Brain Advance Access published December 30, 2015 doi:10.1093/brain/awv381
BRAIN 2015: Page 1 of 4
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LETTER TO THE EDITOR The dorsal cingulate cortex as a critical gateway in the network supporting conscious awareness Guillaume Herbet,1,2 Gilles Lafargue3 and Hugues Duffau1,2
Correspondence to: Guillaume Herbet, Gui de Chauliac Hospital, Department of Neurosurgery, 80, avenue Augustin Fliche, F-34295 Montpellier, France E-mail: [email protected]
Sir, We have read with great interest the recent article by Balestrini et al. (2015) reporting a detailed cortical mapping of the parietal cortex. The work is remarkable in that it is based on the electrostimulation data from an impressive cohort of 172 patients with refractory focal epilepsy (419 cortical sites with a clinical response were unmasked), thus permitting authoritative conclusions about the functions of the different regions of the parietal cortex. In our opinion, one of the major strengths of the study is that it provides rare data on the medial part of this large brain territory, including the posterior cingulate cortex and the precuneus. Neurological insults in these areas are uncommon for biological reasons, and electrostimulation procedures in clinical patients provide a unique opportunity to probe their functional significance. In view of its widespread connections and its central position in several large-scale networks (i.e. default mode network), this transmodal cortex (Mesulam et al., 1998) is likely to participate in a wide-ranging set of high-level cognitive functions or processes, which are to date only suspected to originate through reverse inference from neuroimaging data. Current literature suggests a role in social cognition, autobiographic and topographical memory, auto-projective processes, and more generally in conscious self-awareness
(e.g. mind wandering) (Cavanna et al., 2006; Buckner et al., 2008; Leech and Sharp, 2013 for reviews). On the other hand, functional connectivity MRI studies performed in neurological patients converge towards the idea that this region would be central in the network supporting consciousness (Vogt and Laurey, 2005; Boly et al., 2008). In their study, the authors found that electrostimulation of the posterior cingulate cortex (16 and 34 effective stimulations were analysed in the left and right hemisphere, respectively), anatomically defined as including the ventral and dorsal part of the posterior cingulate, and the retrospenial cortex, mainly evoked motor responses and somatosensory sensations. A finding perhaps not sufficiently highlighted by the authors is that stimulation of the posterior cingulate cortex (no information is given about the precise location of stimulations) also caused—in a few patients—complex subjective experiences, grouped together by the authors under the term of ‘psychic phenomena’, including derealization or depersonalization, or other unclassified phenomena (see Balestrini et al.’s Supplementary material for examples). Although these data are subjective, they are too rare to not deserve attention, and subsequently not be the subject of further developments. To explain such psychic phenomena the authors raised the possibility of
ß The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected]
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1 Department of Neurosurgery, Gui de Chauliac Hospital, Montpellier University Medical Centre, F-34295 Montpellier, France 2 Institute for Neuroscience of Montpellier, INSERM U1051, Team ‘Plasticity of Central Nervous System, Human Stem Cells and Glial Tumours’, Saint Eloi Hospital, Montpellier University Medical Centre, France 3 University Lille, EA 4072, PSITEC: Psychologie, Interactions, Temps, Emotions, Cognition, F-59000, France
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complete method is fully described elsewhere (Tate et al., 2015). Cortical and white matter stimulations were systematically applied throughout the surgical procedure. The clinical responses were directly replaced by the neurosurgeon on immediate postoperative anatomical MRIs based on anatomical landmarks, and subsequently co-registered in the Montreal Neurological Institute (MNI) space. For illustration purposes, a spherical region of interest (radius of 2 mm) was generated for each stimulation point using the MarsBar toolbox (Brett et al., 2002) implemented in Matlab (Release 2014b, The MathWorks, Inc., Natick, Massachusetts). Patient CR had a lesion in the left precuneus (Fig. 1A). Electrostimulation of the white matter fibres very close to the dorsal posterior cingulate (MNI coordinates: 9 43 31) caused a deep state of confusion, three times. The patient stopped the behavioural task being performed, and was unresponsive during the stimulation time (4/5 s). He was confused for a period of 1–2 min after the stimulations, and was unable to precisely describe his experience. Patient AA had a lesion located in the right posterior precuneus, the ventral precuneus and the retrosplenial cortex (Fig. 1B). Transitory disruption of the dorsal posterior cingulate cortex (MNI coordinates: 9 46 30) induced a behavioural unresponsiveness four times (i.e. cessation of the task being performed and absence of responses to verbal solicitations). When questioned retrospectively, the patient reported to have had ‘a gap’ or ‘an absence’, or to have been ‘disconnected.’ Patient JM had a lesion infiltrating the right posterior and middle posterior cingulum (Fig. 1C). Stimulation of the white matter fibres immediately subserving the dorsal posterior cingulate cortex led to six successive major clinical responses (MNI coordinates: 10 36 35). Contrary to other patients, she continued to be responsive during the different electrostimulations, but systematically reported to be immersed in a ‘black whole’ and to have the exponential feeling ‘to lose consciousness’. This was experienced as being very disturbing. Interestingly, two dissociated responses were obtained more anteriorly, at the level of the middle cingulum: somatosensory sensations and motor responses (Fig. 1D). As show in Fig. 1D, the stimulation-induced altered states of consciousness were all situated in a relatively wellcircumscribed sector of the dorsal posterior cingulate cortex. The spatial specificity of stimulation sites was attested by the fact that stimulations were applied with a between-stimulation spacing of 5 mm—corresponding to the spatial resolution of the bipolar stimulator—and that all of the surgery resection boundaries were incorporated by this rigorous mapping. Taken as a whole, the reported findings clearly demonstrate that transient breakdown of the posterior cingulate cortex, and its underlying anatomical connectivity in both hemispheres, impact conscious information processing, albeit in a differing manner across patients. This
Downloaded from http://brain.oxfordjournals.org/ by guest on December 31, 2015
out-of-body experiences or related phenomena. In our opinion, a more likely alternative interpretation is that functional sideration of this medial area disrupts the processes involved in certain forms of self-consciousness such as agentive self-awareness (patient describes feeling ‘like a doll’) and consciousness of the external environment (i.e. patient reports the feeling of ‘being as in a parallel word’; patient describes a sensation of strangeness, unfamiliarity). Such clinical observations are in line with the increasingly acknowledged role of this region in multiple forms of internal, self-directed cognitions and corroborate the pattern of results previously reported in self-related psychopathologies showing an abnormal activity of the posterior medial parietal cortex, and more generally of the default mode network, for example schizophrenia (for a review, see Leech and Sharp, 2013). In a recent paper, we reported the case of a rare patient with a slow growing tumour mainly involving the left precuneus, the ventral posterior cingulate and retrospenial cortex (Herbet et al., 2014). In accordance with our standard approach, a surgery under local anaesthesia with a functional mapping via direct electrostimulation was performed. Remarkably, we found that electrostimulation of the white matter fibres directly serving the dorsal posterior cingulate led in a reproducible manner to an altered state of consciousness characterized by a behavioural unresponsiveness with loss of connectedness. Surprisingly, the patient was still able to retrospectively describe his subjective experience, which was close to those experienced in a dream (e.g. ‘I was as in a dream, there was . . .’), suggesting that some elements of ‘internal awareness’ persisted. Based on this finding, we suggested an involvement of the dorsal posterior cingulate in maintaining consciousness of external environment, an assumption in perfect agreement with the fact that almost all consciousness-related disorders from a neurological origin are associated with an abnormal functional connectivity of this brain area (Vanhaudenhuyse et al., 2010), that its metabolic activity is reduced in drug-induced (Carhart-Harris and Nutt, 2014) or sleeprelated (Horovitz et al., 2009) modified states of consciousness, and that the posterior cingulate may be conceived as a critical nexus allowing between-networks integration (Cocchi et al., 2013). Admittedly, although causally supporting these theories, the reported results were incidental. And it is not commonly appropriate to generalize on the basis of an isolated case. Here we report three new cases of very rare patients with a slow-growing lesion of the medial posterior parietal cortex in whom an altered state of consciousness, although phenomenologically dissimilar, was obtained under electrostimulation during a common awake surgery procedure, enabling both to confirm our previous results and interpretations, and to complete the mapping proposed by Balestrini et al. (2015). In the three patients, electrostimulation was applied with a bipolar electrode (tip-to-tip distance: 5 mm) delivering a biphasic current (parameters: 60 Hz, 1 ms pulse width, current amplitude ranging from 2 to 2.5 mA); the
Letter to the Editor
Letter to the Editor
BRAIN 2015: Page 3 of 4
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Downloaded from http://brain.oxfordjournals.org/ by guest on December 31, 2015
Figure 1 Anatomical data and stimulation site locations. Each patient-related section displays the preoperative fluid-attenuated inversion recovery (FLAIR) MRI, for better visualization of the lesion after surgical intervention, the resection cavity replaced in a 3D rendering (MNI152bet from MRIcronGL software) and the location of the responsive stimulation points in relation to the resection cavity. (A) Patient CR, (B) Patient AA, (C) Patient JM and (D) recapitulative figure with all stimulation points.
consolidates the recent idea that the posterior cingulate cortex, particularly in its dorsal sector, is crucial in regulating global brain dynamics and maintaining arousal and awareness (Leech and Sharp, 2013). Our data may inform current theories of consciousness and extend the mapping of the parietal cortex provided by Balestrini et al. (2015).
References Balestrini S, Francione S, Mai R, Castana L, Casaceli G, Marino D, et al. Multimodal responses induced by cortical stimulation of the parietal lobe: a stereo-electroencephalography study. Brain 2015; 138(Pt 9): 2596–607. Boly M, Phillips C, Tshibanda L, Vanhaudenhuyse A, Schabus M, Dang-Vu TT, et al. Intrinsic brain activity in altered states of
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consciousness: how conscious is the default mode of brain function? Ann N Y Acad Sci 2008: 1129: 119–29. Brett M, Anton JL, Valabregue R, Poline JB. Region of interest analysis using an SPM toolbox. [abstract] at the 8th International Conference of Functional mapping of the Humpan Brain, June 26, 2002, Sendai, Japan. Buckner RL, Andrews-Hanna JR, Schacter DL. The brain’s default network: anatomy, function, and relevance to disease. Ann N Y Acad Sci 2008; 1124: 1–38. Carhart-Harris R, Nutt D. Was it a vision or a waking dream? Front Psychol 2014; 5: 255. Cavanna AE, Trimble MR. The precuneus: a review of its functional anatomy and behavioural correlates. Brain 2006; 129(Pt 3): 564–83. Cocchi L, Zalesky A, Fornito A, Mattingley JB. Dynamic cooperation and competition between brain systems during cognitive control. Trends Cogn Sci 2013; 17: 493–501. Herbet G, Lafargue G, de Champfleur NM, Moritz-Gasser S, le Bars E, Bonnetblanc F, et al. Disrupting posterior cingulate connectivity
Letter to the Editor disconnects consciousness from the external environment. Neuropsychologia 2014; 56C: 239–44. Horovitz SG, Braun AR, Carr WS, Picchioni D, Balkin TJ, Fukunaga M, et al. Decoupling of the brain’s default mode network during deep sleep. Proc Natl Acad Sci 2009; 106(27): 11376–81. Leech R, Sharp DJ. The role of the posterior cingulate cortex in cognition and disease. Brain 2013; 18: 18. Mesulam MM. From sensation to cognition. Brain 1998; 121 (Pt 6): 1013–52. Vanhaudenhuyse A, Noirhomme Q, Tshibanda LJ, Bruno MA, Boveroux P, Schnakers C, et al. Default network connectivity reflects the level of consciousness in non-communicative brain-damaged patients. Brain 2010; 133(Pt 1): 161–71. Vogt BA, Laureys S. Posterior cingulate, precuneal and retrosplenial cortices: cytology and components of the neural network correlates of consciousness. Prog Brain Res 2005; 150: 205–17. Tate MC, Herbet G, Moritz-Gasser S, Tate JE, Duffau H. Probabilistic map of critical functional regions of the human cerebral cortex: Broca’s area revisited. Brain 2015; 2773–82.
Downloaded from http://brain.oxfordjournals.org/ by guest on December 31, 2015
BRAIN 2015: Page 1 of 4
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LETTER TO THE EDITOR The dorsal cingulate cortex as a critical gateway in the network supporting conscious awareness Guillaume Herbet,1,2 Gilles Lafargue3 and Hugues Duffau1,2
Correspondence to: Guillaume Herbet, Gui de Chauliac Hospital, Department of Neurosurgery, 80, avenue Augustin Fliche, F-34295 Montpellier, France E-mail: [email protected]
Sir, We have read with great interest the recent article by Balestrini et al. (2015) reporting a detailed cortical mapping of the parietal cortex. The work is remarkable in that it is based on the electrostimulation data from an impressive cohort of 172 patients with refractory focal epilepsy (419 cortical sites with a clinical response were unmasked), thus permitting authoritative conclusions about the functions of the different regions of the parietal cortex. In our opinion, one of the major strengths of the study is that it provides rare data on the medial part of this large brain territory, including the posterior cingulate cortex and the precuneus. Neurological insults in these areas are uncommon for biological reasons, and electrostimulation procedures in clinical patients provide a unique opportunity to probe their functional significance. In view of its widespread connections and its central position in several large-scale networks (i.e. default mode network), this transmodal cortex (Mesulam et al., 1998) is likely to participate in a wide-ranging set of high-level cognitive functions or processes, which are to date only suspected to originate through reverse inference from neuroimaging data. Current literature suggests a role in social cognition, autobiographic and topographical memory, auto-projective processes, and more generally in conscious self-awareness
(e.g. mind wandering) (Cavanna et al., 2006; Buckner et al., 2008; Leech and Sharp, 2013 for reviews). On the other hand, functional connectivity MRI studies performed in neurological patients converge towards the idea that this region would be central in the network supporting consciousness (Vogt and Laurey, 2005; Boly et al., 2008). In their study, the authors found that electrostimulation of the posterior cingulate cortex (16 and 34 effective stimulations were analysed in the left and right hemisphere, respectively), anatomically defined as including the ventral and dorsal part of the posterior cingulate, and the retrospenial cortex, mainly evoked motor responses and somatosensory sensations. A finding perhaps not sufficiently highlighted by the authors is that stimulation of the posterior cingulate cortex (no information is given about the precise location of stimulations) also caused—in a few patients—complex subjective experiences, grouped together by the authors under the term of ‘psychic phenomena’, including derealization or depersonalization, or other unclassified phenomena (see Balestrini et al.’s Supplementary material for examples). Although these data are subjective, they are too rare to not deserve attention, and subsequently not be the subject of further developments. To explain such psychic phenomena the authors raised the possibility of
ß The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://brain.oxfordjournals.org/ by guest on December 31, 2015
1 Department of Neurosurgery, Gui de Chauliac Hospital, Montpellier University Medical Centre, F-34295 Montpellier, France 2 Institute for Neuroscience of Montpellier, INSERM U1051, Team ‘Plasticity of Central Nervous System, Human Stem Cells and Glial Tumours’, Saint Eloi Hospital, Montpellier University Medical Centre, France 3 University Lille, EA 4072, PSITEC: Psychologie, Interactions, Temps, Emotions, Cognition, F-59000, France
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complete method is fully described elsewhere (Tate et al., 2015). Cortical and white matter stimulations were systematically applied throughout the surgical procedure. The clinical responses were directly replaced by the neurosurgeon on immediate postoperative anatomical MRIs based on anatomical landmarks, and subsequently co-registered in the Montreal Neurological Institute (MNI) space. For illustration purposes, a spherical region of interest (radius of 2 mm) was generated for each stimulation point using the MarsBar toolbox (Brett et al., 2002) implemented in Matlab (Release 2014b, The MathWorks, Inc., Natick, Massachusetts). Patient CR had a lesion in the left precuneus (Fig. 1A). Electrostimulation of the white matter fibres very close to the dorsal posterior cingulate (MNI coordinates: 9 43 31) caused a deep state of confusion, three times. The patient stopped the behavioural task being performed, and was unresponsive during the stimulation time (4/5 s). He was confused for a period of 1–2 min after the stimulations, and was unable to precisely describe his experience. Patient AA had a lesion located in the right posterior precuneus, the ventral precuneus and the retrosplenial cortex (Fig. 1B). Transitory disruption of the dorsal posterior cingulate cortex (MNI coordinates: 9 46 30) induced a behavioural unresponsiveness four times (i.e. cessation of the task being performed and absence of responses to verbal solicitations). When questioned retrospectively, the patient reported to have had ‘a gap’ or ‘an absence’, or to have been ‘disconnected.’ Patient JM had a lesion infiltrating the right posterior and middle posterior cingulum (Fig. 1C). Stimulation of the white matter fibres immediately subserving the dorsal posterior cingulate cortex led to six successive major clinical responses (MNI coordinates: 10 36 35). Contrary to other patients, she continued to be responsive during the different electrostimulations, but systematically reported to be immersed in a ‘black whole’ and to have the exponential feeling ‘to lose consciousness’. This was experienced as being very disturbing. Interestingly, two dissociated responses were obtained more anteriorly, at the level of the middle cingulum: somatosensory sensations and motor responses (Fig. 1D). As show in Fig. 1D, the stimulation-induced altered states of consciousness were all situated in a relatively wellcircumscribed sector of the dorsal posterior cingulate cortex. The spatial specificity of stimulation sites was attested by the fact that stimulations were applied with a between-stimulation spacing of 5 mm—corresponding to the spatial resolution of the bipolar stimulator—and that all of the surgery resection boundaries were incorporated by this rigorous mapping. Taken as a whole, the reported findings clearly demonstrate that transient breakdown of the posterior cingulate cortex, and its underlying anatomical connectivity in both hemispheres, impact conscious information processing, albeit in a differing manner across patients. This
Downloaded from http://brain.oxfordjournals.org/ by guest on December 31, 2015
out-of-body experiences or related phenomena. In our opinion, a more likely alternative interpretation is that functional sideration of this medial area disrupts the processes involved in certain forms of self-consciousness such as agentive self-awareness (patient describes feeling ‘like a doll’) and consciousness of the external environment (i.e. patient reports the feeling of ‘being as in a parallel word’; patient describes a sensation of strangeness, unfamiliarity). Such clinical observations are in line with the increasingly acknowledged role of this region in multiple forms of internal, self-directed cognitions and corroborate the pattern of results previously reported in self-related psychopathologies showing an abnormal activity of the posterior medial parietal cortex, and more generally of the default mode network, for example schizophrenia (for a review, see Leech and Sharp, 2013). In a recent paper, we reported the case of a rare patient with a slow growing tumour mainly involving the left precuneus, the ventral posterior cingulate and retrospenial cortex (Herbet et al., 2014). In accordance with our standard approach, a surgery under local anaesthesia with a functional mapping via direct electrostimulation was performed. Remarkably, we found that electrostimulation of the white matter fibres directly serving the dorsal posterior cingulate led in a reproducible manner to an altered state of consciousness characterized by a behavioural unresponsiveness with loss of connectedness. Surprisingly, the patient was still able to retrospectively describe his subjective experience, which was close to those experienced in a dream (e.g. ‘I was as in a dream, there was . . .’), suggesting that some elements of ‘internal awareness’ persisted. Based on this finding, we suggested an involvement of the dorsal posterior cingulate in maintaining consciousness of external environment, an assumption in perfect agreement with the fact that almost all consciousness-related disorders from a neurological origin are associated with an abnormal functional connectivity of this brain area (Vanhaudenhuyse et al., 2010), that its metabolic activity is reduced in drug-induced (Carhart-Harris and Nutt, 2014) or sleeprelated (Horovitz et al., 2009) modified states of consciousness, and that the posterior cingulate may be conceived as a critical nexus allowing between-networks integration (Cocchi et al., 2013). Admittedly, although causally supporting these theories, the reported results were incidental. And it is not commonly appropriate to generalize on the basis of an isolated case. Here we report three new cases of very rare patients with a slow-growing lesion of the medial posterior parietal cortex in whom an altered state of consciousness, although phenomenologically dissimilar, was obtained under electrostimulation during a common awake surgery procedure, enabling both to confirm our previous results and interpretations, and to complete the mapping proposed by Balestrini et al. (2015). In the three patients, electrostimulation was applied with a bipolar electrode (tip-to-tip distance: 5 mm) delivering a biphasic current (parameters: 60 Hz, 1 ms pulse width, current amplitude ranging from 2 to 2.5 mA); the
Letter to the Editor
Letter to the Editor
BRAIN 2015: Page 3 of 4
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Downloaded from http://brain.oxfordjournals.org/ by guest on December 31, 2015
Figure 1 Anatomical data and stimulation site locations. Each patient-related section displays the preoperative fluid-attenuated inversion recovery (FLAIR) MRI, for better visualization of the lesion after surgical intervention, the resection cavity replaced in a 3D rendering (MNI152bet from MRIcronGL software) and the location of the responsive stimulation points in relation to the resection cavity. (A) Patient CR, (B) Patient AA, (C) Patient JM and (D) recapitulative figure with all stimulation points.
consolidates the recent idea that the posterior cingulate cortex, particularly in its dorsal sector, is crucial in regulating global brain dynamics and maintaining arousal and awareness (Leech and Sharp, 2013). Our data may inform current theories of consciousness and extend the mapping of the parietal cortex provided by Balestrini et al. (2015).
References Balestrini S, Francione S, Mai R, Castana L, Casaceli G, Marino D, et al. Multimodal responses induced by cortical stimulation of the parietal lobe: a stereo-electroencephalography study. Brain 2015; 138(Pt 9): 2596–607. Boly M, Phillips C, Tshibanda L, Vanhaudenhuyse A, Schabus M, Dang-Vu TT, et al. Intrinsic brain activity in altered states of
e4
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consciousness: how conscious is the default mode of brain function? Ann N Y Acad Sci 2008: 1129: 119–29. Brett M, Anton JL, Valabregue R, Poline JB. Region of interest analysis using an SPM toolbox. [abstract] at the 8th International Conference of Functional mapping of the Humpan Brain, June 26, 2002, Sendai, Japan. Buckner RL, Andrews-Hanna JR, Schacter DL. The brain’s default network: anatomy, function, and relevance to disease. Ann N Y Acad Sci 2008; 1124: 1–38. Carhart-Harris R, Nutt D. Was it a vision or a waking dream? Front Psychol 2014; 5: 255. Cavanna AE, Trimble MR. The precuneus: a review of its functional anatomy and behavioural correlates. Brain 2006; 129(Pt 3): 564–83. Cocchi L, Zalesky A, Fornito A, Mattingley JB. Dynamic cooperation and competition between brain systems during cognitive control. Trends Cogn Sci 2013; 17: 493–501. Herbet G, Lafargue G, de Champfleur NM, Moritz-Gasser S, le Bars E, Bonnetblanc F, et al. Disrupting posterior cingulate connectivity
Letter to the Editor disconnects consciousness from the external environment. Neuropsychologia 2014; 56C: 239–44. Horovitz SG, Braun AR, Carr WS, Picchioni D, Balkin TJ, Fukunaga M, et al. Decoupling of the brain’s default mode network during deep sleep. Proc Natl Acad Sci 2009; 106(27): 11376–81. Leech R, Sharp DJ. The role of the posterior cingulate cortex in cognition and disease. Brain 2013; 18: 18. Mesulam MM. From sensation to cognition. Brain 1998; 121 (Pt 6): 1013–52. Vanhaudenhuyse A, Noirhomme Q, Tshibanda LJ, Bruno MA, Boveroux P, Schnakers C, et al. Default network connectivity reflects the level of consciousness in non-communicative brain-damaged patients. Brain 2010; 133(Pt 1): 161–71. Vogt BA, Laureys S. Posterior cingulate, precuneal and retrosplenial cortices: cytology and components of the neural network correlates of consciousness. Prog Brain Res 2005; 150: 205–17. Tate MC, Herbet G, Moritz-Gasser S, Tate JE, Duffau H. Probabilistic map of critical functional regions of the human cerebral cortex: Broca’s area revisited. Brain 2015; 2773–82.
Downloaded from http://brain.oxfordjournals.org/ by guest on December 31, 2015
