Incomplete resection of the intracranial electroencephalographic seizure onset zone is not associated with postsurgical outcomes.

Delineation of seizure onset regions using intracranial electroencephalography (icEEG) is vital in the surgical workup of drug-resistant epilepsy cases. However, it is unknown whether the complete resection of these regions is necessary for seizure freedom, or whether postsurgical seizure recurrence can be attributed to the incomplete removal of seizure onset regions. To address this gap, we retrospectively analyzed icEEG recordings from 63 subjects, identifying seizure onset regions visually and algorithmically. We assessed onset region resection and correlated this with postsurgical seizure control. The majority of subjects had more than half of their onset regions resected (82.46% and 80.65% of subjects using visual and algorithmic methods, respectively). There was no association between the proportion of the seizure onset zone (SOZ) that was subsequently resected and better surgical outcomes (area under the receiver operating characteristic curve [AUC] < .7). Investigating the spatial extent of onset regions, we found no substantial evidence of an association with postsurgical seizure control (all AUC < .7). Although seizure onset regions are typically resected completely or in large part, incomplete resection is not associated with worse postsurgical outcomes. We conclude that postsurgical seizure recurrence cannot be attributed to an incomplete resection of the icEEG SOZ alone. Other network mechanisms beyond icEEG seizure onset likely contribute.

Identifying epileptogenic abnormality by decomposing intracranial EEG and MEG power spectra.

BACKGROUND: Accurate identification of abnormal electroencephalographic (EEG) activity is pivotal for diagnosing and treating epilepsy. Recent studies indicate that decomposing brain activity into periodic (oscillatory) and aperiodic (trend across all frequencies) components can illuminate the drivers of spectral activity changes. NEW METHODS: We analysed intracranial EEG (iEEG) data from 234 subjects, creating a normative map. This map was compared to a cohort of 63 patients with refractory focal epilepsy under consideration for neurosurgery. The normative map was computed using three approaches: (i) relative complete band power, (ii) relative band power with the aperiodic component removed, and (iii) the aperiodic exponent. Abnormalities were calculated for each approach in the patient cohort. We evaluated the spatial profiles, assessed their ability to localize abnormalities, and replicated the findings using magnetoencephalography (MEG). RESULTS: Normative maps of relative complete band power and relative periodic band power exhibited similar spatial profiles, while the aperiodic normative map revealed higher exponent values in the temporal lobe. Abnormalities estimated through complete band power effectively distinguished between good and bad outcome patients. Combining periodic and aperiodic abnormalities enhanced performance, like the complete band power approach. COMPARISON WITH EXISTING METHODS AND CONCLUSIONS: Sparing cerebral tissue with abnormalities in both periodic and aperiodic activity may result in poor surgical outcomes. Both periodic and aperiodic components do not carry sufficient information in isolation. The relative complete band power solution proved to be the most reliable method for this purpose. Future studies could investigate how cerebral location or pathology influences periodic or aperiodic abnormalities.

Chronic intracranial EEG recordings and interictal spike rate reveal multiscale temporal modulations in seizure states.

Many biological processes are modulated by rhythms on circadian and multidien timescales. In focal epilepsy, various seizure features, such as spread and duration, can change from one seizure to the next within the same patient. However, the specific timescales of this variability, as well as the specific seizure characteristics that change over time, are unclear. Here, in a cross-sectional observational study, we analysed within-patient seizure variability in 10 patients with chronic intracranial EEG recordings (185-767 days of recording time, 57-452 analysed seizures/patient). We characterized the seizure evolutions as sequences of a finite number of patient-specific functional seizure network states. We then compared seizure network state occurrence and duration to (1) time since implantation and (2) patient-specific circadian and multidien cycles in interictal spike rate. In most patients, the occurrence or duration of at least one seizure network state was associated with the time since implantation. Some patients had one or more seizure network states that were associated with phases of circadian and/or multidien spike rate cycles. A given seizure network state's occurrence and duration were usually not associated with the same timescale. Our results suggest that different time-varying factors modulate within-patient seizure evolutions over multiple timescales, with separate processes modulating a seizure network state's occurrence and duration. These findings imply that the development of time-adaptive treatments in epilepsy must account for several separate properties of epileptic seizures and similar principles likely apply to other neurological conditions.

Temporal stability of intracranial electroencephalographic abnormality maps for localizing epileptogenic tissue.

OBJECTIVE: Identifying abnormalities on interictal intracranial electroencephalogram (iEEG), by comparing patient data to a normative map, has shown promise for the localization of epileptogenic tissue and prediction of outcome. The approach typically uses short interictal segments of approximately 1 min. However, the temporal stability of findings has not been established. METHODS: Here, we generated a normative map of iEEG in nonpathological brain tissue from 249 patients. We computed regional band power abnormalities in a separate cohort of 39 patients for the duration of their monitoring period (.92-8.62 days of iEEG data, mean = 4.58 days per patient, >4800 hours recording). To assess the localizing value of band power abnormality, we computed D RS -a measure of how different the surgically resected and spared tissue was in terms of band power abnormalities-over time. RESULTS: In each patient, the D RS value was relatively consistent over time. The median D RS of the entire recording period separated seizure-free (International League Against Epilepsy [ILAE] = 1) and not-seizure-free (ILAE > 1) patients well (area under the curve [AUC] = .69). This effect was similar interictally (AUC = .69) and peri-ictally (AUC = .71). SIGNIFICANCE: Our results suggest that band power abnormality D_RS, as a predictor of outcomes from epilepsy surgery, is a relatively robust metric over time. These findings add further support for abnormality mapping of neurophysiology data during presurgical evaluation.

A library of quantitative markers of seizure severity.

OBJECTIVE: Understanding fluctuations in seizure severity within individuals is important for determining treatment outcomes and responses to therapy, as well as assessing novel treatments for epilepsy. Current methods for grading seizure severity rely on qualitative interpretations from patients and clinicians. Quantitative measures of seizure severity would complement existing approaches to electroencephalographic (EEG) monitoring, outcome monitoring, and seizure prediction. Therefore, we developed a library of quantitative EEG markers that assess the spread and intensity of abnormal electrical activity during and after seizures. METHODS: We analyzed intracranial EEG (iEEG) recordings of 1009 seizures from 63 patients. For each seizure, we computed 16 markers of seizure severity that capture the signal magnitude, spread, duration, and postictal suppression of seizures. RESULTS: Quantitative EEG markers of seizure severity distinguished focal versus subclinical seizures across patients. In individual patients, 53% had a moderate to large difference (rank sum r > .3 , p < .05 ) between focal and subclinical seizures in three or more markers. Circadian and longer term changes in severity were found for the majority of patients. SIGNIFICANCE: We demonstrate the feasibility of using quantitative iEEG markers to measure seizure severity. Our quantitative markers distinguish between seizure types and are therefore sensitive to established qualitative differences in seizure severity. Our results also suggest that seizure severity is modulated over different timescales. We envisage that our proposed seizure severity library will be expanded and updated in collaboration with the epilepsy research community to include more measures and modalities.

MEG abnormalities and mechanisms of surgical failure in neocortical epilepsy.

OBJECTIVE: Epilepsy surgery fails to achieve seizure freedom in 30%-40% of cases. It is not fully understood why some surgeries are unsuccessful. By comparing interictal magnetoencephalography (MEG) band power from patient data to normative maps, which describe healthy spatial and population variability, we identify patient-specific abnormalities relating to surgical failure. We propose three mechanisms contributing to poor surgical outcome: (1) not resecting the epileptogenic abnormalities (mislocalization), (2) failing to remove all epileptogenic abnormalities (partial resection), and (3) insufficiently impacting the overall cortical abnormality. Herein we develop markers of these mechanisms, validating them against patient outcomes. METHODS: Resting-state MEG recordings were acquired for 70 healthy controls and 32 patients with refractory neocortical epilepsy. Relative band-power spatial maps were computed using source-localized recordings. Patient and region-specific band-power abnormalities were estimated as the maximum absolute z-score across five frequency bands using healthy data as a baseline. Resected regions were identified using postoperative magnetic resonance imaging (MRI). We hypothesized that our mechanistically interpretable markers would discriminate patients with and without postoperative seizure freedom. RESULTS: Our markers discriminated surgical outcome groups (abnormalities not targeted: area under the curve [AUC] = 0.80, p = .003; partial resection of epileptogenic zone: AUC = 0.68, p = .053; and insufficient cortical abnormality impact: AUC = 0.64, p = .096). Furthermore, 95% of those patients who were not seizure-free had markers of surgical failure for at least one of the three proposed mechanisms. In contrast, of those patients without markers for any mechanism, 80% were ultimately seizure-free. SIGNIFICANCE: The mapping of abnormalities across the brain is important for a wide range of neurological conditions. Here we have demonstrated that interictal MEG band-power mapping has merit for the localization of pathology and improving our mechanistic understanding of epilepsy. Our markers for mechanisms of surgical failure could be used in the future to construct predictive models of surgical outcome, aiding clinical teams during patient pre-surgical evaluations.

Multiple mechanisms shape the relationship between pathway and duration of focal seizures.

A seizure's electrographic dynamics are characterized by its spatiotemporal evolution, also termed dynamical 'pathway', and the time it takes to complete that pathway, which results in the seizure's duration. Both seizure pathways and durations have been shown to vary within the same patient. However, it is unclear whether seizures following the same pathway will have the same duration or if these features can vary independently. We compared within-subject variability in these seizure features using (i) epilepsy monitoring unit intracranial EEG (iEEG) recordings of 31 patients (mean: 6.7 days, 16.5 seizures/subject), (ii) NeuroVista chronic iEEG recordings of 10 patients (mean: 521.2 days, 252.6 seizures/subject) and (iii) chronic iEEG recordings of three dogs with focal-onset seizures (mean: 324.4 days, 62.3 seizures/subject). While the strength of the relationship between seizure pathways and durations was highly subject-specific, in most subjects, changes in seizure pathways were only weakly to moderately associated with differences in seizure durations. The relationship between seizure pathways and durations was strengthened by seizures that were 'truncated' versions, both in pathway and duration, of other seizures. However, the relationship was weakened by seizures that had a common pathway, but different durations ('elasticity'), or had similar durations, but followed different pathways ('semblance'). Even in subjects with distinct populations of short and long seizures, seizure durations were not a reliable indicator of different seizure pathways. These findings suggest that seizure pathways and durations are modulated by multiple different mechanisms. Uncovering such mechanisms may reveal novel therapeutic targets for reducing seizure duration and severity.

Volumetric and structural connectivity abnormalities co-localise in TLE.

Patients with temporal lobe epilepsy (TLE) exhibit both volumetric and structural connectivity abnormalities relative to healthy controls. How these abnormalities inter-relate and their mechanisms are unclear. We computed grey matter volumetric changes and white matter structural connectivity abnormalities in 144 patients with unilateral TLE and 96 healthy controls. Regional volumes were calculated using T1-weighted MRI, while structural connectivity was derived using white matter fibre tractography from diffusion-weighted MRI. For each regional volume and each connection strength, we calculated the effect size between patient and control groups in a group-level analysis. We then applied hierarchical regression to investigate the relationship between volumetric and structural connectivity abnormalities in individuals. Additionally, we quantified whether abnormalities co-localised within individual patients by computing Dice similarity scores. In TLE, white matter connectivity abnormalities were greater when joining two grey matter regions with abnormal volumes. Similarly, grey matter volumetric abnormalities were greater when joined by abnormal white matter connections. The extent of volumetric and connectivity abnormalities related to epilepsy duration, but co-localisation did not. Co-localisation was primarily driven by neighbouring abnormalities in the ipsilateral hemisphere. Overall, volumetric and structural connectivity abnormalities were related in TLE. Our results suggest that shared mechanisms may underlie changes in both volume and connectivity alterations in patients with TLE.

Fluctuations in EEG band power at subject-specific timescales over minutes to days explain changes in seizure evolutions.

Epilepsy is recognised as a dynamic disease, where both seizure susceptibility and seizure characteristics themselves change over time. Specifically, we recently quantified the variable electrographic spatio-temporal seizure evolutions that exist within individual patients. This variability appears to follow subject-specific circadian, or longer, timescale modulations. It is therefore important to know whether continuously recorded interictaliEEG features can capture signatures of these modulations over different timescales. In this study, we analyse continuous intracranial electroencephalographic (iEEG) recordings from video-telemetry units and find fluctuations in iEEG band power over timescales ranging from minutes up to 12 days. As expected and in agreement with previous studies, we find that all subjects show a circadian fluctuation in their iEEG band power. We additionally detect other fluctuations of similar magnitude on subject-specific timescales. Importantly, we find that a combination of these fluctuations on different timescales can explain changes in seizure evolutions in most subjects above chance level. These results suggest that subject-specific fluctuations in iEEG band power over timescales of minutes to days may serve as markers of seizure modulating processes. We hope that future study can link these detected fluctuations to their biological driver(s). There is a critical need to better understand seizure modulating processes, as this will enable the development of novel treatment strategies that could minimise the seizure spread, duration or severity and therefore the clinical impact of seizures.

Normative brain mapping of interictal intracranial EEG to localize epileptogenic tissue.

The identification of abnormal electrographic activity is important in a wide range of neurological disorders, including epilepsy for localizing epileptogenic tissue. However, this identification may be challenging during non-seizure (interictal) periods, especially if abnormalities are subtle compared to the repertoire of possible healthy brain dynamics. Here, we investigate if such interictal abnormalities become more salient by quantitatively accounting for the range of healthy brain dynamics in a location-specific manner. To this end, we constructed a normative map of brain dynamics, in terms of relative band power, from interictal intracranial recordings from 234 participants (21 598 electrode contacts). We then compared interictal recordings from 62 patients with epilepsy to the normative map to identify abnormal regions. We proposed that if the most abnormal regions were spared by surgery, then patients would be more likely to experience continued seizures postoperatively. We first confirmed that the spatial variations of band power in the normative map across brain regions were consistent with healthy variations reported in the literature. Second, when accounting for the normative variations, regions that were spared by surgery were more abnormal than those resected only in patients with persistent postoperative seizures (t = -3.6, P = 0.0003), confirming our hypothesis. Third, we found that this effect discriminated patient outcomes (area under curve 0.75 P = 0.0003). Normative mapping is a well-established practice in neuroscientific research. Our study suggests that this approach is feasible to detect interictal abnormalities in intracranial EEG, and of potential clinical value to identify pathological tissue in epilepsy. Finally, we make our normative intracranial map publicly available to facilitate future investigations in epilepsy and beyond.

Focal to bilateral tonic-clonic seizures are associated with widespread network abnormality in temporal lobe epilepsy.

OBJECTIVE: Our objective was to identify whether the whole-brain structural network alterations in patients with temporal lobe epilepsy (TLE) and focal to bilateral tonic-clonic seizures (FBTCS) differ from alterations in patients without FBTCS. METHODS: We dichotomized a cohort of 83 drug-resistant patients with TLE into those with and without FBTCS and compared each group to 29 healthy controls. For each subject, we used diffusion-weighted magnetic resonance imaging to construct whole-brain structural networks. First, we measured the extent of alterations by performing FBTCS-negative (FBTCS-) versus control and FBTCS-positive (FBTCS+) versus control comparisons, thereby delineating altered subnetworks of the whole-brain structural network. Second, by standardizing each patient's networks using control networks, we measured the subject-specific abnormality at every brain region in the network, thereby quantifying the spatial localization and the amount of abnormality in every patient. RESULTS: Both FBTCS+ and FBTCS- patient groups had altered subnetworks with reduced fractional anisotropy and increased mean diffusivity compared to controls. The altered subnetwork in FBTCS+ patients was more widespread than in FBTCS- patients (441 connections altered at t > 3, p < .001 in FBTCS+ compared to 21 connections altered at t > 3, p = .01 in FBTCS-). Significantly greater abnormalities-aggregated over the entire brain network as well as assessed at the resolution of individual brain areas-were present in FBTCS+ patients (p < .001, d = .82, 95% confidence interval = .32-1.3). In contrast, the fewer abnormalities present in FBTCS- patients were mainly localized to the temporal and frontal areas. SIGNIFICANCE: The whole-brain structural network is altered to a greater and more widespread extent in patients with TLE and FBTCS. We suggest that these abnormal networks may serve as an underlying structural basis or consequence of the greater seizure spread observed in FBTCS.

Band power modulation through intracranial EEG stimulation and its cross-session consistency.

OBJECTIVE: Direct electrical stimulation of the brain through intracranial electrodes is currently used to probe the epileptic brain as part of pre-surgical evaluation, and it is also being considered for therapeutic treatments through neuromodulation. In order to effectively modulate neural activity, a given neuromodulation design must elicit similar responses throughout the course of treatment. However, it is unknown whether intracranial electrical stimulation responses are consistent across sessions. The objective of this study was to investigate the within-subject, cross-session consistency of the electrophysiological effect of electrical stimulation delivered through intracranial electroencephalography (iEEG). APPROACH: We analysed data from 79 epilepsy patients implanted with iEEG who underwent brain stimulation as part of a memory experiment. We quantified the effect of stimulation in terms of band power modulation and compared this effect from session to session. As a reference, we made the same measurements during baseline periods. MAIN RESULTS: In most sessions, the effect of stimulation on band power could not be distinguished from baseline fluctuations of band power. Stimulation effect was consistent in a third of the session pairs, while the rest had a consistency measure not exceeding the baseline standards. Cross-session consistency was highly correlated with the degree of band power increase, and it also tended to be higher when the baseline conditions were more similar between sessions. SIGNIFICANCE: These findings can inform our practices for designing neuromodulation with greater efficacy when using direct electrical brain stimulation as a therapeutic treatment.

Interictal intracranial electroencephalography for predicting surgical success: The importance of space and time.

OBJECTIVE: Predicting postoperative seizure freedom using functional correlation networks derived from interictal intracranial electroencephalography (EEG) has shown some success. However, there are important challenges to consider: (1) electrodes physically closer to each other naturally tend to be more correlated, causing a spatial bias; (2) implantation location and number of electrodes differ between patients, making cross-subject comparisons difficult; and (3) functional correlation networks can vary over time but are currently assumed to be static. METHODS: In this study, we address these three challenges using intracranial EEG data from 55 patients with intractable focal epilepsy. Patients additionally underwent preoperative magnetic resonance imaging (MRI), intraoperative computed tomography, and postoperative MRI, allowing accurate localization of electrodes and delineation of the removed tissue. RESULTS: We show that normalizing for spatial proximity between nearby electrodes improves prediction of postsurgery seizure outcomes. Moreover, patients with more extensive electrode coverage were more likely to have their outcome predicted correctly (area under the receiver operating characteristic curve > 0.9, P « 0.05) but not necessarily more likely to have a better outcome. Finally, our predictions are robust regardless of the time segment analyzed. SIGNIFICANCE: Future studies should account for the spatial proximity of electrodes in functional network construction to improve prediction of postsurgical seizure outcomes. Greater coverage of both removed and spared tissue allows for predictions with higher accuracy.

Seizure pathways change on circadian and slower timescales in individual patients with focal epilepsy.

Personalized medicine requires that treatments adapt to not only the patient but also changing factors within each individual. Although epilepsy is a dynamic disorder characterized by pathological fluctuations in brain state, surprisingly little is known about whether and how seizures vary in the same patient. We quantitatively compared within-patient seizure network evolutions using intracranial electroencephalographic (iEEG) recordings of over 500 seizures from 31 patients with focal epilepsy (mean 16.5 seizures per patient). In all patients, we found variability in seizure paths through the space of possible network dynamics. Seizures with similar pathways tended to occur closer together in time, and a simple model suggested that seizure pathways change on circadian and/or slower timescales in the majority of patients. These temporal relationships occurred independent of whether the patient underwent antiepileptic medication reduction. Our results suggest that various modulatory processes, operating at different timescales, shape within-patient seizure evolutions, leading to variable seizure pathways that may require tailored treatment approaches.

Activin receptor signaling regulates cocaine-primed behavioral and morphological plasticity.

Activin receptor signaling, including the transcription factor Smad3, was upregulated in the rat nucleus accumbens (NAc) shell following withdrawal from cocaine. Direct genetic and pharmacological manipulations of this pathway bidirectionally altered cocaine seeking while governing morphological plasticity in NAc neurons. Thus, Activin/Smad3 signaling is induced following withdrawal from cocaine, and such regulation may be a key molecular mechanism underlying behavioral and cellular plasticity in the brain following cocaine self-administration.

Optogenetic inhibition of D1R containing nucleus accumbens neurons alters cocaine-mediated regulation of Tiam1.

Exposure to psychostimulants results in structural and synaptic plasticity in striatal medium spiny neurons (MSNs). These cellular adaptations arise from alterations in genes that are highly implicated in the rearrangement of the actin-cytoskeleton, such as T-lymphoma invasion and metastasis 1 (Tiam1). Previous studies have demonstrated a crucial role for dopamine receptor 1 (D1)-containing striatal MSNs in mediating psychostimulant induced plasticity changes. These D1-MSNs in the nucleus accumbens (NAc) positively regulate drug seeking, reward, and locomotor behavioral effects as well as the morphological adaptations of psychostimulant drugs. Here, we demonstrate that rats that actively self-administer cocaine display reduced levels of Tiam1 in the NAc. To further examine the cell type-specific contribution to these changes in Tiam1 we used optogenetics to selectively manipulate NAc D1-MSNs or dopamine receptor 2 (D2) expressing MSNs. We find that repeated channelrhodopsin-2 activation of D1-MSNs but not D2-MSNs caused a down-regulation of Tiam1 levels similar to the effects of cocaine. Further, activation of D2-MSNs, which caused a late blunted cocaine-mediated locomotor behavioral response, did not alter Tiam1 levels. We then examined the contribution of D1-MSNs to the cocaine-mediated decrease of Tiam1. Using the light activated chloride pump, eNpHR3.0 (enhanced Natronomonas pharaonis halorhodopsin 3.0), we selectively inhibited D1-MSNs during cocaine exposure, which resulted in a behavioral blockade of cocaine-induced locomotor sensitization. Moreover, inhibiting these NAc D1-MSNs during cocaine exposure reversed the down-regulation of Tiam1 gene expression and protein levels. These data demonstrate that altering activity in specific neural circuits with optogenetics can impact the underlying molecular substrates of psychostimulant-mediated behavior and function.

Transforming growth factor beta receptor 1 is increased following abstinence from cocaine self-administration, but not cocaine sensitization.

The addicted phenotype is characterized as a long-lasting, chronically relapsing disorder that persists following long periods of abstinence, suggesting that the underlying molecular changes are stable and endure for long periods even in the absence of drug. Here, we investigated Transforming Growth Factor-Beta Type I receptor (TGF-ß R1) expression in the nucleus accumbens (NAc) following periods of withdrawal from cocaine self-administration (SA) and a sensitizing regimen of non-contingent cocaine. Rats were exposed to either (i) repeated systemic injections (cocaine or saline), or (ii) self-administration (cocaine or saline) and underwent a period of forced abstinence (either 1 or 7 days of drug cessation). Withdrawal from cocaine self-administration resulted in an increase in TGF-ß R1 protein expression in the NAc compared to saline controls. This increase was specific for volitional cocaine intake as no change in expression was observed following a sensitizing regimen of experimenter-administered cocaine. These findings implicate TGF-ß signaling as a novel potential therapeutic target for treating drug addiction.