Simulated resections and RNS placement can optimize post-operative seizure outcomes when guided by fast ripple networks.

In medication-resistant epilepsy, the objective of epilepsy surgery is to render a patient seizure free with a resection/ablation that is as small as possible to minimize morbidity. The standard of care in planning the margins of epilepsy surgery involves electroclinical delineation of the seizure onset zone (SOZ) in the epilepsy monitoring unit (EMU) by an expert epileptologist, and incorporation of neuroimaging findings from MRI, PET, SPECT, and MEG modalities. Resecting cortical tissue generating high-frequency oscillations (HFOs) has been investigated as a more efficacious alternative to targeting the SOZ. In this study, we used support vector machines (SVMs) to compare the resection volumes of actual resections, defined using the clinical standard of care, with virtual resections of fast ripple (FR 350-600 Hz) networks. Cross-validation of the SVM that labeled patients as seizure free or not seizure free using FR metrics as factors demonstrated an accuracy of 0.78. In all the patients rendered seizure free after surgery, we found that the virtual resection, defined using FR generator sites with highest rate and greatest autonomy, was larger than the actual resection. In the patients who experienced seizures after the actual resection, a virtual resection that included the SOZ and other FR generating regions rendered half of these patients virtually seizure free. We also examined patients implanted with the responsive neurostimulator system (RNS) and virtually targeted the RNS stimulation contacts proximal to sites generating FR. We used the simulations to investigate if the likelihood of a RNS super response (>90% seizure reduction) would be increased.

MTL neurons phase-lock to human hippocampal theta.

Memory formation depends on neural activity across a network of regions, including the hippocampus and broader medial temporal lobe (MTL). Interactions between these regions have been studied indirectly using functional MRI, but the bases for interregional communication at a cellular level remain poorly understood. Here, we evaluate the hypothesis that oscillatory currents in the hippocampus synchronize the firing of neurons both within and outside the hippocampus. We recorded extracellular spikes from 1854 single- and multi-units simultaneously with hippocampal local field potentials (LFPs) in 28 neurosurgical patients who completed virtual navigation experiments. A majority of hippocampal neurons phase-locked to oscillations in the slow (2-4 Hz) or fast (6-10 Hz) theta bands, with a significant subset exhibiting nested slow theta × beta frequency (13-20 Hz) phase-locking. Outside of the hippocampus, phase-locking to hippocampal oscillations occurred only at theta frequencies and primarily among neurons in the entorhinal cortex and amygdala. Moreover, extrahippocampal neurons phase-locked to hippocampal theta even when theta did not appear locally. These results indicate that spike-time synchronization with hippocampal theta is a defining feature of neuronal activity in the hippocampus and structurally connected MTL regions. Theta phase-locking could mediate flexible communication with the hippocampus to influence the content and quality of memories.

A visual paired associate learning (vPAL) paradigm to study memory consolidation during sleep.

Sleep improves the consolidation and long-term stability of newly formed memories and associations. Most research on human declarative memory and its consolidation during sleep uses word-pair associations requiring exhaustive learning. In the present study, we present the visual paired association learning (vPAL) paradigm, in which participants learn new associations between images of celebrities and animals. The vPAL is based on a one-shot exposure that resembles learning in natural conditions. We tested if vPAL can reveal a role for sleep in memory consolidation by assessing the specificity of memory recognition, and the cued recall performance, before and after sleep. We found that a daytime nap improved the stability of recognition memory and discrimination abilities compared to identical intervals of wakefulness. By contrast, cued recall of associations did not exhibit significant sleep-dependent effects. High-density electroencephalography during naps further revealed an association between sleep spindle density and stability of recognition memory. Thus, the vPAL paradigm opens new avenues for future research on sleep and memory consolidation across ages and heterogeneous populations in health and disease.

Pathological neurons generate ripples at the UP-DOWN transition disrupting information transfer.

OBJECTIVE: To confirm and investigate why pathological high-frequency oscillations (pHFOs), including ripples (80-200 Hz) and fast ripples (200-600 Hz), are generated during the UP-DOWN transition of the slow wave and if information transmission mediated by ripple temporal coupling is disrupted in the seizure-onset zone (SOZ). METHODS: We isolated 217 total units from 175.95 intracranial electroencephalography (iEEG) contact-hours of synchronized macro- and microelectrode recordings from 6 patients. Sleep slow oscillation (.1-2 Hz) epochs were identified in the iEEG recording. iEEG HFOs that occurred superimposed on the slow wave were transformed to phasors and adjusted by the phase of maximum firing in nearby units (i.e., maximum UP). We tested whether, in the SOZ, HFOs and associated action potentials (APs) occur more often at the UP-DOWN transition. We also examined ripple temporal correlations using cross-correlograms. RESULTS: At the group level in the SOZ, HFO and HFO-associated AP probability was highest during the UP-DOWN transition of slow wave excitability (p < < .001). In the non-SOZ, HFO and HFO-associated AP was highest during the DOWN-UP transition (p < < .001). At the unit level in the SOZ, 15.6% and 20% of units exhibited more robust firing during ripples (Cohen's d = .11-.83) and fast ripples (d = .36-.90) at the UP-DOWN transition (p < .05 f.d.r. corrected), respectively. By comparison, also in the SOZ, 6.6% (d = .14-.30) and 8.5% (d = .33-.41) of units had significantly less firing during ripples and fast ripples at the UP-DOWN transition, respectively. Additional data shows that ripple and fast ripple temporal correlations, involving global slow waves, between the hippocampus, entorhinal cortex, and parahippocampal gyrus were reduced by >50% in the SOZ compared to the non-SOZ (N = 3). SIGNIFICANCE: The UP-DOWN transition of slow wave excitability facilitates the activation of pathological neurons to generate pHFOs. Ripple temporal correlations across brain regions may be important in memory consolidation and are disrupted in the SOZ, perhaps by pHFO generation.

Subthalamic nucleus physiology is correlated with deep brain stimulation motor and non-motor outcomes.

Subthalamic nucleus deep brain stimulation is commonly indicated for symptomatic relief of idiopathic Parkinson's disease. Despite the known improvement in motor scores, affective, cognitive, voice and speech functions might deteriorate following this procedure. Recent studies have correlated motor outcomes with intraoperative microelectrode recordings. However, there are no microelectrode recording-based tools with predictive values relating to long-term outcomes of integrative motor and non-motor symptoms. We conducted a retrospective analysis of the outcomes of patients with idiopathic Parkinson's disease who had subthalamic nucleus deep brain stimulation at Tel Aviv Sourasky Medical Centre (Tel Aviv, Israel) during 2015-2016. Forty-eight patients (19 women, 29 men; mean age, 58 ± 8 years) who were implanted with a subthalamic nucleus deep brain stimulation device underwent pre- and postsurgical assessments of motor, neuropsychological, voice and speech symptoms. Significant improvements in all motor symptoms (except axial signs) and levodopa equivalent daily dose were noted in all patients. Mild improvements were observed in more posterior-related neuropsychological functions (verbal memory, visual memory and organization) while mild deterioration was observed in frontal functions (personality changes, executive functioning and verbal fluency). The concomitant decline in speech intelligibility was mild and only partial, probably in accordance with the neuropsychological verbal fluency results. Acoustic characteristics were the least affected and remained within normal values. Dimensionality reduction of motor, neuropsychological and voice scores rendered six principal components that reflect the main clinical aspects: the tremor-dominant versus the rigidity-bradykinesia-dominant motor symptoms, frontal versus posterior neuropsychological deficits and acoustic characteristics versus speech intelligibility abnormalities. Microelectrode recordings of subthalamic nucleus spiking activity were analysed off-line and correlated with the original scores and with the principal component results. Based on 198 microelectrode recording trajectories, we suggest an intraoperative subthalamic nucleus deep brain stimulation score, which is a simple sum of three microelectrode recording properties: normalized neuronal activity, the subthalamic nucleus width and the relative proportion of the subthalamic nucleus dorsolateral oscillatory region. A threshold subthalamic nucleus deep brain stimulation score >2.5 (preferentially composed of normalized root mean square >1.5, subthalamic nucleus width >3 mm and a dorsolateral oscillatory region/subthalamic nucleus width ratio >1/3) predicts better motor and non-motor long-term outcomes. The algorithm presented here optimizes intraoperative decision-making of deep brain stimulation contact localization based on microelectrode recording with the aim of improving long-term (>1 year) motor, neuropsychological and voice symptoms.

High-rate leading spikes in propagating spike sequences predict seizure outcome in surgical patients with temporal lobe epilepsy.

Inter-ictal spikes aid in the diagnosis of epilepsy and in planning surgery of medication-resistant epilepsy. However, the localizing information from spikes can be unreliable because spikes can propagate, and the burden of spikes, often assessed as a rate, does not always correlate with the seizure onset zone or seizure outcome. Recent work indicates identifying where spikes regularly emerge and spread could localize the seizure network. Thus, the current study sought to better understand where and how rates of single and coupled spikes, and especially brain regions with high-rate and leading spike of a propagating sequence, informs the extent of the seizure network. In 37 patients with medication-resistant temporal lobe seizures, who had surgery to treat their seizure disorder, an algorithm detected spikes in the pre-surgical depth inter-ictal EEG. A separate algorithm detected spike propagation sequences and identified the location of leading and downstream spikes in each sequence. We analysed the rate and power of single spikes on each electrode and coupled spikes between pairs of electrodes, and the proportion of sites with high-rate, leading spikes in relation to the seizure onset zone of patients seizure free (n = 19) and those with continuing seizures (n = 18). We found increased rates of single spikes in mesial temporal seizure onset zone (ANOVA, P < 0.001, η2 = 0.138), and increased rates of coupled spikes within, but not between, mesial-, lateral- and extra-temporal seizure onset zone of patients with continuing seizures (P < 0.001; η2 = 0.195, 0.113 and 0.102, respectively). In these same patients, there was a higher proportion of brain regions with high-rate leaders, and each sequence contained a greater number of spikes that propagated with a higher efficiency over a longer distance outside the seizure onset zone than patients seizure free (Wilcoxon, P = 0.0172). The proportion of high-rate leaders in and outside the seizure onset zone could predict seizure outcome with area under curve = 0.699, but not rates of single or coupled spikes (0.514 and 0.566). Rates of coupled spikes to a greater extent than single spikes localize the seizure onset zone and provide evidence for inter-ictal functional segregation, which could be an adaptation to avert seizures. Spike rates, however, have little value in predicting seizure outcome. High-rate spike sites leading propagation could represent sources of spikes that are important components of an efficient seizure network beyond the clinical seizure onset zone, and like the seizure onset zone these, too, need to be removed, disconnected or stimulated to increase the likelihood for seizure control.

Dynamic neural representations of memory and space during human ambulatory navigation.

Our ability to recall memories of personal experiences is an essential part of daily life. These episodic memories often involve movement through space and thus require continuous encoding of one's position relative to the surrounding environment. The medial temporal lobe (MTL) is thought to be critically involved, based on studies in freely moving rodents and stationary humans. However, it remains unclear if and how the MTL represents both space and memory especially during physical navigation, given challenges associated with deep brain recordings in humans during movement. We recorded intracranial electroencephalographic (iEEG) activity while participants completed an ambulatory spatial memory task within an immersive virtual reality environment. MTL theta activity was modulated by successful memory retrieval or spatial positions within the environment, depending on dynamically changing behavioral goals. Altogether, these results demonstrate how human MTL oscillations can represent both memory and space in a temporally flexible manner during freely moving navigation.

Fast ripples reflect increased excitability that primes epileptiform spikes.

The neuronal circuit disturbances that drive inter-ictal and ictal epileptiform discharges remain elusive. Using a combination of extra-operative macro-electrode and micro-electrode inter-ictal recordings in six pre-surgical patients during non-rapid eye movement sleep, we found that, exclusively in the seizure onset zone, fast ripples (200-600 Hz), but not ripples (80-200 Hz), frequently occur <300 ms before an inter-ictal intra-cranial EEG spike with a probability exceeding chance (bootstrapping, P < 1e-5). Such fast ripple events are associated with higher spectral power (P < 1e-10) and correlated with more vigorous neuronal firing than solitary fast ripple (generalized linear mixed-effects model, P < 1e-9). During the intra-cranial EEG spike that follows a fast ripple, action potential firing is lower than during an intra-cranial EEG spike alone (generalized linear mixed-effects model, P < 0.05), reflecting an inhibitory restraint of intra-cranial EEG spike initiation. In contrast, ripples do not appear to prime epileptiform spikes. We next investigated the clinical significance of pre-spike fast ripple in a separate cohort of 23 patients implanted with stereo EEG electrodes, who underwent resections. In non-rapid eye movement sleep recordings, sites containing a high proportion of fast ripple preceding intra-cranial EEG spikes correlate with brain areas where seizures begin more than solitary fast ripple (P < 1e-5). Despite this correlation, removal of these sites does not guarantee seizure freedom. These results are consistent with the hypothesis that fast ripple preceding EEG spikes reflect an increase in local excitability that primes EEG spike discharges preferentially in the seizure onset zone and that epileptogenic brain regions are necessary, but not sufficient, for initiating inter-ictal epileptiform discharges.

Minute-scale periodicity of neuronal firing in the human entorhinal cortex.

Grid cells in the entorhinal cortex demonstrate spatially periodic firing, thought to provide a spatial map on behaviorally relevant length scales. Whether such periodicity exists for behaviorally relevant time scales in the human brain remains unclear. We investigate neuronal firing during a temporally continuous experience by presenting 14 neurosurgical patients with a video while recording neuronal activity from multiple brain regions. We report on neurons that modulate their activity in a periodic manner across different time scales-from seconds to many minutes, most prevalently in the entorhinal cortex. These neurons remap their dominant periodicity to shorter time scales during a subsequent recognition memory task. When the video is presented at two different speeds, a significant percentage of these temporally periodic cells (TPCs) maintain their time scales, suggesting a degree of invariance. The TPCs' temporal periodicity might complement the spatial periodicity of grid cells and together provide scalable spatiotemporal metrics for human experience.

A neural code for time and space in the human brain.

Time and space are primary dimensions of human experience. Separate lines of investigation have identified neural correlates of time and space, yet little is known about how these representations converge during self-guided experience. Here, 10 subjects with intracranially implanted microelectrodes play a timed, virtual navigation game featuring object search and retrieval tasks separated by fixed delays. Time cells and place cells activate in parallel during timed navigation intervals, whereas a separate time cell sequence spans inter-task delays. The prevalence, firing rates, and behavioral coding strengths of time cells and place cells are indistinguishable-yet time cells selectively remap between search and retrieval tasks, while place cell responses remain stable. Thus, the brain can represent time and space as overlapping but dissociable dimensions. Time cells and place cells may constitute a biological basis for the cognitive map of spatiotemporal context onto which memories are written.

Pathological neurons generate ripples at the UP-DOWN transition disrupting information transfer.

Objective: To confirm and investigate why pathological HFOs (pHFOs), including Ripples [80-200 Hz] and fast ripples [200-600 Hz], are generated during the UP-DOWN transition of the slow wave and if pHFOs interfere with information transmission. Methods: We isolated 217 total units from 175.95 iEEG contact-hours of synchronized macro- and microelectrode recordings from 6 patients. Sleep slow oscillation (0.1-2 Hz) epochs were identified in the iEEG recording. iEEG HFOs that occurred superimposed on the slow wave were transformed to phasors and adjusted by the phase of maximum firing in nearby units (i.e., maximum UP). We tested whether, in the seizure onset zone (SOZ), HFOs and associated action potentials (AP) occur more often at the UP-DOWN transition. We also examined ripple temporal correlations using cross correlograms. Results: At the group level in the SOZ, HFO and HFO-associated AP probability was highest during the UP-DOWN transition of slow wave excitability (p<<0.001). In the non-SOZ, HFO and HFO-associated AP was highest during the DOWN-UP transition (p<<0.001). At the unit level in the SOZ, 15.6% and 20% of units exhibited more robust firing during ripples (Cohen's d=0.11-0.83) and fast ripples (d=0.36-0.90) at the UP-DOWN transition (p<0.05 f.d.r corrected), respectively. By comparison, also in the SOZ, 6.6% (d=0.14-0.30) and 8.5% (d=0.33-0.41) of units had significantly less firing during ripples and fast ripples at the UP-DOWN transition, respectively. Additional data shows ripple temporal correlations, involving global slow waves, between the hippocampus, entorhinal cortex, and parahippocampal gyrus were reduced by ~50-80% in the SOZ compared to the non-SOZ (N=3). Significance: The UP-DOWN transition of slow wave excitability facilitates the activation of pathological neurons to generate pHFOs. The pathological neurons and pHFOs disrupt ripple temporal correlations across brain regions that transfer information and may be important in memory consolidation.

Consciousness: a neurosurgical perspective.

Neurosurgeons are in a unique position to shed light on the neural basis for consciousness, not only by their clinical care of patients with compromised states of consciousness, but also by employing neurostimulation and neuronal recordings through intracranial electrodes in awake surgical patients, as well as during stages of sleep and anethesia. In this review, we discuss several aspects of consciousness, i.e., perception, memory, and willed actions, studied by electrical stimulation and single neuron recordings in the human brain. We demonstrate how specific neuronal activity underlie the emergence of concepts, memories, and intentions in human consciousness. We discuss the representation of specific conscious content by temporal lobe neurons and present the discovery of "concept cells" and the encoding and retrieval of memories by neurons in the medial temporal lobe. We review prefrontal and parietal neuronal activation that precedes conscious intentions to act. Taken together with other studies in the field, these findings suggest that specific conscious experience may arise from stochastic fluctuations of neuronal activity, reaching a dynamic threshold. Advances in brain recording and stimulation technology coupled with the rapid rise in artificial intelligence are likely to increase the amount and analysis capabilities of data obtained from the human brain, thereby improving the decoding of conscious and preconscious states and open new horizons for modulation of human cognitive functions such as memory and volition.

Augmenting hippocampal-prefrontal neuronal synchrony during sleep enhances memory consolidation in humans.

Memory consolidation during sleep is thought to depend on the coordinated interplay between cortical slow waves, thalamocortical sleep spindles and hippocampal ripples, but direct evidence is lacking. Here, we implemented real-time closed-loop deep brain stimulation in human prefrontal cortex during sleep and tested its effects on sleep electrophysiology and on overnight consolidation of declarative memory. Synchronizing the stimulation to the active phases of endogenous slow waves in the medial temporal lobe (MTL) enhanced sleep spindles, boosted locking of brain-wide neural spiking activity to MTL slow waves, and improved coupling between MTL ripples and thalamocortical oscillations. Furthermore, synchronized stimulation enhanced the accuracy of recognition memory. By contrast, identical stimulation without this precise time-locking was not associated with, and sometimes even degraded, these electrophysiological and behavioral effects. Notably, individual changes in memory accuracy were highly correlated with electrophysiological effects. Our results indicate that hippocampo-thalamocortical synchronization during sleep causally supports human memory consolidation.

Neural evidence for advantaged representation of first items in memory.

Visual areas activated during perception can retain specific information held in memory without the presence of physical stimuli via distributed activity patterns. Neuroimaging studies have shown that the delay-period representation of information in visual areas is modulated by factors such as memory load and task demands, raising the possibility of serial position as another potential modulator. Specifically, enhanced representation of first items during the post-encoding delay period may serve as a mechanism underlying the well-established but not well-understood primacy effect - the mnemonic advantage of first items. To test this hypothesis, 13 males and 16 females performed a human fMRI task, wherein each trial consisted of the sequential encoding of two stimuli (a famous face and landscape, order counterbalanced), followed by a distracting task, a delay period, and then a cued recall of one of the items. Participants exhibited the expected behavioral primacy effect, manifested as faster recall of the first items. In order to elucidate the still debated neural underpinnings of this effect, using multivariate decoding, a classifier was trained on data collected during encoding to differentiate stimulus categories (i.e., faces vs. landscapes) and tested on data collected during the post-encoding period. Greater reactivation of first versus second items was observed in the ventral occipito-temporal cortex during the entire post-encoding period but not during encoding. Moreover, trial-level analyses revealed that the degree of first-item neural advantage during the post-encoding delay predicted the behavioral primacy effect. These findings highlight the role of item reinstatement in ventral occipito-temporal cortex in the primacy effect and are discussed in the context of the uniqueness of the very first item and event boundaries, illuminating putative neural mechanisms underlying the effect.

Outcome of stereo-electroencephalography with single-unit recording in drug-refractory epilepsy.

OBJECTIVE: The aim of this study was to evaluate the utility and safety of "hybrid" stereo-electroencephalography (SEEG) in guiding epilepsy surgery and in providing information at single-neuron levels (i.e., single-unit recording) to further the understanding of the mechanisms of epilepsy and the neurocognitive processes unique to humans. METHODS: The authors evaluated 218 consecutive patients undergoing SEEG procedures from 1993 through 2018 at a single academic medical center to assess the utility and safety of this technique in both guiding epilepsy surgery and providing single-unit recordings. The hybrid electrodes used in this study contained macrocontacts and microwires to simultaneously record intracranial EEG and single-unit activity (hybrid SEEG). The outcomes of SEEG-guided surgical interventions were examined, as well as the yield and scientific utility of single-unit recordings in 213 patients who participated in the research involving single-unit recordings. RESULTS: All patients underwent SEEG implantation by a single surgeon and subsequent video-EEG monitoring (mean of 10.2 electrodes per patient and 12.0 monitored days). Epilepsy networks were localized in 191 (87.6%) patients. Two clinically significant procedural complications (one hemorrhage and one infection) were noted. Of 130 patients who underwent subsequent focal epilepsy surgery with a minimum 12-month follow-up, 102 (78.5%) underwent resective surgery and 28 (21.5%) underwent closed-loop responsive neurostimulation (RNS) with or without resection. Seizure freedom was achieved in 65 (63.7%) patients in the resective group. In the RNS group, 21 (75.0%) patients achieved 50% or greater seizure reduction. When the initial period of 1993 through 2013 before responsive neurostimulator implantation in 2014 was compared with the subsequent period of 2014 through 2018, the proportion of SEEG patients undergoing focal epilepsy surgery grew from 57.9% to 79.7% due to the advent of RNS, despite a decline in focal resective surgery from 55.3% to 35.6%. A total of 18,680 microwires were implanted in 213 patients, resulting in numerous significant scientific findings. Recent recordings from 35 patients showed a yield of 1813 neurons, with a mean yield of 51.8 neurons per patient. CONCLUSIONS: Hybrid SEEG enables safe and effective localization of epileptogenic zones to guide epilepsy surgery and provides unique scientific opportunities to investigate neurons from various brain regions in conscious patients. This technique will be increasingly utilized due to the advent of RNS and may prove a useful approach to probe neuronal networks in other brain disorders.

Fast ripples reflect increased excitability that primes epileptiform spikes.

The neuronal circuit disturbances that drive interictal and ictal epileptiform discharges remains elusive. Using a combination of extraoperative macro- and micro-electrode interictal recordings in six presurgical patients during non-rapid eye movement (REM) sleep we found that, exclusively in the seizure onset zone, fast ripples (FR; 200-600Hz), but not ripples (80-200 Hz), frequently occur <300 msec before an interictal intracranial EEG (iEEG) spike with a probability exceeding chance (bootstrapping, p<1e-5). Such FR events are associated with higher spectral power (p<1e-10) and correlated with more vigorous neuronal firing than solitary FR (generalized linear mixed-effects model, GLMM, p<1e-3) irrespective of FR power. During the iEEG spike that follows a FR, action potential firing is lower than during a iEEG spike alone (GLMM, p<1e-10), reflecting an inhibitory restraint of iEEG spike initiation. In contrast, ripples do not appear to prime epileptiform spikes. We next investigated the clinical significance of pre-spike FR in a separate cohort of 23 patients implanted with stereo EEG electrodes who underwent resections. In non-REM sleep recordings, sites containing a high proportion of FR preceding iEEG spikes correlate with brain areas where seizures begin more than solitary FR (p<1e-5). Despite this correlation, removal of these sites does not guarantee seizure freedom. These results are consistent with the hypothesis that FR preceding EEG spikes reflect an increase in local excitability that primes EEG spike discharges preferentially in the seizure onset zone and that epileptogenic brain regions are necessary, but not sufficient, for initiating interictal epileptiform discharges.

Decoding human spontaneous spiking activity in medial temporal lobe from scalp EEG.

Linking scalp electroencephalography (EEG) signals and spontaneous firing activity from deep nuclei in humans is not trivial. To examine this, we analyzed simultaneous recordings of scalp EEG and unit activity in deeply located sites recorded overnight from patients undergoing pre-surgical invasive monitoring. We focused on modeling the within-subject average unit activity of two medial temporal lobe areas: amygdala and hippocampus. Linear regression model correlates the units' average firing activity to spectral features extracted from the EEG during wakefulness or non-REM sleep. We show that changes in mean firing activity in both areas and states can be estimated from EEG (Pearson r > 0.2, p≪0.001). Region specificity was shown with respect to other areas. Both short- and long-term fluctuations in firing rates contributed to the model accuracy. This demonstrates that scalp EEG frequency modulations can predict changes in neuronal firing rates, opening a new horizon for non-invasive neurological and psychiatric interventions.

[EPILEPSY SURGERY IN CHILDREN: A SUMMARY OF A DECADE AT THE SOURASKY TEL AVIV MEDICAL CENTER].

INTRODUCTION: Drug-resistant epilepsy in children is associated with morbidity, developmental regression and mortality. Over recent years, there is an increase in awareness regarding the role of surgery in the treatment of refractory epilepsy, both in the diagnostic phase and for treatment, reducing the number and magnitude of seizures. Technological advancements have enabled a minimalization of surgery, with reduction in surgical associated morbidity. METHODS: In this retrospective study, we review our experience with cranial surgery for epilepsy between the years 2011-2020. Collected data included information regarding the epileptic disorder, surgery, surgical-related complications and epilepsy outcome. RESULTS: A total of 93 children underwent 110 cranial surgeries over a decade. The main etiologies included cortical dysplasia (29), Rasmussen encephalitis (10), genetic disorders (9), tumors (7) and tuberous sclerosis (7). The main surgeries included lobectomies (32), focal resections (26), hemispherotomies (25), and callosotomies (16). Two children underwent MRI-guided laser interstitial thermal treatment (LITT). The most significant improvements following surgery were following hemispherotomy or tumor resection (100% of children, each). Following resections for cortical dysplasia led to a significant improvement in 70%. In 83% of children undergoing callosotomy, there were no additional drop seizures; 14% of the entire group underwent additional epilepsy surgery; 23% of children had an unexpected complication, in the vast majority with no permanent sequela. There was not mortality. CONCLUSIONS: Epilepsy surgery may lead to significant improvement and even cure of epilepsy. There is a wide span of epilepsy surgical procedures. Ealy referral of children with refractory epilepsy for surgical evaluation may significantly reduce the developmental injury, and improve functional outcomes.

Stimulation better targets fast-ripple generating networks in super responders to the responsive neurostimulator system.

How responsive neurostimulation (RNS) decreases seizure frequency is unclear. Stimulation may alter epileptic networks during inter-ictal epochs. Definitions of the epileptic network vary but fast ripples (FRs) may be an important substrate. We, therefore, examined whether stimulation of FR-generating networks differed in RNS super responders and intermediate responders. In 10 patients, with subsequent RNS placement, we detected FRs from stereo-electroencephalography (SEEG) contacts during pre-surgical evaluation. The normalized coordinates of the SEEG contacts were compared with those of the eight RNS contacts, and RNS-stimulated SEEG contacts were defined as those within 1.5 cm3 of the RNS contacts. We compared the post-RNS placement seizure outcome to (1) the ratio of stimulated SEEG contacts in the seizure-onset zone (SOZ stimulation ratio [SR]); (2) the ratio of FR events on stimulated contacts (FR SR); and (3) the global efficiency of the FR temporal correlational network on stimulated contacts (FR SGe). We found that the SOZ SR (p = .18) and FR SR (p = .06) did not differ in the RNS super responders and intermediate responders, but the FR SGe did (p = .02). In super responders, highly active desynchronous sites of the FR network were stimulated. RNS that better targets FR networks, as compared to the SOZ, may reduce epileptogenicity more.

A wearable platform for closed-loop stimulation and recording of single-neuron and local field potential activity in freely moving humans.

Advances in technologies that can record and stimulate deep brain activity in humans have led to impactful discoveries within the field of neuroscience and contributed to the development of novel therapies for neurological and psychiatric disorders. Further progress, however, has been hindered by device limitations in that recording of single-neuron activity during freely moving behaviors in humans has not been possible. Additionally, implantable neurostimulation devices, currently approved for human use, have limited stimulation programmability and restricted full-duplex bidirectional capability. In this study, we developed a wearable bidirectional closed-loop neuromodulation system (Neuro-stack) and used it to record single-neuron and local field potential activity during stationary and ambulatory behavior in humans. Together with a highly flexible and customizable stimulation capability, the Neuro-stack provides an opportunity to investigate the neurophysiological basis of disease, develop improved responsive neuromodulation therapies, explore brain function during naturalistic behaviors in humans and, consequently, bridge decades of neuroscientific findings across species.