Clinical Neurophysiology 123 (2012) 1319–1327

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

Emotional anticipation rather than processing is altered in patients

with vasovagal syncope q
Giulia Buodo a,⇑, Michela Sarlo a, Silvia Poli a, Franco Giada b, Michela Madalosso c, Cesare Rossi c,
Daniela Palomba a
a
Department of General Psychology, University of Padova, Italy
b
Cardiovascular Department, Sports Cardiology Center, PF Calvi Hospital, Noale-Venice, Italy
c
Cardiovascular Department, Dell’Angelo Hospital, Mestre-Venice, Italy

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

Article history:  Syncopal patients show reduced cortical negativity in anticipation of unpleasant pictures.
Accepted 3 December 2011  Syncopal patients and healthy individuals show similar electrocortical responses to arousing stimuli.
Available online 2 January 2012  Syncopal patients possibly engage in cognitive distraction to down-regulate emotional anticipation.

Keywords:
Anticipation a b s t r a c t
Emotion
Stimulus-Preceding Negativity
Objective: To investigate whether the electrocortical activity underlying the anticipation and processing
Vasovagal syncope of emotional stimuli is enhanced in individuals with recurrent episodes of vasovagal syncope (VVS).
Methods: Fifteen fainters and 15 age-matched healthy controls were presented a S1–S2 task, where the
content of high-arousal pleasant and unpleasant, and neutral pictures (S2) was forecasted by word cues
(S1). Stimulus Preceding Negativity (SPN) amplitude during the S1–S2 interval was computed as a mea-
sure of affective anticipation. The event-related potentials (ERPs) to S1 and S2 were measured to assess
the processing of emotional warning stimuli and pictures.
Results: Relative to controls, fainters showed smaller P300 to warning cues anticipating emotional (and,
particularly, unpleasant) pictures, and smaller SPN during anticipation of unpleasant pictures. No differ-
ences between groups were found with regard to ERP amplitudes during picture processing.
Conclusions: These results suggest that the anticipation, rather than the processing, of aversive stimuli is
altered in syncopal patients.
Significance: The reduced cortical anticipation in fainters might reflect the use of non-adaptive emotion
regulation strategies for reducing the impact of upcoming highly arousing (and, particularly, of unpleas-
ant) events.
Ó 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights
reserved.

1. Introduction accounting for up to 40% of syncopal events evaluated in the out-

Neurally mediated or vasovagal syncope (VVS) is a syndrome
characterized by the co-occurrence of vasodilatation (‘‘vaso’’) and
vagally-mediated bradycardia (‘‘vagal’’), leading to hypotension
and transient loss of consciousness and postural tone as a result
of cerebral hypoperfusion (e.g., Van Lieshout et al., 1997; Benditt
and Goldstein, 2002). VVS is the most common cause of fainting,
q
The present study was conducted at the Department of General Psychology,
University of Padova, Italy.
⇑ Corresponding author. Address: Dipartimento di Psicologia Generale, Via
Venezia 8, 35131 Padova, Italy. Tel.: +39 049 8277476; fax: +39 049 8276600.
E-mail address: giulia.buodo@unipd.it (G. Buodo).
patient setting (Fenton et al., 2000).
VVS ensues when the balance between the mechanisms regu-
lating blood pressure is temporarily disrupted, i.e., excessive ve-
nous pooling to the lower extremities due to decreased
peripheral resistance is not counterbalanced by a compensatory
rise in cardiac output. Vasodilation and bradycardia, instead of
compensatory vasoconstriction and tachycardia, lead to hypoten-
sion and loss of consciousness (e.g., Van Lieshout et al., 1997; Fen-
ton et al., 2000; Hainsworth, 2004).
Recurrent syncopal events of vasovagal nature may occur in
otherwise healthy individuals in response to a variety of determi-
nants. Although the proposed classifications may vary, it has been
recognized that the potential triggers of VVS can be distinguished
into physical factors, i.e., orthostatic stress and specific stimulation

1388-2457/$36.00 Ó 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.clinph.2011.12.003
1320 G. Buodo et al. / Clinical Neurophysiology 123 (2012) 1319–1327
of sensory or visceral afferents, and psychological determinants,
such as emotional distress, intense fear, sudden and severe painful
experiences, or the sight of blood (see Mosqueda-Garcia et al.,
2000; Moya et al., 2009). Because emotional factors are often
pre-eminent, VVS is often referred to as ‘‘emotional fainting’’ (see
Hamer and Bray, 2005). A central, rather than peripheral, neural
pathway is believed to play a key role in the activation of emotion-
ally-mediated syncope. This pathway would originate in neocorti-
cal and limbic structures of the central nervous system implicated
in the evaluation and interpretation of emotional information, and
descend from the cortico-hypothalamic centers to the brainstem
autonomic nuclei that regulate cardiac and vasomotor activity
through sympathetic and parasympathetic efferents (Kaufmann
and Hainsworth, 2001; Kinsella and Tuckey, 2001; Diehl, 2005).
At least three different, but partially overlapping, interpreta-
tions of the psychological mechanisms involved in VVS have been
put forward. According to Graham et al. (1961), VVS is a response
to events which are likely to elicit anxiety. In the presence of a
threatening situation, an emotional response involving subjective
anxiety and increases in heart rate and blood pressure is initially
elicited. With cessation of the threat, relief from anxiety is accom-
panied by a sudden and dramatic drop in both cardiovascular
parameters, and fainting may ensue as a consequence.
Drawing from animal models, Engel (1978) ascribed the break-
down of the homeostatic mechanisms that normally maintain the
reciprocal relationships between cardiovascular processes and so-
matic needs to the presence of an irresolvable conflict between
contrasting action tendencies, namely fight–flight and conserva-
tion–withdrawal. Indeed, VVS typically ensues in situations char-
acterized by uncertainty as to whether active escape or giving up
is the most adaptive response to an impending (real or fantasized)
threat or danger.
Sledge (1978) examined the psychological antecedents of VVS,
and showed that fear, anxiety and feelings of helplessness precede
fainting episodes when a threat to the body (e.g., receiving an injec-
tion or other medical procedures) or psychological harm (i.e., public
ridicule and mortification) was expected in social situations. In all
cases, the subject’s interpretation of the social context, and the feel-
ing that ‘‘giving in’’ to the perceived threat is necessary since active
countermeasures would be socially inappropriate, highlight the role
played by real or fantasized social pressures in the conflict between
preparation for action and helpless resignation to the threat.
To summarize the psychosocial factors accompanying or pre-
ceding emotional fainting appear to include fear of bodily or psy-
chological harm, anxiety, helplessness, and a sense of resignation
to the perceived threat. Surprisingly, while altered anticipatory
processing has been recognized as a critical component of some
mental disorders, such as anxiety disorders (Barlow et al., 1996),
none of the above-mentioned explanations of emotional fainting
specifically emphasizes the role played by anticipation. Anticipa-
tion has a perceptual connotation, in that the individual awaits
the occurrence of a stimulus. Also, anticipation is an active process,
because the organism might be behaviorally passive while await-
ing for perceptual input, but specific brain areas are already active
before its actual delivery. The functional role of anticipatory pro-
cesses is therefore to organize a set of changes in the state of the
organism that ultimately allow for a more efficient interaction
with expected upcoming stimuli (van Boxtel and Böcker, 2004).
However, when brain activity underlying anticipation of relevant
stimuli is either exaggerated or abnormally low (as has been ob-
served in individuals with anxiety disorders of several types,
depending on the specific experimental conditions used to investi-
gate anticipatory processes; e.g., Proulx and Picton, 1984; Klorman
and Ryan, 1980; Kimble et al., 2004), the individual’s behavior be-
comes no longer flexible and adjusted to future environmental de-
mands. On this basis, it is reasonable to hypothesize that in
predisposed individuals the cascade of psychological events that
culminates in fainting might not only involve abnormal respond-
ing, but also altered anticipatory responses to emotionally relevant
or, more specifically, unpleasant situations.
In research using the event-related potentials (ERPs) to investi-
gate the neural correlates of psychological processes, anticipation
is usually studied by means of experimental paradigms that elicit
a slow cortical potential, the Contingent Negative Variation (CNV;
Walter et al., 1964; Brunia and van Boxtel, 2001; van Boxtel and
Böcker, 2004). The CNV develops during the time interval between
a warning signal (S1) and an imperative stimulus (S2), to which the
subject is required to respond (e.g., with a button press). Impor-
tantly, a motor response to S2 is a sufficient, but not a necessary con-
dition to elicit a negative potential between S1 and S2 (Brunia, 1988;
Chwilla and Brunia, 1991; van Boxtel and Brunia, 1994). Non-motor
CNV is termed Stimulus-Preceding Negativity (SPN). The SPN has
been observed during the anticipation of stimuli with both positive
(e.g., erotic pictures; Howard et al., 1992) and negative valence (e.g.,
a mild electric shock, or unpleasant slides; Lumsden et al., 1986;
Rockstroh et al., 1989), and is therefore considered to reflect affec-
tive-motivational anticipation (Brunia et al., 2011). Irrespective of
valence, the amplitude of the SPN is significantly larger preceding
high rather than low arousal pictures, indicating that the SPN is
modulated by the intensity of the motivational engagement as-
cribed to affective stimuli (Poli et al., 2007). The SPN preceding
affective stimuli in picture-anticipation tasks shows a frontal max-
imum, that is particularly evident when the forthcoming stimulus is
negative in valence (see Takeuchi et al., 2005). Importantly, cortical
negativity is larger before S2 stimuli that are expected to be fol-
lowed by aversive outcomes (Regan and Howard, 1995; Amrhein
et al., 2005), suggesting that it might represent a psychophysiolog-
ical indicator of expectancy of negative consequences.
In the present study, we investigated emotional anticipation in
individuals with recurrent episodes of VVS and healthy controls,
using a paradigm where the emotional content of high-arousal
pleasant and unpleasant, and neutral pictures (S2) was signaled
by congruent word stimuli (S1). The amplitude of the SPN preced-
ing the onset of S2 was measured as an index of emotional antici-
pation. Moreover, the amplitudes of the P300 and the following
Late Positive Potential (LPP) of the ERPs to word and picture stimuli
were computed as classic indices of attentional engagement with
emotional stimuli (Palomba et al., 1997; Cuthbert et al., 2000;
Schupp et al., 2000).
Because in daily life emotional situations can trigger fainting
episodes in patients with recurrent episodes of VVS, and consider-
ing that anticipating negative consequences from emotional stim-
uli is reflected in larger electrocortical negativity during
anticipation (Amrhein et al., 2005), the hypothesis could be formu-
lated that SPN in anticipation of high-arousal emotional stimuli
would be enhanced in syncopal patients as compared with healthy
individuals. Syncopal patients were also expected to deploy more
attentional resources to emotional stimuli due to their relevance
as major trigger factors. This would be reflected in larger P300
amplitude to emotional word stimuli and larger P300/LPP ampli-
tude after emotional picture onset.
2. Methods
2.1. Participants
The study group consisted in 15 consecutive patients, aged 22–
53 years, with recurrent syncopal episodes, referred to the Syncope
Unit of the Cardiovascular Department of the Umberto I Hospital
(Venice-Mestre, Italy) for head-up tilt testing evaluation. In order
to be included in the study sample, patients had to meet the
 G. Buodo et al. / Clinical Neurophysiology 123 (2012) 1319–1327
following inclusion criteria: age over 18 years; recurrent syncopal
episodes, with at least two episodes in the last 12 months; positive
head-up tilt testing with vasovagal response and reproduction of
spontaneous symptoms; negative diagnostic work-up for other
causes of syncope. Exclusion criteria were the following: presence
of structural and/or functional heart diseases, alcohol or drug
abuse, declared psychiatric disorders, treatment with psychiatric
drugs. The presence of blood-injection-injury fears was a further
exclusion criterion, as such content-specific fears may confound
possible experimental effects of the unpleasant stimuli used in this
study (see below).
All patients were diagnosed with vasovagal reflex syncope, and
reported strong emotions, fear or pain as the main triggers of syn-
copal episodes. Four patients also reported prolonged standing as
an additional cause of fainting episodes, but none of these patients
was diagnosed with comorbid orthostatic intolerance.
The control group included 15 healthy individuals, aged 20–
59 years, with no history of syncope or pre-syncope (defined as a
partial loss of postural tone accompanied by symptoms of immi-
nent syncope, without complete loss of consciousness).
The two groups did not differ significantly for age (t(28) = 1.37;
p = .17).
The demographic and clinical characteristics of patients and
controls are reported in Table 1.
2.2. Stimuli and procedure
After signing a written informed consent, participants were
seated in a comfortable armchair in a sound-attenuated, dimly-lit
room at a distance of 1.20 m from the computer screen. During
the entire procedure, they were monitored by a closed-circuit vi-
deo camera. The task involved the presentation of a word (S1),
1 s in duration, that signaled the content of a picture (S2) presented
after 5 s and lasting 5 s. Three words (Italian translation of ‘‘erot-
ica’’, ‘‘object’’, and ‘‘injury’’) were selected to match the content
of three picture categories: nude couples during sexual intercourse
(high-arousal Pleasant), household objects (Neutral), and severely
injured bodies (high-arousal Unpleasant). Such high-arousal pleas-
ant and unpleasant picture contents were selected since these have
been observed to induce the largest cortical negativity during
anticipation (Poli et al., 2007) and the largest positive slow wave
during exposure (Cuthbert et al., 2000).
A total of 45 stimuli (15 pictures per category)1 were selected
from the International Affective Picture System (IAPS; Lang et al.,
2008) and presented in two different pseudo-randomized sequences
across subjects.
Participants were asked to attend to the word and to the subse-
quent picture. No motor response to S2 was required. The inter-
trial interval ranged randomly from 8 to 13 s.
The study had been approved by the Ethical Committees of the
Cardiovascular Department of the Umberto I Hospital and of the
Department of General Psychology, University of Padova.
2.3. Physiological recordings and data analysis
The electroencephalogram (EEG) and the electrooculogram
(EOG) were recorded using SynAmps amplifiers (NeuroScan, Inc.,
El Paso, TX). The EEG was continuously recorded from nine tin elec-
trodes (F3, Fz, F4, C3, Cz, C4, P3, Pz, P4) mounted on an elastic cap
1
IAPS picture numbers were as follows: erotic couples: 4608, 4660, 4689, 4656,
4651, 4670, 4677, 4687, 4653, 4611, 4652, 4683, 4650, 4690, 4607; household
objects: 7000, 7002, 7034, 7009, 7010, 7100, 7025, 7030, 7035, 7150, 7050, 7234,
7211, 7233, 7235; injuries: 9410, 9921, 3110, 3120, 3102, 3550, 9250, 3030, 3051,
3130. Five other pictures in this category (numbers 614, 624, 612, 627, 610) were
taken from a set standardized by the Authors and used in previous studies.
1321
Table 1
Demographic and clinical characteristics of fainters and controls.
Controls Fainters
(n = 15) (n = 15)
Age, years (mean ± SD) 28.27 ± 10.63 33.4 ± 9.77
Female gender, n (%) 12 (80) 12 (80)
Syncope lifetime, n (median, range) – 10 (2–100)
Syncope in the last 12 months, n (median, – 2 (2–10)
range)
SD, standard deviation.
(Electro-Cap International, Inc.), referred to linked mastoids. We
acknowledge that the use of tin electrodes for recording slow
potentials might attenuate the low frequencies in the recorded sig-
nal (e.g., Picton et al., 1995). Therefore, SPN amplitudes and, possi-
bly, group differences might have been attenuated as well.
The EOG was recorded from four tin electrodes attached above
and below the right eye and at the outer canthus of each eye, to
monitor eye movements and blinks. Electrode impedance was kept
below 10 kX.
The sampling rate was 500 Hz (16 bit A/D converter; accu-
racy = 0.168 uV/LSB) and filters were set at DC-70 Hz.
The EEG signal was epoched into 11300 ms intervals (from
300 ms before S1 until S2 offset), corrected for eyeblinks (Sem-
litsch et al., 1986), baseline corrected using the 300 ms before S1
onset, re-filtered off-line with a lowpass filter at 30 Hz (12 dB/
oct, zero phase filter), and linear detrended in order to remove
DC drifts. All EEG epochs were visually scored for eye movement
and other artifacts, and each portion of data containing artifacts
greater than ±70 lV in any channel was rejected for all the record-
ing channels prior to further analysis.
The amplitudes of the P300 component to S1 and S2 and the LPP
to S2 were measured with respect to a 100-ms pre-stimulus base-
line. Based on visual inspection of grand-average ERP waveforms,
the P300 was computed as the mean amplitude between 250
and 400 ms after stimulus onset. Two time windows were consid-
ered for the LPP: LPP1 (mean amplitude between 400 and 700 ms
after picture onset) and LPP2 (mean amplitude between 700 and
1000 ms after picture onset).
The SPN was defined as the mean amplitude over the 200-ms
interval preceding S2, relative to a 300 ms baseline preceding S1
(see Chwilla and Brunia, 1991; Hillman et al., 2000).
Repeated-measures ANOVAs were performed on the ampli-
tudes of each ERP component and of the SPN, with Group (Fainters,
Controls) as between-subjects factor, and Category (Pleasant, Neu-
tral, Unpleasant), Region (Frontal, Central, Parietal) and Laterality
(Left, Midline and Right) as within-subjects factors.
The corrected p-values for effects within variables with more
than two levels are reported together with the Geisser–Green-
house epsilon (e) and the uncorrected degrees of freedom. Signifi-
cant main effects and interactions (p < .05) were followed by Tukey
HSD post hoc tests.
Lastly, in the group of Fainters Pearson’s correlations were per-
formed between ERP measures and the number of syncopal epi-
sodes (both lifetime and in the past 12 months).
3. Results
3.1. P300 to S1 onset
Fig. 1 shows the ERPs in response to Pleasant, Neutral and
Unpleasant word cues over Fz, Cz and Pz, in Fainters and Controls.
The analysis on the amplitude of the P300 elicited by word
stimuli yielded significant main effects of Region (F(2, 56) = 5.76,
p = .013; e = .68), indicating larger amplitude in the parietal than
1322 G. Buodo et al. / Clinical Neurophysiology 123 (2012) 1319–1327

Fig. 1. Grand average event-related potentials waveforms following Pleasant, Neutral, and Unpleasant word cues (S1) in Fainters and Controls. The mean amplitude of the
P300 component was measured with respect to a 100-ms pre-stimulus baseline.

in the frontal region (p = .003), and Laterality (F(2, 56) = 7.68,
p = .001; e = .90), indicating larger amplitude over midline and
right than left hemisphere sites (ps < .01).
The main effects of Region and Laterality were modified by the
significant Region  Laterality interaction (F(4, 112) = 3.81;
p = .014; e = .72), showing that in the frontal region P300 ampli-
tude was significantly larger on the right than on the left side
(p = .001); in the central and parietal regions P300 amplitude was
larger over midline and right than left side (ps < .0003 and
<.0001, respectively).
The Group  Category  Laterality interaction (F(4, 112) = 3.26,
p = .032; e = .64) proved to be significant. With regard to between-
group differences, Fainters showed significantly smaller P300
amplitude than Controls to Pleasant word cues over the right side
(p = .007) and to Unpleasant word cues over midline and left sites
(p = .002 and .0002, respectively). Over the right and the left side,
 G. Buodo et al. / Clinical Neurophysiology 123 (2012) 1319–1327 1323

Fainters responded with smaller P300 amplitude to Pleasant and 3.4. P300 and LPP to S2 onset
Unpleasant word cues, which did not differ from each other, than
to Neutral word cues (p = .006 and .043, respectively). Over midline No significant main effects or interactions involving the Group
sites, Fainters exhibited the smallest P300 amplitude to Unpleasant factor were observed.
word cues, followed by Pleasant (p = .037) and Neutral (p = .0003). A significant main effect of Category was found for P300, LPP1
In Controls, no significant differences in P300 amplitude among and LPP2 (F(2, 56) = 38.65, p = .0001; e = .94; F(2, 56) = 60.38,
stimulus categories was found on any side. p = .0001; e = .89; and F(2, 56) = 63.68, p = .0001; e = .96, respec-
tively), showing larger amplitude for Pleasant and Unpleasant as
compared with Neutral pictures (all ps < .001). A significant Region
3.2. Stimulus Preceding Negativity
main effect for the three ERP components was also found (F(2,
56) = 32.81, p = .0001; e = .55; F(2, 56) = 47.31, p = .0001; e = .57,
Fig. 2 shows cortical activity over Fz, Cz and Pz during the antic-
F(2, 56) = 6.09, p = .015; e = .57, respectively), indicating larger
ipation of Pleasant, Neutral and Unpleasant pictures, in Fainters
amplitude in the parietal as compared with central and frontal re-
and Controls.
gions (ps < .004). For LPP1 and LPP2 a significant Laterality main ef-
The significant Category main effect (F(2, 56) = 13.91; p = .0001;
fect (F(2, 56) = 5.26, p = .011, e = .87 and F(2, 56) = 6.43, p = .004,
e = .97) showed that SPN amplitude was larger in anticipation of
e = .87, respectively) indicated larger amplitude on the right as
Pleasant and Unpleasant pictures, which did not differ from each
compared with the left side (ps < .02).
other, as compared with Neutral pictures (ps < .001). As indicated
In order to test whether group differences as a function of cat-
by the significant Region main effect (F(2, 56) = 5.94; p = .013;
egory could emerge in the early ERP components, namely N1 and
e = .63), SPN amplitude was larger over the frontal and central re-
P2, additional analyses were performed on the mean amplitude
gions, which did not differ from each other (p = .10), than over
in the 50–130 ms and 130–200 time-windows, based on visual
the parietal region (ps < .02). Such main effects were modified by
inspection of grand-averaged ERP waveforms.
the significant Category  Region interaction (F(4, 112) = 7.15;
Results did not show any significant main effect of the Group
p = . 001; e = .55), showing that SPN amplitude in anticipation of
factor or significant Group  Category interactions for any compo-
Pleasant pictures was larger over the frontal and central as com-
nent (all Fs < .20, all ps > .54). For the P2 component, a main effect
pared with the parietal region (ps < . 001), whereas no difference
of Category was found (F(2, 56) = 6.42, p = .005, e = .86), showing
as a function of region was observed for SPN in anticipation of
larger amplitude for Pleasant than Neutral pictures (p < .003). No
Unpleasant and Neutral pictures.
significant Category main effect emerged for N1.
The significant Group  Region interaction (F(2, 56) = 4.49;
p = .032; e = .63) showed that SPN amplitude was significantly
smaller in Fainters than in Controls in the parietal region
4. Discussion
(p = .0002), whereas no group differences emerged in the other re-
gions. SPN amplitude in Fainters was larger in the frontal and cen-
Although it has long been recognized that fainting episodes can
tral as compared with the parietal region (ps < .04), whereas in
be triggered by emotional factors, the underlying neural mecha-
Controls no significant differences among regions was observed.
nisms are far from being fully elucidated. Even more so, the involve-
The significant Group  Category  Region interaction (F(4,
ment of anticipatory mechanisms in the cascade of events that may
112) = 3.12; p = .046; e = .55; see Fig. 3) showed that over the fron-
lead to syncope has been suggested (e.g., Sledge, 1978), but to our
tal region Fainters responded with smaller SPN amplitude than
knowledge has never been empirically investigated so far.
Controls in anticipation of Neutral pictures only (p = .048). Fainters
The present study was aimed at investigating whether individ-
displayed a larger SPN amplitude in anticipation of both Pleasant
uals with recurrent episodes of vasovagal syncope (VVS) show en-
and Unpleasant pictures as compared with the SPN preceding Neu-
hanced anticipation and processing of emotional stimuli. To this
tral pictures (ps < .001). In Controls, only the SPN preceding Pleas-
purpose, electrocortical activity was recorded during a picture
ant pictures was significantly larger relative to the SPN preceding
anticipation task, where words forecasted the presentation of
Neutral pictures (p = .0002). In both Fainters and Controls, the
high-arousal pleasant and unpleasant, and neutral pictures.
amplitude of the SPN in anticipation of Pleasant and Unpleasant
Contrary to our hypothesis, emotional anticipation and process-
pictures did not differ from each other. Over the central region,
ing were not found to be enhanced in syncopal patients as com-
Fainters responded with smaller SPN amplitude than Controls in
pared with healthy individuals. However, we obtained findings
anticipation of Unpleasant pictures (p = .026). Fainters again
indicating that the pattern of brain activation during anticipation
showed larger SPN in anticipation of Pleasant and Unpleasant pic-
of affective stimuli was markedly different in patients with VVS
tures, which did not differ from each other, as compared with SPN
and controls.
preceding Neutral pictures (ps < .007). In Controls, only SPN pre-
Patients responded with smaller P300 amplitudes than controls
ceding Unpleasant pictures was larger relative to SPN preceding
to positively valenced words over left hemisphere sites, and to neg-
Neutral (p = .001). Over the parietal region, Fainters showed smal-
atively valenced words over both midline and right hemisphere
ler SPN amplitude than Controls in anticipation of Unpleasant pic-
sites. This finding indicates that, relative to healthy controls, syn-
tures (p = .0001). SPN amplitudes preceding the three picture
copal patients deployed less attentional resources towards warn-
categories did not differ from each other in Fainters. In Controls,
ing cues that anticipated the occurrence of high-arousal affective
SPN preceding Unpleasant pictures was significantly larger relative
stimuli, both pleasant and unpleasant. Thus, the critical factor that
to SPN preceding Neutral (p = .002).
modulated attention to warning cues in fainters was the emotional
salience, rather than the hedonic value of the stimuli. This pattern
3.3. Correlations between SPN amplitude and number of fainting of abnormal responding, which encompasses pleasant and
episodes unpleasant stimuli, may be related to the fact that most patients
reported strong emotional events, and not unpleasant stimuli
No significant correlations were observed for Fainters between (e.g., fear, pain) only, as the main triggers of VVS syncope. This
SPN amplitude and the number of lifetime syncopal episodes or the finding suggests that it is the emotional impact of stimuli and
number of episodes in the past year (rs ranged between .005 and events, and not unpleasantness only, to be of relevance in this con-
.42, ps ranged between .98 and .11). text. It can be hypothesized that the reduced P300 amplitude to
1324 G. Buodo et al. / Clinical Neurophysiology 123 (2012) 1319–1327

Fig. 2. For purposes of illustration, the figure shows the averaged electrocortical activity recorded in Fainters and Controls during the anticipation of Unpleasant, Neutral, and
Pleasant pictures over the Fz, Cz and Pz sites. The time epoch selected for displaying waveforms starts 3500 ms before, and ends 800 ms after picture onset (indicated with the
zero value). The mean amplitude of the Stimulus-Preceding Negativity was calculated relative to a 300-ms baseline preceding S1 (not shown). For the sake of clarity,
waveforms were re-filtered at 10 Hz.

emotional word cues reflects the patients’ attempt to reduce atten-
tional deployment as a means to down-regulate their emotional
response to the upcoming arousing stimuli. Although this hypoth-
esis is admittedly speculative, some support to its plausibility
comes by the observation that intentional self-distraction from
highly arousing emotional stimuli results in reduced activation of
emotion-processing brain regions (Ochsner and Gross, 2005; Kalis-
ch et al., 2006; Thiruchselvam et al., 2011). Although in the present
study the participants were not given instructions to modulate
their emotional responses, the patients may nevertheless have re-
cruited regulatory processes during the anticipation of upcoming
stimuli, with or without conscious awareness.
Whereas healthy subjects showed no differences in P300 ampli-
tude to the three word categories, as already observed by Poli et al.
(2007), the patients showed reduced P300 amplitude in response to
words anticipating emotional pictures (both pleasant and unpleas-
ant), as compared to neutral words. This was observed over both
the right and the left side. Overall, a right hemisphere advantage
 G. Buodo et al. / Clinical Neurophysiology 123 (2012) 1319–1327
Fig. 3. Mean amplitude of the Stimulus-Preceding Negativity in Fainters and Controls during the anticipation of Pleasant, Neutral, and Unpleasant pictures over the frontal,
central, and parietal regions.
for the processing of emotional words might be expected based on
reports of a right-hemisphere superiority in the perception of emo-
tional stimuli, regardless of valence (see Borod, 1992). Alterna-
tively, a right hemisphere advantage for negative stimuli and a
left hemisphere advantage for positive stimuli could be expected
based on the valence hypotheses of hemispheric specialization for
emotional perception (see Davidson, 1995). However, data on the
processing of emotional words are mostly inconsistent with both
hypotheses, and rather suggest that the right and the left hemi-
spheres play complementary roles in the processing of words with
emotional meaning (Abbassi et al., 2011). Consistently, in our study
no hemispheric lateralization emerged with regard to the process-
ing of the emotional words used as warning stimuli.
With regard to the SPN, a cortical measure of emotional antici-
pation, the results of the present study showed that affective mod-
ulation, i.e., larger amplitude of the SPN in anticipation of emotional
relative to neutral pictures, was evident in both individuals with
recurrent episodes of VVS and healthy controls. In particular, in
syncopal patients cortical negativity was larger in anticipation of
both pleasant and unpleasant as compared with neutral pictures
at frontal and central sites. In controls, larger negativity in anticipa-
tion of pleasant than neutral pictures was evident frontally,
whereas larger negativity in anticipation of unpleasant than neutral
pictures was observed centro-parietally. Overall, such findings indi-
cate that brain activity during anticipation reflected the motiva-
tional salience of high-arousal affective stimuli, irrespective of
their valence (Simons et al., 1979; Lumsden et al., 1986; Poli
et al., 2007). This conclusion might seem at odds with what sug-
gested by Böcker and colleagues (2001), who reported larger SPN
amplitudes following threat cues, i.e., during the anticipation of
an aversive shock, than following safe cues. This finding has been
interpreted as an indication that stimulus relevance per se is not a
sufficient condition for the slow cortical negativity to develop
and, rather, that the aversive nature of S2 is likely to be a necessary
condition for the larger part of the negativity preceding aversive
stimuli (see also Damen and Brunia, 1994). This inconsistency be-
tween results might be explained by differences in the stimulus
conditions employed, in that safe cues in the context of a threat-
of-shock paradigm might not represent a genuine appetitive
condition and, possibly, are not as arousing as threat cues. However,
1325
further studies and meta-analytic reviews are needed to clarify
whether SPN amplitude does primarily reflect stimulus valence
(and, in particular, whether it is specifically larger in anticipation
of unpleasant stimuli), or is modulated by emotional arousal.
Importantly, SPN amplitude during anticipation of unpleasant
pictures was significantly smaller in syncopal patients than in con-
trols. Such effect was specifically observed in central and parietal
regions. Considering that a large body of research has consistently
documented that slow cortical negativity during anticipation can
be reduced by distracting stimuli (Tecce and Hamilton, 1973;
Knott, 1985; Rockstroh et al., 1986; Douros et al., 1987; Wagner
et al., 1996; Travis and Tecce, 1998; Kimble et al., 2004), our find-
ing would again suggest that syncopal patients might have sponta-
neously activated cognitive regulation strategies, such as
deploying their attention away from the emotional aspects of the
anticipated unpleasant stimuli. Self-distraction would result in
the reduction of cortical excitability preceding the occurrence of
expected unpleasant stimuli, as reflected in the smaller SPN ampli-
tude as compared with controls. The finding that the SPN ampli-
tude was not correlated with the number of fainting episodes
during lifetime or during the past year suggests that reduced cor-
tical activation during anticipation reflects more an altered cogni-
tive process rather than a specific pathological feature in direct
relationship with the likelihood of recurrent fainting. However, be-
cause participants were not given instructions to use cognitive reg-
ulation strategies, nor were they asked after the experimental
session whether they spontaneously engaged in self-distraction,
our interpretation is necessarily provisional at this stage.
Interestingly enough, the electrocortical activity elicited by
emotional pictures was similar in syncopal patients and healthy
individuals. In fact, the amplitude of P300 and late positive poten-
tials to S2 stimuli was only modulated by the motivational rele-
vance of affective pictures (i.e., larger positivity to emotional,
either pleasant or unpleasant, than neutral pictures), irrespective
of group. The larger amplitude of late positive ERP components
for emotional than neutral pictures, together with the right-parie-
tal topography, replicate well-established findings in the literature
(e.g., Schupp et al., 2000).
Our finding of comparable ERP responses to emotional pictures
in syncopal patients and controls might seem at odd with the
1326 G. Buodo et al. / Clinical Neurophysiology 123 (2012) 1319–1327
reduced electrocortical activity in the stages of processing of the
warning cue and picture anticipation. However, it has been ob-
served that anticipatory distraction, that we hypothesize having
modulated the patients’ cortical activity before picture presenta-
tion, does not influence subsequent emotion processing, i.e., it does
not reduce subsequent activation in brain areas involved in emo-
tional processing (Erk et al., 2006). On the other hand, one might
argue that emotional fainters mostly faint during, and not before,
emotionally relevant situations, and therefore one would expect
that patients differ from controls during exposure to emotional
stimuli. Indeed, previous research (Calandra-Buonaura et al.,
2008) has found no difference in ERPs or cardiovascular measures
between fainters and controls during the viewing of emotional pic-
tures presented for 6 s. Consistent with these findings, our data
point towards comparable emotional processing in fainters and
controls during 5-s exposure. It is possible that the activation of
syncope upon exposure to emotional stimuli involves dysfunc-
tional interaction between subcortical emotional processing and
brainstem regions mediating autonomic cardiovascular regulation.
Therefore, event-related cortical potentials might not be able to de-
tect such alterations. Indeed, recent research reported lower regio-
nal brain volumes within medulla and midbrain in patients with
neurocardiogenic syncope compared to non-fainting controls, and
highlighted negative correlations between volumes in the caudate
nucleus, fainting frequency, and experienced anxiety levels (Beach-
er et al., 2009). Alternatively, exposure to sustained stimulation
might be needed to highlight abnormal emotional responding,
which in most VVS patients develop on a temporal scale ranging
from 30 s to several minutes (Grubb, 2005).
Overall, the potential clinical implications of the findings of the
present study are at least twofold. Firstly, the use of non-adaptive
emotion regulation strategies for reducing the impact of highly
arousing (and, particularly, of unpleasant) events, that we hypoth-
esize to underlie the reduced cortical anticipation in VVS patients,
might be involved in the pathophysiology and/or the maintenance
of emotional fainting. In fact, the failure to activate flexible self-
regulatory responses to emotional stimuli is known to be detri-
mental to psychological and physical health. Indeed, inefficiency
in selecting, attending and responding to emotional information
in the environment is thought to lie at the core of various forms
of pathology, including depression, panic disorder, generalized
anxiety disorder, hypertension, and coronary heart disease (Thayer
and Lane, 2000). Further research should better elucidate how
emotional anticipation and processing are related to emotion reg-
ulation strategies in individuals with VVS, and which neural net-
works and pathways come to interact dysfunctionally in
anticipating emotional information and modulating cardiac and
vasomotor activity (Fenton et al., 2000; Kaufmann and Hainsworth,
2001; Kinsella and Tuckey, 2001).
Secondly, our findings might offer clues to expand existing psy-
chological interventions with individuals with VVS (Gracie et al.,
2004, 2006). The treatment of VVS is still a matter of controversy,
and specific interventions are only recommended in a minority of
patients (Kuriachan et al., 2008). Conventional non-pharmacologi-
cal management of recurrent VVS mainly relies on education and
reassurance (Wieling et al., 2004), but in cases where symptoms
have proved resistant to conventional treatments, cognitive-
behavioral interventions may be beneficial (Newton et al., 2003).
The selective alteration of anticipation, but not of the processing,
of emotional stimuli suggests that cognitive-behavioral interven-
tions in VVS patients might usefully target the cognitive, affective
and physiological responses inherent in the anticipation of emo-
tional events, rather than the responses that take place once such
events are actually occurring. For instance, the use of attention-
focusing strategies during in vivo or imaginal exposure to emo-
tional stimuli has been proven to reduce fear responses in phobic
individuals (see Mohlman and Zinbarg, 2000). Future research
should evaluate whether such strategies might facilitate an effec-
tive regulation of psychophysiological responses during emotional
anticipation in VVS patients.
Acknowledgment
The Authors thank Valentina Perrone for her help during data
collection and analysis.
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