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Clinical Neurophysiology 125 (2014) 287–297

Contents lists available at ScienceDirect

Clinical Neurophysiology
journal homepage: www.elsevier.com/locate/clinph

Insight into the relationship between brain/behavioral speed

and variability in patients with minimal hepatic encephalopathy
S. Schiff a,b,c,⇑, C. D’Avanzo d, G. Cona e, A. Goljahani d, S. Montagnese a,b, C. Volpato c, A. Gatta a,b,
G. Sparacino b,d, P. Amodio a,b,1, P. Bisiacchi b,e,1
a
Department of Medicine, University of Padua, Italy
b
C.I.R.M.A.ME.C., University of Padua, Italy
c
IRCCS San Camillo, Lido di Venice, Italy
d
Department of Information Engineering, University of Padua, Italy
e
Department of General Psychology, University of Padua, Italy

a r t i c l e i n f o h i g h l i g h t s

Article history:
 Single-trial P300 latency increases and amplitude decreases along reaction times (RTs) distribution.
Accepted 8 August 2013
 The relationship between P300 and RTs disappears in patients with Minimal hepatic encephalopathy
Available online 10 September 2013
(MHE).
 Temporal overlap between stimulus and response selection is related to both RTs speed and
Keywords:
Intra-individual variability of RTs variability.
Single-trial P300
Minimal hepatic encephalopathy
Simon task a b s t r a c t
Objective: Intra-individual variability (IIV) of response reaction times (RTs) and psychomotor slowing
were proposed as markers of brain dysfunction in patients with minimal hepatic encephalopathy
(MHE), a subclinical disorder of the central nervous system frequently detectable in patients with liver
cirrhosis. However, behavioral measures alone do not enable investigations into the neural correlates
of these phenomena. The aim of this study was to investigate the electrophysiological correlates of psy-
chomotor slowing and increased IIV of RTs in patients with MHE.
Methods: Event-related potentials (ERPs), evoked by a stimulus–response (S–R) conflict task, were
recorded from a sample of patients with liver cirrhosis, with and without MHE, and a group of healthy con-
trols. A recently presented Bayesian approach was used to estimate single-trial P300 parameters.
Results: Patients with MHE, with both psychomotor slowing and higher IIV of RTs, showed higher P300
latency jittering and lower single-trial P300 amplitude compared to healthy controls. In healthy controls,
distribution analysis revealed that single-trial P300 latency increased and amplitude decreased as RTs
became longer; however, in patients with MHE the linkage between P300 and RTs was weaker or even
absent.
Conclusions: These findings suggest that in patients with MHE, the loss of the relationship between P300
parameters and RTs is related to both higher IIV of RTs and psychomotor slowing.
Significance: This study highlights the utility of investigating the relationship between single-trial ERPs
parameters along with RT distributions to explore brain functioning in normal or pathological conditions.
Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights
reserved.

1. Introduction common observation in most cognitive and neuropsychological

The study of within-person behavioral variability is an emerging
topic in cognitive neuroscience (MacDonald et al., 2006). Indeed, a
⇑ Corresponding author. Address: Department of Medicine – DIMED, University
of Padova, Via Giustiniani, 2, 35128 Padova, Italy. Tel.: +39 049 8218675; fax: +39
049 8754179.
E-mail address: sami.schiff@unipd.it (S. Schiff).
1
PA and PB joint senior authorship.
studies is that results based on subject samples cannot afford indi-
vidual predictions. This is because data on variability within the
same person are largely overshadowed by conventional measures
of central tendency. Increased intra-individual variability (IIV) of re-
sponse speed is detectable in many clinical conditions and could be
considered as a marker of brain dysfunction (Hultsch et al., 2000).
For example, increased IIV of reaction times (RTs) was previously
observed: (i) in dementia (Hultsch et al., 2000; Murtha et al.,

1388-2457/$36.00 Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.clinph.2013.08.004
 Author's personal copy
288 S. Schiff et al. / Clinical Neurophysiology 125 (2014) 287–297
2002; Christensen et al., 2005), (ii) in traumatic brain injury (Burton
et al., 2002; Stuss et al., 1994, 2003), (iii) in attention-deficit
hyperactivity disorder (ADHD; Leth-Steensen et al., 2000;
Castellanos and Tannock, 2002; Castellanos et al., 2006), and (iv)
in schizophrenia (Kaiser et al., 2008).
Minimal hepatic encephalopathy (MHE) refers to the initial
subclinical phase of hepatic encephalopathy which is a condition
characterised by quantifiable neurophysiological (Amodio et al.,
1999a,b, 2001; Marchetti et al., 2011) and neuropsychological
abnormalities including executive/attentional dysfunction and
psychomotor slowing and reduced vigilance (Amodio et al.,
2005a, 2010; Schiff et al., 2005a) related to liver cirrhosis and/or
porto-systemic blood shunting (Del Piccolo et al., 2003).
Two studies have previously investigated IIV of RTs in patients
with cirrhosis on a behavioral basis (Elsass et al., 1985; Schiff et al.,
2006). Specifically, Elsass et al., (1985) demonstrated that patients
with cirrhosis exhibited a higher IIV of RTs during an auditory
simple reaction time task not only compared with healthy individ-
uals, but also with patients with traumatic brain injury. In the
second study, Schiff et al., (2006) used a visual choice reaction time
task and observed both psychomotor slowing and higher IIV of RT
in patients with cirrhosis, both with and without MHE. However,
the neural correlates of psychomotor slowing and increased IIV
of RTs have never been investigated in patients with cirrhosis
so far.
Thus, the scope of the present work is to explore the neural
substrate of psychomotor slowing and IIV of response speed in
patients with MHE. Event-related brain potentials (ERPs) have
higher temporal resolution (i.e. milliseconds) than some other
neuroimaging methods (e.g., function MRI) and are preferred when
the time course of mental operations is under study, in contrast to
the precise neural location. In particular, a specific ERP component
that seems to be particularly suited for investigating the neural
locus of RT variability and the relationship between RTs and brain
activity is the P300 component (Sutton et al., 1965). P300 is gener-
ally assumed to be a reliable neurophysiological correlate of the
stimulus evaluation process (Magliero et al., 1984; Rugg and Coles,
1995; Polich, 2007). However, it was recently suggested that P300
component is not only related to stimulus evaluation but also to
response selection, or at least to some initial decisions on stimu-
lus–response (S–R) association (Verleger, 1997; Verleger et al.,
2005). In agreement with this view, Nieuwenhuis et al. (2005) sug-
gested a key role of the coeruleus–noradrenergic system in the
decision process and in the modulation of cortical P300 responses.
In addition, a link between catecholamines and the IIV of response
speed was recently suggested (Castellanos et al., 2005). Indeed,
catecholamines seem to modulate the signal-to-noise ratio (SNR)
of neural information processing when an organism is engaged in
tasks requiring attention and it contributes towards sustaining
internally generated decision processes (Aston-Jones and Cohen,
2005). Thus, the relationship between signal modulation at the
neural level and P300 suggests a possible link between P300 and
IIV of response latency and psychomotor slowing. Interestingly,
changes in P300 amplitude and/or latency are frequently observed
in populations that also exhibit prolongation and increased IIV of
RTs. For example, IIV of RTs changes throughout the lifespan from
childhood to old age. Indeed, IIV decreased from childhood to
adulthood and subsequently increased in older subjects (Hultsch
et al., 2002; Bunce et al., 2004; Williams et al., 2005; MacDonald
et al., 2006). On the other hand, together with increased IIV of
RTs, older adults show longer RTs, delayed P300 latency and re-
duced P300 amplitude when compared to younger adults (Wal-
hovd et al., 2008; Schiff et al., 2008; Fjell et al., 2009). Segalowitz
and colleagues (1997) studied patients with head injury and found
increased IIV of RTs was well explained by P300 amplitude
reduction.
Usually, P300 amplitude decreases and P300 latency increases
with increasing RTs (Holm et al., 2006; Li et al., 2008); however,
if latency jittering of an ERP component increases, the amplitude
of the wave obtained with the conventional averaging technique
(i.e., the usually adopted technique) decreases, and its latency is
no longer equivalent to the mean latency recorded in each trial
(see e.g., Mouraux and Iannetti, 2008; D’Avanzo et al., 2013 for
clinical and methodological remarks). Recently, single-trial analy-
sis of ERPs was used to determine the brain activity expressed in
each trial during a cognitive task, providing newer information
about the IIV in both normal subjects (Walhovd et al., 2008; Fjell
et al., 2009; Li et al., 2009; D’Avanzo et al., 2011; Saville et al.,
2011) and clinical populations (Roth et al., 2007; Fell, 2007;
De Lucia et al., 2010; Hu et al., 2010). For example, (Lorenzo-Lopez
et al., 2007) showed that low-performing older adults manifest
lower P300 amplitude and increased variability of P300 latency
compared to both younger adults and age-matched high-perform-
ing older adults. Nevertheless, Walhovd et al., (2008) showed that
even if older adults manifest higher variability of P300 latency, the
negative correlation between age and average-based P300 ampli-
tude persists after the correction of P300 latency jittering. Like-
wise, Saville et al., (2011) showed that healthy individuals with
high IIV of RTs manifest both higher P300 latency jittering and re-
duced P300 amplitude also after adequate single-trial correction.
In patients with cirrhosis, studies adopting the classic oddball
paradigm showed that P300 is frequently prolonged in latency
and reduced in amplitude (Klüger, 1996; Saxena et al., 2002; Amo-
dio et al., 2005b). Thus, since both patients with and without MHE
exhibit increased variability of RTs and psychomotor slowing, the
single-trial approach seems to be the most adequate method for
proper investigation of the neural correlates of these phenomena
in patients with cirrhosis. In addition, single-trial analysis allows
investigation of whether the increased variability of single-trial
P300 latencies, or the reduction of P300 amplitude in each sin-
gle-trial response, contribute to the reduction of average-based
P300 amplitude observed in patients with cirrhosis (e.g., Amodio
et al., 2005b).
In the present study, a Bayesian technique (D’Avanzo et al.,
2011) was adopted to estimate single-trial P300 parameters (i.e.,
latency and amplitude) evoked by the Simon task, a choice reaction
times task widely used to investigate spatial S–R compatibility,
from cirrhotic patients with and without MHE. In this task, partic-
ipants are asked to respond using spatially arranged keys to a non-
spatial stimulus feature (i.e., color) of lateralised targets (Simon
and Rudell, 1967; Simon, 2011). The Simon task was previously
used to study the temporal dynamic of S–R compatibility in normal
individuals (Vallesi et al., 2005) and in patients with cirrhosis
(Schiff et al., 2006). The Simon effect refers to the finding that re-
sponse choices are usually faster and more accurate when the
stimulus and the response-hand positions correspond spatially
compared to when they do not, even if stimulus position is task-
irrelevant.
The standard deviation (SD) is usually used to assess within-
subjects IIV of RTs. A more sophisticated approach exploits distri-
butional analysis providing information on the shape and the
skewness of RTs distribution, which offers additional insight into
IIV (Ratcliff, 1979; Castellanos et al., 2006). RT distributions are
well described by an ex-Gaussian distribution: a Gaussian-like dis-
tribution with a longer right-sided tail. Balota and Yap (2011) sug-
gested that a difference in the slopes of RTs distribution is a
measure of a difference in s a parameter that defines the exponen-
tial component of the ex-Gaussian distribution, or in other terms, a
difference in the skewness of the two distributions. The trial-by-
trial association between behavioral responses and P300 parame-
ters provides a clear description of the neural correlates of RT
speed and variability along RTs distribution. Since temporal over-
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S. Schiff et al. / Clinical Neurophysiology 125 (2014) 287–297
lap between early decision processes on S–R association and
response selection may contribute to fast motor responses
(Kornblum et al., 1990), it can be hypothesised that, using the dis-
tribution analysis, a relationship between P300 parameters and
RTs may be detected in healthy individuals: i.e., amplitude
decreases and latency increases with increasing RTs. In contrast,
in patients with psychomotor slowing and higher IIV variability
of RTs, this relationship would be weaker due to a reduced overlap
between the S–R association processes.
In summary, in the present paper we will specifically assess: (i)
if P300 amplitude reduction that has been observed in patients
with cirrhosis and MHE is explained, at least in part, by an
increased variability in single-trial P300 latency, and (ii) if P300
is related to RTs and to their distribution in both patients with
cirrhosis and in healthy individuals.
2. Methods
2.1. Participants
A total of 43 participants were enrolled in the study: 29 patients
with liver cirrhosis (age 51 ± 9 years, mean ± SD; males 66%;
education level 9 ± 4 years), of whom 14 had MHE and 15 did
not, and 14 age-matched healthy controls (age 49 ± 10 years, males
57%, education 13 ± 5 years). Patients and healthy controls did not
differ in age or education level.
None of the participants had a history of neurological or neuro-
psychiatric disorders, or significant cardiovascular, respiratory or
renal impairment; none had taken psychotropic medication or
had an uncorrectable impairment of visual acuity or was color
blind. One of the patients had a history of alcohol misuse, however
he was abstinent for at least 6 months. The diagnosis of cirrhosis
was made on the basis of historical, clinical, laboratory, endoscopic
and radiological findings. The aetiology of liver cirrhosis, the
degree of hepatic failure according to Child–Pugh (Pugh et al.,
1973) and the laboratory variables are reported in Table 1. None
of the patients had overt hepatic encephalopathy and all of them
showed disorientation for time or space at the time of the study
(Bajaj et al., 2011). All the participants provided informed consent
to take part in the study which was approved by the local Hospital
University ethical committee.
2.2. Detection of MHE
MHE was diagnosed based on spectral electroencephalographic
(EEG) features (Amodio et al., 1999a,b, 2001) and performance in
Table 1
Clinical characteristics of the patients.
Clinical characteristics
Aetiology (%) Hepatitis B
Hepatitis C
Alcohol
Other
Child–Pugh classification (%) A 16.7
B 55.6
C 27.8
Biochemical variables Median (SE)
Total Bilirubin (mmol/L) 48.4 (6.9)
Albumin (g/L) 46.6 (14.6)
Protrombin time [PT] (%) 60.6 (3.6)
Venous ammonia (mmol/L) 59.7 (13.5)
Na (mmol/L) 139.4 (0.6)
Urea (mmol/L) 6.7 (8.9)
Creatinine (mmol/L) 87.6 (4.4)
Glucose (mmol/L) 17.8 (8.1)
289
age-and education-adjusted validated paper and pencil psycho-
metric tests, including the Trail-Making test (TMT part A and B),
Symbol-Digit test, and the computerised SCAN test (Amodio
et al., 1998, 2008). Patients were considered to have MHE if at least
one measure (psychometric tests and/or EEG) was abnormal
(Ferenci et al., 2002). On the basis of this criterion, 14 patients were
classified as having MHE.
2.3. Simon task
The experiment took place in a dimly light and sound attenu-
ated room. Each participant (control or patient) was presented
with a red or green target checkerboard on the right or the left side
of the computer screen while a ‘neutral’ black and white checker-
board always appeared on the other side. Checkerboards were pre-
sented for 176 ms and the inter-trial interval ranged from 800 to
1200 ms. The distance between the eyes and the screen was fixed
at 80 cm. A total of 300 experimental trials, balanced for stimulus
color (red or green) and position (left or right), were presented to
the participants in a completely randomised sequence. Before
starting the experimental task, 40 trials were presented for prac-
tise. The participant was asked to press, as fast and accurately as
possible, one of the two keys corresponding to the color of the
checkerboard. Half of the participants were told that button ‘M’
(right side of the keyboard) corresponds to the red checkerboard
and button ‘Z’ (left side of the keyboard) corresponds to the green
checkerboard. The other half of the participants received the oppo-
site S–R association. Speed and accuracy were equally emphasised
when providing the instructions.
2.4. Electrophysiological recordings
The electroencephalogram (EEG) was continuously recorded
(Micromed System Plus, Mogliano Veneto, Italy) by 30 Ag/AgCl elec-
trodes mounted on an elastic cap and positioned according to the
international 10/20 system. The Fpz was used as the ground and
the reference was provided by the linked right and left mastoid elec-
trodes. Two electrodes were placed on the external canthus and un-
der the left eye to monitor horizontal and vertical eye movements
(EOG), respectively. Each channel had its own analogue-to-digital
converter. The EEG and EOG signals were digitalised on-line with a
frequency rate of 512 Hz and a conversion resolution of 0.19 lV/di-
git. Impedance was kept lower than 5 kX. Signals were band-pass
filtered between 0.03 and 30 Hz. The EEG epochs were extracted
using a time-window analysis time of 2300 ms (800 ms pre-stimu-
lus and 1500 post-stimulus) and baseline corrected using a 200 ms
pre-stimulus time interval. Epochs with excessive drift or containing
eye movements/blinks were corrected using an independent com-
ponent analysis algorithm (Jung et al., 2001; Delorme and Makeig,
2004; Makeig et al., 2004). A visual inspection was then performed
in order to reject epochs with significant artefacts and only adequate
epochs were subsequently considered for the analysis.
24.1
Average-based P300 parameters (amplitude and latency) were
48.3
3.5 calculated by identifying the maximum, in the time-window be-
24.1 tween 250 and 600 ms after stimulus onset, of the ERP profile ob-
tained by conventional averaging.
2.5. Estimation of single-trial P300 responses
During the last few years, different mathematical approaches
have been proposed in order to derive ERP parameters, such as
amplitude and latency, from single-trial EEG responses (Jaskowski
and Verleger, 1999, 2000; Jung et al., 2001; Li et al., 2009; Rushby
and Barry, 2009; D’Avanzo et al., 2013).
Here, a single-trial P300 estimate was made using a Bayesian
approach originally proposed by Sparacino et al. (2002) and further
 Author's personal copy
290 S. Schiff et al. / Clinical Neurophysiology 125 (2014) 287–297
developed by D’Avanzo et al. (2011), to which we refer the reader
for further details. Briefly, the method is formulated in two stages.
In the first stage, each of the available raw sweeps is processed by
an individual ‘optimal’ filter, determined using statistical informa-
tion on the background EEG and on the unknown ERP obtained
from pre-stimulus and post-stimulus data, respectively. This
avoids critical assumptions regarding EEG and ERP stationarity.
Then, a mean ERP is determined as the weighted average of the fil-
tered sweeps, where each weight is proportional to the expected
reliability of the sweep. In the second stage, single-sweep estima-
tion is dealt within the same framework by using the average ERP
estimated in the previous stage as an a priori expected response.
The P300 latency and amplitude were determined for each sin-
gle-trial by identifying the maximum of the ERP profile in the
time-window between 250 and 600 ms after stimulus onset. The
assessment of the method made in D’Avanzo et al. (2011) on syn-
thetic data demonstrated its ability in estimating the latency of the
P300 component and its variability (e.g., the correlation coefficient
between the estimated and the true single-trial latency was 0.74
when the SNR was ‘‘high’’ and 0.47 when the SNR was ‘‘low’’; see
the cited paper above for details). However, detecting latency
and amplitude of the P300 component remains a challenging task:
occasional trials with estimated P300 latency resulting at the
boundary of the 250–600 ms time-window (e.g., because of mono-
tonic increasing or decreasing behaviour of the estimated ERP)
were considered not sufficiently robust and were excluded from
the analysis. Notably, these trials occurred in less than 5% of the to-
tal for each subject, except for one subject who had 10% of the tri-
als excluded from the analysis. Finally, the mean of P300 latencies
of all of the trials performed by each participant was computed as
well as the SD, which was used as an index of IIV in P300. Mean la-
tency and amplitude of P300 from each RTs quintile were analysed
in order to determine the relationship between physiological mea-
sures and the RTs distribution.
2.6. Statistics
A series of analyses of variance (ANOVA) for repeated-measures
were run with the group (patients with MHE, patients without
MHE and healthy controls) as a between-subjects factor and the
task condition (Corresponding vs. non-Corresponding) as a with-
in-subjects factor. For behavioral analyses, mean RTs, percentage
of correct response and RTs SDs were considered as dependent
variables. Individual RTs were also ordered from the fastest to
the slowest and were divided into five quintiles (i.e., bins) in order
to study RTs distribution. In this case, the ANOVA also included the
quintile factor as within-factor variable.
For the study of both average-based and single-trial P300
amplitudes and latencies, the ANOVA also included the factor der-
ivation (Pz, Cz, Fz) as a further within-subject factor. Pearson’s cor-
relations were computed to evaluate the goodness of fit of the P300
estimates given by the Bayesian single-trial method and with those
obtained using conventional averaging. Linear multiple regression
analysis was run to assess the role of P300 latency jittering and of
Table 2
Behavioral measures obtained from the Simon task in controls and patients. Mean (standard deviation).
Controls N = 14
Mean RT corresponding (ms) 487 (63)
Mean RT non-corresponding (ms) 510 (67)
IIV. RT corresponding (ms) 110 (25)
IIV. RT non-corresponding (ms) 90 (18)
Response accuracy corresponding (%) 97 (2)
Response accuracy non-corresponding (%) 95 (4)
the mean single-trial P300 amplitude as predictors of the average-
based P300 amplitude.
The mean of single-trial P300 parameters (latency and ampli-
tude) was calculated for each RTs quintile to evaluate the relation-
ship between behavioral and electrophysiological responses along
RTs distribution. Two ANOVAs were computed with the group as
between – subjects factor and task condition, quintile and deriva-
tion as within – subjects factors, to investigate the relationship be-
tween P300 parameters (latency and amplitude) and RTs
distribution. Post-hoc analyses were carried out using Bonferroni
correction for multiple comparisons.
3. Results
3.1. Behavioral analysis
3.1.1. RTs
RTs analysis highlighted the main effects of the task condition
[F(1, 41) = 33.39, p < 0.001; g2p = 0.45] and of the group [F(2,
40) = 10.89; p < 0.001; g2p = 0.35]. Post-hoc comparisons revealed
slower RTs in non-corresponding than corresponding condition
(i.e., Simon effect) and that patients with MHE were slower than
both healthy controls and patients without MHE (all post hoc
p < 0.05). No interaction was observed between group and task
condition [F(1, 41) = 1.42; p = 0.2; g2p = 0.03] (see Table 2).
3.1.2. Response accuracy
The same main effect of task condition and group [F(2, 40)=5.64,
p < 0.01; g2p = 0.2] were found when response accuracy was consid-
ered [F(1, 41) = 9.09, p < 0.005; g2p = 0.18]. Post-hoc tests showed
lower accuracy in the non-corresponding compared to correspond-
ing condition and that patients with MHE were less accurate than
healthy controls (all p < 0.05). Also, in this case, the interaction be-
tween group and task condition was not significant [F(1,
41) = 0.49; p = 0.6; g2p = 0.02].
3.1.3. IIV in RTs
The IIV of RTs was greater in the corresponding compared to
the non-corresponding condition [F(1, 40) = 23.96, p < 0.0001;
g2p = 0.34] (Table 2). Patients with MHE showed higher IIV of RTs
than both healthy controls and patients without MHE [F(2,
40) = 10.96, p < 0.001; g2p = 0.22, post hoc p’s < 0.05]. No difference
in IIV of RTs was observed between healthy controls and patients
without MHE (Fig. 1 left panel). No interaction was observed
between group and task condition [F(1,41) = 0.22; p < 0.64;
g2p = 0.005].
3.1.4. Distribution analysis of RTs
A dynamic image of IIV was provided by the study of RT distri-
bution via quintile analysis. Together with the effect of group
[F(2,40) = 10.86, p < 0.001; g2p = 0.35], quintile [F(4, 164) = 304.00,
p < 0.0001; g2p = 0.87] and task condition [F(1, 41) = 39.4,
p < 0.00001; g2p = 0.47], the interaction between task condition
and quintile [F(4, 160) = 22.29, p < 0.00001; g2p = 0.33] was signfi-
All Patients N = 29 Patients without MHE N = 13 Patients with MHE N = 16
602 (119) 553 (103) 641 (119)
637 (117) 582 (105) 681 (109)
144 (41) 130 (45) 156 (35)
128 (37) 107 (30) 144 (35)
90 (12) 95 (6) 87 (15)
87 (12) 91 (8) 84 (13)
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S. Schiff et al. / Clinical Neurophysiology 125 (2014) 287–297
Fig. 1. Left panel shows IIV of RTs of the three groups of subjects. The IIV of RTs progressively increases from healthy controls to patients with MHE (Bonferroni post hoc test,
p < 0.05). Right panel shows the IIV of single-trial P300 latencies of the three groups of subjects. Patients with MHE showed a higher variability in P300 latency than healthy
controls (post hoc test p < 0.05).
Fig. 2. Distribution analysis of RTs showed that the Simon effect (difference
between non-corresponding and corresponding conditions) decreased with slower
reaction times (solid line). In contrast, as concerning P300 latency, the magnitude of
the Simon effect did not change with longer RTs (dashed line).
cant, revealing – as expected – that the Simon effect decreased
with slower RTs (Fig. 2 continuous line). The quintile per task con-
dition effect interaction was observed in all groups whereas no
interaction was observed between group, task condition and quin-
tile [F(8, 160) = 0.50, p = 0.85; g2p = 0.02]. A more relevant group per
quintile interaction was found [F(8, 160) = 5.61, p < 0.00001;
g2p = 0.21] and post hoc comparisons revealed that the RTs were
more scattered in patients with MHE compared to healthy controls
(all p’s < 0.05) from the 2nd to the 5th quintile (Fig. 3).
3.2. P300. analysis
3.2.1. Average-based P300 measures
Overall, a trend of shorter latency of P300 in the corresponding
compared to the non-corresponding condition was found [F(1,
41) = 3.71, p = 0.06; g2p = 0.8] (Table 3). No difference was observed
in P300 latency between healthy controls and patients with and
without MHE [F(1, 41) = 0.09, p = 0.74; g2p = 0.003], taking into ac-
291
Fig. 3. The distribution analysis of the reaction times (RTs) shows an interaction
between group and quintile. A larger variability in RTs, from faster to slower
quintiles, can be seen in individuals with MHE (squares) compared to healthy
controls (diamonds). Asterisks denote significant differences between patients with
MHE and healthy controls (Bonferroni post-hoc test, p’s < 0.05).
count both task condition [F(1, 41) = 1.51, p = 0.17; g2p = 0.04] and
derivation [F(1, 41) = 0.11; p = 0.9; g2p = 0.003].
P300 amplitude was lower in the non-corresponding compared
to the corresponding condition [F(1, 41) = 18.77, p < 0.0001;
g2p = 0.32]; furthermore, an effect of derivation was also found
[F(2, 82) = 3.32, p < 0.05; g2p = 0.07], showing that P300 was greater
in the Pz compared to the Fz site (p < 0.05). The interaction be-
tween task condition and derivation [F(2, 82) = 3.20, p = 0.05;
g2p = 0.07] showed that the difference between the corresponding
and non-corresponding conditions was greater in the Pz compared
to the Fz site (p < 0.05) (Table 3). A main effect of group was de-
tected [F(2, 40) = 8.19; p < 0.005; g2p = 0.33] revealing that P300
was smaller in patients with MHE compared to healthy controls
but not compared to patients without MHE (post hoc p < 0.05)
(Figs. 4 and 5 left panel). No interaction of task condition or deriva-
tion with the factor group was found (Table 3).
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292 S. Schiff et al. / Clinical Neurophysiology 125 (2014) 287–297

Table 3
Average-based and single-trial estimated P300 latencies and amplitudes in Pz, Cz, Fz Mean (standard deviation).

Group Controls All patients Patients Patients Controls All patients Patients Patients
Derivation without MHE with MHE without MHE with MHE
Latency (ms) Amplitude (lV)
AVG-P300 Pz 346 (56) 361 (71) 352 (52) 369 (69) 9.8 (4.6) 6.3 (3.2) 7 (3.1) 5.8 (3.3)
corresponding Cz 359 (30) 374 (79) 354 (55) 390 (93) 9.7 (4.3) 5.5 (3.1) 7 (3.2) 4.5 (2.6)
Fz 364 (20) 379 (74) 362 (42) 393 (92) 9.0 (3.4) 6.0 (3.0) 7 (3.0) 4.5 (1.9)
AVG-P300 Pz 360 (65) 365 (103) 347 (104) 378 (102) 9.0 (3.5) 5.4 (2.8) 6.0 (3.0) 4.9 (2.6)
non-corresponding Cz 388 (37) 377 (76) 366 (41) 386 (95) 8.8 (3.7) 4.7 (2.9) 5.8 (3.0) 3.9 (2.7)
Fz 373 (32) 379 (86) 367 (40) 388 (111) 7.9 (2.9) 5.1 (2.8) 6.4 (2.9) 4.0 (2.3)
Single-trial P300 Pz 365 (31) 377 (36) 370 (37) 383 (36) 12.6 (4.2) 9.6 (3.4) 9.8 (3.4) 9.4 (3.4)
corresponding Cz 375 (27) 387 (32) 377 (27) 394 (37) 12.7 (4.3) 8.9 (2.9) 9.6 (3.3) 8.0 (2)
Fz 366 (20) 382 (34) 370 (25) 392 (38) 11.4 (3.6) 8.9 (2.6) 9.7 (3.3) 8.3 (1.7)
Single-trial P300 Pz 385 (40) 391 (43) 388 (53) 397 (34) 12.0 (3.4) 9.1 (3) 9.4 (3.2) 8.8 (3.0)
non-corresponding Cz 393 (34) 405 (34) 396 (29) 412 (37) 12.4 (3.8) 8.7 (3) 9.4 (3.3) 8.1 (2.6)
Fz 384 (26) 394 (34) 383 (31) 403 (33) 11.3 (3.3) 8.8 (2.7) 9.0 (3.2) 8.2 (2.2)

Fig. 4. Event-related potentials in Pz, Cz and Fz are plotted separately for corresponding (on the left) and non-corresponding condition (on the right) and group (healthy
controls, pts without MHE, pts with MHE). P300 was larger in amplitude in healthy controls (solid line) compared to patients with MHE (dotted line) but not compared to
patients without MHE (dashed line).

3.2.2. Single-trial-based P300 measures agreement with the results observed using the averaged-based
Contrary to average based analysis, single-trial P300 latency P300 analysis, single-trial analysis also revealed a significant effect
was clearly shorter in the corresponding compared to the non-cor- of derivation [F(2, 41) = 3.57, p < 0.05; g2p = 0.08], showing that
responding condition [F(1, 41) = 76.54, p < 0.00001; g2p = 0.65]. In P300 latency was higher in the Pz compared to the Fz site (post
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S. Schiff et al. / Clinical Neurophysiology 125 (2014) 287–297 293

Fig. 5. Left panel: P300 scalp voltage distributions in the three groups are shown for the corresponding and non-corresponding trials. Right panel: Colour plots of single-trial
P300 responses in Pz are depicted in order of RTs speed (black curves), from the fastest to the slowest, in the three groups. Patients with MHE show an increased P300 latency
jittering, a reduction in P300 amplitude (both in the corresponding and non-corresponding conditions), and a loss of the relationship between P300 responses and RTs.

hoc p < 0.05). Also in this case, P300 latency did not differ between
healthy controls and the patients with cirrhosis, with or without
MHE [F(2, 82)=1.29, p = 0.26; g2p = 0.03] (Table 3) and no interaction
was found between task condition or derivation with the factor
group.
Overall, P300 amplitude was lower in the non-corresponding
condition compared to the corresponding conditions [F(1,
41) = 5.57, p < 0.05; g2p = 0.12). A significant derivation per task
condition interaction was found [F(2, 82) = 7.51, p < 0.005;
g2p = 0.16], showing that the difference between corresponding
and non-corresponding conditions was greater in Pz compared to
both Fz and Cz (all p’s < 0.001) (Table 3). The main effect of group
[F(2, 40) = 5.07, p < 0.05; g2p = 0.19] revealed that patients with
MHE had lower P300 amplitude compared to healthy controls
(p < 0.05) (Table 3). No interaction was found between task condi-
tion or derivation and the factor group.
3.2.3. Relationship between average-based and single-trial P300
measures
In Pz, both average-based latency and amplitude correlated
with the mean of their estimated single-trials counterparts
(r = 0.72, p < 0.0001 and r = 0.90, p < 0.0001, respectively). These
results confirm that the estimated single-trial P300 latencies were
distributed around a value that was very close to the P300 latency
determined by using the ERP waveform obtained with the conven-
tional averaging. In fact, the obtained correlation coefficient was
not surprising since, in the second stage of the method described
in Section 2.5, single-trial estimates were obtained by exploiting
an ‘‘average’’ obtained in stage 1.
The relationship between IIV of single-trial P300 latency and
average-based P300 amplitude was deducible by the inverse corre-
lation between these two measures (r = 0.73, p < 0.0001), show-
ing that the higher the IIV P300 latency, the lower the average-
based P300 amplitude. However, on closer inspection, multivariate
regression analysis showed that the averaged-based P300 ampli-
tude was predicted by both the IIV of single-trial P300 latency
(b = 0.25 ± 0.04 (SE); p < 0.0001) and single-trial P300 amplitude
(b = 0.78 ± 0.04; p < 0.0001). This was also true considering
healthy controls and patients with cirrhosis separately: averaged-
based P300 amplitude vs. IIV of single-trial P300 latency (patients
with cirrhosis and healthy controls: b = 0.33 ± 0.06, p < 0.0001
and b = 0.16 ± 0.06, p < 0.05, respectively), averaged-based P300
amplitude vs. single-trial P300 amplitude (patients with cirrhosis
and healthy controls b = 0.73 ± 0.06, p < 0.0001, and
b = 0.85 ± 0.07, p < 0.0001, respectively). Notably, the ratio be-
tween the Beta’s and their SE (i.e., a measure of the strength of
the association between the dependent variable and its predictor),
was twice as high in patients with cirrhosis compared to healthy
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294 S. Schiff et al. / Clinical Neurophysiology 125 (2014) 287–297

Table 4
IIV of P300 latency obtained by single trial estimate in the derivations Pz, Cz, Fz. Mean (standard deviation).

Electrode Controls All patients Patients without MHE Patients with MHE
Latency (ms)
IIV P300 corresponding Pz 77 (23) 94 (20) 87 (19) 99 (20)
IIV P300 non-corresponding Pz 83 (21) 106 (22) 97 (23) 112 (19)
IIV P300 corresponding Cz 79 (18) 98 (19) 89 (17) 104 (18)
IIV P300 non-corresponding Cz 82 (16) 104 (20) 97 (17) 110 (21)
IIV P300 corresponding Fz 80 (17) 93 (20) 84 (18) 101 (20)
IIV P300 non-corresponding Fz 85 (15) 100 (20) 92 (15) 106 (22)

Fig. 6. Left panel: The relationship between P300 latency and RTs shows an interaction between group and quintile, proving that in healthy controls (diamonds), P300 latency
increased with slower RTs. This relationship can also be observed in patients without MHE (circles) but only with faster RTs (i.e. 1st, 2nd and 3rd). In contrast, the relationship
between P300 latency and RTs disappears in patients with MHE (squares). Right panel: The relationship between P300 amplitude and RTs shows an interaction between
group and quintile proving that P300 amplitude decreased with increasing RTs in healthy controls and in patients without MHE, but not in those with MHE.

controls: 5 and 2.3, respectively. This result showed that the con-
tribution of P300 latency jittering to average-based P300 ampli-
tude was higher in patients with cirrhosis compared to healthy
controls. Thus, not only IIV of RTs but also increased P300 latency
jittering should be considered as pathophysiological markers of
brain dysfunction in patients with cirrhosis.
3.2.4. IIV of P300
The IIV in P300 latency was higher in the non-corresponding
compared to the corresponding condition [F(1, 41) = 11.23,
p < 0.005; g2p = 0.21]. Furthermore, a derivation per task condition
interaction was found [F(2, 82) = 5.45, p < 0.01 g2p = 0.12], showing
that the difference in P300 latency jittering between the corre-
sponding and non-corresponding trials was greater in Pz site (post
hoc p < 0.05). The main effect of group [F(2, 39) = 7.8721, p = 0.005;
g2p = 0.28] revealed higher IIV in P300 latency in patients with MHE
compared to healthy controls, (p < 0.05; see Table 4 and Fig. 1 right
panel); in contrast, a post hoc test between healthy controls and
patients without MHE did not reach statistical significance
(p = 0.08). No interaction was found between task condition and
group [F(1, 41) = 1.1, p = 0.3; g2p = 0.02].
Considering IIV in P300 amplitude, a significant main effect of
site was found [F(2, 82) = 7.95, p < 0.001; g2p = 0.16]. Post-hoc
comparisons revealed that IIV of P300 amplitude was higher in
Cz compared to both Pz and Fz sites (all p’s < 0.05). The ANOVA
did not reveal any other significant effects of IIV in P300 amplitude
concerning the factors task condition [F(1, 41) = 0.37, p = 0.85;
g2p = 0.001] and group [F(1, 41) = 0.35, p = 0.54; g2p = 0.01].
3.2.5. Relationship between single-trial P300 and RT distribution
Regarding single-trial P300 latency, the main effects of task
condition [F(1, 41) = 75.78, p < 0.00001; g2p = 0.65] and quintile
[F(4, 164) = 8.49, p < 0.005; g2p = 0.17] were significant. The effect
of quintile revealed that P300 latency increased with longer RTs
(1st vs. 2nd, 3rd, 4th quintiles; all p’s < 0.05). Unlike with RTs, no
interaction was found between task condition and quintile [F(4,
164) = 0.97, p = 0.4; g2p = 0.02]; see Fig. 2 (dashed line). A relevant
group per quintile interaction was found [F(8, 160) = 5.14,
p < 0.00001; g2p = 0.20], showing that the relationship between
P300 latency and RTs was closer and steeper in healthy controls
than in patients with cirrhosis (Fig. 6 right). Post-hoc tests revealed
that P300 latency increased along RT distribution (1st vs. 3rd, 4th
and 5th quintiles; all p’s < 0.05) in healthy controls, but not in
patients with cirrhosis, either with or without MHE. Indeed, in
patients with cirrhosis the relationship between RTs and P300
latency was completely lost (see Fig. 6 left panel).
The relationship between single-trial P300 amplitude and
RTs distribution highlighted the main effects of task condition
[F(1, 41) = 4.47, p < 0.05; g2p = 0.11], quintile [F(4, 164) = 37.92,
p < 0.0001; g2p = 0.48], and derivation [F(2, 82) = 4.98, p < 0.01;
g2p = 0.48]. The effect of quintile showed that the P300 amplitude
decreased with increasing RTs (1st vs. 2nd, 3rd, 4th and 5th; 2nd
vs. 3rd, 4th and 5th; and 3rd vs. 5th quintiles; all p’s < 0.05). A site
per quintile interaction was also found, showing that the decrease
in amplitude with slower RTs was greater for the Pz and Cz sites
compared to the Fz site (all p’s < 0.05). Furthermore, the significant
effect of group [F(1, 41) = 8.71, p < 0.01; g2p = 0.18] and the signifi-
cant interaction between group and quintile [F(8, 160) = 2.7,
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S. Schiff et al. / Clinical Neurophysiology 125 (2014) 287–297
p < 0.01; g2p = 0.12], revealed that the P300 amplitude was smaller
in patients with MHE and decreased along RTs distribution in
healthy controls (1st vs. 3rd, 4th and 5th quintiles) and in patients
without MHE (1st and 2nd vs. 4th and 5th; 2nd vs. 5th quintiles; all
p’s < 0.05); such a relationship was lost in patients with MHE (1st
vs. 4th quintile; p < 0.05; see Figs. 5 and 6 right panels).
4. Discussion
In the present study, a Bayesian approach was used to estimate
single-trial P300 parameters evoked by a conflict S–R Simon task in
patients with and without minimal metabolic brain dysfunction
due to liver cirrhosis and in a group of healthy controls. In line with
our hypothesis, patients with liver cirrhosis, especially those with
MHE, showed longer RTs and reduced response accuracy as com-
pared with healthy controls. Furthermore, IIV in RTs was greater
in patients with cirrhosis, both with and without MHE, than in
healthy controls. This latter result was confirmed by distribution
analysis of RTs. Patients with cirrhosis had a greater difference be-
tween slower and faster quintiles when compared to healthy con-
trols. Therefore, our data confirm previous observations regarding
increased variability in reaction speed and changes in the slope of
RTs distribution in patients with cirrhosis compared to healthy
controls (Elsass et al., 1985; Schiff et al., 2006).
The first aim of the present study was to investigate whether
patients with or without MHE exhibit increased variability in sin-
gle-trial P300 parameters and to evaluate the relationship between
P300 latency jittering and average-based P300 amplitude. The pat-
tern of results showed that patients with cirrhosis had smaller
P300 amplitude compared to healthy controls; in contrast, P300 la-
tency did not differ between groups. Our data revealed a greater IIV
of P300 latency in patients with cirrhosis, mainly those with MHE,
compared to healthy controls. Furthermore, even if average-based
P300 amplitude was related to both single-trial P300 amplitude
and P300 latency jittering, the contribution of IIV of P300 latency
was double in patients compared to controls. These results suggest
a specific link between P300 amplitude, IIV of P300 latency, and
the metabolic brain dysfunction that characterises patients with
cirrhosis.
The second aim of the study was to evaluate the relationship
between RTs distribution and P300 parameters. Our analysis re-
vealed that in healthy participants, P300 latency increased and
amplitude decreased with increasing RTs. In contrast, the relation-
ships between RTs and P300 parameters were weaker in patients
without MHE and absent in patients with MHE. These results sug-
gest that, in normal conditions, the temporal overlap between
early decision processes on S–R associations and response-related
processes leads to faster RTs and is well described by the changes
in within-subjects P300 parameters along the RTs distribution:
lower P300 amplitude and delayed P300 latency for slower com-
pared to faster RTs. In contrast, in patients with cirrhosis both psy-
chomotor slowing and increase of IIV of RTs might be explained by
the loss of the temporal overlap between the early decision on S–R
association and late response selection processes.
From a pathophysiological point of view, the results described
above suggest that the increased variability in RTs is related to
the altered brain functioning and neurotransmission observed in
patients with cirrhosis (Zafiris et al., 2004; Shah et al., 2008; Pove-
da et al., 2010). The metabolic brain dysfunction in patients with
cirrhosis seems to depend, at least in part, on increased blood/cere-
bral ammonia levels. These lead to changes in cerebral energy
metabolism and neurotransmission, in particular within the gluta-
matergic system (Wilkinson et al., 2010). At the synaptic level,
astrocytes play an important role in removing glutamate (Glu)
from synapses. Glutamate is released by pre-synaptic neurons
295
and astrocytes convert it into glutamine (Gln) before it is returned
to the neurons and recycled. From a neurobiological point of view,
astrocyte swelling with the accumulation of Gln is considered to be
a key mechanism related to hepatic encephalopathy. It can be
hypothesised that this metabolic dysfunction is implicated in
increasing variability in the synchrony of the firing rate of large
neuronal populations, as a consequence increasing the variability
of post-synaptic neural responses, P300 and behavioral response.
Interestingly, a similar mechanism linking neurones and astrocyte
functioning was recently suggested in order to explain increased
IIV in behavioral speed and RTs slowness in subjects with ADHD
(Russell et al., 2006). Following a different perspective on brain
functioning, fMRI studies showed an incomplete deactivation of
the default mode network during task execution, which was corre-
lated with increased variability in behavioral speed (Kelly et al.,
2008). Within this framework, it is important to note that in indi-
viduals with ADHD, a lack of default network suppression was
found and linked to increased response speed variability (Fassb-
ender et al., 2009). Similarly, an abnormal activation of the default
network was also found in patients with cirrhosis when engaged in
a cognitive task (Zhang et al., 2007).
Another observation derived from the present study concerns
the functional meaning of P300. Using a single-trial approach, we
have evaluated the dynamics of the relationship between P300 la-
tency and S–R correspondence along the RTs distribution. Usually,
the Simon effect is explained in terms of competition between a di-
rect visuo-motor transmission route carrying the response linked
to the spatial position of the stimulus, and an indirect route hold-
ing task demands. The activation/suppression model suggests that,
in the non-corresponding condition, the early activation of the
incorrect response spatially corresponding with stimulus position
is proactively suppressed, at a response selection stage, by a late
inhibitory mechanism. This mechanism needs time to be effective
and, for this reason, it affects the magnitude of the Simon effect,
mainly for slower RTs (Ridderinkhof, 2002). In agreement with this
model, the Simon effect usually decreases with longer RTs.
In the present study, the Simon effect (i.e., slower RTs and lower
accuracy in the non-corresponding condition than in the corre-
sponding condition) was detected both in healthy controls and pa-
tients with cirrhosis. Distribution analysis of RTs showed that the
Simon effect decreased in magnitude as RTs increased, both in
healthy controls and patients with cirrhosis, regardless of the pres-
ence of psychomotor slowing. Electrophysiological results confirm
that P300, obtained during the Simon task, is sensitive to S–R cor-
respondence (Valle-Inclan, 1996; Wascher and Wauschkuhn,
1996). A longer P300 latency and a smaller P300 amplitude in
the non-corresponding condition compared to the corresponding
condition were observed both in healthy controls and in patients
with cirrhosis; however, in contrast to behavioral data, when
P300 latency was considered, a suppression of the Simon effect
with longer RTs was not observed. These results suggest that
P300 is related to S–R association but not to late response
inhibition.
Indeed, P300-like responses have been recorded intra-cortically
from several brain sites (Halgren et al., 1995a,b). However, parietal
P300 (P3b) is plausibly generated mainly in the temporal-parietal
junction (Verleger, 1997). Several pieces of evidence suggest that
these regions of the brain are functionally involved in the integra-
tion of visual information and action plans (Rushworth et al., 2001;
Schiff et al., 2011).
On the other hand, Forstmann et al., (2008a,b) showed, using
model-based fMRI, that in the Simon task the early activation of
the prepotent incorrect response correlates with activity of the
anterior cingulate cortex and the pre-supplementary motor area.
In contrast, the late inhibition of the activated incorrect response
was associated with the activity of the inferior frontal cortex. These
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296 S. Schiff et al. / Clinical Neurophysiology 125 (2014) 287–297
results suggest that inhibition can be considered a two-stage
process acting on both the early phase of response activation and
on the late inhibition of an incorrect response (Bar et al., 2006).
In agreement with this view, Wylie et al., (2010) showed that, in
patients with Parkinson’s disease, deep brain stimulation of the
sub-thalamic nucleus affects both the early activation and late
inhibition of a prepotent incorrect response. Thus, in agreement
with Verleger et al., (2005), our results suggest that P300 is sensi-
tive to early coding of the S–R association but independent of
inhibitory processes acting on later response-selection stage.
In conclusion, the present study: (i) supports the convincement
that behavioral and electrophysiological measures of within-
subject variability are useful indicators of brain dysfunctions and
single-trial ERP analysis is a powerful technique both in clinical
studies and basic research especially when within-subject brain re-
sponses are investigated together with RTs distribution, (ii) proves
that in patients with MHE, the higher IIV of RTs is associated with
both a reduction in P300 amplitude and an increase in P300 latency
jittering, and (iii) shows that the loss of a temporal overlap
between P300 and behavioral responses in patients with MHE is
associated with psychomotor slowing, but is independent of late
response inhibition. The present study further suggests that new
technological approaches to EEG signal analysis, such as single-
trial ERPs estimation or automatic detection of individual alpha
frequency (Goljahani et al., 2012), may reveal further electrophys-
iological peculiarities uniquely related to the MHE condition. These
peculiarities may allow development of non-invasive reliable
diagnostic tools.
Acknowledgment
The study was partially supported by the Bial Foundation Grant
No. 146/2008 to P.B., by the Regione Veneto FSE Grants ‘‘Develop-
ment of a system for the analysis of the intraindividual EEG
variability for the early identification of cognitive deficiencies’’
and ‘‘Implementation of methodologies for the quantification of
electrophysiological signals in mild cognitive disorders’’ to C.D.A.
and A.G., and by the University of Padova Grant ‘‘Quantitative
understanding of the human brain functioning through advanced
EEG and NIRS signal processing’’ to G.S.
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