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.

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.

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.

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).

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.

A measure of cortico-cortical potentials evoked by 10 Hz direct electrical stimulation of the brain and by means of a differential recording mode of electrocorticographic signals.

Direct electrical stimulation (DES) at 60 Hz is used to perform real-time functional mapping of the brain during wide-awake neurosurgery. The electrophysiological effects of DES are largely unknown, locally and at a more remote distance. Here, by lowering the DES frequency to 10 Hz and by using a differential recording mode of electro-corticographic (ECoG) signals to improve the focality, we were able to record cortico-cortical evoked potentials easily with standard current amplitude of stimulation (2 mA). DES applied at 10 Hz and differential recording of ECoG could be used to map on-line the connectivity between different sub-cortical and cortical areas with a higher spatial accuracy.

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.

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.