Neuronal Spiking Responses to Direct Electrical Microstimulation in the Human Cortex.

Microstimulation can modulate the activity of individual neurons to affect behavior, but the effects of stimulation on neuronal spiking are complex and remain poorly understood. This is especially challenging in the human brain where the response properties of individual neurons are sparse and heterogeneous. Here we use microelectrode arrays in the human anterior temporal lobe in 6 participants (3 female) to examine the spiking responses of individual neurons to microstimulation delivered through multiple distinct stimulation sites. We demonstrate that individual neurons can be driven with excitation or inhibition using different stimulation sites, which suggests an approach for providing direct control of spiking activity at the single-neuron level. Spiking responses are inhibitory in neurons that are close to the site of stimulation, while excitatory responses are more spatially distributed. Together, our data demonstrate that spiking responses of individual neurons can be reliably identified and manipulated in the human cortex.SIGNIFICANCE STATEMENT One of the major limitations in our ability to interface directly with the human brain is that the effects of stimulation on the activity of individual neurons remain poorly understood. This study examines the spiking responses of neurons in the human temporal cortex in response to pulses of microstimulation. This study finds that individual neurons can either be excited or inhibited depending on the site of stimulation. These data suggest an approach for modulating the spiking activity of individual neurons in the human brain.

Comparative validation of automated presurgical tractography based on constrained spherical deconvolution and diffusion tensor imaging with direct electrical stimulation.

OBJECTIVES: Accurate presurgical brain mapping enables preoperative risk assessment and intraoperative guidance. This cross-sectional study investigated whether constrained spherical deconvolution (CSD) methods were more accurate than diffusion tensor imaging (DTI)-based methods for presurgical white matter mapping using intraoperative direct electrical stimulation (DES) as the ground truth. METHODS: Five different tractography methods were compared (three DTI-based and two CSD-based) in 22 preoperative neurosurgical patients undergoing surgery with DES mapping. The corticospinal tract (CST, N = 20) and arcuate fasciculus (AF, N = 7) bundles were reconstructed, then minimum distances between tractograms and DES coordinates were compared between tractography methods. Receiver-operating characteristic (ROC) curves were used for both bundles. For the CST, binary agreement, linear modeling, and posthoc testing were used to compare tractography methods while correcting for relative lesion and bundle volumes. RESULTS: Distance measures between 154 positive (functional response, pDES) and negative (no response, nDES) coordinates, and 134 tractograms resulted in 860 data points. Higher agreement was found between pDES coordinates and CSD-based compared to DTI-based tractograms. ROC curves showed overall higher sensitivity at shorter distance cutoffs for CSD (8.5 mm) compared to DTI (14.5 mm). CSD-based CST tractograms showed significantly higher agreement with pDES, which was confirmed by linear modeling and posthoc tests (PFWE < .05). CONCLUSIONS: CSD-based CST tractograms were more accurate than DTI-based ones when validated using DES-based assessment of motor and sensory function. This demonstrates the potential benefits of structural mapping using CSD in clinical practice.

More widespread functionality of posterior language area in patients with brain tumors.

Damage to the posterior language area (PLA), or Wernicke's area causes cortical reorganization in the corresponding regions of the contralateral hemisphere. However, the details of reorganization within the ipsilateral hemisphere are not fully understood. In this context, direct electrical stimulation during awake surgery can provide valuable opportunities to investigate neuromodulation of the human brain in vivo, which is difficult through the non-invasive approaches. Thus, in this study, we aimed to investigate the characteristics of the cortical reorganization of the PLA within the ipsilateral hemisphere. Sixty-two patients with left hemispheric gliomas were divided into groups depending on whether the lesion extended to the PLA. All patients underwent direct cortical stimulation with a picture-naming task. We further performed functional connectivity analyses using resting-state functional magnetic resonance imaging (MRI) in a subset of patients and calculated betweenness centrality, an index of the network importance of brain areas. During direct cortical stimulation, the regions showing positive (impaired) responses in the non-PLA group were localized mainly in the posterior superior temporal gyrus (pSTG), whereas those in the PLA group were widely distributed from the pSTG to the posterior supramarginal gyrus (pSMG). Notably, the percentage of positive responses in the pSMG was significantly higher in the PLA group (47%) than in the non-PLA group (8%). In network analyses of functional connectivity, the pSMG was identified as a hub region with high betweenness centrality in both the groups. These findings suggest that the language area can spread beyond the PLA to the pSMG, a hub region, in patients with lesion progression to the pSTG. The change in the pattern of the language area may be a compensatory mechanism to maintain efficient brain networks.

Statistical learning in epilepsy: Behavioral and anatomical mechanisms in the human brain.

OBJECTIVE: Statistical learning, the fundamental cognitive ability of humans to extract regularities across experiences over time, engages the medial temporal lobe (MTL) in the healthy brain. This leads to the hypothesis that statistical learning (SL) may be impaired in patients with epilepsy (PWE) involving the temporal lobe, and that this impairment could contribute to their varied memory deficits. In turn, studies done in collaboration with PWE, that evaluate the necessity of MTL circuitry through disease and causal perturbations, provide an opportunity to advance basic understanding of SL. METHODS: We implemented behavioral testing, volumetric analysis of the MTL substructures, and direct electrical brain stimulation to examine SL across a cohort of 61 PWE and 28 healthy controls. RESULTS: We found that behavioral performance in an SL task was negatively associated with seizure frequency irrespective of seizure origin. The volume of hippocampal subfields CA1 and CA2/3 correlated with SL performance, suggesting a more specific role of the hippocampus. Transient direct electrical stimulation of the hippocampus disrupted SL. Furthermore, the relationship between SL and seizure frequency was selective, as behavioral performance in an episodic memory task was not impacted by seizure frequency. SIGNIFICANCE: Overall, these results suggest that SL may be hippocampally dependent and that the SL task could serve as a clinically useful behavioral assay of seizure frequency that may complement existing approaches such as seizure diaries. Simple and short SL tasks may thus provide patient-centered endpoints for evaluating the efficacy of novel treatments in epilepsy.

Awake brain mapping paradigms for nondominant hemisphere gliomas.

OBJECTIVE: Traditionally, resection of nondominant hemisphere brain tumors was performed under general anesthesia. An improved understanding of right-lateralized neural networks has led to a paradigm shift in recent decades, where the right or nondominant hemisphere is no longer perceived as "functionally silent." There is an increasing interest in awake brain mapping for nondominant hemisphere resections. The objective of this study was to perform a comprehensive review of the existing brain mapping paradigms for patients with nondominant hemisphere gliomas undergoing awake craniotomies. METHODS: In accordance with PRISMA guidelines, systematic searches of the Medline, Embase, and American Psychological Association PsycInfo databases were undertaken from database inception to July 1, 2023. Studies providing a description of the intraoperative mapping paradigm used to assess cognition during an awake craniotomy for resection of a nondominant hemisphere glioma were included. RESULTS: The search yielded 1084 potentially eligible articles. Thirty-nine unique studies reporting on 788 patients were included in the systematic review. The most frequently tested cognitive domains in patients with nondominant hemisphere tumors were spatial attention/neglect (17/39 studies, 43.6%), speech-motor/language (17/39 studies, 43.6%), and social cognition (9/39 studies, 23.1%). Within the frontal lobe, the highest number of positive mapping sites was identified for speech-motor/language, spatial attention/neglect, dual tasking assessing motor and language function, working memory, and social cognition. Within the parietal lobe, eloquence was most frequently found upon testing spatial attention/neglect, speech-motor/language, and calculation. Within the temporal lobe, the assessment of spatial attention/neglect yielded the highest number of positive mapping sites. CONCLUSIONS: Cognitive testing in the nondominant hemisphere is predominantly focused on evaluating two domains: spatial attention/neglect and the motor aspects of speech/language. Multidisciplinary teams involved in awake brain mapping should consider testing an extended range of functions to minimize the risk of postoperative deficits and provide valuable information about anatomo-functional organization of cognitive networks.

Evoked responses to single pulse electrical stimulation reveal impaired striatal excitability in a rat model of Parkinson's disease.

BACKGROUND: Sensorimotor beta oscillations are increased in Parkinson's disease (PD) due to the alteration of dopaminergic transmission. This electrophysiological read-out is reported both in patients and in animal models such as the 6-OHDA rat model obtained with unilateral nigral injection of 6-hydroxydopamine (6-OHDA). Current treatments, based on dopaminergic replacement, transiently normalize this pathological beta activity and improve patients' quality of life. OBJECTIVES: We wanted to assess in vivo whether the abnormal beta oscillations can be correlated with impaired striatal or cortical excitability of the sensorimotor system and modulated by the pharmacological manipulation of the dopaminergic system. METHODS: In the unilateral 6-OHDA rat model and control animals, we used intra-striatal and intra-cortical single-pulse electrical stimulation (SPES) and concurrent local field potentials (LFP) recordings. In the two groups, we quantified basal cortico-striatal excitability from time-resolved spectral analyses of LFP evoked responses induced remotely by intracerebral stimulations. The temporal dependance of cortico-striatal excitability to dopaminergic transmission was further tested using electrophysiological recordings combined with levodopa injection. RESULTS: LFP evoked responses after striatal stimulation showed a transient reduction of power in a large time-frequency domain in the 6-OHDA group compared to the sham group. This result was specific to the striatum, as no significant difference was observed in cortical LFP evoked responses between the two groups. This impaired striatal excitability in the 6-OHDA group was observed in the striatum at least during the first 3 months after the initial lesion. In addition, the striatum responses to SPES during a levodopa challenge showed a transient potentiation of the decrease of responsiveness in frequencies below 40 Hz. CONCLUSION: The spectral properties of striatal responses to SPES show high sensitivity to dopaminergic transmission in the unilateral 6-OHDA rat model. We thus propose that this approach could be used in preclinical models as a time-resolved biomarker of impaired dopaminergic transmission capable of monitoring progressive neurodegeneration and/or challenges to drug intake.

Recovery of Visual Field After Awake Stimulation Mapping of the Optic Pathway in Glioma Patients.

Brain mapping during awake craniotomy for gliomas can help preserve neurological functions, including maintenance of central and peripheral vision. However, the consecutive changes in the visual field remain unknown. We retrospectively assessed 14 patients who underwent awake craniotomy for gliomas infiltrating into the optic radiation. Cortico-subcortical direct electrical stimulation (DES) was intraoperatively applied until transient visual symptoms were elicited and recorded. The visual fields were examined consecutively in the preoperative period and postoperative subacute and chronic periods. To evaluate the anatomo-functional validity of the recordings, all DES-elicited points were overlaid onto a three-dimensional template that included the optic radiation, using voxel-based morphometry (VBM) mapping. All patients experienced visual symptoms that were classified as phosphenes, blurred vision, or hallucinations during DES, and surgical resection was limited to within the functional boundaries. In VBM, almost all the subcortical positive mapping points overlapped with the surface of the optic radiation, and the distribution of sites that induced visual phenomena in the upper or lower visual fields could be differentiated in the anatomical space. We observed no postoperative visual deficit in four patients (29%), time-dependent improvements in five out of eight patients that presented transient quadrantanopia or partial visual defect (36% out of 57%), and permanent hemianopsia (14%) in two patients with occipital lesions. Intraoperative DES that identifies and preserves optic radiation in awake craniotomy for gliomas is a reliable and effective technique to reduce risk of permanent deficits, but has a low success rate in patients with occipital involvement.

Localization patterns of speech and language errors during awake brain surgery: a systematic review.

Awake craniotomy with direct electrical stimulation (DES) is the standard treatment for patients with eloquent area gliomas. DES detects speech and language errors, which indicate functional boundaries that must be maintained to preserve quality of life. During DES, traditional object naming or other linguistic tasks such as tasks from the Dutch Linguistic Intraoperative Protocol (DuLIP) can be used. It is not fully clear which speech and language errors occur in which brain locations. To provide an overview and to update DuLIP, a systematic review was conducted in which 102 studies were included, reporting on speech and language errors and the corresponding brain locations during awake craniotomy with DES in adult glioma patients up until 6 July 2020. The current findings provide a crude overview on language localization. Even though subcortical areas are in general less often investigated intraoperatively, still 40% out of all errors was reported at the subcortical level and almost 60% at the cortical level. Rudimentary localization patterns for different error types were observed and compared to the dual-stream model of language processing and the DuLIP model. While most patterns were similar compared to the models, additional locations were identified for articulation/motor speech, phonology, reading, and writing. Based on these patterns, we propose an updated DuLIP model. This model can be applied for a more adequate "location-to-function" language task selection to assess different linguistic functions during awake craniotomy, to possibly improve intraoperative language monitoring. This could result in a better postoperative language outcome in the future.

Distinct Functional and Structural Connectivity of the Human Hand-Knob Supported by Intraoperative Findings.

Fine motor skills rely on the control of hand muscles exerted by a region of primary motor cortex (M1) that has been extensively investigated in monkeys. Although neuroimaging enables the exploration of this system also in humans, indirect measurements of brain activity prevent causal definitions of hand motor representations, which can be achieved using data obtained during brain mapping in tumor patients. High-frequency direct electrical stimulation delivered at rest (HF-DES-Rest) on the hand-knob region of the precentral gyrus has identified two sectors showing differences in cortical excitability. Using quantitative analysis of motor output elicited with HF DES-Rest, we characterized two sectors based on their excitability, higher in the posterior and lower in the anterior sector. We studied whether the different cortical excitability of these two regions reflected differences in functional connectivity (FC) and structural connectivity (SC). Using healthy adults from the Human Connectome Project (HCP), we computed FC and SC of the anterior and the posterior hand-knob sectors identified within a large cohort of patients. The comparison of FC of the two seeds showed that the anterior hand-knob, relative to the posterior hand-knob, showed stronger functional connections with a bilateral set of parietofrontal areas responsible for integrating perceptual and cognitive hand-related sensorimotor processes necessary for goal-related actions. This was reflected in different patterns of SC between the two sectors. Our results suggest that the human hand-knob is a functionally and structurally heterogeneous region organized along a motor-cognitive gradient.SIGNIFICANCE STATEMENT The capability to perform complex manipulative tasks is one of the major characteristics of primates and relies on the fine control of hand muscles exerted by a highly specialized region of the precentral gyrus, often termed the "hand-knob" sector. Using intraoperative brain mapping, we identify two hand-knob sectors (posterior and anterior) characterized by differences in cortical excitability. Based on resting-state functional connectivity (FC) and tractography in healthy subjects, we show that posterior and anterior hand-knob sectors differ in their functional connectivity (FC) and structural connectivity (SC) with frontoparietal regions. Thus, anteroposterior differences in cortical excitability are paralleled by differences in FC and SC that likely reflect a motor (posterior) to cognitive (anterior) organization of this cortical region.

Imaging the effective networks associated with cortical function through intracranial high-frequency stimulation.

Direct electrical stimulation (DES) is considered to be the gold standard for mapping cortical function. A careful mapping of the eloquent cortex is key to successful resective or ablative surgeries, with a minimal postoperative deficit, for treatment of drug-resistant epilepsy. There is accumulating evidence suggesting that not only local, but also remote activations play an equally important role in evoking clinical effects. By introducing a new intracranial stimulation paradigm and signal analysis methodology allowing to disambiguate EEG responses from stimulation artifacts we highlight the spatial extent of the networks associated with clinical effects. Our study includes 26 patients that underwent stereoelectroencephalographic investigations for drug-resistant epilepsy, having 337 depth electrodes with 4,351 contacts sampling most brain structures. The routine high-frequency electrical stimulation protocol for eloquent cortex mapping was altered in a subtle way, by alternating the polarity of the biphasic pulses in a train, causing the splitting the spectral lines of the artifactual components, exposing the underlying tissue response. By performing a frequency-domain analysis of the EEG responses during DES we were able to capture remote activations and highlight the effect's network. By using standard intersubject averaging and a fine granularity HCP-MMP parcellation, we were able to create local and distant connectivity maps for 614 stimulations evoking specific clinical effects. The clinical value of such maps is not only for a better understanding of the extent of the effects' networks guiding the invasive exploration, but also for understanding the spatial patterns of seizure propagation given the timeline of the seizure semiology.

The Use of Standardized Intraoperative Language Tests in Awake Craniotomies: A Scoping Review.

Assessment of speech and language functions is an essential part of awake craniotomies. Although standardized and validated tests have several advantages compared to homemade (or mixed) batteries, in the literature it is unclear how such tests are used or whether they are used at all. In this study, we performed a scoping review in order to locate standardized and validated intraoperative language tests. Our inquiry included two databases (PubMED and MEDLINE), gray literature, and snowball referencing. We discovered 87 studies reporting use of mixed batteries, which consist of homemade tasks and tests borrowed from other settings. The tests we found to meet the validation and standardization criteria we set were ultimately three (n = 3) and each one has its own advantages and disadvantages. We argue that tests with high sensitivity and specificity not only can lead to better outcomes postoperatively, but they can also help us to gain a better understanding of the neuroanatomy of language.

Cortical mapping in glioma surgery: correlation of fMRI and direct electrical stimulation with Human Connectome Project parcellations.

OBJECTIVE: Noninvasive brain mapping with functional MRI (fMRI) and mapping with direct electrical stimulation (DES) are important tools in glioma surgery, but the evidence is inconclusive regarding the sensitivity and specificity of fMRI. The Human Connectome Project (HCP) proposed a new cortical parcellation that has not been thoroughly tested in a clinical setting. The main goal of this study was to evaluate the correlation of fMRI and DES mapping with HCP areas in a clinical setting, and to evaluate the performance of fMRI mapping in motor and language tasks in patients with glioma, using DES as the gold standard. METHODS: Forty patients with supratentorial gliomas were examined using preoperative fMRI and underwent awake craniotomy with DES. Functional activation maps were visualized on a 3D representation of the cortex, classified according to HCP areas, and compared with surgical mapping. RESULTS: Functional MRI was successful in identifying language and motor HCP areas in most cases, including novel areas such as 55b and the superior longitudinal fasciculus (SLF). Functional MRI had a sensitivity and specificity of 100% and 71%, respectively, for motor function in HCP area 4. Sensitivity and specificity were different according to the area and fMRI protocol; i.e., semantic protocols performed better in Brodmann area (BA) 55b/peri-sylvian language areas with 100% sensitivity and 20% specificity, and word production protocols in BAs 44 and 45 with 70% sensitivity and 80% specificity. Some compensation patterns could be observed, such as motor activation of the postcentral gyrus in precentral gliomas. CONCLUSIONS: HCP areas can be detected in clinical scenarios of glioma surgery. These areas appear relatively stable across patients, but compensation patterns seem to differ, allowing occasional resection of activating areas. Newly described areas such as 55b and SLF can act as critical areas in language networks. Surgical planning should account for these parcellations.

A systematic review of the use of subcortical intraoperative electrical stimulation mapping for monitoring of executive deficits and neglect: what is the evidence so far?

BACKGROUND: Over the past decade, the functional importance of white matter pathways has been increasingly acknowledged in neurosurgical planning. A method to directly study anatomo-functional correlations is direct electrical stimulation (DES). DES has been widely accepted by neurosurgeons as a reliable tool to minimize the occurrence of permanent postoperative motor, vision, and language deficits. In recent years, DES has also been used for stimulation mapping of other cognitive functions, such as executive functions and visuospatial awareness. METHODS: The aim of this review is to summarize the evidence so far from DES studies on subcortical pathways that are involved in visuospatial awareness and in the following three executive functions: (1) inhibitory control, (2) working memory, and (3) cognitive flexibility. RESULTS: Eleven articles reported on intraoperative electrical stimulation of white matter pathways to map the cognitive functions and explicitly clarified which subcortical tract was stimulated. The results indicate that the right SLF-II is involved in visuospatial awareness, the left SLF-III and possibly the right SLF-I are involved in working memory, and the cingulum is involved in cognitive flexibility. CONCLUSIONS: We were unable to draw any more specific conclusions, nor unequivocally establish the critical involvement of pathways in executive functions or visuospatial awareness due to the heterogeneity of the study types and methods, and the limited number of studies that assessed these relationships. Possible approaches for future research to obtain converging and more definite evidence for the involvement of pathways in specific cognitive functions are discussed.

Local and distant responses to single pulse electrical stimulation reflect different forms of connectivity.

Measuring connectivity in the human brain involves innumerable approaches using both noninvasive (fMRI, EEG) and invasive (intracranial EEG or iEEG) recording modalities, including the use of external probing stimuli, such as direct electrical stimulation. To examine how different measures of connectivity correlate with one another, we compared 'passive' measures of connectivity during resting state conditions to the more 'active' probing measures of connectivity with single pulse electrical stimulation (SPES). We measured the network engagement and spread of the cortico-cortico evoked potential (CCEP) induced by SPES at 53 out of 104 total sites across the brain, including cortical and subcortical regions, in patients with intractable epilepsy (N=11) who were undergoing intracranial recordings as a part of their clinical care for identifying seizure onset zones. We compared the CCEP network to functional, effective, and structural measures of connectivity during a resting state in each patient. Functional and effective connectivity measures included correlation or Granger causality measures applied to stereoEEG (sEEGs) recordings. Structural connectivity was derived from diffusion tensor imaging (DTI) acquired before intracranial electrode implant and monitoring (N=8). The CCEP network was most similar to the resting state voltage correlation network in channels near to the stimulation location. In contrast, the distant CCEP network was most similar to the DTI network. Other connectivity measures were not as similar to the CCEP network. These results demonstrate that different connectivity measures, including those derived from active stimulation-based probing, measure different, complementary aspects of regional interrelationships in the brain.

Towards linking diffusion MRI based macro- and microstructure measures with cortico-cortical transmission in brain tumor patients.

We aimed to link macro- and microstructure measures of brain white matter obtained from diffusion MRI with effective connectivity measures based on a propagation of cortico-cortical evoked potentials induced with intrasurgical direct electrical stimulation. For this, we compared streamline lengths and log-transformed ratios of streamlines computed from presurgical diffusion-weighted images, and the delays and amplitudes of N1 peaks recorded intrasurgically with electrocorticography electrodes in a pilot study of 9 brain tumor patients. Our results showed positive correlation between these two modalities in the vicinity of the stimulation sites (Pearson coefficient 0.54±0.13 for N1 delays, and 0.47±0.23 for N1 amplitudes), which could correspond to the neural propagation via U-fibers. In addition, we reached high sensitivities (0.78±0.07) and very high specificities (0.93±0.03) in a binary variant of our comparison. Finally, we used the structural connectivity measures to predict the effective connectivity using a multiple linear regression model, and showed a significant role of brain microstructure-related indices in this relation.

Intracerebral electrical stimulation to understand the neural basis of human face identity recognition.

Recognizing people's identity by their faces is a key function in the human species, supported by regions of the ventral occipito-temporal cortex (VOTC). In the last decade, there have been several reports of perceptual face distortion during direct electrical stimulation (DES) with subdural electrodes positioned over a well-known face-selective VOTC region of the right lateral middle fusiform gyrus (LatMidFG; i.e., the "Fusiform Face Area", FFA). However, transient impairments of face identity recognition (FIR) have been extremely rare and only behaviorally quantified during DES with intracerebral (i.e., depth) electrodes in stereo-electroencephalography (SEEG). The three detailed cases reported so far, summarized here, were specifically impaired at FIR during DES inside different anatomical VOTC regions of the right hemisphere: the inferior occipital gyrus (IOG) and the LatMidFG, as well as a region that lies at the heart of a large magnetic susceptibility artifact in functional magnetic resonance imaging (fMRI): the anterior fusiform gyrus (AntFG). In the first two regions, the eloquent electrode contacts were systematically associated with the highest face-selective and (unfamiliar) face individuation responses as measured with intracerebral electrophysiology. Stimulation in the right AntFG did not lead to perceptual changes but also caused an inability to remember having been presented face pictures, as if the episode was never recorded in memory. These observations support the view of an extensive network of face-selective VOTC regions subtending human FIR, with at least three critical nodes in the right hemisphere associated with differential intrinsic and extrinsic patterns of reentrant connectivity.

Electrophysiological Mapping During Brain Tumor Surgery: Recording Cortical Potentials Evoked Locally, Subcortically and Remotely by Electrical Stimulation to Assess the Brain Connectivity On-line.

Direct electrical stimulation (DES) is used to perform functional brain mapping during awake surgery and in epileptic patients. DES may be coupled with the measurement of Evoked Potentials (EP) to study the conductive and integrative properties of activated neural ensembles and probe the spatiotemporal dynamics of short- and long-range networks. However, its electrophysiological effects remain by far unknown. We recorded ECoG signals on two patients undergoing awake brain surgery and measured EP on functional sites after cortical stimulations and were the firsts to record three different types of EP on the same patients. Using low-intensity (1-3 mA) to evoke electrogenesis we observed that: (i) "true" remote EPs are attenuated in amplitude and delayed in time due to the divergence of white matter pathways; (ii) "false" remote EPs are attenuated but not delayed: as they originate from the same electrical source; (iii) Singular but reproducible positive components in the EP can be generated when the DES is applied in the temporal lobe or the premotor cortex; and (iv) rare EP can be triggered when the DES is applied subcortically: these can be either negative, or surprisingly, positive. We proposed different activation and electrophysiological propagation mechanisms following DES, based on the nature of activated neural elements and discussed important methodological pitfalls when measuring EP in the brain. Altogether, these results pave the way to map the connectivity in real-time between the DES and the recording sites; to characterize the local electrophysiological states and to link electrophysiology and function. In the future, and in practice, this technique could be used to perform electrophysiological mapping in order to link (non)-functional to electrophysiological responses with DES and could be used to guide the surgical act itself.

CLoSES: A platform for closed-loop intracranial stimulation in humans.

Targeted interrogation of brain networks through invasive brain stimulation has become an increasingly important research tool as well as therapeutic modality. The majority of work with this emerging capability has been focused on open-loop approaches. Closed-loop techniques, however, could improve neuromodulatory therapies and research investigations by optimizing stimulation approaches using neurally informed, personalized targets. Implementing closed-loop systems is challenging particularly with regard to applying consistent strategies considering inter-individual variability. In particular, during intracranial epilepsy monitoring, where much of this research is currently progressing, electrodes are implanted exclusively for clinical reasons. Thus, detection and stimulation sites must be participant- and task-specific. The system must run in parallel with clinical systems, integrate seamlessly with existing setups, and ensure safety features are in place. In other words, a robust, yet flexible platform is required to perform different tests with a single participant and to comply with clinical requirements. In order to investigate closed-loop stimulation for research and therapeutic use, we developed a Closed-Loop System for Electrical Stimulation (CLoSES) that computes neural features which are then used in a decision algorithm to trigger stimulation in near real-time. To summarize CLoSES, intracranial electroencephalography (iEEG) signals are acquired, band-pass filtered, and local and network features are continuously computed. If target features are detected (e.g. above a preset threshold for a certain duration), stimulation is triggered. Not only could the system trigger stimulation while detecting real-time neural features, but we incorporated a pipeline wherein we used an encoder/decoder model to estimate a hidden cognitive state from the neural features. CLoSES provides a flexible platform to implement a variety of closed-loop experimental paradigms in humans. CLoSES has been successfully used with twelve patients implanted with depth electrodes in the epilepsy monitoring unit. During cognitive tasks (N=5), stimulation in closed loop modified a cognitive hidden state on a trial by trial basis. Sleep spindle oscillations (N=6) and sharp transient epileptic activity (N=9) were detected in near real-time, and stimulation was applied during the event or at specified delays (N=3). In addition, we measured the capabilities of the CLoSES system. Total latency was related to the characteristics of the event being detected, with tens of milliseconds for epileptic activity and hundreds of milliseconds for spindle detection. Stepwise latency, the actual duration of each continuous step, was within the specified fixed-step duration and increased linearly with the number of channels and features. We anticipate that probing neural dynamics and interaction between brain states and stimulation responses with CLoSES will lead to novel insights into the mechanism of normal and pathological brain activity, the discovery and evaluation of potential electrographic biomarkers of neurological and psychiatric disorders, and the development and testing of patient-specific stimulation targets and control signals before implanting a therapeutic device.

Mapping critical cortical hubs and white matter pathways by direct electrical stimulation: an original functional atlas of the human brain.

OBJECTIVE: The structural and functional organization of brain networks subserving basic daily activities (i.e. language, visuo-spatial cognition, movement, semantics, etc.) are not completely understood to date. Here, we report the first probabilistic cortical and subcortical atlas of critical structures mediating human brain functions based on direct electrical stimulation (DES), a well-validated tool for the exploration of cerebral processing and for performing safe surgical interventions in eloquent areas. METHODS: We collected 1162 cortical and 659 subcortical DES responses during testing of 16 functional domains in 256 patients undergoing awake surgery. Spatial coordinates for each functional response were calculated, and probability distributions for the entire patient cohort were mapped onto a standardized three-dimensional brain template using a multinomial statistical analysis. In addition, matching analyses were performed against prior established anatomy-based cortical and white matter (WM) atlases. RESULTS: The probabilistic maps for each functional domain were provided. The topographical analysis demonstrated a wide spatial distribution of cortical functional responses, while subcortical responses were more restricted, localizing to known WM pathways. These DES-derived data showed reliable matching with existing cortical and WM atlases as well as recent neuroimaging and neurophysiological data. CONCLUSIONS: We present the first integrated and comprehensive cortical-subcortical atlas of structures essential for humans' neural functions based on highly-specific DES mapping during real-time neuropsychological testing. This novel atlas can serve as a complementary tool for neuroscientists, along with data obtained from other modalities, to improve and refine our understanding of the functional anatomy of critical brain networks.

Large scale networks for human hand-object interaction: Functionally distinct roles for two premotor regions identified intraoperatively.

The development of awake intraoperative brain-mapping procedures for resection of brain tumors is of growing interest in neuroscience, because it enables direct testing of brain tissue, previously only possible in non-human primates. In a recent study performed in this setting specific effects can be induced by direct electrical stimulation on different sectors of premotor cortex during the execution of a hand manipulation task. Specifically, direct electrical stimulation applied on a dorsal sector of precentral cortex led to an increase in motor unit recruitment in hand muscles during execution of a hand manipulation task (Recruitment sector). The opposite effect was elicited when electrical stimulation was delivered more ventrally on the precentral cortex (Suppression sector). We studied whether the different effects on motor behavior induced by direct electrical stimulation applied on the two sites of the precentral cortex underlie differences in their functional connectivity with other brain areas, measured using resting state fMRI. Using healthy adults scanned as part of the Human Connectome Project, we computed the functional connectivity of each sector used as seeds. The functional connectivity patterns of the two intraoperative seeds was similar but cross-comparison revealed that the left and right Recruitment sectors had stronger functional connections with the hand region of the sensorimotor cortex, while the right Suppression region displayed stronger functional connectivity with a bilateral set of parieto-frontal areas crucial for the integration of perceptual and cognitive hand-related sensorimotor processes required for goal-related hand actions. Our results suggest that analyzing data obtained in the intraoperative setting with resting state functional magnetic resonance imaging in healthy brains can yield useful insight into the roles of different premotor sectors directly involved in hand-object interaction.