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.

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.

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.

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.

Network-level causal analysis of set-shifting during trail making test part B: A multimodal analysis of a glioma surgery case.

The trail making test part B (TMT-B) is one of the most widely used task for the assessment of set-shifting ability in patients. However, the set of brain regions impacting TMT-B performance when lesioned is still poorly known. In this case report, we provide a multimodal analysis of a patient operated on while awake for a diffuse low-grade glioma located in the right supramarginal gyrus. TMT-B performance was probed intraoperatively. Direct electrical stimulation of the white matter in the depth of the resection generated shifting errors. Using the recent methodology of axono-cortical-evoked potentials (ACEP), we demonstrated that the eloquent fibers were connected to the posterior end of the middle temporal gyrus (MTG). This was further confirmed by a tractography analysis of the postoperative diffusion MRI. Finally, the functional connectivity maps of this MTG seed were assessed in both pre- and post-operative resting state MRI. These maps matched with the Control network B (13th) and Default B (17th) from the 17-networks parcellation of (Yeo et al., 2011). Last but not least, we showed that the dorsal attention B (6th), the control A & B networks (12th and 13th) and the default A (16th) have been preserved here but disconnected after a more extensive resection in a previous glioma case within the same area, and in whom TMT-B was definitively impaired. Taken together, these data support the need of a network-level approach to identify the neural basis of the TMT-B and point to the Control network B as playing an important role in set-shifting.

"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.

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.

Electrophysiological Activity Evoked by Direct Electrical Stimulation of the Human Brain: Interest of the P0 Component.

Direct electrical stimulation (DES) at 60 Hz is used clinically to perform real-time functional mapping of the brain and guide tumor resection during wide-awake neurosurgery. The electrophysiological effects of DES remain by far unknown, both locally and remotely. In this study, by lowering the DES frequency to 9 Hz and by using differential recording of electro-corticographic signals to improve the focality, we were able to observe that the amplitude of the initial P0 component of the direct cortical response increased when the inter-electrode distance was increased and the pulse width was decreased. This result strongly suggests that larger neural elements, including somas and axons of pyramidal neurons buried in deeper layers of the cortical column, are activated. Their activation produce the observed P0 component, which results from the synchronized summation of action potentials triggered by DES. Interestingly, the early P0 component was not observed during the usual 60 Hz DES. The study of the P0 component and subsequent evoked potentials may help decipher the effects of DES on the stimulated cortical column and identify the activation of underlying white matter fibers. This is crucial to better understand the electrophysiological diffusion of DES, especially at higher frequencies (e.g., 60 Hz).

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.

Recovery of functional connectivity of the sensorimotor network after surgery for diffuse low-grade gliomas involving the supplementary motor area.

OBJECTIVE The supplementary motor area (SMA) syndrome is a well-studied lesional model of brain plasticity involving the sensorimotor network. Patients with diffuse low-grade gliomas in the SMA may exhibit this syndrome after resective surgery. They experience a temporary loss of motor function, which completely resolves within 3 months. The authors used functional MRI (fMRI) resting state analysis of the sensorimotor network to investigate large-scale brain plasticity between the immediate postoperative period and 3 months' follow-up. METHODS Resting state fMRI was performed preoperatively, during the immediate postoperative period, and 3 months postoperatively in 6 patients with diffuse low-grade gliomas who underwent partial surgical excision of the SMA. Correlation analysis within the sensorimotor network was carried out on those 3 time points to study modifications of its functional connectivity. RESULTS The results showed a large-scale reorganization of the sensorimotor network. Interhemispheric connectivity was decreased in the postoperative period, and increased again during the recovery process. Connectivity between the lesion side motor area and the contralateral SMA rose to higher values than in the preoperative period. Intrahemispheric connectivity was decreased during the immediate postoperative period and had returned to preoperative values at 3 months after surgery. CONCLUSIONS These results confirm the findings reported in the existing literature on the plasticity of the SMA, showing large-scale modifications of the sensorimotor network, at both inter- and intrahemispheric levels. They suggest that interhemispheric connectivity might be a correlate of SMA syndrome recovery.

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.

The difference between electrical microstimulation and direct electrical stimulation - towards new opportunities for innovative functional brain mapping?

Both electrical microstimulation (EMS) and direct electrical stimulation (DES) of the brain are used to perform functional brain mapping. EMS is applied to animal fundamental neuroscience experiments, whereas DES is performed in the operating theatre on neurosurgery patients. The objective of the present review was to shed new light on electrical stimulation techniques in brain mapping by comparing EMS and DES. There is much controversy as to whether the use of DES during wide-awake surgery is the 'gold standard' for studying the brain function. As part of this debate, it is sometimes wrongly assumed that EMS and DES induce similar effects in the nervous tissues and have comparable behavioural consequences. In fact, the respective stimulation parameters in EMS and DES are clearly different. More surprisingly, there is no solid biophysical rationale for setting the stimulation parameters in EMS and DES; this may be due to historical, methodological and technical constraints that have limited the experimental protocols and prompted the use of empirical methods. In contrast, the gap between EMS and DES highlights the potential for new experimental paradigms in electrical stimulation for functional brain mapping. In view of this gap and recent technical developments in stimulator design, it may now be time to move towards alternative, innovative protocols based on the functional stimulation of peripheral nerves (for which a more solid theoretical grounding exists).

Disrupting the right pars opercularis with electrical stimulation frees the song: case report.

The authors report the first case of a strikingly unusual speech impairment evoked by intraoperative electrostimulation in a 36-year-old right-handed patient, a well-trained singer, who underwent awake surgery for a right fronto-temporo-insular low-grade glioma. Functionally disrupting the pars opercularis of the right inferior frontal gyrus led the patient to automatically switch from a speaking to a singing mode of language production. Given the central role of the right pars opercularis in the inhibitory control network, the authors propose that this finding may be interpreted as possible evidence for a competitive and independent neurocognitive subnetwork devoted to the melodically intoned articulation of words (normal language-based vs singing-based) in subjects with high expertise. From a more clinical perspective, such data may have implications for awake neurosurgery, especially to preserve the quality of life for singers.

A disconnection account of subjective empathy impairments in diffuse low-grade glioma patients.

Human empathic experience is a multifaceted psychological construct which arises from functional integration of multiple neural networks. Despite accumulating knowledge about the cortical circuitry of empathy, almost nothing is known about the connectivity that may be concerned in conveying empathy-related neural information. To bridge this gap in knowledge, we studied dispositional empathy in a large-sized cohort of 107 patients who had undergone surgery for a diffuse low-grade glioma. The self-report questionnaire used enabled us to obtain a global measure of subjective empathy but also, importantly, to assess the two main components of empathy (cognitive and emotional). Data were processed by combining voxelwise and tractwise lesion-symptom analyses. Several major findings emerged from our analyses. First of all, topological voxelwise analyses were inconclusive. Conversely, tractwise multiple regression analyses, including all major associative white matter pathways as potential predictors, yielded to significant models explaining substantial part of the behavioural variance. Among the main results, we found that disconnection of the left cingulum bundle was a strong predictor of a low cognitive empathy (p<0.0005 Bonferroni-corrected). Similarly, we found that disconnection of the right uncinate fasciculus and the right inferior fronto-occipital fasciculus predicted, respectively, a low (p<0.05 Bonferroni-corrected) and a high (p<0.05 Bonferroni-corrected) subjective empathy. Finally, although we failed to relate emotional empathy to disruption of a specific tract, correlation analyses indicated a positive association between this component of empathy and the volumes of residual lesion infiltration in the right hemisphere (p<0.01). Taken as a whole, these findings provide key fundamental insights into the anatomical connectivity of empathy. They may help to better understand the pathophysiology of empathy impairments in pathological conditions characterized by abnormalities of long-range anatomical connectivity, such as autism spectrum disorders, schizophrenia and fronto-temporal dementia.

Functional reorganization of the attentional networks in low-grade glioma patients: a longitudinal study.

Right brain damage often provokes deficits of visuospatial attention. Although the spatial attention networks have been widely investigated in stroke patients as well as in the healthy brain, little is known about the impact of slow growing lesions in the right hemisphere. We here present a longitudinal study of 20 patients who have been undergoing awake brain surgery with per-operative line bisection testing. Our aim was to investigate the impact of tumour presence and of tumour resection on the functional (re)organization of the attention networks. We assessed patients' performance on lateralized target detection, visual exploration and line bisection before surgery, and in the acute and post-acute operative phases after surgery. Clear evidence for transient neglect signs was observed in the acute post-operative phase, although full recovery had invariably occurred in all patients. The resection of the right angular gyrus was associated with transient neglect-like symptoms in all tasks, whereas resection of more anterior regions correlated with transient deficits only in visual exploration or detection (but not in line bisection). The attentional networks showed substantial functional recovery. This impressive pattern of recovery is discussed in terms of involvement of the contralateral left hemisphere and of preservation of long-range white matter pathways within the right hemisphere.

Interfering with the neural activity of mirror-related frontal areas impairs mentalistic inferences.

According to recently proposed interactive dual-process theories, mentalizing abilities emerge from the coherent interaction between two physically distinct neural systems: (1) the mirror network, coding for the low-level embodied representations involved in pre-reflective sociocognitive processes and (2) the mentalizing network per se, which codes for higher level representations subtending the reflective attribution of psychological states. However, although the latest studies have shown that the core areas forming these two neurocognitive systems do indeed maintain effective connectivity during mentalizing, it is unclear whether an intact mirror system (and, more specifically, its anterior node, namely the posterior inferior frontal cortex) is a prerequisite for accurate mentalistic inferences. Intraoperative brain mapping via direct electrical stimulation offers a unique opportunity to address this issue. Electrical stimulation of the brain creates a "virtual" lesion, which provides functional information on well-defined parts of the cerebral cortex. In the present study, five patients were mapped in real time while they performed a mentalizing task. We found six responsive sites: four in the lateral part of the right pars opercularis and two in the dorsal part of the right pars triangularis. On the subcortical level, two additional sites were located within the white matter connectivity of the pars opercularis. Taken as a whole, our results suggest that the right inferior frontal cortex and its underlying axonal connectivity have a key role in mentalizing. Specifically, our findings support the hypothesis whereby transient, functional disruption of the mirror network influences higher order mentalistic inferences.

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.

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.

Disrupting posterior cingulate connectivity disconnects consciousness from the external environment.

Neurophysiological and neuroimaging studies including both patients with disorders of consciousness and healthy subjects with modified states of consciousness suggest a crucial role of the medial posteroparietal cortex in conscious information processing. However no direct neuropsychological evidence supports this hypothesis and studies including patients with restricted lesions of this brain region are almost non-existent. Using direct intraoperative electrostimulations, we showed in a rare patient that disrupting the subcortical connectivity of the left posterior cingulate cortex (PCC) reliably induced a breakdown in conscious experience. This acute phenomenon was mainly characterized by a transient behavioral unresponsiveness with loss of external connectedness. In all cases, when he regained consciousness, the patient described himself as in dream, outside the operating room. This finding suggests that functional integrity of the PPC connectivity is necessary for maintaining consciousness of external environment.