RESEARCH ARTICLE

Vestibular Responses to Direct Stimulation of the Human Insular Cortex Laure Mazzola, MD, PhD,1,2,3 Christophe Lopez, PhD,4 Isabelle Faillenot, PhD,1,2,3 Florian Chouchou, PhD,2 Franc¸ois Mauguie`re, MD, PhD,2,5,6 and Jean Isnard, MD, PhD2,5,6 Objective: The present study provides a functional mapping of vestibular responses in the human insular cortex. Methods: A total of 642 electrical stimulations of the insula were performed in 219 patients, using stereotactically implanted depth electrodes, during the presurgical evaluation of drug-refractory partial epilepsy. We retrospectively identified 41 contacts where stimulation elicited vestibular sensations (VSs) and analyzed their location with respect to (1) their stereotactic coordinates (for all contacts), (2) the anatomy of insula gyri (for 20 vestibular sites), and (3) the probabilistic cytoarchitectonic maps of the insula (for 9 vestibular sites). Results: VSs occurred in 7.6% of the 541 evoked sensations after electrical stimulations of the insula. VSs were mostly obtained after stimulation of the posterior insula, that is, in the granular insular cortex and the postcentral insular gyrus. The data also suggest a spatial segregation of the responses in the insula, with the rotatory and translational VSs being evoked at more posterior stimulation sites than other less definable VSs. No left–right differences were observed. Interpretation: These results demonstrate vestibular sensory processing in the insula that is centered on its posterior part. The present data add to the understanding of the multiple sensory functions of the insular cortex and of the cortical processing of vestibular signals. The data also indicate that lesion or dysfunction in the posterior insula should be considered during the evaluation of vestibular epileptic seizures. ANN NEUROL 2014;76:609–619

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rocessing of vestibular inputs in the human cortex has recently been implicated in a growing number of cognitive functions beyond its contribution to postural and oculomotor reflexes, such as the computing of internal models of gravity,1 the sense of verticality,2 and several aspects of bodily awareness3 and self-consciousness.4 Paradoxically, descriptions of the vestibular cortex are scarce, and its exact location in the human brain is still a matter of debate (for a recent review, see Lopez and Blanke5). Pioneering6,7 as well as more recent8,9 intracranial stimulation studies have suggested vestibular information processing in the cortex surrounding the Sylvian fissure, involving the superior/middle temporal gyri and the inferior parietal lobule. A few case studies also

reported vestibular sensations (VSs) during stimulation of the intraparietal sulcus,10 angular gyrus,4 and precuneus.11 Altogether, these studies indicate a wide distribution of vestibular areas in the human cortex, similar to those identified in nonhuman primates, which include the parietal, insular, temporal, motor, and cingulate cortex, and hippocampus.12–15 Functional neuroimaging studies in healthy humans have also revealed vestibular activations in all brain lobes.16–25 The question thus arises whether there is a core vestibular cortex within this distributed network. Animal data suggest that the parietoinsular vestibular cortex (PIVC) is this core vestibular cortex, because it is interconnected with all other vestibular regions.12,13,15 Yet,

View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.24252 Received Oct 30, 2013, and in revised form Aug 8, 2014. Accepted for publication Aug 11, 2014. Address correspondence to Dr Mazzola, Neurology Department, University Hospital, St-Etienne, 42055 cedex 2, France. E-mail: [email protected] From the 1Neurology Department, University Hospital, St-Etienne; 2Team "Central Integration of Pain", Lyon Neuroscience Research Center, National Institute of Health and Medical Research Unit 1028, National Center for Scientific Research Mixed Unit of Research 5292, Lyon; 3Jean Monnet University, StEtienne; 4Aix Marseille University, National Center for Scientific Research, Integrative and Adaptative Neurosciences Mixed Unit of Research 7260, Marseille; 5 Functional Neurology and Epilepsy Department, Neurological Hospital, Civil Hospices of Lyon, Lyon; and 6Claude Bernard University, Lyon, France. Additional Supporting Information may be found in the online version of this article.

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whereas early electrophysiological studies in Java monkeys identified vestibular-sensitive neurons at the junction of the posterior insula with the lateral sulcus,26 recent recordings in rhesus monkeys did not confirm implication of the insula and localized vestibular neurons more posteriorly.27,28 Vestibular information processing in the insular lobe has also been questioned in humans; some authors proposed an insular localization of the vestibular cortex,29 whereas others localized it in the parietal operculum (OP),20,30,31 in the retroinsular cortex (Ri),31 or in the more lateral “temporoperi-Sylvian vestibular cortex.”8 In addition, although numerous neuroimaging studies reported insula activation by vestibular stimulation,16,18,19,23,24 VSs evoked by direct electrical stimulation of the insula remained rare in the series of Penfield et al6,32 and Kahane et al.8 However, the upper and posterior quadrants of the insula were not systematically explored in Penfield’s work,7,32,33 and no mapping of VSs in the insula has been conducted in large patients populations, as done for somatosensory representations.34,35 In the present study, we provide a functional mapping of vestibular responses in the insular cortex of 219 patients undergoing stereo-electroencephalography (SEEG) and electrical stimulations of the insula, for presurgical evaluation of partial epilepsy. We found that VSs represented 7.6% of the sensations reported after insular stimulations and were mostly related to the posterior insula. The spatial distribution of vestibular responses was compared with recent cytoarchitectonic mapping of the human posterior insula.36 We discuss our findings with respect to recent meta-analytic definitions of vestibular activations in the operculoinsular complex of healthy participants30,31 and with electrophysiological recordings in animal PIVC.26,27 Our findings are relevant for systems neuroscience, but also for interpretation of ictal vestibular symptoms during epileptic seizures.37–39

Patients and Methods Patients The 219 patients (105 women, mean age 5 36 years, range 5 20–59 years) included in this study underwent an SEEG exploration of the perisylvian and insular cortex in our Epilepsy Department, at the Neurological Hospital of Lyon, between March 1997 and December 2012, with the purpose of localizing their epileptogenic area before surgery. The choice of SEEG targets was based on video-EEG recordings of seizures, interictal fluorodeoxyglucose positron emission tomography, interictal and ictal single photon emission computed tomography, and brain magnetic resonance imaging (MRI) data. Electrical stimulation of the cortex is a routine procedure to evaluate the epileptic threshold and to provide a functional map in the explored areas. All patients were fully informed of the purpose and risks of the SEEG procedure and gave their written consent.

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FIGURE 1: Location of all 642 insular sites stimulated during the presurgical evaluation of drug-refractory partial epilepsy in our 219 patients according to Talairach’s stereotactic coordinates (normalized to Talairach’s space using measurements of the distance between the anterior and posterior commissures [AC–PC] for each brain; y coordinates in abscissa, z coordinates in ordinate) is represented by open circles. All sites are projected onto a single plane to facilitate visual representation (x 5 41). Yellow circles show spatial distribution of the 41 contacts where electrical stimulation evoked vestibular sensation (in 29 of the 219 patients). Lines in the background indicate the borders of insular cortex and its central sulcus in the standard Talairach brain. VCA corresponds to the projection of the coronal plane passing through the anterior commissure and perpendicular to the anterior commissure–posterior commissure horizontal plane. Due to interindividual variability of insula anatomy, some contacts are located outside these lines, although they are all located in the insula of the individual patients.

Electrode Stereotactic Implantation and Insular Site Location The stereotactic implantation followed the procedures described in our previous investigations.34,35,40 Electrodes were implanted perpendicular to the midsagittal plane and were left in place chronically up to 15 days. The electrodes had a diameter of 0.8mm and contained from 5 to 15 recording contacts (2mm long) separated by 1.5mm. A cerebral angiogram was performed in stereotactic conditions using an X-ray source 4.85m away from the patient’s head, to eliminate the linear enlargement due to X-ray divergence. The stereotactic coordinates41 of each electrode were calculated preoperatively on the individual cerebral MRI previously enlarged at scale 1. Cerebral MRI and angiographic images were superimposed to avoid any risk of vascular injury during implantation. We confirmed on individual brain MRI that contacts evoking any sensation after electrical stimulation were located in the insular cortex. To localize stimulation sites we used 3 separate approaches according to the following. STEREOTACTIC COORDINATES. All of the 642 stimulated sites (and in particular the 41 stimulation sites evoking VSs) were localized using Talairach’s (x, y, and z) coordinates41 (Fig 1) after normalization based on the distance between the anterior and posterior commissures (AC–PC). Each stimulation site

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FIGURE 2: Spatial distribution of contacts where electrical stimulation evoked vestibular sensation according to the type of vestibular sensation (VS). Red symbols correspond to sensations of rotation, green to translations, and blue to nondirectional sensations of body motion or feelings of unsteadiness. (A) Circles and triangles show the location of the 41 stimulation sites evoking VSs according to stereotactic coordinates after normalization to the distance between the anterior and posterior commissures in the 29 patients in whom VSs could be evoked. Circles represent stimulation sites where VS was the only evoked sensation, and triangles represent stimulation sites where VS was associated with another type of sensation (somatosensory or auditory sensations). (B) Anatomical position of 20 of these vestibular sites that could be localized retrospectively with respect to the individual anatomy of insula gyri without normalization procedure. Squares show contacts that were located by superimposing postimplantation radiography and sagittal sections of individual magnetic resonance imaging (MRI) images (n 5 10 in 8 patients), and diamonds show contacts located directly on postimplantation MRI with MRI-compatible electrodes (n 5 10 in 10 patients). For illustration purposes, all contacts are projected onto a 3-dimensional sagittal view of the insula. Apparent discrepancies in location of stimulation sites between parts A and B are due to individual differences in insula morphology. ASG 5 anterior short gyrus; MSG 5 middle short gyrus; PLG 5 posterior long gyrus; PostCG 5 postcentral gyrus; PreCG 5 precentral gyrus.

was represented by stereotactic coordinates of the point located halfway between the 2 adjacent contacts used for bipolar stimulation (ie, the center of the sphere of neural elements activated by electrical stimulation). We determined the precise location of stimulation sites with respect to insula gyri of each individual without normalization to AC–PC (Fig 2B). This could be achieved for only 20 of the 41 vestibular sites, either when a sagittal MRI slice passing through the insula was available or in patients implanted after the development and the routine use of MRI-compatible electrodes. We localized 10 of these 20 contacts by superimposing postimplantation radiography to individual MRI sagittal sections in 8 patients. The 10 other contacts were localized using postimplantation MRI that was available only in the 10 patients implanted after 2009 with MRI-compatible electrodes. This localization of stimulations sites according to individual insular anatomy could not be achieved in patients explored in the early years of this retrospective study, because sagittal slices of the insular cortex were not available and could not be reconstructed from original MRI numerical files.

ANATOMY OF THE INSULAR GYRI.

PROBABILISTIC CYTOARCHITECTONIC MAPS OF THE INSU-

A third analysis was conducted to localize the stimulation sites with respect to the cytoarchitectonic subdivisions of the insula, which could be achieved only for patients with a postimplantation MRI. Nine of the 10 postimplantation MRIs were normalized with SPM8 (Wellcome Trust Centre for Neuroimaging, London, UK) into the standard Montreal National Institute (MNI) space. One MRI could not be normalized because of a large artifact (due to the presence of metal in the skull) localized in the contralateral frontal cortex, which did not interfere with the localization of electrodes in the insular cortex, but precluded

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normalization using SPM8 software. Normalized MRI were superimposed over the probabilistic cytoarchitectonic maps of the operculoinsular cortex.36,42,43 Because probabilistic cytoarchitectonic maps are not yet available for the anterior insula (see Morel et al44 for a nonprobabilistic description of those maps), we localized the stimulation sites on the basis of a conventional anatomical nomenclature of the insular gyri (Fig 4A).

Stimulation Paradigm Electrical stimulations were delivered while patients were seated in bed and instructed to keep their eyes opened and to relax. A current-regulated neurostimulator designed for a safe diagnostic stimulation of the human brain delivered electrical stimulations according to the routine procedures used in our department.34,35,40 Square pulses of current were applied between 2 adjacent contacts. Only contacts located in the gray matter were used for stimulation. Stimulations were applied at 50Hz, with pulse duration of 0.5 milliseconds, train duration of 5 seconds, and intensity between 0.2 and 3.5mA. These parameters were used to avoid any tissue injury45 (charge density per square pulse < 55mC/cm2). This stimulation paradigm, along with the bipolar mode of stimulation using adjacent contacts, ensured a good spatial specificity to stimulate a target structure.46 Stimulus intensity was raised from 0.2mA by steps of 0.4mA until any sensation was obtained, and to a maximum of 3.5mA. The stimulation threshold was defined as the minimal intensity necessary to evoke a response. This threshold averaged 1.6 6 0.9mA for VSs. No stimulation was delivered at suprathreshold values.

Collection and Processing of Data Subjective reports and clinical observations were collected immediately after each electrical stimulation. EEG data and videos recorded during the stimulations were analyzed

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FIGURE 3: Frequency of the different types of responses obtained during 541 clinically eloquent insula stimulations.

retrospectively to identify the stimulations evoking VSs. Explicit evoked sensations of each patient are reported in Table 1. We considered as VSs sensations of motion of whole body, head, or extrapersonal space. We analyzed EEG data to discard from analysis stimulations that induced an afterdischarge. We did not consider electrical stimulations applied within or around a brain lesion.

Results Of the 642 insular stimulations performed in 219 patients, 541 (84.3%) evoked a sensation, 232 (42.9%) during right and 309 (57.1%) during left insula stimulation. A VS was reported during 41 of these 541 stimulations (7.6%) in 29 patients; 12 of 232 (5.2%) were evoked by right and 29 of 309 (9.3%) by left insula stimulation (chi-square test with Yates correction: p 5 0.10). The stimulation threshold averaged 1.6 6 0.9mA for VSs, and did not vary significantly according to the location of the stimulation site in the insula (correlations between intensity threshold and y or z coordinates: R2 < 0.002; Wilcoxon for difference between intensities applied to posterior and anterior contacts: p 5 0.5). The distribution of all stimulation sites and of those where a VS was evoked is illustrated in Figure 1. The proportion of the other types of response obtained after insular stimulations is shown in Figure 3. The 2 most frequent types of responses were somatosensory (61%) and visceral (15%) sensations. No significant variation of heart rate concomitant to the evoked VS could be evidenced (p 5 0.3). Vestibular Sensations Evoked by Insula Stimulation Patients’ reports of vestibular sensation as well as Talairach’s and MNI stereotactic coordinates of corresponding stimulations sites are detailed in Table 1. The great majority of reported VSs were sensations of body motion 612

(39 of 41, 95.1%), whereas sensations that visual environment was moving were much less frequent (2 of 41, 4.9%). Patients more often reported sensations of translation (14 of 41, 34.1%) than of rotation (9 of 41, 21.9%), but this difference was not significant (chisquare test: p > 0.2). Sensations of translations included feelings of flying or of levitation (5 of 14; Supplementary Video 1), of the body rising (3 of 14), or of falling (6 of 14). For this latter sensation, the sensation of falling was either directed backward (3 of 6) or laterally (3 of 6). The direction of the sensation did not seem to depend on the side of the stimulation because, for example, left insular stimulations caused either backward, left-sided, or right-sided sensations of falling. We classified the sensations of rotation according to 3 anatomical planes8: yaw plane for horizontal rotation around the main vertical body axis, roll plane for rotation in the frontal plane around the anteroposterior axis, and pitch plane for rotation in the sagittal plane. Most rotation sensations (7 of 9) were experienced in the yaw plane, either in clockwise (5 of 7) or counterclockwise (2 of 7) directions (Supplementary Video 2). Stimulations of either the right (3 of 5) or left (2 of 5) insula evoked sensations of rotations in the clockwise direction. Only 2 stimulations (Supplementary Video 3) evoked a sensation of rotation in the roll plane. No VS was reported in the pitch plane. Patients also frequently reported VSs that could not be classified as whole body translations or rotations (here referred to as "other"; 18 of 41, 43.9%). Most of them reported a spinning sensation restricted to their head (n 5 14), or an experience of “instability” (n 5 3). One patient described a “loss a visual landmarks.” Videos showing patients experiencing VSs after insular stimulation are available as supplementary material at the Annals of Neurology website. Supplementary Video 1 shows a translation (levitation) sensation, Supplementary Video 2 a rotation sensation experienced in the yaw plane, and Supplementary Video 3 a rotation sensation in the roll plane. All patients gave their consent for being videotaped and for their images to be used. Most of the VSs evoked by insular stimulations were not associated with other sensations (33 of 41, 80.5%). However, 4 (9.7%) were associated with a somatosensory sensation during right insula stimulation (paresthesias in the feet for 1 patient and in the left hand for another; electrical sensation moving from the chest to both arms for 1 patient and from the left hand to the head for another). Four other VSs (9.7%) were associated with auditory manifestations such as ears whistling or buzzing. There was no significant difference in Volume 76, No. 4

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TABLE 1. Explicit Evoked Sensation, and Talairach and MNI Coordinates of Each Insula Stimulation Site Evoking Vestibular Sensation

Clinical Evoked Response

Talairach Coordinates

MNI Coordinates

x

y

z

Z

Y

Z

Rotatory illusion "spinning head," in yaw plane, clockwise

41

214

1

41

214

0

Dizzy sensation "like in a carousel," in yaw plane, clockwise

34

216

5

34

217

5

Dizzy sensation "like in a carousel," in yaw plane, clockwise; associated with paresthesias in feet

36

216

5

36

217

5

Feeling of spinning on himself, of turning around, in yaw plane, clockwise

34

10

12

34

10

14

Rotatory illusion "spinning head," in yaw plane, clockwise

236

219

3

236

219

2

Rotatory illusion "spinning head," in yaw plane, counterclockwise

236

213

8

236

214

8

Rotatory illusion "spinning head," in yaw plane, counterclockwise

235

221

0

235

222

21

Feeling of oscillatory head movements in roll plane

36

216

10

36

217

10

Feeling that something is having a rocking movement in the head, in roll plane

36

213

22

36

213

23

Feeling of falling backward to left side

40

210

0

40

210

21

Feeling of body rising

40

214

2

40

215

1

Feeling of body rising (like a bubble)

236

29

21

236

29

22

Feeling of falling laterally, on right side of bed

40

211

8

40

212

8

Feeling of falling backward; associated with paresthesias in left hand

35

215

8

35

216

8

Feeling of limbs rising (as if she were flying away); associated with electrical sensation in both hands

33

29

13

33

210

14

Feeling of flying

35

29

13

35

210

14

Feeling of levitation, floating up in the air

40

217

4

40

218

3

Feeling of levitation, floating up in the air

41

211

25

41

211

27

Feeling of levitation

39

218

23

39

218

25

Feeling of being projected, of falling backward; associated with electrical sensation moving from left hand to head

36

212

16

36

213

17

Feeling of falling to right side; associated with auditory illusion (whistling in right ear)

34

28

23

34

28

24

Feeling of falling backward

36

0

11

36

21

12

Feeling of levitation, of floating on water

234

213

27

234

213

29

Dizziness

38

25

12

38

26

13

Light dizziness

33

225

20

33

227

20

Sensations of rotation

Sensations of translation

Other vestibular sensations

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TABLE 1: Continued

Clinical Evoked Response

Talairach Coordinates

MNI Coordinates

x

y

z

Z

Y

Z

Dizziness; associated with auditory illusion (buzzing in both ears)

30

214

22

30

216

23

Light dizziness

39

24

21

39

24

21

Light dizziness

36

6

8

36

6

9

Dizziness associated with general ill feeling

37

6

8

37

6

9

Feeling of instability

34

10

9

34

10

10

Feeling of instability

34

10

9

34

10

10

Dizziness

44

3

0

44

3

0

Dizziness; associated with auditory illusion (whistling in left ear)

35

221

21

35

222

22

Dizziness with loss of visual landmarks; associated with auditory illusion (whistling in left ear)

35

221

21

35

222

22

Dizziness, feeling that visual environment is moving

42

3

0

42

3

0

Dizziness, unpleasant

231

6

24

231

6

24

Dizziness

236

22

210

236

22

212

Dizziness

238

1

24

238

1

25

Feeling of instability

236

210

22

236

210

23

Dizziness

234

28

12

234

29

13

Dizziness

236

214

21

236

214

22

MNI 5 Montreal National Institute.

stimulation intensities between pure VSs and those associated with other types of sensation (respectively, 1.5 6 0.5mA and 1.6 6 0.9mA; Wilcoxon–Mann–Whitney test: p 5 0.92). It is thus unlikely that associated sensations were due to diffusion of electrical current. Location of Insular Sites Where Electrical Stimulation Evoked VSs LOCATION ACCORDING TO STEREOTACTIC COORDINATES. Figure 2A shows that most stimulation sites

where a VS response was observed were located in the posterior insula. Stereotactic coordinates of contacts evoking rotational, translational, or other VSs are presented in Tables 1 and 2. Multivariate Hotelling’s T2 test was used to compare mean location in the Euclidean 3-dimensional (3D) space (Statistica; StatSoft, Tulsa, OK). Analyses showed that 3D location of stimulation sites did not differ for sensations of rotations versus translations (T2 5 2.04, F3,19 5 0.61, p 5 0.614), for sensations of rotations versus 614

other VSs (T2 5 4.28, F3,23 5 1.31, p 5 0.295), or for sensations of translations versus other VSs (T2 5 5.95, F3,28 5 1.85, p 5 0.161). Further nonparametric tests applied separately to y, x, and z coordinates revealed that sites where sensations of rotation (n 5 9) and translation (n 5 14) were evoked were significantly more posterior than those where other types of VS (n 5 18) were obtained (Wilcoxon–Mann–Whitney for y coordinates: p 5 0.04 and p 5 0.03, respectively). There was no significant difference for the x and z coordinates. LOCATION ACCORDING TO THE ANATOMICAL DEFINITION OF THE INSULAR GYRI. Detailed spatial

distribution of the 20 vestibular sites that could be localized with respect to the individual gyral organization of the insula (see Fig 2B) confirmed that most contacts (16 of 20) were located in the posterior insula (long posterior and postcentral insular gyri), whereas only 4 contacts were located close to the anterior bank of the central insular sulcus in the precentral insular gyrus. Volume 76, No. 4

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FIGURE 4: Location of vestibular stimulation sites according to probabilistic cytoarchitectonic maps of the insula. (A) Probabilistic cytoarchitectonic maps of the insula (according to Kurth et al36 and Eickhoff et al42,43) superimposed to the mean MRI of 9 patients in whom a postimplantation MRI was performed and could be normalized in the Montreal National Institute space (see text). For the anterior part of insula, for which such probabilistic maps are not yet available, we used anatomical gyri to delineate subregions, although they may not correspond to cytoarchitectonic subdivisions (see Morel et al44). ASG 5 anterior short gyrus; MCG 5 middle short gyrus; OP 5 parietal operculum; PostCG 5 postcentral gyrus; PreCG 5 precentral gyrus. (B) Summary of the location of vestibular stimulation sites according to the cytoarchitectonic subdivisions and the type of vestibular response. The 4 stimulation sites where stimulations evoked illusions of rotation were located in the granular part of the posterior insula (Ig2). At the 4 other stimulation sites, located in postcentral insular gyrus, or at the border between post- and precentral insular gyri, stimulation produced a sensation of translation (n 5 3) or an indefinable sensation of body motion (n 5 1). (C) Normalized postimplantation MRI of each patient, on which are superimposed cytoarchitectonic probabilistic maps of the insula. Black marks correspond to the signal of electrodes reaching insula cortex or neighboring structures. The stimulation sites inducing vestibular sensations (VSs) when stimulated are encircled in red. Others black marks correspond to other insula contacts in which electrical stimulation was either not performed or did not induce a VS.

LOCATION ACCORDING TO THE PROBABILISTIC CYTOARCHITECTONIC MAPS OF THE INSULA. The

4 stimulation sites evoking sensations of rotation were located in the granular insular cortex (area Ig2) of the posterior insula (see Fig 4C). Four other stimulation sites (3 where a sensation of translation and 1 where an indefinable VS were evoked) were located in the anteroinferior part of the postcentral insular gyrus, and only 1 (evoking an indefinable VS) was located anteriorly to the central sulcus of the insula, in the precentral insular gyrus (see Fig 4B).

Discussion VSs have been reported during electrical stimulations of the superior temporal and parietal cortex,4,6–11,32 but rarely during insula stimulations. Penfield et al collected 7 VSs from 108 stimulations of the temporal lobe,6,7 but none in response to insula stimulation.32 However, their intraoperative stimulations left largely unexplored the upper and caudal parts of the insula,32 which they could October 2014

stimulate only after occasional resections of the parietal or temporal operculum,32,33 whereas they are fully accessible with the intracranial electrodes implanted stereotactically. More recently, Kahane et al8 reported that only 1 TABLE 2. Talairach’s Stereotactic Coordinates (Mean 6 Standard Deviation) of the Insula Contacts Where Electrical Stimulation Evoked Sensations of Rotation, Translation, and Other Sensations of Body Motion

Sensation Rotation Translation Other

x

y

36 6 2

213 6 9a

565

37 6 3

b

468

a,b

469

36 6 4

z

211 6 4

24 6 11

Sites where sensations of rotation and translation were evoked were significantly more posterior than those where other types of vestibular sensations were obtained. a p 5 0.04, bp 5 0.03 difference for y coordinates, Wilcoxon–Mann–Whitney.

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FIGURE 5: Comparison of the location of vestibular information processing in the insula, evaluated by 2 different methods: (1) intracerebral electrical stimulations as reported in the present study, and shown in the same way as in Figure 1; and (2) a meta-analysis of neuroimaging studies31 in healthy participants using caloric vestibular stimulation (red cluster), galvanic vestibular stimulation (green cluster), and auditory stimulation (blue cluster), irrespective of the side of the stimulation. All results are displayed on selected brain slices from a single subject template in the Montreal National Institute space (adapted from Fig 2, Lopez et al31). All values are corrected for false discovery rate (p < 0.05). Clusters of activation were located in the median and posterior part of insula, showing a good congruence with intracerebral electrical stimulation data. Caloric vestibular stimulations and sound stimulations also activated the retroinsular region, which was not explored by our electrodes.

of their 44 stimulations evoking VSs (2.3%) was applied in the insula, but this study focused on lateral temporal and parietal cortices, and it is not known how many insular sites were stimulated, so that the frequency of VSs evoked by insular stimulation cannot be compared with that reported in the present study. Only a few studies reporting a large insula exploration are available. Isnard et al40 reported 5 VSs of 139 evoked responses (4%; these 5 VSs come from patients who are shared with our study and are included in the present data); 2 stimulation sites were in the posterior insula, and 3 were anterior to the central insular sulcus. Nguyen et al47 reported 2 VSs of 67 responses (3%). These responses were obtained after stimulation of only 32 insular sites, so that a VS was elicited by 6% of their stimulations. Stephani et al48 reported no VSs among 62 evoked responses after insula stimulation. These differences in the percentage of VSs can be explained by differences across studies regarding spatial sampling, electrode implantation procedure (oblique vs orthogonal), and stimulation parameters. The present study focused on the insula with low stimulation intensities and reports, to our knowledge, the most extensive sampling and largest number of insular stimulations. A major finding of the present study is that the great majority of VSs are evoked by stimulation of the 616

posterior insula in granular area Ig2 and postcentral insular gyrus. Especially, sensations of rotations seem to be segregated in Ig2. Although the number of stimulations evoking VSs that could be localized according to the probabilistic cytoarchitectonic areas of insula is limited, this result raises the question of whether these structural subdivisions could subserve distinct aspects of vestibular sensory processing. The importance of the posterior insula for vestibular processing revealed in the present study is in agreement with data from recent activation likelihood estimation meta-analyses of vestibular activation in the human operculoinsular complex30,31 (Fig 5). The main regions activated by caloric, galvanic, or auditory stimuli were located in the insula (mainly in its median and posterior part), Ri, frontoparietal operculum, superior temporal gyrus, and cingulate cortex. Conjunction analysis indicated that posterior insula (allocated to cytoarchitectonic area Ig2), Ri, and parietal operculum seem to be regions in which the different vestibular afferents converge.31 Electrophysiological recordings in monkeys also revealed vestibular-responding neurons in the PIVC, “within the most posterior and upper part of the insular cortex.”26 We note that the frequency of VSs (7.6%) found in the present study may appear low if we consider that the insular cortex has often been proposed as a main vestibular cortical site. However, we delivered electrical stimulations at response threshold (ie, the minimal intensity necessary to evoke any sensation) and never used intensities >3.5mA. This procedure may have resulted in underestimating vestibular responses in the insula. Recent recordings in monkeys27,28 suggest that Ri and parietal opercular cortex also contain vestibular neurons. We did not explore the Ri region. Therefore, our findings do not exclude that stimulating the Ri cortex could evoke VSs in humans. The location of VSs reported in the present study compared to that of other types of sensations evoked by insular stimulation reported by Isnard and colleagues40 may suggest a trend to a "modalotopic" organization of the insula (Fig 6). Pain responses were seem mostly in the upper posterior part of the insula, VSs in the posterior part, and auditory responses in the lower posterior part. Nonpainful somatosensory response paresthesias are more scattered, although they are mainly distributed in the posterior insula. However, there is a clear spatial overlap between different modalities in the insula, suggesting rather a multimodal organization. Electrophysiological data showing that vestibular neurons in the animal PIVC are multimodal26,49 and that the posterior insula and parietal operculum contain neurons with large Volume 76, No. 4

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FIGURE 6: Comparison of the localization of (A) our insula stimulation sites evoking vestibular responses (orange circles) and (B–F) stimulation sites evoking other types of responses (B–F are adapted from Isnard et al40). (B) Somatosensory responses. Simple paresthesias are represented in yellow, paresthesias with a warmth sensation in deep blue, and painful paresthesias in red. (C) Viscerosensitive responses are in light blue, except the 1 that was painful (in red). (D) Sensations of laryngeal constriction are in green, except the 2 that were painful (in red). (E) Auditory responses (lilac). (F) Dysarthric speech and missing words (white) and olfactogustatory responses (magenta). White open circles represent the localization of all the 642 sites stimulated in our study (A), and black open circles represent the localization of all 144 stimulation sites in the study of Isnard et al40 (B–F).

tactile receptive fields50,51 support this view. Similar regions in the parietoinsular complex were found activated during vestibulotactile stimulations in human functional MRI (fMRI) studies.52 This convergence of vestibular and somatosensory inputs could explain the somatic sensations reported together with VSs during insula stimulation. Anatomical and neuroimaging data show that the dorsal margin of the posterior insula contains the primary interoceptive cortex, which processes homeostatic sensory inputs.53–55 Of note, the monkey PIVC and the putative human homologous areas in OP2/Ri are located within or immediately posterior to this area.12,27,30,31 This close anatomical relationship between the cortex involved in vestibular processing and interoception is very likely to stem from their common implications in the control of various autonomic functions. According to Balaban,56 vestibuloautonomic convergence suggests that “there may be an integrated representation of gravito-inertial acceleration from vestibular, somatic, and visceral receptors for somatic and visceral motor control.” Gravitoinertial vestibular signals indicating body orientation in space are necessary to adapt blood pressure (ie, orthostatic reflex), heart rate, and respiratory rhythm.57–59 Electrical stimulations and focal lesions of the insula were shown to be associated with heart rate and blood pressure changes,60–62 and ictal asystole has been recently reported during a seizure involving the left insular cortex.63 However, VSs were not associated with any significant variations of heart rate in the present study, presumably because of the very focal and low-intensity stimulation paradigm that was used. October 2014

The retrospective nature of our study and that we did not use a standardized questionnaire dedicated to assess systematically VSs during insular stimulation may have minimized the frequency of vestibular responses and have hampered a more precise description of VSs evoked by insular stimulations. Furthermore, regarding localization of stimulation sites in individual brain images, our study suffers from the use of MRI acquired over 16 years that precluded individual localization of stimulation sites in all patients. However, precise stereotactic coordinates of stimulation sites were available in all patients, thus permitting comparison between our mapping and that provided by functional neuroimaging studies. Our findings also clarify results from fMRI studies of the human vestibular cortex. Most techniques commonly used to activate the vestibular receptors in neuroimaging studies also trigger extravestibular inputs.25,31 Caloric vestibular stimulation is associated with tactile and thermal stimulation of the ear. Galvanic vestibular stimulation may be associated with nociceptive and heat sensation on the skin, and sound-induced vestibular stimulation activates the auditory system. In addition, these methods can also induce nausea. Because thermal, nociceptive, and visceral representations have been found in the insula,33,34,64–66 one may question whether insular activations revealed by neuroimaging studies might be secondary to cortical processing of other inputs.25,31 Direct electrical stimulation of the insula in conscious patients, which bypasses these interferences, permits one to infer a causal relation between evoked VSs and vestibular processing in the human insula. 617

ANNALS

of Neurology

Our results are also helpful for interpreting the origin of partial epileptic seizures with vestibular symptoms. “Vertiginous seizures”7 are often attributed to temporal and parietal foci,37,38,67,68 whereas the present study suggests that the implication of insula should also be considered. In particular, implantation of electrodes in the posterior insula should be considered when VSs are concomitant with other ictal symptoms and when scalp EEG suggests an involvement of the operculoinsular region.40

Acknowledgment C.L. is supported by a grant from the Volkswagen Foundation’s European Platform for Life Sciences, Mind Sciences, and the Humanities, #85639: "The (Un)bound Body Project: Exploring the Constraints of Embodiment and the Limits of Body Representation". The sponsor was not involved in the study design; collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication. We thank the anonymous referee for comments that provided insight into the functional anatomy of the insular cortex and improved the discussion section; and L. Faure for her help with Figure 2B.

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Wiest G, Zimprich F, Prayer D, et al. Vestibular processing in human paramedian precuneus as shown by electrical cortical stimulation. Neurology 2004;62:473–475.

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Guldin WO, Gr€ usser OJ. Is there a vestibular cortex? Trends Neurosci 1998;21:254–259.

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Guldin WO, Akbarian S, Gr€ usser OJ. Cortico-cortical connections and cytoarchitectonics of the primate vestibular cortex: a study in squirrel monkeys (Saimiri sciureus). J Comp Neurol 1992;326:375– 401.

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Akbarian S, Gr€ usser OJ, Guldin WO. Corticofugal projections to the vestibular nuclei in squirrel monkeys: further evidence of multiple cortical vestibular fields. J Comp Neurol 1993;332:89–104.

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Gr€ usser OJ, Guldin WO, Mirring S, Salah-Eldin A. Comparative physiological and anatomical studies of the primate vestibular cortex. In: Albowitz B, Albus K, Kuhnt U, et al, eds. Structural and functional organization of the neocortex. Berlin, Germany: Springer-Verlag, 1994:358–371.

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Bottini G, Sterzi R, Paulesu E, et al. Identification of the central vestibular projections in man: a positron emission tomography activation study. Exp Brain Res 1994;99:164–169.

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Lobel E, Kleine JF, Le Bihan D, et al. Functional MRI of galvanic vestibular stimulation. J Neurophysiol 1998;80:2699–2709.

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Bense S, Stephan T, Yousry TA, et al. Multisensory cortical signal increases and decreases during vestibular galvanic stimulation (fMRI). J Neurophysiol 2001;85:886–899.

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Dieterich M, Bense S, Lutz S, et al. Dominance for vestibular cortical function in the non-dominant hemisphere. Cereb Cortex 2003; 13:994–1007.

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Eickhoff SB, Weiss PH, Amunts K, et al. Identifying human parieto-insular vestibular cortex using fMRI and cytoarchitectonic mapping. Hum Brain Mapp 2006;27:611–621.

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Stephan T, Deutschl€ ander A, Nolte A, et al. Functional MRI of galvanic vestibular stimulation with alternating currents at different frequencies. Neuroimage 2005;26:721–732.

22.

Fasold O, von Brevern M, Kuhberg M, et al. Human vestibular cortex as identified with caloric stimulation in functional magnetic resonance imaging. Neuroimage 2002;17:1384–1393.

Authorship L.M. and C.L. contributed equally to the present study.

Potential Conflicts of Interest L.M.: grant, Novartis.

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