Neuropsychologia 46 (2008) 12901297

Response inhibition in Huntingtons diseaseA study

using ERPs and sLORETA
Christian Beste a,b,c, , Carsten Saft a , Jurgen Andrich a ,
Ralf Gold a , Michael Falkenstein b
a

Department of Neurology, Huntington Centre NRW, St. Josef Hospital, Ruhr-University Bochum, Germany
b Leibniz Research Centre for Working Environment and Human Factors, WHO Collaborating Centre for
Occupational Health and Human Factors, Dortmund, Germany
c Department of Clinical Radiology, University M
unster, Germany
Received 3 July 2007; received in revised form 1 December 2007; accepted 5 December 2007
Available online 23 December 2007

Abstract
Huntingtons disease (HD) is an autosomal dominant inherited neurodegenerative disorder, with neurodegeneration mainly affecting the striatum.
We investigated executive functions related to response inhibition in (HD) and healthy controls by means of event-related potentials (ERP) in a simple
Go/Nogo-task. In Nogo as opposed to Go trials two fronto-central ERP components are elicited: the Nogo-N2 and Nogo-P3. These components
are supposed to depend on (medial) prefrontal regions, especially the anterior cingulate cortex (ACC). The results show that the Nogo-N2 did
not differ between the groups, while the Nogo-P3 demonstrated a strong attenuation in the HD-group, which also showed more false alarms in
the Nogo-condition. Using sLORETA it is shown that this attenuation was related to the medial frontal cortex, especially the ACC, and superior
frontal cortex areas. Moreover, the attenuation was related to the underlying genetic disease load (CAG-index). The decline in inhibition is likely
mediated via a dysfunction in the ACC, which is known to be dysfunctional in HD. Moreover, the results may be interpreted that the decline in
response inhibition in HD is gene-associated. The differentially affected Nogo-components suggest that they rely on different neuronal circuits,
even within the ACC. For HD this suggests that this structure is not entirely dysfunctional.
2008 Elsevier Ltd. All rights reserved.
Keywords: Nogo-N2; Nogo-P3; sLORETA; Dopamine; Genetics; Basal ganglia

1. Introduction
Huntingtons disease (HD) is an autosomal, dominant inherited neuropsychiatric disorder typically characterized by chorea
and complex involuntary movements (Heinsen et al., 1994).
Genetically, HD is caused by an extension of the CAG-repeat
length at the fourth chromosome encoding a large protein,
the huntington (Huntingtons Disease Collaborative Research
Group, 1993). This protein accumulates and caused apoptotic
striatal neuronal death. Neuroanatomical pathology is not limited to the striatum but is also seen in other brain regions (rev:
Gutekunst, Norflus & Hersch, 2002). Changes in several neuro

Corresponding author at: Leibniz Research Centre for Working Environment

and Human Factors, WHO Collaborating Centre for Occupational Health and
Human Factors, Ardeystrasse 67, 44139 Dortmund, Germany.
Tel.: +49 231 1084 212; fax: +49 231 1084 401.
E-mail addresses: beste@ifado.de, christian.beste@cityweb.de (C. Beste).
0028-3932/$ see front matter 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neuropsychologia.2007.12.008

transmitter systems are widespread, yet a hallmark in a HD is a

reduction in dopamine receptor density (Ginovart et al., 1997;
Pavese et al., 2003), which is supposed to be gene-associated
(Antonini, Leenders & Eidelberg 1998; Petersen et al., 2001;
van Oostrom et al., 2005). The dopaminergic dysfunction in HD
is closely related to cognitive deterioration (rev: Craufurd and
Snowden, 2002), especially in executive functions and memory
functions (rev: Craufurd and Snowden, 2002; Lawrence et al.,
1998; Snowden, Craufurd, Thompson & Neary, 2002).
One important executive function is the inhibition of prepared
or prepotent responses. Studies on inhibition in HD relying on
behavioural data indicate alterations of these functions possibly
due to striatal pathology (Aron et al., 2003). Processes related
to inhibition can also be examined by means of event-related
potentials (ERPs) using Go/Nogo tasks. In this task two stimuli
are presented and subjects are asked to respond to one stimulus (Go) and to refrain from responding on the other stimulus
(Nogo). Nogo-stimuli elicit a fronto-central negativepositive

C. Beste et al. / Neuropsychologia 46 (2008) 12901297

complex (Falkenstein, Hoormann & Hohnsbein, 1999) in the

ERP that has been labelled as Nogo-N2 and Nogo-P3 (Bokura,
Yamaguchi & Kobayashi, 2001; Falkenstein et al., 1999). These
components are considered to be indices of different aspects
of inhibition. The Nogo-N2 is assumed to reflect pre-motor
inhibition (e.g. Falkenstein et al., 1999) or response-conflict
(e.g. Nieuwenhuis, Yeung, van den Wildenberg & Ridderinkhof,
2003), whereas the Nogo-P3 is likely to be related to motor inhibition (e.g.Bruin, Wijers & van Staveren, 2001; Burle, Vidal,
Tandonnet & Hasbroucq, 2004), but it is also supposed that
the Nogo-P3 is not related to the inhibition itself, and more
to the evaluation of inhibitory processes (Band & van Boxtel,
1999; Bruin et al., 2001; Roche, Garavan, Foxe & O Mara,
2005). However, these components are likely to originate in the
inferior frontal cortex (Konishi, Nakajima, Uchida, Sekihara &
Miyashita, 1998), but also the anterior cingulate cortex (ACC)
plays an important role (Cabeza & Nyberg, 2000) (see also:
Ridderinkhof, van den Wildenberg, Segalowitz & Carter, 2004).
In addition, also parietal areas were found to play a role in
inhibition. Moreover, it is likely that especially the Nogo-P3
component depends on the dopaminergic system (DA-system),
since research in schizophrenia (Fallgatter & Muller, 2001)
and drug abuse (Fallgatter, Wiesbeck, Weijers, Boening &
Strik, 1998; Hester & Garavan, 2004) account for dopaminedependent variations in this component. A recent study (Bokura,
Yamaguchi & Kobayashi, 2005) in, Parkinsons disease (PD),
which inter alia (rev. Hucho, 1995) also affects the DA-system
and medial frontal systems, showed that both Nogo-N2 and
Nogo-P3 are reduced suggesting impaired inhibitory processing
in PD. In general, the basal ganglia are supposed to be involved in
inhibitory functions (Menon, Leroux, White & Reiss, 2004; van
den Wildenberg, van Boxtel, van der Molen, Bosch, Speelman
& Brunia, 2006). Besides basal ganglia pathology, research in
HD indicates that functions related to the medial frontal system and especially the anterior cingulate cortex (ACC) show
a decline (Bartenstein et al., 1997; Beste, Saft, Andrich, Gold
& Falkenstein, 2006; Beste et al., 2007; Reading et al., 2004;
van Dellen, Deacon, York, Blakemore & Hannan, 2001), which
may be a result of basal ganglia damage, since the basal ganglia
and the ACC are functionally highly connected (Chudasama &
Robbins, 2006). Moreover, the decline in the striatal dopamine
receptor system is likely to be gene-associated in HD (e.g.
Antonini et al., 1998; van Oostrom et al., 2005).
Due to the dependence of the Nogo-N2 and/or Nogo-P3
on the DA-system as well as medial frontal systems, which
are dysfunctional in symptomatic HD, we would expect an
attenuation of Nogo-potential amplitudes in HD compared to
healthy controls. Because of the likely gene-associated decline
of the DA-system, reductions in ERPs (i.e. Nogo-components)
may also a show gene-association as has recently been demonstrated for the error negativity (Ne; Falkenstein, Hohnsbein,
Hoormann & Blanker, 1991) or error-related negativity (ERN;
Gehring, Goss, Coles, Meyer & Donchin, 1993) (Beste et al.,
2006).
Due to the supposed dependence of the Nogo-components
on distinct frontal brain areas we further analysed if a difference
in Nogo-components between HD and healthy controls may be

1291

due to hypoactivations in these brain regions. This was done in

a second step using standardised low-resolution brain electrical
tomography (sLORETA) (Pascual-Marqui, 2002). In summary,
the aim of the present study was to examine response-related
inhibitory processes via ERPs, in HD and healthy controls in
relation to genetic disease load and the underlying neuronal
generators.
2. Materials and methods
2.1. Participants
A group of 13 right-handed, unmedicated HD-patients defined by a positive gene test and manifest clinical symptoms from 26 to 62 years of age
(M = 41.66; S.D. = 10.67) were recruited. All patients agreed to being videotaped
in order to document their neurological status. The mean CAG-length was 46.08
(S.D. = 4.29; range = 4052). All HD-patients underwent neurological investigation and were scored according to the motor scale (MS), total functional capacity
(TFC) and independence scale (IS) of the unified Huntingtons disease rating
scale (UHDRS) (Huntington Study Group, 1996). The motor scale (MS) revealed
a mean score of 24.27 (S.D. = 12.47), indicating symptomatic status. The cognitive score of the UHDRS revealed a mean score of 195.58 (S.D. = 61.87). In
here, the Stroop-test, known to inter alia assess functions related to inhibition,
revealed a mean score of 33.27 (S.D. = 12.86). The total functional capacity scale
(TFC) revealed a mean score of 12 (S.D. = 0.77). The independence scale (IS)
revealed a mean score of 87.72 (S.D. = 8.17). Psychiatric assessment revealed
no severe depression (BDI: M = 4.15; S.D. = 1.67) or mania (YMRS: M = 3.15;
S.D. = 1.46) or any dementia (MMSE: M = 27.84; S.D. = 1.95).
Furthermore, 12 healthy controls from 27 to 57 years of age were recruited
(M = 42.78; S.D. = 8.54). Also in this group the Stroop-test of the UHDRS was
administered and revealed a mean score of 82.66 (S.D. = 5.97) strongly differing
from the corresponding score in the HD-group (F(1, 22) = 59.62; p < . 001). The
same psychiatric assessment using the BDI revealed no depression (M = 2.25;
S.D. = 1.35) or any mania (M = 2.25; S.D. = 1.28) as revealed by the YMRS.
Both groups had a comparable educational background. All participants gave
written informed consent. The study was approved by the ethics committee of
the University of Bochum.

2.2. Stimuli and procedure

To measure inhibitory processes, we used a Go/Nogo-task. One out of two
words was presented on a PC-monitor: press (Go-stimulus) and stop (Nogostimulus). The stimuli were displayed for 300 ms. The response-stimulus interval
was fixed at 1600 ms. Time pressure was administered by asking the subjects to
respond within 550 ms. In trials with reaction times exceeding this deadline a
feedback stimulus (1000 Hz, 60 dB SPL) was given 1200 ms after the response;
this stimulus had to be avoided by the subjects. Two blocks of 60 stimuli each
were presented in this task. Nogo-stimuli and Go-stimuli appeared equally frequently. The subjects had to react with the thumb to Go-stimuli and to refrain
from responding on Nogo-stimuli.

2.3. Data processing and analysis

During the task the EEG was recorded from 24 AgAgCl electrodes (Fpz,
Fp1, Fp2, Fz, F3, F4, F7, F8, FCz, FC3, FC4, FC5, FC6, C3, C4, C7, C8, Pz,
P3, P4, P7, P8, Oz, O1, O2, left mastoid M1, right mastoid M2) against a
reference electrode located on Cz. Additionally, eye movements were monitored
and recorded by means of two lateral and four vertical EOG electrodes. The
sampling rate of all recordings was 500 samples/s, applying a filter bandwidth
080 Hz to the EEG. Electrode impedances were kept below 5 k. EEG was rereferenced off-line to linked mastoids. Artifact rejection procedures were applied
twice: automatically, with an amplitude threshold of 80 V, and visually by
rejecting all trials contaminated by technical artifacts. Horizontal and vertical
eye movements preserved in the accepted trials were corrected by means of a
linear regression method for EOG correction (Gratton, Coles & Donchin, 1983).

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Subsequent to averaging N2 and P3 amplitudes in Go- and Nogo-trials were

evaluated relative to baseline using the accurate trials. For statistical analysis
amplitudes were quantified post to filtering relative to a baseline 200 ms till
stimulus presentation. For statistics an electrode array was analysed consisting of
the electrodes F3, Fz, F4, FC3, FCz, FC4, C3, Cz, C4. This array was analysed
using a repeated measures ANOVA with the factor row (F-electrodes, FCelectrodes, C-electrodes) the factor laterality (left, central, right) and Go
versus Nogo as within-subject factors and group (HD, control) as betweensubject factor. Greenhouse-Geiser corrections were applied and post-hoc tests
were corrected using Bonferroni-correction.
Source localisation was carried out for components that differed between the
groups using sLORETA (Pascual-Marqui, 2002). LORETA (Pascual-Marqui et
al., 1999) is a tomographic technique that gives a single solution to what is
known as the inverse problem of location of cerebral sources (Marco-Pallares,
Grau & Ruffini, 2005). sLORETA is a new version of LORETA. The main difference is that sources are estimated on the basis of standardised current density
(Pascual-Marqui, 2002) allowing a more precise source localisation than the
older LORETA-method (Pascual-Marqui, 2002). Briefly, sLORETA calculates
the standardised current density at each of 6239 voxels in the grey matter and
the hippocampus of the MNI-reference brain. This calculation is based upon
a linear weighted sum of the scalp electric potentials. sLORETA estimates the
underlying sources under the assumption that neighbouring voxels should have
a maximally similar electrical activity (see also: Fallgatter, Bartsch, Zielsack &
Herrmann, 2003). The voxel-based sLORETA-images (6239 voxels at a spatial
resolution of 5 mm) (Pascual-Marqui, 2002) were compared between the groups
(HD versus control) using the sLORETA-built-in voxelwise randomisation tests
(5000 permutations) based on statistical non-parametric mapping (SnPM) (for
details see: Holmes, Blair, Watson & Ford, 1996), corrected for multiple comparisons. The voxels with significant differences (p < .01) were located in specific
brain regions. sLORETA has been proven to achieve a reliable localisation of
possible underlying sources (Greenblatt, Ossadtchi & Pflieger, 2005; Sekihara,
Sahani & Nagarajan, 2005).

3. Results
3.1. Behavioural data
For the reaction times (RTs) the mean and standard error
of the mean (SEM) are given. To assess group differences
in performance RTs, the number of false alarms in Nogotrials and the RTs in these false Nogo-trials were subjected
to separate univariate ANOVAs. For the Go-trials RTs differed
between HDs (394.2 12.2 ms) and controls (317.6 13.2 ms)
(F(1, 23) = 16.06; p = .001). Both groups did not differ in
their accuracy on the Go-trials, as can be seen in the absolute frequency of correct responses (HD: 59.5 0.5; controls:
59.9 0.1) (F(1, 23) = 2.02; p = .168). The absolute frequency
of false alarms on Nogo-trials differed between the groups (HD:
5.46 0.69; controls: 0.91 0.72) (F(1, 23) = 20.28; p < .001).
For the false alarms the RTs differed between the groups
(HD: 323.5 14.5; controls: 255.6 15.1) (F(1, 23) = 10.42;
p = .004). All behavioural data is given for performance across
both experimental blocks. See also Table 1 for summary.
3.2. Event-related potentials: N2
For description of the data the mean and standard error of
the mean (SEM) are given. The ANOVA revealed a significant main effect Go versus Nogo F(1, 23) = 13.46; p = .001)
(Go: 0.31 0.47 V; Nogo: 0.99 0.47 V), i.e. the N2
was stronger (more negative) for Nogo trials (Nogo-N2) than
for Go trials. There was no interaction with the factor group

Table 1
Summary of behavioural performance data and the Nogo-P3 compared between
the control and the HD-group

Reaction time (RT)

Correct (Go-trials)
False alarms
False alarms (reaction times)
Nogo-P3 (V)

Controls

HD

Mean SEM

Mean SEM

Sig.

317.6 (13.2)
59.9 (0.1)
0.91 (0.7)
255.6 (15.1)
11.44 (1.19)

394.2 (12.2)
59.5 (0.5)
5.46(0.6)
323.5 (14.5)
5.97 (1.14)

.001
.168
<.001
.004
.003

(F(1,23) = 0.47; p = .497). All other main or interaction effects

were also not significant (all F < 1.51; p > .225).
3.3. Event-related potentials: P3
For description of the data the mean and standard error of the
mean (SEM) are given. The frontal P3 is illustrated in Fig. 1.
The ANOVA revealed a significant main effect row
(F(2, 46) = 21.20; p < .001). Post-hoc tests showed that activity was stronger at the F-electrode (6.61 0.7 V) and
FC-electrodes (6.7 0.7 V), compared to the C-electrodes
(5.09 0.4 V) (p < .001). The F- and FC-electrodes did not
differ from each other (p = .370). There was no interaction with
the factor group (F(2, 46) = 0.93; p = 399).
The main effect side was also significant (F(2, 46) = 7.53;
p = .001). Post-hoc tests showed that activity was strongest
at midline electrodes (7.00 0.7 V), compared to left(5.7 0.5 V) and right-sided electrodes (5.7 0.6 V)
(p = .011). Activity did not differ between left- and rightsided electrodes (p > .9). This effect was further modulated by
the factor group, as the interaction revealed (F(2, 46) = 9.01;
p < .001). Subsequent univariate ANOVAs revealed that
only activity above the midline row differed between the
groups (F(1, 23) = 5.98; p = 0.23), with the control group
(8.73 1.0 V)showing stronger activity than the HD-group
(5.27 0.9 V).
The main effect Go versus Nogo was significant, too
(F(1, 23) = 37.52; p < .001). It is shown that activity was
stronger in the Nogo (7.61 0.7 V), compared to the
Go-condition (4.71 0.5 V). This effect was also further
modulated by the factor group (F(1, 23) = 22.52; p < .001). Subsequent analyses revealed that the Go-amplitudes did not differ
between the groups (HD: 4.91 0.8 V; control: 4.50 0.8 V)
(F(1, 23) = 0.11; p = .734). In contrast, the Nogo-amplitudes
strongly differed between the groups (F(1, 23) = 8.14; p = .009)
(HD: 5.57 0.9 V; controls: 9.65 1.03 V). No other main
or interaction effects reached the level of significance (all
F < 1.67; p > .205).
3.4. Correlations (neurogenetics)
In a second step we analyzed a possible relation of the genetic
factors to the Nogo-P3. For this purpose we used the CAG-index
(see: Beste et al., 2006), i.e. the number of triplets in excess
(CAGn 35.5), multiplied by the age of the patient. The CAG-

C. Beste et al. / Neuropsychologia 46 (2008) 12901297

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Fig. 1. Potentials related to Go- and Nogo-stimuli including the map of the Nogo-P3 component. The time point 0 denotes the point of Go- or Nogo-stimulus
presentation.

index is an expression of genetic disease load normalized to each

individual (Aylward et al., 2004; Ranen et al., 1995). The mean
CAG-index was 400.1 (S.D. = 144.7). Pearson-correlation was
calculated using electrode FCz. It is revealed that the CAG-index
was inversely correlated with the amplitude of the Nogo-P3 at
FCz (r = .762, R2 = 0.57; p = .002) (see Fig. 2a). In addition,
the CAG-repeat, which is uncorrected for age, also showed a
similar relation to the Nogo-P3 amplitude (r = .756, R2 = 0.54;
p = .002) (see Fig. 2b), underlining the validity of this relation. A
similar relation is also found, when correlating the mean NogoP3 amplitude of the whole analysed grid (CAG-index: r = .646,
R2 = 0.41; p = .012) (CAG: r = .614, R2 = 0.37; p = = .017).
However, one may argue that these relations may be overshadowed by age or disease progression. A regression analysis
with Nogo-P3 amplitude as dependent and CAG-index, age
and duration since motor onset (dAO) as independent variables revealed that the latter parameters were not related to the
Nogo-P3 as the partial correlations show (age: r = .136 p = .506;
dAO: r = .148 p = .493). The same is revealed, when using the

CAG-repeat instead of the CAG-index in this regression analysis

(age: r = .245 p = .456; dAO: r = .250 p = .399).
3.5. sLORETA-analysis
The voxel-based sLORETA-images (6239 voxels at a spatial
resolution of 5 mm) (Pascual-Marqui, 2002) were compared
between the groups (HD versus control) using the sLORETAbuilt-in voxelwise randomisation tests (5000 permutations)
based on statistical non-parametric mapping (SnPM) (for details
see: Holmes et al., 1996), corrected for multiple comparisons.
The voxels with significant differences (p < .01) were located
in specific brain regions. Brodman areas (BA) as well as coordinates in the MNI-brain were provided by the software (www.
unizh.ch/keyinst/NewLORETA/sLORETA/sLORETA.htm)
and given in Table 1 with the critical t-values. The results are
also illustrated in Fig. 2.
As can be seen (Fig. 2, Table 1) significant sources relating to
the difference in the Nogo-P3 between the HD and the control

Fig. 2. Scatterplot of the relation of the Nogo-P3 to the CAG-index (left panel) and the CAG-repeat (right panel).

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C. Beste et al. / Neuropsychologia 46 (2008) 12901297

group are located in the medial frontal gyrus (MFG) (BA 10,
BA 9); the bilateral anterior cingulate cortex (ACC) (BA 24, BA
32), and the left superior frontal gyrus (SFG) (BA 9) and middle
frontal gyrus (BA 9). In all these areas the HD-group showed a
reduced activation relative to healthy controls.
4. Discussion
In this study we examined inhibitory functions in symptomatic HD and healthy controls by means of event-related
potentials (ERPs): Nogo-N2 and Nogo-P3. We accounted for an
attenuation of the Nogo-P3 in HD, whereas the Nogo-N2 was
unaffected. Correlational analyses revealed that the Nogo-P3
amplitude attenuation in the HD-group was related to the underlying genetic alteration. Source localisation using sLORETA
revealed that the difference in Nogo-P3 was related to a hypoactivation in the medial frontal gyrus (MFG) (BA 10), the bilateral
anterior cingulate cortex (ACC) (BA 24, BA 32) and superior
frontal gyrus (SFG) and middle frontal gyrus (BA 9).
4.1. Electrophysiology and sLORETA
The electrophysiological and behavioural data, suggest
impaired inhibitory processes in HD, which is in line with
other studies in HD using behavioural measures (Aron et al.,
2003; Fielding et al., 2006). In contrast to the study in PD by
Bokura et al. (2005), we did not found an alteration (reduction)
of the Nogo-N2. However, in their study (Bokura et al., 2005)
all PD patients were medicated, which may have influenced
their results. Research indicates that Nogo-N2 and Nogo-P3
are assumed to reflect different processes related to inhibition
(Burle et al., 2004; Falkenstein, 2006; Falkenstein et al., 1999;
Nieuwenhuis et al., 2003). The Nogo-N2 is assumed to reflect
pre-motor inhibitory processes (Falkenstein, 2006; Falkenstein
et al., 1999) or conflict processes (Nieuwenhuis et al., 2003).
The Nogo-P3 has been attributed to reflect motor inhibition (e.g.
Burle et al., 2004; Bruin et al., 2001), but some researchers suggested that it peaks too late after the reaction to reflect the action
of inhibition (Naito & Matsumura, 1996; Roche et al., 2005).
Thus it has been proposed that the Nogo-P3 reflects a subsequent
evaluation of the inhibition and not the inhibition itself (Band &
van Boxtel, 1999; Bruin et al., 2001; Roche et al., 2005). Also
in our study, the peak latency of the Nogo-P3 occurred approximately 120 ms after the response in these trials, making a direct
relation to the action of inhibition unlikely (see also: Roche et
al., 2005). The fact that only the Nogo-P3 shows a reduction,
whereas the Nogo-N2 is spared in HD, suggests that these supposed functional distinct components are also related to distinct
neuronal circuits that are differentially dysfunctional in HD.
The topography displayed (fronto-central) in our data is
somewhat different to other studies (e.g. Barcelo, 2003; Easdon,
Izenberg, Armillio, Yu, & Alain, 2005), showing a frontoparietal distribution. The difference may be due to task
differences. In the present as well as in our previous work
(Falkenstein, Hoormann, & Hohnsbein, 2002) we used a fixed
stimulus-response mapping and had our Ss perform right-hand
Go responses only and obtained a clear FCz focus in all our

studies. In contrast, other researchers sometimes had their subjects perform right- and left-hand responses to Go stimuli, and
Easdon et al. (2005) used a SART. Barcelo (2003) used a switch
rather than a Go/Nogo task. Assuming that the Nogo-P3 has a
fixed source (probably the ACC) which can only vary in strength
the topography should be stable. To explain the observed shift in
topography across studies we assume the following: the NogoP3 may be overlaid by a large P3b (this is e.g. suggested by the
data of Barcelo (2003) and Verleger, Paehge, Kolev, Yordanova
and Jaskowski (2006) also in Nogo trials. This P3b may vary
in amplitude or latency with the task. Assuming an early and/or
large P3b the topography of the compound positivity should be
shifted to more posterior leads; assuming a late and/or small P3b
it would stay at more anterior leads. In our data the P3b on Nogo
trials is obviously small hence our compound positivity should
have a more anterior maximum, as we found. Clearly there is
a lack of papers with dense electrode arrays including FCz and
different tasks to explore possible topography changes with task
changes.
The sLORETA-analysis of the Nogo-P3 revealed significant
hypoactivations in the HD-group in the medial frontal gyrus
(BA 9, BA 10), the anterior cingulate cortex (ACC) (BA 24,
BA 32) and the superior and middle frontal gyrus (BA 9). This
pattern of findings suggests that the Nogo-P3 is based upon a
distributed frontal neuronal network and is in line with fMRIfindings in which the dorsomedial and the caudal dorsolateral
prefrontal cortex are shown to be associated with response inhibition (de Zubicaray, Andrew, Zelaya, Williamsn & Dumanoir,
2000; Garavan, Ross, Murphy, Roche & Stein, 2002; for rev.
Ridderinkhof et al., 2004). Especially, our finding of a bilateral
hypoactivation in the ACC (BA 24, BA 32) is in line with several other findings (e.g. Cabeza & Nyberg, 2000; Fallgatter et
al., 2004; Ridderinkhof et al., 2004) and supports research that
the ACC is dysfunctional in HD (Bartenstein et al., 1997; Beste
et al., 2006, 2007; Reading et al., 2004; van Dellen et al., 2001).
Also the Nogo-N2 was found to be related to the ACC (Bekker,
Kenemans, Hoeksama, Talsma & Verbaten, 2005; Mathalon,
Withfield & Ford, 2003; Nieuwenhuis et al., 2003; van Veen
& Carter, 2002), but it was unaffected in HD despite of a likely
ACC-dysfunction.
Yet, despite the results of the sLORETA source localization
are in line with other findings in ERP and fMRI-studies on
response inhibition the sLORETA-results have to be treated cautions, since the sLORETA-results show a lateralized pattern of
sources, but the topography of scalp potentials was quite symmetrical. Source localization techniques rely upon predefined
head models (Slotnik, 2005) taking conductance differences of
different brain tissue types into account. Due to neurodegenerative processes in HD these predefined head models may not
fit to the conditions in HD, and especially in symptomatic HD,
where neurodegenerative processes affect grey and white matter
(Rosas, Feigin & Hersch, 2004). In HD striatal neuropathology
was found to be more evident in the left than the right hemisphere
(Finke, Bublak, Dose, Muller, & Schneider, 2006). As such
the left lateralized sLORETA solution may be a consequence
of left lateralized neuropathological processes (see Fig. 3,
Table 2).

C. Beste et al. / Neuropsychologia 46 (2008) 12901297

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Fig. 3. Graphical representation of the sLORETA results comparing the Nogo-P3 between the control and HD-group. Blue colour indicates local maxima of the
reduced Nogo-P3 component in the HD-group compared to controls in Brodman areas 9, 10, 24, 32.

4.2. Possible mechanisms

The attenuation of the Nogo-P3, partly relates to dysfunctions
in the ACC. The ACC and the basal ganglia are functionally
highly interconnected (Chudasama & Robbins, 2006). Due the
prominent basal ganglia damage in HD, the ACC-dysfunction
leading to an attenuated Nogo-P3 may be a result of dysfunctions
in neural circuits connecting basal ganglia and ACC.
Yet, the ACC is not a unique functional entity, consisting
instead of functional segregated sub-regions mediating different cognitive functions (Braver, Barch, Gray, Molfese &
Snyder, 2001; Menon, Adleman, White, Glover & Reiss, 2001;
Weissman, Warner & Woldorff, 2004). As such, processes supposed to be reflected by the Nogo-N2 (e.g. pre-motor inhibition,
conflict processing) may be mediated via other ACC-subregions/circuits than processes related to the Nogo-P3. Menon
et al. (2001) as well as Braver et al. (2001) showed that different
ACC-areas are likely to underlie error processing and response
inhibition (see also: Bekker et al., 2005). Recent studies (Beste
et al., 2006, 2007), found differences in the amplitude of the
Ne/ERN in HD, reflecting error processing, a function of the
ACC. The Ne/ERN and the Nogo-P3 rely on the ACC and the
dopamine system. Based upon this, processes reflected by the
Nogo-P3 and the Ne/ERN may overlap in some part. This is
likely, since processes that share the same neural circuitry often
share computational mechanisms (Kosslyn & Koenig, 1992).
Since the Nogo-N2 was not changed, it may rely on other neural
mechanisms, which are spared in HD. It may be speculated that
the Nogo-N2 is spared due to functional loops of the basal ganglia. The Nogo-N2 is said to be related to pre-motor processes

involved in inhibition (Falkenstein, 2006; Falkenstein et al.,

1999). Functional models of the basal ganglia (rev. Chudasama
& Robbins, 2006) suggest that motor processes of the basal ganglia are inter alia mediated via the putamen and not the caudate,
which shows the focus of pathology in HD (Mitchell, Cooper &
Griffith, 1999). Since functions reflected by the Nogo-N2 may
be more related to pre-motor processing they may also be more
related to motor loops encompassing the putamen than loops
encompassing the caudate/striatum, which putatively mediates
evaluative functions (Redgrave, Prescott & Gurney, 1999). It
may be hypothesised that the relative sparing of the putamen
in contrast to striatal pathology is reflected in the observed difference of an unchanged Nogo-N2 but affected Nogo-P3. What
may be critical about this alternative interpretation on functional
basal ganglia loops is the fact that in HD motor symptoms are a
hallmark, strongly suggesting for pathology of the basal ganglia
motor loops.
4.3. Correlational data
Correlational analyses showed a relation of the Nogo-P3
amplitude and the CAG-index or the CAG-repeat, respectively
(Aylward et al., 2004; Ranen et al., 1995). A regression analysis revealed that this relation was unbiased due to the age
or disease progression of the patient. Thus the decline of the
Nogo-P3 is a direct expression of the specific genetic factor
associated with pathogenesis in HD: The higher the genetic
disease load, the stronger the attenuation of the Nogo-P3. The
CAG-repeat is shown to be related to the amount of decrease of
striatal dopamine receptors (Antonini et al., 1998; Petersen et al.,

Table 2
Synopsis of the sLORETA-results of the comparison between the control and HD-group in the Nogo-P3
Brodman area

BA32
BA24
BA 10
BA9

Coordinates
X

14
1
5
16
20

35
30
65
40
35

2327
1347
1522
2326
2326

t-Value

Critical t-value for P < .01

6.39
6,95
5.99
6.76
6.76

4 76
4.76
4.76
4.76

Location indicates the Brodmann area (BA) and the respective three-dimensions x-, y- and z-coordinates with corresponding statistical t-values. Additionally, the
t-value of a threshold of p < .01 is given. Only the most significant voxels are given. Note: For the z-coordinate, consecutive coordinates are given.

1296

C. Beste et al. / Neuropsychologia 46 (2008) 12901297

2001; van Oostrom et al., 2005). Several studies investigating the

Nogo-P3 accounted for dopamine-dependent alterations of the
Nogo-P3 (Fallgatter et al., 1998, 2004; Hester & Garavan, 2004).
Thus, the relation of Nogo-P3 attenuation and CAG-repeat may
be mediated via the dopaminergic system (see also: Beste et al.,
2006), which underlines a recent result showing a similar relation of the Ne/ERN and genetic disease load in HD (Beste et al.,
2006). In line with this, one may also assume the Nogo-P3 as a
gene-associated cognitive biomarker in HD (see: Beste et al.,
2006).
5. Conclusions
In summary, the results show a selective attenuation of the
Nogo-P3 in case of HD, which was related to hypo-activations
in the prefrontal cortex and especially the anterior cingulate cortex (ACC). The fact that the Nogo-N2 was not changed despite
a dysfunction of the ACC in HD suggests that Nogo-P3 and
Nogo-N2 may rely on different neuronal circuits even within
the ACC and further suggest that the ACC in HD is only partially dysfunctional, functionally sparing the N2-partition. The
attenuation of the Nogo-P3 in HD may be due to a dopamingeric deficit, which may also mediate the relation to the genetic
disease load. Due to the relation to the genetic disease load,
one may also assume the Nogo-P3 as a gene-associated cognitive biomarker in HD. Future studies should focus on the
presymptomatic stage to disentangle possible early changes of
inhibitory processes in HD and may further incorporate larger
sample sizes. Additionally they may also incorporate a denser
electrode array to further increase the reliability of sourcelocalisation results (Lantz, Grave de Peralta, Spinelli, Seeck &
Michel, 2003).
Acknowledgements
This research was supported by a grant from FoRUM AZ
F479-2005, Ruhr-University of Bochum. The previous support
of Prof. Przuntek and his great enthusiasm in founding the HD
unit are gratefully acknowledged. We thank all participants for
their active support. We thank L. Blanke for committed technical assistance and V. Boyd for linguistic improvements to the
manuscript.
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