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Neuropsychologia 46 (2008) 1279–1289

fMRI reveals altered auditory processing in manifest andpremanifest Huntington’s disease

Carsten Saft a,1, Anne Schuttke b,1, Christian Beste a,b,c, Jurgen Andrich a,Walter Heindel b, Bettina Pfleiderer b,∗

a Department of Neurology, Huntington-Center NRW, St. Josef Hospital, Ruhr University Bochum, Germanyb Department of Clinical Radiology, University of Munster, Albert-Schweitzer-Str. 33, 48129 Munster, Germanyc Leibniz Research Centre for Working Environment and Human Factors, WHO Collaborating Research Centre,

Dortmund, Germany

Received 11 April 2007; received in revised form 2 November 2007; accepted 4 December 2007Available online 14 December 2007

bstract

Structural alterations of the basal ganglia occur in patients with Huntington’s disease (HD). The aim of this exploratory study was to assessuditory processing mechanisms by functional MRI (fMRI) in patients with premanifest (pHD) and manifest HD to gain more insight in possiblelterations in basal ganglia–thalamic circuits. Sixteen HD and 18 pHD as well as corresponding age- and gender-matched controls were included.he pHD group was divided into two subgroups close (cpHD; <10 years) and far pHD (fcHP; >10 years), according to their estimated age of diseasenset (eAO). Tone perception and processing were visualized by 3 T fMRI by employing repeated tone stimulation through digitally generatedulsed (ν = 5 Hz) 800-Hz sine tones. We found altered activation in basal ganglia–thalamic circuits in HD and/or pHD compared to controls. (i)he cpHD group presented predominantly down-regulated processes compared to fpHD and HD. (ii) HD presented stronger bilateral activationf the putamen and (iii) fpHD presented stronger bilateral activation of the thalamus and also right caudatum. (iv) Depending on the progress of

he disease, a shift towards the activation of more right hemispherical areas can be observed. Our findings seem to reflect an altered activationattern to auditory stimulation depending on the progression of neuronal dysfunction in HD and pHD. They also stress the involvement of theasal ganglia–thalamic circuits in the processing of sensory auditory stimuli.

2007 Elsevier Ltd. All rights reserved.

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eywords: Functional magnetic resonance imaging; Auditory processing; Hun

. Introduction

Huntington’s disease (HD) is inherited as an autonomic dom-nant trait and caused by a CAG repeat expansion in the IT-15ene, resulting in an expanded polyglutamine (polyQ) stretch inhe mutant huntingtin (htt) protein (The Huntington’s Diseaseollaborative Research Group, 1993). Huntingtin accumulatesnd causes striatal neuronal death.

Depending on the stage of disease, alterations in striatalnd thalamic structure were reported (Aylward et al., 2004;rafton et al., 1992; Harris et al., 1999; Kassubek, Juengling,

∗ Corresponding author. Tel.: +49 251 83 56153; fax: +49 251 83 52067.E-mail address: pfleide@uni-muenster.de (B. Pfleiderer).

1 These authors contributed equally to this work.

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028-3932/$ – see front matter © 2007 Elsevier Ltd. All rights reserved.oi:10.1016/j.neuropsychologia.2007.12.002

n diseases; Biomarker; Habituation

cker, & Landwehrmeyer, 2005). It was observed that as aonsequence of structural alterations functional alterations alsoccur and it was discussed that neuronal dysfunction ratherhan neuronal loss of the basal ganglia may be an early fea-ure in HD. For instance, studies in premanifest HD (pHD)y functional magnetic resonance imaging (fMRI) revealededuced activation in subcortical regions (caudate and thala-us) in those gene carriers who were close to the estimated

ge of onset (eAO), i.e. less than 12 years to onset (YTO),sing a time-discrimination task. In contrast, participants farrom eAO (>12 YTO) presented a hyperactivation in medialemispheric structures (anterior cingulate, presupplementary

otor area) relative to controls and those participants close

o eAO. It was discussed that this hyperactivation was mainlyue to compensatory processes (Paulsen et al., 2004). More-ver, increasing impairment of striatal structures also seem to

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280 C. Saft et al. / Neuropsyc

ltimately result in altered brain networks (Thiruvady et al.,007).

These data indicate a causal role of striatal-thalamic areas inutomatic inhibitory motor control; others reported that thesereas function additionally as a sensory analyser in centralomatosensory control (Boecker et al., 1999).

Based on previous findings on structural and functional alter-tions of the basal ganglia and thalamus in HD and pHD as wells on evidence that these areas serve multiple functions, not onlyn motor control but also in sensory processing (e.g. Afifi, 2003;aji, Urushihara, Murase, Shimazu, & Goto, 2005), we wanted

o assess the involvement of basal ganglia–thalamic circuits inensory auditory processing in these groups. We focussed onuditory processing, since Kropotov et al. (2000) reported thatfter exposure to different tones, brain responses were not onlyeen in the primary and secondary auditory cortex, but alson basal ganglia–thalamic circuits, thus indicating the involve-

ent of these areas in attentive processing of auditory stimulushanges (Kropotov et al., 2000). Moreover, the putamen alsoeems to be associated with attentive processing of auditorytimuli (Opitz, Schroger, & von Cramon, 2005). It was shownhat when deviant tones were presented in sinusiodal tone blocksn an “oddball” tone design, they caused increased activity inhe bilateral putamen. Since the putamen shows atrophy in HDRosas, Feigin, & Hersch, 2004a, 2004b), it may therefore beypothesized that auditory processing is dysfunctional in HD.tructural alterations are even evident in premanifest HD (pHD)Aylward et al., 2004). Therefore, dysfunctions in auditory pro-essing may not be limited to the manifest stage but rather alsovident in the premanifest stage (pHD). On the other hand theremanifest stage of HD may be characterized by compensatoryrocesses (e.g. Beste et al., 2007; Tarditi et al., 2006). So, audi-ory processing may also be enhanced in premanifest HD. Yetompensation may also be mediated via the recruitment of addi-ional brain areas in large-scale networks (Feigin et al., 2006;oermans et al., 2004).

Auditory transmission is fascilitated by a large-scale neuronaletwork. It is mediated among others, via ventral and dorsalochlear nuclei, lateral lemniscus, inferior colliculus, medialeniculate nuclei (Bernal & Altmann, 2001; Frackowiak et al.,004), and lastly the medial geniculate nuclei projects to the pri-ary auditory cortex (Bernal & Altmann, 2001; Frackowiak et

l., 2004). Each auditory cortex receives information from bothochlea. The primary auditory cortex–Brodmann area (BA) 41,2; Heschl’s gyrus (Lancaster et al., 2000), transfers informa-ion to several adjacent association areas, the secondary auditoryortices of the temporal lobe, e.g. Brodmann area 22 (Lancastert al., 2000). Further connections to the prefrontal cortex or theimbic system are described in literature (Bernal & Altmann,001; Jancke, Shah, Posse, Grosse-Ruyken, & Muller-Gartner,998; Pandya, 1995). The left hemisphere is usually dominantor sine tone processing (LoCasto, Krebs-Noble, Gullapalli, &urton, 2004; Pfleiderer, Ostermann, Michael, & Heindel, 2002;

chonwiesner, Krumbholz, Rubsamen, Fink, & von Cramon,006; Zatorre & Belin, 2001). If compensation effects are medi-ted via the recruitment of additional brain areas, it may alsoe possible that the known left-sided lateralization is changed.

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ia 46 (2008) 1279–1289

wo recent studies (Finke, Bublak, Dose, Muller, & Schneider,006) (Beste et al., 2007) suggest a more left-lateralized atro-hy in HD. It may therefore be speculated that predominantlyeft-sided atrophy may cause auditory functions to be processed

ore right lateralized in order to maintain auditory process-ng. Auditory processing itself can be studied in habituationaradigms (Pfleiderer et al., 2002). When an auditory stimu-us is presented repeatedly for a long time habituation occursBernal & Altmann, 2001; Jancke et al., 1998; Pandya, 1995;fleiderer et al., 2002; Rose & Rankin, 2001). Habituation isefined as a decreased response to a stimulus during a contin-al exposure due to a lack of reinforcement and is accompaniedy a decline in neuronal activity. These processes are usuallynterpreted as a top-down effect on sound representation in theuditory cortex (Schonwiesner et al., 2006; Sussman, Winkler,uotilainen, Ritter, & Naatanen, 2002).In this current exploratory study we examined how auditory

ensory processing is modulated in different stages of HD due toither degenerative or compensatory processes. This was accom-lished by means of an already established paradigm of auditoryrocessing (habituation) by repeated presentation of sine tonesPfleiderer et al., 2002). We postulated that even in pHD dueo structural alterations in the basal ganglia and thalamus, audi-ory processing is affected and presents compensatory-increasedctivation of brain areas.

. Patients and methods

.1. Subjects

Sixteen patients with genetically confirmed and clinically manifest HD inhe earliest stage (Shoulson, 1981) were included in this study. Additionally,8 premanifest mutation carriers defined by a positive gene test and absence ofpecific clinical symptoms were recruited from our HD center. For each of theremanifest subjects, expected age at onset was estimated using a formula basedn the length of the subject’s trinucleotide repeat and the parental age at onset assed already by several other groups (estimated age at onset = [−0.81 × repeatength] + [0.51 × parental onset age] + 54.87) (Aylward et al., 2004; Harris et al.,999; Ranen et al., 1995) to have comparable data. YTO for the pHD subjects inhis study was calculated by subtracting the subject’s age at the time of the initialcan from his or her estimated onset age. The median YTO for these subjectsas 10.35 years (S.D. 8.34; range: −3.0 to 23.8). pHD were assigned – basedn this calculation – to two groups: close to eAO (n = 9; cpHD; YTO < 10) andar from eAO (n = 9; fpHD; YTO > 10).

As expected, manifest HD and premanifest HD gene carriers significantlyiffered in age and in all tests reflecting functional decline, such as TFC and ISTable 1). There was, however, no significant difference between both groupsegarding the CAG repeat lengths or in the severity of depressive symptomsssessed by the HAMD and BDI. There were also no significant differencesetween the cpHD and the fpHD subgroups. Three additionally enrolled manifestD subjects had to be excluded from further investigation due to claustrophobic

ymptoms in the scanner or hyperkinetic motion artefacts.All HD participants underwent neurological investigation and were scored

ccording to the motor scale (MS), total functional capacity (TFC) and inde-endence scale (IS) of the unified Huntington’s disease rating scale. Cognitiveerformance was evaluated by the verbal fluency test, symbol digit test andtroop interference test. The results of these tests were summarized as “cogni-ive score” (CS; UHDRS; Huntington Study Group, 1996). Fine motor skills

ere measured by simple (tapping; higher motor impairment leads to lower test

esults) and complex (peg insertion; higher motor impairment leads to higherest results) instrumental movement tests, in order to have an additional methodor detection and evaluation of motor impairment in HD (Saft, Andrich, Meisel,rzuntek, & Muller, 2003; Saft, Andrich, Meisel, Przuntek, & Muller, 2006). To

C. Saft et al. / Neuropsychologia 46 (2008) 1279–1289 1281

Table 1Characteristics of manifest HD and premanifest HD

Parameter Manifest HD (n = 16) Premanifest HD (n = 18) Subgroup cpHD (n = 9) Subgroup fpHD (n = 9)

Age (years) 42.1 ± 12.0a** 36.3 ± 9.4 43.9 ± 5.4b** 28.8 ± 5.5Gender (m/f) 9/7 7/11 6/3 5/4Handedness (r/l) 16/0 16/2 8/1 8/1AO (years) 40.2 ± 13.3 NA NA NADuration (years) 2.5 ± 2.2 NA NA NAeAO (years) NA 46.5 ± 4.4 46.8 ± 4.6 46.2 ± 4.4YTO (years) NA 10.2 ± 8.3 3.0 ± 4.2b** 17.4 ± 3.6CAG normal 17.9 ± 2.8 18.2 ± 3.9 17.1 ± 4.0 19.3 ± 3.6CAG expanded 45.6 ± 4.8 42.6 ± 1.6 42.8 ± 4.0 42.3 ± 1.9UHDRS MS 26.9 ± 12.0 0 0 0UHDRS TFC 11.7 ± 1.1a** 12.9 ± 0.3 12.8 ± 0.4 13.0 ± 0UHDRS IS 89.1 ± 8.2a** 99.4 ± 2.4 98.9 ± 3.3 100 ± 0UHDRS CS 216.6 ± 64.4a** 317.8 ± 50.6 307.5 ± 68.3 328.0 ± 23.2Hamilton 8.1 ± 5.8 6.9 ± 8.9 9.8 ± 10.6 4.1 ± 6.1BDI 6.4 ± 5.6 7.6 ± 8.0 9.3 ± 9.1 5.9 ± 6.9Pegboard r 537.9 ± 118.8a** 388.0 ± 60.2 402.5 ± 80.0 373.4 ± 28.6Pegboard l 588.4 ± 133.2a** 424.5 ± 39.3 439.7 ± 43.7 409.3 ± 29.1Tapping r 156.4 ± 41.3a** 185.7 ± 29.3 188.8 ± 39.7 182.6 ± 14.9Tapping l 121.4 ± 37.2a** 161.8 ± 15.6 164.6 ± 20.0 159.1 ± 10.1

Values are given as mean ± S.D. Abbreviations: AO, age at symptom onset; eAO, estimated AO, YTO, years to estimated AO; NA, not applicable; UHDRS, unifiedHuntington’s disease rating scale; BDI, Beck’s depression inventory; IS, independence scale; TFC, total functional capacity; MS, motor score; CS, cognitive score;r, right; l, left; m/f, male/female; close to estimated age of onset premanifest HD gene carriers (cpHD; YTO < 10 years); far from estimated age of onset premanifestH expan

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dAS2wareas, cross-correlation analysis with a basis set (boxcar function) was used

D gene carriers (fpHD; YTO > 10 years). Note the unequal variance for CAGa Significant differences between HD and pHD (nonparametric Mann–Whitnb Significant differences between cpHD and fpHD (nonparametric Mann–Wh

ssess severity of depressive symptoms, the Hamilton depression rating scaleHAMD; Hamilton, 1960) and Beck’s depression inventory (BDI) were used. Allatients and 16 of 18 mutation carriers were right-handed based on the Edin-urgh handedness inventory (Oldfield, 1971). Exclusion criteria were severeyperkinesia (UHDRS chorea subscore not more than 2 per item) or pronouncedognitive problems (UHDRS cognitive score less than 100) interfering with testerformance. Subjects with a medical history of drug abuse or other neurologicalisorders were excluded. Since there is a known impact of dopamine-system toompounds on fMRI patterns, we included only drug-free participants (Peterst al., 2003; Schmid et al., 2004). There was only one pHD on a low dose ofntidepressants (50 mg of trimipramine), but she paused more than 3 days prioro the MR scan.

Separate age- and gender-matched healthy volunteers were recruited bydvertisement in the University hospital Munster, serving as controls for HDatients (n = 16, male = 11, age: 42.1 ± 12.1 years) or premanifest mutation car-iers (n = 18, male = 7, age: 35.8 ± 9.8 years). All participants gave their writtennformed consent. All patients and pHD’s, except two, accepted to be video-aped in order to document their neurological status. The study was approvedy the ethics committee of the Ruhr-University Bochum (Vote no. 2485) andhe studies have been performed in accordance with the Declaration of Helsinki.he clinical and genetic characteristics of HD patients and mutation carriers arerovided in Table 1 in detail.

.2. MRI data acquisition

MRI data were acquired in a 3 T whole body scanner (Gyroscan Intera30, Philips, Best, NL) with a circularly polarized transmit/receive bird-age head coil. 36 T1-weighted anatomical spin–echo images (TR = 480 ms,E = 15 ms, flip angle 90◦, matrix dimensions: 256 × 256 and field of view

FOV) = 210 mm, slice thickness 3.6 mm) were acquired before the fMRIata sets. For fMRI, 60 gradient echo-planar imaging (GE-EPI) images in

dentical localization were obtained (TR = 11.5 s, TE = 60 ms, matrix dimen-ions: 64 × 64, FOV = 210 mm, slice thickness = 3.6 mm: in-plane resolution.6 mm × 3.6 mm, 36 transversal slices orientated parallel to the anteriorommissure–posterior commissure (AC–PC) line, scan time = 3.4 s). A TR of1.5 s was used (“sparse” imaging Belin, Zatorre, Hoge, Evans, & Pike, 1999;

(2o(r

sion and age differences.est; *, p < 0.05; **, p < 0.001).U test; *, p < 0.05; **, p < 0.001).

den, Joseph, Brown, Brown, & Zeffiro, 1999): auditory stimuli are presentedithout interfering with scanner noise in long interscan intervals to overcome

he confounding effects of scanner noise on the experiments). To reduce move-ent artefacts, subjects were fixed by a tape around his/her forehead inside the

oil.

.3. Experimental design

The auditory stimulation paradigm consisted of three stimulation cycles1–A3 of digitally generated pulsed (frequency 5 Hz) 800 Hz sine tones ofmin duration (ON), which alternated with rest periods R1–R3 of 1 min dura-

ion (OFF). This type of stimulation combined with the “sparse” imaging schemerevented habituation within the blocks A1–A3 (Pfleiderer et al., 2002). Theones were generated by the Cool Edit program (Syntrillium Software Corpo-ation, Phoenix, Arizona, USA). Auditory stimulation was presented binaurallyia pneumatic headphones (tube and headphones were acoustically shielded toeduce outside and gradient noise). For all subjects, the hearing threshold wasetermined within the magnet, and each subject was stimulated with the sameound pressure level of 85 dB above the individual hearing threshold (Pfleiderert al., 2002).

.4. fMRI data analysis

Image processing and statistical analysis of the fMRI images wereone by SPM2 standard routines and templates (www.fil.ion.ucl.ac.uk/spm).fter pre-processing the data, individual data analysis was performed usingPM2. Images were realigned, normalized and re-sliced to a voxel size ofmm × 2 mm × 2 mm, and smoothed with an 8 mm kernel. Data were filteredith a high-pass filter (cut-off period of 128 s). For visualization of activated

r = 0.2) (Huettel, Singermann, & McCarthy, 2001; Yang, Engelien, Xu, & Stern,000). A cluster filter of four contiguous pixels was applied. For determinationf the mean baseline levels, the first two of six measurements during rest periodOFF) were omitted, since only after 20 s it is assured that the hemodynamicesponse to the stimulus can be neglected (Yang et al., 2000).

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trlltdifferences in activation compared to controls were found in dur-ing the third activation. Results are summarized in Table 3a. Incontrast none of the HD presented less activation (controls > HD)in during auditory stimulation with our given threshold.

Table 2Comparison of activation intensities between left and right hemisphere for con-trols and HD

Mean intensity–lefthemisphere

Mean intensity–righthemisphere

ControlsFirst stimulation BA44, −0.28 ± 0.89a* BA 44, −0.55 ± 0.70

BA32, 0.16 ± 0.66b* BA 32, −0.14 ± 0.51

Third stimulation BA44, 0.31 ± 0.72c* BA44, −0.08 ± 0.97BA22, 0.38 ± 1.10d** BA22, −0.21 ± 1.47

HDThird stimulation BA22, −0.44 ± 0.93e* BA22, 0.18 ± 1.61

*, p < 0.05; **, p < 0.01; significance levels are indicated for the more dominatehemisphere. Only significant results are presented in the table.

282 C. Saft et al. / Neuropsyc

.4.1. Cluster analysisTo obtain activation maps for either patients (HD, pHD, fpH, cPH) or con-

rols the functional data were combined in a random-effects analysis to identifyctivated brain areas (uncorrected for multiple comparisons, p < 0.001, extenthreshold/minimum cluster size k = 10 voxels, one sample t-tests). Contrastshat were found to be significant in the random-effect analysis constituted theasis for further hypothesis-directed analysis with the activation intensities inhe activated areas. Anatomical localization of activated brain regions was deter-

ined by reference to the standard stereotactic atlas by Talairach and Tournoux1988).

.4.2. Second level analysis (patients vs. controls)In a second analysis, the activation differences between HD and controls,

HD and controls, HD and pHD, and fpHD and controls, cpHD and controls andpHD and cpHD were analysed, respectively (second level t-test, SPM2, p uncorr.0.001, minimum cluster size = 10 voxels) and standard stereotaxic coordi-ates (Talairach & Tournoux, 1988) of activated brain regions were determined.ctivated areas were superimposed on anatomical images for an anatomic local-

zation. In cases of significant age differences between groups (HD vs. pHD andpHD vs. fpHD) ANCOVA with age as cofactor was performed.

.5. Activation intensities

To assess differences of auditory perception and processing between patientsnd controls in more detail, mean signal intensities of the individual auditoryortex and associated brain areas (BA’s 22, 42, 44) were calculated for all con-itions in patients as well as in healthy controls, in addition to the results ofecond level analysis. The auditory cortical areas (primary and secondary) wereefined according to their relation to the Heschl’s gyri and were similar to thoseeported in the literature (Bilecen, Scheffler, Schmid, Tschopp, & Seelig, 1998;ashimoto, Homae, Nakajima, Miyashita, & Sakai, 2000; Moffat, Hampson, &ee, 1998).

Additionally, using a priori information, brain areas being part of the knowntriato-thalamo cortical network to be altered in HD (medial–dorsal thalamus,utamen (n.lentformis); Aylward et al., 2004; Harris et al., 1996; Kassubek etl., 2004; Montoya, Price, Menear, & Lepage, 2006) and one other brain areasnown to be affected in HD, the anterior cingulated cortex (BA 32/24) as a limbictructure (Bartenstein et al., 1997; Beste, Saft, Andrich, Gold, & Falkenstein,006; Pavese et al., 2006) were analyzed. We chose the putamen as a region ofnterest, because its important role in attentive processing of auditory stimulin the cortico-striatal circuits has already been reported by others (Opitz et al.,005).

The following procedure was used: individual activation maxima of the cor-esponding areas were determined. Then, regions of interest (ROIs) for eachubject by defining a sphere with a radius of 4 mm around these activation max-ma were used. For each subject the blood oxygen level-dependent (BOLD)ignal intensity (defined by the corresponding weighted β-values) during eachondition within this sphere was assessed.

Data were analyzed in a complete exploratory way. A nonparametricNOVA was applied to compare results, however results did not reach statistical

ignificance. Intensity differences in activation between various conditions A1s. A3 (�A1R1 vs. �A3R3) of left or right auditory cortex brain areas were cal-ulated by a nonparametric paired Wilcoxon-test. Intensity differences betweenatients and controls were measured with nonparametric Mann–Whitney testnd within subjects (left vs. right with a nonparametric paired Wilcoxon U test).orrelation of activation intensities with depression ratings (HAMD), UHDRSere performed using nonparametric Spearman correlations. Data were consid-

red to be significant at a level of p < 0.05. We did not perform a correlationnalysis between clinical characteristics and activation for subgroups (cpHDnd fpHD), since the number of subjects in each group was too small.

. Results

The auditory paradigm comprised of three stimulation cyclesA1, A2 and A3) of pulsed sine tones of 2 min duration alter-ating with 1 min rest periods (Pfleiderer et al., 2002). Our

ia 46 (2008) 1279–1289

esults will focus on the first and third stimulation block of thisaradigm, since we were interested in a comparison of the firstnd third presentation of tones as a model for a distinct andeproducible processing of auditory stimuli, here habituation.

.1. Controls

.1.1. Activation intensitiesComparing the mean activation intensities between the left

nd right hemisphere within the group of all controls, thereas significant higher intensities of left hemispheral Broca’s

rea (BA44) in the first and third cycle, as well as the anterioringulate (BA 24, BA 32) in A1 and a secondary auditory asso-iated area (BA 22) in A3 (Fig. 1c). Mean activation intensitieshich were significantly different between the right and left side

re provided in Table 2. Comparing mean activations betweenhe first activation cycle and the third one within the group ofontrols, we observed a significant higher activation of left sec-ndary auditory cortex (Wilcoxon-test, p = 0.002, Z = −3.16),nd left Broca’s area (Wilcoxon-test, p = 0. 003, Z = −2.9)uring the third activation and the right BA 9 (Wilcoxon-est, p = 0.035, Z = −2.11) and right thalamus (Wilcoxon-test,= 0.04, Z = −2.0) during the first stimulation.

.2. Manifest HD

.2.1. BOLD activation pattern in HD vs. controlsDuring the first stimulation HDs presented a higher activa-

ion strength compared to controls of the right anterior cingulate,ight Broca’s area (BA 44), right precentral gyrus (BA 6, BA 4),eft and right secondary auditory areas (Fig. 2, upper row; secondevel analysis (uncorrected p = 0.001, 10 voxels)), right middleemporal gyrus (BA 21) and right prefrontal cortex (BA9). No

a p = 0.036, Z = −2.10.b p = 0.05, Z = −1.95.c p = 0.014, Z = −2.46.d p = 0.005, Z = −2.79.e p = 0.028, Z = −2.2 (all paired Wilcoxon-test).

C. Saft et al. / Neuropsychologia 46 (2008) 1279–1289 1283

Fig. 1. Boxplots of mean left and right activation intensities, respectively, with S.D. at first (A1) and third auditory stimulation (A3) for HD (n = 16), cPHD (n = 9),fpHD (n = 9) and controls (n = 32) of (A) putamen, (B) medio-dorsal thalamus and (C) secondary auditory cortex (BA 22). a.u. = arbitrary units. *p < 0.05 (Wilcoxon;A1 vs. A3); **p < 0.001 (Wilcoxon; A1 vs. A3). Levels of significance are only indicated for results within one group. Depending of disease progression and comparedt

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.2.2. Activation intensitiesActivation intensity analysis revealed a significant differ-

nce between manifest HD subjects and controls (Fig. 1a–c).anifest HD subjects exhibited higher intensities in the

ight BA44 (Mann–Whitney U, p = 0.022; Z = −2.28) dur-ng the first stimulation and lower activation of the left BA2 (Mann–Whitney U, p = 0.01; Z = −2.58) and left BA 44Mann–Whitney U, p = 0.007; Z = −2.67) compared controlsuring the third stimulation. In addition there was a significantigher activation during the first auditory stimulation com-

ared to third in the bilateral putamen in HD (see Fig. 1a;ilcoxon, p = 0.017; Z = −2.40 (left); Wilcoxon, p = 0.05;= −1.96 (right)) and the left BA 22 (Wilcoxon, p = 0.044;= −2.02).

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.3. Premanifest HD gene carriers (pHD)

.3.1. BOLD activation pattern in pHD vs. controlsMainly left-lateralized activation was observed for pHD after

he first stimulation cycle, an increased activation compared toontrols was seen for the anterior cingulate and left precentralyrus (BA 6; see Fig. 2, lower row). After the third stimulationycle, pHD showed an increased activation in the left middlerontal gyrus (BA 46), while a lower activation compared toontrols was found in the left insula and precentral gyrus (BA

4), as well as in the right postcentral gyrus (BA 40), right supe-ior frontal gyrus (BA 10) and primary auditory cortices (BA1, BA 42; all results provided in Table 3b). Additional anal-sis of intensities of areas of interest revealed no significant

1284 C. Saft et al. / Neuropsychologia 46 (2008) 1279–1289

Fig. 2. Activations are shown at x = 10, y = 8, z = 48. Activation after first auditory stimulation cycle with sine tones, A1, and corresponding glass brain (second levelss row)c t-lateA exhib

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pm2, two sided t-test: k = minimum 10 voxels, p (uncorrected) = 0.001). (Upperortex (BA 22), 3 = right Broca’s area (BA 44). HD exhibited mainly higher righCC, 4 = left medial frontal gyrus (BA 6). Remarkably, pHD in contrast to HD

ifferences between premanifest HD and controls during eachuditory stimulation.

Remarkably, when comparing HD and pHD, we observedhigher activation for HD (HD > pHD) in A1 for the bilateral

utamen and right secondary auditory cortex (see Fig. 3A) andn A3 for the right thalamus.

.3.2. Activation intensitiesAnalysis of the activation intensities further corroborated

ur findings of activation differences between manifest HDnd premanifest HD. Manifest HD subjects exhibited signifi-antly higher intensities in the bilateral putamen during the firsttimulation (Mann–Whitney U, p = 0.004; Z = −2.89 (left)) andp = 0.039; T = −2.06 (right)) during the third stimulation.

.3.3. BOLD activation pattern in premanifest in HD genearriers close to AO (cpHD)

None of the cpHD’s revealed higher activation compared toontrols in A1 and A3. There was significant less activationcpHD < controls) in A1 for the left inferior parietal lobe (BA4)nd in A3 in the right ACC (BA 24, 31), the right medial frontalyrus (BA 6) and the right insula (see Table 4a).

.3.4. Activation intensitiesAnalysis of the activation intensities presented for cpHD sig-

ificant less activation (cpHD < controls) in A1 for the righthalamus (Mann–Whitney U; p = 0.024; Z = −2.24; see also

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HD > controls, 1a = right anterior cingulate (ACC), 2: right secondary auditoryralized brain areas compared to controls. (Lower row) pHD > controls. 1b = leftit stronger left-lateralized activations compared to controls.

ig. 1b) and in A3 for the right BA 42 (Mann–Whitney U;= 0.042; Z = −2.01) and left BA 44 (Mann–Whitney; p = 0.007;= −2.62).

.3.5. BOLD activation pattern in premanifest HD genearriers far from AO (fpHD)

There was a higher activation in A1 for the right N. caudatusfpHD > controls; Fig. 3B) and right globus pallidus in A3 forhe left ACC (BA 24 and 32), left precuneus (BA7), left inferiorrontal gyrus (BA 46) and right cerebellum (see Table 4b).

.3.6. Activation intensitiesWhen analyzing intensities A1 vs. A3 within the group of

pHD, there was only one significant difference (A1 > A3) forhe bilateral thalamus (Fig. 1b; Wilcoxon; p = 0.008; Z = −2.67left) and p = 0.05, Z = −1.95 (right)).

.4. Premanifest HD gene carriers close to AO vs. far fromO (cpHD vs. fpHD)

.4.1. Activation intensities

ubjects compared to cpHD exhibited significantly higher inten-ities in the bilateral thalamus (Fig. 1b; Wilcoxon; p = 0.05;= −1.99 (left) and p = 0.024; Z = −2.21 (right)) in A1 (see alsoig. 3C) and in the right BA 44 (Wilcoxon; p = 0.006; Z = −2.71).

C. Saft et al. / Neuropsychologia 46 (2008) 1279–1289 1285

Table 3Comparison of (a) manifest HD and (b) pHD with controls in a second level analysis (uncor. p = 0.001, minimum cluster size k = 10 voxels, in MM (Talairach &Tournoux, 1988)

Coordinatesa,b Activated brain areaa Coordinatesb,c Activated brain areac

x y z x y z

(a) First stimulation (HD > C)−64 −32 2 BA 22 44 −14 60 BA 4

12 8 54 BA 642 −10 6044 10 32 BA 954 8 4058 −48 6 BA2160 −46 4 BA2210 8 52 BA 2410 8 52 BA3252 10 12 BA 44

(b) First stimulation (pHD > C)−18 38 18 BA 32 4 36 12 BA 24−42 −10 48 BA 6

First stimulation (C > pHD)44 −30 22 Insula

Third stimulation (pHD > C)−48 40 14 BA 46

Third stimulation (C > pHD)−38 10 6 Insula 28 58 22 BA 10−42 6 6 BA 44 60 −26 16 BA 40

58 −22 12 BA 4160 −22 12 BA 42

HD > C; HD: stronger activations than controls; C > HD; HD: lower activations than controls; pHD > C: pHD: stronger activations than controls; C > pHD; pHD:lower activations than controls.

a Left hemisphere.b Standard stereotaxic coordinates.c Right hemisphere.

Table 4Comparison of (a) pHD close to eAO (cpHD) and (b) pHD far from eAO (fpHD) with controls in a second level analysis (uncor. p = 0.001, minimum cluster sizek = 10 voxels, in MM (Talairach & Tournoux, 1988)

Coordinatesa,b Activated brain areaa Coordinatesb,c Activated brain areac

x y z x y z

(a) Third stimulation (C > cpHD)14 −12 54 BA 640 12 −4 BA 13

6 −4 34 BA 2410 −12 50 BA 31

(b) First stimulation (fpHD > C)18 18 2 N. caudatus14 10 −10 Putamen16 −2 8 Pallidus

Third stimulation (fpHD > C)−20 −68 32 BA 7 12 −38 −26 Cerebellum−16 2 46 BA 24−20 6 48 BA 32−50 44 12 BA 46

Third stimulation (C > fpHD)20 22 62 BA 6

cpHD > C: cpHD: stronger activations than controls; C > cpHD; cpHD: lower activations than controls; fpHD > C: fpHD: stronger activations than controls; C > fpHD;fpHD: lower activations than controls.

a Left hemisphere.b Standard stereotaxic coordinates.c Right hemisphere.

1286 C. Saft et al. / Neuropsychologia 46 (2008) 1279–1289

Fig. 3. (A) Activation after first auditory stimulation cycle with sine tones, first cycle, A1: HD > controls. Symptomatic patients presented a higher activation ofthe bilateral putamen when sine tones are presented compared to premanifest HD. Activations are shown at x = 10, y = 8, z = 48; Pu = putamen. (B) Activation aftert t highs C = rif s bilat

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hird auditory stimulation cycle, A3: fpHD > controls. fpHD revealed a distincine tones compared controls. Activations are shown at x = 20, y = 0, z = −2; NpHD > cpHD. HD far from the eAO showed stronger activation of the thalamu

. Discussion

Major findings are differences in activation patterns andateralization effects of activation between HD, pHD and con-rols, which were dependent on the progression of disease.isease progression is mirrored in hyperactivation in fpHD ofasal ganglio-thalamico structures, followed by hypoactivationn cpHD and finally resulting in hyperactivation in manifest HDTables 3 and 4, Fig. 1) compared to controls. This seems toe independent to the paradigm chosen and seems not to bexclusively associated with auditory processing.

.1. BOLD activation pattern

According to literature, this activation pattern, in particularypoactivation in pHD compared to controls has been describedor various different stimuli: A reduced fMRI response in pHDas also described by (Hennenlotter et al., 2004; Reading et al.,004), without assessment of the eAO for the subjects. Inter-stingly, despite the fact that Paulsen et al. (2004) used anotheraradigm, they also found a reduced activation in their cpHD

roup (<12 YTO) compared to controls in the caudate and tha-amus, but an increased activation in ACC and BA 6 in theirpHD group (>12 YTO), which are in line with our observa-ions.

tm

t

er activation of the right caudate after processing of repeated presentation ofght nucleus caudate. (C) After first auditory stimulation cycle with sine tones:erally. Activations are shown at x = 22, y = −24, z = 4; Th = thalamus.

Paulsen et al. (2004) discussed this unexpected result in theirpHD group as either a compensatory mechanism also seen inanifest HD or as early abnormal cell processes that are direct

egative effects of the HD-causing CAG expansion and mayignal primary HD dysfunction (Paulsen et al., 2004). Sincehe mechanisms underlying these findings are still unclear onean only speculate about different reasons for these altered pro-esses, which are also detectable in electrophysiological studiesBeste et al., 2007).

Intriguing in light of this interpretation of the results of theHD groups, is the result of increased activation in manifest HD,.g. in the putamen (see Table 3). It may be speculated that thisattern is a consequence of functional reorganization processesimed at maintaining auditory processing functions even in latetages of disease.

Our findings of hyperactivation in manifest HD corroborateork of others, all describing increased activity in certain brain

reas in functional imaging (fMRI and PET) (Clark, Lai, &eckel, 2002; Dierks et al., 1998; Paulsen et al., 2004; Rosas

t al., 2004a,b; Voermans et al., 2004). We can, however, notxclude that the early alterations in subjects far from AO and

he alterations in manifest HD may be different mechanisms to

aintain function.The HD-group (Figs. 2 and 3A) presented higher activation of

he putamen compared to healthy controls during the first audi-

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C. Saft et al. / Neuropsyc

ory stimulation and the group far from eAO (Fig. 3B) revealedigher activation of the caudate compared to healthy controlsuring the third repeated stimulation.

These results indicate that the putamen and basal gangliaeem to play an important role in auditory sensory process-ng (see also Opitz et al., 2005). This notion is supported byrecent work of Opitz et al. in healthy subjects, who discussed

hat the activity in the putamen might reflect the involvementf the basal ganglia–thalamic circuits in attentive processing ofuditory stimuli (Opitz et al., 2005). Normally, the putamen isot activated in healthy controls during habituation of repetitiveone presentation (Fig. 1a; Pfleiderer et al., 2002). Yet, since therimary auditory cortex–BA’s 41, 42; Heschl’s gyrus (Lancastert al., 2000) is connected to various other brain areas and net-orks including the prefrontal cortex, limbic system and theasal ganglia (Bernal & Altmann, 2001; Jancke et al., 1998;ropotov et al., 2000; Pandya, 1995) and does not only trans-

er information to several adjacent auditory association areasLancaster et al., 2000), it is feasible to assume that these areasay be used in compensatory strategies. In line with that, acti-

ation of the putamen in HD after repeated stimuli is most likelyart of a network, which may have been recruited to compen-ate for structural alterations and related neuronal dysfunctionn HD. This mirrors the involvement of basal ganglia circuitsn the processing of auditory stimuli to maintain their function.onversely, dysfunction in the basal ganglia circuits may result

n functional alterations of auditory processing itself.Activation found in the thalamus in our fpHD study popula-

ion, but not in controls (Figs. 1b and 3c) suggest that alterationsn thalamic gating mechanisms may also contribute to this phe-omenon. Moreover, it has been discussed that frontal structuresnd especially the ACC were involved in the processing of tonesKropotov et al., 2000; Mitchell, Morey, Inan, & Belger, 2005;chonwiesner et al., 2006). This is corroborated by our find-

ngs of increased activation in ACC (BA 24, BA 32) and frontaltructures (BA 6 and BA 9) in manifest HD as well as in pre-anifest HD (Fig. 2). It has already been described that the

ormer were affected early in the HD pathology (Bartenstein etl., 1997; Pavese et al., 2003, 2006; Rosas et al., 2004a, 2004b;witserlood, 1996).

.2. Lateralization effects

In controls, mainly the left hemisphere was activated inesponse to presentation of sine tones (compare Table 2), whichas expected and has been described earlier (LoCasto et al.,004; Pfleiderer et al., 2002; Schonwiesner et al., 2006; Zatorre

Belin, 2001). Yet, in manifest HD a reversed lateralizationnd thus a higher right hemispheric lateralization was observedTable 2; Fig. 2), which was an unexpected finding. While thepHD group still presented a trend to more activation on theeft side (BA 22), the cpHD group revealed no differences atll between the right and left hemisphere (Table 2). These find-

ngs of altered functional cerebral asymmetry may be regardedn terms of compensatory mechanisms which may counteractmpairment in striato-thalamic circuits. Some recent studieseport a significant grey matter volume loss, in particular with

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eft-sided atrophy in the caudate in premanifest HD, detectedy tensor based MRI morphometry (Kipps et al., 2005) andoxel based MRI morphometry (Thieben et al., 2002). Alsoata by Finke et al. (2006) and Beste et al. (2007) suggestmore left-lateralized atrophy in HD. Since the left hemi-

phere is usually dominant for sine tone processing (LoCastot al., 2004; Pfleiderer et al., 2002; Schonwiesner et al., 2006;atorre & Belin, 2001), it may be speculated that a predom-

nantly left-sides atrophy may cause auditory functions to berocessed more right lateralized in order to maintain auditoryrocessing.

.3. Limitations

This study was analyzed in a complete exploratory design.ince there were great interindividual differences in activation

n our manifest HD and cpHD group, most likely due to differ-nt states of disease, the number of participants was too lowo monitor further differences in activation. Since the groupize included in this study was limited, generalization shoulde treated cautiously, due to a possible weakness in statisticalower.

The strength of this 3 T fMRI study is the assessment of theetermination of individual activation intensities in our ROIs,hat the eAO was taken into account and that medication was noofactor, since all participants were free of medication.

. Conclusion

In conclusion our study gives further evidence for the involve-ent of basal ganglia–thalamic circuits in sensory processing in

remanifest HD gene carriers and manifest HD. Our data reflectsn altered activation pattern to auditory stimulation dependingn the progression of neuronal dysfunction in HD and pHD. ThepHD group presented predominantly down-regulated processesompared to fpHD and HD. In the fpHD group up-regulatedrocesses are present compared to controls and mainly seemo reflect pathological processes. In the manifest HD group up-egulated processes can be observed compared to controls andainly seem to mirror compensatory processes. Subsequently,

uture studies in HD ought not only to distinguish between pre-anifest and manifest HD, but also regarding the time to eAO

n premanifest HD.

cknowledgements

This study was supported by the Ruhr-University BochumFoRUM grant 479/05). We thank all patients and controls par-icipating in this study. The previous support of Prof. H. Przunteknd his great enthusiasm in founding the HD unit are greatlycknowledged. We thank Prof. R. Gold for helpful criticism onhe manuscript and Vivian Brockelmann for proof-reading.

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