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Neurophysiologie
Clinique/Clinical
Neurophysiology
(2012)
42,
325—336
Disponible
en
ligne
sur
www.sciencedirect.com
REVIEW/MISE
AU
POINT
Cognitive
aspects
of
nociception
and
pain.
Bridging
neurophysiology
with
cognitive
psychology
Aspects
cognitifs
de
la
nociception
et
de
la
douleur.
Le
rapprochement
de
la
neurophysiologie
et
de
la
psychologie
cognitive
V.
Legraina,∗,b,c,
F.
Mancinid,e,f,
C.F.
Sambof,
D.M.
Tortag,
I.
Rongaf,h,
E.
Valentini i,j
aDepartment
of
Experimental
Clinical
and
Health
Psychology,
Ghent
University,
Henri
Dunantlaan
2,
9000
Ghent,
Belgium
bInstitute
of
Neuroscience,
Université
catholique
de
Louvain,
Louvain-la-Neuve,
Belgium
cInstitute
of
Neuroscience,
Université
catholique
de
Louvain,
Brussels,
Belgium
dInstitute
of
Cognitive
Neuroscience,
University
College
London,
London,
United
Kingdom
eDepartment
of
Psychology,
Università
degli
Studi
di
Milano-Bicocca,
Milan,
Italy
fDepartment
of
Neuroscience,
Physiology
&
Pharmacology,
University
College
London,
London,
United
Kingdom
gDepartment
of
Psychology,
Università
degli
Studi
di
Torino,
Turin,
Italy
hDepartment
of
Neuroscience,
Università
degli
Studi
di
Torino,
Turin,
Italy
iDepartment
of
Psychology,
Sapienza-Università
di
Roma,
Rome,
Italy
jFondazione
Santa
Lucia,
Istituto
di
Ricovero
e
Cura
a
Carattere
Scientifico,
Rome,
Italy
Received
25
November
2011;
accepted
25
June
2012
Available
online
20
July
2012
KEYWORDS
Nociception;
Pain;
Event-related
potentials;
Cognition;
Attention;
Executive
functions;
Body;
Space
Summary
The
event-related
brain
potentials
(ERPs)
elicited
by
nociceptive
stimuli
are
largely
influenced
by
vigilance,
emotion,
alertness,
and
attention.
Studies
that
specifically
investi-
gated
the
effects
of
cognition
on
nociceptive
ERPs
support
the
idea
that
most
of
these
ERP
components
can
be
regarded
as
the
neurophysiological
indexes
of
the
processes
underlying
detection
and
orientation
of
attention
toward
the
eliciting
stimulus.
Such
detection
is
deter-
mined
both
by
the
salience
of
the
stimulus
that
makes
it
pop
out
from
the
environmental
context
(bottom-up
capture
of
attention)
and
by
its
relevance
according
to
the
subject’s
goals
and
moti-
vation
(top-down
attentional
control).
The
fact
that
nociceptive
ERPs
are
largely
influenced
by
information
from
other
sensory
modalities
such
as
vision
and
proprioception,
as
well
as
from
motor
preparation,
suggests
that
these
ERPs
reflect
a
cortical
system
involved
in
the
detec-
tion
of
potentially
meaningful
stimuli
for
the
body,
with
the
purpose
to
respond
adequately
to
potential
threats.
In
such
a
theoretical
framework,
pain
is
seen
as
an
epiphenomenon
of
warning
∗Corresponding
author.
Tel.:
+32
92
64
91
43;
fax:
+32
92
64
64
89.
E-mail
address:
valery.legrain@ugent.be
(V.
Legrain).
0987-7053/$
–
see
front
matter
©
2012
Elsevier
Masson
SAS.
All
rights
reserved.
http://dx.doi.org/10.1016/j.neucli.2012.06.003
326
V.
Legrain
et
al.
processes,
encoded
in
multimodal
and
multiframe
representations
of
the
body,
well
suited
to
guide
defensive
actions.
The
findings
here
reviewed
highlight
that
the
ERPs
elicited
by
selective
activation
of
nociceptors
may
reflect
an
attentional
gain
apt
to
bridge
a
coherent
perception
of
salient
sensory
events
with
action
selection
processes.
©
2012
Elsevier
Masson
SAS.
All
rights
reserved.
MOTS
CLÉS
Nociception
;
Douleur
;
Potentiels
évoqués
;
Cognition
;
Attention
;
Fonctions
exécutives
;
Corps
;
Espace
Résumé
Les
potentiels
évoqués
cérébraux
(PE)
induits
par
des
stimuli
nociceptifs
sont
large-
ment
influencés
par
la
vigilance,
les
émotions,
l’attention-alerte
et
l’attention
sélective.
Les
études
ayant
spécifiquement
exploré
les
effets
de
facteurs
cognitifs
sur
les
PE
nociceptifs
sou-
tiennent
l’idée
selon
laquelle
la
plupart
des
composantes
de
ces
PE
peuvent
être
considérées
comme
les
indices
neurophysiologiques
des
processus
sous-jacents
de
détection
et
d’orientation
de
l’attention
vers
le
stimulus
évoquant.
Cette
détection
est
déterminée
par
la
saillance
du
stimulus
qui
le
rend
particulièrement
émergeant
par
rapport
au
contexte
environnemental
(cap-
ture
ascendante
de
l’attention)
et
par
sa
pertinence
par
rapport
aux
objectifs
cognitifs
et
à
la
motivation
du
sujet
(contrôle
attentionnel
descendant).
Le
fait
que
les
PE
nociceptifs
sont
largement
influencés
par
les
informations
provenant
d’autres
modalités
sensorielles
comme
la
vision
et
la
proprioception,
ainsi
que
par
la
préparation
motrice
suggère
que
ces
PE
reflè-
tent
un
système
cortical
impliqué
dans
la
détection
des
stimuli
potentiellement
significatifs
pour
l’organisme
dans
le
but
de
répondre
adéquatement
aux
menaces
éventuelles.
Dans
un
tel
cadre
théorique,
la
douleur
est
considérée
comme
un
épiphénomène
des
processus
d’alerte,
intégrés
dans
des
représentations
multimodales
et
multi-référentielles
du
corps
dont
le
but
est
de
guider
la
réalisation
des
comportements
de
défense.
Les
données
présentées
dans
cet
article
soulignent
que
les
PE
obtenus
en
réponses
à
des
stimulations
sélectives
des
nocicepteurs
peuvent
représenter
l’activité
des
mécanismes
de
contrôle
du
gain
attentionnel
permettant
de
coordonner
de
fac¸on
cohérente
la
perception
d’événements
sensoriels
saillants
et
la
sélection
de
la
réponse.
©
2012
Elsevier
Masson
SAS.
Tous
droits
réservés.
Introduction
Since
the
first
recordings
of
computer-averaged
event-
related
potentials
(ERPs)
and
event-related
magnetic
fields
(ERFs),
these
techniques
were
proposed
as
suitable
methods
to
investigate
human
cognition
[98,109],
i.e.
the
cortical
operations
‘‘by
which
the
sensory
input
is
transformed,
reduced,
elaborated,
stored,
recovered,
and
used’’
[77].
When
for
the
first
time
Carmon
et
al.
[12]
obtained
ERPs
in
response
to
selective
activation
of
nociceptive
A␦-
and
C-
fibres
by
laser
radiant
thermal
stimulation,
they
noticed
that
the
nociceptive
ERPs
were
less
sensitive
to
variations
of
the
physical
parameters
of
the
stimulation
than
to
variations
of
the
subject’s
perception.
As
a
matter
of
fact,
later
studies
showed
that
nociceptive
ERPs
are
largely
modified
by
vigi-
lance
[3,6,83],
emotional
state
[19,21],
alertness
[69],
and,
even
more,
by
the
attention
given
to
the
stimulus
[63].
The
first
generation
of
studies
were
mostly
designed
to
investi-
gate
the
influence
of
these
factors
in
order
to
control
them
and
to
establish
a
reliable
ERP
recording
protocol
to
be
used
in
clinical
settings
[63].
Indeed,
the
primary
interest
was
to
use
nociceptive-specific
ERPs
to
assess
dysfunction
of
the
nociceptive
pathways
[103].
Therefore,
these
studies
aimed
to
dissociate
the
so-called
exogenous
components
of
the
nociceptive
ERPs
(supposed
to
reflect
the
selective
and
spe-
cific
processing
of
the
sensory
inputs)
from
the
endogeneous
ERP
components
(thought
to
reflect
undesired
psychological
reactions
of
the
patients).
By
contrast,
the
last
decade
of
research
tackled
the
issue
of
how
nociceptive
ERPs
are
mod-
ulated
by
cognitive
factors,
fostering
the
understanding
of
those
processes
underlying
detection,
analysis,
and
reaction
to
the
nociceptive
event,
i.e.
those
processes
underlying
the
interpretation
of
a
nociceptive
stimulus
as
a
sensory
event
able
to
induce
physical
harm
to
the
body.
Data
from
this
new
course
have
been
determinant
in
changing
the
under-
standing
of
the
functional
significance
of
cortical
processes
reflected
by
the
nociceptive
ERPs.
This
article
attempts
to
provide
a
synopsis
of
the
lit-
erature
relative
to
the
cognitive
modulations
of
the
ERPs
elicited
by
nociceptive
and
painful
stimuli.1After
a
short
review
of
the
first
generation
of
studies
(first
paragraph;
[63]),
a
more
in-depth
discussion
will
deal
with
the
role
of
cognitive
factors
underlying
the
detection
and
the
reaction
to
sensory
stimuli
perceived
as
potential
bodily
threats.
Directing
vs.
distracting
attention
It
is
largely
admitted
that
paying
attention
to
a
nociceptive
stimulus
makes
it
more
painful.
On
the
contrary,
focus-
ing
attention
either
on
another
perceptual
object
or
on
another
task
reduces
pain
[107].
The
studies
that
have
explored
the
influence
of
attention
on
the
nociceptive
ERPs
were
mostly
inspired
by
the
theoretical
framework
pro-
posed
by
the
limited-capacity
models
of
human
cognition
[9]
and
adapted
to
pain
research
by,
for
example,
Leven-
thal
and
Everhart
[60],
and
McCaul
and
Malott
[65].
These
authors
proposed
that
sensory
inputs
—
including
nociceptive
1In
this
paper,
the
term
‘‘nociceptive’’
is
used
to
describe
stimuli
that
selectively
activate
the
nociceptive
system,
while
the
term
‘‘painful’’
is
used
to
describe
stimuli
that
elicit
a
perception
of
pain,
regardless
of
the
selectivity
of
the
eliciting
inputs.
Cognitive
aspects
of
nociception
and
pain
327
ones
—
may
exceed
processing
capacity,
and
hence
require
attention
to
give
priority
to
some
inputs
over
others.
Therefore
directing
the
subject’s
attention
away
from
the
nociceptive
stimuli
would
decrease
the
amount
of
atten-
tional
resources
allocated
to
process
the
nociceptive
inputs
and
thus
reduce
the
resulting
pain.
Based
on
these
models,
authors
built
paradigms
in
which
nociceptive
stimuli
were
intermixed
with
stimuli
from
another
sensory
modality
and
the
partici-
pants
were
instructed
either
to
attend
the
nociceptive
stimuli
by
performing
a
task
(e.g.
counting
them
all
[38,67,75,82,83,106,110]
or
some
of
them
[93],
rating
their
intensity
[6,22],
or
even
attending
the
stimuli
without
any
specific
instruction
[35,111,112]),
or
to
distract
their
atten-
tion
from
the
nociceptive
stimuli
by
performing
a
task
on
stimuli
from
another
modality
(e.g.
arithmetic
calculation
[6,22,82,83,106,111—113],
reading
a
book
[93],
performing
an
oddball
auditory
task
[38],
a
word
puzzle
[67]
or
a
memory
test
[35]).
Sometimes,
in
the
distraction
condition,
participants
were
simply
asked
to
ignore
the
nociceptive
stimuli
without
any
control
procedure
[93,110].
The
most
recurrent
result
of
these
studies
(except
[82])
was
a
reduc-
tion
of
the
magnitude
of
the
vertex
positivity
of
the
ERPs
(i.e.
P2),
which
is
supposed
to
mainly
reflect
the
activity
of
the
anterior
cingulate
cortex
(ACC)
[37],
when
attention
was
directed
to
the
pain-unrelated
task.
This
was
the
case
both
in
studies
that
used
nociceptive-specific
stimuli
deli-
vered
by
laser
heat
stimulator
[6,35,38,83,93,106,112,113]
and
studies
that
used
non-specific
electrocutaneous
stimuli
whose
intensity
was
rated
as
painful
[22,67,111].
This
P2
amplitude
reduction
was
accompanied
by
a
reduction
of
pain
rating,
measured
after
each
stimulation
block
[35,38,82]
or
after
the
experiment
[67],
except
in
the
study
by
Zaslansky
et
al.
[113]
who
did
not
find
any
modulation
of
pain
rating.
While
the
late
N2
component
was
also
often
found
to
be
modulated
by
attention
[6,38,112],
results
were
less
consistent
regarding
the
early
N1
component
and
its
magneto-encephalographic
counterpart
(mN1),
reflec-
ting
the
earliest
cortical
processing
in
the
somatosensory
cortices
[37,104].
At
first
glance,
N1/mN1
was
not
found
to
be
modulated
by
attention
[38,106,111,112].
These
results
were
interpreted
as
evidence
that
the
early
N1
reflected
sensory
processing
impervious
to
cognitive
modulation,
whereas
the
late
P2
reflected
perceptual
processing
under
the
influence
of
attention.
Therefore,
it
was
proposed
that
N1
was
more
suited
for
clinical
examination
than
P2.
However,
these
conclusions
were
rapidly
challenged
by
studies
that
found
a
clear
modulation
of
the
earliest
ERP
and
ERF
components
with
similar
paradigms
[75,110]
or
with
paradigms
in
which
the
spatial
location
of
the
stimuli
on
the
body
was
manipulated
[5,54,91]
(see
[8,45]
for
conflicting
results).
This
strongly
supports
the
conclusions
of
neuroimaging
studies
[11,81,92]
that
almost
all
cortical
areas
processing
nociceptive
inputs
may
have
their
activity
modulated
as
a
function
of
the
attention
directed
to
the
stimulus
[78],
in
keeping
with
what
has
been
reported
in
other
sensory
modalities
[40,74,84,88].
Based
on
the
results
of
the
above-reviewed
studies,
standard
stimulation
protocols
were
proposed
to
assess
noci-
ceptive
processing
by
controlling
the
level
of
attention
given
to
the
stimuli
[103].
However,
the
paradigms
were
built
in
such
a
way
that
it
was
difficult
to
disentangle
the
effects
due
to
the
intrinsic
attentional
modulation
of
nociceptive
cortical
responses
from
the
effects
due
to
over-
lapping
unspecific
brain
activities.
For
instance,
standard
paradigms
required
the
subjects
to
count
or
to
rate
the
nociceptive/painful
stimuli
delivered
at
a
slow
rate.
Noci-
ceptive
ERPs
recorded
in
such
conditions,
especially
the
P2,
could
therefore
be
contaminated
by
unspecific
ERP
components
such
as
the
P300/P3b
related
to
decision
mak-
ing
[4,39,43,44,48,54,55,79,93,102,113].
Similarly,
the
slow
rate
of
stimulation
facilitated
the
generation
of
ERP
com-
ponents
related
to
attentional
orientation
such
as
the
P3a
[48,54].
Bottom-up
capture
of
attention
According
to
modern
theories
of
attention,
sensory
inputs
compete
to
be
represented
in
the
neural
system
[20,46].
Attention
operates
by
biasing
the
processing
and
by
select-
ing
the
most
appropriate
information
for
the
ongoing
behavioural
and
cognitive
goals
in
order
to
guarantee
cohe-
rent
sensory-motor
processing
and
to
avoid
the
interfer-
ence
of
irrelevant
distracters.
Such
an
attentional
selection
implies
choices
that
should
be
made
in
order
to
voluntarily
control
the
information
flow
(top-down
control).
Neverthe-
less,
attention
can
also
be
captured
by
sensory
stimuli,
independently
of
voluntary
control,
when
these
are
salient
enough
to
impose
their
own
processing
priority
[29,46].
The
salience
of
a
stimulus
refers
to
its
physical
distinctiveness
and
its
ability
to
stand
out
against
other
sensory
stimuli
[29].
This
property
confers
to
a
stimulus
more
ability
to
cap-
ture
attention.
Therefore,
the
bottom-up
selection
involves
a
shift
of
attention
from
its
current
focus
to
another
one,
so
as
to
adapt
behaviour
to
contextual
constraints,
such
as
the
sudden
occurrence
of
a
potentially
damaging
stimulus
[56].
The
ability
of
painful
stimuli
to
involuntarily
capture
attention
was
already
observed
in
behavioural
studies
show-
ing
performance
deterioration
in
auditory
discrimination
tasks
when
the
task
was
performed
in
the
presence
of
task-
irrelevant
painful
stimuli,
resulting
from
a
shift
of
attention
from
the
auditory
target
towards
the
painful
distracter
[15].
Noteworthy,
the
ability
of
stimuli
to
capture
attention
does
not
depend
on
their
painfulness,
and,
more
generally,
on
their
sensory
modality,
but
rather
on
the
contextual
rela-
tionship
between
co-occurring
stimuli
(i.e.
their
salience)
and
on
the
relative
importance
of
each
sensory
event
for
the
subject’s
goals
(i.e.
their
relevance;
see
next
section)
[56].
Novelty
is
an
important
determinant
to
stimulus
salience:
sensory
events
that
are
presented
for
the
first
time
or
infrequent
events
that
differ
from
recent
past
events
are
highly
distracting,
i.e.
they
are
more
susceptible
to
cap-
ture
attention
from
its
focus
and
disrupt
other
ongoing
cognitive
activities
[33].
To
investigate
the
effect
of
nov-
elty
on
nociceptive
ERPs,
Legrain
et
al.
[57]
presented
their
participants
with
series
of
visual
stimuli,
each
of
them
pre-
ceded
by
a
nociceptive
laser
stimulus.
Participants
were
instructed
to
perform
a
task
on
the
visual
stimuli
while
the
nociceptive
stimuli
were
presented
as
irrelevant
dis-
tracters.
During
most
of
the
trials,
nociceptive
stimuli
were
delivered
on
a
specific
area
of
the
hand
(standard
trials).
328
V.
Legrain
et
al.
Occasionally
and
unexpectedly,
the
position
of
the
laser
beam
was
shifted
to
another
area
of
the
hand.
During
these
novel
trials,
the
reaction
times
to
the
visual
targets
were
slower
compared
to
trials
in
which
nociceptive
stimuli
were
regularly
presented
on
the
same
hand
area.
This
suggests
that
nociceptive
distracters
captured
the
attention
more
when
they
were
novel
than
when
they
were
familiar.
Inte-
restingly,
novel
nociceptive
stimuli
elicited
ERPs
of
larger
amplitude
than
those
elicited
by
standard
nociceptive
stim-
uli,
despite
the
fact
that
stimuli
from
the
two
conditions
had
exactly
the
same
energy.
Similar
increases
in
ERP
mag-
nitude
associated
with
stimulus
novelty
were
observed
when
the
location
of
the
nociceptive
stimuli
was
occasionally
shifted
from
one
hand
to
the
other
[48]
or
when
their
inten-
sity
was
occasionally
changed
[49,54,55],
suggesting
that
modification
of
the
ERP
waveform
was
not
conditioned
by
the
physical
dimension
in
which
the
change
took
place,
but
rather
by
the
fact
that
the
stimulus
was
detected
as
deviant.
In
Dowman’s
experiments,
painful
electrical
stimuli
of
different
intensities
were
delivered
on
the
right
vs.
left
sural
nerve,
and,
before
each
trial,
the
most
likely
spatial
location
of
the
forthcoming
stimulus
was
cued
[23,25].
In
other
experiments,
somatosensory
stimuli
were
intermixed
with
visual
stimuli,
and
the
most
likely
modality
of
the
forthcoming
stimulus
was
pre-cued
[24].
Occasionally,
in
a
small
proportion
of
trials,
the
target
stimulus
was
invalidly
cued:
it
appeared
at
the
wrong
location,
or
belonged
to
the
wrong
modality.
In
these
invalid
infrequent
conditions,
sti-
muli
elicited
ERPs
with
greater
amplitude,
despite
the
fact
that
these
stimuli
were
unattended.
Dowman
[25]
inter-
preted
these
modifications
of
ERP
amplitude
as
reflecting
the
activity
of
neural
threat
detectors,
while
other
authors
argued
that
such
modifications
are
not
dependent
on
the
threat
value
and
on
the
sensory
modality
of
the
eliciting
stimulus
[56,57,73].
These
studies
showed
that
significant
ERP
modula-
tions
may
take
place
when
a
change
occurs
occasionally,
even
unattended,
in
the
stream
of
sensory
events.
Other
experiments
reported
similar
ERP
modulations
when
the
nociceptive
stimulus
is
absolutely
new
(i.e.
presented
after
a
long
break).
Indeed,
by
administrating
trains
of
three
con-
secutive
laser
stimuli
of
identical
intensity
at
a
constant
inter-stimulus
time
interval,
the
largest
ERP
amplitude
was
observed
for
the
very
first
stimulus
of
the
trains,
while
the
magnitude
of
the
ERPs
evoked
by
the
second
and
third
sti-
muli
was
reduced,
without
any
significant
reduction
of
pain
perception
[42].
This
magnitude
modulation
concerned
all
ERP
components,
including
the
early
N1.
In
successive
expe-
riments,
the
same
group
tested
the
influence
of
changes
introduced
within
the
trains
(bottom-up
modulation),
and
controlled
for
the
role
of
the
participants’
prior
knowledge
of
these
changes
(top-down
modulation)
[101,105].
In
these
experiments,
while
the
second
stimulus
was
a
repetition
of
the
first
one,
the
third
stimulus
could
either
belong
to
a
dif-
ferent
modality
(e.g.
a
nociceptive
stimulus
following
two
auditory
stimuli)
[105],
or
be
delivered
on
a
different
body
location
[101].
While
the
spatial
change
produced
rather
small
effects,
the
introduction
of
a
change
of
modality
pro-
duced
a
ERP
dishabituation,
i.e.
a
significant
increase
of
ERP
magnitude
for
a
mismatching
third
stimulus,
as
com-
pared
with
ERPs
elicited
by
the
third
stimuli
preceded
by
identical
stimuli.
Such
dishabituation
was
observed
regard-
less
of
top-down
expectations.
Altogether,
these
data
show
that
nociceptive
laser
stimuli
and
painful
electrical
stimuli
elicit
ERPs
of
larger
ampli-
tude
when
they
are
novel,
i.e.
when
they
are
delivered
for
the
first
time
and
after
a
long
break
or
when
they
represent
a
change
relatively
to
preceding
sensory
events.
The
fact
that
these
modifications
were
observed
even
when
nociceptive
stimuli
were
completely
irrelevant
for
the
task
and
when
attention
was
initially
directed
to
another
body
location
or
to
a
stimulus
of
a
different
sensory
modality
[49,54,57]
suggests
that
stimulus
novelty
boosted
cortical
processing
of
nociceptive
and
painful
stimuli
irrespective
of
top-down
factors
such
as
the
expectation
of
the
occurrence
of
the
change
[101,105].
However,
it
does
not
mean
that
these
modifications
reflect
mechanisms
completely
inde-
pendent
from
voluntary
control.
Indeed,
both
task-relevant
and
task-irrelevant
novel
stimuli
evoke
ERPs
of
large
ampli-
tude,
but
this
effect
is
larger
when
the
novel
stimulus
is
the
target
of
the
task
[54]
(Fig.
1)
and
when
the
primary
visual
task
requires
a
minimal
level
of
attention
resources
to
allow
attentional
shifting
to
the
nociceptive
distracters
[49].
Therefore,
ERP
components
such
as
the
P2
would
reflect
the
actual
engagement
of
attention
to
the
stimulus,
instead
of
a
pure
automatic
detection
of
novelty
[57].
As
the
effect
of
novelty
on
N1
and
N2
amplitude
was
less
recurrently
observed
[49,57,105],
further
studies
are
mandatory
to
elu-
cidate
the
effect
of
the
bottom-up
capture
of
attention
on
early-latency
nociceptive
ERPs.
Interestingly,
the
modulation
of
the
P2
amplitude
induced
by
novel
nociceptive
stimuli
is
highly
similar
to
the
modu-
lation
observed
for
ERPs
evoked
by
auditory,
visual
and
tactile
stimuli
(i.e.
P3a)
[33].
These
data
further
support
the
notion
of
a
multimodal
salience
detection
system
that
involves,
among
others,
brain
structures
such
as
the
insular
and
cingulate
cortices
[26,27].
This
multimodal
nature
of
the
nociceptive
ERPs
cannot
be
interpreted
as
direct
index
of
the
subjective
experience
of
pain
[56,73].
Top-down
control
of
attention
and
executive
functions
As
pain
can
be
modified
by
attention
[107],
the
manipulation
of
attention
represents
a
potentially
efficient
therapeutic
strategy
in
the
clinical
management
of
pain
[70].
More-
over,
it
is
also
hypothesized
that
attention
is
involved
in
the
persistence
of
pain
symptoms
[18].
However,
clinical
psy-
chologists
might
wonder
how
to
help
patients
to
voluntarily
control
their
attention
to
pain
as
painful
stimuli
are
highly
susceptible
to
capture
attention
involuntarily.
As
mentioned
in
the
previous
section,
attention
modifies
sensory
process-
ing
for
the
purpose
of
achieving
ongoing
cognitive
goals
or
satisfying
high-order
motivational
drives,
defining
the
relevance
of
the
stimulus,
and
inhibits
interference
from
distracters.
Recently,
three
factors
were
proposed
as
gua-
rantors
of
an
efficient
attentional
control
over
pain
stim-
uli
[53,58].
First,
attention
should
be
engaged
in
the
processing
of
stimuli
that
are
largely
unrelated
to
pain
and,
more
broadly,
to
somatosensation.
This
hypothe-
sis
originates
from
the
notion
of
attentional
set
that
defines
a
mental
set
of
information
corresponding
to
Cognitive
aspects
of
nociception
and
pain
329
Figure
1
Bottom-up
attentional
effects
on
the
nociceptive
ERPs.
Graphs
illustrate
ERPs
recorded
in
different
sessions
in
response
to
laser
stimulus
of
the
same
intensity,
but
with
different
probabilities
of
occurrence.
Laser
stimuli
were
delivered
either
in
regular
and
standard
series
of
stimulation
(green,
80%
of
trials),
or
in
series
of
mismatching
novel
stimulation
(i.e.
their
intensity
was
different
than
the
standard
stimuli
delivered
in
the
same
block,
blue,
20%
of
trials).
The
stimulated
hand
was
either
attended
(left
panel,
red
solid
box),
or
unattended
(right
panel,
orange
dashed
box).
In
the
former
case
the
novel
stimuli
were
the
targets
of
the
task,
in
the
latter
case
the
novel
stimuli
were
non-target
stimuli
with
the
same
physical
properties
and
the
same
probability
of
occurrence
than
the
targets.
Amplitude
of
the
P2
component,
elicited
at
the
vertex
(see
topographical
maps,
all
conditions
merged),
was
larger
in
response
to
novel
stimuli
than
in
response
to
standard
stimuli,
both
on
the
attended
hand
and
unattended
hand.
However,
the
difference
due
to
stimulus
novelty
was
larger
on
the
attended
than
on
the
unattended
hand.
Also
note
that
the
presence
of
a
parietal
P3
component
(or
P300/P3b)
was
significantly
observed
only
in
response
to
the
novel
stimuli
on
the
attended
hand
(i.e.
the
targets)
(the
map
in
this
time-window
illustrates
only
the
topography
of
the
ERPs
elicited
by
the
rare
targets).
This
suggests
that
the
participants
only
responded
to
the
rare
targets,
and
not
to
rare
non-targets.
As
a
consequence
the
magnitude
increase
for
the
P2
was
indeed
related
to
novelty-detection
processes
and
partially
independent
from
the
voluntary
decision
to
detect
the
targets. Adapted
from
[54].
the
stimulus
features
the
subject
needs
to
identify
in
order
to
perform
a
task
[34].
Thus,
the
more
segre-
gated
is
the
competing
sensory
information
with
respect
to
the
ongoing
pain
the
better
will
be
the
control
over
pain.
Second,
the
engagement
of
attention
should
be
effortful
[1].
The
more
attentional
resources
are
loaded
on
the
achievement
of
a
particular
cognitive
acti-
vity,
the
less
they
are
available
to
process
the
distracters
(attentional
load)
[47].
Finally,
the
engagement
of
attention
toward
pain-unrelated
information
should
be
controlled
by
executive
functions
that
guarantee
the
full
achievement
of
cognitive
goals
[66]
and
inhibit
the
intrusion
of
distracters
[68].
One
important
consequence
of
the
concept
of
atten-
tional
set
is
that
stimuli,
which
share
common
features
with
the
relevant
target,
even
if
task-irrelevant,
will
cap-
ture
attention
more
easily.
This
could
explain
why
people
who
are
hyper-responsive
to
body-related
information
are
more
easily
distracted
by
somatosensory
stimuli
[16,17].
In
an
ERP
experiment,
during
laser
stimulation
randomly
delivered
on
the
two
hands,
participants
were
instructed
to
identify
target
stimuli
delivered
on
a
specific
hand.
All
the
stimuli
delivered
on
the
relevant
hand
elicited
ERPs
of
larger
amplitude,
irrespective
of
whether
these
were
tar-
gets
or
non-targets
of
the
task,
as
compared
to
the
ERPs
elicited
by
similar
stimuli
delivered
when
the
opposite
hand
was
relevant
[54]
(Fig.
2).
It
was
thereby
proposed
that
nociceptive
processing
was
biased
by
cognitive
goals
hav-
ing
set,
in
the
present
case,
the
spatial
location
of
the
sti-
muli
as
a
relevant
feature
for
the
task.
Since
the
amplitude
modulation
also
affected
the
N1
component,
these
biases
could
affect
the
very
early
stage
of
cortical
processing,
as
shown
in
other
sensory
modalities
[40,84].
More
interest-
ingly,
it
was
shown
that
the
novelty
effect
on
the
P2
(i.e.
330
V.
Legrain
et
al.
Figure
2
Top-down
attentional
effects
on
the
nociceptive
ERPs.
Laser
stimuli
were
delivered
randomly
on
the
dorsum
of
the
two
hands.
Participants
were
instructed
to
attend
to
the
stimuli
delivered
on
one
hand
and
to
detect
occasional
changes
of
stimulus
intensity
(i.e.
targets),
while
ignoring
all
the
stimuli
delivered
on
the
other
hand.
Graphs
illustrate
the
ERPs
elicited
by
attended
and
unattended
non-targets
stimuli.
The
left
panel
represents
the
ERPs
recorded
over
the
left
hemisphere
in
response
to
right
hand
stimulation,
the
right
panel
the
ERPs
recorded
over
the
right
hemisphere
in
response
to
left
hand
stimulation.
Topographical
maps
illustrate
ERPs
in
the
time-window
of
the
N1
and
N2
components
(all
‘‘attention’’
conditions
merged).
Nociceptive
stimuli
of
the
right
hand
elicited
ERPs
of
larger
amplitude
when
the
right
hand
was
attended
(red)
than
when
the
left
hand
was
attended
(blue).
Similarly,
left
hand
stimuli
elicited
ERPs
of
larger
amplitude
when
the
left
hand
was
attended
(blue)
than
when
the
right
hand
was
attended
(red).
This
modulation
was
observed
as
early
as
during
the
latency
of
the
first
laser-evoked
component,
i.e.
N1.
Adapted
from
[54].
the
magnitude
increase
observed
in
response
to
occasional
stimulus
change)
was
larger
for
novel
stimuli
delivered
to
the
attended
hand
(i.e.
the
target
of
the
tasks)
than
for
novel
irrelevant
stimuli
with
similar
physical
properties
but
delivered
to
the
unattended
hand
(Fig.
1).
This
finding
sup-
ports
the
idea
that
the
bottom-up
effect
induced
by
stimulus
novelty
was
under
the
control
of
the
attentional
set.
The
role
of
attentional
load
was
investigated
in
an
ERP
experiment
in
which
nociceptive
stimuli
of
the
same
inten-
sity
were
delivered
either
in
regular
and
homogenous
series
or
as
novel
stimuli
in
series
containing
regular
stimuli
of
lower
intensity
[49].
When
the
participants
were
instructed
to
perform
a
low-demanding
visual
task,
novel
nociceptive
stimuli
elicited
ERPs
(N2
and
P2)
of
larger
amplitude.
In
addition,
reaction
times
to
visual
targets
were
slower
if
the
nociceptive
stimulation
series
contained
the
novel
stimuli.
But
when
the
visual
task
required
a
higher
load
of
attentional
resources,
the
novelty
effect
on
P2
magnitude
(i.e.
the
dif-
ference
between
the
P2
evoked
by
novel
stimuli
and
the
P2
evoked
by
regular
stimuli)
was
reduced.
These
results
were
complemented
by
neuroimaging
studies
showing
a
signifi-
cant
reduction
of
metabolic
activity
in
response
to
painful
stimuli
when
the
participants
performed
high-demanding
pain-unrelated
tasks
[2,7,92].
However,
it
is
important
to
note
that
increasing
the
attentional
load
on
the
visual
task
was
not
sufficient
to
reduce
the
disruptive
effect:
reac-
tion
times
remained
slower
during
the
stimulation
series
with
novel
nociceptive
stimuli,
and
participants
made
more
errors
[49].
This
suggests
that
an
experimental
design
which
establishes
an
attentional
set
unrelated
to
pain
(or
to
bodily
information)
does
not
fully
prevent
involuntary
attentional
shift
as
well
as
distraction
from
salient
irrelevant
stimuli
to
take
place.
Therefore,
it
was
proposed
that
an
efficient
attentional
control
over
nociception
and
pain
should
also
involve
exec-
utive
functions.
For
instance,
working
memory
might
help
guiding
attention
to
goal-relevant
information
[94],
by
main-
taining
active
the
attentional
set
during
the
achievement
of
cognitive
goals,
and
by
shielding
goal-relevant
information
from
interference.
The
role
of
working
memory
in
the
atten-
tional
control
of
nociception
was
recently
tested
[51—53].
Participants
were
asked
to
perform
a
task
on
visual
stimuli,
Cognitive
aspects
of
nociception
and
pain
331
each
of
them
being
shortly
preceded
by
a
somatosensory
distracter.
Distracters
were
non-painful
median-nerve
elec-
trical
stimuli
occasionally
replaced
by
nociceptive
laser
stimuli.
Because
of
the
novelty
of
the
nociceptive
distracter,
reaction
times
were
longer
in
response
to
visual
targets
preceded
by
a
nociceptive
distracter
than
in
response
to
similar
targets
preceded
by
a
standard
tactile
distracter.
However,
when
participants
were
asked
to
rehearse
in
work-
ing
memory
some
features
of
the
visual
targets
from
trial
to
trial,
the
disruption
was
reduced:
there
was
no
difference
between
visual
targets
coupled
with
novel
distracters
and
visual
targets
with
standard
somatosensory
distracters
[53],
regardless
of
the
attentional
overload
generated
by
the
task
[51].
In
addition,
the
magnitude
of
the
N1
and
N2
ERPs
was
reduced
during
the
working
memory
condition,
suggesting
a
control
by
working
memory
over
early
cortical
processing
of
nociceptive
inputs
[52].
Surprisingly,
the
P2
magnitude
was
reduced
only
during
a
working
memory
task
consisting
in
delaying
the
response
to
a
target
to
the
next
trial.
Because
this
task
is
thought
to
manipulate
the
representation
of
the
response
associated
to
the
target
stimulus,
it
was
therefore
hypothesized
that
the
modulation
of
the
nociceptive-evoked
P2
would
reflect
attentional
processing
associated
with
the
selection
of
the
motor
response
(see
last
paragraph).
Con-
versely,
P2
amplitude
was
not
affected
by
the
instruction
to
rehearse
in
working
memory
the
sensory
features
of
the
visual
target.
Multimodal
interaction
and
spatial
representations
of
the
body
The
studies
described
above
provide
converging
evidence
that
the
cortical
processing
of
a
nociceptive
stimulus,
as
sampled
with
classic
neurophysiological
and
neuroimaging
techniques,2is
strongly
determined
by
the
salience
and
the
relevance
of
the
stimulus.
Therefore,
it
was
proposed
that
ERPs
elicited
by
nociceptive
stimuli
mainly
reflect
corti-
cal
processes
involved
in
the
orientation
of
attention
when
the
stimulus
is
sufficiently
distinctive
to
receive
priority
processing
over
other
sensory
inputs
[56].
This
hypothe-
sis
has
received
strong
support
from
studies
demonstrating
that
ERPs
elicited
by
nociceptive
and
painful
stimuli
are
not
specifically
related
to
the
perception
of
pain
[42]
but
represent
a
pattern
of
cortical
activities
that
can
also
be
generated
by
stimuli
from
other
sensory
modalities
[73].
Therefore,
the
nociceptive
ERPs
could
reflect
the
activities
of
a
cortical
network
involved
in
an
important
but
non-
specific
function
of
pain:
that
of
detecting
salient
sensory
events
and
prompting
the
appropriate
response.
Because
salient
stimuli
can
represent
events
with
significant
impact
2It
is
important
to
emphasise
that
the
claim
according
to
which
the
cortical
activity
elicited
by
a
nociceptive
stimuli
does
not
reflect
the
perception
of
pain
[42,56,73]
is
not
meant
to
dismiss
the
exis-
tence
of
any
cortical
activity
specifically
involved
in
the
generation
of
pain.
Nevertheless,
there
is
converging
evidence
that
such
an
activity
is
not
accessible
to
classic
methodologies
used
to
record
and
analyse
brain
activity
[56].
This
evidence
calls
for
developing
novel
methods
to
characterise
the
cortical
activity
elicited
by
a
nociceptive
stimulus
and
its
relationship
to
the
perception
of
pain
[14,114].
on
the
organism
in
terms
of
adaptation,
it
was
proposed
that
this
network
could
be
particularly
important
to
process
significant
sensory
stimuli
for
the
physical
integrity
of
the
body
[56].
In
other
words,
nociceptive
ERPs
would
reflect
the
activity
of
a
cortical
system
that
could
be
used
as
a
defen-
sive
mechanism
to
detect,
localize,
and
react
to
physical
threat,
whatever
the
modality
of
the
threatening
stimulus.
An
efficient
localization
of
external
sensory
events
involves
the
ability
of
the
brain
to
represent
space
according
to
different
frames
of
reference
[13].
In
addition,
it
is
known
that
the
brain
can
construct
coherent
spatial
representa-
tions
of
the
body
and
of
the
surrounding
space
by
integrating
information
from
different
sources,
i.e.
somatosensory,
pro-
prioceptive,
vestibular,
visual
[95].
The
role
of
multimodal
representations
of
the
body
and
the
peripersonal
space
is
well
documented
by
studies
investigating
tactile
processing,
including
ERP
studies
[88].
Indeed,
it
has
been
consistently
shown
that
viewing
the
stimulated
body
part
or
visual
cues
close
to
the
stimulated
body
part
enhances
the
magnitude
of
the
ERPs
induced
by
tactile
stimulation
of
that
body
part
[30,31,89,99],
and
that
such
a
modulation
is
also
influenced
by
body
posture
[32].
These
studies
have
shown
that
the
influence
of
vision
on
tactile
processing
depends
on
the
close
spatial
proximity
between
the
visual
stimulus
and
the
tactile
stimulation
of
the
body
[87].
Although
multimodal
integration
of
nociception
with
stimuli
from
the
other
sensory
modalities
has
received
less
attention,
there
is
some
evidence
that
nociceptive
pro-
cessing
is
largely
modulated
by
vision
and
proprioception.
This
claim
is
supported
by
clinical
neuropsychological
stud-
ies.
For
instance,
Hoogenraad
et
al.
[41]
reported
a
case
of
a
neglect
patient
with
a
right
parietal
lesion
who
suf-
fered
from
hemianesthesia
for
both
nociception
and
touch,
which
manifested
specifically
when
the
stimulus
was
applied
while
the
patient
had
his
eyes
closed.
In
contrast,
when
the
patient
had
his
eyes
open
and
saw
the
sensory
test-
ing
tool
approaching
his
contralesional
limb,
he
reported
a
sensation
of
burning
pain
in
the
arm.
In
addition,
it
was
shown
that
patients
suffering
from
complex
regional
pain
syndrome
(CRPS)
tend
to
neglect
their
affected
limb
[50].
More
importantly,
their
neglect-like
symptoms
are
influ-
enced
by
the
vision
of
the
limbs
[72]
and
by
the
posture
[71],
thus
suggesting
that
neglect
symptoms
of
CRPS
do
not
depend
on
a
purely
somatotopic
representation
of
pain
[50,71].
Intriguingly,
when
CRPS
patients
were
asked
to
indi-
cate
in
the
dark
what
they
estimated
to
be
the
midline
of
their
body,
they
neglected
the
opposite
side
of
space,
i.e.
the
side
corresponding
to
the
location
of
the
healthy
limb
[96,97].
When
the
visual
field
of
the
patients
was
shifted
by
prismatic
glasses
toward
the
hemispace
corre-
sponding
to
the
unaffected
limb,
CRPS
symptoms,
including
neglect-like
symptoms
and
pain,
were
alleviated
[10,96].
In
healthy
participants,
an
ERP
study
showed
a
significant
influence
of
viewing
the
stimulated
hand
on
the
magnitude
of
laser-evoked
potentials
[61].
Participants
were
looking
directly
at
their
stimulated
hand
or
an
image
of
that
hand
manipulated
through
a
mirror
illusion
[85].
In
this
latter
condition,
the
stimulated
hand
was
placed
behind
a
mirror
aligned
with
the
participant’s
sagittal
plane
and
the
illu-
sion
of
seeing
that
hand
was
created
while
the
participant
was
actually
seeing
the
mirror-reflected
image
of
the
oppo-
site
hand.
This
illusion
was
created
in
order
to
disambiguate
332
V.
Legrain
et
al.
Figure
3
Modulation
of
hand
blink
reflex
by
hand
position.
Blink
reflex
was
elicited
by
intense
electrical
stimulation
of
the
median
nerve
at
the
wrist,
and
electromyographic
activity
was
recorded
from
the
orbicularis
oculi
muscle
(hand
blink
reflex
or
HBR).
HBR
was
induced
when
the
stimulated
hand
was
near
to
the
face
(red
lines)
vs.
far
from
the
face
(blue
lines).
The
hand
was
positioned
ipsilaterally
(solid
lines)
vs.
contralaterally
(dashed
lines)
to
the
recording
sites.
The
HBR
had
a
significantly
greater
magnitude
when
the
stimulated
hand
was
near
to
the
face
than
when
it
was
far,
and
when
the
stimulated
hand
was
ipsilateral
than
contralateral
to
the
eye
over
which
the
HBR
was
recorded.
This
shows
that
brainstem
activities
mediating
defensive
reflexes
can
receive
top-down
modulation
in
order
to
respond
adequately
to
external
potential
threats
with
respects
to
the
position
of
the
body
parts.
Adapted
from
[90].
whether
the
effect
was
driven
by
viewing
one’s
own
hand
or
the
threatening
stimulus
on
the
hand
(i.e.
the
laser
beam).
As
compared
to
control
conditions
in
which
the
stimulated
hand
was
out
of
sight
and
masked
by
a
neutral
object,
or
the
participants
were
looking
at
the
experimenter’s
hand,
laser
stimuli
were
rated
as
less
intense
and
evoked
ERPs
of
smaller
amplitude
when
the
participants
looked
at
their
own
stimulated
hand.
Similarly,
Mancini
et
al.
[64]
showed
that
viewing
one’s
own
hand
increases
pain
threshold,
in
comparison
to
viewing
an
object
in
the
same
location.
They
demonstrated
that
the
visual
appearance
of
the
hand
fur-
ther
modulates
pain
perception.
The
participants’
hand
was
observed
through
a
distorting
mirror
so
that
the
size
of
the
visual
image
appeared
magnified
or
minified.
Enlarging
the
visual
image
of
the
hand
enhanced
the
reduction
of
pain,
while
reducing
the
visual
image
of
the
hand
decreased
the
reduction
of
pain.
The
results
from
the
two
latter
studies
[61,64]
are
surprising
as,
based
on
the
known
mechanisms
of
spatial
attention,
one
should
expect
that
looking
at
the
hand
would
direct
spatial
attention
in
a
cross-modal
way
to
that
location
[30],
which
would
amplify
nociceptive
pro-
cessing
[54],
and
therefore
increase
pain
[108].
In
contrast,
it
was
proposed
that
the
reduction
of
pain
by
viewing
the
body
could
be
mediated
by
an
integration
of
the
body
part
in
pain
within
a
stable
representation
of
the
body
[62].
Noteworthy
is
that
the
reverse
pattern
was
observed
in
CRPS
patients
[72],
perhaps
due
to
specific
aspects
of
CRPS
pathophysiology.
Regarding
the
influence
of
proprioception,
Gallace
et
al.
[36]
showed
a
modulatory
effect
of
hand
posture
on
nociceptive
ERPs.
Non-nociceptive
electrocutaneous
and
nociceptive
laser
stimuli
were
applied
distinctly
on
one
of
the
hands,
while
the
vision
of
the
hands
was
precluded
by
a
screen.
Participants
were
tested
with
the
hands
in
a
canonical
posture
vs.
in
a
crossed
posture
(relatively
to
the
sagittal
midline
of
the
trunk).
Both
the
perceived
intensity
and
the
magnitude
of
the
evoked
ERPs
(N2/P2,
but
not
N1)
were
reduced
for
stimuli
applied
during
the
crossed
pos-
ture
relative
to
the
canonical
posture.
Finally,
a
recent
study
provided
compelling
evidence
that
body
posture
modulates
not
only
the
cortical
processing
but
also
the
subcortical
activity
elicited
by
electrocutaneous
stimulation.
Sambo
et
al.
[90]
showed
that
the
proximity
of
the
hand
to
the
face,
which
was
manipulated
both
by
changing
the
position
of
the
hand
and
by
rotating
the
head,
modulated
the
excitability
of
the
brainstem
circuits
mediating
the
blink
reflex
elicited
by
intense
electrical
stimulation
of
the
median
nerve
at
the
wrist.
That
is,
when
the
hand
entered
the
proximal
space
surrounding
the
face,
the
electromyographic
corre-
late
of
the
blink
reflex
elicited
by
the
stimulation
of
the
hand
showed
an
earlier
onset,
longer
duration,
and
greater
amplitude
(Fig.
3).
This
suggests
that
multimodal
areas
responsible
for
remapping
the
location
of
somatosensory
stimuli
according
to
the
current
body
posture
exert
a
tonic
modulation
of
the
brainstem
circuits
of
the
hand-elicited
blink
reflex.
From
sensory
processing
to
action
The
P2
wave
elicited
by
nociceptive
stimuli
is
reduced
when
the
participants
have
to
keep
in
working
memory
the
representation
of
the
response
associated
to
a
concurrent
visual
target,
but
not
when
it
involves
the
rehearsal
of
the
sensory
features
of
that
visual
target
[52].
Other
authors
showed
that
the
delivery
of
laser
stimuli
during
the
prepa-
ration
of
a
motor
response
to
a
visual
stimulus
elicited
ERPs
of
weaker
amplitude
if
the
laser
stimuli
were
ipsilat-
eral
to
the
prepared
hand
movement
[59].
These
findings
may
hint
to
interpret
the
P2
wave
as
reflecting
processes
related
to
the
selection
of
motor
responses.
This
hypothesis
finds
supporting
evidence
in
the
identification
of
the
mid-
section
of
the
cingulate
cortex
as
the
main
generator
of
P2
[37],
an
area
involved
in
motor
processing
[28,100].
Primary
motor
and
supplementary
motor
areas
were
also
proposed
as
potential
generators
of
the
nociceptive
ERPs
[80].
There-
Cognitive
aspects
of
nociception
and
pain
333
fore,
one
might
hypothesize
that
the
P2
generators
(or
at
least
part
of
them)
could
reflect
the
selection
and
the
preparation
of
the
appropriate
action
in
response
to
the
most
salient
stimulus
in
the
environment.
However,
to
date,
most
of
the
electrophysiological
studies
that
directly
inves-
tigated
the
relationship
between
nociception
and
motor
function
tested
the
effect
of
movements
on
the
nocicep-
tive
ERPs
with
the
aim
to
understand
the
neurophysiological
mechanisms
underlying
the
analgesic
effect
of
motor
cor-
tex
stimulation
(e.g.
[76]).
Thus,
further
investigation
on
the
role
of
the
P2
vertex
positivity
as
an
index
of
corti-
cal
processes
related
to
action
preparation
and
selection
is
needed.
Conclusion
This
review
supports
the
idea
that
classic
ERPs
elicited
by
nociceptive
stimuli
represent
the
cortical
activity
related
to
an
important
but
non-specific
function
of
pain:
to
detect
and
react
against
stimuli
that
are
potentially
significant
for
the
physical
integrity
of
the
body.
In
such
theoretical
frame-
work,
these
cortical
responses
could
represent
the
joined
activity
of
three
major
processes.
The
first
process
detects
and
orients
attention
selectively
to
the
most
salient
sen-
sory
event
in
order
to
prioritize
its
processing.
The
salience
of
a
stimulus
is
defined
by
its
physical
properties
making
it
contextually
conspicuous
with
respect
to
other
surround-
ing
stimuli.
But
it
can
be
modulated
by
the
relevance
of
the
stimuli
in
relation
to
the
subject’s
cognitive
goals,
on
the
effort
exerted
to
achieve
these
goals
and
on
the
exec-
utive
control
over
interference
between
competing
sensory
inputs.
The
second
process
is
involved
in
the
spatial
local-
ization
of
the
stimulus
using
spatial
frames
of
reference
that
integrate
the
stimulus
in
global
and
multimodal
representa-
tions
of
the
body
and
the
proximal
space.
The
third
process
reflects
cognitive
operations
apt
to
bridge
a
coherent
per-
ception
of
salient
sensory
events
with
action
selection
in
order
to
prepare
and
trigger
the
most
appropriate
motor
response
to
the
stimulus.
Such
perspective
provides
support
to,
and
is
in
turn
supported
by,
clinical
applications.
Indeed,
the
therapeu-
tic
potential
to
alleviate
pain
experience
in
chronic
pain
patients
[10,96],
as
shown
by
the
mirror
box
[85]
and
the
prism
adaptation
technique
[86],
is
largely
grounded
on
the
notion
of
a
multimodal
representation
of
the
body.
These
clinical
studies,
in
addition
to
the
ERP
stud-
ies
reviewed
here,
support
the
idea
of
a
close
interplay
between
the
processing
of
sensory
inputs
arising
from
multi-
ple
sources
and
cognitive
functions
ranging
from
attentional
capture
to
action
selection.
This
highlights
the
potential
synergy
between
medical
intervention
and
neuropsyholog-
ical
rehabilitation
for
the
treatment
of
pain
and
other
sensory-motor
deficits
associated
with
chronic
pain
diseases
[50].
Disclosure
of
interest
The
authors
declare
that
they
have
no
conflicts
of
interest
concerning
this
article.
Acknowledgements
Valéry
Legrain
is
supported
by
the
Research
Foundation
Flan-
ders
(FWO),
Belgium.
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