- Email: [email protected]
Challenging the Myth of Right Nondominant Hemisphere: Lessons from Corticosubcortical Stimulation Mapping in Awake Surgery and Surgical Implications
Accepted Manuscript Challenging the myth of right "non-dominant" hemisphere: Lessons from corticosubcortical stimulation mapping in awake surgery and surgical implications Tatiana Vilasboas, MD, Guillaume Herbet, PhD, Hugues Duffau, MD, PhD PII:
S1878-8750(17)30516-8
DOI:
10.1016/j.wneu.2017.04.021
Reference:
WNEU 5538
To appear in:
World Neurosurgery
Received Date: 8 February 2017 Revised Date:
2 April 2017
Accepted Date: 5 April 2017
Please cite this article as: Vilasboas T, Herbet G, Duffau H, Challenging the myth of right "nondominant" hemisphere: Lessons from cortico-subcortical stimulation mapping in awake surgery and surgical implications, World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.04.021. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Challenging the myth of right "non-dominant" hemisphere: Lessons from cortico-subcortical stimulation mapping in awake surgery
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and surgical implications
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Tatiana Vilasboas, MD1, Guillaume Herbet, PhD2,3, Hugues Duffau, MD, PhD2,3*
Department of Neurosurgery, Sao Paulo, Brazil
2
Department of Neurosurgery, Gui de Chauliac Hospital, Montpellier University Medical Center,
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1
Montpellier, France 3
Team “Plasticity of Central Nervous System, Stem Cells and Glial Tumors,” INSERM U1051,
Institute for Neurosciences of Montpellier, Montpellier, France *
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Address correspondence to: Pr. Hugues Duffau, M.D., Ph.D. Department of Neurosurgery, Gui de Chauliac Hospital, Montpellier University Medical Center 80, avenue Augustin Fliche, 34295 Montpellier E-mail: [email protected] Telephone number: +33 (0)4 67 33 66 12; Fax number: +33 (0)4 67 33 69 12
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Financial disclosure: none
Conflicts of interest: none
Short title: Awake surgery for right-sided lesions
Abbreviations list: RH = right hemisphere; LH = left hemisphere; LGG = low-grade glioma; QoL = Quality of life; DES = Direct electrical stimulation; SLF = Superior longitudinal fascicle; MNI = Montreal Neurological Institute; PPTT = Pyramids and Palm Trees Test; IFOF = Inferior fronto-occipital fascicle; MRI = Magnetic resonance imaging
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ABSTRACT For a long time, the right hemisphere (RH) was considered as "non-dominant", especially in right-handers. In neurosurgical practice, this dogma resulted in the selection of awake procedure with language mapping only for lesions of the left "dominant" hemisphere.
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Conversely, surgery under general anesthesia (possibly with motor mapping) was usually proposed for right lesions. However, when objective neuropsychological assessments were performed, they frequently revealed cognitive and behavioral deficits following brain surgery, even in the RH. Therefore, to preserve an optimal quality of life, especially in
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patients with a long survival expectancy (as in low-grade gliomas), awake surgery with cortical and axonal electrostimulation mapping has recently been proposed for right tumors
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resection. Here, we review new insights gained from intraoperative stimulation into the pivotal role of the RH in movement execution and control, visual processes and spatial cognition, language and non-verbal semantic processing, executive functions (e.g. attention), and social cognition (mentalizing and emotion recognition). Such original findings, that break with the myth of a "non-dominant" RH, may have important implications in cognitive neurosciences, by improving our knowledge of the functional connectivity of the RH, as well
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as for the clinical management of patients with a right lesion. Indeed, in brain surgery, awake mapping should be considered more systematically in the RH. Moreover, neuropsychological examination must be achieved in a more systematic manner before and after surgery within the RH, to optimize the care by predicting the likelihood of functional recovery and by
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elaborating specific programs of rehabilitation.
Keywords: Right hemisphere; awake surgery; electrical mapping; glioma; neuroplasticity; brain connectivity
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INTRODUCTION Following the lesion works of Broca1 and Wernicke2, a preeminent role of the left hemisphere (LH) in language was established. Later, Geschwind (1965)3 emphasized the critical role of left white matter connections for language. These studies led to the concept of
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left hemispheric “dominance”, and implicitly, to the dogma of a right "non-dominant" hemisphere.
Yet, using the Wada procedure, Rasmussen and Milner4 showed that, in non-righthanded patients, speech was represented in the LH in nearly a third of the group, in the right hemisphere (RH) in half the group, and bilaterally in the remainder. Moreover, cases of
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crossed aphasia, resulting from a right lesion in right-handers, have regularly been reported5. The notion of inter-individual variability of language lateralization was reinforced by
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functional neuroimaging,6 knowing that concordance between handedness and language lateralization does not exceed chance level at least in a statistical model deliberately enriched in left-handers.7 The RH implication in other cerebral functions, including sensorimotor, attention, visuo-spatial, emotion and social functions, has been supported by many lesion and neuroimaging studies.8-11
Despite these reports, in neurosurgical routine, the dogma of the "non-dominant" RH
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resulted in the selection of awake procedure with language mapping only in patients bearing a lesion of the left "dominant" hemisphere. In contrast, surgery under general anesthesia (possibly with motor mapping) is usually proposed in right lesions, including in patients
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enjoying a normal life before resection, as in diffuse low-grade glioma (LGG). Typically, this tumor involves young patients with no or only mild neurologic deficits, due to neuroplasticity allowing functional reorganization in reaction to the slow growth of the glioma.12 LGG is
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generally revealed by seizures, but its incidental detection is currently increasing as access to brain imaging broadens worldwide, raising the question of preventive surgery.13,14 Indeed, an increased amount of data supported the significant impact of early and maximal surgical resection of LGG on overall survival.15-18 Thus, surgery is currently the first treatment in LGG patients, on the condition to preserve the quality of life (QoL).13,19 Yet, when objective postoperative neuropsychological assessments are performed, they frequently reveal cognitive and behavioral deficits following glioma surgery, even in the RH.20,21 Therefore, to preserve an optimal QoL, especially in patients with a long survival expectancy (e.g. LGG), awake surgery with cortical and axonal direct electrical stimulation (DES) mapping has recently been proposed for resection of right sided tumors. This 3
ACCEPTED MANUSCRIPT technique represents a unique opportunity to perform a real-time investigation of the functions of both the cortex and the white matter fibers.22 The principle of DES is to mimic a genuine "virtual transient lesion", by disrupting a neural subcircuit (and not a focal single site) during a few seconds, with the possibility to check whether the same functional disturbances are reproduced when repeated stimulations are applied over the same structure.
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By gathering all cortical and axonal sites where the same type of errors were observed when stimulated, one would build up the subnetwork of the disrupted subfunction. Thus, DES permits to detect the structures essential for brain functions, in vivo in humans, with a great accuracy and reproducibility.22
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Here, we review new insights gained from intraoperative DES into the pivotal role of the RH in movement execution and control, some aspects of language, vision, spatial cognition, executive functions (e.g. attention and working memory), and social cognition
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(mentalizing). Such original findings, that break with the myth of a "non-dominant" RH, may have important implications in cognitive neurosciences, by improving our knowledge of the functional connectivity of the RH, and for the surgical management of patients with a right lesion.
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NEW LIGHTS INTO THE FUNCTIONAL ROLE OF THE RH: DATA ISSUED FROM DES
Role of the RH in sensorimotor function Since the description of the homonculus using intraoperative DES23, a somatotopic
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organization of the sensorimotor system was demonstrated in humans, with a crucial role of the RH in the execution of left hemibody (face, upper limb, lower limb) movements.
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Recently, hundreds sites of positive intraoperative cortical and axonal stimulations were plotted onto a MNI template brain space using regional anatomic landmarks.24, 25 Motor and somatosensory map for the RH was constructed, confirming using these probabilistic corticosubcortical atlases based on DES the expected localization of motor and somatosensory functions within the precentral and postcentral gyri, and at the level of their corresponding pyramidal and thalamo-cortical tracts, respectively (Figures 1A and 1B). Furthermore, by means of DES in awake patients, a network subserving motor control has recently been described. Axonal stimulation of this circuit in patients performing continuous movement generates disturbances of motor initiation and control, which may range from complete arrest to involuntary acceleration of movement.26 A somatotopic 4
ACCEPTED MANUSCRIPT distribution of this motor control network was shown using axonal DES.27 Moreover, unilateral subcortical DES of the RH can not only disrupt left movement, but also movement of both hands during a task of bimanual coordination.28 These findings support the RH involvement in a bilateral modulatory cortico-subcortical network supervising the interlimb movement, and constituted by fibers anterior to the corticospinal tract, coming from the
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supplementary motor area, lateral premotor cortex and the depth of the precentral sulcus, which runs to the striatum - i.e. the fronto-striatal tract.27,29 An additional tract goes to the anterior arm of the internal capsule, indicating a likely course toward the spinal cord, while
Role of RH in vision and visuospatial cognition
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another part of the network runs posterior to primary somatosensory fibers.26
By showing two images spread over two opposite quadrants on the same screen,
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visual pathways have been mapped by DES in awake patients, especially in the RH. Beyond the primary visual cortex, a transient left visual field deficit subjectively described by the patient can be elicited during DES of the right optic radiations, with objective confirmation thanks to this test (only the right picture can be seen and therefore named).30 DES may evoke either "inhibitory phenomena" (e.g. blurred vision or impression of shadow) or "excitatory
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phenomena" (e.g. phosphenes or visual hallucinations as zoopsia or metamorphopsia).31 Additionally, DES of the right inferior longitudinal fascicle may produce left visual hemiagnosia, by disrupting the occipital visual input and higher-level processes in the fusiform gyrus and temporal pole.32 These data support the pivotal role of the inferior
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longitudinal fascicle in visual recognition, with an involvement of this pathway in high-order processing in the RH. Moreover, DES of the supramarginal gyrus and the second branch of the superior longitudinal fascicle (SLF) in the RH evokes disturbances of spatial cognition,
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with rightward deviation during a line bisection test.33-35 Such findings suggest that spatial awareness is underpinned by a right cortico-subcortical fronto-parietal network enabling to process visual scenes. Axonal DES of another subpathway in the right SLF can also generate a central vestibular syndrome with vertigo, by disrupting the vestibular inputs assembled in the temporo-parietal areas and the prefrontal cortex. This supports the role of RH in coordinating body posture and spatially oriented actions that controls vestibular function.36
Role of RH in language Recent DES investigations have been achieved to map language during awake surgery for right lesion in left-handers, ambidextrous and in right-handed patients with language 5
ACCEPTED MANUSCRIPT disturbances during seizures or on presurgical neuropsychological assessment.24,37,38 Cortically, in frontal regions, DES elicited articulatory disorders (ventral premotor cortex), anomia (dorsal premotor cortex) and semantic paraphasia (dorsolateral prefrontal cortex). Parietal stimulation induced phonemic paraphasias, and temporal stimulation semantic paraphasias and/or anomia.37 These cortical sites were projected onto a probabilistic atlas
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plotted in the MNI space (Figure 1A).24 These cortical DES data in the right and left hemispheres of left-handed/ambidextrous patients suggest an analogous anatomical pattern of speech output and naming to right-handers. Subcortically, the SLF/arcuate fascicle (inducing phonological disturbances when stimulated), inferior occipito-frontal fascicle (IFOF, eliciting
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semantic disturbances during stimulation), frontal aslant tract (generating control disturbances as perseverations when stimulated), and fronto-striatal tract (inducing articulatory disorders during stimulation) were identified in the RH - as summarized in a
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recent functional atlas of white matter tracts derived from intrasurgical subcortical DES (Figure 1B).25 If these cortical and subcortical structures are surgically preserved, permanent aphasia is avoided, despite a transient immediate postoperative language worsening.37,38 Such findings based upon intraoperative DES results and postsurgical transitory dysphasia support the major role of the RH in language in left-handers, ambidextrous and even in some atypical right-handed patients in whom an intrasurgical crossed aphasia was
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elicited by DES.38 They also provide new insights into the structural-functional corticosubcortical organization of language networks in the RH, suggesting a “mirror” configuration in comparison to the LH39 - especially with a dorsal stream involved in articulatory and
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phonological processing, and with a parallel ventral stream involved in semantics.37
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Role of RH in high-order cognitive functions Although studies concerning the involvement of the left ventral route in verbal
semantics are proficient, little is known about the possible role of this left ventral stream in non-verbal semantics. By using a semantic association task (as Pyramids and Palm Trees Test [PPTT]), axonal DES of the left IFOF (connecting a wide subnetwork comprising the left posterior temporal areas and dorso-lateral prefrontal cortex) generated disturbances of nonverbal semantic processing.40 Recently, the implication of the right ventral pathway in nonverbal semantics was also explored. Patients with a right LGG involving the ventral stream underwent awake surgery, while performing both a visual non-verbal semantic task and a verbal (control) semantic task (oral picture naming task).41 At the cortical level, non-verbal semantic-related sites were detected in the RH in structures commonly associated with verbal 6
ACCEPTED MANUSCRIPT semantic processes in the LH, including the right superior temporal gyrus, the right pars triangularis and the right dorsolateral prefrontal cortex. Semantic verbal impairments (semantic paraphasia during the naming task) were also observed in left-handed patients, at the level of the pars triangularis and opercularis, and the dorsolateral prefrontal cortex, as mentioned above. At the subcortical level, non-verbal semantic-related sites were also
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identified in the RH, a minority of them being multimodal (i.e. axonal DES also induced verbal semantic impairments). All these responsive stimulation points were located on the spatial course of the right IFOF, supporting a crucial role of the right ventral stream in multimodal semantic cognition.41
Multimodal (verbal and non-verbal) working memory and attention functions have
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also be investigated in patients with a right lesion.42,43 Simultaneous recruitment of these subnetworks mediating high-order functions is necessary in addition to the distinct circuits
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specifically involved in each modal function (e.g. language or spatial cognition) when the patient performs a sustained double task during surgery, combining for instance limb movement and naming or PPTT every 4 seconds during hours - as regularly asked to awake patients during DES to increase the reliability of functional mapping44. Recently, in 30 right gliomas, attention was tested longitudinally.43 The resection of the right angular gyrus was
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associated with transient neglect-like symptoms in all tasks, whereas resection of more anterior regions correlated with transient deficits only in visual exploration or detection. The attention networks showed functional recovery, thanks to the preservation of the right SLF,
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supporting the critical role of RH in high-order cognitive functions.43
Role of RH in mentalizing and consciousness
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Recently, complex emotion recognition tasks have been administrated during awake surgery for a right tumor, in order to preserve structures subserving mentalizing (theory of mind).45 Intraoperative DES combined with pre- and post-operative behavioral assessments demonstrated that this function is made possible by parallel functioning of two subsystems in the RH.46 The first subnetwork processes low-level perceptual aspects (mirror system), i.e. the ability to appreciate other people's emotions (emotional empathy): this circuit is underpinned by the right arcuate fascicle/SLF complex. The second subcircuit is pivotal for high-level mental processing of this sociocognitive function (high-level inferential mentalizing), i.e. the ability to attribute intention to others. This social metacognitive skill is mediated mainly by the right cingulum.46
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ACCEPTED MANUSCRIPT Because the cingulum connects the rostral medial prefrontal cortex/anterior cingulate and the medial posterior parietal cortex (including the posterior cingulate cortex and ventral precuneus), this pathway seems to be involved in the default mode network and could participate in some aspects of conscious information processing. Disrupting the subcortical connectivity of the right (and left) posterior cingulate cortex through its DES may generate a
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breakdown in conscious experience of awake patients.47 They experienced a transitory behavioral unresponsiveness with loss of external connectedness during axonal stimulation. This supports a crucial role of the RH in maintaining arousal since functional integrity of the right posterior cingulate connectivity is necessary for consciousness of external
IMPLICATIONS IN CLINICAL PRACTICE
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environment.47
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From fundamental neurosciences to surgical applications: the case of RH Although strong interactions between cognitive neurosciences and brain surgery are generally fruitful, they may however be harmful. In particular, the classical dogma of localizationism implicitly resulted in the principle of a similar cerebral functional anatomy between individuals. According to this rigid view of neural distribution, numerous patients
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with a brain tumor or intractable epilepsy that justified surgery were a priori not selected for resection and lost a chance to be treated because the lesion was located within so-called "eloquent" areas in the left "dominant hemisphere", as Broca's area or Wernicke's area. Applying this concept of a fixed organization to the right "non-dominant" hemisphere led
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neurosurgeons to consider surgical resection (under general anesthesia) in the RH in a more systematic way because, in this philosophy, the risk to generate permanent deficits is
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theoretically low - except regarding a possible motor impairment. Nonetheless,
brain
mapping
techniques
(non-invasive
neuroimaging
and
intraoperative DES) demonstrated a considerable interindividual structural and functional variability, especially at the cortical level, explained by a networking organization of the brain, in which one function is not mediated by one specific area, but by interactions between large-scale delocalized subcircuits.48 Beyond physiological variation in healthy volunteers, in brain-damaged patients, neural reshaping may occur to compensate injury, increasing this interindividual variability.12 Furthermore, functional remapping was also described in the same patients over time. Thus, in practice, brain functions cannot be reliably localized on anatomic criteria alone.48,49 Unfortunately, the variance in functional cortical sites is not
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ACCEPTED MANUSCRIPT completely recognized by neurosurgeons, as demonstrated by the recent use of statistical probabilistic anatomical maps to perform "presurgical mapping".50 Therefore, thanks to the better understanding of this dynamic brain organization, individual mapping is crucial to optimize extent of resection while preserving QoL. Due to methodological limitations regarding functional neuroimaging, this technique is not reliable
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enough at the individual level.51-53 The actual impact of DES has recently been validated in a meta-analysis with 8,091 adult patients who had resective surgery for glioma: tumor removals using intraoperative stimulation mapping were associated with fewer late severe neurologic deficits and more extensive resection, and they involved "eloquent" locations more frequently. Thus, intraoperative DES should be considered in all patients with no or
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only mild preoperative deficits.54
Based on this paradigmatic shift, an increased amount of surgical series for brain
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tumor or epilepsy used DES in the recent literature. Yet, in most of cases, awake surgery was selected for language mapping only when the lesion was located within the "left dominant hemisphere", with little considerations concerning the RH. It was thought that surgical resection within the right "non-dominant" hemisphere could not result in permanent functional worsening, on the condition that the central region and its corresponding white
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matter tracts was preserved. Therefore, surgery in the RH is traditionally achieved under general anesthesia, with only motor mapping using DES and/or electrophysiological monitoring to avoid paresis.55-57 Yet, the recent results summarized above, issued from surgery for a right lesion, changed our view of RH processing (Figure 2). This new
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connectomal model of the RH should lead in proposing more systematically awake mapping
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for resection in the right side.
Awake mapping for surgery in the RH Although it is classically claimed that the use of intraoperative evoked potentials
under general anesthesia is sufficient during surgery in the RH to avoid paresis, this technique is nonetheless not sensitive enough to allow an optimal preservation of complex movements.58 Indeed, even after a "recovery" from a transient postoperative supplementary motor area (SMA) syndrome with akinesia, patients may experience objective deficits in complex movement such as bimanual coordination - which can prevent a return to work, e.g. for a musician or a surgeon.28,59 As mentioned, this deficit is related to a damage to the motor control network, that can be accurately mapped only in awake patients, by eliciting arrest or acceleration of movements.26,27 In practice, all patients who will undergo surgical removal of 9
ACCEPTED MANUSCRIPT a tumor involving SMA should be extensively informed before surgery, with the goal to decide whether the limits of resection should be represented by the traditional corticospinal tract (to avoid left paresis) or by the motor control circuit - with a lesser extent of resection but a better preservation of QoL. In other words, intraoperative detection and preservation of the fronto-striatal tract underpinning motor control,29 which is located in front of the
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pyramidal pathways mediating motor output, can prevent the onset of postoperative SMA syndrome - or at least will result in a very transitory (a few days and not a few weeks) and a mild deficit (without complete akinesia) with a complete functional recovery - including bimanual coordination.26,27 Of note, even though the same principle can be applied to the LH
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with respect to movement, when removing a left lesion, the frontal aslant tract (that connects the SMA to the frontal operculum and that evokes slowness or arrest of speech during stimulation) has also to be mapped and spared if the patient wants to prevent the occurrence
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of an immediate postoperative mustism.29 This example illustrates well the concept of "oncofunctional balance" in tumor surgery.60 Furthermore, a subtle somatosensory mapping is not possible under general anesthesia, while an awake patient can precisely describe somesthetic responses during DES:61 preservation of the sensory feedback is crucial for complex movement, e.g. to run after surgery within the right paracentral lobule.
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Damage of the visual pathways in the RH can induce disabling deficit in daily life. Indeed, injury of the right optic radiation will generate left homonymous hemianopia, preventing in many countries the patient from driving for medicolegal issues. Oculomotor pathway may also be injuried.62 Moreover, lesion of the right inferior longitudinal fascicle
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may elicit prosopagnosia, which can have negative impact on social cognition, or visual agnosia. Damage of the right SLF can result in left hemineglect, with also consequences on
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QoL - e.g. in a dancer, unable to return to work. Again, currently, intraoperative DES mapping under local anesthesia is the sole tool to identify and preserve this circuit within the RH with a high reliability.30-36,62 Similarly, awake craniotomy is the best technique to map language, with less than 2%
of aphasia in surgical series for left tumors.63,64 However, recent DES results detailed above demonstrated that RH may play a critical role for language in many patients, especially lefthanders and ambidextrous: therefore, these patients should benefit from awake mapping even when bearing a right lesion.37,39 In right-handed patients, if language disturbances are detected during seizures or on presurgical neuropsychological assessment, especially when right activations are observed on language functional MRI, intraoperative awake language mapping should be considered.38 Moreover, mapping non-verbal understanding in patients 10
ACCEPTED MANUSCRIPT who would like to preserve a high-level of cognition (e.g. lawyers or managers) should be proposed, because injury of the ventral stream may generate deficit of multimodal semantic processing,40 even in the RH.41 The clinical relevance of intra-operative mapping of calculation in patients undergoing surgery in the right parietal area has also been highlighted.65,66 Finally, a lesion involving the mentalizing system in the RH may result in
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postoperative social cognition disorders with possible change in behavior and personality, and thus may prevent patients to resume a normal occupational life - e.g. for medical doctors or nurses who should preserve their empathy.21,45
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Usefulness for postoperative rehabilitation
Based on DES in 231 patients who underwent awake surgery, neuroplasticity potential in brain-damaged patients was mapped by elaborating a probabilistic atlas of
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functional plasticity.67 This atlas demonstrated the critical role of the subcortical connectivity of the RH that should be preserved to avoid permanent deficit.12,25 This is a unique tool for predicting the likelihood of functional recovery after surgery, and for identifying patients who require functional rehabilitation, especially following a right lesion. Postoperative objective neuropsychological assessments are helpful for the elaboration of individualized programs of neurologic, cognitive and behavioral rehabilitation, adapted to an improved
CONCLUSIONS
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knowledge of the right connectome.67
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Original data recently provided by intraoperative DES mapping in awake patients undergoing surgery for a right lesion have led to better understand the functional connectivity
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of the RH and to rethink its actual role in many brain functions - as in movement execution and control, vision, spatial cognition, language and non-verbal semantic processing, executive functions (as attention), and emotional process (as empathy) (Figure 2). These findings challenge the myth of a "non-dominant" RH. The clinical implication of this improved knowledge of the functional anatomy of RH
is that, in neurosurgical practice, awake mapping has to be considered in a more systematic manner for surgery of right lesions. Indeed, when extensive postsurgical neuropsychological examinations are achieved, they frequently find cognitive and behavioral disturbances after glioma surgery, even in the RH.20,21 Therefore, risks of such subtle deficits should be extensively explained to the patient and his/her family before surgery within the RH, in order
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ACCEPTED MANUSCRIPT to give him/her the possibility to decide whether (slight) permanent cognitive or emotional disorders can be compatible or not with his/her QoL - according notably to the work or the hobbies of the patient (e.g. to avoid left visual field deficit in a taxi driver, or left hemineglect in a sportsman, or mentalizing disturbances in a politician or an actor, etc...). Appropriate selection of tasks for intraoperative DES mapping can be achieved accordingly, to enable the
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patient to resume normal familial, social and professional lives. Standardized testing paradigms enabling the neurosurgeons to adapt awake craniotomy techniques for RH tumors in their practice are now in progress (e.g. PPTT or mentalizing tests).
Furthermore, a probabilistic atlas of functional plasticity derived from intraoperative DES is now available in order to predict the likelihood of functional recovery, especially after
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surgery within the RH.67 Thus, objective pre- and post-operative neuropsychological examinations must be achieved in all patients with surgery in the RH to adapt specific
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programs of rehabilitation - a strategy rarely applied in the current literature.
Disclosure
The authors have no personal, financial, or institutional interest in any of the drugs,
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materials, or devices described in this article.
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27. Rech F, Herbet G, Moritz-Gasser S, Duffau H. Somatotopic organization of the white
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28. Rech F, Herbet G, Moritz-Gasser S, Duffau H. Disruption of bimanual movement by unilateral subcortical stimulation. Hum Brain Mapp. 2014;35:3439-3345. 29. Kinoshita M, de Champfleur NM, Deverdun J, Moritz-Gasser S, Herbet G, Duffau H. Role of fronto-striatal tract and frontal aslant tract in movement and speech: an axonal mapping study. Brain Struct Funct. 2015;220:3399-412. 30. Gras-Combes G, Moritz-Gasser S, Herbet G, Duffau H. Intraoperative subcortical electrical mapping of optic radiations in awake surgery for glioma involving visual pathways. J Neurosurg. 2012;117:466-473. 31. Duffau H, Velut S, Mitchell MC, Gatignol P, Capelle L. Intra-operative mapping of the subcortical visual pathways using direct electrical stimulations. Acta Neurochir (Wien). 2004;146:265-269. 14
ACCEPTED MANUSCRIPT 32. Fernández Coello A, Duvaux S, De Benedictis A, Matsuda R, Duffau H. Involvement of the right inferior longitudinal fascicle in visual hemiagnosia: a brain stimulation mapping study. J Neurosurg. 2013;118:202-205. 33. Thiebaut de Schotten M, Urbanski M, Duffau H, Volle E, Lévy R, Dubois B, Bartolomeo P. Direct evidence for a parietal-frontal pathway subserving spatial awareness in humans.
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38. Vassal M, Le Bars E, Moritz-Gasser S, Menjot N, Duffau H. Crossed aphasia elicited by intraoperative cortical and subcortical stimulation in awake patients. J Neurosurg. 2010;113:1251-1258.
39. Chang EF Chang EF, Wang DD, Perry DW, Barbaro NM, Berger MS. Homotopic
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40. Moritz-Gasser S, Herbet G, Duffau H. Mapping the connectivity underlying multimodal (verbal and non-verbal) semantic processing: a brain electrostimulation study. Neuropsychologia. 2013;51:1814-1822. 41. Herbet G, Moritz-Gasser S, Duffau H. Direct evidence for the contributive role of the right inferior fronto-occipital fasciculus in non-verbal semantic cognition. Brain Struct Funct. 2016 Aug 27. [Epub ahead of print] 42. Teixidor P, Gatignol P, Leroy M, Masuet-Aumatell C, Capelle L, Duffau H. Assessment of verbal working memory before and after surgery for low-grade glioma. J Neurooncol. 2007;81:305-313.
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ACCEPTED MANUSCRIPT 43. Charras P, Herbet G, Deverdun J, de Champfleur NM, Duffau H, Bartolomeo P, Bonnetblanc F. Functional reorganization of the attentional networks in low-grade glioma patients: A longitudinal study. Cortex. 2015;63:27-41. 44. Fernandez Coello A, Moritz-Gasser S, Martino J, Matsuda A, Duffau H. Selection of intraoperative tasks for awake mapping based on relationships between tumor location
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46. Herbet G, Lafargue G, Bonnetblanc F, Menjot de Champfleur N, Duffau H. Inferring a dual-stream model of mentalizing from associative white matter fiber disconnection. Brain. 2014;137:944-959.
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47. Herbet G, Lafargue G, Duffau H. The dorsal cingulate cortex as a critical gateway in the network supporting conscious awareness. Brain. 2016;139:e23. 48. Duffau H. A two-level model of interindividual anatomo-functional variability of the brain and its implications for neurosurgery. Cortex. 2017;86:303-313. 49. Duffau H. Lessons from brain mapping in surgery for low-grade glioma: insights into
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associations between tumour and brain plasticity. Lancet Neurol. 2005;4:476-486. 50. Kim JS, Cheon GJ, Lim SM. Presurgical mapping of brain tumors using statistical probabilistic anatomical maps. J Biomedical Science and Engineering. 2015;8:653-658. 51. Duffau H. The dangers of magnetic resonance imaging diffusion tensor tractography in
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brain surgery. World Neurosurg. 2014;81:56-58. 52. Kuchcinski G, Mellerio C, Pallud J, Dezamis E, Turc G, Rigaux-Viodé O, Malherbe C,
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Roca P, Leclerc X, Varlet P, Chrétien F, Devaux B, Meder JF, Oppenheim C. Three-tesla functional MR language mapping: comparison with direct cortical stimulation in gliomas. Neurology. 2015;84:560-568. 53. Pujol S, Wells W, Pierpaoli C, Brun C, Gee J, Cheng G, Vemuri B, Commowick O, Prima S, Stamm A, Goubran M, Khan A, Peters T, Neher P, Maier-Hein KH, Shi Y, Tristan-Vega A, Veni G, Whitaker R, Styner M, Westin CF, Gouttard S, Norton I, Chauvin L, Mamata H, Gerig G, Nabavi A, Golby A, Kikinis R. The DTI Challenge: Toward standardized evaluation of Diffusion Tensor Imaging tractography for neurosurgery. J Neuroimaging. 2015;25:875-882.
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ACCEPTED MANUSCRIPT 54. De Witt Hamer PC, Robles SG, Zwinderman AH, Duffau H, Berger MS. Impact of intraoperative stimulation brain mapping on glioma surgery outcome: a meta-analysis. J Clin Oncol. 2012;30:2559-2565. 55. Bello L, Riva M, Fava E, Ferpozzi V, Castellano A, Raneri F, Pessina F, Bizzi A, Falini A, Cerri G. Tailoring neurophysiological strategies with clinical context enhances
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resection and safety and expands indications in gliomas involving motor pathways. Neuro Oncol. 2014;16:1110-1128.
56. Nossek E, Korn A, Shahar T, Kanner AA, Yaffe H, Marcovici D, Ben-Harosh C, Ben Ami H, Weinstein M, Shapira-Lichter I, Constantini S, Hendler T, Ram Z. Intraoperative
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mapping and monitoring of the corticospinal tracts with neurophysiological assessment and 3-dimensional ultrasonography-based navigation. J Neurosurg. 2011;114:738-746. 57. Shiban E, Krieg SM, Haller B, Buchmann N, Obermueller T, Boeckh-Behrens T,
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Wostrack M, Meyer B, Ringel F. Intraoperative subcortical motor evoked potential stimulation: how close is the corticospinal tract? J Neurosurg. 2015;123:711-720. 58. Wiedemayer H, Sandalcioglu IE, Armbruster W, Regel J, Schaefer H, Stolkke D. False negative findings in intraoperative SEP monitoring: analysis of 658 consecutive neurosurgical cases and review of published reports. J Neurol Neurosurg Psychiatry.
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2004;75:280-286.
59. Krainik A, Lehéricy S, Duffau H, Vlaicu M, Poupon F, Capelle L, Cornu P, Clemenceau S, Sahel M, Valery CA, Boch AL, Mangin JF, Bihan DL, Marsault C. Role of the supplementary motor area in motor deficit following medial frontal lobe surgery.
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Neurology. 2001;57:871-878.
60. Duffau H, Mandonnet E. The "onco-functional balance" in surgery for diffuse low-grade
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glioma: integrating the extent of resection with quality of life. Acta Neurochir (Wien). 2013;155:951-957.
61. Maldonado IL, Moritz-Gasser S, de Champfleur NM, Bertram L, Moulinié G, Duffau H. Surgery for gliomas involving the left inferior parietal lobule: new insights into the functional anatomy provided by stimulation mapping in awake patients. J Neurosurg. 2011;115:770-779. 62. Montemurro N, Herbet G, Duffau H. Right Cortical and Axonal Structures Eliciting Ocular Deviation During Electrical Stimulation Mapping in Awake Patients. Brain Topogr. 2016 Jul;29:561-71. 63. Sanai N, Mirzadeh Z, Berger MS. Functional outcome after language mapping for glioma resection. N Engl J Med. 2008;358:18-27. 17
ACCEPTED MANUSCRIPT 64. Duffau H, Gatignol P, Mandonnet E, Capelle L, Taillandier L. Contribution of intraoperative subcortical stimulation mapping of language pathways: a consecutive series of 115 patients operated on for a grade II glioma in the left dominant hemisphere. J Neurosurg. 2008;109:461-471. 65. Della Puppa A, De Pellegrin S, d'Avella E, Gioffrè G, Munari M, Saladini M, Salillas E,
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Scienza R, Semenza C. Right parietal cortex and calculation processing: intraoperative functional mapping of multiplication and addition in patients affected by a brain tumor. J Neurosurg. 2013;119:1107-1111.
66. Della Puppa A, De Pellegrin S, Lazzarini A, Gioffrè G, Rustemi O, Cagnin A, Scienza R,
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Semenza C. Subcortical mapping of calculation processing in the right parietal lobe. J Neurosurg. 2015;122:1038-1041.
67. Herbet G, Maheu M, Costi E, Lafargue G, Duffau H. Mapping the neuroplastic potential
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in brain-damaged patients. Brain. 2016;139:829-844.
Figure 1 Fig 1A
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FIGURE LEGENDS
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Probabilistic 3D digitized map of cortical DES mapping data in the right hemisphere demonstrating the wide distribution of cortical representation within and between critical functions of the human brain: motor (green), sensory (yellow), speech arrest (red), anomia (blue), dysarthria (orange) (from24 with permission). Fig 1B
3D representation of functional response errors collected with subcortical DES mapping in the right hemisphere. Different colors represent the different functional response errors. The small colored points represent the projections of functional response errors on the x–y and x–z planes of the Montreal Neurological Institute space (from25 with permission).
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ACCEPTED MANUSCRIPT Figure 2 Proposal of a connectomal model of functional anatomy in the right hemisphere. The model was constructed on the basis of structural–functional correlations derived from intraoperative DES, and incorporates anatomical constraints. Abbreviations: IFOF,
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inferior frontal occipital fascicle; SLF, superior longitudinal fascicle.
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Disclosure The authors report no conflict of interest regarding the materials or methods used in this study or the findings specified in this paper.
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There is no any financial disclosure.
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Hugues DUFFAU
S1878-8750(17)30516-8
DOI:
10.1016/j.wneu.2017.04.021
Reference:
WNEU 5538
To appear in:
World Neurosurgery
Received Date: 8 February 2017 Revised Date:
2 April 2017
Accepted Date: 5 April 2017
Please cite this article as: Vilasboas T, Herbet G, Duffau H, Challenging the myth of right "nondominant" hemisphere: Lessons from cortico-subcortical stimulation mapping in awake surgery and surgical implications, World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.04.021. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Challenging the myth of right "non-dominant" hemisphere: Lessons from cortico-subcortical stimulation mapping in awake surgery
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and surgical implications
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Tatiana Vilasboas, MD1, Guillaume Herbet, PhD2,3, Hugues Duffau, MD, PhD2,3*
Department of Neurosurgery, Sao Paulo, Brazil
2
Department of Neurosurgery, Gui de Chauliac Hospital, Montpellier University Medical Center,
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1
Montpellier, France 3
Team “Plasticity of Central Nervous System, Stem Cells and Glial Tumors,” INSERM U1051,
Institute for Neurosciences of Montpellier, Montpellier, France *
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Address correspondence to: Pr. Hugues Duffau, M.D., Ph.D. Department of Neurosurgery, Gui de Chauliac Hospital, Montpellier University Medical Center 80, avenue Augustin Fliche, 34295 Montpellier E-mail: [email protected] Telephone number: +33 (0)4 67 33 66 12; Fax number: +33 (0)4 67 33 69 12
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Financial disclosure: none
Conflicts of interest: none
Short title: Awake surgery for right-sided lesions
Abbreviations list: RH = right hemisphere; LH = left hemisphere; LGG = low-grade glioma; QoL = Quality of life; DES = Direct electrical stimulation; SLF = Superior longitudinal fascicle; MNI = Montreal Neurological Institute; PPTT = Pyramids and Palm Trees Test; IFOF = Inferior fronto-occipital fascicle; MRI = Magnetic resonance imaging
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ABSTRACT For a long time, the right hemisphere (RH) was considered as "non-dominant", especially in right-handers. In neurosurgical practice, this dogma resulted in the selection of awake procedure with language mapping only for lesions of the left "dominant" hemisphere.
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Conversely, surgery under general anesthesia (possibly with motor mapping) was usually proposed for right lesions. However, when objective neuropsychological assessments were performed, they frequently revealed cognitive and behavioral deficits following brain surgery, even in the RH. Therefore, to preserve an optimal quality of life, especially in
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patients with a long survival expectancy (as in low-grade gliomas), awake surgery with cortical and axonal electrostimulation mapping has recently been proposed for right tumors
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resection. Here, we review new insights gained from intraoperative stimulation into the pivotal role of the RH in movement execution and control, visual processes and spatial cognition, language and non-verbal semantic processing, executive functions (e.g. attention), and social cognition (mentalizing and emotion recognition). Such original findings, that break with the myth of a "non-dominant" RH, may have important implications in cognitive neurosciences, by improving our knowledge of the functional connectivity of the RH, as well
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as for the clinical management of patients with a right lesion. Indeed, in brain surgery, awake mapping should be considered more systematically in the RH. Moreover, neuropsychological examination must be achieved in a more systematic manner before and after surgery within the RH, to optimize the care by predicting the likelihood of functional recovery and by
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elaborating specific programs of rehabilitation.
Keywords: Right hemisphere; awake surgery; electrical mapping; glioma; neuroplasticity; brain connectivity
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INTRODUCTION Following the lesion works of Broca1 and Wernicke2, a preeminent role of the left hemisphere (LH) in language was established. Later, Geschwind (1965)3 emphasized the critical role of left white matter connections for language. These studies led to the concept of
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left hemispheric “dominance”, and implicitly, to the dogma of a right "non-dominant" hemisphere.
Yet, using the Wada procedure, Rasmussen and Milner4 showed that, in non-righthanded patients, speech was represented in the LH in nearly a third of the group, in the right hemisphere (RH) in half the group, and bilaterally in the remainder. Moreover, cases of
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crossed aphasia, resulting from a right lesion in right-handers, have regularly been reported5. The notion of inter-individual variability of language lateralization was reinforced by
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functional neuroimaging,6 knowing that concordance between handedness and language lateralization does not exceed chance level at least in a statistical model deliberately enriched in left-handers.7 The RH implication in other cerebral functions, including sensorimotor, attention, visuo-spatial, emotion and social functions, has been supported by many lesion and neuroimaging studies.8-11
Despite these reports, in neurosurgical routine, the dogma of the "non-dominant" RH
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resulted in the selection of awake procedure with language mapping only in patients bearing a lesion of the left "dominant" hemisphere. In contrast, surgery under general anesthesia (possibly with motor mapping) is usually proposed in right lesions, including in patients
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enjoying a normal life before resection, as in diffuse low-grade glioma (LGG). Typically, this tumor involves young patients with no or only mild neurologic deficits, due to neuroplasticity allowing functional reorganization in reaction to the slow growth of the glioma.12 LGG is
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generally revealed by seizures, but its incidental detection is currently increasing as access to brain imaging broadens worldwide, raising the question of preventive surgery.13,14 Indeed, an increased amount of data supported the significant impact of early and maximal surgical resection of LGG on overall survival.15-18 Thus, surgery is currently the first treatment in LGG patients, on the condition to preserve the quality of life (QoL).13,19 Yet, when objective postoperative neuropsychological assessments are performed, they frequently reveal cognitive and behavioral deficits following glioma surgery, even in the RH.20,21 Therefore, to preserve an optimal QoL, especially in patients with a long survival expectancy (e.g. LGG), awake surgery with cortical and axonal direct electrical stimulation (DES) mapping has recently been proposed for resection of right sided tumors. This 3
ACCEPTED MANUSCRIPT technique represents a unique opportunity to perform a real-time investigation of the functions of both the cortex and the white matter fibers.22 The principle of DES is to mimic a genuine "virtual transient lesion", by disrupting a neural subcircuit (and not a focal single site) during a few seconds, with the possibility to check whether the same functional disturbances are reproduced when repeated stimulations are applied over the same structure.
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By gathering all cortical and axonal sites where the same type of errors were observed when stimulated, one would build up the subnetwork of the disrupted subfunction. Thus, DES permits to detect the structures essential for brain functions, in vivo in humans, with a great accuracy and reproducibility.22
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Here, we review new insights gained from intraoperative DES into the pivotal role of the RH in movement execution and control, some aspects of language, vision, spatial cognition, executive functions (e.g. attention and working memory), and social cognition
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(mentalizing). Such original findings, that break with the myth of a "non-dominant" RH, may have important implications in cognitive neurosciences, by improving our knowledge of the functional connectivity of the RH, and for the surgical management of patients with a right lesion.
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NEW LIGHTS INTO THE FUNCTIONAL ROLE OF THE RH: DATA ISSUED FROM DES
Role of the RH in sensorimotor function Since the description of the homonculus using intraoperative DES23, a somatotopic
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organization of the sensorimotor system was demonstrated in humans, with a crucial role of the RH in the execution of left hemibody (face, upper limb, lower limb) movements.
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Recently, hundreds sites of positive intraoperative cortical and axonal stimulations were plotted onto a MNI template brain space using regional anatomic landmarks.24, 25 Motor and somatosensory map for the RH was constructed, confirming using these probabilistic corticosubcortical atlases based on DES the expected localization of motor and somatosensory functions within the precentral and postcentral gyri, and at the level of their corresponding pyramidal and thalamo-cortical tracts, respectively (Figures 1A and 1B). Furthermore, by means of DES in awake patients, a network subserving motor control has recently been described. Axonal stimulation of this circuit in patients performing continuous movement generates disturbances of motor initiation and control, which may range from complete arrest to involuntary acceleration of movement.26 A somatotopic 4
ACCEPTED MANUSCRIPT distribution of this motor control network was shown using axonal DES.27 Moreover, unilateral subcortical DES of the RH can not only disrupt left movement, but also movement of both hands during a task of bimanual coordination.28 These findings support the RH involvement in a bilateral modulatory cortico-subcortical network supervising the interlimb movement, and constituted by fibers anterior to the corticospinal tract, coming from the
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supplementary motor area, lateral premotor cortex and the depth of the precentral sulcus, which runs to the striatum - i.e. the fronto-striatal tract.27,29 An additional tract goes to the anterior arm of the internal capsule, indicating a likely course toward the spinal cord, while
Role of RH in vision and visuospatial cognition
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another part of the network runs posterior to primary somatosensory fibers.26
By showing two images spread over two opposite quadrants on the same screen,
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visual pathways have been mapped by DES in awake patients, especially in the RH. Beyond the primary visual cortex, a transient left visual field deficit subjectively described by the patient can be elicited during DES of the right optic radiations, with objective confirmation thanks to this test (only the right picture can be seen and therefore named).30 DES may evoke either "inhibitory phenomena" (e.g. blurred vision or impression of shadow) or "excitatory
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phenomena" (e.g. phosphenes or visual hallucinations as zoopsia or metamorphopsia).31 Additionally, DES of the right inferior longitudinal fascicle may produce left visual hemiagnosia, by disrupting the occipital visual input and higher-level processes in the fusiform gyrus and temporal pole.32 These data support the pivotal role of the inferior
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longitudinal fascicle in visual recognition, with an involvement of this pathway in high-order processing in the RH. Moreover, DES of the supramarginal gyrus and the second branch of the superior longitudinal fascicle (SLF) in the RH evokes disturbances of spatial cognition,
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with rightward deviation during a line bisection test.33-35 Such findings suggest that spatial awareness is underpinned by a right cortico-subcortical fronto-parietal network enabling to process visual scenes. Axonal DES of another subpathway in the right SLF can also generate a central vestibular syndrome with vertigo, by disrupting the vestibular inputs assembled in the temporo-parietal areas and the prefrontal cortex. This supports the role of RH in coordinating body posture and spatially oriented actions that controls vestibular function.36
Role of RH in language Recent DES investigations have been achieved to map language during awake surgery for right lesion in left-handers, ambidextrous and in right-handed patients with language 5
ACCEPTED MANUSCRIPT disturbances during seizures or on presurgical neuropsychological assessment.24,37,38 Cortically, in frontal regions, DES elicited articulatory disorders (ventral premotor cortex), anomia (dorsal premotor cortex) and semantic paraphasia (dorsolateral prefrontal cortex). Parietal stimulation induced phonemic paraphasias, and temporal stimulation semantic paraphasias and/or anomia.37 These cortical sites were projected onto a probabilistic atlas
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plotted in the MNI space (Figure 1A).24 These cortical DES data in the right and left hemispheres of left-handed/ambidextrous patients suggest an analogous anatomical pattern of speech output and naming to right-handers. Subcortically, the SLF/arcuate fascicle (inducing phonological disturbances when stimulated), inferior occipito-frontal fascicle (IFOF, eliciting
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semantic disturbances during stimulation), frontal aslant tract (generating control disturbances as perseverations when stimulated), and fronto-striatal tract (inducing articulatory disorders during stimulation) were identified in the RH - as summarized in a
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recent functional atlas of white matter tracts derived from intrasurgical subcortical DES (Figure 1B).25 If these cortical and subcortical structures are surgically preserved, permanent aphasia is avoided, despite a transient immediate postoperative language worsening.37,38 Such findings based upon intraoperative DES results and postsurgical transitory dysphasia support the major role of the RH in language in left-handers, ambidextrous and even in some atypical right-handed patients in whom an intrasurgical crossed aphasia was
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elicited by DES.38 They also provide new insights into the structural-functional corticosubcortical organization of language networks in the RH, suggesting a “mirror” configuration in comparison to the LH39 - especially with a dorsal stream involved in articulatory and
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phonological processing, and with a parallel ventral stream involved in semantics.37
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Role of RH in high-order cognitive functions Although studies concerning the involvement of the left ventral route in verbal
semantics are proficient, little is known about the possible role of this left ventral stream in non-verbal semantics. By using a semantic association task (as Pyramids and Palm Trees Test [PPTT]), axonal DES of the left IFOF (connecting a wide subnetwork comprising the left posterior temporal areas and dorso-lateral prefrontal cortex) generated disturbances of nonverbal semantic processing.40 Recently, the implication of the right ventral pathway in nonverbal semantics was also explored. Patients with a right LGG involving the ventral stream underwent awake surgery, while performing both a visual non-verbal semantic task and a verbal (control) semantic task (oral picture naming task).41 At the cortical level, non-verbal semantic-related sites were detected in the RH in structures commonly associated with verbal 6
ACCEPTED MANUSCRIPT semantic processes in the LH, including the right superior temporal gyrus, the right pars triangularis and the right dorsolateral prefrontal cortex. Semantic verbal impairments (semantic paraphasia during the naming task) were also observed in left-handed patients, at the level of the pars triangularis and opercularis, and the dorsolateral prefrontal cortex, as mentioned above. At the subcortical level, non-verbal semantic-related sites were also
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identified in the RH, a minority of them being multimodal (i.e. axonal DES also induced verbal semantic impairments). All these responsive stimulation points were located on the spatial course of the right IFOF, supporting a crucial role of the right ventral stream in multimodal semantic cognition.41
Multimodal (verbal and non-verbal) working memory and attention functions have
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also be investigated in patients with a right lesion.42,43 Simultaneous recruitment of these subnetworks mediating high-order functions is necessary in addition to the distinct circuits
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specifically involved in each modal function (e.g. language or spatial cognition) when the patient performs a sustained double task during surgery, combining for instance limb movement and naming or PPTT every 4 seconds during hours - as regularly asked to awake patients during DES to increase the reliability of functional mapping44. Recently, in 30 right gliomas, attention was tested longitudinally.43 The resection of the right angular gyrus was
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associated with transient neglect-like symptoms in all tasks, whereas resection of more anterior regions correlated with transient deficits only in visual exploration or detection. The attention networks showed functional recovery, thanks to the preservation of the right SLF,
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supporting the critical role of RH in high-order cognitive functions.43
Role of RH in mentalizing and consciousness
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Recently, complex emotion recognition tasks have been administrated during awake surgery for a right tumor, in order to preserve structures subserving mentalizing (theory of mind).45 Intraoperative DES combined with pre- and post-operative behavioral assessments demonstrated that this function is made possible by parallel functioning of two subsystems in the RH.46 The first subnetwork processes low-level perceptual aspects (mirror system), i.e. the ability to appreciate other people's emotions (emotional empathy): this circuit is underpinned by the right arcuate fascicle/SLF complex. The second subcircuit is pivotal for high-level mental processing of this sociocognitive function (high-level inferential mentalizing), i.e. the ability to attribute intention to others. This social metacognitive skill is mediated mainly by the right cingulum.46
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ACCEPTED MANUSCRIPT Because the cingulum connects the rostral medial prefrontal cortex/anterior cingulate and the medial posterior parietal cortex (including the posterior cingulate cortex and ventral precuneus), this pathway seems to be involved in the default mode network and could participate in some aspects of conscious information processing. Disrupting the subcortical connectivity of the right (and left) posterior cingulate cortex through its DES may generate a
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breakdown in conscious experience of awake patients.47 They experienced a transitory behavioral unresponsiveness with loss of external connectedness during axonal stimulation. This supports a crucial role of the RH in maintaining arousal since functional integrity of the right posterior cingulate connectivity is necessary for consciousness of external
IMPLICATIONS IN CLINICAL PRACTICE
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environment.47
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From fundamental neurosciences to surgical applications: the case of RH Although strong interactions between cognitive neurosciences and brain surgery are generally fruitful, they may however be harmful. In particular, the classical dogma of localizationism implicitly resulted in the principle of a similar cerebral functional anatomy between individuals. According to this rigid view of neural distribution, numerous patients
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with a brain tumor or intractable epilepsy that justified surgery were a priori not selected for resection and lost a chance to be treated because the lesion was located within so-called "eloquent" areas in the left "dominant hemisphere", as Broca's area or Wernicke's area. Applying this concept of a fixed organization to the right "non-dominant" hemisphere led
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neurosurgeons to consider surgical resection (under general anesthesia) in the RH in a more systematic way because, in this philosophy, the risk to generate permanent deficits is
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theoretically low - except regarding a possible motor impairment. Nonetheless,
brain
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techniques
(non-invasive
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and
intraoperative DES) demonstrated a considerable interindividual structural and functional variability, especially at the cortical level, explained by a networking organization of the brain, in which one function is not mediated by one specific area, but by interactions between large-scale delocalized subcircuits.48 Beyond physiological variation in healthy volunteers, in brain-damaged patients, neural reshaping may occur to compensate injury, increasing this interindividual variability.12 Furthermore, functional remapping was also described in the same patients over time. Thus, in practice, brain functions cannot be reliably localized on anatomic criteria alone.48,49 Unfortunately, the variance in functional cortical sites is not
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ACCEPTED MANUSCRIPT completely recognized by neurosurgeons, as demonstrated by the recent use of statistical probabilistic anatomical maps to perform "presurgical mapping".50 Therefore, thanks to the better understanding of this dynamic brain organization, individual mapping is crucial to optimize extent of resection while preserving QoL. Due to methodological limitations regarding functional neuroimaging, this technique is not reliable
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enough at the individual level.51-53 The actual impact of DES has recently been validated in a meta-analysis with 8,091 adult patients who had resective surgery for glioma: tumor removals using intraoperative stimulation mapping were associated with fewer late severe neurologic deficits and more extensive resection, and they involved "eloquent" locations more frequently. Thus, intraoperative DES should be considered in all patients with no or
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only mild preoperative deficits.54
Based on this paradigmatic shift, an increased amount of surgical series for brain
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tumor or epilepsy used DES in the recent literature. Yet, in most of cases, awake surgery was selected for language mapping only when the lesion was located within the "left dominant hemisphere", with little considerations concerning the RH. It was thought that surgical resection within the right "non-dominant" hemisphere could not result in permanent functional worsening, on the condition that the central region and its corresponding white
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matter tracts was preserved. Therefore, surgery in the RH is traditionally achieved under general anesthesia, with only motor mapping using DES and/or electrophysiological monitoring to avoid paresis.55-57 Yet, the recent results summarized above, issued from surgery for a right lesion, changed our view of RH processing (Figure 2). This new
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connectomal model of the RH should lead in proposing more systematically awake mapping
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for resection in the right side.
Awake mapping for surgery in the RH Although it is classically claimed that the use of intraoperative evoked potentials
under general anesthesia is sufficient during surgery in the RH to avoid paresis, this technique is nonetheless not sensitive enough to allow an optimal preservation of complex movements.58 Indeed, even after a "recovery" from a transient postoperative supplementary motor area (SMA) syndrome with akinesia, patients may experience objective deficits in complex movement such as bimanual coordination - which can prevent a return to work, e.g. for a musician or a surgeon.28,59 As mentioned, this deficit is related to a damage to the motor control network, that can be accurately mapped only in awake patients, by eliciting arrest or acceleration of movements.26,27 In practice, all patients who will undergo surgical removal of 9
ACCEPTED MANUSCRIPT a tumor involving SMA should be extensively informed before surgery, with the goal to decide whether the limits of resection should be represented by the traditional corticospinal tract (to avoid left paresis) or by the motor control circuit - with a lesser extent of resection but a better preservation of QoL. In other words, intraoperative detection and preservation of the fronto-striatal tract underpinning motor control,29 which is located in front of the
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pyramidal pathways mediating motor output, can prevent the onset of postoperative SMA syndrome - or at least will result in a very transitory (a few days and not a few weeks) and a mild deficit (without complete akinesia) with a complete functional recovery - including bimanual coordination.26,27 Of note, even though the same principle can be applied to the LH
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with respect to movement, when removing a left lesion, the frontal aslant tract (that connects the SMA to the frontal operculum and that evokes slowness or arrest of speech during stimulation) has also to be mapped and spared if the patient wants to prevent the occurrence
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of an immediate postoperative mustism.29 This example illustrates well the concept of "oncofunctional balance" in tumor surgery.60 Furthermore, a subtle somatosensory mapping is not possible under general anesthesia, while an awake patient can precisely describe somesthetic responses during DES:61 preservation of the sensory feedback is crucial for complex movement, e.g. to run after surgery within the right paracentral lobule.
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Damage of the visual pathways in the RH can induce disabling deficit in daily life. Indeed, injury of the right optic radiation will generate left homonymous hemianopia, preventing in many countries the patient from driving for medicolegal issues. Oculomotor pathway may also be injuried.62 Moreover, lesion of the right inferior longitudinal fascicle
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may elicit prosopagnosia, which can have negative impact on social cognition, or visual agnosia. Damage of the right SLF can result in left hemineglect, with also consequences on
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QoL - e.g. in a dancer, unable to return to work. Again, currently, intraoperative DES mapping under local anesthesia is the sole tool to identify and preserve this circuit within the RH with a high reliability.30-36,62 Similarly, awake craniotomy is the best technique to map language, with less than 2%
of aphasia in surgical series for left tumors.63,64 However, recent DES results detailed above demonstrated that RH may play a critical role for language in many patients, especially lefthanders and ambidextrous: therefore, these patients should benefit from awake mapping even when bearing a right lesion.37,39 In right-handed patients, if language disturbances are detected during seizures or on presurgical neuropsychological assessment, especially when right activations are observed on language functional MRI, intraoperative awake language mapping should be considered.38 Moreover, mapping non-verbal understanding in patients 10
ACCEPTED MANUSCRIPT who would like to preserve a high-level of cognition (e.g. lawyers or managers) should be proposed, because injury of the ventral stream may generate deficit of multimodal semantic processing,40 even in the RH.41 The clinical relevance of intra-operative mapping of calculation in patients undergoing surgery in the right parietal area has also been highlighted.65,66 Finally, a lesion involving the mentalizing system in the RH may result in
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postoperative social cognition disorders with possible change in behavior and personality, and thus may prevent patients to resume a normal occupational life - e.g. for medical doctors or nurses who should preserve their empathy.21,45
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Usefulness for postoperative rehabilitation
Based on DES in 231 patients who underwent awake surgery, neuroplasticity potential in brain-damaged patients was mapped by elaborating a probabilistic atlas of
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functional plasticity.67 This atlas demonstrated the critical role of the subcortical connectivity of the RH that should be preserved to avoid permanent deficit.12,25 This is a unique tool for predicting the likelihood of functional recovery after surgery, and for identifying patients who require functional rehabilitation, especially following a right lesion. Postoperative objective neuropsychological assessments are helpful for the elaboration of individualized programs of neurologic, cognitive and behavioral rehabilitation, adapted to an improved
CONCLUSIONS
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knowledge of the right connectome.67
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Original data recently provided by intraoperative DES mapping in awake patients undergoing surgery for a right lesion have led to better understand the functional connectivity
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of the RH and to rethink its actual role in many brain functions - as in movement execution and control, vision, spatial cognition, language and non-verbal semantic processing, executive functions (as attention), and emotional process (as empathy) (Figure 2). These findings challenge the myth of a "non-dominant" RH. The clinical implication of this improved knowledge of the functional anatomy of RH
is that, in neurosurgical practice, awake mapping has to be considered in a more systematic manner for surgery of right lesions. Indeed, when extensive postsurgical neuropsychological examinations are achieved, they frequently find cognitive and behavioral disturbances after glioma surgery, even in the RH.20,21 Therefore, risks of such subtle deficits should be extensively explained to the patient and his/her family before surgery within the RH, in order
11
ACCEPTED MANUSCRIPT to give him/her the possibility to decide whether (slight) permanent cognitive or emotional disorders can be compatible or not with his/her QoL - according notably to the work or the hobbies of the patient (e.g. to avoid left visual field deficit in a taxi driver, or left hemineglect in a sportsman, or mentalizing disturbances in a politician or an actor, etc...). Appropriate selection of tasks for intraoperative DES mapping can be achieved accordingly, to enable the
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patient to resume normal familial, social and professional lives. Standardized testing paradigms enabling the neurosurgeons to adapt awake craniotomy techniques for RH tumors in their practice are now in progress (e.g. PPTT or mentalizing tests).
Furthermore, a probabilistic atlas of functional plasticity derived from intraoperative DES is now available in order to predict the likelihood of functional recovery, especially after
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surgery within the RH.67 Thus, objective pre- and post-operative neuropsychological examinations must be achieved in all patients with surgery in the RH to adapt specific
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programs of rehabilitation - a strategy rarely applied in the current literature.
Disclosure
The authors have no personal, financial, or institutional interest in any of the drugs,
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materials, or devices described in this article.
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Figure 1 Fig 1A
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FIGURE LEGENDS
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Probabilistic 3D digitized map of cortical DES mapping data in the right hemisphere demonstrating the wide distribution of cortical representation within and between critical functions of the human brain: motor (green), sensory (yellow), speech arrest (red), anomia (blue), dysarthria (orange) (from24 with permission). Fig 1B
3D representation of functional response errors collected with subcortical DES mapping in the right hemisphere. Different colors represent the different functional response errors. The small colored points represent the projections of functional response errors on the x–y and x–z planes of the Montreal Neurological Institute space (from25 with permission).
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ACCEPTED MANUSCRIPT Figure 2 Proposal of a connectomal model of functional anatomy in the right hemisphere. The model was constructed on the basis of structural–functional correlations derived from intraoperative DES, and incorporates anatomical constraints. Abbreviations: IFOF,
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inferior frontal occipital fascicle; SLF, superior longitudinal fascicle.
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Disclosure The authors report no conflict of interest regarding the materials or methods used in this study or the findings specified in this paper.
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There is no any financial disclosure.
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Hugues DUFFAU