentity of the second player

ResultsBehavioural data and ratingsImage data analysisTime series analysisCorrelational analysis

Effect of second player

DiscussionBehavioural dataFeedback on own performanceTime series analysisEffect of second playerLimitations

ConclusionCompeting interestsFundingAcknowledgementsSupplementary dataReferences

Documents

Irritability