Interfering with the neural activity of mirror-related frontal areas impairs mentalistic inferences

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ArticleTitle Interfering with the neural activity of mirror-related frontal areas impairs mentalistic inferences

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Article CopyRight Springer-Verlag Berlin Heidelberg(This will be the copyright line in the final PDF)

Journal Name Brain Structure and Function

Corresponding Author Family Name DuffauParticle

Given Name HuguesSuffix

Division Department of Neurosurgery, CHRU Montpellier

Organization Gui de Chauliac Hospital

Address 80, Avenue Augustin Fliche, Montpellier, 34295, France

Division Institute for Neuroscience of Montpellier, INSERM 1051

Organization Hôpital Saint Eloi

Address Montpellier, 34091, France

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Address

Email [email protected]

Author Family Name HerbetParticle

Given Name GuillaumeSuffix

Division Department of Neurosurgery, CHRU Montpellier

Organization Gui de Chauliac Hospital

Address 80, Avenue Augustin Fliche, Montpellier, 34295, France

Division Institute for Neuroscience of Montpellier, INSERM 1051

Organization Hôpital Saint Eloi


Division

Organization University of Montpellier 1


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Author Family Name LafargueParticle

Given Name GillesSuffix

Division Functional Neuroscience and Pathologies Lab, EA-4559

Organization Lille Nord de France University

Address Loos, 59120, France

Email

Author Family Name Moritz-Gasser

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Given Name SylvieSuffix

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Author Family Name BonnetblancParticle

Given Name FrançoisSuffix

Division Cognition, Action and Sensorimotor Plasticity Lab, INSERM U-1093, UFRSTAPS

Organization University of Bourgogne

Address Dijon, 27877, France

Division LIRMM, DEMAR Team, CNRS, INRIA



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Organization University Institute of France

Address Paris, 75005, France

Email

Schedule

Received 1 December 2013

Revised

Accepted 11 April 2014

Abstract According to recently proposed interactive dual-process theories, mentalizing abilities emerge from thecoherent interaction between two physically distinct neural systems: (1) the mirror network, coding for thelow-level embodied representations involved in pre-reflective sociocognitive processes and (2) thementalizing network per se, which codes for higher level representations subtending the reflective attributionof psychological states. However, although the latest studies have shown that the core areas forming thesetwo neurocognitive systems do indeed maintain effective connectivity during mentalizing, it is unclearwhether an intact mirror system (and, more specifically, its anterior node, namely the posterior inferior frontalcortex) is a prerequisite for accurate mentalistic inferences. Intraoperative brain mapping via direct electricalstimulation offers a unique opportunity to address this issue. Electrical stimulation of the brain creates a“virtual” lesion, which provides functional information on well-defined parts of the cerebral cortex. In thepresent study, five patients were mapped in real time while they performed a mentalizing task. We found sixresponsive sites: four in the lateral part of the right pars opercularis and two in the dorsal part of the right parstriangularis. On the subcortical level, two additional sites were located within the white matter connectivityof the pars opercularis. Taken as a whole, our results suggest that the right inferior frontal cortex and itsunderlying axonal connectivity have a key role in mentalizing. Specifically, our findings support thehypothesis whereby transient, functional disruption of the mirror network influences higher order mentalisticinferences.

Keywords (separated by '-') Mentalizing system - Mirror system - Pars opercularis - Brain mapping - Direct electrical stimulation - Socialcognition

Footnote Information Electronic supplementary material The online version of this article (doi:10.1007/s00429-014-0777-x)contains supplementary material, which is available to authorized users.

Metadata of the article that will be visualized in OnlineAlone

Electronic supplementarymaterial

Below is the link to the electronic supplementary material.Video 1.avi: A sample extract of theintraoperative stimulation procedure. This video shows a sample extract of the cortical mappingprocedure in patient FC while she was performing the mentalizing task.MOESM1: Supplementary material 1 (MP4 18380 kb).MOESM2: Supplementary material 2 (PDF 249 kb).MOESM3: Supplementary material 3 (PDF 196 kb).

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ORIGINAL ARTICLE1

2 Interfering with the neural activity of mirror-related frontal areas

3 impairs mentalistic inferences

4 Guillaume Herbet • Gilles Lafargue •

5 Sylvie Moritz-Gasser • Francois Bonnetblanc •

6 Hugues Duffau

7 Received: 1 December 2013 / Accepted: 11 April 20148 � Springer-Verlag Berlin Heidelberg 2014

9 Abstract According to recently proposed interactive

10 dual-process theories, mentalizing abilities emerge from

11 the coherent interaction between two physically distinct

12 neural systems: (1) the mirror network, coding for the low-

13 level embodied representations involved in pre-reflective

14 sociocognitive processes and (2) the mentalizing network

15 per se, which codes for higher level representations sub-

16 tending the reflective attribution of psychological states.

17 However, although the latest studies have shown that the

18 core areas forming these two neurocognitive systems do

19 indeed maintain effective connectivity during mentalizing,

20 it is unclear whether an intact mirror system (and, more

21 specifically, its anterior node, namely the posterior inferior

22 frontal cortex) is a prerequisite for accurate mentalistic

23 inferences. Intraoperative brain mapping via direct elec-

24 trical stimulation offers a unique opportunity to address

25 this issue. Electrical stimulation of the brain creates a

26‘‘virtual’’ lesion, which provides functional information on

27well-defined parts of the cerebral cortex. In the present

28study, five patients were mapped in real time while they

29performed a mentalizing task. We found six responsive

30sites: four in the lateral part of the right pars opercularis

31and two in the dorsal part of the right pars triangularis. On

32the subcortical level, two additional sites were located

33within the white matter connectivity of the pars opercu-

34laris. Taken as a whole, our results suggest that the right

35inferior frontal cortex and its underlying axonal connec-

36tivity have a key role in mentalizing. Specifically, our

37findings support the hypothesis whereby transient, func-

38tional disruption of the mirror network influences higher

39order mentalistic inferences. 40

41Keywords Mentalizing system � Mirror system � Pars

42opercularis � Brain mapping � Direct electrical stimulation �

43Social cognition

A1 Electronic supplementary material The online version of thisA2 article (doi:10.1007/s00429-014-0777-x) contains supplementaryA3 material, which is available to authorized users.

A4 G. Herbet � H. Duffau (&)

A5 Department of Neurosurgery, CHRU Montpellier,

A6 Gui de Chauliac Hospital, 80, Avenue Augustin Fliche,

A7 34295 Montpellier, France

A8 e-mail: [email protected]

A9 G. Herbet � H. Duffau

A10 Institute for Neuroscience of Montpellier, INSERM 1051,

A11 Hopital Saint Eloi, 34091 Montpellier, France

A12 G. Herbet � S. Moritz-Gasser

A13 University of Montpellier 1, 34967 Montpellier, France

A14 G. Lafargue

A15 Functional Neuroscience and Pathologies Lab, EA-4559,

A16 Lille Nord de France University, 59120 Loos, France

A17 F. Bonnetblanc

A18 Cognition, Action and Sensorimotor Plasticity Lab,

A19 INSERM U-1093, UFR STAPS, University of Bourgogne,

A20 27877 Dijon, France

A21 F. Bonnetblanc

A22 LIRMM, DEMAR Team, CNRS, INRIA, University of

A23 Montpellier 2, 34095 Montpellier, France

A24 F. Bonnetblanc

A25 University Institute of France, 75005 Paris, France

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44 Introduction

45 In the field of social neuroscience, the nature of the cog-

46 nitive processes involved in mentalizing (i.e., the socio-

47 cognitive function that enables human beings to attribute

48 mental states to others; Premack and Woodruff 1978) is

49 subject to much debate On the neurocognitive level, two

50 complex, brain-wide neural systems have been repeatedly

51 pinpointed by researchers as having particular functional

52 significance in mentalizing––the so-called mirror system

53 on the one hand and the mentalizing system per se on the

54 other (Coricelli 2005; Uddin et al. 2007; Keysers and

55 Gazzola 2007; Lombardo et al. 2010a; Bohl and van den

56 Bos 2012; Kennedy and Adolphs 2012; Barrett and Satpute

57 2013; Molnar-Szakacs and Uddin 2013).

58 The putative mirror neuron system is formed by a

59 number of areas located throughout the brain, including (at

60 least) the ventral premotor cortex and its neighboring

61 posterior inferior frontal cortex, the rostral part of the

62 inferior parietal lobule and the intraparietal sulcus (Riz-

63 zolatti and Craighero 2004). This frontoparietal mirror

64 network may subserve the low-level, pre-reflective,

65 embodied processes subtending basic sociocognitive

66 functions such as emotional empathy, basic emotion rec-

67 ognition, and motor intention decoding (Carr et al. 2003;

68 Iacoboni et al. 2005; Shamay-Tsoory et al. 2009). Indeed,

69 the mirror network may provide a rapid means of auto-

70 matically identifying another person’s affective and

71 intentional states through sensorimotor-based, intersubjec-

72 tive resonance mechanisms (the simulationist approach;

73 Carruthers and Smith 1996; Gallese and Goldman 1998).

74 Even though this hypothesis has been recently challenged

75 (ex. Hamilton 2013), it has nevertheless been postulated

76 that dysfunction of mirror mechanisms accounts for a set of

77 pathological conditions in which impaired social cognition

78 is frequent (notably autism spectrum disorders) (Dapretto

79 et al. 2006; Gallese et al. 2013).

80 The mentalizing system per se is generally considered to

81 involve a set of midline brain structures (including the

82 mesial prefrontal cortex, the rostral part of the anterior

83 cingulate cortex, the posterior cingulate cortex and the

84 ventral part of the precuneus) and some more lateral pos-

85 terior regions (notably the temporoparietal junctions). The

86 existence of this type of frontotemporoparietal system is

87 now well established, thanks to data from numerous lesion

88 and fMRI studies and recent efforts to summarize this

89 knowledge through authoritative, qualitative and quantita-

90 tive meta-analyses (Gallagher and Frith 2003; Amodio and

91 Frith 2006; Carrington and Bailey 2009; Van Overwalle

92 2009; Van Overwalle and Baetens 2009; Mar 2011).

93 Unlike the mirror neuron system, the mentalizing system

94 may be involved in sustaining the higher level processes

95 needed to reflectively infer another person’s psychological

96state––such as proximal intentions, motives and complex

97emotions. This network overlaps markedly with a more

98domain-general network (i.e., the so-called default mode

99network) involved in self-referential processing and meta-

100cognition (Schilbach et al. 2008, 2012; Spreng et al. 2009;

101Mars et al. 2012).

102Although the mirror and mentalizing systems are both

103generally acknowledged to be clearly dissociated from an

104anatomical standpoint, their respective contributions to

105mentalizing is subject to debate––especially with respect to

106whether mentalizing might arise from a dynamic, coordi-

107nated interaction between the two networks. Until recently,

108most researchers considered that mirror neuron network

109was rather weakly involved in mentalizing; this was mainly

110because the brain areas forming the respective neurocog-

111nitive systems were rarely found to be co-activated during

112fMRI paradigms (Van Overwalle and Baetens 2009).

113However, this view was contradicted by recent quantitative

114meta-analyses of fMRI datasets using the activation likeli-

115hood estimation method (Mar 2011; Spreng et al. 2009;

116Bzdok et al. 2012). These analyses showed that the posterior

117inferior cortex (a critical node within the mirror system,

118including the pars opercularis and the pars triangularis)

119made a significant contribution during mentalizing tasks.

120These results have been directly confirmed in brain con-

121nectivity studies. Cortical areas belonging to both the mirror

122and mentalizing systems indeed showed effective connec-

123tivity or functional coupling during the reflective attribution

124of emotions or intentions (Lombardo et al. 2010a; Spunt and

125Lieberman 2012, 2013; Kana et al. 2014); these findings

126provide genuine support for the integrative, interactive,

127dual-process theory of mentalizing processes (Uddin et al.

1282007; Keysers and Gazzola 2007; Lieberman 2007; Molnar-

129Szakacs and Uddin 2013; Herbet et al. 2014). However, on

130the behavioral level, it is still not clear whether an intact

131mirror system is required for accurate mentalizing. Two

132recent lesion studies shed some light on this question and

133have provided evidence of a substantial role for the pars

134opercularis in the accurate attribution of mental states

135(Shamay-Tsoory et al. 2009; Herbet et al. 2013).

136Direct electrical stimulation (DES) of the brain during

137neurosurgery under local anesthesia (i.e., awake surgery)

138offers a unique opportunity to gain insight into the role of

139the mirror neuron system during mentalizing. The DES of

140brain tissue induces a transient, ‘‘virtual’’ lesion in a spa-

141tially and topographically well-defined part of the cerebral

142cortex. The effectiveness of this intraoperative brain

143mapping method has been repeatedly confirmed in cogni-

144tive neuroscience (for a critical review, see Desmurget

145et al. 2013), ranging from older but detailed studies by

146Penfield and Jasper (1954) and Whitaker and Ojemann

147(1977); Ojemann and Mateer (1979) to current work

148focusing on the functional role of the long-range axonal

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149 connectivity that subserves complex, brain-wide neuro-

150 cognitive systems (Duffau et al. 2002, 2005, 2013; Moritz-

151 Gasser et al. 2013; Rech et al. 2013; Schucht et al. 2013;

152 Khan et al. 2013). In the present study, we used DES to

153 functionally disrupt (on-line) the mirror network’s anterior

154 node while the patient was performing a mentalizing task

155 (i.e., attributing complex affective mental states). We

156 developed a straightforward hypothesis: if functionally

157 intact mirror areas are required for accurate mentalistic

158 inferences, stimulating the posterior inferior frontal cortex

159 (and, consequently, its underlying anatomical connectivity)

160 should impair performance in social inferences. As

161 explained in detail below, our study results supported this

162 hypothesis.

163 Materials and methods

164 Neurological participants

165 Five patients with a diffuse, low-grade, right-hemisphere

166 glioma were included in the study (see Table 1 for soci-

167 odemographic and clinical data). In line with our classical

168 surgical approach, they were operated on under local

169 anesthesia (i.e., awake surgery) by the same well-experi-

170 enced neurosurgeon (HD, the senior author), while cortical-

171 subcortical brain mapping was performed via DES. Awake

172 resection with DES enables the surgeon to avoid brain

173 structures involved in certain cognitive processes and,

174 consequently, reduces the incidence of long-term cognitive

175 disorders (Duffau et al. 2002, 2005). All patients were also

176 mapped for visuospatial cognition, language processes,

177 speech articulation and motor cognition.

178 The behavioral task and preoperative assessments

179 On the day before the surgery, patients were asked to

180 perform the revised version of the ‘‘Reading the Mind in

181 the Eyes’’ (RME) test (Baron-Cohen et al. 2001). This task

182consists in the presentation of 36 photographs of the eye

183region of human faces. Participants are asked to say which

184of the four mental states best describes what the character

185‘‘is feeling or thinking’’. In our study, each photograph was

186presented separately on a PowerPoint� slide. Patients were

187required to respond as accurately and as rapidly as possible.

188Previous fMRI-based studies have shown that this behav-

189ioral paradigm engages both the mirror neural network and

190the mentalizing network (Baron-Cohen et al. 1999, 2006;

191Russell et al. 2000; Adams et al. 2010; Castelli et al. 2010;

192Moor et al. 2012; Schurz et al. 2014).

193Behavioral data on 24 control healthy subjects (obtained

194from two recent studies (Herbet et al. 2013, 2014) were

195used to transform the patients’ individual scores into age-

196adjusted Z scores. The subjects were divided into three age

197classes (n = 8 subjects per group) with an equal number of

198females and males mean ± SD (range) age:

19925.3 ± 2.61 years (22–29) in Group 1; 37.75 ± 3.01

200(34–42) in Group 2; 57.25 ± 4.83 (51–65) in Group 3.

201Patient FC’s score was transformed using the normative

202data from the Group 1 [mean RME score: 26.75 ± 2.37

203(range 24–30)]. The scores for patients FI, DT and GC

204were transformed using the normative data from Group 2

205[mean RME score: 25.5 ± 2.82 (22–30)]. Lastly, patient

206ZP’s score was transformed using the normative data from

207Group 3 [mean RME score: 21.25 ± 3.32 (17–27)].

208The intraoperative task and the DES procedures

209Intraoperative DES has been extensively characterized in

210previous research (Whitaker and Ojemann 1977; Ojemann

211and Mateer 1979; Duffau et al. 2002, 2005). Biphasic

212electrical current was delivered with a bipolar electrode

213(tip-to-tip distance: 5 mm), using the following parameters:

214a pulse frequency of 60 Hz, a single pulse phase duration

215of 1 ms, and an amplitude ranging from 2 to 4 mA. In

216accordance with the well-defined method developed by

217Ojemann and Mateer (1979), stimulation was never con-

218secutively applied twice at the same location.

Table 1 Sociodemographic and clinical data

Patient Sociodemographic data Clinical data

Age Gender Educ. Handed. IQ Site Volume (cc) RMEa scores Age-adjusted Z scores

FC 25 F 17 R 110 IFC–vmPFC 23 28 0.53

FI 36 F 17 R 108 PFC 74 31 1.95

DT 37 M 17 R 106 SMA–mPFC 46 29 1.35

GC 34 F 17 R 115 FTI 120 28 0.89

ZP 60 M 9 R 101 Ant/mid TC 48 20 -0.38

IFC inferior frontal cortex, vmPFC ventromedial prefrontal cortex, PFC prefrontal cortex, SMA supplementary motor area, mPFC medial

prefrontal cortex, FTI fronto-temporo-insular, ant/mid TC anterior/middle temporal cortexa Preoperative results obtained with the revised version of the Reading the Mind in the Eyes task

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219 Figure 1 illustrates the intraoperative experimental

220 design. The task used during neurosurgery was adapted to

221 raise its sensitivity. Specifically, only two items [the cor-

222 rect response (CR) and an outlying response] were pro-

223 posed. Moreover, the choice of items was based on the CRs

224 obtained during the preoperative evaluation. This individ-

225 ualized, intraoperative task was implemented in a MAT-

226 LAB environment (http://www.mathworks.com); and the

227 script was generated with the Cogent 2000 toolbox (http://

228 www.vislab.ucl.ac.uk/cogent_2000). The task was admin-

229 istered on a laptop computer (Inter� CoreTM 17-2820QM,

230 2.30 GHz CPU, 4 processors, 16.0 Go).

231 Each trial was initiated by the neuropsychologist. At that

232 moment, a sound signal informed the neurosurgeon that the

233 trial had begun. Stimuli were presented 500 ms after the

234 sound signal, so that stimulations could be delivered

235 simultaneously. Reponses were given verbally, and the

236 neuropsychologist recorded them as quickly as possible by

237 pressing key 1 (left response) or key 2 (right response). The

238 program automatically determined whether the response

239 was correct (‘‘correct’’ in green type was then displayed on

240 the screen) or incorrect (‘‘incorrect’’ in red type was then

241 displayed on the screen). As in the preoperative assess-

242 ment, the patients were asked to give their responses as

243 accurately and as rapidly as possible. Electrical stimulation

244 was not applied to the brain tissue for more than 5 s at

245 time, to maintain specificity (i.e., by limiting the spatial

246 diffusion of the electrical current). Importantly, both the

247 patient and the neuropsychologist were fully blinded to

248 whether or not electrical stimulation was applied during a

249 given trial, to make the assessment as objective as possible.

250 The neurosurgeon decided on the number of responsive

251 stimulations required for good reproducibility.

252 Statistical analyses

253 We used Fisher’s exact test to determine the statistical

254 significance of our results (variable 1: DES applied: yes vs.

255no; variable 2: patient’s response: correct vs. incorrect). An

256error or the absence of a response (defined as a response

257time[12 s) was considered to be an incorrect response.

258Stimulation sites

259Responsive and non-responsive cortical DES sites were

260directly registered on the three-dimensional Montreal

261Neurological Institute template, on the basis of intraoper-

262ative photos (responsive sites were labeled with number

263tags during surgery) and a video of the functional mapping

264session. Brain sulci and rami were used as anatomical

265landmarks (i.e., relative to the precentral sulcus, the infe-

266rior frontal sulcus, the anterior ascending ramus and the

267anterior horizontal ramus, for stimulations applied to the

268inferior frontal gyrus). This method is much more precise

269than registering the stimulation coordinates on original

270MRI scans via a neuronavigation system. Slow-growing

271lesions (and resection of the latter) can induce slight dis-

272placements in brain structures, which potentially skew the

273exact locations of the stimulation sites. To ensure the

274accuracy of our work, stimulation site registration was

275carried out independently by two investigators (the neu-

276rosurgeon and the lead author). The resulting cortical maps

277were then compared and (in the event of disparities)

278modified by consensus.

279Results

280Preoperative behavioral performance

281Sociodemographic and clinical data are summarized in

282Table 1. At the preoperative stage (the day before surgery),

283mentalizing was assessed with the revised version of the

284RME task (Baron-Cohen et al. 2011). All patients showed

285normal performance levels when compared with closely

286age-matched, healthy participants.

Fig. 1 The mentalizing task and the intraoperative procedure

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287 Cortical mapping

288 As detailed in the ‘‘Methods’’ section and Fig. 1, the

289 intraoperative task was individually modified and simpli-

290 fied (relative to the preoperative task), to substantially

291 increase its sensitivity. The video ESM_1.mpg provides an

292 extract of the intraoperative stimulation procedure. Fig-

293 ure 2 summarizes the functional mapping results for each

294 patient (including the responsive and the non-responsive

295 anatomical sites). The figure ESM_2.pdf shows intraoper-

296 ative photos on which the locations of responsive sites are

297 indicated by number tags).

298 In patient FC, the overall right inferior frontal gyrus was

299 thoroughly mapped. Electrical stimulation was applied in

300 21 of the 38 trials. Two cortical sites were found to induce

301 changes in behavioral performance: (1) the lateral part of

302 the pars opercularis (1 CR out of 5; p = 0.009) and the

303 dorsal part of the pars triangularis (2 CRs out of 5,

304 p = 0.055). Stimulation of other sites did not lead to errors

305 (n = 11). Fifteen of the 17 stimulation-free trials were

306 completed successfully. Figure 3a provides a detailed

307 functional cortical map for patient FC.

308 In patient FI, both the right inferior frontal gyrus and the

309 posterior part of the middle frontal gyrus were mapped.

310 Electrical stimulation was applied in 10 of the 20 trials. A

311 responsive site was detected in the ventrolateral sector of

312the pars opercularis (4 stimulations: one error, two non-

313responses, and one CR, p = 0.033). Stimulation of other

314sites did not lead to errors (n = 6), and all 10 of the

315stimulation-free trials were completed successfully.

316In patient DT, the pars triangularis and opercularis and

317the posterior middle frontal gyrus were mapped. Electrical

318stimulation was applied in 12 of the 26 trials. A responsive

319site was detected in the lateral part of the pars triangularis

320(3 stimulations: one error, and two non-responses,

321p = 0.001). Stimulation of other sites did not lead to errors

322(n = 9), and all 14 of the stimulation-free trials were

323completed successfully.

324In patient GC, the cortical mapping was centered on the

325inferior frontal gyrus and the anterior and middle parts of

326the superior temporal gyrus. Electrical stimulation was

327applied in 16 of the 40 trials. A responsive site was found

328in the dorsal part of the pars triangularis (2 out of 5 CRs;

329p = 0.018), It is noteworthy that one of the responsive

330stimulations induced three successive errors. Stimulation of

331other sites did not lead to errors (n = 11), and 21 of the 24

332stimulation-free trials were completed successfully.

333In patient ZP, the cortical mapping involved the pos-

334terior inferior frontal gyrus, the superior and middle tem-

335poral gyrus, and the temporoparietal junction as well.

336Electrical stimulation was applied in 13 of the 28 trials.

337The lateral part of the pars opercularis was found to be

Fig. 2 Cortical mapping results. Black lightning flashes indicate sites

that responded to DES. White diamonds indicate non-responsive

stimulation sites. The red area on the three-dimensional template

indicates the resection cavity. The overall responses are summarized

in the central figure (bottom). Figure S1 indicates the site locations on

intraoperative photos

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338 responsive (1/3 CRs, p = 0.033) Stimulation of other sites

339 did not lead to errors (n = 10). All the stimulation-free

340 trials were succeeded (15).

341 Subcortical mapping

342 Axonal connectivity was also mapped in two patients (FC

343 and FI). Two sites were identified in the deep posterior

344 inferior frontal gyrus, within the associative white matter

345 connectivity (see Fig. 3b for patient FC; see ESM_3.pdf for

346 both patients).

347 Discussion

348 In the present study, we used intraoperative DES as a novel

349 tool for establishing whether functionally intact anterior

350 mirror areas are required for the accurate assessment of

351 another person’s psychological state. Our observations

352 argue in favor of this hypothesis. When functionally dis-

353 rupted by DES, six anatomical sites within the posterior

354 inferior frontal gyrus were associated with significant

355 impairments of mentalizing accuracy. Two additional sites

356 were detected within the associative white matter connec-

357 tivity deep under this brain region. Below, we discuss our

358 results’ implications with regard to the recently proposed

359 dual-process models of social cognition and mentalizing.

360 We also speculate on the white matter connectivity

361 underlying the mirror system.

362 An emerging view in social cognitive neuroscience is

363 that mentalizing should not solely be considered as the

364 byproduct of neural computation by the intrinsic (infer-

365 ence-based) mentalizing network (defined in its strict sense

366 as being composed of the brain’s midline structures and the

367 temporoparietal junctions). In fact, this sociocognitive

368function may be better addressed through its reciprocal

369functional interactions with the older (from an evolutionary

370point of view (Gallese and Goldman 1998) mirror mech-

371anisms (Coricelli 2005; Uddin et al. 2007; Keysers and

372Gazzola 2007; Lombardo et al. 2010a; Bohl and van den

373Bos 2012; Kennedy and Adolphs 2012; Zaki and Ochsner

3742012; Barrett and Satpute 2013; Molnar-Szakacs and Ud-

375din 2013). This type of dual-process theory has been un-

376derpinned by recent studies showing that certain cortical

377areas from both the mirror and mentalizing networks dis-

378play functional coupling or effective connectivity during

379the inference of psychological states (Zaki et al. 2009;

380Lombardo et al. 2010; Spunt and Lieberman 2012). How-

381ever, the significance of this functional integration is much

382less well understood. In particular, a key issue is to what

383extent the mirror neuron system (performing low-level,

384pre-reflective processes) contributes to the accuracy of

385higher order reflective inferences about mental states. Our

386present results provide some important clues in this respect

387and indicate that the transient absence of neural activity in

388several sites in the right posterior inferior frontal gyrus has

389a significant impact on behavioral performance levels. Our

390observations were highly specific, in as such as stimulation

391of many other numerous anatomical sites (covering the

392prefrontal, temporal and, to a lesser extent, posterior pari-

393etal cortex) never induced incorrect attributions. Further-

394more, functional mapping of the inferior frontal gyrus for

395other cognitive processes (including visuospatial cognition,

396language, speech articulation and motor cognition) was

397inconclusive, which strengthens our results in terms of

398functional specificity. First and foremost, our results echo

399(at the behavioral level) those obtained in a recent fMRI-

400based study by Zaki et al. (2009), in which the level of

401neural activity in both systems predicted the accuracy of

402(explicit) empathic judgments.

403The lateral part of the pars opercularis was identified as

404a key structure in mentalizing accuracy. In line with our

405starting hypothesis, one can justifiably attribute the DES-

406triggered impairments in mentalizing to transient dys-

407function of the mirror network. It is well established that

408the pars opercularis harbors neurons with mirror properties.

409Almost all fMRI studies using ‘‘mirror’’ tasks have pin-

410pointed this brain region as a central cortical node in the

411mirror system (Molenberghs et al. 2009; Caspers et al.

4122010). Furthermore, pars opercularis damage is known to

413impair mirror-related functions, such as emotional empathy

414(Shamay-Tsoory et al. 2009) and face-based perceptual

415mentalizing (Herbet et al. 2013). Abnormal neural activity

416within the mirror network (and especially within the pars

417opercularis) is known to characterize psychopathological

418conditions (such as autistic spectrum disorders) with

419archetypal impairments in social perception and cognition

420(including mentalizing) (Baron-Cohen et al. 1994; Iacoboni

bFig. 3 Illustrative cortical and subcortical mapping result for a

representative patient (FC). a Cortical mapping results. Two sites

induced mentalizing impairments when stimulated: one in the lateral

sector of the pars opercularis (label 3) and the other in the dorsal

sector of the pars triangularis (label 4). Stimulation of other sites in

the inferior frontal gyrus [including the dorsal opercularis (op2), the

caudal (t1), ventral (t2), rostral (t3) sector of the pars triangularis, and

three sites in the pars orbitalis (o1, o2, o3)] did not lead to mentalizing

impairments. Video 1 shows a sample extract of the cortical mapping

procedure in this patient. b Subcortical mapping results. A decrease in

mentalizing accuracy was also induced by stimulating the associative

white matter connectivity, deep within the posterior inferior frontal

gyrus (label 49). Another site was found to induce a slowing in

response times (label 50) in the white matter in contact with the head

of the caudate nucleus (which could be observed by eye during

surgery). It is well known that the caudate nucleus is involved in

cognitive control. DES: direct electrical stimulation. Labels 1 and 2

on the intraoperative photos correspond, respectively, to anarthria

(during stimulation of the ventral premotor cortex) and facial

deviation (during stimulation of the face’s primary motor area)

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421 and Dapretto 2006). Very recently, functional under-con-

422 nectivity between areas of the mentalizing system and the

423 mirror system (including the posterior inferior frontal

424 gyrus) was observed in patients with autism performing an

425 intention attribution task (Kana et al. 2014). These results

426 suggests that the two networks act in concert when inten-

427 tions are explicitly inferred and that the lack of functional

428 integration between these networks may account for the

429 inaccurate causal attributions observed in this patient

430 population (compared with healthy subjects) (see also

431 Lombardo et al. 2010b).

432 An interpretation in terms of mirror mechanism dys-

433 function is less obvious for the neighboring pars triangu-

434 laris, where two responsive sites were detected in the dorsal

435 part of this structure. Although the pars triangularis is not

436 generally considered to be a mirror area, all the meta-

437 analyses of fMRI studies using ‘‘mirror paradigms’’ have

438 systematically identified it as a region of interest (Grezes

439 and Decety 2001; Molenberghs et al. 2009, 2012; Caspers

440 et al. 2010). Neurons in the dorsal portion of the right pars

441 triangularis discharge during action and emotional face

442 perception (Caspers et al. 2010). However, these neurons

443 do not seem to be activated during execution––a necessary

444 condition for classification as mirror neurons (Rizzolati and

445 Craighero 2004). Only one study has provided evidence to

446 suggest that imitation and observation of faces expressing

447 emotional states activate the pars triangularis as well as the

448 classical anterior mirror areas (e.g., the pars opercularis and

449 the ventral premotor cortex) (Carr et al. 2003). In this

450 context, stimulating the dorsal pars triangularis might dis-

451 rupt a perceptual neural representation required in face-

452 related affective state identification rather than the senso-

453 rimotor resonance processes subtending by the mirror

454 neurons per se. This could explain why we found two

455 responsive sites (in the lateral pars opercularis and the

456 dorsal pars triangularis) in patient FC. At the task-specific

457 level, it is noteworthy that both the pars triangularis and the

458 pars opercularis are activated when subjects process an

459 RME task (Adams et al. 2010; Moor et al. 2012).

460 Our detection of two responsive sites in the deep pos-

461 terior inferior frontal gyrus (within the associative white

462 matter connectivity) is striking in at least two respects.

463 Firstly, it suggests that mentalizing impairments induced

464 by stimulation of the cortex (a local effect) can be repro-

465 duced by disrupting the network itself (a large-scale, non-

466 local, distributed effect). When DES is applied to long-

467 range associative pathways, it mimics a disconnection

468 syndrome (Duffau et al. 2002, 2005) (i.e., altered func-

469 tional coupling between the spatially distributed cortical

470 nodes of a given neurocognitive network, which leads to

471 functional impairment). Secondly, these findings provide

472 potentially important information on associative white

473 matter connectivity which may convey mirror-related

474neural information. This topic has not been extensively

475explored in the literature, even though it was discussed in a

476recent DTI-based comparative study (Hecht et al. 2013). In

477view of the perisylvian network’s connections with mirror

478cortical areas (as demonstrated in DTI-based and anatom-

479ical dissection studies), the structure is a good candidate for

480the sustenance of mirror-like processes (Iacoboni and

481Dapretto 2006; Hecht et al. 2013). Indeed, the two parallel

482associative pathways involved in this complex connectivity

483(i.e. the arcuate fasciculus and the lateral/superficial

484superior longitudinal fasciculus (AF/lSLF)) have cortical

485terminations within classical frontoparietal mirror areas.

486The lSLF connects the rostral posterior parietal cortex and

487the intraparietal sulcus to anterior mirror areas (particularly

488the ventral part of precentral gyrus) (Makris et al. 2005;

489Rilling et al. 2008; Martino et al. 2013). One can therefore

490speculate that stimulation of the perisylvian network’s

491anterior connections induced mentalizing impairments.

492This would agree with recent suggestions that perisylvian

493connectivity is important for social cognition [particularly

494for emotional empathy (Parkinson and Wheatley 2012), a

495basic mirror-related function (Shamay-Tsoory et al. 2009)]

496and, more generally, emotional and social intelligence

497(Barbey et al. 2012). Above all, the present findings fit

498perfectly with the results of our very recent lesion study, in

499which behavioral performances in a low-level, face-based

500task (as used in the present study) and in a higher level,

501inference-based mentalizing task were negatively and

502specifically correlated with the degree of disconnection of

503the right perisylvian network (including the AF and the

504lSLF) and the right medial-cingulum networks, respec-

505tively (Herbet et al. 2014). These findings lay the ana-

506tomical foundations for a hodotopical, dual-stream model

507of mentalizing.

508It could be argued that our present results were task-

509specific. It is possible that the use of other tasks may have

510led to a dissimilar pattern of observations. Mentalizing

511tasks are not all built in the same way and the weighting

512between low-level, pre-reflective processes and high-level,

513reflective processes needed for optimal mentalizing per-

514formance is likely to depend on environmental/experi-

515mental demands (Lombardo et al. 2010). Although RME

516task necessarily recruits the inference-based mentalizing

517network (involved in making reflective judgments about

518another person’s mental state), as described in activation-

519related fMRI studies (Baron-Cohen et al. 2006; Adams

520et al. 2010; Moor et al. 2012), the mirror neuron system

521may assist with successful completion of the task because

522of its strong perceptual component. This is exactly what

523was been predicted and demonstrated in our recent lesion

524study; we showed that damage to the pars opercularis was

525clearly detrimental for the performance of the RME task,

526whereas medial prefrontal damage was not (Herbet et al.

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527 2013). In contrast, medial prefrontal damage dramatically

528 slowed the inferential process in an intention attribution

529 task, whereas pars opercularis damage did not lead to this

530 type of behavioral effect. Importantly, small, but significant

531 impairments in inferential processes were detected for

532 certain patients with damage to the pars opercularis, in

533 agreement with the classical view in which mirror mech-

534 anisms are involved in understanding intentions and

535 actions (Iacoboni et al. 2005).

536 One potential limitation of the present study relates to the

537 nature of the patients’ lesion. As diffuse low-grade glioma

538 progresses slowly, it can induce marked functional remod-

539 eling phenomena (Desmurget et al. 2007)––as shown in

540 fMRI studies (e.g., Krainik et al. 2004) and electrostimula-

541 tion studies (van Geemen et al. 2013). It could therefore be

542 argued that the spatial location of responsive sites may be

543 topographically biased. This potential limitation can be

544 discounted for at least two reasons. Firstly, none of the

545 functional sites identified here had been infiltrated by the

546 lesion. Secondly, the eloquent sites in the pars opercularis

547 were in approximately the same location, despite the fact that

548 the lesions/resections damaged brain regions that were

549 sometimes far apart and did not belong to the mirror network

550 (e.g., patient ZP’s lesion was located in the temporal cortex).

551 In summary, our present findings fit well with the social

552 neuroscience literature and lend substantial support to the

553 view that an intactmirror network is required for the accurate

554 assessment of another person’s mental state. Our result are

555 thus in good agreement with the interactive, integrative dual-

556 process theories inwhich functional integration of (cortically

557 distributed) low-level; embodied; simulative representations

558 and high-level, inference-based representations is required

559 for optimal sociocognitive functioning (Coricelli 2005;

560 Uddin et al. 2007; Keysers and Gazzola 2007; Lombardo

561 et al. 2010a; Bohl and van den Bos 2012; Kennedy and

562 Adolphs 2012; Barrett and Satpute 2013; Molnar-Szakacs

563 and Uddin 2013; Herbet et al. 2013, 2014). Furthermore, the

564 present study provides novel information on long-range

565 white matter connectivity that may subserve mirror-like

566 processes. Overall, our findings may open up new opportu-

567 nities for understanding pathological conditions in which

568 mentalizing function and the mirror mechanism are clearly

569 impaired (such as autism spectrum disorders).

570 Acknowledgments Guillaume Herbet received a fellowship from571 the Association pour la Recherche sur le Cancer (Grant Number:572 DOC20120605069).

573

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Interfering with the neural activity of mirror-related frontal areas impairs mentalistic inferences

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