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.

Patterns of axono-cortical evoked potentials: an electrophysiological signature unique to each white matter functional site?

BACKGROUND: Brain-to-brain evoked potentials constitute a new methodology that could help to understand the network-level correlates of electrical stimulation applied for brain mapping during tumor resection. In this paper, we aimed to describe the characteristics of axono-cortical evoked potentials recorded from distinct, but in the same patient, behaviorally eloquent white matter sites. METHODS: We report the intraoperative white matter mapping and axono-cortical evoked potentials recordings observed in a patient operated on under awake condition of a diffuse low-grade glioma in the left middle frontal gyrus. Out of the eight behaviorally eloquent sites identified with 60-Hz electrical stimulation, five were probed with single electrical pulses (delivered at 1 Hz), while recording evoked potentials on two electrodes, covering the inferior frontal gyrus and the precentral gyrus, respectively. Postoperative diffusion-weighted MRI was used to reconstruct the tractograms passing through each of the five stimulated sites. RESULTS: Each stimulated site generated an ACEP on at least one of the recorded electrode contacts. The whole pattern-i.e., the specific contacts with ACEPs and their waveform-was distinct for each of the five stimulated sites. CONCLUSIONS: We found that the patterns of ACEPs provided unique electrophysiological signatures for each of the five white matter functional sites. Our results could ultimately provide neurosurgeons with a new tool of intraoperative electrophysiologically based functional guidance.

Axono-cortical evoked potentials as a new method of IONM for preserving the motor control network: a first study in three cases.

BACKGROUND: White matter stimulation in an awake patient is currently the gold standard for identification of functional pathways. Despite the robustness and reproducibility of this method, very little is known about the electrophysiological mechanisms underlying the functional disruption. Axono-cortical evoked potentials (ACEPs) provide a reliable technique to explore these mechanisms. OBJECTIVE: To describe the shape and spatial patterns of ACEPs recorded when stimulating the white matter of the caudal part of the right superior frontal gyrus while recording in the precentral gyrus. METHODS: We report on three patients operated on under awake condition for a right superior frontal diffuse low-grade glioma. Functional sites were identified in the posterior wall of the cavity, whose 2-3-mA stimulation generated an arrest of movement. Once the resection was done, axono-cortical potentials were evoked: recording electrodes were put over the precentral gyrus, while stimulating at 1 Hz the white matter functional sites during 30-60 s. Unitary evoked potentials were averaged off-line. Waveform was visually analyzed, defining peaks and troughs, with quantitative measurements of their amplitudes and latencies. Spatial patterns of ACEPs were compared with patients' own and HCP-derived structural connectomics. RESULTS: Axono-cortical evoked potentials (ACEPs) were obtained and exhibited complex shapes and spatial patterns that correlated only partially with structural connectivity patterns. CONCLUSION: ACEPs is a new IONM methodology that could both contribute to elucidate the propagation of neuronal activity within a distributed network when stimulating white matter and provide a new technique for preserving motor control abilities during brain tumor resections.

Attenuation and Delay of Remote Potentials Evoked by Direct Electrical Stimulation During Brain Surgery.

Direct electrical stimulation (DES) is used to perform functional brain mapping during awake surgery but its electrophysiological effects remain by far unknown. DES may be coupled with the measurement of evoked potentials (EPs) to study the conductive and integrative properties of activated neural ensembles and probe the spatiotemporal dynamics of short- and long-range networks. We recorded ECoG signals on two patients undergoing awake brain surgery and measured EPs on functional sites after cortical stimulations, using combinations of stimulation parameters. EPs were similar in shape but delayed in time and attenuated in amplitude when elicited from a different gyrus or remotely from the recording site. We were able to trigger remote EPs using low stimulation intensities. We propose different activation and electrophysiological propagation mechanisms following DES based on activated neural elements.

"I do not feel my hand where I see it": causal mapping of visuo-proprioceptive integration network in a surgical glioma patient.

A recent tasked-based fMRI study unveiled a network of areas implicated in the process of visuo-proprioceptive integration of the right hand. In this study, we report a case of a patient operated on in awake conditions for a glioblastoma of the left superior parietal lobule. When stimulating a white matter site in the anterior wall of the cavity, the patient spontaneously reported a discrepancy between the visual and proprioceptive perceptions of her right hand. Using several multimodal approaches (axono-cortical evoked potentials, tractography, resting-state functional connectivity), we demonstrated converging support for the hypothesis that tumor-induced plasticity redistributed the left-lateralized network of right-hand visuo-proprioceptive integration towards its right-lateralized homolog.

Alterations of EEG rhythms during motor preparation following awake brain surgery.

Slow-growing, infiltrative brain tumours may modify the electrophysiological balance between the two hemispheres. To determine whether and how asymmetry of EEG rhythms during motor preparation might occur following "awake brain surgery" for this type of tumour, we recorded electroencephalograms during a simple visuo-manual reaction time paradigm performed by the patients between 3 and 12 months after surgery and compared them to a control group of 8 healthy subjects. Frequency analyses revealed imbalances between the injured and healthy hemispheres. More particularly, we observed a power increase in the δ frequency band near the lesion site and a power increase in the α and ß frequency bands. Interestingly, these alterations seem to decrease for the two patients whose surgery were anterior to 9 months, independently of the size of the lesion. Reaction times did not reflect this pattern as they were clearly not inversely related to the anteriority of the surgery. Electrophysiology suggests here different processes of recovery compared to behavioral data and brings further insights for the understanding of EEG rhythms that should not be systematically confounded or assimilated with cognitive performances. EEG monitoring is rare for these patients, especially after awake brain surgery, however it is important.

Longitudinal Changes in Cerebellar and Thalamic Spontaneous Neuronal Activity After Wide-Awake Surgery of Brain Tumors: a Resting-State fMRI Study.

Hypometabolism has been observed in the contralesional cerebellar hemisphere after various supratentorial cortical lesions. It is unknown whether the consequences of the dee- and deafferentation subsequent to wide-awake surgery for brain diffuse low-grade glioma can be assessed within remote and unresected subcortical structures such as the cerebellum or thalamus. To answer this question, we have conducted several regional analyses. More specifically, we have performed amplitude of low-frequency fluctuations (neuronal activity magnitude) and regional homogeneity (local temporal correlations) analyses on resting state functional magnetic resonance imaging (rs-fMRI) data and at different time points, before and after surgery. Our main results demonstrated that it is possible to evaluate subtle subcortical changes using these tools dedicated to the analysis of rs-fMRI data. The observed variations of spontaneous neuronal activity were particularly significant within the cerebellum which showed altered regional homogeneity and neuronal activity intensity in very different, specialized and non-overlapping subregions, in accordance to its neuro-anatomo-functional topography. These variations were moreover observed in the immediate postoperative period and recovered after 3 months.

Inferring a dual-stream model of mentalizing from associative white matter fibres disconnection.

In the field of cognitive neuroscience, it is increasingly accepted that mentalizing is subserved by a complex frontotemporoparietal cortical network. Some researchers consider that this network can be divided into two distinct but interacting subsystems (the mirror system and the mentalizing system per se), which respectively process low-level, perceptive-based aspects and high-level, inference-based aspects of this sociocognitive function. However, evidence for this type of functional dissociation in a given neuropsychological population is currently lacking and the structural connectivities of the two mentalizing subnetworks have not been established. Here, we studied mentalizing in a large sample of patients (n = 93; 46 females; age range: 18-65 years) who had been resected for diffuse low-grade glioma-a rare tumour that migrates preferentially along associative white matter pathways. This neurological disorder constitutes an ideal pathophysiological model in which to study the functional anatomy of associative pathways. We mapped the location of each patient's resection cavity and residual lesion infiltration onto the Montreal Neurological Institute template brain and then performed multilevel lesion analyses (including conventional voxel-based lesion-symptom mapping and subtraction lesion analyses). Importantly, we estimated each associative pathway's degree of disconnection (i.e. the degree of lesion infiltration) and built specific hypotheses concerning the connective anatomy of the mentalizing subnetworks. As expected, we found that impairments in mentalizing were mainly related to the disruption of right frontoparietal connectivity. More specifically, low-level and high-level mentalizing accuracy were correlated with the degree of disconnection in the arcuate fasciculus and the cingulum, respectively. To the best of our knowledge, our findings constitute the first experimental data on the structural connectivity of the mentalizing network and suggest the existence of a dual-stream hodological system. Our results may lead to a better understanding of disorders that affect social cognition, especially in neuropathological conditions characterized by atypical/aberrant structural connectivity, such as autism spectrum disorders.

Balance control in aging: improvements in anticipatory postural adjustments and updating of internal models.

Postural stability of older subjects can be estimated during orthostatic equilibrium. However, dynamic equilibrium is also important to investigate risks of fall. It implies different interpretations of measures given by force plates. Same dependant variables (e.g. center of pressure displacement) cannot be interpreted the same ways depending of the type of equilibrium that is investigated. In particular, sways increases during dynamic equilibrium and before movement execution may reflect an improvement of feedforward control.

Asymmetries of bilateral isometric force matching with movement intention and unilateral fatigue.

During bilateral coordination, some level of inter-hemispheric remapping (i.e., the congruency between afferent and efferent force signals from both hemispheres) is required. In this case, sensory-motor information is exchanged between the two hemispheres, but it remains unclear whether this information exchange is always equivalent or not, especially in a bilateral isometric force-matching task. We used unilateral fatigue applied to one arm in order to determine whether inter-hemispheric remapping can vary asymmetrically during a bilateral isometric matching task. Because fatigue is considered to bias the sensory-motor system, we hypothesized that if bimanual coordination is modulated solely in function of the state of the sensory-motor system (motor efferences, inter-hemispheric inhibitions, and sensory reafferences), we should not observe any asymmetric effect of fatigue with movement intention (leading vs. matching arm). However, if any other process could participate in the modulation of inter-hemispheric remapping, we should observe an interaction between movement intentions and fatigue on the force produced. We found that, when the leading arm was the non-fatigued arm, participants succeeded in reproducing the force level with their fatigued arm. By contrast, when the leading arm was fatigued, subjects over-estimated the force level produced with their non-fatigued arm. Hence, lateralized fatigue exacerbates an asymmetric behavior that seems modulated by movement intention (leading vs. matching). In other words, when unilateral fatigue is introduced in a bilateral isometric force-matching task, inter-hemispheric remapping is asymmetrical. Intensity levels of motor commands sent to both arms (directly or modulated through inter-hemispheric inhibitions) and sensory reafferences alone cannot explain these observations. Some attentional focus may be not balanced continuously between both arms but may be mainly directed toward the matching arm.

Asymmetric interhemispheric excitability evidenced by event-related potential amplitude patterns after "wide-awake surgery" of brain tumours.

Slow-growing, infiltrative brain tumours may modify the electrophysiological balance between the two hemispheres. To determine whether and how asymmetry in interhemispheric excitability might occur following "wide-awake surgery" for this type of tumour, we recorded electroencephalograms during a simple visuo-manual reaction time paradigm performed by five patients between 3 and 12 months after surgery. Interhemispheric excitability asymmetries were computed by comparing the amplitudes of event-related potentials (ERPs) in the injured hemisphere to those in the healthy hemisphere. For the two patients with the smallest lesions (7.1 and 11.5 cm(3), respectively), increased excitability within the ipsilesional hemisphere was evidenced by characteristics increases in the ERP amplitude at several sites, with few occurrences in the contralesional hemisphere. For smaller lesions (and under certain experimental conditions), cortical excitability in the injured hemisphere may increase in order to maintain local compensation. In addition, we observed and increased excitability in the contralesional frontal homologue for one patient who underwent an extensive resection. Post-operative monitoring of interhemispheric asymmetries in ERP amplitudes is of value for determining task constraints inducing electrophysiological imbalance and guiding rehabilitation.

Inter-hemispheric remapping between arm proprioception and vision of the hand is disrupted by single pulse TMS on the left parietal cortex.

Parietal cortical areas are involved in sensori-motor transformations for their respective contralateral hemifield/body. When arms of the subjects are crossed while their gaze is fixed straight ahead, vision of the hand is processed by the hemisphere ipsilateral to the arm position and proprioception of the arm by the contralateral hemisphere. It induces interhemispheric transfer and remapping. Our objective was to investigate whether a single pulse TMS applied to the left parietal cortical area would disturb interhemispheric remapping in a similar case, and would increase a simple reaction time (RT) with respect to a control single pulse TMS applied to the frontal cortical area. Two LED were superimposed and located in front of the subjects on the saggital axis. Subjects were asked to carefully fixate on these LED during each trial. The lighting of the red LED was used as a warning signal. Following the green one was illuminated after a variable delay and served as a go-signal. The hand for the response was determined before the start of each trial. TMS was applied to the left parietal, the left frontal cortical areas, or not applied to the subject. Results revealed that: (1) Irrespective of its location, single pulse TMS induced a non-specific effect similar to a startle reflex and reduced RT substantially (15ms on average) with respect to a control condition without TMS (mean value=153ms). (2) Irrespective of TMS, RT were shorter when the right or the left hand was positioned in the right visual hemi-field (i.e. normal and crossed positions respectively). (3) Finally, RT increased when single pulse TMS was applied to the left parietal area and when hands were crossed irrespective of which hand was used. We concluded that interhemispheric sensori-motor remapping was disrupted by a single pulse TMS that was applied to the left parietal cortex. This effect was also combined with some visual attention directed towards the hand located on the right visual hemi-field.

How far does electrical stimulation activate white matter tracts? A computational modeling study.

OBJECTIVE: The aim of this study was to model how the different parameters of electrical stimulation (intensity, pulse shape, probe geometry) influence the extent of white matter activation. METHODS: The electrical potentials generated by the stimulating electrodes were determined by solving Laplace equation. The temporal evolution of membrane potentials at each nodes of Ranvier of an axon was then computed by solving the coupled system of differential equations describing membrane dynamics and cable propagation. RESULTS: Regions of unilateral propagation were observed for monophasic pulses delivered with a bipolar probe aligned along the tract. For biphasic pulses, the largest activation areas and depths were found with a high inter-electrode-distance (IED) bipolar probe, oriented orthogonally to the tract. The smallest activation areas and depths were found for bipolar stimulations with the probe aligned parallel to the tract and low IED. For isotropic white matter regions, the activation area and depth were three times larger than for anisotropic white matter tracts. CONCLUSIONS: Bipolar probes with biphasic pulses offer the greatest versatility: an orthogonal orientation acts as two monopolars (increased sensitivity when searching for a tract), whereas a parallel orientation corresponds to a single monopolar (increased specificity). Activation is more superficial when stimulating highly anisotropic tracts. SIGNIFICANCE: This knowledge is essential for interpreting the behavorial effects of stimulation and the recordings of axono-cortical evoked potentials.

Short-range axono-cortical evoked-potentials in brain tumor surgery: Waveform characteristics as markers of direct connectivity.

OBJECTIVE: Intraoperative measurement of axono-cortical evoked potentials (ACEP) has emerged as a promising tool for studying neural connectivity. However, it is often difficult to determine if the activity recorded by cortical grids is generated by stimulated tracts or by spurious phenomena. This study aimed to identify criteria that would indicate a direct neurophysiological connection between a recording contact and a stimulated pathway. METHODS: Electrical stimulation was applied to white matter fascicles within the resection cavity, while the evoked response was recorded at the cortical level in seven patients. RESULTS: By analyzing the ACEP recordings, we identified a main epicenter characterized by a very early positive (or negative) evoked response occurring just after the stimulation artifact (<5 ms, |Amplitude| > 100 µV) followed by an early and large negative (or positive) monophasic evoked response (<40 ms; |Amplitude| > 300 µV). The neighboring activity had a different waveform and was attenuated compared to the hot-spot activity. CONCLUSIONS: It is possible to distinguish the hotspot with direct connectivity to the stimulated site from neighboring activity using the identified criteria. SIGNIFICANCE: The electrogenesis of the ACEP at the hotspot and neighboring activity is discussed.

Ultra-fast recovery from right neglect after 'awake surgery' for slow-growing tumor invading the left parietal area.

It is now possible to perform resections of slow-growing tumors in awake patients. Using direct electrical stimulation, real-time functional mapping of the brain can be used to prevent the resection of essential areas near the tumor. Simple clinical observations of patients with a resection of slow-growing tumors have demonstrated substantial recovery within a few days of such 'awake surgery'. The aim of this study was to investigate the kinetics of recovery following the resection of slow-growing tumors invading the left parietal area and to focus mainly on its rapidity. Two patients were assessed by standard line bisection tests and compared with eight healthy individuals. Independently of the pure nature of the symptoms, we report that the patients rapidly and substantially recovered from pronounced right neglect. They were tested 48 hours after the surgery and the recovery was significant for both patients after less than 4 hours. Strikingly, for one patient, recovery was ultra fast and substantial in the first practice session within less than 7 minutes: it occurred without verbal feedback and was substantially retained during the following testing session. Its rapidity suggests a process of unmasking redundant networks. With the slow growth of the lesion, the contralesional hemisphere is probably progressively prepared for rapid unmasking of homologue networks. These results have major clinical implications. For patients with an invading left-side tumor, it is now clear that line bisections are required before, during, and after awake surgery to: plan the surgery, control the quality of the resection, and also optimize the rehabilitation of the patient.

Manual reaction times and brain dynamics after 'awake surgery' of slow-growing tumours invading the parietal area. A case report.

PRIMARY OBJECTIVES: Awake surgeries of slow-growing tumours invading the brain and guided by direct electrical stimulation induce major brain reorganizations accompanied with slight impairments post-operatively. In most cases, these deficits are so slight after a few days that they are often not detectable on classical neuropsychological evaluations. Consequently, this study investigated whether simple visuo-manual reaction time paradigms would sign some level of functional asymmetries between both hemispheres. Importantly, the visual stimulus was located in the saggital plane in order to limit attentional biases and to focus mainly on the inter-hemispheric asymmetry. METHODS AND PROCEDURES: Three patients (aged 41, 59 and 59 years) after resections in parietal regions and a control group (age = 44, SD = 6.9) were compared during simple uni- and bimanual reaction times (RTs). MAIN OUTCOMES AND RESULTS: Longer RTs were observed for the contralesional compared to the ipsilesional hand in the unimanual condition. This asymmetry was reversed for the bimanual condition despite longer RTs. CONCLUSION AND CLINICAL IMPLICATIONS: Reaction time paradigms are useful in these patients to monitor more precisely their functional deficits, especially their level of functional asymmetry, and to understand brain (re)organization following slow-growing lesions.

Integration of proprioceptive signals and attentional capacity during postural control are impaired but subject to improvement in dyslexic children.

Children with developmental dyslexia suffer from delayed reading capabilities and may also exhibit attentional and sensori-motor deficits. The objective of this study was twofold. First, we aimed at investigating whether integration of proprioceptive signals in balance control was more impaired in dyslexic children when the attentional demand was varied. Secondly, we checked whether this effect was reduced significantly by using a specific treatment to improve eye control deficits and certain postural signs that are often linked to dyslexia (Quercia et al. in J Fr Ophtalmol 28:713-723, 2005, J Fr Ophtalmol 30:380-89, 2007). Thirty dyslexic and 51 treated dyslexic children (> 3 months of treatment) were compared with 42 non-dyslexic children in several conditions (mean age: 136.2 ± 23.6, 132.2 ± 18.7 and 140.2 ± 25 months, respectively). Co-vibration of ankle muscles was effected in order to alter proprioceptive information originating from the ankle. In two vibration conditions, ankle muscles were either not vibrated or vibrated at 85 Hz without illusion of any movement. These two vibration conditions were combined with two attentional conditions. In the first such condition, children maintained balance while merely fixing their gaze on a point in front of them. In the second condition, they had to look for smaller or larger stars in a panel showing forty of each kind. Balance was assessed by means of a force plate. Results indicated that the mean velocity (i.e. the total length) of the center of pressure (CoP) displacement in the 85-Hz vibration condition increased significantly more (compared with no vibration) in the dyslexic and the treated dyslexic groups than in the control group, irrespective of the attention task. Interestingly, in the condition without vibration, the attentional performance of treated children was similar to that of the control group, whereas the attentional performance of the untreated dyslexic children was significantly impaired. Altogether, these results suggest that integration of proprioceptive signals in balance control and attentional capacity are impaired in dyslexic children. However, attention capacity during the control of stance could be improved significantly.

Modular control of pointing beyond arm's length.

Hand reaching and bipedal equilibrium are two important functions of the human motor behavior. However, how the brain plans goal-oriented actions combining target reaching with equilibrium regulation is not yet clearly understood. An important question is whether postural control and reaching are integrated in one single module or controlled separately. Here, we show that postural control and reaching motor commands are processed by means of a modular and flexible organization. Principal component and correlation analyses between pairs of angles were used to extract global and local coupling during a whole-body pointing beyond arm's length. A low-dimensional organization of the redundant kinematic chain allowing simultaneous target reaching and regulation of the center of mass (CoM) displacement in extrinsic space emerged from the first analysis. In follow-up experiments, both the CoM and finger trajectories were constrained by asking participants to reach from a reduced base of support with or without knee flexion, or by moving the endpoint along a predefined trajectory (straight or semicircular trajectories). Whereas joint covaried during free conditions and under equilibrium restrictions, it was decomposed in two task-dependent and task-independent modules, corresponding to a dissociation of arm versus legs, trunk, and head coordination, respectively, under imposed finger path conditions. A numerical simulation supported the idea that both postural and focal subtasks are basically integrated into the same motor command and that the CNS is able to combine or to separate the movement into autonomous functional synergies according to the task requirements.

Equilibrium constraints do not affect the timing of muscular synergies during the initiation of a whole body reaching movement.

The aim of this study was to determine whether the timing of the muscular synergies was influenced by the reduction of the base of support when we initiate a whole body reaching movement. To answer this question, we performed a principal component analysis on electromyographic activities of 24 muscles recorded on the leg, the trunk, and the arm. Our results demonstrated that during the initiation of the whole body pointing movement, only three principal components accounted for at least 95% of the variance for the overall muscular data, both when the equilibrium constraints were normal and when the base of support was reduced. These principal components were strongly correlated despite the fact that the center of mass forward displacement and the center of pressure backward displacements significantly decreased when the base of support was reduced. It suggests that the central nervous system did not change the overall timing of the muscular synergies when new equilibrium constraints were introduced in the task but was rather able to tune their amplitude as evidenced by the modification of the center of mass and center of pressure displacements.