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Integrating datasets from multiple sites and scanners can increase statistical power for neuroimaging studies but can also introduce significant inter‐site confounds. We evaluated the effectiveness of ComBat, an empirical Bayes approach, to combine longitudinal preclinical MRI data acquired at 4.7 or 9.4 T at two different sites in Australia. Male Sprague Dawley rats underwent MRI on Days 2, 9, 28, and 150 following moderate/severe traumatic brain injury (TBI) or sham injury as part of Project 1 of the NIH/NINDS‐funded Centre Without Walls EpiBioS4Rx project. Diffusion‐weighted and multiple‐gradient‐echo images were acquired, and outcomes included QSM, FA, and ADC. Acute injury measures including apnea and self‐righting reflex were consistent between sites. Mixed‐effect analysis of ipsilateral and contralateral corpus callosum (CC) summary values revealed a significant effect of site on FA and ADC values, which was removed following ComBat harmonization. Bland–Altman plots for each metric showed reduced variability across sites following ComBat harmonization, including for QSM, despite appearing to be largely unaffected by inter‐site differences and no effect of site observed. Following harmonization, the combined inter‐site data revealed significant differences in the imaging metrics consistent with previously reported outcomes. TBI resulted in significantly reduced FA and increased susceptibility in the ipsilateral CC, and significantly reduced FA in the contralateral CC compared with sham‐injured rats. Additionally, TBI rats also exhibited a reversal in ipsilateral CC ADC values over time with significantly reduced ADC at Day 9, followed by increased ADC 150 days after injury. Our findings demonstrate the need for harmonizing multi‐site preclinical MRI data and show that this can be successfully achieved using ComBat while preserving phenotypical changes due to TBI. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: We used the lateral fluid percussion injury (LFPI) model of moderate‐to‐severe traumatic brain injury (TBI) to identify early plasma biomarkers predicting injury, early post‐traumatic seizures or neuromotor functional recovery (neuroscores), considering the effect of levetiracetam, which is commonly given after severe TBI. Methods: Adult male Sprague–Dawley rats underwent left parietal LFPI, received levetiracetam (200 mg/kg bolus, 200 mg/kg/day subcutaneously for 7 days [7d]) or vehicle post‐LFPI, and were continuously video‐EEG recorded (n = 14/group). Sham (craniotomy only, n = 6), and naïve controls (n = 10) were also used. Neuroscores and plasma collection were done at 2d or 7d post‐LFPI or equivalent timepoints in sham/naïve. Plasma protein biomarker levels were determined by reverse phase protein microarray and classified according to injury severity (LFPI vs. sham/control), levetiracetam treatment, early seizures, and 2d‐to‐7d neuroscore recovery, using machine learning. Results: Low 2d plasma levels of Thr231‐phosphorylated tau protein (pTAU‐Thr231) and S100B combined (ROC AUC = 0.7790) predicted prior craniotomy surgery (diagnostic biomarker). Levetiracetam‐treated LFPI rats were differentiated from vehicle treated by the 2d‐HMGB1, 2d‐pTAU‐Thr231, and 2d‐UCHL1 plasma levels combined (ROC AUC = 0.9394) (pharmacodynamic biomarker). Levetiracetam prevented the seizure effects on two biomarkers that predicted early seizures only among vehicle‐treated LFPI rats: pTAU‐Thr231 (ROC AUC = 1) and UCHL1 (ROC AUC = 0.8333) (prognostic biomarker of early seizures among vehicle‐treated LFPI rats). Levetiracetam‐resistant early seizures were predicted by high 2d‐IFNγ plasma levels (ROC AUC = 0.8750) (response biomarker). 2d‐to‐7d neuroscore recovery was best predicted by higher 2d‐S100B, lower 2d‐HMGB1, and 2d‐to‐7d increase in HMGB1 or decrease in TNF (P < 0.05) (prognostic biomarkers). Significance: Antiseizure medications and early seizures need to be considered in the interpretation of early post‐traumatic biomarkers. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Drug‐resistant epilepsy (DRE) affects approximately one‐third of the patients with epilepsy. Based on experimental findings from animal models and brain tissue from patients with DRE, different hypotheses have been proposed to explain the cause(s) of drug resistance. One is the intrinsic severity hypothesis that posits that drug resistance is an inherent property of epilepsy related to disease severity. Seizure frequency is one measure of epilepsy severity, but frequency alone is an incomplete measure of severity and does not fully explain basic research and clinical studies on drug resistance; thus, other measures of epilepsy severity are needed. One such measure could be pathological high‐frequency oscillations (HFOs), which are believed to reflect the neuronal disturbances responsible for the development of epilepsy and the generation of spontaneous seizures. In this manuscript, we will briefly review the intrinsic severity hypothesis, describe basic and clinical research on HFOs in the epileptic brain, and based on this evidence discuss whether HFOs could be a clinical measure of epilepsy severity. Understanding the mechanisms of DRE is critical for producing breakthroughs in the development and testing of novel strategies for treatment. [ABSTRACT FROM AUTHOR]

Objective: We examined whether posttraumatic epilepsy (PTE) is associated with measurable perturbations in gut microbiome. Methods: Adult Sprague Dawley rats were subjected to lateral fluid percussion injury (LFPI). PTE was examined 7 months after LFPI, during 4‐week continuous video‐electroencephalographic monitoring. 16S ribosomal RNA gene sequencing was performed in fecal samples collected before LFPI/sham‐LFPI and 1 week, 1 month, and 7 months thereafter. Longitudinal analyses of alpha diversity, beta diversity, and differential microbial abundance were performed. Short‐chain fatty acids (SCFAs) were measured in fecal samples collected before LFPI by liquid chromatography with tandem mass spectrometry. Results: Alpha diversity changed over time in both LFPI and sham‐LFPI subjects; no association was observed between alpha diversity and LFPI, the severity of post‐LFPI neuromotor impairments, and PTE. LFPI produced significant changes in beta diversity and selective changes in microbial abundances associated with the severity of neuromotor impairments. No association between LFPI‐dependent microbial perturbations and PTE was detected. PTE was associated with beta diversity irrespective of timepoint vis‐à‐vis LFPI, including at baseline. Preexistent fecal microbial abundances of four amplicon sequence variants belonging to the Lachnospiraceae family (three enriched and one depleted) predicted the risk of PTE, with area under the curve (AUC) of.73. Global SCFA content was associated with the increased risk of PTE, with AUC of.722, and with 2‐methylbutyric (depleted), valeric (depleted), isobutyric (enriched), and isovaleric (enriched) acids being the most important factors (AUC =.717). When the analyses of baseline microbial and SCFA compositions were combined, AUC to predict PTE increased to.78. Significance: Whereas LFPI produces no perturbations in the gut microbiome that are associated with PTE, the risk of PTE can be stratified based on preexistent microbial abundances and SCFA content. [ABSTRACT FROM AUTHOR]

High‐frequency oscillations (HFOs) in intracranial electroencephalography (EEG) are a promising biomarker of the epileptogenic zone and tool for surgical planning. Many studies have shown that a high rate of HFOs (number per minute) is correlated with the seizure‐onset zone, and complete removal of HFO‐generating brain regions has been associated with seizure‐free outcome after surgery. In order to use HFOs as a biomarker, these transient events must first be detected in electrophysiological data. Because visual detection of HFOs is time‐consuming and subject to low interrater reliability, many automated algorithms have been developed, and they are being used increasingly for such studies. However, there is little guidance on how to select an algorithm, implement it in a clinical setting, and validate the performance. Therefore, we aim to review automated HFO detection algorithms, focusing on conceptual similarities and differences between them. We summarize the standard steps for data pre‐processing, as well as post‐processing strategies for rejection of false‐positive detections. We also detail four methods for algorithm testing and validation, and we describe the specific goal achieved by each one. We briefly review direct comparisons of automated algorithms applied to the same data set, emphasizing the importance of optimizing detection parameters. Then, to assess trends in the use of automated algorithms and their potential for use in clinical studies, we review evidence for the relationship between automatically detected HFOs and surgical outcome. We conclude with practical recommendations and propose standards for the selection, implementation, and validation of automated HFO‐detection algorithms. [ABSTRACT FROM AUTHOR]

Summary: There are no reliable nonictal biomarkers for epilepsy, electroencephalography (EEG) or otherwise, but efforts to identify biomarkers that would predict the development of epilepsy after a potential epileptogenic insult, diagnose the existence of epilepsy, or assess the effects of antiseizure or antiepileptogenic interventions are relying heavily on electrophysiology. The most promising EEG biomarkers to date are pathologic high‐frequency oscillations (pHFOs), brief EEG events in the range of 100 to 600 Hz, which are believed to reflect summated action potentials from synchronously bursting neurons. Studies of patients with epilepsy, and experimental animal models, have been based primarily on direct brain recording, which makes pHFOs potentially useful for localizing the epileptogenic zone for surgical resection, but application for other diagnostic and therapeutic purposes is limited. Consequently, recent efforts have involved identification of HFOs recorded with scalp electrodes, and with magnetoencephalography, which may reflect the same pathophysiologic mechanisms as pHFOs recorded directly from the brain. The search is also on for other EEG changes that might serve as epilepsy biomarkers, and candidates include arcuate rhythms, which may reflect repetitive pHFOs, reduction in theta rhythm, which correlates with epileptogenesis in several rodent models of epilepsy, and shortened sleep spindles that correlate with ictogenesis. [ABSTRACT FROM AUTHOR]

Objective: Intracellular recordings from cells in entorhinal cortex tissue slices show that low-voltage fast (LVF) onset seizures are generated by inhibitory events. Here, we determined whether increased firing of interneurons occurs at the onset of spontaneous mesial-temporal LVF seizures recorded in patients.Methods: The seizure onset zone (SOZ) was identified using visual inspection of the intracranial electroencephalogram. We used wavelet clustering and temporal autocorrelations to characterize changes in single-unit activity during the onset of LVF seizures recorded from microelectrodes in mesial-temporal structures. Action potentials generated by principal neurons and interneurons (ie, putative excitatory and inhibitory neurons) were distinguished using waveform morphology and K-means clustering.Results: From a total of 200 implanted microelectrodes in 9 patients during 13 seizures, we isolated 202 single units; 140 (69.3%) of these units were located in the SOZ, and 40 (28.57%) of them were classified as inhibitory. The waveforms of both excitatory and inhibitory units remained stable during the LVF epoch (p > > 0.05). In the mesial-temporal SOZ, inhibitory interneurons increased their firing rate during LVF seizure onset (p < 0.01). Excitatory neuron firing rates peaked 10 seconds after the inhibitory neurons (p < 0.01). During LVF spread to the contralateral mesial temporal lobe, an increase in inhibitory neuron firing rate was also observed (p < 0.01).Interpretation: Our results suggest that seizure generation and spread during spontaneous mesial-temporal LVF onset events in humans may result from increased inhibitory neuron firing that spawns a subsequent increase in excitatory neuron firing and seizure evolution. Ann Neurol 2018;84:588-600. [ABSTRACT FROM AUTHOR]

Neurosurgery is an underutilized treatment that can potentially cure drug-refractory epilepsy. Careful, multidisciplinary presurgical evaluation is vital for selecting patients and to ensure optimal outcomes. Advances in neuroimaging have improved diagnosis and guided surgical intervention. Invasive electroencephalography allows the evaluation of complex patients who would otherwise not be candidates for neurosurgery. We review the current state of the assessment and selection of patients and consider established and novel surgical procedures and associated outcome data. We aim to dispel myths that may inhibit physicians from referring and patients from considering neurosurgical intervention for drug-refractory focal epilepsies. Ann Neurol 2018;83:676-690. [ABSTRACT FROM AUTHOR]

Objective Differentiating pathologic and physiologic high-frequency oscillations ( HFOs) is challenging. In patients with focal epilepsy, HFOs occur during the transitional periods between the up and down state of slow waves. The preferred phase angles of this form of phase-event amplitude coupling are bimodally distributed, and the ripples (80-150 Hz) that occur during the up-down transition more often occur in the seizure-onset zone ( SOZ). We investigated if bimodal ripple coupling was also evident for faster sleep oscillations, and could identify the SOZ. Methods Using an automated ripple detector, we identified ripple events in 40-60 min intracranial electroencephalography ( iEEG) recordings from 23 patients with medically refractory mesial temporal lobe or neocortical epilepsy. The detector quantified epochs of sleep oscillations and computed instantaneous phase. We utilized a ripple phasor transform, ripple-triggered averaging, and circular statistics to investigate phase event-amplitude coupling. Results We found that at some individual recording sites, ripple event amplitude was coupled with the sleep oscillatory phase and the preferred phase angles exhibited two distinct clusters (p < 0.05). The distribution of the pooled mean preferred phase angle, defined by combining the means from each cluster at each individual recording site, also exhibited two distinct clusters (p < 0.05). Based on the range of preferred phase angles defined by these two clusters, we partitioned each ripple event at each recording site into two groups: depth iEEG peak-trough and trough-peak. The mean ripple rates of the two groups in the SOZ and non-SOZ (NSOZ) were compared. We found that in the frontal (spindle, p = 0.009; theta, p = 0.006, slow, p = 0.004) and parietal lobe (theta, p = 0.007, delta, p = 0.002, slow, p = 0.001) the SOZ incidence rate for the ripples occurring during the trough-peak transition was significantly increased. Significance Phase-event amplitude coupling between ripples and sleep oscillations may be useful to distinguish pathologic and physiologic events in patients with frontal and parietal SOZ. [ABSTRACT FROM AUTHOR]

High-frequency oscillations ( HFOs) are a type of brain activity that is recorded from brain regions capable of generating seizures. Because of the close association of HFOs with epileptogenic tissue and ictogenesis, understanding their cellular and network mechanisms could provide valuable information about the organization of epileptogenic networks and how seizures emerge from the abnormal activity of these networks. In this review, we summarize the most recent advances in the field of HFOs and provide a critical evaluation of new observations within the context of already established knowledge. Recent improvements in recording technology and the introduction of optogenetics into epilepsy research have intensified experimental work on HFOs. Using advanced computer models, new cellular substrates of epileptic HFOs were identified and the role of specific neuronal subtypes in HFO genesis was determined. Traditionally, the pathogenesis of HFOs was explored mainly in patients with temporal lobe epilepsy and in animal models mimicking this condition. HFOs have also been reported to occur in other epileptic disorders and models such as neocortical epilepsy, genetically determined epilepsies, and infantile spasms, which further support the significance of HFOs in the pathophysiology of epilepsy. It is increasingly recognized that HFOs are generated by multiple mechanisms at both the cellular and network levels. Future studies on HFOs combining novel high-resolution in vivo imaging techniques and precise control of neuronal behavior using optogenetics or chemogenetics will provide evidence about the causal role of HFOs in seizures and epileptogenesis. Detailed understanding of the pathophysiology of HFOs will propel better HFO classification and increase their information yield for clinical and diagnostic purposes. [ABSTRACT FROM AUTHOR]

Objective Ripples (80-150 Hz) recorded from clinical macroelectrodes have been shown to be an accurate biomarker of epileptogenic brain tissue. We investigated coupling between epileptiform spike phase and ripple amplitude to better understand the mechanisms that generate this type of pathologic ripple (pRipple) event. Methods We quantified phase amplitude coupling ( PAC) between epileptiform electroencephalography ( EEG) spike phase and ripple amplitude recorded from intracranial depth macroelectrodes during episodes of sleep in 12 patients with mesial temporal lobe epilepsy. PAC was determined by (1) a phasor transform that corresponds to the strength and rate of ripples coupled with spikes, and a (2) ripple-triggered average to measure the strength, morphology, and spectral frequency of the modulating and modulated signals. Coupling strength was evaluated in relation to recording sites within and outside the seizure-onset zone ( SOZ). Results Both the phasor transform and ripple-triggered averaging methods showed that ripple amplitude was often robustly coupled with epileptiform EEG spike phase. Coupling was found more regularly inside than outside the SOZ, and coupling strength correlated with the likelihood a macroelectrode's location was within the SOZ (p < 0.01). The ratio of the rate of ripples coupled with EEG spikes inside the SOZ to rates of coupled ripples in non- SOZ was greater than the ratio of rates of ripples on spikes detected irrespective of coupling (p < 0.05). Coupling strength correlated with an increase in mean normalized ripple amplitude (p < 0.01), and a decrease in mean ripple spectral frequency (p < 0.05). Significance Generation of low-frequency (80-150 Hz) pRipples in the SOZ involves coupling between epileptiform spike phase and ripple amplitude. The changes in excitability reflected as epileptiform spikes may also cause clusters of pathologically interconnected bursting neurons to grow and synchronize into aberrantly large neuronal assemblies. [ABSTRACT FROM AUTHOR]

Objective Posttraumatic epilepsy ( PTE) accounts for 20% of acquired epilepsies. Experimental models are important for studying epileptogenesis. We previously reported that repetitive high-frequency oscillations with spikes ( rHFOSs) occur early after lateral fluid percussion injury (FPI) and may be a biomarker for PTE. The objective of this study was to use multiple electrodes in rat hippocampal and neocortical regions to describe the long-term electroencephalographic and behavioral evolution of rHFOSs and epileptic seizures after traumatic brain injury (TBI). Methods Adult male rats underwent mild, moderate, or severe FPI or sham injury followed by video-electroencephalography ( EEG) recordings with a combination of 16 neocortical and hippocampal electrodes at an early, intermediate, or late time-point after injury, up to 52 weeks. Recordings were analyzed for the presence of rHFOSs and seizures. Results Analysis was done on 28 rats with FPI and 7 shams. Perilesional rHFOSs were recorded in significantly more rats after severe (70.3%) than mild (20%) injury or shams (14.3%). Frequency of occurrence was significantly highest in the early (10.8/h) versus late group (3.2/h). Late focal seizures originating from the same electrodes were recorded in significantly more rats in the late (87.5%) versus early period (22.2%), occurring almost exclusively in injured rats. Seizure duration increased significantly over time, averaging 19 s at the beginning of the early period and 27 s at the end of the late period. Seizure frequency also increased significantly over time, from 4.4 per week in the early group to 26.4 per week in the late group. Rarely, rats displayed early seizures or generalized seizures. Significance FPI results in early rHFOSs and later spontaneous focal seizures arising from peri-lesional neocortex, supporting its use as a model for PTE. Epilepsy severity increased over time and was related to injury severity. The association between early rHFOSs and later focal seizures suggests that rHFOSs may be a potential noninvasive biomarker of PTE. [ABSTRACT FROM AUTHOR]

Objective To investigate possible electroencephalography ( EEG) correlates of epileptogenesis after traumatic brain injury ( TBI) using the fluid percussion model. Methods Experiments were conducted on adult 2- to 4-month-old male Sprague-Dawley rats. Two groups of animals were studied: (1) the TBI group with depth and screw electrodes implanted immediately after the fluid percussion injury ( FPI) procedure, and (2) a naive age-matched control group with the same electrode implantation montage. Pairs of tungsten microelectrodes (50 μm outer diameter) and screw electrodes were implanted in neocortex inside the TBI core, areas adjacent to TBI, and remote areas. EEG activity, recorded on the day of FPI, and continuously for 2 weeks, was analyzed for possible electrographic biomarkers of epileptogenesis. Video- EEG monitoring was also performed continuously in the TBI group to capture electrographic and behavioral seizures until the caps came off (28-189 days), and for 1 week, at 2, 3, and 6 months of age, in the control group. Results Pathologic high-frequency oscillations ( pHFOs) with a central frequency between 100 and 600 Hz, were recorded from microelectrodes, beginning during the first two post- FPI weeks, in 7 of 12 animals in the TBI group (58%) and never in the controls. pHFOs only occurred in cortical areas within or adjacent to the TBI core. These were associated with synchronous multiunit discharges and popSpikes, duration 15-40 msec. Repetitive pHFOs and EEG spikes ( rHFOSs) formed paroxysmal activity, with a unique arcuate pattern, in the frequency band 10-16 Hz in the same areas as isolated pHFOs, and these events were also recorded by screw electrodes. Although loss of caps prevented long-term recordings from all rats, pHFOs and rHFOSs occurred during the first 2 weeks in all four animals that later developed seizures, and none of the rats without these events developed late seizures. Significance pHFOs, similar to those associated with epileptogenesis in the status rat model of epilepsy, may also reflect epileptogenesis after FPI. rHFOSs could be noninvasive biomarkers of epileptogenesis. [ABSTRACT FROM AUTHOR]

Objective To characterize local field potentials, high frequency oscillations, and single unit firing patterns in microelectrode recordings of human limbic onset seizures. Methods Wide bandwidth local field potential recordings were acquired from microelectrodes implanted in mesial temporal structures during spontaneous seizures from six patients with mesial temporal lobe epilepsy. Results In the seizure onset zone, distinct epileptiform discharges were evident in the local field potential prior to the time of seizure onset in the intracranial EEG. In all three seizures with hypersynchronous ( HYP) seizure onset, fast ripples with incrementally increasing power accompanied epileptiform discharges during the transition to the ictal state (p < 0.01). In a single low voltage fast ( LVF) onset seizure a triad of evolving HYP LFP discharges, increased single unit activity, and fast ripples of incrementally increasing power were identified ~20 s prior to seizure onset (p < 0.01). In addition, incrementally increasing fast ripples occurred after seizure onset just prior to the transition to LVF activity (p < 0.01). HYP onset was associated with an increase in fast ripple and ripple rate (p < 0.05) and commonly each HYP discharge had a superimposed ripple followed by a fast ripple. Putative excitatory and inhibitory single units could be distinguished during limbic seizure onset, and heterogeneous shifts in firing rate were observed during LVF activity. Significance Epileptiform activity is detected by microelectrodes before it is detected by depth macroelectrodes, and the one clinically identified LVF ictal onset was a HYP onset at the local level. Patterns of incrementally increasing fast ripple power are consistent with observations in rats with experimental hippocampal epilepsy, suggesting that limbic seizures arise when small clusters of synchronously bursting neurons increase in size, coalesce, and reach a critical mass for propagation. [ABSTRACT FROM AUTHOR]

Summary Purpose: Patient studies have not provided consistent evidence for interictal neuronal hyperexcitability inside the seizure-onset zone (SOZ). We hypothesized that gray matter (GM) loss could have important effects on neuronal firing, and quantifying these effects would reveal significant differences in neuronal firing inside versus outside the SOZ. Methods: Magnetic resonance imaging (MRI) and computational unfolding of mesial temporal lobe (MTL) subregions was used to construct anatomic maps to compute GM loss in presurgical patients with medically intractable focal seizures in relation to controls. In patients, these same maps were used to locate the position of microelectrodes that recorded interictal neuronal activity. Single neuron firing and burst rates were evaluated in relation to GM loss and MTL subregions inside and outside the SOZ. Key Findings: MTL GM thickness was reduced inside and outside the SOZ in patients with respect to controls, yet GM loss was associated more strongly with firing and burst rates in several MTL subregions inside the SOZ. Adjusting single neuron firing and burst rates for the effects of GM loss revealed significantly higher firing rates in the subregion consisting of dentate gyrus and CA2 and CA3 (CA23DG), as well as CA1 and entorhinal cortex (EC) inside versus outside the SOZ where normalized MRI GM loss was ≥1.40 mm. Firing rates were higher in subicular cortex inside the SOZ at GM loss ≥1.97 mm, whereas burst rates were higher in CA23DG, CA1, and EC inside than outside the SOZ at similar levels of GM loss. Significance: The correlation between GM loss and increased firing and burst rates suggests GM structural alterations in MTL subregions are associated with interictal neuronal hyperexcitability inside the SOZ. Significant differences in firing rates and bursting in areas with GM loss inside compared to outside the SOZ indicate that synaptic reorganization following cell loss could be associated with varying degrees of epileptogenicity in patients with intractable focal seizures. [ABSTRACT FROM AUTHOR]

The article discusses the new imaging approaches of focal epilepsy. It mentions that the first approach includes the structural anatomic surface modeling which utilizes statistical parametric mapping (SPM) to recognize epilepsy linked with abnormalities of magnetic resonance imaging (MRI) of neocortex and hippocampus. It states that the other approach involves functionalized magnetonanoparticles (MNPs) unified to bioactive ligands so as to image exact local cerebral function using MRI.

Objectives There is compelling evidence that pathological high-frequency oscillations (HFOs), called fast ripples (FR, 150-500Hz), reflect abnormal synchronous neuronal discharges in areas responsible for seizure genesis in patients with mesial temporal lobe epilepsy (MTLE). It is hypothesized that morphological changes associated with hippocampal atrophy (HA) contribute to the generation of FR, yet there is limited evidence that hippocampal FR-generating sites correspond with local areas of atrophy. Methods Interictal HFOs were recorded from hippocampal microelectrodes in 10 patients with MTLE. Rates of FR and ripple discharge from each microelectrode were evaluated in relation to local measures of HA obtained using 3-dimensional magnetic resonance imaging (MRI) hippocampal modeling. Results Rates of FR discharge were 3 times higher in areas of significant local HA compared with rates in nonatrophic areas. Furthermore, FR occurrence correlated directly with the severity of damage in these local atrophic regions. In contrast, we found no difference in rates of ripple discharge between local atrophic and nonatrophic areas. Interpretation The proximity between local HA and microelectrode-recorded FR suggests that morphological changes such as neuron loss and synaptic reorganization may contribute to the generation of FR. Pathological HFOs, such as FR, may provide a reliable surrogate marker of abnormal neuronal excitability in hippocampal areas responsible for the generation of spontaneous seizures in patients with MTLE. Based on these data, it is possible that MRI-based measures of local HA could identify FR-generating regions, and thus provide a noninvasive means to localize epileptogenic regions in hippocampus. Ann Neurol 2009;66:783-791 [ABSTRACT FROM AUTHOR]

Current evidence suggests that the mechanisms underlying depth electrode–recorded seizures beginning with hypersynchronous (HYP) onset patterns are functionally distinct from those giving rise to low-voltage fast (LVF) onset seizures. However, both groups have been associated with hippocampal atrophy (HA), indicating a need to clarify the anatomic correlates of each ictal onset type. We used three-dimensional (3D) hippocampal mapping to quantify HA and determine whether each onset group exhibited a unique distribution of atrophy consistent with the functional differences that distinguish the two onset morphologies. Sixteen nonconsecutive patients with medically refractory epilepsy were assigned to HYP or LVF groups according to ictal onset patterns recorded with intracranial depth electrodes. Using preimplant magnetic resonance imaging (MRI), levels of volumetrically defined HA were determined by comparison with matched controls, and the distribution of local atrophy was mapped onto 3D hippocampal surface models. HYP and LVF groups exhibited significant and equivalent levels of HA ipsilateral to seizure onset. Patients with LVF onset seizures also showed significant contralateral volume reductions. On ipsilateral contour maps HYP patients exhibited an atrophy pattern consistent with classical hippocampal sclerosis (HS), whereas LVF atrophy was distributed more laterally and diffusely. Contralateral LVF maps also showed regions of subicular atrophy. The HS-like distribution of atrophy and the restriction of HA to the ipsilateral hippocampus in HYP patients are consistent with focal hippocampal onsets, and suggest a mechanism utilizing intrahippocampal circuitry. In contrast, the bilateral distribution of nonspecific atrophy in the LVF group may reflect mechanisms involving both hippocampal and extrahippocampal networks. [ABSTRACT FROM AUTHOR]

High-frequency oscillations (HFOs) in the 80–200 Hz range can be recorded from normal hippocampus and parahippocampal structures of humans and animals. They are believed to reflect inhibitory field potentials, which facilitate information transfer by synchronizing neuronal activity over long distances. HFOs in the range of 250–600 Hz (fast ripples, FRs) are pathologic and are readily recorded from hippocampus and parahippocampal structures of patients with mesial temporal lobe epilepsy, as well as rodent models of this disorder. These oscillations, and similar HFOs recorded from neocortex of patients, appear to identify brain tissue capable of spontaneous ictogenesis and are believed to reflect the neuronal substrates of epileptogenesis and epileptogenicity. The distinction between normal and pathologic HFOs (pHFOs), however, cannot be made on the basis of frequency alone, as oscillations in the FR frequency range can be recorded from some areas of normal neocortex, whereas oscillations in the ripple frequency range are present in epileptic dentate gyrus where normal ripples never occur and, therefore, appear to be pathologic. The suggestion that FRs may be harmonics of normal ripples is unlikely, because of their spatially distinct generators, and evidence that FRs reflect synchronized firing of abnormally bursting neurons rather than inhibitory field potentials. These synchronous population spikes, however, can fire at ripple frequencies, and their harmonics appear to give rise to FRs. Investigations into the fundamental neuronal processes responsible for pHFOs could provide insights into basic mechanisms of epilepsy. The potential for pHFOs to act as biomarkers for epileptogenesis and epileptogenicity is also discussed. [ABSTRACT FROM AUTHOR]

To determine whether hippocampal sclerosis might form an anatomical substrate for pathological high-frequency oscillations in patients with temporal lobe epilepsy (TLE). Intracerebral wide bandwidth electroencephalogram was recorded in patients with medically intractable complex partial seizures. A computer-automated program detected interictal normal ripples (80–150 Hz) and pathologic fast ripples (FR, 151–500 Hz) from microelectrodes within hippocampus, entorhinal, and subicular cortices. Hippocampal MRI volumetric analysis and cell density measurements were correlated with rates of FR and ripple discharge. In all 13 patients, higher rates of FR (p = 0.03) and ratios of FR to ripple discharges (p = 0.02) were observed in sites ipsilateral to seizure onset compared with rates within contralateral nonictal sites. Higher ratios of FR to ripple discharge were associated with smaller ipsilateral hippocampal volumes (p = 0.02) and lower fascia dentata (FD; p = 0.02) and Ammon's horn (p = 0.0005) neuron densities. While reduced FD and Ammon's horn neuron densities correlated with higher ratios of discharges, stepwise multiple regression analysis revealed that decreased neuron densities within CA1 and prosubiculum regions most strongly predicted ratios of FR to ripples (r2= 0.78, p = 0.008). In surgical patients with TLE, higher ratios of FR to ripple discharges are associated with histopathologic changes found in hippocampal sclerosis. These findings support the hypothesis that pathological alterations linked with hippocampal cell loss and synaptic reorganization promote FR and reduce ripple generation. [ABSTRACT FROM AUTHOR]

Fast electrical oscillations (FOs;>200 Hz), superimposed on vibrissa-evoked slow potentials, may support rapid sensory integration in neocortex. Yet, while it is well established that the positive/negative (P1/N1) slow wave of the somatosensory evoked potential primarily reflects sequential activation of supragranular and infragranular pyramidal cells mediated chiefly via excitatory chemical synaptic pathways, little is known about the generation of FOs. In this study, laminar current source–density analysis and principal component analysis indicated that FOs are generated by two dipolar current sources situated in the supra- and infragranular layers, similar in laminar location to the two current dipoles associated with the slow wave. However, exogenous GABA application reversibly abolished the N1 slow wave, leaving the P1 intact, while the FO was unaffected by GABA. Furthermore, reductions in both supra- and infragranular cortical unit discharge during application of GABA suggests that FO generation is not dependent on the same intracortical synaptic circuits that are associated with the N1 slow wave. These data suggest a marked functional dissociation between neural mechanisms underlying the slow and fast components of the vibrissa-evoked response. [ABSTRACT FROM AUTHOR]

This review systematically analyzes potential biomarker candidates for post‐traumatic epilepsy (PTE) in humans who have experienced moderate to severe traumatic brain injury (TBI). Focusing on biomarkers across biofluid‐based protein, genetic, neuroimaging, and neurophysiological categories, this review distinguishes between TBI patients who develop PTE and those who do not. The review adheres to established methodologies outlined in the Cochrane Handbook for Systematic Reviews of Interventions. Data presentation follows the Meta‐analyses of Observational Studies (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. Medline, Embase, and Web of Science were systematically searched and yielded 7538 records, of which 18 met inclusion criteria (moderate–severe TBI in humans, follow‐up of at least 6 months, and no prior history of epilepsy). The review aggregates data from 15 cohort and 3 case–control studies (risk of bias was assessed using the Newcastle‐Ottawa Scale). Statistically significant biomarkers were identified, with neurophysiological biomarkers showing the strongest effect size in a two‐study meta‐analysis. PTE, a severe long‐term outcome of TBI affecting 2% to 53% of individuals with TBI, lacks validated biomarkers for forecasting development, crucial for designing preventive clinical trials. A multimodal approach, integrating biofluid‐based protein, genetic, neuroimaging, and neurophysiological data, offers a promising strategy to enhance the predictability of PTE development and, potentially, its treatment. The study's protocol is registered in the International Prospective Register of Systematic Reviews PROSPERO (Registration ID: CRD42023470245). [ABSTRACT FROM AUTHOR]

Pathologic high-frequency oscillations, believed to reflect basic neuronal disturbances responsible for epilepsy, are promising biologic markers that may be used in clinical studies to optimize surgical treatment of medically refractory epilepsy, and studies that seek to develop new therapies for treatment, and possible prevention, of epilepsy. For an expanded treatment of this topic see Jasper's Basic Mechanisms of the Epilepsies, Fourth Edition (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds) published by Oxford University Press (available on the National Library of Medicine Bookshelf [NCBI] at ). [ABSTRACT FROM AUTHOR]