Single Pulse Electrical Stimulation Research Articles

The neural tides of sleep and consciousness revealed by single-pulse electrical brain stimulation.

Wakefulness and sleep arise from global changes in brain physiology that may also govern the flow of neural activity between cortical regions responsible for perceptual processing versus planning and action. To test whether and how the sleep/wake cycle affects the overall propagation of neural activity in large-scale brain networks, we applied single-pulse electrical stimulation (SPES) in patients implanted with intracranial EEG electrodes for epilepsy surgery. SPES elicited cortico-cortical spectral responses at high-gamma frequencies (CCSRHG, 80-150 Hz), which indexes changes in neuronal population firing rates. Using event-related causality (ERC) analysis, we found that the overall patterns of neural propagation among sites with CCSRHG were different during wakefulness and different sleep stages. For example, stimulation of frontal lobe elicited greater propagation toward parietal lobe during slow-wave sleep than during wakefulness. During REM sleep, we observed a decrease in propagation within frontal lobe, and an increase in propagation within parietal lobe, elicited by frontal and parietal stimulation, respectively. These biases in the directionality of large-scale cortical network dynamics during REM sleep could potentially account for some of the unique experiential aspects of this sleep stage. Together these findings suggest that the regulation of conscious awareness and sleep is associated with differences in the balance of neural propagation across large-scale frontal-parietal networks.

Intracranial network stimulation as a method to suppress epileptic activity

Purpose: In patients with focal epilepsy in eloquent cortex, cortical stimulation may be effective in seizure reduction. At the same time, stimulation within eloquent areas may itself cause symptoms, and it would be attractive when stimulation outside, but connected to such areas, were also effective. We used Single Pulse Electrical Stimulation (SPES) in a subdurally implanted patient to map local effective networks around a seizure onset zone with continuous spiking and saw that stimulating a directly connected electrode diminishes spontaneous spikes there.

A Comparison of Evoked and Non-evoked Functional Networks

The growing interest in brain networks to study the brain’s function in cognition and diseases has produced an increase in methods to extract these networks. Typically, each method yields a different network. Therefore, one may ask what the resulting networks represent. To address this issue we consider electrocorticography (ECoG) data where we compare three methods. We derive networks from on-going ECoG data using two traditional methods: cross-correlation (CC) and Granger causality (GC). Next, connectivity is probed actively using single pulse electrical stimulation (SPES). We compare the overlap in connectivity between these three methods as well as their ability to reveal well-known anatomical connections in the language circuit. We find that strong connections in the CC network form more or less a subset of the SPES network. GC and SPES are related more weakly, although GC connections coincide more frequently with SPES connections compared to non-existing SPES connections. Connectivity between the two major hubs in the language circuit, Broca’s and Wernicke’s area, is only found in SPES networks. Our results are of interest for the use of patient-specific networks obtained from ECoG. In epilepsy research, such networks form the basis for methods that predict the effect of epilepsy surgery. For this application SPES networks are interesting as they disclose more physiological connections compared to CC and GC networks.

Chronic Social Isolation Stress during Peri-Adolescence Alters Presynaptic Dopamine Terminal Dynamics via Augmentation in Accumbal Dopamine Availability.

Chronic peri-adolescent stress in humans increases risk to develop a substance use disorder during adulthood. Rats reared in social isolation during peri-adolescence (aSI; 1 rat/cage) period show greater ethanol and cocaine intake compared to group housed (aGH; 4 rats/cage) rats. In addition, aSI rats have a heightened dopamine response in the nucleus accumbens (NAc) to rewarding and aversive stimuli. Furthermore, single pulse electrical stimulation in slices containing NAc core elicits greater dopamine release in aSI rats. Here, we further investigated dopamine release kinetics and machinery following aSI. Dopamine release, across a wide range of stimulation intensities and frequencies, was significantly greater in aSI rats. Interestingly, subthreshold intensity stimulations also resulted in measurable dopamine release in accumbal slices from aSI but not aGH rats. Extracellular [Ca2+] manipulations revealed augmented calcium sensitivity of dopamine release in aSI rats. The readily releasable pools of dopamine, examined by bath application of Ro-04-1284/000, a vesicular monoamine transporter 2 (VMAT2) inhibitor, were depleted faster in aGH rats. Western blot analysis of release machinery proteins (VMAT2, Synaptogyrin-3, Syntaxin-1, and Munc13-3) showed no difference between the two groups. Tyrosine hydroxylase (TH) protein expression levels, however, were elevated in aSI rats. The greater dopamine release could potentially be explained by higher levels of TH, the rate-limiting step for dopamine synthesis. This augmented responsivity of the dopamine system and heightened dopamine availability post-aSI may lead to an increased risk of addiction vulnerability.

Functional mapping and effective connectivity of the human operculum

The operculum, defined as the cortex adjacent to the insula, is a large structure encompassing three lobes, with a recognized role in a variety of neurologic and psychiatric conditions. Its complex functions include sensory, motor, autonomic and cognitive processing. In humans, these are extended with the addition of language. These functions are implemented by highly specialized neuronal populations and their widespread connections, which our study aims at mapping in detail. We studied a group of 31 patients that were explored with intracranial electrodes during the pre-surgical workup for drug-resistant epilepsy. We have selected the subset of contacts implanted in non-epileptogenic opercular cortex and we analyzed the neurophysiological and behavioral responses to direct electrical stimulation. The functional mapping was performed by applying 1 Hz and 50 Hz electrical stimulation on 252 contact pairs and recording the threshold for evoking clinical effects. The effective connectivity was assessed using cortico-cortical evoked potentials elicited by single-pulse electrical stimulation in a subset of 19 patients.The locations of the effects grouped in twelve distinct semiological classes were analyzed. The most frequent effects evoked by stimulation of the frontal operculum were language related (29%). The Rolandic area produced most often oropharyngeal symptoms (47%), the parietal operculum produced somatosensory effects (67%), while the temporal evoked auditory (58%) semiology. The connectivity pattern was complex, with these structures having widespread ipsilateral and contralateral projections. The local connections between the opercular subregions and with the insula, as well as with more distant areas like the cingulate gyrus, were distinguished by strength and between-subjects consistency.In conclusion, we demonstrate specific opercular functionality, distinct from the one of the insular cortex. The study is complemented by a literature review on the opercular functional connectome in human and non-human primates.

Phase-Locked Stimulation during Cortical Beta Oscillations Produces Bidirectional Synaptic Plasticity in Awake Monkeys

The functional role of cortical beta oscillations, if any, remains unresolved. During oscillations, the periodic fluctuation in excitability of entrained cells modulates transmission of neural impulses and periodically enhances synaptic interactions. The extent to which oscillatory episodes affect activity-dependent synaptic plasticity remains to be determined. In nonhuman primates, we delivered single-pulse electrical cortical stimulation to a "stimulated" site in sensorimotor cortex triggered on a specific phase of ongoing beta (12-25Hz) field potential oscillations recorded at a separate "triggering" site. Corticocortical connectivity from the stimulated to the triggering site as well as to other (non-triggering) sites was assessed by cortically evoked potentials elicited by test stimuli to the stimulated site, delivered outside of oscillatory episodes. In separate experiments, connectivity was assessed by intracellular recordings of evoked excitatory postsynaptic potentials. The conditioning paradigm produced transient (1-2s long) changes in connectivity between the stimulated and the triggering site that outlasted the duration of the oscillatory episodes. The direction of the plasticity effect depended on the phase from which stimulation was triggered: potentiation in depolarizing phases, depression in hyperpolarizing phases. Plasticity effects were also seen at non-triggering sites that exhibited oscillations synchronized with those at the triggering site. These findings indicate that cortical beta oscillations provide a spatial and temporal substrate for short-term, activity-dependent synaptic plasticity in primate neocortex and may help explain the role of oscillations in attention, learning, and cortical reorganization.

Evoked directional network characteristics of epileptogenic tissue derived from single pulse electrical stimulation.

We investigated effective networks constructed from single pulse electrical stimulation (SPES) in epilepsy patients who underwent intracranial electrocorticography. Using graph analysis, we compared network characteristics of tissue within and outside the epileptogenic area. In 21 patients with subdural electrode grids (1 cm interelectrode distance), we constructed a binary, directional network derived from SPES early responses (<100 ms). We calculated in‐degree, out‐degree, betweenness centrality, the percentage of bidirectional, receiving and activating connections, and the percentage of connections toward the (non‐)epileptogenic tissue for each node in the network. We analyzed whether these network measures were significantly different in seizure onset zone (SOZ)‐electrodes compared to non‐SOZ electrodes, in resected area (RA)‐electrodes compared to non‐RA electrodes, and in seizure free compared to not seizure‐free patients. Electrodes in the SOZ/RA showed significantly higher values for in‐degree and out‐degree, both at group level, and at patient level, and more so in seizure‐free patients. These differences were not observed for betweenness centrality. There were also more bidirectional and fewer receiving connections in the SOZ/RA in seizure‐free patients. It appears that the SOZ/RA is densely connected with itself, with only little input arriving from non‐SOZ/non‐RA electrodes. These results suggest that meso‐scale effective network measures are different in epileptogenic compared to normal brain tissue. Local connections within the SOZ/RA are increased and the SOZ/RA is relatively isolated from the surrounding cortex. This offers the prospect of enhanced prediction of epilepsy‐prone brain areas using SPES.

Delayed high-frequency suppression after automated single-pulse electrical stimulation identifies the seizure onset zone in patients with refractory epilepsy

ObjectiveSingle-pulse electrical stimulation (SPES) of intracranial electrodes evokes responses that may help identify the seizure onset zone (SOZ); however, lack of automation and response variability has limited clinical adoption of this technique. We evaluated whether automated delivery of low-current SPES could evoke delayed high-frequency suppression (DHFS) of ongoing electrocorticography (ECoG) signals that, when combined with objective analytic techniques, may provide a reliable marker of this zone. MethodsLow-current SPES (1-ms, 3.5-mA biphasic pulses) was delivered to 652 electrodes across 10 patients undergoing ECoG for seizure focus localization. DHFS was measured by calculating the normalized trial-averaged time-frequency power (70–250 Hz) 0.4–1 sec post-stimulation. Electrodes that evoked suppression when stimulated or recorded suppression when stimulation was nearby were used to estimate the SOZ. ResultsThe estimated SOZ significantly identified the clinical SOZ in 6 of 10 patients (5 of 7 temporal foci) with a false-positive rate of 0–0.06. Stimulation required <2 h, was undetectable by patients, and did not induce seizures or after-discharges. ConclusionsWe show that DHFS provides accurate estimates of the clinical SOZ in patients with refractory epilepsy. SignificanceThis approach may increase the safety, speed, and reproducibility of SOZ identification while reducing cost, subjectivity, and patient discomfort.

Characterizing EEG Cortical Dynamics and Connectivity with Responses to Single Pulse Electrical Stimulation (SPES).

To model cortical connections in order to characterize their oscillatory behavior and role in the generation of spontaneous electroencephalogram (EEG). We studied averaged responses to single pulse electrical stimulation (SPES) from the non-epileptogenic hemisphere of five patients assessed with intracranial EEG who became seizure free after contralateral temporal lobectomy. Second-order control system equations were modified to characterize the systems generating a given response. SPES responses were modeled as responses to a unit step input. EEG power spectrum was calculated on the 20[Formula: see text]s preceding SPES. 121 channels showed responses to 32 stimulation sites. A single system could model the response in 41.3% and two systems were required in 58.7%. Peaks in the frequency response of the models tended to occur within the frequency range of most activity on the spontaneous EEG. Discrepancies were noted between activity predicted by models and activity recorded in the spontaneous EEG. These discrepancies could be explained by the existence of alpha rhythm or interictal epileptiform discharges. Cortical interactions shown by SPES can be described as control systems which can predict cortical oscillatory behavior. The method is unique as it describes connectivity as well as dynamic interactions.

Electrical stimulation of the midbrain excites the auditory cortex asymmetrically

BackgroundAuditory midbrain implant users cannot achieve open speech perception and have limited frequency resolution. It remains unclear whether the spread of excitation contributes to this issue and how much it can be compensated by current-focusing, which is an effective approach in cochlear implants. ObjectiveThe present study examined the spread of excitation in the cortex elicited by electric midbrain stimulation. We further tested whether current-focusing via bipolar and tripolar stimulation is effective with electric midbrain stimulation and whether these modes hold any advantage over monopolar stimulation also in conditions when the stimulation electrodes are in direct contact with the target tissue. MethodsUsing penetrating multielectrode arrays, we recorded cortical population responses to single pulse electric midbrain stimulation in 10 ketamine/xylazine anesthetized mice. We compared monopolar, bipolar, and tripolar stimulation configurations with regard to the spread of excitation and the characteristic frequency difference between the stimulation/recording electrodes. ResultsThe cortical responses were distributed asymmetrically around the characteristic frequency of the stimulated midbrain region with a strong activation in regions tuned up to one octave higher. We found no significant differences between monopolar, bipolar, and tripolar stimulation in threshold, evoked firing rate, or dynamic range. ConclusionThe cortical responses to electric midbrain stimulation are biased towards higher tonotopic frequencies. Current-focusing is not effective in direct contact electrical stimulation. Electrode maps should account for the asymmetrical spread of excitation when fitting auditory midbrain implants by shifting the frequency-bands downward and stimulating as dorsally as possible.

T103. The connectivity index: A novel metric to grade epileptogenicity

To investigate the performance of a metric of functional connectivity to classify and grade excitable brain regions based on cortical-evoked potentials to single pulse electrical stimulation (SPES) compared to non-epileptic sites. Patients who received 1-Hz frequency stimulation in 2003–2014 at Yale, were included. The stimulated contacts were classified as seizure onset zone (SOZ), irritative zone (IZ, frequent or periodic spiking, and early ictal propagation within 5 s of seizure onset) or control. Stimulation intensities ranged 9–12 mA (or lower if not tolerated or if auras were triggered) and pulse width of 250–300 μs. Evoked responses were reproduced at least once and averaged from 45–110 single pulse stimulations. Response contacts were classified as seizure onset zone (SOZ), active interictal (IZ), quiet or other when data did not indicate whether a contact was involved in an epileptic activity or not. The normalized number of responses was defined as the number of contacts with any evoked responses divided by the total number of contacts, and the normalized distance is the ratio of the average distances between the site of stimulation and sites of evoked responses to all other recording contacts. A new metric we labeled the connectivity index (Ci) is defined as the product of the two values. Fifty-seven stimulation sessions in 22 patients were analyzed. Stimulation of SOZ contacts evoked cortical potentials at significantly higher rates than control sites (medians 0.72 vs. 0.26, respectively p 0.0003). These differences were even stronger when normalized to the average distance of recorded responses from the stimulation site i.e. metric we labeled connectivity index Ci (median 0.74 vs. 0.16, respectively, p 0.0002). The evoked cortical potentials after stimulation of SOZ were seen at a further distance from the site of stimulation (median of normalized distance 0.96 vs. 0.62, p 0.0005). It was 1.8 times more likely to record an evoked response from the SOZ than non-epileptic contacts after stimulation of a remote-control site. Habitual partial seizures or auras were triggered in 27% of the patients and 35% of the SOZ contacts that were stimulated (median stimulation intensity 4 mA) but in none of the control or IZ contacts. Non-SOZ contacts in multifocal or poor surgical outcome cases had a higher (Ci) than those in localizable onsets (medians Ci of 0.5 vs. 0.12, p 0.04). There was a correlation between the stimulation current intensity and the normalized number of evoked responses (r = + 0.49, p 0.01) but not with distance (r = + 0.1, p 0.64). The SOZ has an enhanced connectivity with more distant sites compared to non-epileptic contacts. The responses evoked by stimulation of the SOZ have longer average latencies and durations. Auras and seizures provoked by SPES are predictive of brain sites involved in seizure generation. There was a correlation between the Ci of non-SOZ contacts and the duration of epilepsy.

F154. Machine learning for the analysis of single pulse stimulation in electrocorticography

In patients with drug-resistant focal epilepsy, surgery can be considered. The goal is to remove the epileptogenic tissue, while sparing the eloquent cortex. Prior to surgery, a prolonged electroencephalography (ECoG) recording can assist in the delineation of epileptogenic tissue and functionality of the surrounding cortex. During these recordings, Single Pulse Electrical Stimulation (SPES) of the intra-cranial electrodes is performed to evoke pathological responses from the epileptogenic tissue, which occur >100 ms after stimulation. These responses are called delayed responses (DR). In the UMC Utrecht, they are visually analyzed by use of time-frequency images from approximately 2 s. around stimulation. Each image is scored by two human observers on the presence of an evoked DR in three different frequency bands, namely Spikes (S, 10–80 Hz), Ripples (R, 80–250 Hz) and Fast Ripples (F, 250–510 Hz). This visual analysis is very labor intensive. Therefore, we trained a Support Vector Machine (SVM) and a Convolutional Neural Network (CNN) to mimic the human observer in scoring the images. The training data consisted of 47,197 images from 15 patients, with the consensus of two human observers as ground truth. The algorithms were tested on a total of 11,394 images from 4 other patients. For the SVM, 9 features were defined and extracted from each image. The CNN used the whole image as an input. Classification was based on 5 different outputs. F1 scores were calculated for all classes separately. The CNN achieved an average F1 score of 0.55. The SVM did slightly better with 0.60. Sensitivity and precision for the DRs were 0.88 and 0.65 for the SVM vs 0.96 and 0.42 for the CNN. Two machine learning algorithms were trained to score time-frequency responses of SPES. Both models showed a high sensitivity but a lower specificity for DRs. This was more pronounced for the CNN than for the SVM. Nonetheless, a drastical decrease in time and effort needed for the analysis of SPES is already achieved. More data of the underrepresented classes should be created for the algorithms to improve. The algorithms will be applied to additional patient data to see whether the agreement with human observers is comparable with the inter-rater agreement. Future research will aim at relating the found DRs to the seizure onset zone.

S128. Oscillatory responses evoked by single-pulse electrical stimulation in human cerebral cortex – A Cortico-Cortical Evoked Potential (CCEP) study

Introduction Human brain operates with oscillatory activity in different frequency bands. For example, mu rhythm is well known as an idling rhythm observed in the central area related to motor function. We observed some rhythmic pattern in the averaged waveforms in the CCEP investigation (called “oscillatory response” here), which is originally a method to trace connectivity by single electrical pulse stimulation. We report on the frequency and distribution of the oscillatory responses in CCEP. Methods Subjects are 5 intractable epilepsy patients who underwent chronic implantation of subdural electrodes for presurgical evaluation. Written informed consents were obtained from all subjects. Single-pulse stimuli (0.3 ms, 8–10 mA, alternating polarity, 30 × 2 trials) were applied through two adjacent electrodes (52.8 ± 15.3 stimulus sites per patient). CCEP was recorded from subdural electrodes (105.2 ± 31.8 electrodes per patient) placed on the lateral and medial aspect of the cerebral hemisphere. Lateral fronto-parietal area was covered in all subjects. An oscillatory response in CCEP was detected by visual inspection on the averaged waveform according to the following criteria; (1) it has at least two pairs of peak and trough spaced equally, (2) it can be overlapped with other evoked responses (typical N1/ N2 response). If more than one rhythms with different frequencies were observed in the same electrode, we counted the largest one in amplitude. Results Totally, 2362 oscillatory responses (7.9%) were detected in 29891 observations in 5 subjects, including 443 alpha-band responses (7.5–13.5 Hz), 312 beta-band responses (13.5–30 Hz) and 1505 theta-band responses (3.5–7.5 Hz). Theta rhythm was observed predominantly in the temporal lobe including the basal temporal area (the occurrence rate was 12.45%). Alpha rhythm was observed more often in the parietal lobe including the postcentral gyrus (the occurrence rate was 4.57%), while beta rhythm was often observed around precentral gyrus (the occurrence rate was 1.98%). The frequency of the resting rhythmic activity was equal to that of oscillatory CCEP response in the alpha band in the postcentral gyrus in all subjects. This alpha activity was considered as mu rhythm in all the 3 subjects who performed a hand grasping task. Conclusion Single pulse electrical stimulation evoked oscillatory CCEP responses preferentially in the temporal lobe and the perirolandic area. The correspondence of frequency between the oscillatory response and mu rhythm implies the phase resetting of the physiological oscillation by exogenous input. This unique oscillatory CCEP may help to map these functionally important cortical regions.

Cortical Responses to Input From Distant Areas are Modulated by Local Spontaneous Alpha/Beta Oscillations.

Any given area in human cortex may receive input from multiple, functionally heterogeneous areas, potentially representing different processing threads. Alpha (8-13 Hz) and beta oscillations (13-20 Hz) have been hypothesized by other investigators to gate local cortical processing, but their influence on cortical responses to input from other cortical areas is unknown. To study this, we measured the effect of local oscillatory power and phase on cortical responses elicited by single-pulse electrical stimulation (SPES) at distant cortical sites, in awake human subjects implanted with intracranial electrodes for epilepsy surgery. In 4 out of 5 subjects, the amplitudes of corticocortical evoked potentials (CCEPs) elicited by distant SPES were reproducibly modulated by the power, but not the phase, of local oscillations in alpha and beta frequencies. Specifically, CCEP amplitudes were higher when average oscillatory power just before distant SPES (-110 to -10 ms) was high. This effect was observed in only a subset (0-33%) of sites with CCEPs and, like the CCEPs themselves, varied with stimulation at different distant sites. Our results suggest that although alpha and beta oscillations may gate local processing, they may also enhance the responsiveness of cortex to input from distant cortical sites.

Exploring the consequences of social defeat stress and intermittent ethanol drinking on dopamine dynamics in the rat nucleus accumbens

The current study aimed to explore how presynaptic dopamine (DA) function is altered following brief stress episodes and chronic ethanol self-administration and whether these neuroadaptations modify the acute effects of ethanol on DA dynamics. We used fast-scan cyclic voltammetry to evaluate changes in DA release and uptake parameters in rat nucleus accumbens brain slices by analyzing DA transients evoked through single pulse electrical stimulation. Adult male rats were divided into four groups: ethanol-naïve or ethanol drinking (six week intermittent two-bottle choice) and stressed (mild social defeat) or nonstressed. Results revealed that the mild stress significantly increased DA release and uptake in ethanol-naïve subjects, compared to nonstressed controls. Chronic ethanol self-administration increased the DA uptake rate and occluded the effects of stress on DA release dynamics. Bath-applied ethanol decreased stimulated DA efflux in a concentration-dependent manner in all groups; however, the magnitude of this effect was blunted by either stress or chronic ethanol, or by a combination of both procedures. Together, these findings suggest that stress and ethanol drinking may promote similar adaptive changes in accumbal presynaptic DA release measures and that these changes may contribute to the escalation in ethanol intake that occurs during the development of alcohol use disorder.

Structural and effective connectivity in focal epilepsy.

Patients with medically-refractory focal epilepsy may be candidates for neurosurgery and some may require placement of intracranial EEG electrodes to localise seizure onset. Assessing cerebral responses to single pulse electrical stimulation (SPES) may give diagnostically useful data. SPES produces cortico-cortical evoked potentials (CCEPs), which infer effective brain connectivity. Diffusion-weighted images and tractography may be used to estimate structural brain connectivity. This combination provides the opportunity to observe seizure onset and its propagation throughout the brain, spreading contiguously along the cortex explored with electrodes, or non-contiguously. We analysed CCEPs and diffusion tractography in seven focal epilepsy patients and reconstructed the effective and structural brain networks. We aimed to assess the inter-modal similarity of the networks at a large scale across the cortex, the effective and structural connectivity of the ictal-onset zone, and investigate potential mechanisms of non-contiguous seizure spread. We found a significant overlap between structural and effective networks. Effective network CCEP amplitude, baseline variation, and outward connectivity was higher at ictal-onset zones, while structural connection strength within the ictal-onset zone tended to be higher. These findings support the concept of hyperexcitable cortex being associated with seizure generation. The high prevalence of structural and effective connections from the ictal-onset zone to sites of non-contiguous spread suggests that macroscopic structural and effective connections are plausible routes for non-contiguous seizure spread.

The Hippocampus and Amygdala Are Integrators of Neocortical Influence: A CorticoCortical Evoked Potential Study

Brain stimulation is increasingly viewed as an effective approach to treat neuropsychiatric disease. The brain's organization in distributed networks suggests that the activity of a remote brain structure could be modulated by stimulating cortical areas that strongly connect to the target. Most connections between cerebral areas are asymmetric, and a better understanding of the relative direction of information flow along connections could improve the targeting of stimulation to influence deep brain structures. The hippocampus and amygdala, two deep-situated structures that are crucial to memory and emotions, respectively, have been implicated in multiple neurological and psychiatric disorders. We explored the directed connectivity between the hippocampus and amygdala and the cerebral cortex in patients implanted with intracranial electrodes using corticocortical evoked potentials (CCEPs) evoked by single-pulse electrical stimulation. The hippocampus and amygdala were connected with most of the cortical mantle, either directly or indirectly, with the inferior temporal cortex being most directly connected. Because CCEPs assess the directionality of connections, we could determine that incoming connections from cortex to hippocampus were more direct than outgoing connections from hippocampus to cortex. We found a similar, although smaller, tendency for connections between the amygdala and cortex. Our results support the roles of the hippocampus and amygdala to be integrators of widespread cortical influence. These results can inform the targeting of noninvasive neurostimulation to influence hippocampus and amygdala function.

Closed-loop interaction with the cerebral cortex using a novel micro-ECoG-based implant: the impact of beta vs. gamma stimulation frequencies on cortico-cortical spectral responses

Medical brain implants for closed-loop interaction with the cerebral cortex promise new treatment options for brain disorders, and thus great efforts are being made to develop devices for long-term application. Closed-loop interaction can be implemented using electrophysiological recording techniques, and can be used to modulate local cortical activity or long-range functional connectivity. In a case study performed in sheep chronically implanted with a novel micro-electrocorticography-based device, we show that (1) open-loop single-pulse electrical stimulation (SPES) elicited the well-known cortico-cortical evoked potentials (CCEPs), and (2) closed-loop repetitive-pulse electrical stimulation (RPES) elicited specific cortico-cortical spectral responses (CCSRs). CCSRs were spatially focalized in the gamma band, compared with beta band independent of RPES frequency. The topography of CCSRs was different compared with CCEPs, suggesting that CCEPs and CCSRs capture different aspects of cortico-cortical connectivity. We propose that CCSRs provide new useful measures of functional connectivity, and that in particular gamma-band CCSRs may be an optimal choice if spatially precise closed-loop interaction is desired. However, the parameter space of micro-electrocorticography stimulation patterns and associated changes in μECoG frequency bands needs to be further explored and many questions remain before closed-loop brain implants can be used in clinical applications.

Safety of single-pulse electrical stimulation for cortico-cortical evoked potentials in epileptic human cerebral cortex

Safety of single-pulse electrical stimulation for cortico-cortical evoked potentials in epileptic human cerebral cortex

P241 Insula connectivity during wakefulness and sleep studied through single pulse electrical stimulation during seeg recordings

Objective We aim to study the connections of the posterior insula (pI) and anterior insula (aI) through cortico-cortical evoked potentials (CCEP) by single pulse electrical stimulation (SPES). Method We performed SPES stimulation protocol in a group of 8 refractory epilepsy patients presurgically explored with intracerebral depth electrodes, out of which 6 were operated on and are currently seizure-free. We selected the early responses (ER) obtained from contacts of 24 electrodes that were included in the anterior and posterior insula, when this structure was outside the seizure onset zone (SOZ). Responses were analyzed in terms of amplitude variations during wakefulness and sleep. Effective connectivity betweeen cortical was calculated based on the measured CCEPs. Results The ER amplitudes by SPES stimulation in the insula during wakefulness compared to sleep showed statistically significant ( p 0.05 ) differences in 6 patients. There are constant connections between aI and pI. We identified connectivity of the pI with language-related brain stuctures during wakefulness, and with the temporal mesial structures during sleep, possibly influenced by the SOZ. Right pI stimulation seems to elicit ampler reponses in the rolandic operculum and parietal structures during wakefulness, and in the primary motor and premotor cortex during sleep. Anterior insula has preferential connectivity with anterior cingulate gyrus during wakefulness and with the fusiform gyrus during sleep. Discussions Connectivity of the aI versus pI, as well as right versus left insula during wakefulness and sleep is different, partially supporting previous observations. Conclusion Sleep has been shown to alter the physiological connectivity of the insula. Further investigations are in progress to confirm these results. Significance These findings describe insular connectivity and variability during sleep, with possible implications in epilepsy surgery, sleep disorders understanding and language studies.