Neurophysiologie Clinique/Clinical Neurophysiology (2012) 42, 187—197

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REVIEW/MISE AU POINT

Objective pain diagnostics: Clinical neurophysiology

Diagnostic objectif de la douleur : neurophysiologie clinique

L. Garcia-Larrea ∗

Inserm U1028, Central Integration of Pain Unit, Centre for Neuroscience of Lyon, University Claude-Bernard Lyon, University
Hospital Pain Center (CETD), Neurological Hospital, 69003 Lyon, France

Received 17 February 2012; accepted 4 March 2012

Available online 30 March 2012

KEYWORDS Summary Neurophysiological techniques help in diagnosis, prognosis and treatment of chronic
Pain; pain, and are particularly useful to determine its neuropathic origin. According to current stan-
Chronic pain; dards, the diagnosis of definite neuropathic pain (NP) needs objective confirmation of a lesion
Neuropathic pain; or disease of somatosensory systems, which can be provided by neurophysiological testing.
Evoked potentials; Lesions causing NP mostly concern the pain-temperature pathways, and therefore neurophysi-
Diagnosis; ological procedures allowing the specific testing of these pathways (i.e., A-delta and C-fibres,
Therapy; spino-thalamo-cortical tracts) are essential for objective diagnosis. Different techniques to
Human stimulate selectively pain-temperature pathways are discussed. Of these, laser-evoked poten-
tials (LEPs) appear as the easiest and most reliable neurophysiological method of assessing
nociceptive function, and their coupling with autonomic responses (e.g., galvanic skin response)
and psychophysics (quantitative sensory testing - QST) can still enhance their diagnostic yield.
Neurophysiological techniques not exploring specifically nociception, such as standard nerve
conduction velocities (NCV) and SEPs to non-noxious stimulation, should be associated to the
exploration of nociceptive systems, not only because both may be simultaneously affected
to different degrees, but also because some specific painful symptoms, such as paroxysmal
discharges, may depend on specific alteration of highly myelinated A-beta fibres. The choice
of techniques is determined after anamnesis and clinical exam, and tries to answer a num-
ber of questions: (a) is the pain-related to injury of somatosensory pathways?; (b) to what
extent are different subsystems affected?; (c) are mechanisms and lesion site in accordance
with imaging data?; (d) are results of use for diagnostic or therapeutic follow-up? Neuropathic
pain (NP) affects more than 15 million people in Western countries, and its belated diagnosis
leads to insufficient or delayed therapy. The use of neurofunctional approaches to obtain a
‘‘physiological photograph’’ of somatosensory function is therefore highly relevant, as it yields
significant clues about the type and mechanisms of pain, thus prompting rapid and optimised
therapy.
© 2012 Elsevier Masson SAS. All rights reserved.

∗ Hôpital neurologique, 59, boulevard Pinel, 69003 Lyon, France. Tel.: +33 4 72 35 78 88.
E-mail address: luis.larrea@univ-lyon1.fr

0987-7053/$ – see front matter © 2012 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.neucli.2012.03.001
188 L. Garcia-Larrea

Résumé Les techniques de neurophysiologie aident au diagnostic, à l’établissement d’un

MOTS CLÉS
pronostic et au traitement de la douleur chronique. Les critères actuels pour affirmer le diagnos-
Douleur ; tic de douleur neuropathique (DN) nécessitent la confirmation objective d’une lésion ou d’une
Douleur chronique ; maladie des systèmes somesthésiques : l’exploration neurophysiologique permet d’obtenir cette
Diagnostic ; confirmation. Les lésions responsables des DN concernent essentiellement les voies de la
Douleur douleur et de la température ; l’évaluation de ces systèmes (fibres de petit calibre A-delta
neuropathique et C en périphérie, système spino-thalamocortical au niveau central) est par conséquent essen-
tielle pour le diagnostic objectif. Différentes méthodes pour activer sélectivement les voies
thermo-algiques sont discutées dans cet article ; parmi elles, les potentiels évoqués par laser
(PEL) apparaissent comme la technique la plus simple et fiable d’évaluer la fonction thermo-
nociceptive. Son efficacité diagnostique est augmentée par le couplage avec les réponses
végétatives (e.g., cutanées sympathiques) et les réponses psychophysiques (analyse sensorielle
quantitative, ASQ). L’exploration des voies nociceptives doit être associée aux techniques stan-
dard explorant les fibres de gros calibre et le système lemniscal, l’électroneurographie (ENG)
et les PES à la stimulation non douloureuse et ce non seulement parce que les deux systèmes
peuvent être atteints à des degrés différents, mais également parce que certains symptômes
douloureux, en particulier les décharges paroxystiques, peuvent dépendre d’une altération
sélective des fibres de gros calibre A-beta. L’objectif de l’exploration devrait permettre de
répondre aux questions: (a) la douleur est-elle liée à une atteinte des voies somesthésiques ?
(b) si oui, quel est le degré d’altération des différents sous-systèmes ? ; (c) les mécanismes
et la topographie des lésions sont-ils en accord avec l’imagerie ? et (d) les résultats seront-ils
utiles au suivi thérapeutique ? La douleur neuropathique atteint plus de 15 millions de personnes
dans les pays industrialisés et son diagnostic différé conduit à des délais et/ou des échecs du
traitement. L’obtention d’une « photographie neurophysiologique » est hautement pertinente
dès lors qu’elle fournit des indices sur le type et les mécanismes de la douleur, permettant ainsi
l’instauration rapide d’une thérapie appropriée.
© 2012 Elsevier Masson SAS. Tous droits réservés.

Introduction and general considerations
This article aims to provide a concise approach to the neu-
rophysiological assessment of the chronic pain patient, and
addresses the questions ‘‘why, when and how to do it’’.
Electrophysiological approaches give access to the study
of ‘‘normal’’ (‘‘physiological’’) pain and its mechanisms
of transmission, perception, and cortical control, but also
to the assessment of abnormal chronic pain — essentially
of neuropathic origin. In the latter case, electrophysiology
uniquely contributes to diagnosis, and helps respond to one
most frequently asked clinical question, namely ‘‘is this a
real neuropathic pain?’’ In a number of cases, neurophysi-
ological studies may also provide information of prognostic
value for the development, or the evolution, of NP. Lastly,
electrophysiological techniques may be also useful to guide
therapeutic procedures, either by predicting their efficacy
or inefficacy, or by minimising the chances of pain devel-
opment through real-time neurophysiological monitoring,
for instance during potentially nerve-injuring surgery. The
goal of neurophysiological pain assessment will be in general
terms to support, clarify, and quantify the patient’s subjec-
tive report, and in some cases to contradict such report if it
appears incompatible with the objective neurophysiological
data.
Pain by excess of nociception (‘‘nociceptive pain’’) is
transmitted by an intact nervous system following stimula-
tion of nociceptors, while the so-called ‘‘neuropathic pain’’
(NP), is transmitted by an altered or diseased somatosensory
system. The classical definition of NP was for long a pain
caused by ‘‘lesion or dysfunction of the nervous system’’.
As the term ‘‘dysfunction’’ is imprecise and a source of mis-
understanding, a proposal of change was launched by the
Special Interest Group on NP from the International Asso-
ciation for the Study of Pain (IASP), which suggested to
restrict the definition of NP to pain ‘‘arising as a direct
consequence of a lesion or disease of the somatosensory sys-
tems’’ [66]. This definition is the one we shall be following
here.
A first-line observation is that neuro-imaging data,
including functional imaging, have proved so far insufficient
to predict, or even to establish, whether a given patient
suffers or is susceptible to develop NP. Thus, while lateral
medullary lesions (Wallenberg’s syndrome) can induce NP
in 25—50% of cases [47,58], whether or not a given patient
will develop pain after this type of lesion cannot be cur-
rently established based on CT-, MRI or angiographic data.
Because of the lack of a specific diagnostic tool for NP, a
grading system of ‘‘definite’’, ‘‘probable’’, and ‘‘possible’’
NP was recently proposed [66], whereby the diagnostic of
‘‘definite neuropathic pain’’ can be considered only in the
presence of:
• a neuroanatomically plausible distribution of pain;
• a history suggestive of somatosensory lesion/disease;
• at least one objective confirmatory test of the existence
of relevant somatosensory lesion or disease.
Neurophysiological testing can provide such confirma-
tory test. The main available neurophysiological techniques
are, first, those of the standard electrophysiological exam-
ination: electroneurography with nerve conduction velocity
Objective pain diagnostics: Clinical neurophysiology
studies (NCV) and standard somatosensory evoked potentials
to electrical stimulation of large fibres (SEPs). Both tech-
niques essentially explore non-nociceptive pathways: large
myelinated (A␤) fibres in the periphery, and the dorsal col-
umn — medial lemniscus system at central level. Techniques
to explore specifically the nociceptive system (fibres A␦
and C in the periphery, the spinothalamic system at central
level) are nociceptive flexion reflexes (‘‘RIII reflexes’’) and
evoked potentials to radiant or contact-heat (laser-evoked
potentials, LEPs, or contact-heat evoked potentials, CHEPs).
Other techniques such as microneurography, which allows
investigating either large or thin fibres by introducing a nee-
dle within the nerve itself [61], are also important, but not
currently of clinical use and will not be dealt within this arti-
cle. Neither will be treated neurophysiological techniques
such as transcranial magnetic (TMS) or direct current (tDCS)
cortical stimulation, which may have therapeutic value in
NP, but are not used as diagnostic tools.
Standard investigations: electroneurography
and somatosensory evoked potentials
Considerable evidence has accumulated showing that NP
is most especially associated with lesions of temperature
and pain pathways, either peripheral [52,70], spinal [17]
or supraspinal [5,6,30], while the involvement of the large
fibres-dorsal-column-lemniscal system is not crucial for most
cases of NP. Inasmuch as standard nerve conduction studies
or SEPs do not explore the pain and temperature systems,
but rather the non-nociceptive pathways, we might consider
that their importance for the study of NP patients is very
limited. However, the study of NCV/SEPs remains of con-
siderable importance in the evaluation of pain patients, for
several reasons. First, large and thin peripheral fibres are
anatomically mixed in nerves, plexuses and spinal roots,
without spatial segregation up to the dorsal root entry
zone (DREZ, [62]), and therefore peripheral lesions, in par-
ticular traumatic or metabolic, tend to affect large and
thin fibres indistinctly. Mixed impairment of large and thin
fibres in peripheral nerves can be used to detect impend-
ing lesions during intraoperative monitoring. For instance, in
patients undergoing thoracotomy, non-specific nerve lesions
assessed by SEPs were correlated with the postoperative
development of NP, which could be prevented by using
muscle-sparing thoracotomy [4]. Second, NCV and SEP stud-
ies are readily available in most hospitals, provide robust
and topographically precise data, and their abnormality to
stimulation of a painful territory is objective evidence of
somatosensory involvement — thus giving support to the
diagnosis of NP. In this domain, one important localising sign
is given by the proximal or distal location of the somatosen-
sory lesion relative to the dorsal root ganglia. A proximal
lesion (between the ganglion and the spinal cord) allows
axonal flux to remain normal in the peripheral portion of
the corresponding nerves, distal to the ganglion, and there-
fore action potentials and peripheral nerve conduction are
preserved when such nerves are stimulated, despite pro-
found hypaesthesia. Conversely, lesions that are distal to
dorsal root ganglia (neuropathies or plexopathies) reduce
distal axonal flux and considerably alter NCV studies. This
may have important consequences, both diagnostic and
189
therapeutic, as illustrated by the distinction between plexus
and root lesion in Fig. 1.
Besides the high probability of mixed lesions in periphe-
ral trauma, some specific features of NP, in particular parox-
ysmal pain, might be specifically linked to a functional
impairment of large A␤ fibres, probably demyelination, and
therefore can be associated with abnormalities in standard
NCV and SEPs [68,69]. Association between paroxysmal pain
and large fibre dysfunction is also supported by pain in
trigeminal neuralgia, linked to segmental demyelination at
the root-brainstem entry zone, and by the ‘‘Lhermitte’s
sign’’, closely associated with demyelination of spinal dor-
sal columns. The assessment of dorsal column function by
SEPs has significant predictive value as to the efficacy or fai-
lure of spinal cord stimulation (SCS) [63]. Indeed, abnormal
or absent SEPs at central level (abnormal central conduc-
tion time) indicate degeneration of dorsal column pathways,
the activity of which appears essential for SCS efficacy [32].
Preoperative assessment of dorsal column function would
be for some authors more effective and have a lower rate
of false positive results than the classical percutaneous
test that is usually performed before definitive implanta-
tion [63]. Last but not least, in patients with central lesions
the respective contribution of spinothalamic and lemniscal
system abnormalities might play a role in the development
and characteristics of central pain [53,74].
Given the above considerations, and the fact that stan-
dard NCV and SEP studies are readily obtainable in most
neurophysiological departments, it follows that a standard
neurophysiological assessment with NVC/SEPs should remain
a first-line approach in case of suspected NP, before (or in
parallel to) more selective examinations of the pain and
temperature pathways.
Specific assessment of nociceptive pathways
Nociceptive reflexes
Spinal nociceptive reflexes are polysynaptic flexor responses
specifically related to nociception. These are obtained by
peripheral stimulation of a sensory nerve, in general the
sural nerve at the ankle or the cutaneous superficial radial
branch at the wrist, and recording the withdrawal motor
response over a flexor muscle of same metameric level. The
label ‘‘RIII reflex’’ comes from the fact that, under certain
conditions, the afferent branch of this reflex is formed by
‘‘type III’’ fibres of Lloyd classification (corresponding to
A␦ fibres in Gasser and Erlanger’s nomenclature) [20,36]. In
practice, nociceptive reflexes are most commonly obtained
on the lower limbs, applying trains of electrical shocks to
the sural nerve and recording surface EMG over the ipsila-
teral biceps femoris muscle [59]. Nociceptive flexor reflexes
can also be recorded in upper limbs, stimulating the median,
ulnar or radial nerve, and recording the EMG over forearm
muscles such as the flexor carpi ulnaris or radialis. How-
ever, the abundance of non-nociceptive reflexes in the upper
limbs (reflexes linked to motor control) makes it difficult
the individualisation of purely nociceptive components, con-
trary to lower limbs. The clinical use of nociceptive flexor
reflexes relies on the concordance between the threshold
of the reflex and that of a subjective painful sensation,
190 L. Garcia-Larrea

Figure 1 Somatosensory evoked potentials (SEPs) to non-painful stimulation of median nerves in a patient presenting with pain
and dysesthesiae in the right arm, involving the radial aspect of the forearm with non-systematised root distribution, following
a car accident. Plexus responses distal to ganglion are normal bilaterally (upper traces) while responses from dorsal horn and
caudal brainstem (2nd and 3rd rows) are attenuated and delayed to right median-nerve stimulation. Cortical responses (bottom
line), albeit bilaterally present, are also delayed after right median-nerve stimulation. These results show axonal loss and abnormal
transmission time between spinal ganglion and the spinal cord with a C6-C7 level on the right side. Although standard SEPs only
reflect conduction in large non-nociceptive fibres, these results demonstrate impairment of dorsal roots and/or the dorsal root
entry zone over a territory consistent with pain distribution, and therefore substantiate the diagnosis of neuropathic pain.

first demonstrated by Hugon [36] and Willer et al. [75].
Thus, when a given stimulation is able to trigger a segmen-
tal nociceptive reflex in normal individuals, it is commonly
also able to activate the ascending nociceptive pathways
and generate a subjective sensation of pain, and this allows
characterising states of hyper- or hypo-algesia as well as
studying possible dissociations between reflex responses and
subjective pain [59]. However, it should be underlined that
nociceptive reflexes are polysynaptic responses, which are
highly sensitive to descending, inhibitory or facilitatory,
controls; attention and distraction can drastically modify
response characteristics, so that very strict conditions of
sustained attention are mandatory when these responses are
used for clinical purposes.
Despite its theoretical advantages, the RIII reflex has
been so far little used as a diagnostic tool [59]. This
response can be useful in the diagnosis of small-fibre neu-
ropathy; indeed, the coexistence of normal standard NCV
and preserved sensory thresholds to low-intensity stimuli,
but increased pain thresholds and attenuated or abolished
nociceptive reflexes is a signature of this condition. Also,
the recording of both RIII reflexes and concomitant pain
sensations in response to low-intensity stimuli is an objec-
tive sign of allodynia, while dissociation between preserved
reflexes but abolished pain sensation suggest a spinothala-
mic lesion rostral to the spinal level of reflex integration
[24]. The RIII reflex has also been used as a criterion of
‘‘quality control’’ testing the efficacy of spinal or motor
cortex stimulation, whereby attenuation of the RIII reflex
during these procedures has been shown to be associ-
ated with a good clinical efficacy at short, and perhaps
middle-term [23,26]. The possible predictive value of this
phenomenon in the long-term has not, however, yet been
determined.
Nociceptive evoked potentials
Given the significant link between the involvement of
pain/temperature pathways and the development of NP, it is
logical that much energy has been devoted in past years to
develop stimulation procedures aiming at obtaining a selec-
tive activation of thin fibres (A␦ and C) in the periphery and
spino-thalamo-cortical pain systems at central level. The
next sections summarises this.
Noxious electrical stimuli
Transcutaneous electrical stimulation at pain threshold is
efficient to get nociceptive spinal reflexes, as the effer-
ent reflex branch is specifically triggered when nociceptive
afferents are activated (see above). Conversely, such stimuli
are clearly inadequate to obtain cortical responses reflect-
ing specifically the pain/temperature ascending volleys.
Indeed, whenever an electrical stimulus reaches painful lev-
els, it stimulates concomitantly large and small periphe-
ral afferents, but the resulting cortical potentials are
largely dominated by the non-nociceptive signals [16]. This
Objective pain diagnostics: Clinical neurophysiology 191

Figure 2 Laser-evoked potentials (LEPs) in a patient with neuropathic pain after brachial plexus avulsion. Abnormal LEPs after
stimulation of the painful dermatome (C6). Stimulation of the contiguous, affected but non-painful dermatome (C5), as well as
that of the contralateral side, yielded normal LEPs. The figure illustrates both the ability of LEPs to detect A␦-fibre impairment in a
single radicular territory, and the association of such impairment to the development of neuropathic pain (modified from ref. [14]).

phenomenon has been labelled the ‘‘first come, first
served’’ principle. It stipulates that when several groups of
fibres of different conduction velocities reach the cortex
sequentially, cortical responses tend to reflect preferen-
tially those arriving first [29,67]. This principle entails
that, in order to get evoked potentials that are spe-
cific to nociceptive input, such input should be devoid of
any contamination by large non-nociceptive fibres. Elec-
trical stimulation of special organs exclusively innervated
by small fibres, such as the tooth pulp, yields scalp
responses that, at least theoretically, are specific to noci-
ception, and whose amplitude correlates positively with
the pain sensation [21,33]. The main drawbacks of these
methods are technical difficulty, confinement to just one
territory, and the fact that the tooth pulp may also
contain some A␤ fibres [12], perhaps explaining why ‘‘pre-
pain’’ sensations other than pinprick may be obtained
with such stimulation [2]. Experimental blocks of large
peripheral fibres by direct current can provide a selec-
tive nociceptive input [48,76]. Although this method is
certainly useful, it is not appropriate for clinical appli-
cation, as the large fibre blocks are only effective on
exposed nerves. Compression blocks are time-consuming
and restricted to few territories, mostly the superficial
radial nerve at the wrist. Intraneural microstimulation [64]
is a powerful technique to stimulate selectively small-
diameter afferents. However, its technical difficulties,
together with the duration of the test and its unpleasant
character, make this procedure hardly applicable in pain
patients, and mainly restricted to experimental settings
[61].
Intracutaneous stimulations were described as early as
1984 to activate preferentially thin epidermal afferents
[8]. However, current spread of such stimulations most
probably entails the simultaneous activation of A␦ fibres,
which makes the stimulation non-selective. This is indeed
suggested by the very short-latency of scalp potentials
recorded with this method, which may be as low as 30—40 ms
[35]. Inui and co-workers [38] introduced a new method
of intra-epidermal electrical stimulation using the tip of
a stainless steel needle inserted 0.2 mm in the epidermis.
This intra-epidermal technique did not produce any scalp
response earlier than 100 ms, and estimated conduction
velocity of the activated fibres was about 15 m/s, thus con-
sistent with selective A␦ stimulation. However, recent data
suggested that such selectiveness may disappear for sti-
mulus intensities approaching nociceptive ranges [51], thus
limiting possible clinical application of the technique. The
same criticism holds true for the ‘‘planar concentric elec-
trode’’, whish has also been recently described [42,43]:
despite its clever design, this electrode also significantly co-
activates large A␤ fibres [18], and failed to detect proven
lesions of pain pathways [56].
Responses to contact-heat (CHEPs)
Standard thermodes such as those used in functional ima-
ging studies do not allow temperature changes rapid enough
to evoke EPs (review in [55]). New generations of fast-
acting heat foil thermodes permit temperature rise times
up to 70 ◦ C per second and can evoke cortical responses
[11,40]. Rapid thermode heating generally evokes a pinprick
sensation, and CHEPs have therefore been attributed to A␦
fibre stimulation, although CHEP latencies are delayed by
200—300 ms relative to the A␦ EPs obtained using laser pulses
192 L. Garcia-Larrea

Figure 3 This 65-year woman underwent a minor head trauma (temporal concussion, no loss of consciousness) and a CT-scan
performed in the emergency room was considered normal at supratentorial level. Four weeks later, she developed burning pain in
the right upper limb, which was not considered neuropathic despite a new CT-scan that showed an asymmetry at midbrain level (June
2006). Standard SEPs were normal. While malingering was being seriously considered, laser-evoked potentials (LEPs) demonstrated
significant abnormalities of conduction in pain-temperature pathways after stimulation of the painful right hand (bottom left) and
remained normal to stimulation of the non-painful side (top left). A gradient-echo (T2*) MRI showed a hyposignal image in the
posterior left midbrain, suggesting a haemorrhagic sequel. This small midbrain lesion impinged with spinothalamic conduction and
was responsible of the neuropathic pain.

[40]. Such differences suggest that the peripheral afferent
CHEP volley is triggered relatively late during the heating
ramp; accordingly, single thalamic units appear to respond
up to 300 ms after the maximal thermode temperature has
been reached [57]. The precise moment of afferent-fibre
activation during the thermode heating ramp is hard to
establish, as it may change from one individual to another,
and from one trial to the following; this may explain the
variability reported in the CHEP latencies from different
laboratories (see [10] vs. [11] vs. [40]). With further refine-
ments, the CHEP technique may become a useful tool to
study pain-related responses, as the technique appears safe
and is applicable over most body territories. Substantial
work is however needed to standardise techniques, estab-
lish the nature of the stimulated fibres, explain the sources
of latency variability, and determine the possible influence
of mechanoreceptor activation by the contact probe [31].
Last but not least, methods should be devised to keep
constant the energy transfer, which depends on the pres-
sure of a flat thermode against cutaneous surfaces that are
rarely flat.
Responses to radiant heat stimulation:
laser-evoked potentials (LEPs)
Most of the difficulties inherent to electrical or contact-
heat stimuli, described above, can be circumvented using
radiant heat stimulation with laser pulses. Laser beams pro-
vide a rapid, synchronous and selective activation of A␦
and C- thermosensitive nociceptors in the hairy skin, with-
out any concomitant activation of mechano-receptors and
A␤ fibres. Although other sources of thermal stimulation
such as light bulbs or Xenon lamps also permit selective
activation of thermo-receptors, they cannot ensure their
synchronous activation, and therefore are hardly useful for
recording neurophysiological responses. Furthermore, con-
ventional heat sources mainly emit in the visible spectral
range, where skin energy absorption is poor and widely
affected by changes in skin pigmentation, thus making
the control of heat transfer virtually impossible (review
in [55]). Most if not all of these problems are avoided by
using monochromatic high-intensity light sources such as
those provided by laser stimulators, of which gas (CO2 )
Objective pain diagnostics: Clinical neurophysiology 193

Figure 4 Post-thoracotomy neuropathic pain with selective abnormality of laser-evoked responses to stimulation of C-fibres. In
the upper part of the figure, standard laser stimulation using high energy laser pulses with small spot size (Nd:YAP; 80 mJ/mm2,
4 mm spot) yields normal and symmetrical responses from the painful and non-affected territories. In the lower panel, selective
stimulation of C-warmth fibres using lower energy densities and a larger spot size (30 mJ/mm2, 20 mm spot diameter) yielded
significantly attenuated C-LEPs (left) and sympathetic skin responses (right) to stimulation of the painful region exclusively. Please
note that the time bases are different for A␦ and C-fibre responses.

and solid-state (Th:YAG/Nd:YAP) laser stimulators are the
most commonly used. Solid-state lasers beams are easily
transported via optic fibres, rendering manipulation of the
stimulation much easier than with CO2 lasers, and allowing
stimulating virtually any body territory.
Energy density of infrared laser pulses increases local
temperature with a ramp up to 10 000 ◦ C/sec, which allows
rapid and synchronised activation of free nerve endings of A␦
and C-fibres, and thus recording of LEPs. Depending on the
ramp and the temperature achieved, either both A␦ and C-
fibres, or the latter alone can be activated. Inconveniences
linked to this type of stimulation are the need of strict
laboratory conditions, the possibility of skin lesions due to
manipulation errors (extremely rare with solid-state lasers).
Besides, a common drawback to all nociceptive EPs, as
compared with standard (A␤) SEPs, is the fact that only corti-
cal responses can be recorded satisfactorily. Indeed, the low
number of stimuli delivered, together with the lack of spa-
tial summation and the high time-dispersion of A␦ afferent
volleys in thin fibres, render the recording of peripheral or
spinal potentials almost inaccessible. Both source modelling
and intracranial recordings have permitted to determine
the main cortical origin of LEPs recorded within the first
400 milliseconds following nociceptive laser stimulation.
The earliest responses (scalp N1/P1 or N160/P160) reflect
activation of the operculo-insulair cortex (SII and poste-
rior insula) in the suprasylvian region, with a simultaneous
and weak contribution of the first somatosensory areas. The
‘‘vertex complex’’, or ‘‘N2/P2’’, which has been the most
frequently used in the clinics, reflects a combined activa-
tion of the middle cingulate and bilateral insulae, with some
contribution of parietal and prefrontal regions [22,28,72].
It is important to note here that the positive component of
the vertex complex, or ‘‘P2’’, is a mixed wave loaded with
late cognitive components, the amplitude of which may vary
widely with attention, vigilance and other cognitive factors
[3,25,45,46]. Thus, for clinical purposes it is advisable to
rely, whenever possible, on early responses N1 and N2, which
are less subject to cognitive modulation [25,46].
Although laser stimulation activates simultaneously A␦
and C-fibres, the cortical responses that are obtained with
standard techniques reflect almost exclusively the A␦ com-
ponent of the afferent volley. Selective excitation of the
C-fibre component is however possible by a diversity of
procedures. The earliest methods described were based on
experimental pressure-block of group A fibres [9] or spec-
tral analysis of the expected time windows [1]. Since then,
a number of easier techniques have been proposed, such
as the stimulation of tiny skin areas [7,54], selection of
single trials devoid of A␦-LEPs [65] or stimulation at low
intensity [13,49,67]. Each of these procedures is based on
different physiological principles. The use of tiny stimula-
tion surfaces (0.15—0.30 mm2 ) for the selective activation
of C-fibres takes advantage of the higher density of C — with
194
respect to A␦ receptors (review in [55]), while the use of
low stimulus intensities (below the A␦ activation threshold)
stands on the fact that the heat threshold is lower in C than
in A␦ nociceptors. Purely warm sensations related to C-fibre
activation can be evoked by laser pulses that irradiate a
large skin area (50—200 mm2 ), and this appears the easi-
est technique so far to obtain C-evoked cortical potentials
[13,37,67]. ‘‘Ultra-late’’ LEPs related to C-fibre activation
culminate later than standard A␦ LEPs, the positive vertex
component peaking at 800—1200 ms following upper limb
stimulation.
Conclusions
SEPs and LEPs are techniques easy to implement in any
laboratory of clinical neurophysiology. They reflect accu-
rately and objectively the somatosensory transmission,
respectively within lemniscal (SEPs) and spinothalamic
pain/temperature pathways (LEPs). Their use is now beco-
ming a ‘‘standard’’ to document the possible involvement
of somatosensory systems in patients with suspected NP
(hence fulfilling the requirements for NP diagnosis, [66]). In
particular, during the last 10 years LEPs have proved their
ability to detect even minute lesions within nociceptive
pathways, including monoradicular lesions (Fig. 2) or very
small lesions at brainstem, thalamic or cortical level (Fig. 3).
Results gathered during these years have led to a number of
conclusions regarding the utilisation of evoked potentials in
pain medicine, summarised as follows.
Conclusion no 1: Abnormal somatosensory
responses to stimulation of a painful territory
substantiate the neuropathic origin of the pain
Providing objective evidence of conduction abnormalities in
somatosensory pathways makes pain enter the definition of
NP, as indicated in Heading 1. Study of thermo-algesic path-
ways using LEPs is very often a crucial step for diagnosis of
NP, since standard exams such as NCV or SEPs will be normal
in a substantial proportion of NP patients. Significant abnor-
mality of LEPs to stimulation of a painful territory should
be considered as an electrophysiological signature of NP,
and can be commonly observed in small-fibre neuropathy,
central spinal lesions (syringomyelia), as well as brainstem,
thalamic or cortical stroke. The exquisite sensitivity of LEPs
to spinothalamic impairment allows the detection of minute
lesions and give to LEPs medico-legal value in a number
of European countries. An illustrative case is presented in
Fig. 3.
Conclusion no 2: The type of laser-evoked
potential abnormality depends both on the lesion
site and on pain pathophysiology
Ischemic necrosis interrupting transmission where the
spinothalamic tract occupies a small volume (e.g. brain-
stem lesions) will entail profound LEP abnormalities, to a
greater extent than slowly progressive lesions that tend
to distort structures without much axonal loss, as is often
the case of syringomyelia. Also, focal thalamic lesions may
L. Garcia-Larrea
produce very discrete alterations of LEPs, thus underscoring
the fact that spinothalamic terminals within the thalamus
reach multiple sites including lateral and medial targets, as
well as the posterior suprageniculate group (including the
thalamic region called VMpo). Dissociations between lemnis-
cal and spinothalamic responses (SEPs and LEPs) have been
described in thalamic lesions [53].
Conclusion no 3. Partial preservation and
desynchronisation of laser-evoked potentials in
neuropathic pain increase the probability of
allodynic phenomena
Although this conclusion would benefit from further valida-
tion, it is physiologically plausible and has been supported
by a number of independent studies so far. A study on
54 patients reported that complete obliteration of LEPs to
stimulation of the painful territory was associated with a
very small proportion of allodynic or hyperalgesic pheno-
mena, while the prevalence of these phenomena increased
significantly when LEP alteration was only partial, and in
particular when LEPs appeared desynchronised or included
late abnormal components [27]. These data have been con-
firmed by independent studies in patients with peripheral
or spinal NP, in whom both LEPs and thermal thresholds
were more severely affected in patients with ongoing pain
than in those with provoked pain (allodynia/hyperalgesia)
[19,34,70].
Conclusion no 4. Normal or enhanced evoked
potentials to stimulation of a painful territory
suggest the functional integrity of somatosensory
pathways and do not support a diagnosis of
neuropathic pain
This assertion, which mirrors Conclusion no 1, also stems
from the definition of NP. Demonstration of unaltered
somatosensory transmission at peripheral and central
levels after stimulation of a territory alleged as painful
tends to exclude the diagnosis of NP, or at least empowers
a reasonable doubt. In case of normal LEPs, it is how-
ever important to ascertain that normal responses are also
obtained to the selective stimulation of C-fibres, as the lat-
ter may prove to be selectively abnormal while A␦ LEPs
remain within normal limits. An illustrative case is shown
in Fig. 4.
Association of chronic pain with normal or enhanced
LEPs is the rule in fibromyalgia, chronic myofascial pain,
chronic fatigue syndrome, tension headache, and migraine,
which underlines pathophysiological differences between
these conditions and NP. In some of these diseases, notably
migraine and fibromyalgia, a deficit of LEP habituation to
repeated series of stimuli has been described [71], which
may imply some alteration of mechanisms of pain control,
rather than a primary dysfunction of nociceptive trans-
mission per se. It is noteworthy that the hypothesis of a
dysfunction of descending controls mechanisms in fibromyal-
gia has been also supported by studies of the nociceptive RIII
reflex in these patients [41].
Objective pain diagnostics: Clinical neurophysiology
Conclusion no 5. Evoked potential interpretation
benefits from joint recording of subjective
measures of sensation and vegetative responses
The interpretation of EP results, and in particular of
nociceptive EPs, greatly benefits from the simultaneous
analysis of reaction times, subjective intensity reports,
and vegetative skin responses, as well as from determi-
nation of subjective sensory and nociceptive thresholds.
Thresholds should be obtained preferentially before initi-
ating the electrophysiological exam, of which they serve
as useful guide. The electrophysiological investigation
of a pain patient should always be performed together
with a clinical somatosensory exam, which will indi-
cate the territory to be stimulated and the stimulation
modalities. Obtaining normal responses to stimulation of
a non-affected region have no clinical value; therefore,
stimulation should always concern the painful territory,
results being compared whenever possible with its con-
tralateral homologue [15]. Simultaneous with long-latency
evoked potentials, the motor reaction times (RT) and sym-
pathetic skin responses (SSR) can be recorded using a
single bipolar montage between the palm and the dor-
sum of the hand (recording respectively the SSR and the
surface EMG). RT latencies commonly are in the same
range as vertex potentials, while SSRs develop during
3—8 seconds following the stimulus [60], and need therefore
long inter-stimulus intervals. SSR is a peripheral mani-
festation of stimulus-related arousal [73], and in healthy
subjects correlates with both subjective intensity ratings
and amplitude of cortical responses [44,60]. Dissociation
between these variables has therefore diagnostic relevance,
in particular in patients suspected of conversion disorder or
malingering.
Conclusion no 6. Laser-evoked potential
abnormalities reflect a lesion in thermo-algesic
transmission, but do not reflect pain itself
Somatosensory evoked potentials provide objective infor-
mation on the functional status of somatosensory pathways,
the lesion of which is the crucial element of the NP
‘‘paradox’’ -i.e. the association of hypaesthesia (notably
thermo-algesic) and chronic pain. While this is important
for diagnosis, it is important to remind that we detect
the lesion — not the pain itself. So far, neither electro-
physiology nor functional imaging have been able to devise
clinical routine tests detecting neuronal activities directly
and univocally associated with the subjective sensation of
NP. While exceptions might apply to certain invasive tests
such as microneurography or intracerebral EEG recordings
[39], these techniques cannot be applied in clinical rou-
tine. Cortical activities sub-tending the NP experience are
likely to be spatially and time-dispersed, and show too lit-
tle synchrony to be recorded with classical evoked potential
techniques. More sophisticated approaches; such as time-
frequency wavelet decomposition [50] might be able in the
future to address in a more direct way the detection of the
NP sensation, of which the lesion of nociceptive pathways is
just the primum movens.
195
Disclosure of interest
The author declares that he has no conflicts of interest con-
cerning this article.
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