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NeuroImage 31 (2006) 1268 – 1277

Distraction affects frontal alpha rhythms related to expectancy

of pain: An EEG study

Claudio Del Percio,a,b,c,d,* Domenica Le Pera,e Lars Arendt-Nielsen,b Claudio Babiloni,a,c

Alfredo Brancucci,a,b,d Andrew C.N. Chen,f Liala De Armas,e Roberto Miliucci,g

Domenico Restuccia,g Massimiliano Valeriani,h and Paolo Maria Rossini c,i

aDipartimento di Fisiologia Umana e Farmacologia, Universita ‘‘La Sapienza’’, Rome, ItalybHuman Brain Mapping and Cortical Imaging Laboratory/SMI, University of Aalborg, DenmarkcA.Fa.R. Dip.Neuroscienze-Ospedale Fatebenefratelli Isola Tiberina, Rome, ItalydInstituto di Medicina e Scienza dello Sport, CONI Servizi, Rome, ItalyeCasa di Cura San Raffaele Pisana, Tosinvest Sanita, Rome, ItalyfCenter for Functional Human Brain Mapping, Capital University of Medical Sciences, Beijing, ChinagDipartimento di Neurologia, Universita Cattolica del Sacro Cuore, Rome, ItalyhDivisione di Neurologia, Ospedale Pediatrico Bambino Gesu IRCCS, Rome, ItalyiIRCCS ‘‘S. Giovanni di Dio-FBF’’, Brescia and Clinica Neurologica, Universita ‘‘Campus Biomedico’’, Rome, Italy

Received 30 March 2005; revised 13 October 2005; accepted 20 January 2006

Available online 10 March 2006

Previous electroencephalographic (EEG) evidence has shown event-

related desynchronization (ERD) of alpha rhythms before predictable

painful stimuli, as a possible neural concomitant of attentional

preparatory processes (Babiloni, C., Brancucci, A., Babiloni, F.,

Capotosto, P., Carducci, F., Cincotti, F., Arendt-Nielsen, L., Chen,

A.C., Rossini, P.M., 2003. Anticipatory cortical responses during the

expectancy of a predictable painful stimulation. A high-resolution

electroencephalography study. Eur. J. Neurosci. 18 (6) 1692–700). This

study tested the hypothesis that alpha ERD before predictable painful

stimuli is reduced as an effect of distraction. A visual warning stimulus

preceded a laser painful stimulation, which was strictly followed by

visual imperative stimuli. In the Pain (control) condition, no task was

required after the imperative stimuli. In the Pain + Movement

condition, subjects had to perform a movement of the right index

finger. In the Pain + Cognition condition, they had to mentally perform

an arithmetical task. EEG data were recorded in 10 subjects from 30

electrodes. Artifact-free recordings were spatially enhanced by surface

Laplacian transformation. Alpha ERD was computed at three alpha

sub-bands according to subjects’ individual alpha frequency peak (i.e.,

about 6–8 Hz, 8–10 Hz, 10–12 Hz). Compared to the control

condition, the subjects reported a significantly lower stimulus intensity

perception and unpleasantness in the Pain + Movement and Pain +

Cognition conditions. In addition, there was a cancellation of the alpha

3 ERD (i.e., about 10–12 Hz) in Pain + Cognition condition and even a

generation of a statistically significant alpha 3 ERS in Pain +

Movement condition. These effects were maximum over fronto-central

1053-8119/$ - see front matter D 2006 Elsevier Inc. All rights reserved.

doi:10.1016/j.neuroimage.2006.01.013

* Corresponding author. Dipartimento di Fisiologia Umana e Farm-

acologia, Universita degli Studi di Roma ‘‘La Sapienza’’, P.le Aldo Moro, 5,

00185 Rome, Italy. Fax: +39 06 4991 0989 0917.

E-mail address: claudio.delpercio@uniroma1.it (C. Del Percio).

Available online on ScienceDirect (www.sciencedirect.com).

midline. These results suggest that distraction during the expectancy of

pain is related to a reduced neural desynchronization of fronto-central

midline alpha rhythms (i.e., reduced cortical activation) towards an

overt hyper-synchronization (cortical idling).

D 2006 Elsevier Inc. All rights reserved.

Keywords: Electroencephalography (EEG); Alpha rhythms; Event-related

desynchronization/synchronization (ERD/ERS); Pain; Sensorimotor inter-

actions; Cognition; Distraction

Introduction

Investigations measuring regional cerebral blood flow (rCBF)

have shown that activity of nociceptive cortical areas was observed

not only during pain experience but also during the expectancy of

predictable pain stimulations (Ingvar, 1999; Treede et al., 1999;

Hsieh et al., 1999; Petrovic et al., 2000). Among these areas,

primary somatosensory cortex would be mainly devoted to the

anticipation of sensory discrimination (Porro et al., 1998, 2002;

Treede et al., 1999; Schnitzler and Ploner, 2000; Petrovic and

Ingvar, 2002). Conversely, midline cingulate and frontal areas

would be engaged in the anticipation of affective/cognitive aspects

of pain experience, selection of proper viscero-sensorimotor/

behavioral responses, and event memorization (Rainville et al.,

1997; Porro et al., 1998, 2002; Hsieh et al., 1999; Ingvar, 1999;

Treede et al., 1999; Ploghaus et al., 1999; Petrovic and Ingvar,

2002; Petrovic et al., 2000; Schnitzler and Ploner, 2000; Garcia-

Larrea et al., 2003).

C. Del Percio et al. / NeuroImage 31 (2006) 1268–1277 1269

Anticipatory cortical processes can also be probed by electro-

magnetic brain signals named event-related potentials (ERPs),

which might denote affective-motivational cortical processes and

preparatory sensorimotor processes (Bocker et al., 2001; Bocker

and Van Boxtel, 1997). These potentials are termed contingent

negative variation (CNV) when a motor response is required after a

warned imperative stimulus (Brunia, 1999; Brunia and van Boxtel,

2001). On the whole, the CNV can be considered as a global sign of

anticipatory cortical excitability (Brunia, 1999; Bastiaansen and

Brunia, 2001). Before nonpainful or painful somatosensory stimuli,

no ERP has been shown despite its biological significance (Babiloni

et al., 2003). In contrast, there was a CNV before nonpainful and

painful stimuli (left hand) concomitant with a Go/NoGo motor task,

presumably elicited by inter-hemispheric flow of information

involving both primary (Babiloni et al., 2004a, 2005a) and

secondary (Babiloni et al., 2005b) sensorimotor areas.

In parallel, anticipatory cortical processes can be investigated by

electroencephalographic (EEG) rhythms at an extended alpha band

ranging about from 6 to 12 Hz (Neuper and Pfurtscheller, 2001;

Bastiaansen et al., 2001; Brunia and van Boxtel, 2001). During

sensorimotor or cognitive events, the lower the amplitude of alpha

rhythms (event-related desynchronization, ERD), the better the

information transfer (‘‘gating’’) through sensorimotor thalamo-

cortical and cortico-cortical pathways (Pfurtscheller and Lopes da

Silva, 1999; Klimesch, 1999). In contrast to the negligible CNV

before painful stimuli, anticipatory alpha ERD has been found to be

clearly evident over primary somatosensory cortex contralateral to

the stimulation (Babiloni et al., 2003). Furthermore, that anticipa-

tory alpha ERD increased in magnitude over primary sensorimotor

areas before nonpainful and painful stimuli to the left hand

concomitant with a Go/NoGo motor task for the right hand

(Babiloni et al., 2004a, 2005b). This was true even if painful

stimulation was concomitant with a working memory task replacing

the Go/NoGo motor one (Babiloni et al., 2004c). According to

previous EEG evidence (Rockstroh et al., 1989), these findings

have been interpreted as an anticipatory facilitation of nociceptive

thalamo-cortical and cortico-cortical channels. However, it is still

an open issue whether and how such anticipatory modulation of

nociceptive channels is related to attentional processes as reflected

by trial-by-trial stimulus evaluation.

Previous studies have investigated how cortical processes

linked with pain are affected by distraction due to concomitant

sensorimotor and cognitive demands (Nakata et al., 2004a,b,

2005). Distraction reduced subjective pain sensation (Eccleston,

1995). Furthermore, pain or anticipation of pain reduced cognitive

performance, probably as a result of subtraction of attentional

resources from cognitive operations (De Pascalis et al., 1995;

Kuhajda et al., 2002; Lieberman et al., 2002). That reduction of

cognitive performance occurred as a function of task complexity,

age of the subjects, endogenous variations in hormone level (i.e.,

menstrual cycle), and individual differences of reactivity to

stressful agents (Pauli et al., 1993; Kumari and Corr, 1998).

Relationships between pain, distraction, and cortical activity

have been investigated by neuroimaging studies estimating rCBF.

Pain sensation (cold pressure test) and simultaneous attention-

demanding maze task induced an increase of orbitofrontal rCBF

(Petrovic et al., 2000). Pain stimuli associated with attentional

(Stroop) demands increased activity of perigenual anterior cingu-

late (ACC) and orbitofrontal cortices, while the opposite was true

at thalamus, insular cortex and caudal parts of ACC (Bantick et al.,

2002). A similar modulation of attention also increased rCBF in

periaqueductal gray, which modulates descending pain inhibitory

systems (Tracey et al., 2002). Taken together, these neuroimaging

studies suggest that distraction tasks reduce subjective pain

sensation and decrease rCBF in cerebral areas such as perigenual

ACC, orbitofrontal, and insular cortices (Petrovic and Ingvar,

2002; Petrovic et al., 2000; Bantick et al., 2002; Frankenstein et al.,

2001). A reasonable hypothesis is that alpha rhythms are

implicated in the attentional ‘‘gating’’ of painful stimuli across

the mentioned node of the nociceptive circuits.

The present EEG study aims at investigating relationships

among pain, distraction, and cortical alpha rhythms in order to test

the hypothesis that concurrent motor or cognitive demands reduce

both the evaluation of pain (distraction effects) and alpha ERD

preceding predictable pain stimuli.

Materials and methods

Subjects

Ten healthy volunteers (mean age = 24 years, range: 20–32

years) participated to the present study. All subjects gave their

written informed consent according to the Declaration of Helsinki

and could freely request an interruption of the investigation at any

time. The local Institutional Ethics Committee approved the

research aims and procedures.

Experimental design

A sketch of the experimental design is shown in Fig. 1. This

design included three conditions, namely Pain, Pain + Movement

and Pain + Cognition. In all conditions, a visual warning stimulus

(red screen, duration 200 ms) preceded the laser painful stimulation

of 600 ms, which was delivered to the dorsum of the right hand.

The laser painful stimulation was followed after 600 ms by visual

imperative stimulus (green screen, duration 200 ms). The interval

between laser painful stimulations of two subsequent trials was

9600 ms, a time period sufficient to make negligible the effects of

habituation to painful stimulation and to reset the brain processes

specifically related to such kind of stimulation (Bromm and

Lorenz, 1998). In the Pain condition, no task was required to the

subjects. In the Pain + Movement condition, the subjects had to

perform a right index movement after the imperative stimulus. In

the Pain + Cognition condition, they had to perform an arithmetical

mental task after that stimulus. Namely, they had to cyclically

subtract 7 starting from 1000. For each condition, 30 trials were

collected. At the end of each trial, subjects had to rate the level of

intensity of painful sensation by a scale from 0 to 100 (0 = no pain,

1 = pain threshold, 100 = unbearable pain). Furthermore, in a

separate experimental session, the subjects evaluated the level of

unpleasantness of painful sensation by a scale from 0 to 100. This

was true for all three conditions (Pain, Pain + Movement and Pain +

Cognition). Of note, the level of intensity and unpleasantness was

evaluated in separate sessions to avoid distraction and artificial

correlations between the two subjective measurements. The order

of conditions was randomly changed across the subjects.

Laser stimulation

In all conditions, the painful stimulations were delivered by a

CO2 laser (10.6 mm wave length, 2 mm beam diameter; ELEN,

Fig. 1. Sketch of the experimental design including 3 conditions: Pain, Pain +

Movement and Pain + Cognition. In all conditions, a visual warning stimulus

(red screen, duration 200 ms) preceded the laser painful stimulation of 600

ms, which was delivered to the dorsum of the right hand. The painful

stimulation was followed after 600 ms by a visual imperative stimulus (green

screen, duration 200 ms). The interval between two painful stimulations was

9600 ms. The number of painful stimulations was 30 for each conditions.

In the Pain condition, no task was required to the subjects. In the Pain +

Movement condition, subjects had to perform a movement of the right

hand after the imperative stimulus. In the Pain + Cognition condition,

subjects had to perform an arithmetical mental tasks after the imperative

stimulus. The arithmetical tasks consisted in subtracting cyclically 7

starting from 1000. (For interpretation of the references to colour in this

figure legend, the reader is referred to the web version of this article.)

C. Del Percio et al. / NeuroImage 31 (2006) 1268–12771270

Florence, Italy) on the dorsum of the right hand. The stimulation site

was visualized by a He–Ne laser beam. The location of the impact

on the skin was moved slightly between two successive stimula-

tions, to avoid skin burns and nociceptor fatigue (Schwarz et al.,

2000).

Magnitude of the painful stimulation was determined at the

beginning of each recording. During the setting of the stimulus

intensity, subjects had to indicate verbally when the stimulus

reached a moderate pain level, that is 30 in a scale ranging from 0

(no pain) to 100 (unbearable pain). The same laser pulse intensity,

corresponding to the pain threshold, was used in all conditions

(Pain, Pain + Movement and Pain + Cognition).

Recordings

The subjects were seated in a comfortable chair in front of a

computer monitor (about 1 m). A brief training session served to

minimize blinking and eye movements and to make stable and

reproducible the motor performance during the Pain + Movement

condition.

Bio-signals were recorded from 30 electroencephalographic

(EEG) electrodes placed according to an augmented 10–20

system. The reference electrode was on the nose and the ground

on the forehead. The electrode impedance was kept around 5

KOhm. To monitor blinking and eye movements, vertical EOG

electrode was recorded. To monitor also involuntary and

voluntary hand motor responses (during the Pain + Movement

condition), electromyographic activity was collected from exten-

sor digitorum muscle. Recording parameters for all data were:

real bandpass of 0.3–20 Hz, sampling rate of 64 Hz, and

acquisition time from �4.8 s to +4.8 s after the onset of laser

painful stimulation. Thirty EEG trials were collected for each

condition and subject. At the end of each EEG trial, as

aforementioned, subjects rated the level of intensity of painful

sensation by a scale from 0 to 100 (level of unpleasantness was

evaluated by a scale from 0 to 100 in a separate experimental

session with no EEG recording).

To avoid contamination of the pain-related anticipatory alpha

ERD by the visual warning stimulus evoked potential, we

preliminarily removed EEG phase-locked activity related to the

first visual stimulation (i.e., warning stimulus). To this purpose, a

correction factor was calculated for each EEG individual trial by

cross-correlation between the evoked potential and the on-going

EEG of that trial. This factor was used to weight the subtraction of

the visual evoked potential related to the information flow through

the screen from that EEG single trial. A similar technique has been

successfully used in previous studies (Kalcher and Pfurtscheller,

1995; Babiloni et al., 2004b).

Off-line preliminary data analysis

Two experimenters rejected EEG single trials associated with

mirror or involuntary finger movements (less than 5%), slight

muscle activation, and instrumental artifacts.

The spatial resolution of the artifact-free EEG data was

enhanced by surface Laplacian estimation (regularized 3-D spline

function; Babiloni et al., 1996, 1998). The surface Laplacian

estimation acts as a spatial filter that reduces head volume

conductor effects and annuls electrode reference influence (Nunez,

1995; Babiloni et al., 1996). In some cases, the Laplacian values at

the border electrodes were zeroed because of unreliability of the

spline Laplacian estimate for these electrodes.

The single trial analysis was carefully repeated on the

Laplacian-transformed EEG data, to discard the single trials

contaminated by residual computational artifacts. The mean of

the individual artifact-free EEG data was of 26.1 (T0.7 standard

error, SE) single trials for the Pain condition, of 25.4 (T0.9 SE)

single trials for the Pain + Movement condition, and of 26.2 (T0.3SE) for the Pain + Cognition condition (no statistical difference

among the conditions; F2,9 = 0.6; P = 0.55).

The final statistical data analysis considered the electrodes

roughly overlying prefrontal and anterior cingulate (Fz site);

supplementary motor area and mid cingulate (Cz site); superior

parietal cortex and posterior cingulate (Pz site); and sensorimotor

cortex contralateral (C3 site) and ipsilateral (C4 site) to the

painful stimulation. These areas were of interest for their role in

sensorimotor interactions and related attentional processes

(Ingvar, 1999; Treede et al., 1999; Hsieh et al., 1999; Petrovic

and Ingvar, 2002; Petrovic et al., 2000; Babiloni et al., 2004a,

2005a). Of note, F3 and F4 electrodes overlying frontal lateral

regions were not considered here, although previous EEG studies

Fig. 2. Mean values subjective evaluation of pain intensity and pain

unpleasantness.

C. Del Percio et al. / NeuroImage 31 (2006) 1268–1277 1271

using anticipation of an aversive outcome have consistently

described an anterior negativity (Regan and Howard, 1995; Flor

et al., 1996; Baas et al., 2002; Pizzagalli et al., 2003). This was

due to the need for a data reduction before statistical analysis.

Indeed, the experimental group was formed by 10 subjects, so a

proper statistical design including three conditions (Pain, Pain +

Movement, Pain + Cognition) could just include a limited

number of levels for the spatial factor (i.e., Fz, C3, Cz C4, and

Pz). Of note, the analysis focused on selected electrodes did not

make it useless multi-channel recordings. Indeed, the surface

Laplacian estimation used the spatial information of all 30 EEG

electrodes to spatially enhance the potentials at the mentioned

five electrodes of interest (Babiloni et al., 1996).

Determination of individual alpha bands

The power spectrum analysis was based on a standard FFT

approach using Welch technique and Hanning windowing

function. For the determination of the individual alpha bands,

an anchor frequency was selected according to literature guide-

lines. It is called the individual alpha frequency (IAF) peak

(Klimesch, 1996, 1999; Klimesch et al., 1998). Practically, the

IAF was defined as the frequency showing the higher power

density in the 6–12 Hz spectrum. With reference to the IAF, the

frequency bands of interest were as follows: alpha 1 as IAF-4 Hz

to IAF-2 Hz, alpha 2 as IAF-2 Hz to IAF, and alpha 3 as IAF to

IAF + 2 Hz. Of note, the mean IAF peak was 9 Hz (T0.3 SE) for

each condition.

Computation of alpha event-related desynchronization/

synchronization (ERD/ERS)

To quantify the event-related changes of EEG power, we used

the well-tested procedure called event-related desynchronization/

synchronization (ERD/ERS; Pfurtscheller and Aranibar, 1979;

Pfurtscheller and Neuper, 1994; Pfurtscheller and Lopes da Silva,

1999; Pfurtscheller et al., 1997). The ERD/ERS of the individual

alpha 1, alpha 2 and alpha 3 bands was computed by:

ERD=ERS% ¼ E � Rð ÞR

4100;

where E indicates the power density at the ‘‘event’’ period

(lasting 500 ms) and R the power density at the ‘‘baseline or rest’’

period (lasting 500 ms). Negative values of event-related

percentage changes of alpha band power represented the ERD

(Pfurtscheller and Lopes da Silva, 1999; Pfurtscheller et al., 1997,

1999). On the contrary, positive values indicated the so-called

event-related synchronization (ERS; Pfurtscheller and Lopes da

Silva, 1999). The ‘‘rest’’ period was defined as the period of 500

ms before the visual warning stimulus, whereas the ‘‘event’’

period was defined as the period of 500 ms before the painful

stimulation.

Topographic mapping

Topographic maps (256 hues) of the alpha ERD/ERS were

calculated on a 3-D cortical model by a spline interpolating

function (Babiloni et al., 1995, 1996). This model is based on

the magnetic resonance data of 152 subjects digitized at Brain

Imaging Center of the Montreal Neurological Institute (SPM96,

www.mni.mcgill.ca) and is commonly considered as an

acceptable template for the rendering of group neuroimaging

data.

Statistical analysis

Statistical comparisons were performed by ANOVAs for

repeated measures. With the ANOVA analysis, Mauchly’s test

evaluated the sphericity assumption when necessary. Correction

of the degrees of freedom was made by Greenhouse–Geisser

procedure and Duncan test was used for post hoc comparisons

(P < 0.05). In total, five statistical ANOVA analyses were

performed.

According to the working hypothesis of the present study, the

following ANOVA analyses were performed. Firstly, an ANOVA

analysis tested the ‘‘distraction’’ hypothesis that subjective evalu-

ation of the painful stimulus intensity (dependent variable) was

different between Pain, Pain + Movement and Pain + Cognition

conditions. The ANOVA factor was Condition (Pain, Pain +

Movement, Pain + Cognition).

Secondly, an ANOVA analysis tested the ‘‘distraction’’

hypothesis that subjective evaluation of the painful stimulus

unpleasantness (dependent variable) was different between the

three experimental conditions. The ANOVA factor was Condition

(Pain, Pain + Movement, Pain + Cognition). Of note, instru-

mental problems prevented the estimation of the stimulus

unpleasantness in 2 out of 10 subjects. Consequently, subjective

reports of only 8 subjects were used for such a statistical

analysis.

Thirdly, 3 ANOVA analyses tested the ‘‘distraction’’ hypothesis

that amplitude of anticipatory alpha ERD (dependent variable)

presented differences among the Pain, Pain + Movement and Pain +

Cognition conditions. Namely, an ANOVA analysis for each alpha

sub-band (alpha 1, alpha 2, and alpha 3). The ANOVA factors were

Fig. 3. Across subjects mean three-dimensional color maps of alpha 1,

alpha 2 and alpha 3 event-related desynchronization/synchronization (ERD/

ERS) during the period (500 ms) preceding the painful stimulation for the

three experimental conditions (Pain, Pain + Movement, Pain + Cognition).

Color scale: maximum ERD and ERS are coded in white and violet,

respectively. The maximal % value of the ERD/ERS is reported.

C. Del Percio et al. / NeuroImage 31 (2006) 1268–12771272

Condition (Pain, Pain + Movement, Pain + Cognition) and

Electrode of interest (Fz, C3, Cz, C4, Pz).

Results

Subjective perception of stimulus intensity and unpleasantness

The ANOVA analysis for the subjective evaluation of the

painful stimulus intensity showed a main statistical effect for

Condition (F2,9 = 13.6; P < 0.001). Duncan post hoc indicated that

Table 1

Electrodes of interest (Fz, Cz, Pz, C3, C4) showing the maximum alpha ERD fo

Subject Alpha 1 Alpha 2

Pain Pain + Movement Pain + Cognition Pain Pain + Move

s1 C3 C3 C3 C3 C3

s2 Fz Pz Fz Fz Cz

s3 C3 Pz Pz Cz Pz

s4 Cz C3 Cz C3 C3

s5 Cz Cz C3 Cz Cz

s6 C3 C3 C4 C3 C3

s7 Pz Pz Fz C3 Pz

s8 Pz Cz C4 C3 C3

s9 C3 C3 Cz Cz C3

s10 Cz Fz C3 Pz Pz

The electrodes in questions were reported for the three conditions (Pain, Pain +

alpha 3).

intensity level was stronger in Pain (mean T SE = 27.7 T 4; Fig. 2)

than Pain + Movement (18.3 T 4; P < 0.05) and Pain + Cognition

(12.8 T 3; P < 0.001) conditions. Furthermore, the level of painful

stimulus was stronger in Pain + Movement than Pain + Cognition

condition (P < 0.01).

Similarly, the ANOVA analysis for the evaluation of un-

pleasantness level of the painful stimulus showed a main

statistical effect for Condition (F2,9 = 3.8; P = 0.04). Duncan

post hoc testing indicated that level of unpleasantness was

stronger in Pain (25.2 T 6; Fig. 2) than Pain + Movement

(13.9 T 3; P < 0.05) and Pain + Cognition (12.9 T 4; P < 0.05)

conditions. Therefore, the statistical results are in line with the

‘‘distraction’’ hypothesis, which predicted higher values of

subjective stimulus intensity in Pain than Pain + Movement

and Pain + Cognition conditions.

Topography of the alpha ERD/ERS

Fig. 3 shows the topographical maps of alpha 1, alpha 2, and

alpha 3 ERD/ERS during 500 ms period preceding the laser painful

stimulation. The topographical maps refer to the three experimental

conditions, i.e., Pain, Pain + Movement, and Pain + Cognition. In

general, anticipatory alpha ERD was observed at all alpha sub-

bands. For the Pain condition, the maximum anticipatory alpha

ERD (all band) was observed in central and parietal areas.

Anticipatory alpha 1 ERD was more evident at left than right

central areas. Finally, a sustained alpha 3 ERD was observed also

in medial frontal area. Compared to the Pain condition, the maps of

Pain + Movement and Pain + Cognition conditions showed a

decrease of anticipatory alpha 3 ERD and even an occurrence of

alpha 3 ERS at medial frontal and central areas.

Table 1 reports for each subject (i.e., 10 subjects) and for each

condition (i.e., Pain, Pain + Movement, and Pain + Cognition) the

electrodes of interest (Fz, Cz, Pz, C3, C4) showing the maximum

alpha ERD value.

Statistical comparison of alpha ERD/ERS among the three

conditions

There was no statistically significant differences in ERD

amplitude among the three conditions (Pain, Pain + Movement,

Pain + Cognition) as revealed by two separate ANOVA analyses

for alpha 1 and alpha 2 sub-bands (P > 0.4).

r each subject

Alpha 3

ment Pain + Cognition Pain Pain + Movement Pain + Cognition

C3 Pz C3 C3

Fz Cz C4 C3

Pz Cz C3 C4

C3 Cz C3 Pz

C3 Fz C4 C4

C4 C4 C3 C4

Cz Fz Pz C3

C4 C4 Pz C4

Fz Cz C3 Fz

C3 C4 C4 C3

Movement, Pain + Cognition) and for the three bands (alpha 1, alpha 2,

Fig. 4. Across subject means (Tstandard error) of the alpha 3 ERD/ERS

amplitudes as provided by the ANOVA design. In particular, these means

refer to a statistical interaction between the factors Condition (Pain, Pain +

Movement, Pain + Cognition) and Electrode of interest (Fz, C3, Cz, C4,

Pz). The results of the Duncan post hoc testing are indicated by one asterisk

if P < 0.05.

C. Del Percio et al. / NeuroImage 31 (2006) 1268–1277 1273

ANOVA analysis of alpha 3 ERD showed a statistically

significant interaction (F8,72 = 2.13, P = 0.04) between the factors

Condition (Pain, Pain + Movement, Pain + Cognition) and

Electrode of interest (Fz, C3, Cz, C4, Pz). Fig. 4 illustrates the

means (TSE) of alpha 3 ERD. Duncan post hoc testing indicated

that alpha 3 ERD amplitude was stronger in Pain than Pain +

Movement and Pain + Cognition conditions at Fz (P < 0.02) and

Cz (P < 0.02) electrodes. Therefore, the statistical results are in line

with the ‘‘distraction’’ hypothesis, which predicted higher ampli-

tude of anticipatory alpha ERD in Pain than Pain + Movement and

Pain + Cognition conditions.

Control analyses

A first control analysis aimed at investigating possible

hemispheric asymmetries in the activation pattern during the

expectancy. As aforementioned, the topographical mapping

showed an anticipatory alpha 1 ERD stronger in left than right

central areas. An ANOVA analysis was carried out to verify

whether such a lateralization of alpha 1 ERD was statistically

significant. The ANOVA factors were Condition (Pain, Pain +

Movement, Pain + Cognition) and Electrode of interest (C3, C4).

There was a statistical main effect for the factor Electrode of

interest (F1,9 = 1.8; P < 0.012), indicating that the alpha 1 ERD

was stronger in left (at C3 electrode site) than right central area

regardless the specific condition. This indicated that the inter-

individual variance of the alpha 1 ERD did not allow to disclose

statistically significant differences in asymmetry of the alpha 1

ERD among the experimental conditions, at least with the present

group size.

A second control analysis was aimed at verifying whether the

alpha 3 ERD for Pain condition and the alpha 3 ERS for Pain +

Movement and Pain + Cognition conditions over frontocentral

midline electrodes were true statistically significant effects, i.e.,

whether ERD/ERS was significantly different in the baseline and

expectancy periods. Three ANOVA analyses were carried out for

Pain, Pain + Movement, and Pain + Cognition conditions,

respectively. The absolute amplitude of alpha 3 power density

was used as a dependent variable. The ANOVA factors were Event

(Baseline, Expectancy) and Electrode of interest (Fz, Cz). The

ANOVA analysis for Pain condition showed a statistical main

effect for the factor Event (F1,9 = 16.5; P < 0.002) indicating that,

regardless from the electrode site (Fz and Cz), the amplitude of

alpha 3 power density was lower at expectancy than baseline

period (namely, a significant alpha ERD). The results for Pain +

Movement condition pointed to a statistical interaction between the

factors Event and Electrode of interest (F1,9 = 7.9; P < 0.02).

Duncan post hoc indicated that the amplitude of alpha 3 power

density at Fz and Cz electrode was stronger (P < 0.05) at

expectancy than baseline period (namely, a statistically significant

alpha ERS). Finally, the results of the ANOVA analysis carried out

for the Pain + Cognition condition showed no significant effects.

The lack of a statistically significant ERS in the Pain + Cognition

condition (Fz and Cz) means that from a statistical point of view,

the effect of the distraction in that condition is the cancellation of

the alpha ERD rather than the generation of a statistically

significant alpha ERS.

Discussion

Distraction reduces pain-related anticipatory alpha ERD

The results of the present study showed that, during the

expectancy of painful stimuli, alpha ERD was maximum over

contralateral primary sensorimotor cortex in all experimental

conditions, in line with previous evidence (Babiloni et al., 2003).

As a novelty, there was a cancellation of the alpha ERD when the

painful stimulation was immediately followed by cognitive

demands and even a generation of a statistically significant alpha

ERS when the painful stimulation was immediately followed by

movements. These effects were maximum over fronto-central

midline. That cancellation of anticipatory alpha ERD or generation

of alpha ERS in fronto-central midline was paralleled by a

reduction of subjective pain intensity and unpleasantness, possibly

reflecting a decline of subject’s attention to the stimulation. In line

with the common meaning of alpha ERD/ERS (Hari and Salmelin,

1997; Pfurtscheller and Lopes da Silva, 1999; Pfurtscheller et al.,

1997, 1999), the distraction from pain would be related not only to

reduced frontocentral cortical excitation (alpha ERD) but also to

increased frontocentral cortical idling (alpha ERS). The explana-

tion of alpha ERS as cortical idling is supported by the results of

previous studies using transcranial magnetic stimulations showing

that cortical excitability increases during sensorimotor events

usually inducing alpha ERD and it decreases after these events

when usually ERS replaces ERD (Chen et al., 1998, 1999). The

present alpha ERD/ERS modulation suggests a deactivation of

frontal and anterior cingulate areas as a reflection of distraction

from pain (Petrovic and Ingvar, 2002; Petrovic et al., 2000; Bantick

et al., 2002; Frankenstein et al., 2001). These results confirm the

importance of underlying anterior cingulate cortex in the evalua-

tion of biologically relevant stimuli such as painful ones

(Derbyshire et al., 1997; Price, 2000; Sawamoto et al., 2000;

Ferretti et al., 2003; Bentley et al., 2003; Valet et al., 2004) and

disclose its modulatory role in the generation of alpha rhythms

preceding painful stimuli.

The present study also extends previous findings showing

prominent high-band alpha ERD during the anticipation of

sensorimotor events (Foxe et al., 1998; Bastiaansen et al., 1999;

C. Del Percio et al. / NeuroImage 31 (2006) 1268–12771274

Pfurtscheller et al., 1999; Babiloni et al., 2003, 2004a,d) and

confirms that modulation of high-band alpha ERD tends to be more

localized at those cortical areas playing a task-specific role

(Pfurtscheller and Klimesch, 1992; Klimesch, 1999). According

to a modern view of alpha rhythms, alpha 3 ERD reflects an

opening of thalamo-cortical channel as operated by reticular

thalamic neurons (Steriade and Llinas, 1988; Bastiaansen et al.,

1999; Brunia, 1999; Pfurtscheller and Lopes da Silva, 1999).

However, a contribution of cortico-cortical functional connections

cannot be excluded.

The evaluation of pain intensity was stronger in the motor than

cognitive task. It can be speculated that during the motor task,

attention is still in part directed towards the sensorimotor channel

of the body district that receives the painful stimulation. On the

contrary, attention is mainly dismissed from the body district

stimulated with pain during cognitive information processing

(Petrovic et al., 2000).

Functional meaning of anticipatory alpha rhythm (Klimesch et

al., 1996; Klimesch, 1996, 1997, 1999) and the fact that here the

effects of distraction on alpha ERD were localized over frontal

regions suggest a top-down attentional mechanism effective during

diversion from pain (Hopfinger et al., 2001; Babiloni et al., 2004c).

Top-down attentional mechanisms sub-serve the direction of

attention and brain information processing to an upcoming

important task by means of an involvement of higher-order frontal

cortex (Miyashita, 2004). The process then would extend to

multiple prefrontal, parietal, and cingulate cortical areas (Mesulam,

1981, 1998). Such a model of attentional networks has recently

received substantial evidence by functional neuroimaging studies

(Luks et al., 2002). Taken together these data and concepts, it can

be speculated that here the sensorimotor or cognitive tasks would

interfere with frontal alpha rhythms and associated top-down

attentional processes directed towards incoming painful stimulus.

This would cause a reduction of alpha ERD and an underestimation

of pain intensity and its emotional impact (i.e., unpleasantness), in

line with previous findings (Levine et al., 1982; Suls and Fletcher,

1985; Miron et al., 1989; Arntz and de Jong, 1993). Involvement of

frontal alpha ERD during the expectancy of pain complements

previous neuroimaging evidence showing that attentional modula-

tion accompanying noxious heat pain stimuli reduced the

activation of anterior cingulate cortex (Bantick et al., 2002; Hsieh

et al., 1999; Treede et al., 1999; Schnitzler and Ploner, 2000; Porro

et al., 2002). Indeed, previous functional neuroimaging studies

have shown that cingulate areas are engaged in the anticipation of

affective/cognitive aspects of pain experience, selection of proper

viscero-sensorimotor/behavioral responses, and event memoriza-

tion (Rainville et al., 1997; Porro et al., 1998, 2002; Hsieh et al.,

1999; Ingvar, 1999; Treede et al., 1999; Ploghaus et al., 1999;

Petrovic and Ingvar, 2002; Petrovic et al., 2000; Schnitzler and

Ploner, 2000). Furthermore, it has been demonstrated that these

cortical regions are important for the control of the motor Go/

action and NoGo/inhibition together with prefrontal, and posterior

parietal areas (Bokura et al., 2001; Garavan et al., 2002, Yamanaka

et al., 2002). Finally, anterior cingulate and medial orbitofrontal

areas are up-regulated during the anticipation of an unlearned and

unpredictable painful stimulus, possibly to recruit resources for the

management of the incoming event (Hsieh et al., 1999). Of note, it

should be mentioned that distraction could impinge not only upon

the reduction of the midline alpha ERD but also upon the decrease

of the midline theta ERS. Indeed, previous studies have reported

that cognitive demands including working memory and feedback

processing modulate the midline theta rhythms as a function of the

mental workload (Gevins et al., 1997; Luu et al., 2003).

It is conceivable that distraction due to motor preparation

concomitant to pain expectancy is based on a physiological

mechanism similar to that acting during sensorimotor interactions

due to simultaneous ongoing sensory and motor events. This

mechanism would be a consequence of corollary discharge from

the acting motor area to the sensory areas, and would result in an

attenuation (gating) cortical somatosensory responses during

movements. Similar results are those found with median-nerve

somatosensory evoked potentials recorded during the movement of

the stimulated limb (Rossini et al., 1991). This effect results from

interfering influences of the motor cortex on cortical, brainstem,

and spinal somatosensory relays (centrifugal gating; Cheron and

Borenstein, 1991; Rossini et al., 1996) or from interfering effects

of somatosensory inputs (centripetal gating; Cheron and Boren-

stein, 1991; Rossini et al., 1989). These findings suggest a cortical

sensorimotor interaction between anticipatory processes related to

the encoding of the incoming painful events and motor preparation.

At first glance, the present results on sensorimotor interactions

can appear at variance with those of a previous EEG study carried

out by our group (Babiloni et al., 2005a). Indeed, in that study, an

increase rather than a decrease of anticipatory high-band alpha

ERD was found when preparatory motor activity was added to pain

expectancy. However, it should be noted that, in the previous study

(Babiloni et al., 2005a), the painful stimulus was applied to left

index finger and the movement was performed by the opposite

(right) hand. Therefore, the increase of alpha ERD during the

sensorimotor interaction implied facilitatory physiological mecha-

nisms based on inter-hemispheric callosal connections as previ-

ously described (Buchner et al., 1995; Rossini et al., 1999). At

variance, painful stimulus and movement regarded the same hand

in the present study.

Clinical implications

The present results may have implications for the understanding

of central chronic pain. It should be remarked that, at this research

stage, the link between modulation of anticipatory processes and

chronic pain is speculative and requires specific experimental

evaluation. However, there are some pieces of evidence showing

the important role of distraction or hyperattention in the attentional/

cognitive variables on chronic pain (Logan et al., 1996; Al-Obaidi

et al., 2000; Pfingsten et al., 2001) linked with appraisal of harm

(Eccleston, 1994, 1995) and/or fear of pain (Roelofs et al., 2002).

According to this view, chronic pain is maintained through

abnormal anticipatory attentional processes towards painful sensa-

tions and subsequent avoidance. In this vein, patients with chronic

pain would selectively attend to sensory aspects of nociceptive

stimuli (Dehghani et al., 2003). Furthermore, a loss of inhibition of

expectancy processes from attentional fronto-thalamic systems is

suggested by a recent study using structural magnetic resonance

imaging (Apkarian, 2004), which showed a reduction of gray

matter density in bilateral dorsolateral prefrontal cortex and right

thalamus in chronic pain patients.

Conclusions

This high-resolution EEG study tested the hypothesis that alpha

ERD before predictable painful stimulation is reduced when pain is

accompanied by motor or cognitive task, as an effect of distraction.

C. Del Percio et al. / NeuroImage 31 (2006) 1268–1277 1275

Compared to the control condition, the subjects reported a

significantly lower stimulus intensity perception and unpleasant-

ness in the Pain + Movement and Pain + Cognition conditions. In

these conditions, there was also there was a cancellation of the

alpha 3 ERD (i.e., about 10–12 Hz) in Pain + Cognition condition

and even a generation of a statistically significant alpha 3 ERS in

Pain + Movement condition. These effects were maximum over

fronto-central midline. These results suggest that distraction during

the expectancy of pain is related to a reduced neural desynchro-

nization of fronto-central midline alpha rhythms (i.e., reduced

cortical activation) towards an overt hyper-synchronization (corti-

cal idling).

Acknowledgment

This research was granted by AFaR (Associazione Fatebene-

fratelli per la Ricerca).

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