rstb.royalsocietypublishing.org Review Cite 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: [email protected]Revealing humans’ sensorimotor functions with electrical cortical stimulation Michel Desmurget 1,2 and Angela Sirigu 1,2 1 Centre de Neuroscience Cognitive, CNRS, UMR 5229, 67 boulevard Pinel, Bron 69500, France 2 Universite ´ 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 brain functions 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’e ˆtre 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. & 2015 The Author(s) Published by the Royal Society. All rights reserved. on August 20, 2018 http://rstb.royalsocietypublishing.org/ Downloaded from
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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
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).
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,
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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.
on August 20, 2018http://rstb.royalsocietypublishing.org/Downloaded from
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