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ReviewCite this article: Desmurget M, Sirigu A.

2015 Revealing humans’ sensorimotor

functions with electrical cortical stimulation.

Phil. Trans. R. Soc. B 370: 20140207.

http://dx.doi.org/10.1098/rstb.2014.0207

Accepted: 13 March 2015

One contribution of 15 to a theme issue

‘Controlling brain activity to alter perception,

behaviour and society’.

Subject Areas:neuroscience

Keywords:electrical stimulation, sensorimotor maps,

somatotopy, homunculus, language, human

Author for correspondence:Angela Sirigu

e-mail: sirigu@isc.cnrs.fr

& 2015 The Author(s) Published by the Royal Society. All rights reserved.

Revealing humans’ sensorimotor functionswith electrical cortical stimulation

Michel Desmurget1,2 and Angela Sirigu1,2

1Centre de Neuroscience Cognitive, CNRS, UMR 5229, 67 boulevard Pinel, Bron 69500, France2Universite Claude Bernard, Lyon 1, 43 boulevard du 11 novembre 1918, Villeurbanne 69100, France

Direct electrical stimulation (DES) of the human brain has been used by

neurosurgeons for almost a century. Although this procedure serves only clini-

cal purposes, it generates data that have a great scientific interest. Had DES not

been employed, our comprehension of the organization of the sensorimotor

systems involved in movement execution, language production, the emer-

gence of action intentionality or the subjective feeling of movement

awareness would have been greatly undermined. This does not mean, of

course, that DES is a gold standard devoid of limitations and that other

approaches are not of primary importance, including electrophysiology,

modelling, neuroimaging or psychophysics in patients and healthy subjects.

Rather, this indicates that the contribution of DES cannot be restricted, in

humans, to the ubiquitous concepts of homunculus and somatotopy. DES is

a fundamental tool in our attempt to understand the human brain because it

represents a unique method for mapping sensorimotor pathways and inter-

fering with the functioning of localized neural populations during the

performance of well-defined behavioural tasks.

1. Electrical stimulation: a unique approach for probing brainfunctions

One of the most important discoveries in modern neuroscience can indisputa-

bly be attributed to Luigi Galvani, who showed that electrical stimulation of

the sciatic nerve in a severed frog leg caused the attached muscle to contract

[1]. This finding sparked a flurry of research activity that has persisted up to

the present. In animals, the first systematic use of direct electrical stimulation

(DES) was conducted by Gustav Fritsch and Eduard Hitzig in Germany [2]

and David Ferrier in England [3]. These authors showed that stimulating the

cerebral cortex of dogs and monkeys evoked topographically organized

muscle contractions in the contralateral hemibody [4]. They also established

that lesions of the regions from which a movement was evoked caused a deficit

in the realization of this movement and even, sometimes, a total paralysis. In

the following years, DES was progressively generalized to human patients

with various levels of success and ethical concerns [5]. However, this technique

only reached its apogee in the 1930s with the well-known work of Wilder

Penfield [6]. Since then, the approach has remained roughly unchanged,

beyond minor technical and procedural adaptations [7,8].

Of course, in humans, the unique raison d’etre of DES is (and has to be) clinical.

If neurosurgeons now use this mapping procedure almost universally, it is with

the purpose of identifying cerebral areas, resection of which could cause major

functional deficits [9,10]. Consistent with this goal, it has been shown that the sur-

gical use of DES dramatically reduces the occurrence of permanent post-operative

sequelae in patients with brain tumours, while significantly improving long-term

survival [11–15]. However, the pre-eminence of clinical goals is not inconsistent

with the existence of fundamental inquiries. Obviously, the behavioural and

neurophysiological observations collected in per-operative contexts can also be

of major interest for fundamental research and, in particular, for understanding

the organization of the human brain.

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Certainly, this does not mean that DES is devoid of

limitations. In particular, the range of questions it allows us

to address is strongly restricted by clinical demands and per-

operative constraints. This is why the results obtained with

this technique have to be interpreted in light of a more general

knowledge, generated by other approaches [16]. Consider, for

instance, neuroimaging (functional magnetic resonnance ima-

ging—fMRI, positron emission tomography—PET) and

electrophysiology (electro and magneto encephalography—

EEG, MEG). During the past three decades these methods

have obviously played a major role in improving our under-

standing of the sensorimotor organization of the human

brain. However, it should not be forgotten that they too bear

important limitations [17–19]. In particular, they do not

allow us to neatly determine whether a responsive area is

truly critical for the expression of an investigated function

and whether an activated region receives afferent information,

sends efferent signals to the muscles or subserves compu-

tational processing. DES opens a window to this type of

knowledge. Of course, nobody would seriously argue that

this technique recruits neural populations as autogenous pro-

cesses do. It should be evident that DES produces unnatural

patterns of cellular activation. However, such a limitation

does not, by any means, call into question the usefulness of

the method. Indeed, even if it relies on unnatural patterns of

neural activation, DES remains unparalleled in its ability to:

(i) drive descending pathways for identifying cortical regions

with outputs to motoneurons (e.g. [6,20]); (ii) elicit positive sen-

sorimotor effects through the recruitment of neural populations

associated with the expression of high- (e.g. motor intention;

e.g. [21,22]) or low-level (e.g. sensory feelings; e.g. [6,20]) func-

tions; (iii), elicit negative sensorimotor effects through

disruption of an endogenous neural activity involved in the

realization of an ongoing task (whether motor or cognitive;

e.g. [23,24]). It is true that interpretative biases related to a poss-

ible spread of the electrical current have always been a subject

of concern for researchers [25,26]. However, during the past

two decades solid evidence has been gathered, at least for the

high-intensity/high-frequency stimulation parameters typically

used in surgical protocols, that DES effects are typically

mediated by the cell population being stimulated [27–29]. In

other words, DES does not spread in a meaningless jumble.

It operates primarily at a local level and, doing so, offers an

invaluable way to investigate the anatomo-functional organiz-

ation of the human brain. Among the multiple elements

supporting this conclusion (see [27,28] for detailed reviews),

the most convincing evidence comes probably from the suc-

cessful use of DES for mapping brain functions in per-

operative contexts. If, as is sometimes claimed [26], DES effects

were reflective of an artificial spread of current at distant sites,

then this method should be ineffective at preventing post-oper-

ative deficits in neurosurgical contexts. As reported above, this

is clearly not what the clinical literature demonstrates [11–15].

This being said, in the present review, we will focus on the

specificity and fundamental importance of DES. At a first

level, we intend to show that if this technique had not been

exploited in the past decades, several of our pillar concepts

and much of our knowledge on the anatomo-functional

organization of the sensorimotor system would be dramati-

cally undermined. At a second level, we plan to emphasize

recent studies and technical developments to demonstrate

that DES remains a major approach for understanding

brain functions.

2. Mapping the sensorimotor systemAt a time when the theory of brain localization was still

strongly questioned [30,31], Penfield’s work proved ground

breaking. As is the rule (see above), this neurosurgeon used

DES for clinical reasons ‘to define the motor area of the hemi-

sphere so that an infiltrating tumour could be removed as

widely as possible without producing paralysis [and. . .] as a

preliminary to radical extirpation of an epileptogenic focus’

[6, p. 396]. However, using this approach he also reported

results of great fundamental interest. In particular, he was

the first to show, in humans, that functional specialization

existed not only across brain areas, but also within them.

In his main pioneering work, Penfield used DES in 163

patients, among whom 126 provided useful results [6]. He

observed that movements could be triggered from only a lim-

ited number of cortical regions, including the primary motor

cortex (M1), the primary somatosensory cortex (S1), the pre-

motor cortex (PM) and the supplementary motor area (SMA).

Sensations were mostly evoked from the same regions. It is

unclear, however, whether stimulations (and how many)

were performed in non-central regions including the prefrontal

or posterior parietal cortices. Penfield found that more move-

ments were triggered from the precentral gyrus, while more

body sensations were evoked from the post-central gyrus,

although sensory and motor responses were identified in

both of these two regions. He also reported that different corti-

cal loci triggered movements and sensations in different body

parts. These observations led to the key idea that sensorimotor

regions are somatotopically organized in such a way that each

part of the body is represented within a different cortical space

in the pre- and post-central gyri. To formalize this finding, Pen-

field introduced the now famous concept of the homunculus.

According to him, within the central area, ‘toes begin at the

top and the members follow in order as though representing

a man hung upside down, but that thumb is followed by the

head as though the head and neck were erect and not inverted

(. . .) The homunculus may be said to be both motor and sen-

sory as the sequence pattern is roughly the same, although

there are differences’ [6, pp. 431–432]. Most major biology text-

books still mention Penfield’s idea and display a version of his

drawing of the human homunculus (e.g. [32,33]).

The idea that M1 and S1 are somatotopically organized is

probably one of the very few proposals that have withstood

the test of time in modern neuroscience. The concept of

the homunculus has seen its general validity supported by

numerous neuroimaging and electrophysiological studies in

humans [34–41]. However, recent evidence has started to

suggest that this consensus may rely, when carefully con-

sidered, on a rather weak ground [42–45]. According to this

view, the concept of the homunculus would mainly be an

emerging artefact of inter-individual averaging. It would

have no validity at the intra-individual level, where major

organizational differences are observed. In other words, the

homunculus as we know it would not represent a biological rea-

lity but rather a statistical construct that ‘does not appear to

exist’ [44, p. 292]. The same kind of criticism has been raised

with respect to neuroimaging data which ‘can produce the illu-

sion of a localized process by emphasizing fortuitous regions of

overlap to the exclusion of the more widely distributed active

regions in the individual subjects’ [46, p. 197].

Clearly, these claims are consistent with the observa-

tion that the synoptic, regularly ordered sequence of body

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movements and sensations described by Penfield on the basis

of the responses he recorded [6] is almost never observed at

the individual level. Although initial evidence came from

electrophysiological studies in monkeys [47–49], recent data

have confirmed that this is also true in humans, where

sensory and motor maps are typically organized as an inter-

mingled mosaic of neural populations related to different

body parts [43,44,50,51]. Major violations of Penfield’s

regular ordering are commonly found. It happens, for

instance, that mouth and face responses are represented

above finger or leg responses [43]. Moreover, both monkeys

[52] and humans [44] exhibit large variations of the sensori-

motor cortical organization from individual to individual

and between hemispheres. More generally, recent data have

also suggested that the functional segregation between M1

and S1 might not be as strict as initially postulated by

Penfield [53]. In humans, in particular, it was found that

the hand ‘hot spot’, defined as the cortical area that evokes

hand or finger responses at the lowest electrical intensity,

was located in the post-central gyrus in a significant fraction

of subjects [54,55]. At a first level, this puzzling result high-

lights the necessity of considering Penfield’s anatomical

maps with caution. Indeed, 100 years ago, neuronavigation

tools were not available and localizing stimulation sites

was not easy. For instance, as acknowledged by Penfield &

Boldrey, there was a strong bias toward associating motor

response with M1 stimulation because ‘the Rolandic fissure

can hardly be recognized until after stimulation has identified

it’ [6, p. 398]. However, the idea that the hand hot spot

is commonly localized in S1 was recently contradicted by

clinical observations showing, in a large population of 165

patients, that motor responses were scarcely evoked from

the post-central gyrus [20]. This conclusion is consistent

with monkey data showing that the level of current required

to trigger overt movements is almost systematically lower in

M1 than S1 [56,57]. In fact, as shown by a study aiming at

comparing the output properties of these two regions, the

motor responses evoked from S1 are rare, weak and often

inhibitory [58]. Strikingly, in monkey experiments, the lowest

motor threshold is consistently identified in regions located

within the bank of the central sulcus for both M1 (Brodmann

area 4) and S1 (Brodmann area 3a). In humans, however,

these intrasulcal areas are not accessible and DES is only per-

formed over the convexity of the pre- and post-central gyri.

Together with the limited number of sites that can be stimu-

lated in each subject, this may explain why the hand hotspot

has sometimes been reported in S1 in humans.

The recent questioning of Penfield’s homunculus does not

seem surprising. In truth, what appears to be really puzzling

is the ubiquity of this schematic representation and how it

became so universally accepted. Indeed, looking at Penfield’s

own data, it seems quite clear that the nice arrangement of

body parts he described along the pre- and post-central gyri

is functionally deceitful, although, of course, graphically con-

venient. This can be seen in figure 1 for a few representative

examples. The left side of the three first panels (figure 1a–c)

shows the individual stimulation sites identified as eloquent

by Penfield [6]. The right side displays the classical homunculus

he constructed from these data.

Figure 1a investigates the claim that an ordered somato-

topy exist for the fingers. Really, considering the actual

stimulation data, it seems hard to see any justification for

this hypothesis. Thumb contractions (coloured in blue), for

instance, are observed along the whole extent of the central

sulcus; they are not clustered in the medio-lateral region

and do not appear to be consistently medial with respect to

the responses recorded for other fingers, including the little

one (coloured in red). In fact, rather than observing indepen-

dent contractions for each finger, Penfield reported, in most

cases, motor responses that involved all fingers together

without individual segregation (black dots). Recently, this

combined activation has been reproduced in monkeys,

where microstimulation was found to trigger organized pat-

terns of finger synergies [60]. Also, data gathered in these

animals have clearly challenged the idea of a sequential rep-

resentation of each individual finger along a medio-lateral

axis going from the little finger to the thumb [49,61].

Figure 1b displays, on the same plot, upper limb (shoulder,

elbow, wrist, hand, undissociated by Penfield, coloured in red)

and finger responses (coloured in blue). Eloquent sites for these

two segments exhibit a major level of overlap and redundancy.

It is hard to figure out how Penfield went from these inter-

mingled responses to the nice sequential ordering presented

on the right panel, where upper limb representations are

located more medially than finger representations.

Data from the third panel (figure 1c) are even more dis-

concerting. They show face and neck representations.

Placing the neck above the face from these recordings really

seems questionable considering that all neck responses

except one are represented more laterally than face responses.

From a scientific point of view, the logic that led Penfield

to identify a precisely ordered homunculus on the basis of

his scattered data is hard to infer. However, a plausible

hypothesis might be that he got, at some point, the idea

of an inverted body map lined up over the cortical surface.

This map, drawn by Penfield himself in his pioneering work

[6], is shown on figure 1d. It implies, for instance, that the

neck should be represented more medially than the face.

Based on these remarks, it is tempting to speculate that

Penfield did not go from the data to the model, but was

rather biased toward forcing his clinical observations into

a predetermined map of representations.

In summary, DES has been a key approach for understand-

ing the organization of the primary sensorimotor regions. The

early work of Wilder Penfield, in particular, proved fundamen-

tal for establishing the central idea that brain functions are

localized and that the sensorimotor system is organized

somatotopically in such a way that specific cortical sites control

specific muscles. Nevertheless, Penfield also went too far in his

attempt to describe a nicely ordered map of sensorimotor

representations within the central regions. Both recent results

[42–44,50] and a re-evaluation of his original observations

show that sensorimotor representations are not organized in

a sequential rigidly ordered way, but rather in a mosaic of inter-

mingled representations where body parts overlap in multiple

non-contiguous areas. Such a fractured arrangement (a term

coined by Welker and his co-workers for describing the

somatosensory organization of the cerebellum [62]) has been

claimed to favour the production of complex motor responses

by making it easier to combine elemental body movements

within coordinated muscle synergies [59,61,63–65].

3. Mapping complex sensorimotor synergiesFrom the data above, it appears that DES typically evokes

simple meaningless movements in humans. Nevertheless,

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complex motor synergies in monkeys

reach-to-grasp

climbing/leaping

hand inlower space

manipulate in central space

defense

hand to mouth

chewing/licking

hand/mouth synergies in humans

hand-to-mouth movements

perioral exploration

(a) (b)

Figure 2. (a) Action zones in the precentral gyrus of the monkey where complex movements are evoked in response to long-train electrical stimulations (adaptedfrom [65], with permission). (b) Sites where complex hand/mouth synergies are evoked by electrical stimulation in the human precentral gyrus. The top panel of thefigure displays motor sites (black squares) evoking hand-to-mouth synergies resembling self-feeding, in which DES causes the closing hand to progressively approachthe opening mouth. The bottom panel of the figure displays multimodal sites (black squares) that evoke hand/arm actions when stimulated while receiving mouthsensory inputs. Adapted from [69], with permission.

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following cortical stimulation some studies have reported the

development of relatively complex, apparently purposeful

actions, including joint hand–mouth responses, coordinated

arm–eye–head aversive synergies and organized reach-to-

grasp gestures [6,22,43,66,67]. Unfortunately, when observed,

these movements were generally not described in detail.

Also, they were often said to be artefactual and reflective of

the unspecific recruitment, through current spread, of body

parts having contiguous cortical representations [43].

Technically, a reason why complex movements have not

been more commonly observed in response to DES could be

related to the tendency of clinicians (in humans) and exper-

imenters (in animals) to use short trains of stimulations.

As noted by Penfield & Welch [67, p. 310], for instance, it is

plausible that some of the simple motor responses they

found in their patients ‘would, with more prolonged stimu-

lations, have gone on to become more elaborate and to have

approached the full synergic employment of all extremities

and the trunk. The stimulating electrode has frequently been

removed at the first evidence of response, and thus the oppor-

tunity of producing more of the elaborate synergic responses

may have been missed’. Michael Graziano et al. were the first

to investigate this possibility in awake macaque monkeys

[68]. These authors stimulated the precentral gyrus using

stimulation trains of long duration. They found that some

motor responses that would have had the form of simple

muscle twitches in the context of short train stimulations,

unfolded into complex coordinated actions when the duration

of the stimulation lasted long enough. These actions included,

for instance, self-feeding movements in which the hand closed

into a grip while moving toward the opening mouth; reach-to-

grasp synergies in which the arm extended while the fingers

opened progressively; defensive gestures in which the facial

muscles squinted while the head turned sharply to one

side and the arm flung up; etc. Interestingly, as shown in

figure 2a, each of these categories of action was evoked from

different, well-localized, zones of the precentral gyrus.

Recently, Graziano’s pioneering observations were repro-

duced in New World monkeys and prosimian galagos by

John Kaas and his co-workers [70,71]. Also, they were gener-

alized to human subjects in a study aiming to investigate

whether hand–mouth synergies, a prominent example of

human behaviour with high ethological value, were rep-

resented as motor primitives in the precentral gyrus [69]. In

this study, electromyographic activity evoked by cortical

stimulation was recorded from the face and upper-limb

muscles in patients undergoing brain surgery. As shown in

figure 2b (top panel), this allowed identification of an inte-

grated motor primitive resembling self-feeding, in which

DES caused the closing hand to progressively approach the

opening mouth. Of course, not all responses evoked by

long train stimulations evolved into complex movements

and coordinated hand–mouth synergies intermingled with

simpler isolated movements over the whole surface of the

precentral gyrus. This anatomical dispersion contrasted

with the more clustered pattern found in monkeys (figure

2b). Two main hypotheses may account for this difference.

First, it is possible that this cortical region is differently orga-

nized in humans and monkeys [72,73]. Second, the

pioneering data reported by Graziano et al. in monkeys [68]

could be biased toward intra-individual variability (multiple

replications in few animals), while the data gathered in

humans could be rather slanted toward inter-individual

variability (few replications in multiple subjects).

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Notably, the true ethological nature of the complex syner-

gies evoked through DES was recently questioned by Cheney

and colleagues. In monkeys, these authors provided evidence

that postural synergies evoked through cortical stimulation

were not produced by natural patterns of EMG activity but

instead resulted from an unnatural co-contraction of numerous

‘hijacked’ muscles that forced the limb to an equilibrium point

[74,75]. However, the generality of these observations remains

debatable for at least three reasons. First, muscle hijacking was

not observed in several studies where evoked-EMG and kin-

ematic responses were found to be strikingly similar to the

responses seen in natural behaviours [60,68,76]. Second, the

non-teleonomic nature of the ‘hijacking’ hypothesis seems

hardly compatible with the repeated failure of DES to evoke

non-functional synergies where, for instance, the opening

hand would approach the closing mouth or the closing hand

would move away from the opening mouth [68,69]. Third,

beyond its ability to explain the emergence of postural equili-

bria, the ‘hijacking’ model cannot easily account for the

finesse and high functional specificity of some very complex

multi-segmental synergies. This includes, for instance, multi-

joint defensive postures specifically triggered from bimodal

neurons with tactile/visual receptive fields and made of the

following complementary elements (in Graziano’s terms): ‘a

facial grimmace, a squinting of the eye, a turning of the head

away from the side of the sensory receptive fields, a hunching

of the shoulders, a fast thrusting of the hand into the space

beside the head, and a turning of the hand such that the

palm faced outward, away from the head’ (fig. 4 in [77]).

Beyond these observations, it may be worth noting that

motor responses involving the coordinated recruitment of

distinct body segments were not the only type of complex

representation identified in the human precentral gyrus. Com-

bined recording of motor and somatosensory evoked potentials

revealed that this region also harbours motor-sensory represen-

tations where cross-signal integration is realized at specific

cortical sites that generate hand/arm actions while receiving

mouth sensory inputs. It is tempting to speculate that these

multimodal sites underlie the behavioural process of perioral

exploration. Indeed, they are shaped as a hardwired feedback

loop capable of binding oral sensory inputs with upper limb

motor commands or, in other words, capable of guiding hand

movements according to mouth sensations. This view is consist-

ent with a recent study on upper-limb reaching movements

showing, in humans and monkeys, that M1 contains fast feed-

back control loops integrating sensory and motor signals [78].

As shown in figure 2b (lower panel), complex hand–mouth sen-

sorimotor sites are not evenly distributed over the precentral

surface of the patients. They are clustered in the dorsal sector of

the precentral gyrus, where hand/arm movements are most

commonly represented.

In summary, using long trains of stimulation, researchers

and clinicians have provided convincing (although still

disputed) evidence that specific sensorimotor synergies with

a high ethological value are represented as integrated motor

primitives in the precentral gyrus. This cortical region cannot

be seen any more as a sort of keyboard, where segregated

populations of neurons can be recruited in a specific spatio-

temporal order to form complex symphonies of movements.

Overall, the use of DES reveals the complexity of primary

sensorimotor structures that can probably accommodate differ-

ent types of representations with various levels of complexity

[79]. This hypothesis fits well with the suggestion that

sensorimotor organization has been shaped by primate evol-

ution to optimize the production of ethologically relevant

behaviours while preserving the ability to learn new complex

synergies [64,65,70].

4. Mapping high-level functionsPer-operative mapping is not only useful for identifying brain

areas that evoke movements or sensations when stimulated.

This approach can also be used for probing the functional con-

tribution of a given cortical region. In this case, DES is applied

while the subject is performing a sensorimotor task such as

opening–closing the hand, reading or counting. The effect of

the stimulation on the ongoing behaviour is then evaluated.

In an alternative approach, the neurosurgeon can also interfere

with brain activity at rest and ask the patients to report the

thoughts or feelings they have experienced in response to

the stimulation.

To date, per-operative evaluations of high-level functions

have been mainly conducted for language mapping in awake

patients [80–83]. Based on this approach, large amounts of

data have been collected and used for producing probabilistic

maps of anatomo-functional correlations [13,20]. In other

words, using DES in large populations of patients, neurosur-

gical teams were able to associate specific cortical regions

with particular language disorders such as speech arrest

(cessation of speech output in the absence of evoked motor

response); dysarthria (improper articulation of speech);

anomia (inability to name objects while still being able to

speak or repeat sentences); alexia (inability to read while

still being able to spell words or write); receptive aphasia

(fluent but meaningless speech and inability to understand

simple sentences); expressive aphasia (impaired speech

production); etc.

Together with neuroimaging and lesion observations, these

per-operative results proved of major interest for improving

our understanding of the neural bases of language com-

prehension and production [84–88]. A striking example

concerns Broca’s area, the long-postulated role of which as a

speech output region remains debated in neuroimaging and

lesion studies [89–92]. A recent per-operative investigation

involving 165 patients provides an important, potentially deci-

sive, contribution to this issue [20]. As reported by the authors,

stimulation of Broca’s area only produces speech arrest in 4% of

the subjects, compared with 83% when the dorsal premotor

cortex (dPM) is targeted. The latter proportion is independent

of the localization of the tumour, i.e. of whether Broca’s area is

lesioned or not. Based on these results, it is tempting to suggest

that Broca’s area should no longer be considered a motor

region coordinating speech articulation but should rather be

viewed as a cognitive structure involved in high-level functions

such as verbal working memory, language comprehension or

lexical retrieval [20,93].

However, in the linguistic domain, the identification of

well-defined anatomo-functional correlations in response to

DES does not seem to be the norm. Indeed, a very striking

feature of per-operative evaluations of language abilities lies

in the wide distribution of functional sites across brain struc-

tures (figure 3). In contrast to the relatively circumscribed

networks that sometimes emerge from careful syntheses of

the lesion and neuroimaging literature (e.g. [90,94–96]), it

appears that highly specific aspects of language production

cortical sites for speech arrest [13] cortical sites for anomia [13]

cortical sites for alexia [13] cortical sites for speech arrest and anomia [20]

(a) (b)

(c) (d)

Figure 3. Language maps indicating, for the (left) dominant hemisphere, the cortical locations where DES induced speech dysfunctions in two large studies invol-ving, respectively, 250 [13] and 165 [20] consecutive patients with gliomas. (a) Brain sites inducing speech arrest per square centimetre of the cortical surface(reconstructed from [13]). (b) Brain sites inducing anomia per square centimetre of the cortical surface (reconstructed from [13]). (c) Brain sites inducingalexia per square centimetre of the cortical surface (reconstructed from [13]). (d ) Brain sites inducing speech arrest (red circles) and anomia (blue circles).Each individual circle represents a positive observation. Adapted from [20], with permission.

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can be impaired through stimulations delivered over very

different cortical zones. Anomia or alexia, for instance, is

consistently found after stimulation of wide (sometimes over-

lapping) regions in the frontal, temporal and parietal cortices

(figure 3). This high level of scattering is not totally surpris-

ing. It can have two main origins. On the one hand, it may

mirror the multiplicity of the neural processing required for

naming an object or reading a word [90]. On the other

hand, it may also reflect the existence of a tremendous level

of inter-individual variability in the localization of language

functional sites [13]. Obviously, part of this variability is

owing to the plastic changes that occur in brain organization

in response to slow-growing tumoural invasion [97].

Together with the existence of substantial differences in the

tasks being evaluated [98], these changes could explain

some of the above-mentioned discrepancies between DES,

acute lesion and neuroimaging studies.

This being said, language is far from being the only

high-level function open to per-operative evaluation [99].

Recently, this approach has been used to study, for instance,

visuo-spatial processing [100], action inhibition [23], move-

ment awareness [101,102] and sensorimotor intentionality

[103,104]. While reviewing the contribution made by DES

to all these fields would be beyond the scope of the present

paper, a brief focus on sensorimotor awareness and intention-

ality should help us provide another example of the unique

fruitfulness of this method.

Technically, sensorimotor intentionality has been very

difficult to address with classical electrophysiological, clinical

and neuroimaging tools given, in particular, the difficulty of

separating intentional and attentional processing [105,106].

Fortunately, DES does not have to deal with this ambiguity.

This was first shown by Penfield, who reported that some

frontal sites evoked a desire to move when stimulated [6].

Subsequent studies were able to confirm this observation,

but located the neural source of this desire on the frontal

medial wall, in a region encompassing the supplementary

and cingulate motor areas [22,107,108]. During stimulation,

the subjective experiences of the patients were characterized

by an uncontrollable urge to act. For instance, an epileptic

woman stimulated in the anterior cingulate sulcus at low

intensity through implanted intracerebral electrodes exhib-

ited ‘an irresistible urge to grasp something, resulting in

exploratory eye movements scanning both sides of the

visual field, and accompanied by a wandering arm move-

ment contralateral to the stimulation side. Then, after the

patient had visually localised a potential target, her left

hand moved towards the object to grasp it, as if mimicking

a spontaneous movement. This irrepressible need started

and ended with stimulation, and the patient was unable to

control it. Yet, the patient was aware of both her inability

to resist and of the movement she thus performed and

could describe very precisely’ [107, p. 265]. The same type

of urge was observed in another study, still in epileptic

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patients. In this case, however, the stimulation was located in

the supplementary motor area. This caused the participants

to experience an ‘urge to move the right leg inward’, an

‘urge to move the right thumb and finger’ or an ‘urge to

move the right arm away’ [22, p. 3661]. Although no movement

was evoked in response to these subjective feelings, overt

motor responses were observed when the intensity of the

stimulation was raised. For instance, a patient who reported

a ‘strong urge to raise the right elbow’ at 5 mA, experienced

a right-arm abduction at 6 mA [22, p. 3661].

Interestingly, the frontal medial wall is not the only cortical

area where intentional responses can be evoked. The emer-

gence of a subjective desire to move was also reported

following stimulation of the inferior parietal lobule [21]. In

this case, however, the subjective feelings reported by the sub-

jects were quite different from the ones observed after

stimulation of the supplementary and cingulate motor areas.

There was no dimension of urge or irrepressibility. Also, the

patients were unable to precisely describe the movements

they wanted to perform. When prompted to try, they either

said that they did not know or provided a very general descrip-

tion of their intentions in terms of action class. Representative

exchanges were as follows ([21]; electronic supplementary

material): (1) (Experimenter) Did you feel something? ; (Patient)Yes. . . It felt like I wanted to move my foot. Not sure how to explain;(E) Which foot? (P; showing the left leg): This one. (E) How did youwant to move it? ; (P): I don’t know, I just wanted to move it ; (2) (E)

Did you feel something? ; (P) I had a desire to do something ; (show-ing her chest) Here I have a desire to do. . . (E) In the chest? (P) Yes ;(E) And what did you feel? ; (P) Like a, like a will to move.

Another striking specificity of the parietal intentional sites

lies in the absence of motor response when the intensity of

the stimulation was increased. When a higher current was

used, the patients experienced illusory movements; they felt

that the movements they wanted to make at low intensity

had actually occurred in the absence of any overt or electro-

myographic motor response. A representative exchange was

as follows ([21]; electronic supplementary material). (5 mA)

(Experimenter) Did you move?; (Patient) No. I had a desire toroll my tongue. . . ; (E) To roll what? ; (P) To roll my tongue inmy mouth. (8 mA, same site) (E) Did you move? ; (P) Yes, yes,a corner of the mouth ; (E) Did you move the mouth? ; (P) Yes.

To account for this phenomenon, it was hypothesized that

higher currents did not simply prime a motor representation

to consciousness (giving rise to motor intention), but also

recruited the executive network responsible for movement

monitoring through forward modelling, a process that is

known to rely on posterior parietal computations [109,110].

In sharp contrast to the illusory movements evoked

through parietal stimulation, it was also found that actual

motor responses evoked by stimulating the dPM were not

consciously perceived by the patients. In other words,

although overt mouth and contralateral limb movements

were observed following stimulation of this region, the patients

firmly denied that they had moved [21]. This result highlights

clinical data showing that dPM is the most commonly lesioned

region in hemiplegic patients with anosognosia [111]. It also

echoes neuroimaging observations showing that the dPM is

important for comparing the actual and expected sensory sig-

nals [112]. It is tempting to speculate that when dPM is

prevented from performing its function, no error signal is gen-

erated in response to an unexpected muscle contraction, which

causes the ongoing movement to remain undetected [101].

Putting these observations together, a general model of

linking conscious motor intention and movement awareness

could be proposed that takes into account the functional

specificity of the parietal and frontal intentional regions

[103,104]. In brief, it was suggested that a general, unspecific

intention to act first emerges into consciousness within the

inferior parietal lobule. This intention is the neural signal

that triggers actual motor preparation. While the movement

is being planned, the cingulate and supplementary motor

regions exert inhibitory control over the motor output

regions. This is done to prevent an early, unwanted, release

of the motor command. Once the movement is ready, this

proactive inhibition is waived, which amounts to the emis-

sion of a ‘go’ signal that gives rise to a compulsive urge to

act. After movement onset, parietal control mechanisms

monitor action progression independently of sensory

inputs, through forward modelling. When an error is

detected that cannot be corrected through online control pro-

cesses (e.g. the arm does not move when it should), dPM

emits a warning signal that reaches consciousness. Of

course, this model is not only based on the outcomes of

DES studies but also on a large array of clinical, neuroima-

ging and electrophysiological data. However, DES was a

key method through which the material generated by each

of these approaches could be interpreted and aggregated [16].

5. Concluding remarksTo summarize, the data above show that DES has provided

a unique body of knowledge since its pioneering use by

Wilder Penfield, in humans, almost a century ago [6]. Had

this technique not been employed, our comprehension of

the organization of the sensorimotor systems involved in

movement execution, language production, the emergence

of action intentionality or the subjective feeling of movement

awareness would have been greatly undermined. This is not

to say, of course, that DES is a gold standard devoid

of limitations, nor to deny the major importance of other

clinical, eletrophysiological, modelling or neuroimaging

approaches [27]. This just means that DES represents a

unique way to map sensorimotor pathways and interfere

with the functioning of localized neural populations during

the performance of well-defined behavioural tasks. Recent

advances suggest that there is still a lot to learn from this

technique. In particular, many structures remain to be care-

fully investigated including, for instance, the cerebellum

[113]. Also, cortico-cortical connectivity continues to be a dif-

ficult challenge that DES could help to address in humans

[114,115]. Finally, the use of probabilistic maps taking into

account inter-individual variability to link structures and

functions will allow a better targeting, during per-operative

evaluations, of the functions that are at risk for a given

lesion. Such a ‘tailored’ approach will favour the develop-

ment of finer evaluation protocols and lead, potentially, to

a much better comprehension of the functional fine-grained

organization of the brain.

Authors’ contributions. Both authors contributed equally to the redactionof this review paper.

Competing interests. We declare we have no competing interests.

Funding. This work was funded by CNRS, the ‘Cortex’ Labex Programand the Agence Nationale de la Recherche (ANR-11BSV40271; ANR-12-BSV4001801) to A.S. and M.D.

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