Single Pulse Electrical Stimulation Research Articles

CARLA: Adjusted common average referencing for cortico-cortical evoked potential data

Human brain connectivity can be mapped by single pulse electrical stimulation during intracranial EEG measurements. The raw cortico-cortical evoked potentials (CCEP) are often contaminated by noise. Common average referencing (CAR) removes common noise and preserves response shapes but can introduce bias from responsive channels. We address this issue with an adjusted, adaptive CAR algorithm termed “CAR by Least Anticorrelation (CARLA)”.CARLA was tested on simulated CCEP data and real CCEP data collected from four human participants. In CARLA, the channels are ordered by increasing mean cross-trial covariance, and iteratively added to the common average until anticorrelation between any single channel and all re-referenced channels reaches a minimum, as a measure of shared noise.We simulated CCEP data with true responses in 0 to 45 of 50 total channels. We quantified CARLA’s error and found that it erroneously included 0 (median) truly responsive channels in the common average with ≤42 responsive channels, and erroneously excluded ≤2.5 (median) unresponsive channels at all responsiveness levels. On real CCEP data, signal quality was quantified with the mean R2 between all pairs of channels, which represents inter-channel dependency and is low for well-referenced data. CARLA re-referencing produced significantly lower mean R2 than standard CAR, CAR using a fixed bottom quartile of channels by covariance, and no re-referencing.CARLA minimizes bias in re-referenced CCEP data by adaptively selecting the optimal subset of non-responsive channels. It showed high specificity and sensitivity on simulated CCEP data and lowered inter-channel dependency compared to CAR on real CCEP data.

Reciprocal inhibition of the thigh muscles in humans: A study using transcutaneous spinal cord stimulation.

Evaluating reciprocal inhibition of the thigh muscles is important to investigate the neural circuits of locomotor behaviors. However, measurements of reciprocal inhibition of thigh muscles using spinal reflex, such as H-reflex, have never been systematically established owing to methodological limitations. The present study aimed to clarify the existence of reciprocal inhibition in the thigh muscles using transcutaneous spinal cord stimulation (tSCS). Twenty able-bodied male individuals were enrolled. We evoked spinal reflex from the biceps femoris muscle (BF) by tSCS on the lumber posterior root. We examined whether the tSCS-evoked BF reflex was reciprocally inhibited by the following conditionings: (1) single-pulse electrical stimulation on the femoral nerve innervating the rectus femoris muscle (RF) at various inter-stimulus intervals in the resting condition; (2) voluntary contraction of the RF; and (3) vibration stimulus on the RF. The BF reflex was significantly inhibited when the conditioning electrical stimulation was delivered at 10 and 20 ms prior to tSCS, during voluntary contraction of the RF, and during vibration on the RF. These data suggested a piece of evidence of the existence of reciprocal inhibition from the RF to the BF muscle in humans and highlighted the utility of methods for evaluating reciprocal inhibition of the thigh muscles using tSCS.

A prospective observational study comparing outcomes application of low-frequency pulse electrical combined with target-oriented rehabilitation therapy in postoperative nerve function rehabilitation of patients with distal humeral fracture and radial nerve injury.

The aim of the present study was to compare the effect of low-frequency pulse electrical stimulation combined with target-oriented rehabilitation therapy and single low-frequency pulse electrical stimulation therapy on postoperative neurological improvement in patients with radial nerve injury and humeral condylar fracture. A total of 88 patients with humeral condyle fracture and radial nerve injury admitted to our hospital from April 2019 to January 2022 were randomly divided into a combined group and a control group, with 44 patients in each group. The patients in the combined group received low-frequency pulse electrical stimulation combined with target-oriented rehabilitation therapy, while those in the control group received low-frequency pulse electrical stimulation therapy. The recovery rate of radial nerve function, the recovery of finger extensor and wrist extensor muscle strength, and the occurrence of postoperative complications were evaluated in all patients. After treatment, the recovery rate in the combined group (77.27%) was higher than that in the control group (50.00%) (p < 0.05). There was no significant difference in finger extensor and wrist extensor muscle strength before treatment between the two groups (p > 0.05). After treatment, both groups showed improvement compared to before treatment (p < 0.05), and the recovery in the combined group was better than that in the control group (p < 0.05). There was no significant difference in MCV and amplitude before treatment between the two groups (p > 0.05). After treatment, both groups showed improvement compared to before treatment (p < 0.05), and the recovery in the combined group was better than that in the control group (p < 0.05). The fracture healing time in the combined group was shorter than that in the control group (p < 0.05). During the treatment period, there was one case of infection and one case of joint pain in the combined group, with a complication rate of 4.55%. In the control group, there was one case of infection and two cases of joint pain, with a complication rate of 6.82%. There was no significant difference in the complication rate between the two groups (p > 0.05). The DHI score in the combined group was better than that in the control group (p < 0.05). The ESCA score in the combined group was better than that in the control group (p < 0.05). Low-frequency pulse electrical stimulation combined with target-oriented rehabilitation therapy can promote muscle strength and functional recovery after radial nerve injury, accelerate fracture healing time, and no additional risk of complications. https://www.researchregistry.com/, researchregistry9461.

The effect of propofol on effective brain networks

ObjectiveWe compared the effective networks derived from Single Pulse Electrical Stimulation (SPES) in intracranial electrocorticography (ECoG) of awake epilepsy patients and while under general propofol-anesthesia to investigate the effect of propofol on these brain networks. MethodsWe included nine patients who underwent ECoG for epilepsy surgery evaluation. We performed SPES when the patient was awake (SPES-clinical) and repeated this under propofol-anesthesia during the surgery in which the ECoG grids were removed (SPES-propofol). We detected the cortico-cortical evoked potentials (CCEPs) with an automatic detector. We constructed two effective networks derived from SPES-clinical and SPES-propofol. We compared three network measures (indegree, outdegree and betweenness centrality), the N1-peak-latency and amplitude of CCEPs between the two effective networks. ResultsFewer CCEPs were observed during SPES-propofol (median: 6.0, range: 0–29) compared to SPES-clinical (median: 10.0, range: 0–36). We found a significant correlation for the indegree, outdegree and betweenness centrality between SPES-clinical and SPES-propofol (respectively rs = 0.77, rs = 0.70, rs = 0.55, p < 0.001). The median N1-peak-latency increased from 22.0 ms during SPES-clinical to 26.4 ms during SPES-propofol. ConclusionsOur findings suggest that the number of effective network connections decreases, but network measures are only marginally affected. SignificanceThe primary network topology is preserved under propofol.

Utilizing Excitatory and Inhibitory Activity Derived from Interictal Intracranial Electroencephalography as Potential Biomarkers for Epileptogenicity.

Epileptogenic zones (EZs), where epileptic seizures cease after resection, are localized by assessing the seizure-onset zone using ictal electroencephalography (EEG). Owing to the difficulty in capturing unpredictable seizures, biomarkers capable of identifying EZs from interictal EEG are anticipated. Recent studies using intracranial EEG have identified several potential candidate biomarkers for epileptogenicity. High-frequency oscillation (HFO) was initially expected to be a robust biomarker of abnormal excitatory activity in the ictogenic region. However, HFO-guided resection failed to improve seizure prognosis. Meanwhile, the regularity of low-gamma oscillations (30-80 Hz) indicates inhibitory interneurons' hypersynchronization, which could be used to localize the EZ. Besides resting-state EEG assessments, evoked potentials elicited by single-pulse electrical stimulation, such as corticocortical evoked potentials (CCEP), became valuable tools for assessing epileptogenic regions. CCEP responses recorded in the cortex remote from the stimulation site indicate functional connectivity, revealing increased internal connectivity within the ictogenic region and elevated inhibitory input from the non-involved regions to the ictogenic region. Conversely, large responses close to the stimulation site reflect local excitability, manifesting as an increased N1 amplitude and overriding HFO. Further research is required to establish whether these novel electrophysiological methods, either individually or in combination, can function as robust biomarkers of epileptogenicity and hold promise for improving seizure prognosis.

Effective connectivity relates seizure outcome to electrode placement in responsive neurostimulation.

Responsive neurostimulation is a closed-loop neuromodulation therapy for drug resistant focal epilepsy. Responsive neurostimulation electrodes are placed near ictal onset zones so as to enable detection of epileptiform activity and deliver electrical stimulation. There is no standard approach for determining the optimal placement of responsive neurostimulation electrodes. Clinicians make this determination based on presurgical tests, such as MRI, EEG, magnetoencephalography, ictal single-photon emission computed tomography and intracranial EEG. Currently functional connectivity measures are not being used in determining the placement of responsive neurostimulation electrodes. Cortico-cortical evoked potentials are a measure of effective functional connectivity. Cortico-cortical evoked potentials are generated by direct single-pulse electrical stimulation and can be used to investigate cortico-cortical connections in vivo. We hypothesized that the presence of high amplitude cortico-cortical evoked potentials, recorded during intracranial EEG monitoring, near the eventual responsive neurostimulation contact sites is predictive of better outcomes from its therapy. We retrospectively reviewed 12 patients in whom cortico-cortical evoked potentials were obtained during stereoelectroencephalography evaluation and subsequently underwent responsive neurostimulation therapy. We studied the relationship between cortico-cortical evoked potentials, the eventual responsive neurostimulation electrode locations and seizure reduction. Directional connectivity indicated by cortico-cortical evoked potentials can categorize stereoelectroencephalography electrodes as either receiver nodes/in-degree (an area of greater inward connectivity) or projection nodes/out-degree (greater outward connectivity). The follow-up period for seizure reduction ranged from 1.3-4.8 years (median 2.7) after responsive neurostimulation therapy started. Stereoelectroencephalography electrodes closest to the eventual responsive neurostimulation contact site tended to show larger in-degree cortico-cortical evoked potentials, especially for the early latency cortico-cortical evoked potentials period (10-60 ms period) in six out of 12 patients. Stereoelectroencephalography electrodes closest to the responsive neurostimulation contacts (≤5 mm) also had greater significant out-degree in the early cortico-cortical evoked potentials latency period than those further away (≥10 mm) (P < 0.05). Additionally, significant correlation was noted between in-degree cortico-cortical evoked potentials and greater seizure reduction with responsive neurostimulation therapy at its most effective period (P < 0.05). These findings suggest that functional connectivity determined by cortico-cortical evoked potentials may provide additional information that could help guide the optimal placement of responsive neurostimulation electrodes.

SEEG electrode shaft affects amplitude and latency of potentials evoked with single pulse electrical stimulation

BackgroundLong and thin shaft electrodes are implanted intracerebrally for stereoelectroencephalography (SEEG) in patients with pharmacoresistant focal epilepsies. Two adjacent contacts of one of such electrodes can deliver a train of single pulse electrical stimulations (SPES), and evoked potentials (EPs) are recorded on other contacts. In this study we assess if stimulating and recording on the same shaft, as opposed to different shafts, has an impact on common EP features. New methodWe leverage the large volume of SEEG data gathered in the F-TRACT database and analyze data from nearly one thousand SEEG implantations in order to verify whether stimulation and recording from the same shaft influence the EP pattern. ResultsWe found that when the stimulated and the recording contacts were located on the same shaft, the mean and median amplitudes of an EP are greater, and its mean and median latencies are smaller than when the contacts were located on different shafts. This effect is small (Cohen’s d ∼ 0.1), but robust (p-value < 10-3) across the SEEG database. Comparison with existing method(s)Our study is the first one to address this question. Due to the choice of commonly used EP features, our method is congruent with other studies. ConclusionsThe magnitude of the reported effect does not obligate all standard analyses to correct for it, unless they aim at high precision. The source of the effect is not clear. Manufacturers of SEEG electrodes could examine it and potentially minimize the effect in their future products.

Single-pulse electrical stimulation artifact removal using the novel matching pursuit-based artifact reconstruction and removal method (MPARRM)

Objective. Single-pulse electrical stimulation (SPES) has been widely used to probe effective connectivity. However, analysis of the neural response is often confounded by stimulation artifacts. We developed a novel matching pursuit-based artifact reconstruction and removal method (MPARRM) capable of removing artifacts from stimulation-artifact-affected electrophysiological signals. Approach. To validate MPARRM across a wide range of potential stimulation artifact types, we performed a bench-top experiment in which we suspended electrodes in a saline solution to generate 110 types of real-world stimulation artifacts. We then added the generated stimulation artifacts to ground truth signals (stereoelectroencephalography signals from nine human subjects recorded during a receptive speech task), applied MPARRM to the combined signal, and compared the resultant denoised signal with the ground truth signal. We further applied MPARRM to artifact-affected neural signals recorded from the hippocampus while performing SPES on the ipsilateral basolateral amygdala in nine human subjects. Main results. MPARRM could remove stimulation artifacts without introducing spectral leakage or temporal spread. It accommodated variable stimulation parameters and recovered the early response to SPES within a wide range of frequency bands. Specifically, in the early response period (5–10 ms following stimulation onset), we found that the broadband gamma power (70–170 Hz) of the denoised signal was highly correlated with the ground truth signal ( R=0.98±0.02 , Pearson), and the broadband gamma activity of the denoised signal faithfully revealed the responses to the auditory stimuli within the ground truth signal with 94%±1.47% sensitivity and 99%±1.01% specificity. We further found that MPARRM could reveal the expected temporal progression of broadband gamma activity along the anterior-posterior axis of the hippocampus in response to the ipsilateral amygdala stimulation. Significance. MPARRM could faithfully remove SPES artifacts without confounding the electrophysiological signal components, especially during the early-response period. This method can facilitate the understanding of the neural response mechanisms of SPES.

Physiological and pathological neuronal connectivity in the living human brain based on intracranial EEG signals: the current state of research.

Over the past decades, studies of human brain networks have received growing attention as the assessment and modelling of connectivity in the brain is a topic of high impact with potential application in the understanding of human brain organization under both physiological as well as various pathological conditions. Under specific diagnostic settings, human neuronal signal can be obtained from intracranial EEG (iEEG) recording in epilepsy patients that allows gaining insight into the functional organisation of living human brain. There are two approaches to assess brain connectivity in the iEEG-based signal: evaluation of spontaneous neuronal oscillations during ongoing physiological and pathological brain activity, and analysis of the electrophysiological cortico-cortical neuronal responses, evoked by single pulse electrical stimulation (SPES). Both methods have their own advantages and limitations. The paper outlines available methodological approaches and provides an overview of current findings in studies of physiological and pathological human brain networks, based on intracranial EEG recordings.

Signatures of Electrical Stimulation Driven Network Interactions in the Human Limbic System.

Stimulation-evoked signals are starting to be used as biomarkers to indicate the state and health of brain networks. The human limbic network, often targeted for brain stimulation therapy, is involved in emotion and memory processing. Previous anatomic, neurophysiological, and functional studies suggest distinct subsystems within the limbic network (Rolls, 2015). Studies using intracranial electrical stimulation, however, have emphasized the similarities of the evoked waveforms across the limbic network. We test whether these subsystems have distinct stimulation-driven signatures. In eight patients (four male, four female) with drug-resistant epilepsy, we stimulated the limbic system with single-pulse electrical stimulation. Reliable corticocortical evoked potentials (CCEPs) were measured between hippocampus and the posterior cingulate cortex (PCC) and between the amygdala and the anterior cingulate cortex (ACC). However, the CCEP waveform in the PCC after hippocampal stimulation showed a unique and reliable morphology, which we term the "limbic Hippocampus-Anterior nucleus of the thalamus-Posterior cingulate, HAP-wave." This limbic HAP-wave was visually distinct and separately decoded from the CCEP waveform in ACC after amygdala stimulation. Diffusion MRI data show that the measured end points in the PCC overlap with the end points of the parolfactory cingulum bundle rather than the parahippocampal cingulum, suggesting that the limbic HAP-wave may travel through fornix, mammillary bodies, and the anterior nucleus of the thalamus (ANT). This was further confirmed by stimulating the ANT, which evoked the same limbic HAP-wave but with an earlier latency. Limbic subsystems have unique stimulation-evoked signatures that may be used in the future to help network pathology diagnosis.SIGNIFICANCE STATEMENT The limbic system is often compromised in diverse clinical conditions, such as epilepsy or Alzheimer's disease, and characterizing its typical circuit responses may provide diagnostic insight. Stimulation-evoked waveforms have been used in the motor system to diagnose circuit pathology. We translate this framework to limbic subsystems using human intracranial stereo EEG (sEEG) recordings that measure deeper brain areas. Our sEEG recordings describe a stimulation-evoked waveform characteristic to the memory and spatial subsystem of the limbic network that we term the "limbic HAP-wave." The limbic HAP-wave follows anatomic white matter pathways from hippocampus to thalamus to the posterior cingulum and shows promise as a distinct biomarker of signaling in the human brain memory and spatial limbic network.

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

BackgroundSensorimotor 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. ObjectivesWe 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. MethodsIn 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. ResultsLFP 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. ConclusionThe 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.

Localization of Epileptic Brain Responses to Single-Pulse Electrical Stimulation by Developing an Adaptive Iterative Linearly Constrained Minimum Variance Beamformer.

Delayed responses (DRs) to single pulse electrical stimulation (SPES) in patients with severe refractory epilepsy, from their intracranial recordings, can help to identify regions associated with epileptogenicity. Automatic DR localization is a large step in speeding up the identification of epileptogenic focus. Here, for the first time, an adaptive iterative linearly constrained minimum variance beamformer (AI-LCMV) is developed and employed to localize the DR sources from intracranial electroencephalogram (EEG) recorded using subdural electrodes. The prime objective here is to accurately localize the regions for the corresponding DRs using an adaptive localization method that exploits the morphology of DRs as the desired sources. The traditional closed-form linearly constrained minimum variance (CF-LCMV) solution is meant for tracking the sources with dominating power. Here, by incorporating the morphology of DRs, as a constraint, to an iterative linearly constrained minimum variance (LCMV) solution, the array of subdural electrodes is used to localize the low-power DRs, some not even visible in any of the electrode signals. The results from the cases included in this study also indicate more distinctive locations compared to those achievable by conventional beamformers. Most importantly, the proposed AI-LCMV is able to localize the DRs invisible over other electrodes.

Human anterior thalamic stimulation evoked cortical potentials align with intrinsic functional connectivity

Characterizing human thalamocortical network is fundamental for understanding a vast array of human behaviors since the thalamus plays a central role in cortico-subcortical communication. Over the past few decades, advances in functional magnetic resonance imaging have allowed for spatial mapping of intrinsic resting-state functional connectivity (RSFC) between both cortical regions and in cortico-subcortical networks. Despite these advances, identifying the electrophysiological basis of human thalamocortical network architecture remains challenging. By leveraging stereoelectroencephalography electrodes temporarily implanted into distributed cortical regions and the anterior nucleus of the thalamus (ANT) of 10 patients with refractory focal epilepsy, we tested whether ANT stimulation evoked cortical potentials align with RSFC from the stimulation site, derived from a normative functional connectome (n = 1000). Our study identifies spatial convergence of ANT stimulation evoked cortical potentials and normative RSFC. Other than connections to the Papez circuit, the ANT was found to be closely connected to several distinct higher-order association cortices, including the precuneus, angular gyrus, dorsal lateral prefrontal cortex, and anterior insula. Remarkably, we found that the spatial distribution and magnitude of cortical-evoked responses to single-pulse electrical stimulation of the ANT aligned with the spatial pattern and strength of normative RSFC of the stimulation site. The present study provides electrophysiological evidence that stimulation evoked electrical activity flows along intrinsic brain networks connected on a thalamocortical level.

An in–vivo validation of ESI methods with focal sources

Electrophysiological source imaging (ESI) aims at reconstructing the precise origin of brain activity from measurements of the electric field on the scalp. Across laboratories/research centers/hospitals, ESI is performed with different methods, partly due to the ill-posedness of the underlying mathematical problem. However, it is difficult to find systematic comparisons involving a wide variety of methods. Further, existing comparisons rarely take into account the variability of the results with respect to the input parameters. Finally, comparisons are typically performed using either synthetic data, or in-vivo data where the ground-truth is only roughly known. We use an in-vivo high-density EEG dataset recorded during intracranial single pulse electrical stimulation, in which the true sources are substantially dipolar and their locations are precisely known. We compare ten different ESI methods, using their implementation in the MNE-Python package: MNE, dSPM, LORETA, sLORETA, eLORETA, LCMV beamformers, irMxNE, Gamma Map, SESAME and dipole fitting. We perform comparisons under multiple choices of input parameters, to assess the accuracy of the best reconstruction, as well as the impact of such parameters on the localization performance. Best reconstructions often fall within 1 cm from the true source, with most accurate methods hitting an average localization error of 1.2 cm and outperforming least accurate ones erring by 2.5 cm. As expected, dipolar and sparsity-promoting methods tend to outperform distributed methods. For several distributed methods, the best regularization parameter turned out to be the one in principle associated with low SNR, despite the high SNR of the available dataset. Depth weighting played no role for two out of the six methods implementing it. Sensitivity to input parameters varied widely between methods. While one would expect high variability being associated with low localization error at the best solution, this is not always the case, with some methods producing highly variable results and high localization error, and other methods producing stable results with low localization error. In particular, recent dipolar and sparsity-promoting methods provide significantly better results than older distributed methods. As we repeated the tests with “conventional” (32 channels) and dense (64, 128, 256 channels) EEG recordings, we observed little impact of the number of channels on localization accuracy; however, for distributed methods denser montages provide smaller spatial dispersion. Overall findings confirm that EEG is a reliable technique for localization of point sources and therefore reinforce the importance that ESI may have in the clinical context, especially when applied to identify the surgical target in potential candidates for epilepsy surgery.

Causal evidence for the processing of bodily self in the anterior precuneus

To probe the causal importance of the human posteromedial cortex (PMC) in processing the sense of self, we studied a rare cohort of nine patients with electrodes implanted bilaterally in the precuneus, posterior cingulate, and retrosplenial regions with a combination of neuroimaging, intracranial recordings, and direct cortical stimulations. In all participants, the stimulation of specific sites within the anterior precuneus (aPCu) caused dissociative changes in physical and spatial domains. Using single-pulse electrical stimulations and neuroimaging, we present effective and resting-state connectivity of aPCu hot zone with the rest of the brain and show that they are located outside the boundaries of the default mode network (DMN) but connected reciprocally with it. We propose that the function of this subregion of the PMC is integral to a range of cognitive processes that require the self's physical point of reference, given its location within a spatial environment.

Canonical Response Parameterization: Quantifying the structure of responses to single-pulse intracranial electrical brain stimulation.

Single-pulse electrical stimulation in the nervous system, often called cortico-cortical evoked potential (CCEP) measurement, is an important technique to understand how brain regions interact with one another. Voltages are measured from implanted electrodes in one brain area while stimulating another with brief current impulses separated by several seconds. Historically, researchers have tried to understand the significance of evoked voltage polyphasic deflections by visual inspection, but no general-purpose tool has emerged to understand their shapes or describe them mathematically. We describe and illustrate a new technique to parameterize brain stimulation data, where voltage response traces are projected into one another using a semi-normalized dot product. The length of timepoints from stimulation included in the dot product is varied to obtain a temporal profile of structural significance, and the peak of the profile uniquely identifies the duration of the response. Using linear kernel PCA, a canonical response shape is obtained over this duration, and then single-trial traces are parameterized as a projection of this canonical shape with a residual term. Such parameterization allows for dissimilar trace shapes from different brain areas to be directly compared by quantifying cross-projection magnitudes, response duration, canonical shape projection amplitudes, signal-to-noise ratios, explained variance, and statistical significance. Artifactual trials are automatically identified by outliers in sub-distributions of cross-projection magnitude, and rejected. This technique, which we call "Canonical Response Parameterization" (CRP) dramatically simplifies the study of CCEP shapes, and may also be applied in a wide range of other settings involving event-triggered data.

Electrical Stimulation of Temporal and Limbic Circuitry Produces Distinct Responses in Human Ventral Temporal Cortex.

The human ventral temporal cortex (VTC) is highly connected to integrate visual perceptual inputs with feedback from cognitive and emotional networks. In this study, we used electrical brain stimulation to understand how different inputs from multiple brain regions drive unique electrophysiological responses in the VTC. We recorded intracranial EEG data in 5 patients (3 female) implanted with intracranial electrodes for epilepsy surgery evaluation. Pairs of electrodes were stimulated with single-pulse electrical stimulation, and corticocortical evoked potential responses were measured at electrodes in the collateral sulcus and lateral occipitotemporal sulcus of the VTC. Using a novel unsupervised machine learning method, we uncovered 2-4 distinct response shapes, termed basis profile curves (BPCs), at each measurement electrode in the 11-500 ms after stimulation interval. Corticocortical evoked potentials of unique shape and high amplitude were elicited following stimulation of several regions and classified into a set of four consensus BPCs across subjects. One of the consensus BPCs was primarily elicited by stimulation of the hippocampus; another by stimulation of the amygdala; a third by stimulation of lateral cortical sites, such as the middle temporal gyrus; and the final one by stimulation of multiple distributed sites. Stimulation also produced sustained high-frequency power decreases and low-frequency power increases that spanned multiple BPC categories. Characterizing distinct shapes in stimulation responses provides a novel description of connectivity to the VTC and reveals significant differences in input from cortical and limbic structures.SIGNIFICANCE STATEMENT Disentangling the numerous input influences on highly connected areas in the brain is a critical step toward understanding how brain networks work together to coordinate human behavior. Single-pulse electrical stimulation is an effective tool to accomplish this goal because the shapes and amplitudes of signals recorded from electrodes are informative of the synaptic physiology of the stimulation-driven inputs. We focused on targets in the ventral temporal cortex, an area strongly implicated in visual object perception. By using a data-driven clustering algorithm, we identified anatomic regions with distinct input connectivity profiles to the ventral temporal cortex. Examining high-frequency power changes revealed possible modulation of excitability at the recording site induced by electrical stimulation of connected regions.

N°83 – Are cortico-cortical evoked potentials reproducible during single-pulse electrical stimulation?

N°83 – Are cortico-cortical evoked potentials reproducible during single-pulse electrical stimulation?

Multisite thalamic recordings to characterize seizure propagation in the human brain.

Neuromodulation of the anterior nuclei of the thalamus (ANT) has shown to be efficacious in a subset of patients with refractory focal epilepsy. One important uncertainty is to what extent thalamic subregions other than the ANT could be recruited more prominently in the propagation of focal onset seizures. We designed the current study to simultaneously monitor the engagement of the ANT, mediodorsal (MD) and pulvinar (PUL) nuclei during seizures in patients who could be candidates for thalamic neuromodulation. We studied 11 patients with clinical manifestations of presumed temporal lobe epilepsy (TLE) undergoing invasive stereo-encephalography (sEEG) monitoring to confirm the source of their seizures. We extended cortical electrodes to reach the ANT, MD and PUL nuclei of the thalamus. More than one thalamic subdivision was simultaneously interrogated in nine patients. We recorded seizures with implanted electrodes across various regions of the brain and documented seizure onset zones (SOZ) in each recorded seizure. We visually identified the first thalamic subregion to be involved in seizure propagation. Additionally, in eight patients, we applied repeated single pulse electrical stimulation in each SOZ and recorded the time and prominence of evoked responses across the implanted thalamic regions. Our approach for multisite thalamic sampling was safe and caused no adverse events. Intracranial EEG recordings confirmed SOZ in medial temporal lobe, insula, orbitofrontal and temporal neocortical sites, highlighting the importance of invasive monitoring for accurate localization of SOZs. In all patients, seizures with the same propagation network and originating from the same SOZ involved the same thalamic subregion, with a stereotyped thalamic EEG signature. Qualitative visual reviews of ictal EEGs were largely consistent with the quantitative analysis of the corticothalamic evoked potentials, and both documented that thalamic nuclei other than ANT could have the earliest participation in seizure propagation. Specifically, pulvinar nuclei were involved earlier and more prominently than ANT in more than half of the patients. However, which specific thalamic subregion first demonstrated ictal activity could not be reliably predicted based on clinical semiology or lobar localization of SOZs. Our findings document the feasibility and safety of bilateral multisite sampling from the human thalamus. This may allow more personalized thalamic targets to be identified for neuromodulation. Future studies are needed to determine if a personalized thalamic neuromodulation leads to greater improvements in clinical outcome.

Towards optimizing single pulse electrical stimulation: High current intensity, short pulse width stimulation most effectively elicits evoked potentials

BackgroundWhile single pulse electrical stimulation (SPES) is increasingly used to study effective connectivity, the effects of varying stimulation parameters on the resulting cortico-cortical evoked potentials (CCEPs) have not been systematically explored. ObjectiveWe sought to understand the interacting effects of stimulation pulse width, current intensity, and charge on CCEPs through an extensive testing of this parameter space and analysis of several response metrics. MethodsWe conducted SPES in 11 patients undergoing intracranial EEG monitoring using five combinations of current intensity (1.5, 2.0, 3.0, 5.0, and 7.5 mA) and pulse width at each of three charges (0.750, 1.125, and 1.500 μC/phase) to study how CCEP amplitude, distribution, latency, morphology, and stimulus artifact amplitude vary with each parameter. ResultsStimulations with a greater charge or a greater current intensity and shorter pulse width at a given charge generally resulted in greater CCEP amplitudes and spatial distributions, shorter latencies, and increased waveform correlation. These effects interacted such that stimulations with the lowest charge and highest current intensities resulted in greater response amplitudes and spatial distributions than stimulations with the highest charge and lowest current intensities. Stimulus artifact amplitude increased with charge, but this could be mitigated by using shorter pulse widths. ConclusionsOur results indicate that individual combinations of current intensity and pulse width, in addition to charge, are important determinants of CCEP magnitude, morphology, and spatial extent. Together, these findings suggest that high current intensity, short pulse width stimulations are optimal SPES settings for eliciting strong and consistent responses while minimizing charge.