Integrating direct electrical brain stimulation with the human connectome.

Neurological and neurodevelopmental conditions are a major public health concern for which new therapies are urgently needed. The development of effective therapies relies on the precise mapping of the neural substrates causally involved in behaviour generation. Direct electrical stimulation (DES) performed during cognitive and neurological monitoring in awake surgery is currently considered the gold standard for the causal mapping of brain functions. However, DES is limited by the focal nature of the stimulation sites, hampering a real holistic exploration of human brain functions at the network level. We used 4137 DES points derived from 612 glioma patients in combination with human connectome data-resting-state functional MRI, n = 1000 and diffusion weighted imaging, n = 284-to provide a multimodal description of the causal macroscale functional networks subtending 12 distinct behavioural domains. To probe the validity of our procedure, we (i) compared the network topographies of healthy and clinical populations; (ii) tested the predictive capacity of DES-derived networks; (iii) quantified the coupling between structural and functional connectivity; and (iv) built a multivariate model able to quantify single subject deviations from a normative population. Lastly, we probed the translational potential of DES-derived functional networks by testing their specificity and sensitivity in identifying critical neuromodulation targets and neural substrates associated with postoperative language deficits. The combination of DES and human connectome data resulted in an average 29.4-fold increase in whole brain coverage compared to DES alone. DES-derived functional networks are predictive of future stimulation points (97.8% accuracy) and strongly supported by the anatomical connectivity of subcortical stimulations. We did not observe any significant topographical differences between the patients and the healthy population at both group and single subject level. Showcasing concrete clinical applications, we found that DES-derived functional networks overlap with effective neuromodulation targets across several functional domains, show a high degree of specificity when tested with the intracranial stimulation points of a different stimulation technique and can be used effectively to characterize postoperative behavioural deficits. The integration of DES with the human connectome fundamentally advances the quality of the functional mapping provided by DES or functional imaging alone. DES-derived functional networks can reliably predict future stimulation points, have a strong correspondence with the underlying white matter and can be used for patient specific functional mapping. Possible applications range from psychiatry and neurology to neuropsychology, neurosurgery and neurorehabilitation.

Development of an educational method to rethink and learn oncological brain surgery in an "a la carte" connectome-based perspective.

BACKGROUND: Understanding the structural connectivity of white matter tracts (WMT) and their related functions is a prerequisite to implementing an "a la carte" "connectomic approach" to glioma surgery. However, accessible resources facilitating such an approach are lacking. Here we present an educational method that is readily accessible, simple, and reproducible that enables the visualization of WMTs on individual patient images via an atlas-based approach. METHODS: Our method uses the patient's own magnetic resonance imaging (MRI) images and consists of three main steps: data conversion, normalization, and visualization; these are accomplished using accessible software packages and WMT atlases. We implement our method on three common cases encountered in glioma surgery: a right supplementary motor area tumor, a left insular tumor, and a left temporal tumor. RESULTS: Using patient-specific perioperative MRIs with open-sourced and co-registered atlas-derived WMTs, we highlight the critical subnetworks requiring specific surgical monitoring identified intraoperatively using direct electrostimulation mapping with cognitive monitoring. The aim of this didactic method is to provide the neurosurgical oncology community with an accessible and ready-to-use educational tool, enabling neurosurgeons to improve their knowledge of WMTs and to better learn their oncologic cases, especially in glioma surgery using awake mapping. CONCLUSIONS: Taking no more than 3-5 min per patient and irrespective of their resource settings, we believe that this method will enable junior surgeons to develop an intuition, and a robust 3-dimensional imagery of WMT by regularly applying it to their cases both before and after surgery to develop an "a la carte" connectome-based perspective to glioma surgery.

Intraoperative functional remapping unveils evolving patterns of cortical plasticity.

The efficiency with which the brain reorganizes following injury not only depends on the extent and the severity of the lesion, but also on its temporal features. It is established that diffuse low-grade gliomas (DLGG), brain tumours with a slow-growth rate, induce a compensatory modulation of the anatomo-functional architecture, making this kind of tumours an ideal lesion model to study the dynamics of neuroplasticity. Direct electrostimulation (DES) mapping is a well-tried procedure used during awake resection surgeries to identify and spare cortical epicentres which are critical for a range of functions. Because DLGG is a chronic disease, it inevitably relapses years after the initial surgery, and thus requires a second surgery to reduce tumour volume again. In this context, contrasting the cortical mappings obtained during two sequential neurosurgeries offers a unique opportunity to both identify and characterize the dynamic (i.e. re-evolving) patterns of cortical re-arrangements. Here, we capitalized on an unprecedented series of 101 DLGG patients who benefited from two DES-guided neurosurgeries usually spaced several years apart, resulting in a large DES dataset of 2082 cortical sites. All sites (either non-functional or associated with language, speech, motor, somatosensory and semantic processing) were recorded in Montreal Neurological Institute (MNI) space. Next, we used a multi-step approach to generate probabilistic neuroplasticity maps that reflected the dynamic rearrangements of cortical mappings from one surgery to another, both at the population and individual level. Voxel-wise neuroplasticity maps revealed regions with a relatively high potential of evolving reorganizations at the population level, including the supplementary motor area (SMA, Pmax = 0.63), the dorsolateral prefrontal cortex (dlPFC, Pmax = 0.61), the anterior ventral premotor cortex (vPMC, Pmax = 0.43) and the middle superior temporal gyrus (STG Pmax = 0.36). Parcel-wise neuroplasticity maps confirmed this potential for the dlPFC (Fisher's exact test, PFDR-corrected = 6.6 × 10-5), the anterior (PFDR-corrected = 0.0039) and the ventral precentral gyrus (PFDR-corrected = 0.0058). A series of clustering analyses revealed a topological migration of clusters, especially within the left dlPFC and STG (language sites); the left vPMC (speech arrest/dysarthria sites) and the right SMA (negative motor response sites). At the individual level, these dynamic changes were confirmed for the dlPFC (bilateral), the left vPMC and the anterior left STG (threshold free cluster enhancement, 5000 permutations, family-wise error-corrected). Taken as a whole, our results provide a critical insight into the dynamic potential of DLGG-induced continuing rearrangements of the cerebral cortex, with considerable implications for re-operations.

Constant Multi-Tasking With Time Constraint to Preserve Across-Network Dynamics Throughout Awake Surgery for Low-Grade Glioma: A Necessary Step to Enable Patients Resuming an Active Life.

Awake surgery for brain gliomas improves resection while minimizing morbidity. Although intraoperative mapping was originally used to preserve motor and language functions, the considerable increase of life expectancy, especially in low-grade glioma, resulted in the need to enhance patients' long-term quality of life. If the main goal of awake surgery is to resume normal familial and socio-professional activities, preventing hemiparesis and aphasia is not sufficient: cognitive and emotional functions must be considered. To monitor higher-order functions, e.g., executive control, semantics or mentalizing, further tasks were implemented into the operating theater. Beyond this more accurate investigation of function-specific neural networks, a better exploration of the inter-system communication is required. Advances in brain connectomics led to a meta-network perspective of neural processing, which emphasizes the pivotal role of the dynamic interplay between functional circuits to allow complex and flexible, goal-directed behaviors. Constant multi-tasking with time constraint in awake patients may be proposed during intraoperative mapping, since it provides a mirror of the (dys)synchronization within and across neural networks and it improves the sensitivity of behavioral monitoring by increasing cognitive demand throughout the resection. Electrical mapping may hamper the patient to perform several tasks simultaneously whereas he/she is still capable to achieve each task in isolation. Unveiling the meta-network organization during awake mapping by using a more ecological multi-demand testing, more representative of the real-life conditions, constitutes a reliable way to tailor the surgical onco-functional balance based upon the expectations of each patient, enabling him/her to resume an active life with long-lasting projects.

Jargonaphasia as a disconnection syndrome: A study combining white matter electrical stimulation and disconnectome mapping.

BACKGROUND: In jargonaphasia, speech is fluent but meaningless. While neuropsychological evaluation may distinguish a neologistic component characterised by non-word production and a semantic component where pronounced words are real but speech is senseless, how this relates to the underlying white matter anatomy is debated. OBJECTIVE: To identify white matter pathways causally involved in jargonaphasia. METHODS: We retrospectively screened the intraoperative brain mapping data of 571 awake oncological resections using direct cortico-subcortical electrostimulation. Jargonaphasia was induced in 17 patients (19 sites) during a naming task. Stimulation sites were normalized to the Montreal Neurological Institute template space and used to generate individual disconnectome maps. Non-parametric voxelwise one and two sample t-tests were performed to identify the underlying white matter anatomy. RESULTS: Jargonaphasia was induced only during stimulation of the left hemisphere. No cortical stimulation generated jargonaphasia. Subcortical sites causally associated with jargonaphasia clustered in 3 regions: in the temporal lobe (middle to inferior temporal gyri; n = 12), in the parietal lobe (supramarginal gyrus; n = 3) and in the temporal stem (n = 4). Disconnectome analysis indicated the inferior-fronto-occipital fasciculus (IFOF) was damaged in both neologistic and semantic jargonaphasia, while the involvement of the arcuate fasciculus was specific to neologistic jargonaphasia. CONCLUSION: For the first time, we show that jargonaphasia is induced by white matter stimulation, hinting at disconnection. As IFOF disconnection unites both variants, these may represent a continuum of disorders distinguished by semantic impairment. Conversely, damage to the arcuate fasciculus in addition to the IFOF is specific to neologistic jargonaphasia, thus suggesting a dual-disconnection syndrome.

White matter disconnectivity fingerprints causally linked to dissociated forms of alexia.

For over 150 years, the study of patients with acquired alexia has fueled research aimed at disentangling the neural system critical for reading. An unreached goal, however, relates to the determination of the fiber pathways that root the different visual and linguistic processes needed for accurate word reading. In a unique series of neurosurgical patients with a tumor close to the visual word form area, we combine direct electrostimulation and population-based streamline tractography to map the disconnectivity fingerprints characterizing dissociated forms of alexia. Comprehensive analyses of disconnectivity matrices establish similarities and dissimilarities in the disconnection patterns associated with pure, phonological and lexical-semantic alexia. While disconnections of the inferior longitudinal and posterior arcuate fasciculi are common to all alexia subtypes, disconnections of the long arcuate and vertical occipital fasciculi are specific to phonological and pure alexia, respectively. These findings provide a strong anatomical background for cognitive and neurocomputational models of reading.

Combining Electrostimulation With Fiber Tracking to Stratify the Inferior Fronto-Occipital Fasciculus.

The inferior fronto-occipital fasciculus (IFOF) is one of the longest association fiber tracts of the brain. According to the most recent anatomical studies, it may be formed by several layers, suggesting a role in multiple cognitive functions. However, to date, no attempt has been made to dissociate the functional contribution of the IFOF subpathways. In this study, real-time, cortico-subcortical mapping with direct electrostimulation was performed in 111 patients operated on in wide-awake surgery for a right low-grade glioma. Patients performed two behavioral tasks during stimulation, tapping, respectively, mentalizing and visual semantic cognition-two functions supposed to be partly mediated by the IFOF. Responsive white matter sites were first subjected to a clustering analysis to assess potential topological differences in network organization. Then they were used as seeds to generate streamline tractograms based on the HC1021 diffusion dataset (template-based approach). The tractograms obtained for each function were overlapped and contrasted to determine whether some fiber pathways were more frequently involved in one or the other function. The obtained results not only provided strong evidence for a role of the right IFOF in both functions, but also revealed that the tract is dissociable into two functional strata according to a ventral (semantic) and dorsal (mentalizing) compartmentalization. Besides, they showed a high degree of anatomo-functionnal variability across patients in the functional implication of the IFOF, possibly related to symmetrical/hemispheric differences in network organization. Collectively, these findings support the view that the right IFOF is a functionally multi-layered structure, with nevertheless interindividual variations.

Disrupting self-evaluative processing with electrostimulation mapping during awake brain surgery.

Brain awake surgery with cognitive monitoring for tumor removal has become a standard of treatment for functional purpose. Yet, little attention has been given to patients' interpretation and awareness of their own responses to selected cognitive tasks during direct electrostimulation (DES). We aim to report disruptions of self-evaluative processing evoked by DES during awake surgery. We further investigate cortico-subcortical structures involved in self-assessment process and report the use of an intraoperative self-assessment tool, the self-confidence index (SCI). Seventy-two patients who had undergone awake brain tumor resections were selected. Inclusion criteria were the occurrence of a DES-induced disruption of an ongoing task followed by patient's failure to remember or criticize these impairments, or a dissociation between patient's responses to an ongoing task and patient's SCI. Disruptions of self-evaluation were frequently associated with semantic disorders and critical sites were mostly found along the left/right ventral semantic streams. Disconnectome analyses generated from a tractography-based atlas confirmed the high probability of the inferior fronto-occipital fasciculus to be transitory 'disconnected'. These findings suggest that white matters pathways belonging to the ventral semantic stream may be critically involved in human self-evaluative processing. Finally, the authors discuss the implementation of the SCI task during multimodal intraoperative monitoring.