“The essential is invisible to the eyes.”
—Antoine de Saint Exupéry
In surgical neurooncology, the goal is to achieve a maximal safe resection, since optimized tumor removal significantly increases overall survival.1,2 When functionally possible, a complete or even a supratotal resection is currently recommended, in low-grade gliomas (LGG)3 and high-grade gliomas.4 However, preservation of the eloquent networks is essential to resume a normal familial, social, and professional life. Thus, a functional-based surgical resection should be performed, up to the individual functional boundaries, at both cortical and subcortical levels. Optimizing the oncofunctional balance means that the extent of resection (EOR) will depend on the involvement by the tumor of neural circuits critical for brain functions, or not.5 This is particularly true in diffuse glioma, because the purpose of surgery is to remove the cerebral parenchyma invaded by the tumoral disease on the condition
that it can be compensated, thanks to mechanisms of neuroplasticity.6
Redefining the quality of life (QoL) in neurooncology is of utmost importance, because diagnosis is currently made earlier. For example, surgery for incidental LGG has been initiated, since enabling a better EOR: a rate of 95.7% of EOR has recently been reported, with 58.1% of patients who underwent supratotal or total resection.7 This led to the proposal of a screening in the general population.8 Because more and more brain tumor patients have a normal life before surgery, they need to enjoy a similar QoL after resection, especially since life expectancy will be prolonged. Therefore, to be able to walk and to talk following surgery is not sufficient for numerous patients who not only want to survive, but also want to return to an active life. Preventing aphasia or hemiplegia is nowadays not satisfactory in a large number of human beings in whom cognition and emotion should also be preserved in order to give them the opportunity to recover their behavior and personality. Consequently, intraoperative motor and language mapping is not enough when removing a cerebral tumor. Identifying and sparing neural networks that subserve cognition (movement control, visuospatial cognition, executive functions, multimodal semantics, metacognition) and mentalizing (theory of mind, which plays a key role for social cognition) in awake patients is essential to resume a normal way of life.
Here, the aim is to review when and how to map and monitor these critical functions, which have been neglected for many decades by neurosurgeons. The disorders generated by surgical injuries of circuits underpinning nonmotor and nonspeech functions are usually not immediately visible on postoperative standard clinical examination, leading the physician to believe that the patient has no deficit. Yet, cognitive or emotional disturbances may subsequently prevent to return to an active life, as to work full time. A new connectome-based surgical approach should be more systematically considered in the management of cerebral tumor to preserve or even to improve QoL. First, a systematic neuropsychological assessment must be performed before surgery, in addition to an in-depth interview with the patient and the family to detail his/her needs according to his/her job, hobbies, and lifestyle. Second, a tailored intraoperative awake mapping combined with real-time monitoring of higher cognitive functions throughout the resection must be achieved to preserve the functional connectome, regardless of the tumor location. Third, a tailored cognitive rehabilitation should be proposed, based on an objective postoperative neuropsychological evaluation and on the wishes of each patient.
FROM INTRAOPERATIVE MOTOR/LANGUAGE MAPPING TO COGNITION/EMOTION MAPPING AND MONITORING
Due to a considerable structural-functional variability of cerebral organization across patients, especially in LGG due to progressive reconfiguration of neural networks in reaction to the slow growth of the tumor,9 intraoperative mapping using direct electrical stimulation (DES) became the gold standard for glioma surgery.10 A meta-analysis evidenced that DES mapping permitted a significant decrease of the rate of severe persistent neurological deteriorations, even in eloquent areas, while improving the EOR.10 DES has been used under general anesthesia to map the motor cortex and pyramidal pathways, optionally combined with motor evoked potentials for tumor within the Rolandic cortex or the insula.11 When the neoplasm involved language areas, awake DES mapping resulted in a decrease of postoperative permanent aphasias, with a rate <2% in large series.12,13 Furthermore, awake mapping became a new tool to investigate the brain connectome, by providing the unique opportunity to study directly in vivo in humans the functions of both the cortex and white matter tracts.14 In neurosciences, DES participated in the exploration of the language pathways and in the elaboration of an original model of anatomofunctional organization.15 This model is based on a dorsal phonological and articulatory stream underpinned by the arcuate fasciculus (AF)/superior longitudinal fasciculus (SLF) complex16-18 and by a ventral semantic stream, itself mediated by a direct pathway (the inferior fronto-occipital fasciculus [IFOF])19 as well as by an indirect pathway composed of the inferior longitudinal fasciculus (ILF),20 and then a relay at the temporal pole and the uncinate fasciculus.21 These findings have recently been popularized in brain tumor surgery in order to help neurosurgeons for intrasurgical language mapping.22
Even though DES mapping has allowed a significant decrease of postoperative permanent motor and speech deteriorations, preservation of movement and language is not enough. Cognitive or affective disorders not identified on a routine neurological examination may have more negative impact on the long-term QoL than “visible” deficits. Typically, disturbances of executive functions, such as attention or working memory,23 could prevent work resumption. Indeed, lexical access speed during naming is significantly correlated to the return to professional activities.24 The paradox is that a patient with some missing words that can be observed by the physician and the family can more easily resume an active life (if his/her executive functions have been preserved) than a patient with normal scores at the simple naming task but with an increase of reaction time, related to deterioration of higher order cognitive functions passed unnoticed. Similarly, despite the lack of language deficit, nonverbal semantic processing, which is critical for semantic memory and noetic consciousness (ie, the awareness of knowing and understanding the world and the self, and the ability to be aware of such an awareness), can be disturbed following glioma resection, resulting in behavioral changes.25 Moreover, a patient with deficit of mentalizing, which enables the understanding and prediction of other's behavior, may have difficulties for social communication.26,27 Patients who underwent LGG surgery without neurological deficits may nonetheless experience heightened schizotypal traits (attenuated psychotic-like symptoms) with possible consequences on social and familial life.28
Other troubles missed by the clinician in the postoperative period may also have repercussions on the QoL. For instance, despite the lack of monoparesis or hemiparesis, disturbances of complex bimanual coordination could be disabling for doing sport or playing musical instrument.29 Disorders of conscious awareness, especially due to damages of the cingulate, a structure involved in the default-mode network,30 could have negative impact on creativity and could harm the QoL of artists.31 Furthermore, these deficits traditionally thought to be “subtle” may have different consequences according to the social environment. For example, although visual disturbances can have direct impact on the social activities for medical reasons, such as face recognition disturbances,32 an indirect negative effect could be related to medico-legal issues, eg, the official authorization to drive in case of visual field deficit, that may vary across countries.33 The patients can also be more or less demanding according to the cultural and socioeconomic environment.33 Thus, when cognitive mapping and monitoring was not achieved intraoperatively, the level of functional recovery is not optimal.
These data support the need to go beyond the classical concept underlying surgery of “eloquent areas” tumors, namely to achieve awake mapping only when the lesion involves the presumed language regions in the so-called dominant hemisphere (generally the left side). Indeed, resection of tumors near or within the Rolandic cortex and its fibers is traditionally performed under general anesthesia using only DES motor mapping, especially in the right “nondominant” hemisphere. It is time to challenge this simplistic and dogmatic view in order to evolve to a personalized “mapping à la carte” based on the wishes of the patient. All explanations should be given to the patient and the family before surgery, by insisting on the risk not only to induce “visible” motor or language deterioration but also to generate more insidious neuropsychological, affective, or behavioral changes. The goal is to give the choice to each patient to benefit (or not) from a more extensive and sensitive neurocognitive mapping and monitoring during surgery adapted to his/her lifestyle, the absolute need (or not) to get his/her life back (especially to return to full-time work7), and the possible acceptance (or not) of some degrees of cognitive or emotional impairments, as well as adapted to his/her familial, cultural, and social environment. While it could be objected that the incorporation of more tasks during awake surgery could result in a reduced EOR, the reverse has been proven, since mapping nonverbal semantics or mentalizing did not prevent to achieve supratotal resection.34 Indeed, if the tumor actually involves critical motor or language structures, the resection will be interrupted according to these “basic functions,” without adding more complex tasks intraoperatively. However, if the neoplasm involves the so-called noneloquent areas, such as the right hemisphere outside the central region in a right-handed patient, or the left frontal or temporal pole, rather than to perform a classical surgery under general anesthesia, the aim is to achieve awake procedure with DES mapping of the higher order functions (Figures 1 and 2). As in language areas, the principle is to pursue the resection until the cognitive and emotional functional boundaries have been encountered, not before. In this functional-based surgical philosophy, a “safety oncological margin” will be resected (without generating any permanent deficit even regarding behavioral functions) in a subgroup of patients in whom only the tumor visible on magnetic resonance imaging (MRI) would have been removed under general anesthesia, in a traditional imaging-guided surgical philosophy. Such an optimization of the oncofunctional balance, thanks to a more comprehensive intrasurgical mapping, was demonstrated by postoperative objective neuropsychological assessment35 that evidenced recovery even regarding higher order functions as theory of mind36 or metacognition.37
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FIGURE 1.: Awake resection of a right premotor diffuse low-grade glioma. A, Preoperative axial fluid-attenuated inversion recovery (FLAIR)-weighted MRI achieved in a 44-yr-old right-handed woman, medical doctor, who experienced seizures that allowed the discovery of a right premotor diffuse low-grade glioma. The neurological examination was normal. Nonetheless, the preoperative neuropsychological evaluation revealed a slight deficit of working memory and empathy. B, Intraoperative view before resection in awake patient. The anterior part of the right hemisphere is on the left and its posterior part is on the right. Letter tags correspond to the projection on the cortical surface of the tumor boundaries identified using ultrasonography. Number tags show zones of positive DES mapping (2 mA) as follows (within the precentral gyrus, from lateral to mesial): 3, ventral premotor cortex (inducing anarthria during stimulation); 1, primary motor cortex of the face; 4, negative motor area (generating arrest of counting and movement of the left upper limb during stimulation); 2 and 5, primary motor cortex of the left upper limb. Furthermore, in the pars opercularis of the right inferior frontal gyrus, tag 6: site of mentalizing disturbances during DES. C, Intraoperative view after resection, achieved up to eloquent structures, at both cortical and subcortical levels. Indeed, in addition to the eloquent cortical sites already described, DES of white matter tracts enabled the identification of the following subcortical neural networks: mesially, the frontostriatal tract, inducing arrest of movement of the left lower limb (tag 50) and of the left upper limb (tag 49), with also slowness of speech (tag 47) during stimulation: this bundle represented the posteromesial and deep limit of the resection; posteriorly, the pyramidal tract (48) generating involuntary dystonic movement of the left upper limb when stimulated, and the oculomotor tract (tag 44), with involuntary saccades during stimulation (with then the impossibility to perform the PPTT task): both tracts represented the posterior and deep limit of the resection; laterally, the frontal part of the inferior fronto-occipital fasciculus, eliciting semantic disorders during the PPTT (tag 46) and mentalizing disturbances (tag 43) when stimulated: this bundle represented the posterolateral limit of the resection. D, Postoperative axial FLAIR-weighted MRI (performed 3 mo after resection) demonstrating a complete resection. The patient resumed a normal familial, social, and professional life within 3 mo following surgery, with an improvement of the neuropsychological examination, thanks to a postsurgical cognitive rehabilitation. A diffuse WHO grade II astrocytoma (IDH1 mutated, non-codeleted) was diagnosed, and no adjuvant treatment was administrated. The imaging is stable with 2 yr of follow-up, and the patient continues to enjoy an active life, working full time, with no symptoms.
FIGURE 2.: Awake resection of a left anterior frontomesial diffuse low-grade glioma. A, Preoperative axial fluid-attenuated inversion recovery (FLAIR)-weighted MRI achieved in a 39-year-old right-handed woman, working in marketing, who experienced headaches that enabled the incidental discovery of a left anterior frontomesial diffuse low-grade glioma. The neurological and neuropsychological assessments were normal. B, Intraoperative view before resection in awake patient. The anterior part of the left hemisphere is on the right and its posterior part is on the left. Letter tags correspond to the projection on the cortical surface of the tumor boundaries identified using ultrasonography. Number tags show zones of positive DES mapping (2.5 mA) as follows: 1, 2: ventral premotor cortex (inducing anarthria during stimulation); 3: area involved in phonological processing (generating phonemic paraphasia during stimulation of the pars opercularis of the left inferior frontal gyrus); 4: area involved in semantic processing (generating semantic paraphasia during stimulation of the dorsolateral prefrontal cortex); C, Intraoperative view after resection, achieved up to eloquent structures, both at cortical and subcortical levels. Indeed, in addition to the eloquent cortical sites already described, DES of white matter tracts enabled the identification of the following subcortical neural networks: mesially, the frontal aslant tract, inducing speech arrest (tag 48) during stimulation: this bundle represented the posteromesial limit of the resection; posterolaterally, the frontostriatal tract (49), running to the head of the caudate and generating verbal perseveration during stimulation: this bundle represented the posterolateral and deep limit of the resection; laterally, the frontal part of the inferior fronto-occipital fasciculus, eliciting semantic paraphasia during naming task (tag 50) when stimulated: this bundle represented the lateral limit of the resection. D, Postoperative axial FLAIR-weighted MRI (performed 6 h after resection) demonstrating a supracomplete resection. The patient resumed a normal familial, social, and professional life within 3 mo following surgery. A diffuse WHO grade II oligodendroglioma (IDH1 mutated, codeleted) was diagnosed, and no adjuvant treatment was administrated. The imaging is stable with 3 yr of follow-up, and the patient continues to enjoy an active life, working full time, with no symptoms.
NEURAL FOUNDATIONS OF NONMOTOR/NONSPEECH FUNCTIONS: PRACTICAL IMPLICATIONS FOR SELECTION OF TASKS DURING AWAKE SURGERY
Sparing higher-order functions implies a better understanding of the neural basis mediating neurocognition and emotion, in order to adapt the surgical strategy to the individual functional organization of neural networks. Stronger interactions between cognitive neurosciences and surgical neurooncology should be developed to lay the foundations of “connectomal surgery.”38
During the presurgical meeting, the decision to achieve awake surgery, including in presumed “noneloquent areas,” and the selection of intraoperative tasks should be made by the patient him/herself after a comprehensive discussion based not only on the anatomical location of the tumor, but also on the results of the objective neuropsychological assessment, the subjective patient's complaints (very frequent, even in incidental discovery),39 and the details of his/her familial, social, and professional lifestyle.40 The patient must define his/her own optimal oncofunctional balance, following an actual “informed consent” as defined by the Hippocratic oath, and not after a simplistic “standard explanation” showing the statistical results of overall survival with or without resection versus the statistical surgical risks to induce hemiplegia/aphasia according to the classical literature. At the extreme, if the patient does not want to experience any permanent deficit, including with regard to higher-order functions, the neurosurgeon must adapt the therapeutic attitude, for example by proposing a multistage surgical approach based upon an incomplete tumor resection during the first operation (to preserve a perfect QoL), followed by a postoperative functional rehabilitation with the goal to induce mechanisms of neuroplasticity, and then to achieve a subsequent reoperation a few months or years later (depending on the neoplasm) with an increase of the EOR (so without any loss of chance from an oncological perspective) while again avoiding any permanent neurological deterioration.41 Even if this strategy is still debated, cortical tumors with sharp borders are associated with a higher potential of neuroplasticity, and then correlated with a greater EOR and earlier recovery at reoperation, contrary to tumors invading the subcortical connectivity, since white matter tracts represent the main limitation of plastic mechanisms.41
Thus, it is impossible to apply a standardized surgical protocol to all patients, since each patient has not only a different tumoral behavior, but also a different brain organization and different wishes, with a distinct definition of QoL.42 Of note, functional neuroimaging (functional MRI and tractography) is not very helpful for surgical selection and planning at the individual level,43 not only because this technique is not reliable,44 especially concerning language,45 but because it is still in infancy concerning higher cognitive functions as mentalizing.46 Thus, all neurosurgeons should have the best knowledge as possible, according to the state of the art of neurosciences, of the neural bases mediating cognitive and emotional functions in order to maximize the benefit/risk ratio for each brain tumor resection, especially by selecting the appropriate tasks during the different stages of awake surgery.
Beyond Motor Mapping Under General Anesthesia: Monitoring of Complex Movement in Awake Patients
Usually, preserving movement means preventing severe hemiparesis. However, even though a patient is not hemiplegic following surgery, he is not systematically capable to perform complex movements, particularly involving bimanual coordination, as needed for a carpenter, a surgeon, a sportsman, or a violinist, etc. Beyond the cortico-spinal pathway, another network is involved in the control of movement, comprising a mosaic of cortical areas47 connected by nonpyramidal pathways,48,49 including the frontostriatal tract (FST).50 DES of this circuit in awake patient generates arrest of movement (Figure 1), explaining why this network cannot be reliably monitored under general anesthesia. Therefore, the choice should be given to the patient to benefit from awake mapping and monitoring of such a “negative motor network,” even for a tumor situated near the Rolandic area in the right hemisphere. Recently, an intraoperative hand manipulation task was proposed to assess the praxis circuit and to decrease the risk of postoperative long-term apraxia.51 Moreover, the somatosensory feedback is critical for fine movements, explaining why awake DES mapping of the thalamocortical fibers and corresponding cortex is necessary, even for right parietal tumors.52 Beyond somesthetic processing, awareness of body scheme should also be preserved, particularly for tumor involving the precuneus, to prevent complex disorders such as microsomatognosia, autotopagnosia, or fading limb, commonly not detected by the physicians but possibly disabling for patients (eg, difficulties during walking activities due to macrosomatognosia).53
Visuospatial Cognition
To prevent visual field deficit, visual agnosia, and hemineglect, awake surgery can be proposed with incorporation of additional intraoperative tasks. First, to avoid hemianopia (preventing to drive in many countries),33 the patient is asked to name or to read 2 pictures in quadrant on the same slide, while looking at a red cross on the center of the screen.54 DES of the optic tracts causes a transitory shadow or reduction of the visual field: the patient is not able to see both items. DES may also elicit positive phenomena like phosphenes or visual distortion.55
Stimulation of the ILF may elicit visual hemiagnosia, including in the right hemisphere.56 In bilateral lesion of ILF, eg, in multicentric gliomas involving both temporal lobes, the patient can suffer from permanent prosopagnosia, which may be very disabling, whereas the classical neurological examination is normal.32 Furthermore, a line bisection task may be added to map and monitor spatial cognition, a complex function subserved by the junction between the supramarginal gyrus and the posterior part of the superior temporal gyrus at the cortical level, as well as the part II of the SLF, especially in the right hemisphere.52,57-59
Beyond Language: Verbal Versus Nonverbal Semantics
Awake mapping is increasingly proposed in surgery within language structures, at cortical15 and subcortical levels.14,16 The neural foundations of language are better understood, particularly thanks to DES,15 regarding subnetworks underpinning articulation,18 phonology,19 syntax,60 lexical access,20 repetition,61 reading,62 and semantics.19 Nonetheless, semantic processing does not rely only on verbal understanding, but also on nonverbal semantics.25 This function, which is crucial for noetic consciousness and metacognition (namely “knowing about knowing”),37 is mainly mediated by the IFOF, ie, the major pathway of the ventral semantic route, including within the right hemisphere63,64 that connects the superior parietal lobule, occipital lobe, and posterior temporal lobe to the prefrontal areas.65 During DES of the dorsolateral prefrontal cortex (DLPFC), dissociations were evidenced between the cortical sites involved in verbal semantics and those involved in nonverbal semantic cognition, which are more bilaterally distributed.66 A semantic association task, as the Pyramidal Palm Tree Task (PPTT), may be used intraoperatively27,66 in addition to the classical language tests (eg, picture naming), whatever the hemisphere (Figures 1 and 2).
Executive Functions
Preservation of language can be conceived only if higher-order cognitive functions have also been spared, due to strong interactions between networks devoted to speech and executive control. For instance, in multilingual patients, whereas the subcircuits underpinning each language can be partly distinct,67,68 mapping every language is not sufficient: the structures involved in language switching should also be identified.69 The patient should regularly switch from one language to another one during surgical resection, according to his/her wishes to spare such executive functions, eg, in professional translator. DES of the frontal cortex or the SLF may disrupt voluntary switch, or may generate involuntary switch.69 The onset of perseverations during surgery is also a good reflect of executive control disorders. In agreement with the Cognitive Complexity and Control theory's key claim that coordinating conflicting rules is critical to overcoming perseveration,70 a new striatal deafferentation model was proposed based upon DES, which generates verbal perseveration during stimulation of the left IFOF, FST, and the caudate.71
Attentional processing may also be preserved.72 The patient has to perform one or several tasks every 4 to 5 s (by checking that reaction time does not increase)24 without any rest for the duration of the tumor removal, thus monitoring sustained attention. Direct mapping of structures involved in attentional processing can be also considered, like the frontal eye field (FEF) and its fibers.73 FEF is part of a higher-order associative system that participates in controlling the spatial orienting of attention.74 FEF and oculomotor fibers may be mapped using DES, especially in awake patients for resection of a right frontal glioma (Figure 1): thanks to this additional monitoring, they did not experience permanent attentional disturbances following surgery.73 Also for tumors within the nondominant frontal lobe, a Stroop task was incorporated to preserve the structures involved in inhibition of automatic responses, decreasing the incidence of postoperative executive functions deficits,75 while increasing the EOR.76 For glioma involving the right temporo-parietal junction, due to the risk of severe impairment of cognitive control capacities, eg, set-shifting capacities, the intraoperative use of Trail making test part B was proposed to preserve the network underlying cognitive flexibility.77 Verbal and spatial working memory has also been mapped using the digit span and visual N-back tasks in patients with right superior frontal gyrus tumors, with normal postoperative neurocognitive scores thanks to the preservation of positive sites within the DLPFC.78
Finally, many activities in daily life require processing several matters simultaneously. Such a multitasking capacity necessitates maintaining different tasks to be achieved at the same time and concurrently allocating attention among them. Intraoperatively, this complex ability may be monitored by asking the patient to perform 2 tests constantly, eg, to combine movement and naming or PPTT task throughout the surgical resection. A multitasking disorder is diagnosed if the patient is not capable anymore to achieve both tasks simultaneously, whereas he/she is still able to perform each test separately.35,42
Emotion and Behavior
Mentalizing (or “theory of mind”), ie understanding and predicting others’ behavior, is one of the main foundations of social cognition.79 This capability encompasses a variety of subprocesses, eg, emotion processing, inferential reasoning, understanding of causality, and self/other distinction. It is disrupted in a large range of neuropsychiatric disorders in which social communication is highly problematic, such as in autism spectrum disorders and schizophrenia. Because patients may experience postoperative mentalizing impairment, especially after resection of the right inferior frontal gyrus,26 theory of mind can be mapped intrasurgically for patients who would like to preserve an optimal social cognition. An adapted version of a mentalizing task (The Read the Mind in the Eyes Task) may be added intraoperatively (Figure 1), based upon the presentation of photographs depicting the eye region of human faces.80 Different affective states are proposed and patients have to select the one that best describes what the person is feeling or thinking. This task allows to map the lower, prereflective, and automatic aspect of mentalizing.79,80 It has recently been proposed to map the networks underpinning high-level (reflective) mentalizing during resection within the right hemisphere, because surgical damage of the right orbitofrontal cortex and structural connectivity of the SLF (III) and FST may generate deficit of mentalizing.81
This complex skill is made possible due to parallel functioning and interaction between subnetworks bilaterally distributed. A first subpathway, crucial for low-level perceptual aspect of theory of mind (the mirror system, which permits to perceive other people's emotions), implied in emotional empathy, is mainly mediated by the posteroinferior frontal gyrus and the DLPFC, which are connected to posterior temporoparietal regions by the right AF/SLF complex.79 A second subcircuit processes the high-level inferential mentalizing, which enables to attribute mental states to others. This social metacognitive ability is mostly sustained by both cinguli, which link the rostral medial prefrontal cortex/anterior cingulate with the medial posterior parietal cortex, including the posterior cingulate cortex and ventral precuneus.30 Thirdly, in addition to the dorsal stream, critical structures have also been detected by DES along the inferior IFOF and in the white matter fibers running to the DLPFC.36 Based upon these original findings, a triple-stream model of mentalizing was proposed, with strong implications for awake mapping.82
Conscious Awareness
Thanks to intrasurgical monitoring of patients’ behavior, DES can map circuits involved in the maintenance of conscious awareness. For instance, DES of the subcortical white matter pathway coming from the dorsal posterior cingulate cortex may evoke a transient breakdown in conscious information processing, ie a behavioral unresponsiveness with loss of external connectedness. After DES, the patient described himself as a dream, outside the operating theater.83 These observations support that functional integrity of the posterior cingulate connectivity is necessary to maintain conscious awareness of the environment.30
To sum up, by mapping the functional networks using intraoperative DES, it is possible to have real insights into the “true functional connectome.”84 Indeed, DES mapping is able to distinguish essential from merely participating cerebral structures with a high temporo-spatial resolution. Second, beyond the identification of critical hubs within a specialized functional network (eg, dedicated to movement or language), DES may disturb markedly dual-tasking capabilities (so intersystems interactions) but not the capacity to achieve both tasks in a serial manner, illustrating how DES mapping can also detect the cortico-subcortical areas relevant for network coordination. On this basis, DES led to the elaboration of an atlas of critical nodal architecture of the brain connectome that reported a normalized dataset of 1821 cortical and subcortical functional responses collected during DES in patients undergoing awake brain surgery. This atlas, which detailed pathways essential not only for motor and language functions but also for cognitive and behavorial functions, is now available for brain tumor surgeons, opening the door to a “connectome-based neurosurgery”.85
HOW TO MAP HIGHER-ORDER FUNCTIONS IN CLINICAL ROUTINE
The first step to achieve monitoring of higher-order functions is to build a multidisciplinary team with a neuropsychologist in addition to a speech therapist, in order to start by performing preoperative neuropsychological assessment. This examination is crucial to identify the frequent cognitive and behavioral disturbances related to the tumor, not detected by a classical neurological and language evaluation.35,39 These results, correlated to the location of the tumor, will be helpful to guide the preoperative conversations with the patient on what postoperative expectations should be, especially regarding transient worsening in the immediate postsurgical period. For example, beyond the risk of hemiparesis and/or speech disorders, in frontoprecentral tumors (Figures 1 and 2), there is a risk of complex movement (as bimanual coordination) deficit due to the FST posteriorly (with a possible supplementary motor area syndrome if this tract is removed),49,50 of semantic cognition troubles due to the IFOF laterally,64 of attentional disturbances due to the FEF and its pathway,73 of mentalizing worsening due to the cingulate79 or to the right AF.27 For parietoretrocentral tumor, there is a risk of somatosensory deficit due to the thalamocortical pathways anteriorly,52 of visuospatial disturbances due to the optic tracts or right SLF,57-59 and of conscious awareness troubles due to the precuneus and posterior cingulate connectivity.30,83 For temporal tumors, there is a risk of verbal and or nonverbal semantic deficit due to the IFOF,25 which is also involved in face-based mentalizing36; of visual field deficit related to optic tracts54; and of visual recognition disorders due to the ILF.32 In insular tumors, the ventral semantic pathway will represent the deep limit of the resection into the contact of the IFOF running into the temporal stem.65 The Table summarizes which cognitive tasks (beyond motor and language tasks) should be used based on tumor location. Intraoperatively, to detect and preserve these pathways, the electrical parameters of DES are similar to those used for motor and language mapping.85 The team of anesthesiologists should be trained in awake surgery because the patient must be very collaborative throughout the resection, under the guidance of neuropsychologist/speech therapist who achieve a cognitive and emotion monitoring in real time.35 Finally, they will also perform an immediate postoperative neuropsychological assessment in order to tailor a personalized cognitive rehabilitation as well as a few months later to check if the patient objectively recovered regarding higher-order functions.
TABLE. -
Intraoperative Cognitive Tasks to Be Used Based on Tumor Location (Beyond Motor and Language Mapping)
| Tumor location |
Pathways to be identified |
Intraoperative tasks |
Risk of transient postoperative worsening |
| Frontoprecentral |
FST (posteriorly) DLPFC and IFOF (laterally) FEF and its fibers (posterolaterally) Cingulate fibers (medially)/AF(laterally) |
Bimanual coordination/fine movement task29,47-51 Semantic association task (PPTT)25,66 Dual task every 4 s/n-back task/Stroop72,73,75,76 Mentalizing task (RME)79-81
|
Complex movement deficits Verbal and/or nonverbal semantic disorders Attentional/executive functions deficits Behavioral disturbances |
| Parietoretrocentral |
Thalamocortical tracts (anteriorly) Posterior cingulate fibers (medially) Optic tracts (posteriorly) Right SLF part II (laterally) Frontoparietal connections |
Somatosensory52 Bodily awareness30,53,83 Visual field testing54,55 Line bisection57,58,59 Dual task every 4 s/TMTB72,73,77
|
Somesthetic deficits Body schema deficits Visual field deficits Spatial cognition disturbances Attentional/executive functions disorders |
| Temporal |
IFOF (upper limit of resection) ILF (posteriorly)/optic tracts |
PPTT/RME25,36,64 Visual recognition32,56
|
Semantic/behavioral deficits Visual hemiagnosia/Visual field deficits |
| Insula |
IFOF (deep limit of resection) Thalamocortical tracts (posteriorly) |
PPTT/RME25,36,64 Somatosensory38
|
Semantic/behavioral deficits Somesthetic deficits |
AF = arcuate fasciculus; DLPFC = dorsolateral prefrontal cortex; FEF = frontal eye fields; FST = frontostriatal tract; IFOF = inferior fronto-occipital fasciculus; ILF = inferior longitudinal fasciculus; PPTT = Pyramidal Palm Tree Task; RME = Read the Mind in the Eyes Task; SLF = superior longitudinal fasciculus; TMTB = trail making test part B.
POSTOPERATIVE COGNITIVE REHABILITATION AND REPEAT SURGERIES THANKS TO FUNCTIONAL REMAPPING
Transitory deficits are frequent in the immediate postoperative period, due to edema and changes in the functional connectivity, particularly when the resection was pushed to eloquent structures. For instance, the well-known supplementary area syndrome, which combines akinesia and mutism in the left hemisphere, is related to a transient decrease of the interhemispheric connectivity, as demonstrated by longitudinal resting-state functional MRI investigation.86 Nonetheless, besides dramatic motor and/or language impairments in the days/weeks following functional-based surgery, cognitive and behavioral disturbances may easily be overlooked. Therefore, a postoperative objective neuropsychological assessment should be performed, in order to detect possible deteriorations compared with the preoperative level concerning higher-order cognitive functions such as memory and executive functions.87,88
The interest of this examination before the discharge is to develop a specific program of cognitive rehabilitation therapy (CRT), which aims at improving cognitive abilities through compensation or retraining. Several CRT programs were proposed in brain tumor patients, especially after surgery.89-91 These studies, which included randomized controlled trials,91-93 evidenced improvements in cognitive test performance concerning executive functions, memory, attention, and visuospatial functions,89,91,92,94,95 as well as regarding subjective cognitive functioning,93 both in LGG96 and high-grade glioma.89 CRT must begin as early as possible following surgical resection.91 Indeed, precocious CRT program for patients who underwent surgery for primary brain tumor demonstrated that neurocognition already improved after a few weeks of training.91 In practice, tailored CRT programs adapted to the patient needs can be performed at home, possibly by means of telerehabilitation.90
However, despite these positive results, only a few number of brain tumor patients currently benefit from CRT97 while many glioma patients exhibit cognitive disorders, particularly after resective surgery.98 Early and intensive postoperative CRT adjusted to the immediate postsurgical neuropsychological assessment should be considered more systematically because it will facilitate neuroplasticity mechanisms. Serial functional MRI studies before and after LGG resection near language networks have shown that, following CRT, patients recovered from their transitory deficit thanks to dynamic within and intersystems reorganization.99,100 For instance, picture naming recovery was dependent on the semantic and attentional networks, showing that language cannot be seen in isolation, but that interaction across language and higher-order cognitive functions must be taken into consideration.100 Interestingly, such a cerebral remapping may also indirectly optimize the oncological results by reopening the window to repeat surgeries with an improvement of the EOR (and then survival) while preserving the QoL.41
CONCLUSION
Our better knowledge of the brain connectome, its potentials as well as limitations of adaptive redistribution in reaction to cerebral neoplasms and their surgical resection, must result in new concepts in the management of brain tumor patients. The dichotomy between awake surgery in presumed language areas (traditionally in the “dominant hemisphere”) and asleep surgery in presumed nonlanguage areas (deemed as “noneloquent”, classically in the “nondominant hemisphere”) should be abandoned. Due to the strong interactions between movement, language, cognitive, and emotional networks,14 awake surgery with intraoperative mapping and monitoring of higher-order neurocognitive functions must be proposed to all patients with a preoperative (sub)normal life, in order to spare the neural structures critical (noncompensable) for the QoL of this given patient as defined by him(her)self before surgery. The selection of intraoperative tasks should be made based upon the results of the preoperative neuropsychological assessment, allowing a mapping “à la carte” regardless the lobar location of the tumor (Figure 1), while possibly resulting in a supratotal resection (Figure 2). Furthermore, a cognitive rehabilitation must be envisioned based on the immediate postoperative neuropsychological scores, in order to optimize the chance to resume an active life, including concerning socioprofessional considerations: it is thus crucial to take account of possible nonmotor nonspeech disturbances, which were neglected for many decades despite their negative impact in daily life. Finally, a multistage surgical approach can be anticipated since the first meeting with the patient and his/her family, in order to maximize not only the functional outcomes but also the overall survival, by means of potentiation of neuroplastic mechanisms that allow repeat surgeries over time. Surgical neurooncologists should evolve from a “ready-to-wear” attitude based upon the application of a standardized protocol which relies on a rigid localizationist view of cerebral organization and which “only” aims at avoiding hemiplegia/aphasia, to a “high-fashion” surgical philosophy, which results in the elaboration of individualized dynamic strategies based on a flexible connectomal account of brain networking, and which ultimately aims of (re)considering the patient as a human being with his/her complex and unique cognition, behavior and personality.
Funding
This study did not receive any funding or financial support.
Disclosures
The author has no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.
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COMMENT
The authors make a very important appeal to tumor neurosurgeons to map not only motor and language function, but also to include higher order cognitive mapping as an effort to improve our patients’ quality of life, including executive function, semantic processing, etc. I highly commend them on their efforts and their mastery of the subject, and I completely agree that our field needs to advance further with our mapping techniques. Their argument is strong and any surgeon with experience has seen the effects of neglecting these important higher order functions on the quality of life of patients, especially those with lower grade lesions.
The difficulties that often limit most tumor neurosurgeons from such mapping is lack of familiarity with the techniques and the consideration that such tasks are too complicated. I am certain this manuscript will shed some light on mapping these complex, yet critical functions.
I congratulate the authors on their work.
Wajd N. Al-Holou
Ann Arbor, Michigan
