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Neuronal firing and waveform alterations through ictal recruitment in humans

Merricks, Edward M; Smith, Elliot H; Emerson, Ronald G; Bateman, Lisa M; McKhann, Guy M; Goodman, Robert R; Sheth, Sameer A; Greger, Bradley; House, Paul A; Trevelyan, Andrew J; Schevon, Catherine A
Analyzing neuronal activity during human seizures is pivotal to understanding mechanisms of seizure onset and propagation. These analyses, however, invariably using extracellular recordings, are greatly hindered by various phenomena that are well established in animal studies: changes in local ionic concentration, changes in ionic conductance, and intense, hypersynchronous firing. The first two alter the action potential waveform, whereas the third increases the "noise"; all three factors confound attempts to detect and classify single neurons. To address these analytical difficulties, we developed a novel template-matching based spike sorting method, which enabled identification of 1,239 single neurons in 27 patients (13 female) with intractable focal epilepsy, that were tracked throughout multiple seizures. These new analyses showed continued neuronal firing with widespread intense activation and stereotyped action potential alterations in tissue that was invaded by the seizure: neurons displayed increased waveform duration (p < 0.001) and reduced amplitude (p < 0.001), consistent with prior animal studies. By contrast, neurons in "penumbral" regions (those receiving intense local synaptic drive from the seizure but without neuronal evidence of local seizure invasion) showed stable waveforms. All neurons returned to their pre-ictal waveforms after seizure termination. We conclude that the distinction, between "core" territories invaded by the seizure, versus "penumbral" territories, is evident at the level of single neurons. Furthermore, the increased waveform duration and decreased waveform amplitude are neuron-intrinsic hallmarks of seizure invasion that impede traditional spike sorting and could be used as defining characteristics of local recruitment.SIGNIFICANCE STATEMENTAnimal studies consistently show marked changes in action potential waveform during epileptic discharges, but acquiring similar evidence in humans has proven difficult. Assessing neuronal involvement in ictal events is pivotal to understanding seizure dynamics and in defining clinical localization of epileptic pathology. Using a novel method to track neuronal firing, we analyzed microelectrode array recordings of spontaneously occurring human seizures, and here report two dichotomous activity patterns. In cortex that is recruited to the seizure, neuronal firing rates increase and waveforms become longer in duration and shorter in amplitude as the neurons are recruited to the seizure, while penumbral tissue shows stable action potentials, in keeping with the "dual territory" model of seizure dynamics.
PMID: 33229500
ISSN: 1529-2401
CID: 4680412

Dual mechanisms of ictal high frequency oscillations in human rhythmic onset seizures

Smith, Elliot H; Merricks, Edward M; Liou, Jyun-You; Casadei, Camilla; Melloni, Lucia; Thesen, Thomas; Friedman, Daniel J; Doyle, Werner K; Emerson, Ronald G; Goodman, Robert R; McKhann, Guy M; Sheth, Sameer A; Rolston, John D; Schevon, Catherine A
High frequency oscillations (HFOs) are bursts of neural activity in the range of 80 Hz or higher, recorded from intracranial electrodes during epileptiform discharges. HFOs are a proposed biomarker of epileptic brain tissue and may also be useful for seizure forecasting. Despite such clinical utility of HFOs, the spatial context and neuronal activity underlying these local field potential (LFP) events remains unclear. We sought to further understand the neuronal correlates of ictal high frequency LFPs using multielectrode array recordings in the human neocortex and mesial temporal lobe during rhythmic onset seizures. These multiscale recordings capture single cell, multiunit, and LFP activity from the human brain. We compare features of multiunit firing and high frequency LFP from microelectrodes and macroelectrodes during ictal discharges in both the seizure core and penumbra (spatial seizure domains defined by multiunit activity patterns). We report differences in spectral features, unit-local field potential coupling, and information theoretic characteristics of high frequency LFP before and after local seizure invasion. Furthermore, we tie these time-domain differences to spatial domains of seizures, showing that penumbral discharges are more broadly distributed and less useful for seizure localization. These results describe the neuronal and synaptic correlates of two types of pathological HFOs in humans and have important implications for clinical interpretation of rhythmic onset seizures.
PMCID:7645614
PMID: 33154490
ISSN: 2045-2322
CID: 4664412

A model for focal seizure onset, propagation, evolution, and progression

Liou, Jyun-You; Smith, Elliot H; Bateman, Lisa M; Bruce, Samuel L; McKhann, Guy M; Goodman, Robert R; Emerson, Ronald G; Schevon, Catherine A; Abbott, L F
We developed a neural network model that can account for major elements common to human focal seizures. These include the tonic-clonic transition, slow advance of clinical semiology and corresponding seizure territory expansion, widespread EEG synchronization, and slowing of the ictal rhythm as the seizure approaches termination. These were reproduced by incorporating usage-dependent exhaustion of inhibition in an adaptive neural network that receives global feedback inhibition in addition to local recurrent projections. Our model proposes mechanisms that may underline common EEG seizure onset patterns and status epilepticus, and postulates a role for synaptic plasticity in the emergence of epileptic foci. Complex patterns of seizure activity and bi-stable seizure end-points arise when stochastic noise is included. With the rapid advancement of clinical and experimental tools, we believe that this model can provide a roadmap and potentially an in silico testbed for future explorations of seizure mechanisms and clinical therapies.
PMCID:7089769
PMID: 32202494
ISSN: 2050-084x
CID: 4357532

Role of paroxysmal depolarization in focal seizure activity

Tryba, Andrew K; Merricks, Edward M; Lee, Somin; Pham, Tuan; Cho, SungJun; Nordli, Douglas R; Eissa, Tahra L; Goodman, Robert R; McKhann, Guy M; Emerson, Ronald G; Schevon, Catherine A; van Drongelen, Wim
We analyze the role of inhibition in sustaining focal epileptic seizure activity. We review ongoing seizure activity at the mesoscopic scale that can be observed with microelectrode arrays as well as at the macroscale of standard clinical EEG. We provide clinical, experimental, and modeling data to support the hypothesis that paroxysmal depolarization (PD) is a critical component of the ictal machinery. We present dual-patch recordings in cortical cultures showing reduced synaptic transmission associated with presynaptic occurrence of PD, and we find that the PD threshold is cell size related. We further find evidence that optically evoked PD activity in parvalbumin neurons can promote propagation of neuronal excitation in neocortical networks in vitro. Spike sorting results from microelectrode array measurements around ictal wave propagation in human focal seizures demonstrate a strong increase in putative inhibitory firing with an approaching excitatory wave, followed by a sudden reduction of firing at passage. At the macroscopic level, we summarize evidence that this excitatory ictal wave activity is strongly correlated with oscillatory activity across a centimeter-sized cortical network. We summarize Wilson-Cowan-type modeling showing how inhibitory function is crucial for this behavior. Our findings motivated us to develop a network motif of neurons in silico, governed by a reduced version of the Hodgkin-Huxley formalism, to show how feedforward, feedback, PD, and local failure of inhibition contribute to observed dynamics across network scales. The presented multidisciplinary evidence suggests that the PD not only is a cellular marker or epiphenomenon but actively contributes to seizure activity.NEW & NOTEWORTHY We present mechanisms of ongoing focal seizures across meso- and macroscales of microelectrode array and standard clinical recordings, respectively. We find modeling, experimental, and clinical evidence for a dual role of inhibition across these scales: local failure of inhibition allows propagation of a mesoscopic ictal wave, whereas inhibition elsewhere remains intact and sustains macroscopic oscillatory activity. We present evidence for paroxysmal depolarization as a mechanism behind this dual role of inhibition in shaping ictal activity.
PMID: 31461373
ISSN: 1522-1598
CID: 4145262

The Relationship Between Ictal Multi-Unit Activity and the Electrocorticogram

Eissa, Tahra L; Schevon, Catherine A; Emerson, Ronald G; Mckhann, Guy M; Goodman, Robert R; Van Drongelen, Wim
During neocortical seizures in patients with epilepsy, microelectrode array recordings from the ictal core show a strong correlation between the fast, cellular spiking activities and the low-frequency component of the potential field, reflected in the electrocorticogram (ECoG). Here, we model the relationship between the cellular spike activity and this low-frequency component as the input and output signals of a linear time invariant system. Our approach is based on the observation that this relationship can be characterized by a so-called sinc function, the unit impulse response of an ideal (brick-wall) filter. Accordingly, using a brick-wall filter, we are able to convert ictal cellular spike inputs into an output that significantly correlates with the observed seizure activity in the ECoG [Formula: see text], while ECoG recordings of subsequent seizures within patients also show significant, but lower, correlations [Formula: see text]. Furthermore, we can produce seizure-like output signals using synthetic spike trains with ictal properties. We propose a possible physiological mechanism to explain the observed properties associated with an ideal filter, and discuss the potential use of our approach for the evaluation of anticonvulsant strategies.
PMID: 30001641
ISSN: 0129-0657
CID: 3200162

Cross-scale effects of neural interactions during human neocortical seizure activity

Eissa, Tahra L; Dijkstra, Koen; Brune, Christoph; Emerson, Ronald G; van Putten, Michel J A M; Goodman, Robert R; McKhann, Guy M; Schevon, Catherine A; van Drongelen, Wim; van Gils, Stephan A
Small-scale neuronal networks may impose widespread effects on large network dynamics. To unravel this relationship, we analyzed eight multiscale recordings of spontaneous seizures from four patients with epilepsy. During seizures, multiunit spike activity organizes into a submillimeter-sized wavefront, and this activity correlates significantly with low-frequency rhythms from electrocorticographic recordings across a 10-cm-sized neocortical network. Notably, this correlation effect is specific to the ictal wavefront and is absent interictally or from action potential activity outside the wavefront territory. To examine the multiscale interactions, we created a model using a multiscale, nonlinear system and found evidence for a dual role for feedforward inhibition in seizures: while inhibition at the wavefront fails, allowing seizure propagation, feedforward inhibition of the surrounding centimeter-scale networks is activated via long-range excitatory connections. Bifurcation analysis revealed that distinct dynamical pathways for seizure termination depend on the surrounding inhibition strength. Using our model, we found that the mesoscopic, local wavefront acts as the forcing term of the ictal process, while the macroscopic, centimeter-sized network modulates the oscillatory seizure activity.
PMCID:5635869
PMID: 28923948
ISSN: 1091-6490
CID: 3068532

Multivariate regression methods for estimating velocity of ictal discharges from human microelectrode recordings

Liou, Jyun-You; Smith, Elliot H; Bateman, Lisa M; McKhann, Guy M; Goodman, Robert R; Greger, Bradley; Davis, Tyler S; Kellis, Spencer S; House, Paul A; Schevon, Catherine A
OBJECTIVE:Epileptiform discharges, an electrophysiological hallmark of seizures, can propagate across cortical tissue in a manner similar to traveling waves. Recent work has focused attention on the origination and propagation patterns of these discharges, yielding important clues to their source location and mechanism of travel. However, systematic studies of methods for measuring propagation are lacking. APPROACH/METHODS:We analyzed epileptiform discharges in microelectrode array recordings of human seizures. The array records multiunit activity and local field potentials at 400 micron spatial resolution, from a small cortical site free of obstructions. We evaluated several computationally efficient statistical methods for calculating traveling wave velocity, benchmarking them to analyses of associated neuronal burst firing. MAIN RESULTS/RESULTS:Over 90% of discharges met statistical criteria for propagation across the sampled cortical territory. Detection rate, direction and speed estimates derived from a multiunit estimator were compared to four field potential-based estimators: negative peak, maximum descent, high gamma power, and cross-correlation. Interestingly, the methods that were computationally simplest and most efficient (negative peak and maximal descent) offer non-inferior results in predicting neuronal traveling wave velocities compared to the other two, more complex methods. Moreover, the negative peak and maximal descent methods proved to be more robust against reduced spatial sampling challenges. Using least absolute deviation in place of least squares error minimized the impact of outliers, and reduced the discrepancies between local field potential-based and multiunit estimators. SIGNIFICANCE/CONCLUSIONS:Our findings suggest that ictal epileptiform discharges typically take the form of exceptionally strong, rapidly traveling waves, with propagation detectable across millimeter distances. The sequential activation of neurons in space can be inferred from clinically-observable EEG data, with a variety of straightforward computation methods available. This opens possibilities for systematic assessments of ictal discharge propagation in clinical and research settings.
PMCID:5728389
PMID: 28332484
ISSN: 1741-2552
CID: 3080892

Brain-responsive neurostimulation in patients with medically intractable mesial temporal lobe epilepsy

Geller, Eric B; Skarpaas, Tara L; Gross, Robert E; Goodman, Robert R; Barkley, Gregory L; Bazil, Carl W; Berg, Michael J; Bergey, Gregory K; Cash, Sydney S; Cole, Andrew J; Duckrow, Robert B; Edwards, Jonathan C; Eisenschenk, Stephan; Fessler, James; Fountain, Nathan B; Goldman, Alicia M; Gwinn, Ryder P; Heck, Christianne; Herekar, Aamar; Hirsch, Lawrence J; Jobst, Barbara C; King-Stephens, David; Labar, Douglas R; Leiphart, James W; Marsh, W Richard; Meador, Kimford J; Mizrahi, Eli M; Murro, Anthony M; Nair, Dileep R; Noe, Katherine H; Park, Yong D; Rutecki, Paul A; Salanova, Vicenta; Sheth, Raj D; Shields, Donald C; Skidmore, Christopher; Smith, Michael C; Spencer, David C; Srinivasan, Shraddha; Tatum, William; Van Ness, Paul C; Vossler, David G; Wharen, Robert E Jr; Worrell, Gregory A; Yoshor, Daniel; Zimmerman, Richard S; Cicora, Kathy; Sun, Felice T; Morrell, Martha J
OBJECTIVE: Evaluate the seizure-reduction response and safety of mesial temporal lobe (MTL) brain-responsive stimulation in adults with medically intractable partial-onset seizures of mesial temporal lobe origin. METHODS: Subjects with mesial temporal lobe epilepsy (MTLE) were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. RESULTS: There were 111 subjects with MTLE; 72% of subjects had bilateral MTL onsets and 28% had unilateral onsets. Subjects had one to four leads placed; only two leads could be connected to the device. Seventy-six subjects had depth leads only, 29 had both depth and strip leads, and 6 had only strip leads. The mean follow-up was 6.1 +/- (standard deviation) 2.2 years. The median percent seizure reduction was 70% (last observation carried forward). Twenty-nine percent of subjects experienced at least one seizure-free period of 6 months or longer, and 15% experienced at least one seizure-free period of 1 year or longer. There was no difference in seizure reduction in subjects with and without mesial temporal sclerosis (MTS), bilateral MTL onsets, prior resection, prior intracranial monitoring, and prior vagus nerve stimulation. In addition, seizure reduction was not dependent on the location of depth leads relative to the hippocampus. The most frequent serious device-related adverse event was soft tissue implant-site infection (overall rate, including events categorized as device-related, uncertain, or not device-related: 0.03 per implant year, which is not greater than with other neurostimulation devices). SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including patients with unilateral or bilateral MTLE who are not candidates for temporal lobectomy or who have failed a prior MTL resection.
PMID: 28398014
ISSN: 1528-1167
CID: 2609592

Feasibility of eliciting the H reflex in the masseter muscle in patients under general anesthesia

Ulkatan, Sedat; Jaramillo, Ana Maria; Téllez, Maria J; Goodman, Robert R; Deletis, Vedran
OBJECTIVE:To explore the feasibility of eliciting the brainstem H reflex in the masseter muscle in patients under general anesthesia. METHODS:We electrically stimulated the masseteric nerve, a branch of the trigeminal nerve, and recorded ipsilateral masseteric and temporalis muscle responses. We tested eight patients who presented with trigeminal neuralgia; one patient had a temporal bone tumor and one patient had a brainstem arteriovenous malformation. All responses were elicited when patients were under general anesthesia and before the initiation of surgery. RESULTS:The H reflex in the masseter muscle was reliably elicited in 70% of the patients. The reflexes met the usual criteria for the H reflex because they were elicited below the threshold of the direct M response, and their amplitudes decreased when the M response increased with stronger stimuli. The mean onset latencies of the masseter H reflex and the M response were 5.4±1.3ms and 2.6±0.6ms, respectively. CONCLUSIONS:In the present study, we provide evidence of the feasibility of eliciting the H reflex in the masseter muscles of patients under general anesthesia. SIGNIFICANCE/CONCLUSIONS:The H reflex of the masseter muscle may represent a new method available for intraoperative monitoring. Specifically, this method may be important for the monitoring of brainstem functional integrity, particularly in the midbrain and mid-pons, in addition to the trigeminal nerve path.
PMID: 27888745
ISSN: 1872-8952
CID: 3094372

The ictal wavefront is the spatiotemporal source of discharges during spontaneous human seizures

Smith, Elliot H; Liou, Jyun-you; Davis, Tyler S; Merricks, Edward M; Kellis, Spencer S; Weiss, Shennan A; Greger, Bradley; House, Paul A; McKhann, Guy M; Goodman, Robert R; Emerson, Ronald G; Bateman, Lisa M; Trevelyan, Andrew J; Schevon, Catherine A
The extensive distribution and simultaneous termination of seizures across cortical areas has led to the hypothesis that seizures are caused by large-scale coordinated networks spanning these areas. This view, however, is difficult to reconcile with most proposed mechanisms of seizure spread and termination, which operate on a cellular scale. We hypothesize that seizures evolve into self-organized structures wherein a small seizing territory projects high-intensity electrical signals over a broad cortical area. Here we investigate human seizures on both small and large electrophysiological scales. We show that the migrating edge of the seizing territory is the source of travelling waves of synaptic activity into adjacent cortical areas. As the seizure progresses, slow dynamics in induced activity from these waves indicate a weakening and eventual failure of their source. These observations support a parsimonious theory for how large-scale evolution and termination of seizures are driven from a small, migrating cortical area.
PMCID:4820627
PMID: 27020798
ISSN: 2041-1723
CID: 3109742