Temporal and morphological characteristics of high-frequency oscillations in an acute in vivo model of epilepsy.

Approximately 30% of patients with epilepsy do not respond to anti-epileptogenic drugs. Surgical removal of the epileptogenic zone (EZ), the brain regions where the seizures originate and spread, can be a possible therapy for these patients, but localizing the EZ is challenging due to a variety of clinical factors. High-frequency oscillations (HFOs) in intracranial electroencephalography (EEG) are a promising biomarker of the EZ, but it is currently unknown whether HFO rates and HFO morphology modulate as pathological brain networks evolve in a way that gives rise to seizures. To address this question, we assessed the temporal evolution of the duration of HFO events, amplitude of HFO events, and rates of HFOs per minute. HFO events were quantified using the 4AP in vivo rodent model of epilepsy, inducing seizures in two different brain areas. We found that the duration and amplitude of HFO events were significantly increased for the cortex model when compared to the hippocampus model. Additionally, the duration and amplitude increased significantly between baseline and pre-ictal HFOs in both models. On the other hand, the two models did not display a consistent increasing or decreasing trend in amplitude, duration or rate when comparing ictal and postictal intervals. Clinical Relevance- We assessed the amplitude, duration, and rate of HFOs in two acute in vivo rodent models of epilepsy. The significant modulation of HFO morphology from baseline to pre-ictal periods suggests that these features may be a robust biomarker for pathological tissue involved in epileptogenesis. Moreover, the differences in HFO morphology observed between cortex and hippocampus animal models possibly indicate that different structural network characteristics of the EZ cause this modulation. In all, we found that HFO features modulate significantly with the onset of seizures, further highlighting the need to consider of HFO morphology in EZ-localizing studies.

Dynamic compartmental computations in tuft dendrites of layer 5 neurons during motor behavior.

Tuft dendrites of layer 5 pyramidal neurons form specialized compartments important for motor learning and performance, yet their computational capabilities remain unclear. Structural-functional mapping of the tuft tree from the motor cortex during motor tasks revealed two morphologically distinct populations of layer 5 pyramidal tract neurons (PTNs) that exhibit specific tuft computational properties. Early bifurcating and large nexus PTNs showed marked tuft functional compartmentalization, representing different motor variable combinations within and between their two tuft hemi-trees. By contrast, late bifurcating and smaller nexus PTNs showed synchronous tuft activation. Dendritic structure and dynamic recruitment of the N-methyl-d-aspartate (NMDA)-spiking mechanism explained the differential compartmentalization patterns. Our findings support a morphologically dependent framework for motor computations, in which independent amplification units can be combinatorically recruited to represent different motor sequences within the same tree.

State-Dependent Synchrony and Functional Connectivity in the Primary and Secondary Whisker Somatosensory Cortices.

Synchronized activity plays an important role in sensory coding and memory and is a hallmark of functional network connectivity. However, the effect of sensory activation on synchronization and cortical functional connectivity is largely unknown. In this study, we investigated the effect of whisker activation on synchronization and functional connectivity of the primary (wS1) and secondary (wS2) whisker somatosensory cortices at the single-cell level. The results showed that during the spontaneous pre-stimulus state, neurons tended to be functionally connected with nearby neurons which shared similar tuning characteristics. Whisker activation using either ramp-and-hold stimulation or artificial whisking against sandpaper has significantly reduced the average overall pairwise synchronization and functional connectivity within the wS1 barrel and wS2 cortices. Whisker stimulation disconnected approximately a third of neuronal pairs that were functionally connected during the unstimulated state. Nearby neurons with congruent tuning properties were more likely to remain functionally connected during whisker activation. The findings of this study indicated that cortical somatosensory networks are organized in non-random small world networks composed of neurons sharing relatively similar tuning properties. Sensory whisker activation intensifies these properties and further subdivides the cortical network into smaller more functionally uniform subnetworks, which possibly serve to increase the computational capacity of the network.

Intrinsic Disruption of the M1 Cortical Network in a Mouse Model of Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) disrupts motor performance by affecting the basal ganglia system. Yet, despite the critical position of the primary motor cortex in linking basal ganglia computations with motor performance, its contribution to motor disability in PD is largely unknown. The objective of this study was to characterize the role of the primary motor cortex in PD-related motor disability. METHODS: Two-photon calcium imaging and optogenetic stimulation of primary motor cortex neurons was done during performance of a dexterous reach-to-grasp motor task in control and 6-hydroxydopamine-induced PD mice. RESULTS: Experimental PD disrupted performance of the reach-to-grasp motor task and especially initiation of the task, which was partially restored by optogenetic activation of the primary motor cortex. Two-photon calcium imaging during task performance revealed experimental-PD affected the primary motor cortex in a cell-type-specific manner. It suppressed activation of output layer 5 pyramidal tract neurons, with greater effects on freeze versus nonfreeze trials. In contrast, it did not attenuate the initial movement-related activation response of layer 2/3 pyramidal neurons while diminishing the late inhibitory phase of their response. At the network level, experimental PD disrupted movement-related population dynamics of the layer 5 pyramidal tract network while almost not affecting the dynamics of the layer 2/3 neuronal population. It also disrupted short- and long-term robustness and stability of the pyramidal tract subnetwork, with reduced intertrial temporal accuracy and diminished reproducibility of motor parameter encoding and temporal recruitment of the output pyramidal tract neurons over repeated daily sessions. CONCLUSIONS: Experimental PD disrupts both external driving and intrinsic properties of the primary motor cortex. Motor disability in experimental PD results primarily from the inability to generate robust and stable output motor sequences in the parkinsonian primary motor cortex output layer 5 pyramidal tract subnetwork. © 2021 International Parkinson and Movement Disorder Society.

Network Fragility for Seizure Genesis in an Acute in vivo Model of Epilepsy.

Epilepsy affects over 50 million people worldwide and 30% of patients' seizures are medically refractory. The process of localizing and removing the epileptogenic zone is error-prone and ill-posed in part because we do not understand how epilepsy manifests. It has recently been proposed that the epileptic cortex is fragile in the sense that seizures manifest through small perturbations in the synaptic connections that render the entire cortical network unstable. If the fragility of the cortical network could be computed over a period in which seizure genesis occurs, then it might elucidate network mechanisms correlated to the epileptogenic zone. In this study, we used local field potentials (LFP) from neocortex by implementing an acute model of epilepsy in mice. These recordings were used to develop a dynamical network model that quantifies the fragility of the nodes from LFP epochs of baseline activity, preictal and ictal states. Fragility was quantified by the generation of a linear time-varying model to which we then applied a perturbation to determine the sensitivity of nodes in the network. Spatiotemporal fragility maps showed clear quantifiable changes in the epileptogenic network's properties throughout different states of seizure genesis. We quantified this difference over a baseline, preictal and ictal periods to show that network fragility is modulated in the manifestation of epilepsy.

Cell-Type-Specific Outcome Representation in the Primary Motor Cortex.

Adaptive movements are critical for animal survival. To guide future actions, the brain monitors various outcomes, including achievement of movement and appetitive goals. The nature of these outcome signals and their neuronal and network realization in the motor cortex (M1), which directs skilled movements, is largely unknown. Using a dexterity task, calcium imaging, optogenetic perturbations, and behavioral manipulations, we studied outcome signals in the murine forelimb M1. We found two populations of layer 2-3 neurons, termed success- and failure-related neurons, that develop with training, and report end results of trials. In these neurons, prolonged responses were recorded after success or failure trials independent of reward and kinematics. In addition, the initial state of layer 5 pyramidal tract neurons contained a memory trace of the previous trial's outcome. Intertrial cortical activity was needed to learn new task requirements. These M1 layer-specific performance outcome signals may support reinforcement motor learning of skilled behavior.

Layer- and Cell-Specific Recruitment Dynamics during Epileptic Seizures In Vivo.

OBJECTIVE: To investigate the network dynamics mechanisms underlying differential initiation of epileptic interictal spikes and seizures. METHODS: We performed combined in vivo 2-photon calcium imaging from different targeted neuronal subpopulations and extracellular electrophysiological recordings during 4-aminopyridine-induced neocortical spikes and seizures. RESULTS: Both spikes and seizures were associated with intense synchronized activation of excitatory layer 2/3 pyramidal neurons (PNs) and to a lesser degree layer 4 neurons, as well as inhibitory parvalbumin-expressing interneurons (INs). In sharp contrast, layer 5 PNs and somatostatin-expressing INs were gradually and asynchronously recruited into the ictal activity during the course of seizures. Within layer 2/3, the main difference between onset of spikes and seizures lay in the relative recruitment dynamics of excitatory PNs compared to parvalbumin- and somatostatin-expressing inhibitory INs. Whereas spikes exhibited balanced recruitment of PNs and parvalbumin-expressing INs, during seizures IN responses were reduced and less synchronized than in layer 2/3 PNs. Similar imbalance was not observed in layers 4 or 5 of the neocortex. Machine learning-based algorithms we developed were able to distinguish spikes from seizures based solely on activation dynamics of layer 2/3 PNs at discharge onset. INTERPRETATION: During onset of seizures, the recruitment dynamics markedly differed between neuronal subpopulations, with rapid synchronous recruitment of layer 2/3 PNs, layer 4 neurons, and parvalbumin-expressing INs and gradual asynchronous recruitment of layer 5 PNs and somatostatin-expressing INs. Seizures initiated in layer 2/3 due to a dynamic mismatch between local PNs and inhibitory INs, and only later spread to layer 5 by gradually and asynchronously recruiting PNs in this layer. ANN NEUROL 2020;87:97-115.

A chemogenetic approach for treating experimental Parkinson's disease.

BACKGROUND: PD is a common neurodegenerative disease primarily affecting the cortico-basal ganglia loop. OBJECTIVE: To investigate whether chemogenetic-mediated neuromodulation of various nuclei and pathways can counterbalance basal ganglia network abnormalities and improve motor disability in experimental PD. METHODS: Experimental PD was induced by stereotactic injection of 6-OHDA to the medial forebrain bundle. Designer receptors exclusively activated by designer drugs were expressed in different basal ganglia nuclei by stereotactic injections of adeno-associated viral vectors. We compared motor performance, monitored by the open-field and rotarod tests, after random and blinded application of either normal saline or the synthetic receptor activator, clozapine-N-oxide. RESULTS: Motor performance, as measured by movement velocity, rotations, and rotarod scores, were significantly improved in PD mice by enhancing the activity of the GPe with Gq custom receptors and by reducing basal ganglia output activity, targeting the output nuclei GPi and SNr with Gi custom receptors. CONCLUSION: Our findings support the hypothesis that enhanced inhibitory output activity of the basal ganglia complex underlie motor signs in PD, and point to the therapeutic potential of chemogenetic based treatments in PD patients. © 2018 International Parkinson and Movement Disorder Society.

Ultra Broad Band Neural Activity Portends Seizure Onset in a Rat Model of Epilepsy.

Epilepsy affects over 70 million people worldwide and 30% of patients' seizures cannot be controlled with medications, motivating the development of alternative therapies such as electrical stimulation. Current stimulation strategies attempt to stop seizures after they start, but none aim to prevent seizures altogether. Preventing seizures requires knowing when the brain is entering a preictal state (i.e., approaching seizure onset). Here we show that such preictal activity can be detected by an informative neural signal that progressively and monotonically changes as the brain approaches a seizure event. Specifically, we use local field potentials (LFP) from a rat model of epilepsy to develop an innovative measure of signal novelty relative to nonseizure activity, that shows the presence of progressive neural dynamics in an ultra broad band (4 Hz - 5 kHz). The measure is extracted from functional connectivity features computed from the LFPs which are used as an input to a one-class Support Vector Machine (SVM). The SVM outputs a scalar signal which quantifies how novel the current activity looks relative to baseline (non-seizure) activity and shows a progression towards seizure onset minutes ahead of time. The use of ultra broad band multivariate features into the SVM results in a novelty signal that has a significantly higher slope in the progression to seizure onset when compared to using power in conventional frequency bands (4 - 500 Hz) on individual channels as input features to the SVM. Functional connectivity in conjunction with the SVM is a strategy that generates a new measurement of novelty that can be used by closed-loop systems for seizure forecasting and prevention.

[UTILITY OF INPATIENT LONG TERM VIDEO EEG MONITORING].

INTRODUCTION: Ambulatory interictal EEG cannot always clarify the nature of spells in patients with suspected epilepsy. Long term Video EEG Monitoring can help to diagnose the nature of recurrent attacks, classify epileptic seizures and aid with the localization of seizures in preoperative epilepsy surgery candidates. OBJECTIVES: The aim of this study was to investigate the usefulness of performing long term video EEG monitoring in patients undergoing this test in Rambam's epilepsy unit. METHODS: This study is a retrospective study that included all consecutive patients undergoing monitoring in our unit from January 2001 to July 2009. Demographic, clinical and monitoring results were collected retrospectively from the patients' files. RESULTS: A total of 722 consecutive monitorings with a total of 637 patients were included in the study. Epileptic seizures were observed in 194 patients (30.5%), non-epileptic events were observed in 220 patients (34.5%), epileptic seizures and psychogenic non-epileptic seizures were observed in ten patients (1.6% ), no events were observed in 200 patients (31.4%) and in 13 patients (2%) we could not determine the nature of the attacks. CONCLUSIONS: Long term video EEG monitoring is highly efficient. In order to maintain its efficacy or even improve it, mainly patients with high seizure frequency should be referred to this test. Due to the low availability of this test in northern Israel, in our opinion, there is a room to expand this service.

Feedforward motor information enhances somatosensory responses and sharpens angular tuning of rat S1 barrel cortex neurons.

The primary vibrissae motor cortex (vM1) is responsible for generating whisking movements. In parallel, vM1 also sends information directly to the sensory barrel cortex (vS1). In this study, we investigated the effects of vM1 activation on processing of vibrissae sensory information in vS1 of the rat. To dissociate the vibrissae sensory-motor loop, we optogenetically activated vM1 and independently passively stimulated principal vibrissae. Optogenetic activation of vM1 supra-linearly amplified the response of vS1 neurons to passive vibrissa stimulation in all cortical layers measured. Maximal amplification occurred when onset of vM1 optogenetic activation preceded vibrissa stimulation by 20 ms. In addition to amplification, vM1 activation also sharpened angular tuning of vS1 neurons in all cortical layers measured. Our findings indicated that in addition to output motor signals, vM1 also sends preparatory signals to vS1 that serve to amplify and sharpen the response of neurons in the barrel cortex to incoming sensory input signals.

The antiepileptic and ictogenic effects of optogenetic neurostimulation of PV-expressing interneurons.

Parvalbumin (PV)-expressing interneurons exert powerful inhibitory effects on the normal cortical network; thus optogenetic activation of PV interneurons may also possess antiepileptic properties. To investigate this possibility we expressed channelrhodopsin 2 in PV interneurons by locally injecting the Cre-dependent viral vector AAV2/1-EF1a-DIO-ChETA-EYFP into the S1 barrel cortex of PV-Cre mice. Approximately 3-4 wk later recurrent electrographic seizures were evoked by local application of the chemoconvulsant 4-aminopyridine (4-AP); the ECoG and unit activity were monitored with extracellular silicone electrodes; and PV interneurons were activated optogenetically during the ictal and interictal phases. Five- to ten-second optogenetic activation of PV interneurons applied during electrographic seizures (ictal phase) terminated 33.7% of electrographic seizures compared with only 6% during sham stimulation, and the average electrographic seizure duration shortened by 38.7 ± 34.2% compared with sham stimulation. In contrast, interictal optogenetic activation of PV interneurons showed powerful and robust ictogenic effects. Approximately 60% of interictal optogenetic stimuli resulted in electrographic seizure initiation. Single-unit recordings revealed that presumptive PV-expressing interneurons markedly increased their firing during optogenetic stimulation, while many presumptive excitatory pyramidal neurons showed a biphasic response, with initial suppression of firing during the optogenetic pulse followed by a synchronized rebound increase in firing at the end of the laser pulse. Our findings indicated that ictal activation of PV-expressing interneurons possesses antiepileptic properties probably due to suppression of firing in pyramidal neurons during the laser pulse. However, in addition interictal activation of PV-expressing interneurons possesses powerful ictogenic properties, probably due to synchronized postinhibition rebound firing of pyramidal neurons.

Yield of Non-Invasive Phase 1 Presurgical Evaluation in Drug-Resistant Epilepsy Patients.

BACKGROUND: Resective epilepsy surgery is an accepted treatment option for patients with drug-resistant epilepsy (DRE). Presurgical evaluation consists of a phase 1 non-invasive evaluation and a phase 2 invasive evaluation, when necessary. OBJECTIVES: To assess the results of phase 1 evaluation in patients with focal DRE. METHODS: This observational retrospective study was performed in all consecutive DRE patients admitted to our clinic from January 2001 to July 2010, and who underwent a presurgical evaluation which included at least magnetic resonance imaging (MRI) scan and long-term video EEG monitoring (LTVEM). RESULTS: A total of 253 consecutive patients with a diagnosis of DRE (according to the ILAE recommendations) who underwent presurgical evaluation were extracted from our clinic and department registry. In 45 of these patients either imaging or ictal video EEG data were missing; the final analysis therefore involved 208 patients. The combined result of the LTVEM and the MRI scan were as follows: 102 patients (49% of the cohort) had a lesion on the MRI scan, in 77 patients (37% of the cohort) the LTVEM results were localizing and congruent with the MRI findings, and in 25 patients (12% of the cohort) the LTVEM results were either non-localizing or incongruent with the MRI findings. In 106 patients (51% of the cohort) the MRI scan was normal or had a non-specific lesion. The LTVEM was localizing in 66 of these patients (31.7% of the cohort) and non-localizing in 40 (19.2% of the cohort). CONCLUSIONS: Although some of the patients with focal DRE can be safely treated with resective surgery based solely on the findings of phase 1 evaluation, a substantial percent of patients do need to undergo a phase 2 evaluation before a final surgical decision is made.

Texture coarseness responsive neurons and their mapping in layer 2-3 of the rat barrel cortex in vivo.

Texture discrimination is a fundamental function of somatosensory systems, yet the manner by which texture is coded and spatially represented in the barrel cortex are largely unknown. Using in vivo two-photon calcium imaging in the rat barrel cortex during artificial whisking against different surface coarseness or controlled passive whisker vibrations simulating different coarseness, we show that layer 2-3 neurons within barrel boundaries differentially respond to specific texture coarsenesses, while only a minority of neurons responded monotonically with increased or decreased surface coarseness. Neurons with similar preferred texture coarseness were spatially clustered. Multi-contact single unit recordings showed a vertical columnar organization of texture coarseness preference in layer 2-3. These findings indicate that layer 2-3 neurons perform high hierarchical processing of tactile information, with surface coarseness embodied by distinct neuronal subpopulations that are spatially mapped onto the barrel cortex.

Termination of chemoconvulsant-induced seizures by synchronous and asynchronous electrical stimulation of the hippocampus in-vivo.

BACKGROUND: Neurostimulation has been proposed as a potential new treatment modality for pharmacoresistant epilepsy. Yet the effect of the different stimulation parameters on the efficacy of stimulation is not sufficiently known. OBJECTIVE: Investigate the effect of different stimulation parameters on the efficacy of neurostimulation in terminating acute chemoconvulsant-induced hippocampal seizures in-vivo. METHODS: Seizures were induced in rats in-vivo either by systemic or local intra hippocampal application of chemoconvulsants, and bipolar electrical stimulation was applied during seizures by stimulating the perforant pathway of the hippocampus. The stimulus intensity, frequency, and duration were altered. RESULTS: Increasing the stimulus intensity and train duration increased the probability for seizure termination. The efficacy of stimulus intensity peaked at 250-300 µA. Low stimulation frequencies (≤13 Hz) were inefficient in terminating seizures. Increasing the stimulation frequency (up to 250 Hz) enhanced seizure termination, reaching a plateau effect at frequencies of 50-100 Hz. When we simultaneously applied the same stimulation frequency in two adjacent electrodes (synchronous stimulation) the probability for seizure termination did not significantly change. In contrast when the two stimulating electrodes were simultaneously activated with different asynchronous stimulation frequencies (30 and 100 Hz or 60 and 200 Hz, asynchronous stimulation) the probability for terminating seizures more than doubled. Similar results were also observed with local intra hippocampal-induced seizures. CONCLUSIONS: Asynchronous stimulation paradigms enhanced the antiepileptic efficacy of neurostimulation, possibly by desynchronizing and functionally subdividing the network.

The Israeli retrospective multicenter open-label study evaluating vagus nerve stimulation efficacy in children and adults.

BACKGROUND: The management of intractable epilepsy in children and adults is challenging. For patients who do not respond to anti-epileptic drugs and are not suitable candidates for epilepsy surgery, vagal nerve stimulation (VNS) is a viable alternative for reducing seizure frequency. METHODS: In this retrospective multicenter open-label study we examined the efficacy and tolerability of VNS in patients in five adult and pediatric epilepsy centers in Israel. All patients had drug-resistant epilepsy and after VNS implantation in 2006-2007 were followed for a minimum of 18 months. Patients were divided into two age groups: < 21 and > 21 years old. RESULTS: Fifty-six adults and children had a stimulator implanted in 2006-2007. At 18 months post-VNS implantation, none of the patients was seizure-free, 24.3% reported a reduction in seizures of > or = 75%, 19% reported a 50-75% reduction, and 10.8% a 25-50% reduction. The best response rate occurred in patients with complex partial seizures. Among these patients, 7 reported a > or = 75% reduction, 5 patients a 50-75% reduction, 3 patients a 25-50% reduction, and 8 patients a < 25% reduction. A comparison of the two age groups showed that the older group (< 21 years old) had fewer seizures than the younger group. CONCLUSIONS: VNS is a relatively effective and safe palliative method for treating refractory epilepsy in both adults and children. It is an alternative treatment for patients with drug-resistant epilepsy, even after a relatively long disease duration, who are not candidates for localized epilepsy surgery.

Prolonged ictal aphasia: a diagnosis to consider.

Aphasia is a common symptom encountered by clinical neurologists. It is usually caused by strokes or lesions involving language regions of the brain, yet prolonged aphasia is rarely the sole manifestation of a simple partial status epilepticus. We report six patients, who suffered from prolonged ictal aphasia. All but one patient had a structural lesion in the left hemisphere, only three suffered from clinical seizures during or shortly prior to the aphasic episode. All patients had ictal patterns on the electroencephalogram (EEG), four of whom had periodic lateralized epileptiform discharges, and five showed frequent recurrent electrographic seizures during the aphasic state. The aphasia lasted several days in all patients, and it resolved after administration of antiepileptic drug treatment. In conclusion, prolonged ictal aphasia is a rare but important treatable cause of aphasia. Surface EEG recordings should be obtained in all patients with unexplained prolonged aphasia to diagnose this rare but treatable entity.

Atrial fibrillation associated with epileptic seizures.

BACKGROUND: Epileptic seizures are often associated with changes in cardiac autonomic function. Yet atrial fibrillation (AFib) or atrial flutter (AFlu) following epileptic seizures has only rarely been reported in the past. OBJECTIVES: To describe and characterize patients who experienced lone AFib or AFlu as a consequence of epileptic seizures. DESIGN: Case reports. SETTING: University teaching hospital. PATIENTS: We describe 4 patients who developed transient AFib following epileptic seizures and 1 patient who developed transient AFlu following epileptic seizures. RESULTS: In all patients, AFib and AFlu followed a generalized tonic-clonic seizure. The arrhythmia usually lasted a few hours and converted spontaneously to a normal sinus rhythm. In 3 patients, AFib or AFlu developed during the first seizure they experienced, and none of the patients developed drug-resistant epilepsy. Moreover, none of the patients had a known cardiac disease, yet, in 2 patients, the cardiological workup demonstrated mild abnormalities on the cardiac stress test. CONCLUSIONS: Atrial fibrillation is the most common type of arrhythmia, with an estimated prevalence of 1%. Despite the fact that AFib can cause syncope, it is important to consider the possibility of AFib developing secondary to an epileptic seizure in cases of AFib and transient loss of consciousness.

Development of hypersynchrony in the cortical network during chemoconvulsant-induced epileptic seizures in vivo.

The prevailing view of epileptic seizures is that they are caused by increased hypersynchronous activity in the cortical network. However, this view is based mostly on electroencephalography (EEG) recordings that do not directly monitor neuronal synchronization of action potential firing. In this study, we used multielectrode single-unit recordings from the hippocampus to investigate firing of individual CA1 neurons and directly monitor synchronization of action potential firing between neurons during the different ictal phases of chemoconvulsant-induced epileptic seizures in vivo. During the early phase of seizures manifesting as low-amplitude rhythmic ß-electrocorticography (ECoG) activity, the firing frequency of most neurons markedly increased. To our surprise, the average overall neuronal synchronization as measured by the cross-correlation function was reduced compared with control conditions with ~60% of neuronal pairs showing no significant correlated firing. However, correlated firing was not uniform and a minority of neuronal pairs showed a high degree of correlated firing. Moreover, during the early phase of seizures, correlated firing between 9.8 ± 5.1% of all stably recorded pairs increased compared with control conditions. As seizures progressed and high-frequency ECoG polyspikes developed, the firing frequency of neurons further increased and enhanced correlated firing was observed between virtually all neuronal pairs. These findings indicated that epileptic seizures represented a hyperactive state with widespread increase in action potential firing. Hypersynchrony also characterized seizures. However, it initially developed in a small subset of neurons and gradually spread to involve the entire cortical network only in the later more intense ictal phases.