Scalp Ripples Can Predict Development of Epilepsy After First Unprovoked Seizure in Childhood.

OBJECTIVE: Identification of children at risk of developing epilepsy after a first unprovoked seizure can be challenging. Interictal epileptiform discharges are associated with higher risk but have limited sensitivity and specificity. High frequency oscillations (HFOs) are newer biomarkers for epileptogenesis. We prospectively evaluated the predictive value of HFOs for developing epilepsy in scalp electroencephalogram (EEG) of children after a first unprovoked seizure. METHODS: After their first seizure, 56 children were followed prospectively over 12 months and then grouped in "epilepsy" or "no epilepsy." Initial EEGs were visually analyzed for spikes, spike ripples, and ripples. Inter-group comparisons of spike-rates and HFO-rates were done by Mann-Whitney U test. Predictive values and optimal thresholds were calculated by receiver operating characteristic (ROC) curves. RESULTS: In the epilepsy group (n = 26, 46%), mean rates of ripples (0.3 vs 0.09 / minute, p < 0.0001) and spike ripples (0.6 vs 0.06 / minute, p < 0.05) were significantly higher, with no difference in spike rates (1.7 vs 3.0 / minute, p = 0.38). Of those 3 markers, ripples showed the best predictive value (area under the curve [AUC]ripples = 0.88). The optimal threshold for ripples was calculated to be ≥ 0.125 / minute with a sensitivity of 87% and specificity of 85%. Ripple rates were negatively correlated to days passing before epilepsy-diagnosis (R = -0.59, p < 0.0001) and time to a second seizure (R = -0.64, 95% confidence interval [CI] = -0.77 to 0.43, p < 0.0001). INTERPRETATION: We could show that in a cohort of children with a first unprovoked seizure, ripples predict the development of epilepsy better than spikes or spike ripples and might be useful biomarkers in the estimation of prognosis and question of treatment. ANN NEUROL 2021;89:134-142.

Interictal spikes with and without high-frequency oscillation have different single-neuron correlates.

Interictal epileptiform discharges (IEDs) are a widely used biomarker in patients with epilepsy but lack specificity. It has been proposed that there are truly epileptogenic and less pathological or even protective IEDs. Recent studies suggest that highly pathological IEDs are characterized by high-frequency oscillations (HFOs). Here, we aimed to dissect these 'HFO-IEDs' at the single-neuron level, hypothesizing that the underlying mechanisms are distinct from 'non-HFO-IEDs'. Analysing hybrid depth electrode recordings from patients with temporal lobe epilepsy, we found that single-unit firing rates were higher in HFO- than in non-HFO-IEDs. HFO-IEDs were characterized by a pronounced pre-peak increase in firing, which coincided with the preferential occurrence of HFOs, whereas in non-HFO-IEDs, there was only a mild pre-peak increase followed by a post-peak suppression. Comparing each unit's firing during HFO-IEDs to its baseline activity, we found many neurons with a significant increase during the HFO component or ascending part, but almost none with a decrease. No such imbalance was observed during non-HFO-IEDs. Finally, comparing each unit's firing directly between HFO- and non-HFO-IEDs, we found that most cells had higher rates during HFO-IEDs and, moreover, identified a distinct subset of neurons with a significant preference for this IED subtype. In summary, our study reveals that HFO- and non-HFO-IEDs have different single-unit correlates. In HFO-IEDs, many neurons are moderately activated, and some participate selectively, suggesting that both types of increased firing contribute to highly pathological IEDs.

Anxiety of families after first unprovoked or first febrile seizure - A prospective, randomized pilot study.

OBJECTIVES: Parents of children with a first unprovoked seizure report high levels of stress and anxiety. Little is known however about interventions that might help to reduce anxiety. We aimed to evaluate anxiety of parents and children after a first unprovoked seizure and assess the anxiety-reducing effect of a semi-structured follow-up in a first seizure clinic (FSC). In comparison, parents of children with febrile seizures are also evaluated, as an example of anxiety evolution without follow-up intervention after provoked seizures. STUDY DESIGN: In this prospective, interventional study, patients presenting with a first unprovoked seizure were randomized to early care (EC) with follow-up in FSC within 3 weeks and late care (LC), follow-up in FSC after 4 months. Anxiety levels of parents and patients were scored with the State Trait Anxiety Inventory (STAI) after the initial seizure (T0), 3 and 12 months (T1, T2). To assess the effect of the semi-structured follow-up, anxiety scores were compared between the two groups at baseline, at T1 (i.e., after intervention in EC but prior to intervention in LC) and at T2. Parents of children with febrile seizures (FS) were prospectively followed up without intervention. RESULTS: Fifty two patients were included (EC n = 18, LC n = 18, FS n = 15). Initial state anxiety in parents was high in all groups. At T1 (i. e. after intervention in EC but not LC) state anxiety was significantly higher in LC (52.2 (16.7) vs. 33.3 (5.3), p < 0.01). This effect persisted after 12 months, despite intervention in LC in the meantime (39.0 (11.7) vs. 28.8 (6.2); p < 0.01)). The effect in children was similar (T1: 40.6 (8.3) vs. 29.8 (5.1); p < 0.05 and T2: 33.5 (4.7) vs. 24.7 (3.6); p < 0.01). State anxiety in FS decreased within 3 months without intervention (50.0 (14.5) to 33.7 (9.2)). CONCLUSIONS: A timely and structured follow-up in a FSC offers effective and sustained reduction of anxiety-levels after first unprovoked seizure in children. In contrast, anxiety after a first febrile seizure decreases over time without additional intervention.

Expectations and knowledge of cannabidiol therapy for childhood epilepsy - A German caregiver survey.

BACKGROUND: Cannabidiol (CBD) has gained popularity among parents of children with epilepsy, even before evidence of efficacy and safety was available. The aim of our survey was to gain information about parental attitude to CBD, as well as expectations and knowledge of CBD for treatment of their child's epilepsy. METHODS: A survey using an open-access online questionnaire for parents or caregivers of children with epilepsy within German-speaking countries from March to June 2019 was used. RESULTS: Of 378 complete questionnaires (mean age of children: 11.1 (standard deviation [SD] 7.4) years), 28% (n = 106) reported previous or current CBD treatment over a mean time of 17.31 months (SD: 19.74), whereas 72% had no personal experience with CBD. Treatment was proposed by parents and not by physicians in 83% of cases and was mainly carried out with prescription-only products (71%, n = 67). Nevertheless, 29% used unregulated, artisanal products. Of all parents with previous experience, n = 77 (73%) reported that they expected CBD to be more efficient than the common antiseizure drugs (ASDs) at the beginning. Forty-five percent reported that their expectations were not met during therapy. Consistently, lack of seizure reduction was the most common reason to discontinue CBD (12/26). Of those responders without CBD experience, 93% would consider CBD for their child. However, the self-reported level of information was considered to be poor or very poor regarding efficacy (76%, n = 177), tolerance (83%, n = 191), interaction with other medication (91%, n = 211), and potential long-term effects (87%, n = 212). CONCLUSIONS: There is a huge interest in CBD but includes potentially unrealistic expectations of its efficacy and tolerance combined with a low level of information. Neuropediatricians should address parents of children with epilepsy regarding potential motivation and expectations of CBD. In addition, parental education, especially on interactions and potential side effects, is strongly recommended.

Fast ripple analysis in human mesial temporal lobe epilepsy suggests two different seizure-generating mechanisms.

OBJECTIVE: The distinction of hypersynchronous (HYP) and low-voltage fast (LVF) onset seizures in mesial temporal lobe epilepsy (MTLE) is well established, but classifying individual seizures and patients is often challenging. Experimental work indicates a strong association of HYP with fast ripples (250-500 Hz) and of LVF with ripples (80-250 Hz). We aimed to investigate whether analysis of high-frequency oscillations can be useful for characterizing the process of seizure generation in human MTLE patients. METHODS: We retrospectively compared 19 HYP and 14 LVF onset clinical seizures from ten and six consecutive MTLE patients with a predominance of the respective pattern. Five-second intervals of stereotactic EEGs from the seizure onset zone were selected, each representing the onset of HYP and LVF, the corresponding pre-ictal periods and, after the large spikes of HYP onsets, the LVF-like pattern that frequently followed. RESULTS: Pre-ictal fast ripple density and rate were higher for HYP than for LVF seizures (p < .05). This association was also found for initial ictal segments (p < .001). Furthermore, fast ripple density and rate were higher during the LVF-like pattern after HYP spikes than during LVF without preceding HYP (p < .01). Ripple density and rate in contrast did not differ significantly (p > .05). Fast ripple (p < .01) and ripple (p < .001) amplitude was higher during the LVF-like pattern after HYP spikes when compared to LVF without preceding HYP. SIGNIFICANCE: Our findings indicate a clear connection between experimental findings and human epilepsy. The association of fast ripples with HYP suggests that out-of-phase firing of different pyramidal cell clusters contributes specifically to generation of these seizures, rather than to LVF onsets. Both during and immediately before seizures, fast ripple analysis may facilitate classification.

Valproate associated brain volume-loss in pediatric epilepsy-A case series.

Brain atrophy associated with valproate therapy is known from single case reports and is frequently accompanied by cognitive deterioration. We present a case series of incidental findings of brain volume loss in children treated with valproate and employed automatic brain volumetry to assess the effect size of volume loss. 3D T1w datasets were automatically segmented into white matter, gray matter, and cerebrospinal fluid using the SPM-12 algorithm. Respective volumes of cerebrum and cerebellum were read out and normalized to the total intracranial volume. We identified six patients (median age 148.5 [85-178] months) who had received valproate for a median time of 5 (2-23) months prior to MRI in which a loss of brain volume was noted. None had reported the occurrence of new clinical symptoms. Volumetry showed a volume loss of up to 28% for cerebral GM, 25% for cerebellar GM, 10% for cerebral WM, and 20% for cerebellar WM. A volume loss of >5% in at least one of the subvolumes was found in all patients, with the more prominent volume loss in the cerebrum and in gray matter. In one patient, post-valproate MRI was available and showed normalization of brain volume. Our case series indicates that valproate therapy might be associated with an asymptomatic volume loss of brain parenchyma in children with epilepsy and that this volume loss is assessable with automatic volumetry.

Ictal Occurrence of High-Frequency Oscillations Correlates With Seizure Severity in a Rat Model of Temporal Lobe Epilepsy.

High-frequency oscillations (HFOs, ripples 80-250 Hz, fast ripples 250-500 Hz) are biomarkers of epileptic tissue. They are most commonly observed over areas generating seizures and increase in occurrence during the ictal compared to the interictal period. It has been hypothesized that their rate correlates with the severity of epilepsy and seizure in affected individuals. In the present study, it was aimed to investigate whether the HFO count mirrors the observed behavioral seizure severity using a kainate rat model for temporal lobe epilepsy. Seizures were selected during the chronic epilepsy phase of this model and classified by behavioral severity according to the Racine scale. Seizures with Racine scale 5&6 were considered generalized and severe. HFOs were marked in 24 seizures during a preictal, ictal, and postictal EEG segment. The duration covered by the HFO during these different segments was analyzed and compared between mild and severe seizures. HFOs were significantly increased during ictal periods (p < 0.001) and significantly decreased during postictal periods (p < 0.03) compared to the ictal segment. Ictal ripples (p = 0.04) as well as fast ripples (p = 0.02) were significantly higher in severe seizures compared to mild seizures. The present study demonstrates that ictal HFO occurrence mirrors seizure severity in a chronic focal epilepsy model in rats. This is similar to recent observations in patients with refractory mesio-temporal lobe epilepsy. Moreover, postictal HFO decrease might reflect postictal inhibition of epileptic activity. Overall results provide additional evidence that HFOs can be used as biomarkers for measuring seizure severity in epilepsy.

Distinction of Physiologic and Epileptic Ripples: An Electrical Stimulation Study.

Ripple oscillations (80-250 Hz) are a promising biomarker of epileptic activity, but are also involved in memory consolidation, which impairs their value as a diagnostic tool. Distinguishing physiologic from epileptic ripples has been particularly challenging because usually, invasive recordings are only performed in patients with refractory epilepsy. Here, we identified 'healthy' brain areas based on electrical stimulation and hypothesized that these regions specifically generate 'pure' ripples not coupled to spikes. Intracranial electroencephalography (EEG) recorded with subdural grid electrodes was retrospectively analyzed in 19 patients with drug-resistant focal epilepsy. Interictal spikes and ripples were automatically detected in slow-wave sleep using the publicly available Delphos software. We found that rates of spikes, ripples and ripples coupled to spikes ('spike-ripples') were higher inside the seizure-onset zone (p < 0.001). A comparison of receiver operating characteristic curves revealed that spike-ripples slightly delineated the seizure-onset zone channels, but did this significantly better than spikes (p < 0.001). Ripples were more frequent in the eloquent neocortex than in the remaining non-seizure onset zone areas (p < 0.001). This was due to the higher rates of 'pure' ripples (p < 0.001; median rates 3.3/min vs. 1.4/min), whereas spike-ripple rates were not significantly different (p = 0.87). 'Pure' ripples identified 'healthy' channels significantly better than chance (p < 0.001). Our findings suggest that, in contrast to epileptic spike-ripples, 'pure' ripples are mainly physiological. They may be considered, in addition to electrical stimulation, to delineate eloquent cortex in pre-surgical patients. Since we applied open source software for detection, our approach may be generally suited to tackle a variety of research questions in epilepsy and cognitive science.

Effect of Cannabidiol on Interictal Epileptiform Activity and Sleep Architecture in Children with Intractable Epilepsy: A Prospective Open-Label Study.

BACKGROUND: Cannabidiol has been shown to be effective in seizure reduction in patients with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis. However, very little is known about its potential to reduce interictal epileptiform activity and improve sleep architecture. OBJECTIVE: The objective of this prospective study was to evaluate the influence of cannabidiol therapy on the frequency of interictal epileptiform discharges (IEDs) and sleep microstructure in a cohort of children with drug-resistant epilepsy. METHODS: Children with drug-resistant epilepsy were prospectively followed from November 2019 to January 2021 during an open-label trial of cannabidiol at a dose of 20 mg/kg/day (to a maximum of 50 mg/kg/day) and stable concomitant medication. Electroencephalograms were recorded at baseline (T0) and after 3 months (T1). Two independent raters, blinded to clinical outcome, evaluated 5-min segments of sleep stage 2 or low-noise awake state. IEDs were visually identified and rates per minute calculated. Sleep microstructure was considered improved if sleep structures were seen at T1 that were not present at T0. IED rates at T0 and T1 were compared and correlated with seizure outcome, cannabidiol dose, initial IED rate, and disease duration. RESULTS: In total, 35 children (mean ± standard deviation age 10.1 ± 0.86) were included. The IED rate at T1 was significantly lower than at T0 (19.6 ± 19.5 vs. 36.8 ± 27.2, respectively; p < 0.0001). We found a moderate correlation between IED reduction and percentage of seizure reduction compared with baseline (Pearson's r = 0.39; p = 0.02), a moderate negative correlation between IED reduction and IED rate at T0 (r = - 0.34; p = 0.04), and a trend towards a moderate negative correlation between IED reduction and disease duration (r = - 0.32; p = 0.06). Sleep was recorded in 23 patients. Sleep microstructure was initially abnormal in 56.5% of sleep recordings and improved in 84.6% of those cases. CONCLUSION: Our results strongly suggest the utility of cannabidiol in reducing IEDs and improving sleep microstructure in children with drug-resistant epilepsy. Larger controlled studies are needed to evaluate the clinical relevance of this effect in different epilepsy types. TRIAL REGISTRATION: DRKS00013177; 25 June 2019.

Telehealth for Children With Epilepsy Is Effective and Reduces Anxiety Independent of Healthcare Setting.

Objectives: The use of telemedicine has grown exponentially as an alternative to providing care to patients with epilepsy during the pandemic. We investigated the impact of the current pandemic among children with epilepsy from two distinct pediatric epilepsy centers. We also compared perceptions among those who received telemedicine against those who did not. Methods: We developed a questionnaire and invited families followed in Freiburg, Germany, and Calgary, Alberta, Canada, to participate during the initial 9 months of the pandemic. The survey contained 32 questions, 10 of which were stratified according to telemedicine exposure. Results: One hundred twenty-six families (80 in Freiburg, 46 in Calgary) participated, and 40.3% received telemedicine care. Most children (mean age 10.4 years, SD 5.1) had chronic epilepsy but poorly controlled seizures. Negative impacts were reported by 36 and 65% of families who had to reschedule appointments for visits and diagnostics, respectively. Nearly two-thirds of families reported no change in seizure frequency, while 18.2% reported either worsening or improvement of seizures. Although most families did not note behavioral changes, 28.2% reported behavior worsening. Families who received telemedicine care had a statistically significant reduction of parental self-reported anxiety level after virtual visits compared to those who did not experience telemedicine. Families with telemedicine consultations were more likely to consider future virtual care (84 vs. 65.2% of those without), even after the pandemic. Patient data safety, easy access to specialized services, and consistency with the same healthcare provider were graded as important in both centers, while a shorter waiting time was most relevant in Calgary. Conclusion: In our cohort, some children with epilepsy experienced increased seizures and worsening behavior during the first 9 months of the current pandemic. In addition, our data suggest that telemedicine might reduce parental anxiety symptoms, and families who experienced telehealth were more positive and open to similar appointments in the future.

Facilitation of drug-resistant epilepsy and catastrophic status epilepticus in children with combined pituitary hormone deficiency.

PURPOSE: Clinicians and researchers often focus on the primary cause of seizures and epilepsy, but outcomes in individual patients also depend on multiple other variables, which might be easy to adjust. Previous studies suggest mutual interactions between endocrine disorders and epilepsy. We therefore hypothesized that combined pituitary hormone deficiency (CPHD) facilitates seizures and epilepsy. METHODS: This is a retrospective study from a pediatric center. We determined the proportion of CPHD patients with epilepsy and examined basic clinical features in this group. Patients with super-refractory status epilepticus (SRSE) were reviewed to identify subjects with co-morbid CPHD. Those cases were analyzed in detail. RESULTS: 12 of 73 CPHD patients (16%) also had epilepsy. Various etiologies of CPHD were represented, though five subjects had a cranial tumor or cortical malformation. Epilepsy was drug resistant in all but one patient. Among 12 identified patients with SRSE, 4 were unexpected new-onset cases. Three of these subjects also had CPHD with ACTH deficiency and a febrile infection prior to SRSE. Another common feature was the devastating clinical course: In all three patients, initial MRI already suggested severe neuronal damage, SRSE persisted for at least one week with ongoing need for anesthetic coma, and outcome was poor (two patients survived with major sequelae, one child deceased during the episode). CONCLUSION: Our findings indicate that CPHD may predispose for drug-resistant epilepsy and refractory seizures with catastrophic outcome. We suggest that in children with new-onset SRSE, screening for CPHD should be considered.

Interictal Fast Ripples Are Associated With the Seizure-Generating Lesion in Patients With Dual Pathology.

Rationale: Patients with dual pathology have two potentially epileptogenic lesions: One in the hippocampus and one in the neocortex. If epilepsy surgery is considered, stereotactic electroencephalography (SEEG) may reveal which of the lesions is seizure-generating, but frequently, some uncertainty remains. We aimed to investigate whether interictal high-frequency oscillations (HFOs), which are a promising biomarker of epileptogenicity, are associated with the primary focus. Methods: We retrospectively analyzed 16 patients with dual pathology. They were grouped according to their seizure-generating lesion, as suggested by ictal SEEG. An automated detector was applied to identify interictal epileptic spikes, ripples (80-250 Hz), ripples co-occurring with spikes (IES-ripples) and fast ripples (250-500 Hz). We computed a ratio R to obtain an indicator of whether rates were higher in the hippocampal lesion (R close to 1), higher in the neocortical lesion (R close to -1), or more or less similar (R close to 0). Results: Spike and HFO rates were higher in the hippocampal than in the neocortical lesion (p < 0.001), particularly in seizure onset zone channels. Seizures originated exclusively in the hippocampus in 5 patients (group 1), in both lesions in 7 patients (group 2), and exclusively in the neocortex in 4 patients (group 3). We found a significant correlation between the patients' primary focus and the ratio Rfast ripples, i.e., the proportion of interictal fast ripples detected in this lesion (p < 0.05). No such correlation was observed for interictal epileptic spikes (p = 0.69), ripples (p = 0.60), and IES-ripples (p = 0.54). In retrospect, interictal fast ripples would have correctly "predicted" the primary focus in 69% of our patients (p < 0.01). Conclusions: We report a correlation between interictal fast ripple rate and the primary focus, which was not found for epileptic spikes. Fast ripple analysis could provide helpful information for generating a hypothesis on seizure-generating networks, especially in cases with few or no recorded seizures.

High-frequency oscillations mirror severity of human temporal lobe seizures.

OBJECTIVE: Many patients with epilepsy have both focal and bilateral tonic-clonic seizures (BTCSs), but it is largely unclear why ictal activity spreads only sometimes. Previous work indicates that interictal high-frequency oscillations (HFOs), traditionally subdivided into ripples (80-250 Hz) and fast ripples (250-500 Hz), are a promising biomarker of epileptogenicity. We aimed to investigate whether HFOs correlate with the emergence of seizure activity and whether they differ between focal seizures (FSs) with impaired awareness and BTCSs. METHODS: We retrospectively analyzed 15 FSs and 13 BTCSs from seven patients with mesial temporal lobe epilepsy, each of them with at least one BTCS and at least one FS. Representative intervals of intracranial electroencephalography from the seizure onset zone (SOZ) and remote non-SOZ areas were selected to compare pre-ictal, complex focal, tonic-clonic, and postictal periods. Ripples and fast ripples were visually identified and their density, that is, percentage of time occupied by the respective events, computed. RESULTS: Ripple and fast ripple densities increased inside the SOZ after seizure onset (P < 0.01) and in remote areas after progression to BTCSs (P < 0.01). Postictal SOZ ripple density dropped below pre-ictal levels (P < 0.001). Prior to onset of bilateral tonic-clonic movements, ripple density inside the SOZ is higher in BTCSs than in FSs (P < 0.05). INTERPRETATION: Ripples and fast ripples correlate with onset and spread of ictal activity. Abundant ripples inside the SOZ may reflect the activation of specific neuronal networks related to imminent spread of seizure activity.

Chiari-like displacement due to spontaneous intracranial hypotension in an adolescent: Successful treatment by epidural blood patch.

BACKGROUND: Spontaneous intracranial hypotension is a rarely diagnosed cause of headache, especially in children and adolescents. It is due to cerebrospinal fluid (CSF) leakage via spinal fistulae occurring without major trauma. CASE PRESENTATION: An adolescent patient presented with a 3-month history of strictly postural headache. Cranial magnetic resonance imaging (MRI) showed pronounced Chiari-like prolapse of the cerebellar tonsils, narrow ventricles and enlarged cerebral veins. On spinal MRI, myelographic sequences revealed a large collection of CSF around the first sacral roots. CT myelography proved extensive spinal CSF leakage. Hence, we applied epidural patches at multiple levels. Afterwards, symptoms and radiologic findings, including Chiari-like displacement, completely resolved. CONCLUSION: A Chiari-like descent of the cerebellar tonsils alone does not secure the diagnosis of a Chiari I malformation. Especially if other findings indicate spinal CSF leakage, a systematic work-up should be initiated. In most cases, interventional techniques seal the leak successfully, resulting in a favorable outcome.

Lamina-specific contribution of glutamatergic and GABAergic potentials to hippocampal sharp wave-ripple complexes.

The mammalian hippocampus expresses highly organized patterns of neuronal activity which form a neuronal correlate of spatial memories. These memory-encoding neuronal ensembles form on top of different network oscillations which entrain neurons in a state- and experience-dependent manner. The mechanisms underlying activation, timing and selection of participating neurons are incompletely understood. Here we studied the synaptic mechanisms underlying one prominent network pattern called sharp wave-ripple complexes (SPW-R) which are involved in memory consolidation during sleep. We recorded SPW-R with extracellular electrodes along the different layers of area CA1 in mouse hippocampal slices. Contribution of glutamatergic excitation and GABAergic inhibition, respectively, was probed by local application of receptor antagonists into s. radiatum, pyramidale and oriens. Laminar profiles of field potentials show that GABAergic potentials contribute substantially to sharp waves and superimposed ripple oscillations in s. pyramidale. Inhibitory inputs to s. pyramidale and s. oriens are crucial for action potential timing by ripple oscillations, as revealed by multiunit-recordings in the pyramidal cell layer. Glutamatergic afferents, on the other hand, contribute to sharp waves in s. radiatum where they also evoke a fast oscillation at ~200 Hz. Surprisingly, field ripples in s. radiatum are slightly slower than ripples in s. pyramidale, resulting in a systematic shift between dendritic and somatic oscillations. This complex interplay between dendritic excitation and perisomatic inhibition may be responsible for the precise timing of discharge probability during the time course of SPW-R. Together, our data illustrate a complementary role of spatially confined excitatory and inhibitory transmission during highly ordered network patterns in the hippocampus.