Spike Afterhyperpolarizations Govern Persistent Firing Dynamics in Rat Neocortical and Hippocampal Pyramidal Cells.

Persistent firing is commonly reported in both cortical and subcortical neurons under a variety of behavioral conditions. Yet the mechanisms responsible for persistent activity are only partially resolved with support for both intrinsic and synaptic circuit-based mechanisms. Little also is known about physiological factors that enable epochs of persistent firing to continue beyond brief pauses and then spontaneously terminate. In the present study, we used intracellular recordings in rat (both sexes) neocortical and hippocampal brain slices to assess the ionic mechanisms underlying persistent firing dynamics. Previously, we showed that blockade of ether-á-go-go-related gene (ERG) potassium channels abolished intrinsic persistent firing in the presence of low concentrations of muscarinic receptor agonists and following optogenetic activation of cholinergic axons. Here we show the slow dynamics of ERG conductance changes allows persistent firing to outlast the triggering stimulus and even to initiate discharges following ∼7 s poststimulus firing pauses. We find that persistent firing dynamics is regulated by the interaction between ERG conductance and spike afterhyperpolarizations (AHPs). Increasing the amplitude of spike AHPs using either SK channel activators or a closed-loop reactive feedback system allows persistent discharges to spontaneously terminate in both neocortical neurons and hippocampal CA1 pyramidal cells. The interplay between ERG and the potassium channels that mediate spike AHPs grades the duration of persistent firing, providing a novel, generalizable mechanism to explain self-terminating persistent firing modes observed behaving animals.SIGNIFICANCE STATEMENT Many classes of neurons generate prolonged spiking responses to transient stimuli. These discharges often outlast the stimulus by seconds to minutes in some in vitro models of persistent firing. While recent work has identified key synaptic and intrinsic components that enable persistent spiking responses, less is known about mechanisms that can terminate and regulate the dynamics of these responses. The present study identified the spike afterhyperpolarizations as a potent mechanism that regulates the duration of persistent firing. We found that amplifying spike afterpotentials converted bistable persistent firing into self-terminating discharges. Varying the spike AHP amplitude grades the duration of persistent discharges, generating in vitro responses that mimic firing modes associated with neurons associated with short-term memory function.

Extra-glomerular excitation of rat olfactory bulb mitral cells by depolarizing GABAergic synaptic input.

Principal cells in the olfactory bulb (OB), mitral and tufted cells, receive direct sensory input and generate output signals that are transmitted to downstream cortical targets. Excitatory input from glutamatergic receptor neurons are the primary known sources of rapid excitation to OB principal cells. Principal cells also receive inhibitory input from local GABAergic interneurons in both the glomerular and plexiform layers. Previous work suggests that the functional effect of these inhibitory inputs, including numerous dendrodendritic synapses with GABAergic granule cells, is to reduce firing probability. In this study, we use in vitro patch clamp recordings to demonstrate that rat (of both sexes) OB mitral cells also can be excited by GABAergic synapses formed outside the glomerular layer. Depolarizing GABAergic responses to focal extracellular stimulation were revealed when fast ionotropic glutamate receptors were blocked, and occurred with short, monosynaptic latencies. These novel synaptic responses were abolished by gabazine, bicuculline and picrotoxin, three structurally dissimilar GABAA receptor antagonists. The likely location of depolarizing GABAergic input to mitral cells was the proximal axon based on the actions of focally applied gabazine and GABA near this region. Excitatory GABAergic synaptic responses, commonly studied in cortical brain regions, have not been reported previously in OB principal cells. Excitatory GABAergic responses promote action potential firing and provide a mechanism for mitral cells to be excited independently of olfactory sensory input.SIGNIFICANCE STATEMENTOdor stimuli generate distinctive activity patterns in olfactory bulb neurons through a combination of excitatory and inhibitory synaptic interactions. Most of the excitatory drive to each principal cell is assumed to arise from a highly restricted subset of sensory neurons. This study describes a novel second source of synaptic excitation to principal cells to arises from GABAergic inputs to the proximal axon, a common site of action potential initiation. This new pathway provides a synaptic mechanism to excite OB principal cells that is independent of the canonical excitatory sensory input contained in the glomerular layer.

Activation of Granule Cell Interneurons by Two Divergent Local Circuit Pathways in the Rat Olfactory Bulb.

The olfactory bulb (OB) serves as a relay region for sensory information transduced by receptor neurons in the nose and ultimately routed to a variety of cortical areas. Despite the highly structured organization of the sensory inputs to the OB, even simple monomolecular odors activate large regions of the OB comprising many glomerular modules defined by afferents from different receptor neuron subtypes. OB principal cells receive their primary excitatory input from only one glomerular channel defined by inputs from one class of olfactory receptor neurons. By contrast, interneurons, such as GABAergic granule cells (GCs), integrate across multiple channels through dendodendritic inputs on their distal apical dendrites. Through their inhibitory synaptic actions, GCs appear to modulate principal cell firing to enhance olfactory discrimination, although how GCs contribute to olfactory function is not well understood. In this study, we identify a second synaptic pathway by which principal cells in the rat (both sexes) OB excite GCs by evoking potent nondepressing EPSPs (termed large-amplitude, nondendrodendritic [LANDD] EPSPs). LANDD EPSPs show little depression in response to tetanic stimulation and, therefore, can be distinguished other EPSPs that target GCs. LANDD EPSPs can be evoked by both focal stimulation near GC proximal dendrites and by activating sensory inputs in the glomerular layer in truncated GCs lacking dendrodendritic inputs. Using computational simulations, we show that LANDD EPSPs more reliably encode the duration of principal cell discharges than DD EPSPs, enabling GCs to compare contrasting versions of odor-driven activity patterns.SIGNIFICANCE STATEMENT The olfactory bulb plays a critical role in transforming broad sensory input patterns into odor-selective population responses. How this occurs is not well understood, but the local bulbar interneurons appear to be centrally involved in the process. Granule cells, the most common interneuron in the olfactory bulb, are known to broadly integrate sensory input through specialized synapses on their distal dendrites. Here we describe a second class of local excitatory inputs to granule cells that are more powerful than distal inputs and fail to depress with repeated stimulation. This second, proximal pathway allows bulbar interneurons to assay divergent versions of the same sensory input pattern.

Functional Specialization of Interneuron Dendrites: Identification of Action Potential Initiation Zone in Axonless Olfactory Bulb Granule Cells.

Principal cells in the olfactory bulb (OB), mitral and tufted cells, play key roles in processing and then relaying sensory information to downstream cortical regions. How OB local circuits facilitate odor-specific responses during odor discrimination is not known but involves GABAergic inhibition mediated by axonless granule cells (GCs), the most abundant interneuron in the OB. Most previous work on GCs has focused on defining properties of distal apical dendrites where these interneurons form reciprocal dendrodendritic connections with principal cells. Less is known about the function of the proximal dendritic compartments. In the present study, we identified the likely action potentials (AP) initiation zone by comparing electrophysiological properties of rat (either sex) GCs with apical dendrites severed at different locations. We find that truncated GCs with long apical dendrites had active properties that were indistinguishable from intact GCs, generating full-height APs and short-latency low-threshold Ca2+ spikes. We then confirmed the presumed site of AP and low-threshold Ca2+ spike initiation in the proximal apical dendrite using two-photon Ca2+ photometry and focal TTX application. These results suggest that GCs incorporate two separate pathways for processing synaptic inputs: an already established dendrodendritic input to the distal apical dendrite and a novel pathway in which the cell body integrates proximal synaptic inputs, leading to spike generation in the proximal apical dendrite. Spikes generated by the proximal pathway likely enables GCs to regulate lateral inhibition by defining time windows when lateral inhibition is functional.SIGNIFICANCE STATEMENT The olfactory bulb plays a central role in processing sensory input transduced by receptor neurons. How local circuits in the bulb function to facilitate sensory processing during odor discrimination is not known but appears to involve inhibition mediated by granule cells, axonless GABAergic interneurons. Little is known about the active conductances in granule cells including where action potentials originate. Using a variety of experimental approaches, we find the Na+-based action potentials originate in the proximal apical dendrite, a region targeted by cortical feedback afferents. We also find evidence for high expression of low-voltage activated Ca2+ channels in the same region, intrinsic currents that enable GCs to spike rapidly in response to sensory input during each sniff cycle.

Direct Recording of Dendrodendritic Excitation in the Olfactory Bulb: Divergent Properties of Local and External Glutamatergic Inputs Govern Synaptic Integration in Granule Cells.

The olfactory bulb contains excitatory principal cells (mitral and tufted cells) that project to cortical targets as well as inhibitory interneurons. How the local circuitry in this region facilitates odor-specific output is not known, but previous work suggests that GABAergic granule cells plays an important role, especially during fine odor discrimination. Principal cells interact with granule cells through reciprocal dendrodendritic connections that are poorly understood. While many studies examined the GABAergic output side of these reciprocal connections, little is known about how granule cells are excited. Only two previous studies reported monosynaptically coupled mitral/granule cell connections and neither attempted to determine the fundamental properties of these synapses. Using dual intracellular recordings and a custom-built loose-patch amplifier, we have recorded unitary granule cell EPSPs evoked in response to mitral cell action potentials in rat (both sexes) brain slices. We find that the unitary dendrodendritic input is relatively weak with highly variable release probability and short-term depression. In contrast with the weak dendrodendritic input, the facilitating cortical input to granule cells is more powerful and less variable. Our computational simulations suggest that dendrodendritic synaptic properties prevent individual principal cells from strongly depolarizing granule cells, which likely discharge in response to either concerted activity among a large proportion of inputs or coactivation of a smaller subset of local dendrodendritic inputs with coincidence excitation from olfactory cortex. This dual-pathway requirement likely enables the sparse mitral/granule cell interconnections to develop highly odor-specific responses that facilitate fine olfactory discrimination.SIGNIFICANCE STATEMENT The olfactory bulb plays a central role in converting broad, highly overlapping, sensory input patterns into odor-selective population responses. How this occurs is not known, but experimental and theoretical studies suggest that local inhibition often plays a central role. Very little is known about how the most common local interneuron subtype, the granule cell, is excited during odor processing beyond the unusual anatomical arraignment of the interconnections (reciprocal dendrodendritic synapses). Using paired recordings and two-photon imaging, we determined the properties of the primary input to granule cells for the first time and show that these connections bias interneurons to fire in response to spiking in large populations of principal cells rather than a small group of highly active cells.

Purkinje Cell Collaterals Enable Output Signals from the Cerebellar Cortex to Feed Back to Purkinje Cells and Interneurons.

Purkinje cells (PCs) provide the sole output from the cerebellar cortex. Although PCs are well characterized on many levels, surprisingly little is known about their axon collaterals and their target neurons within the cerebellar cortex. It has been proposed that PC collaterals transiently control circuit assembly in early development, but it is thought that PC-to-PC connections are subsequently pruned. Here, we find that all PCs have collaterals in young, juvenile, and adult mice. Collaterals are restricted to the parasagittal plane, and most synapses are located in close proximity to PCs. Using optogenetics and electrophysiology, we find that in juveniles and adults, PCs make synapses onto other PCs, molecular layer interneurons, and Lugaro cells, but not onto Golgi cells. These findings establish that PC output can feed back and regulate numerous circuit elements within the cerebellar cortex and is well suited to contribute to processing in parasagittal zones.

In-depth performance analysis of an EEG based neonatal seizure detection algorithm.

OBJECTIVE: To describe a novel neurophysiology based performance analysis of automated seizure detection algorithms for neonatal EEG to characterize features of detected and non-detected seizures and causes of false detections to identify areas for algorithmic improvement. METHODS: EEGs of 20 term neonates were recorded (10 seizure, 10 non-seizure). Seizures were annotated by an expert and characterized using a novel set of 10 criteria. ANSeR seizure detection algorithm (SDA) seizure annotations were compared to the expert to derive detected and non-detected seizures at three SDA sensitivity thresholds. Differences in seizure characteristics between groups were compared using univariate and multivariate analysis. False detections were characterized. RESULTS: The expert detected 421 seizures. The SDA at thresholds 0.4, 0.5, 0.6 detected 60%, 54% and 45% of seizures. At all thresholds, multivariate analyses demonstrated that the odds of detecting seizure increased with 4 criteria: seizure amplitude, duration, rhythmicity and number of EEG channels involved at seizure peak. Major causes of false detections included respiration and sweat artefacts or a highly rhythmic background, often during intermediate sleep. CONCLUSION: This rigorous analysis allows estimation of how key seizure features are exploited by SDAs. SIGNIFICANCE: This study resulted in a beta version of ANSeR with significantly improved performance.

NMDA receptor binding in focal epilepsies.

OBJECTIVE: To demonstrate altered N-methyl-d-aspartate (NMDA) receptor availability in patients with focal epilepsies using positron emission tomography (PET) and [(18)F]GE-179, a ligand that selectively binds to the open NMDA receptor ion channel, which is thought to be overactive in epilepsy. METHODS: Eleven patients (median age 33 years, 6 males) with known frequent interictal epileptiform discharges had an [(18)F]GE-179 PET scan, in a cross-sectional study. MRI showed a focal lesion but discordant EEG changes in two, was non-localising with multifocal EEG abnormalities in two, and was normal in the remaining seven patients who all had multifocal EEG changes. Individual patient [(18)F]GE-179 volume-of-distribution (VT) images were compared between individual patients and a group of 10 healthy controls (47 years, 7 males) using Statistical Parametric Mapping. RESULTS: Individual analyses revealed a single cluster of focal VT increase in four patients; one with a single and one with multifocal MRI lesions, and two with normal MRIs. Post hoc analysis revealed that, relative to controls, patients not taking antidepressants had globally increased [(18)F]GE-179 VT (+28%; p<0.002), and the three patients taking an antidepressant drug had globally reduced [(18)F]GE-179 VT (-29%; p<0.002). There were no focal abnormalities common to the epilepsy group. CONCLUSIONS: In patients with focal epilepsies, we detected primarily global increases of [(18)F]GE-179 VT consistent with increased NMDA channel activation, but reduced availability in those taking antidepressant drugs, consistent with a possible mode of action of this class of drugs. [(18)F]GE-179 PET showed focal accentuations of NMDA binding in 4 out of 11 patients, with difficult to localise and treat focal epilepsy.

Successful private-public funding of paediatric medicines research: lessons from the EU programme to fund research into off-patent medicines.

UNLABELLED: The European Paediatric Regulation mandated the European Commission to fund research on off-patent medicines with demonstrated therapeutic interest for children. Responding to this mandate, five FP7 project calls were launched and 20 projects were granted. This paper aims to detail the funded projects and their preliminary results. Publicly available sources have been consulted and a descriptive analysis has been performed. Twenty Research Consortia including 246 partners in 29 European and non-European countries were created (involving 129 universities or public-funded research organisations, 51 private companies with 40 SMEs, 7 patient associations). The funded projects investigate 24 medicines, covering 10 therapeutic areas in all paediatric age groups. In response to the Paediatric Regulation and to apply for a Paediatric Use Marketing Authorisation, 15 Paediatric Investigation Plans have been granted by the EMA-Paediatric Committee, including 71 studies of whom 29 paediatric clinical trials, leading to a total of 7,300 children to be recruited in more than 380 investigational centres. CONCLUSION: Notwithstanding the EU contribution for each study is lower than similar publicly funded projects, and also considering the complexity of paediatric research, these projects are performing high-quality research and are progressing towards the increase of new paediatric medicines on the market. Private-public partnerships have been effectively implemented, providing a good example for future collaborative actions. Since these projects cover a limited number of off-patent drugs and many unmet therapeutic needs in paediatrics remain, it is crucial foreseeing new similar initiatives in forthcoming European funding programmes.

Voltage-dependent intrinsic bursting in olfactory bulb Golgi cells.

In the mammalian olfactory bulb (OB), local synaptic circuits modulate the evolving pattern of activity in mitral and tufted cells following olfactory sensory stimulation. GABAergic granule cells, the most numerous interneuron subtype in this brain region, have been extensively studied. However, classic studies using Golgi staining methods identified many other, nongranule cell types in the OB whose function remains mysterious. Within just the granule cell layer (GCL), Ramón y Cajal described multiple morphologically distinct subtypes of nongranule interneurons including large spiny Blanes cells which exhibit intrinsic persistent activity. Here, we define the intrinsic electrophysiology of a different nongranule interneuronal cell type in the GCL described by Ramón y Cajal, sparsely spiny Golgi cells in the rat OB. Golgi cells exhibit two distinct firing modes depending on the membrane potential: tonic firing and bursting. Golgi cells also generate rebound bursts following the offset of hyperpolarizing steps. We find that both low-threshold burst responses to depolarizing inputs and rebound bursts are blocked by nickel, an antagonist of T-type voltage-gated Ca2+ current. The state-dependent firing behavior we report in OB Golgi cells suggests that the function of these interneurons may dynamically shift from providing rhythmic potent inhibition of postsynaptic target neurons at sniffing frequencies to tonic, subtractive inhibition based on centrifugal modulatory input.

Metabotropic glutamate receptors drive global persistent inhibition in the visual thalamus.

Within the dorsal lateral geniculate nucleus (dLGN) of the thalamus, retinal ganglion cell (RGC) projections excite thalamocortical (TC) cells that in turn relay visual information to the cortex. Local interneurons in the dLGN regulate the output of TC cells by releasing GABA from their axonal boutons and specialized dendritic spines. Here we examine the functional role of these highly specialized interneurons and how they inhibit TC cells in mouse brain slices. It was widely thought that activation of metabotropic glutamate receptor type 5 (mGluR5) on interneuron spines leads to local GABA release restricted to sites receiving active RGC inputs. We reexamined experiments that supported this view, and found that in the presence of TTX, mGluR5 agonists evoked GABA release that could instead be explained by interneuron depolarization and widespread intracellular calcium increases. We also examined GABA release evoked by RGC activation and found that high-frequency stimulation induces a long-lasting subthreshold afterdepolarization, persistent firing, or prolonged plateau potentials in interneurons and evokes sustained GABA release. mGluR5 antagonists virtually eliminated sustained spiking and the resulting widespread calcium-signals, and reduced inhibition by >50%. The remaining inhibition appeared to be mediated by a fraction of interneurons in which plateau potentials produced large and widespread calcium increases. Local calcium signals required for local GABA release were not observed. These findings indicate that, contrary to the previous view, RGC activation does not simply evoke localized GABA release by activating mGluR5, rather, synaptic activation of mGluR5 acts primarily by depolarizing interneurons and evoking widespread dendritic GABA release.

Cholinergic activation of M2 receptors leads to context-dependent modulation of feedforward inhibition in the visual thalamus.

In many brain regions, inhibition is mediated by numerous classes of specialized interneurons, but within the rodent dorsal lateral geniculate nucleus (dLGN), a single class of interneuron is present. dLGN interneurons inhibit thalamocortical (TC) neurons and regulate the activity of TC neurons evoked by retinal ganglion cells (RGCs), thereby controlling the visually evoked signals reaching the cortex. It is not known whether neuromodulation can regulate interneuron firing mode and the resulting inhibition. Here, we examine this in brain slices. We find that cholinergic modulation regulates the output mode of these interneurons and controls the resulting inhibition in a manner that is dependent on the level of afferent activity. When few RGCs are activated, acetylcholine suppresses synaptically evoked interneuron spiking, and strongly reduces disynaptic inhibition. In contrast, when many RGCs are coincidently activated, single stimuli promote the generation of a calcium spike, and stimulation with a brief train evokes prolonged plateau potentials lasting for many seconds that in turn lead to sustained inhibition. These findings indicate that cholinergic modulation regulates feedforward inhibition in a context-dependent manner.

Muscarinic receptor activation modulates granule cell excitability and potentiates inhibition onto mitral cells in the rat olfactory bulb.

The olfactory bulb is a second-order brain region that connects sensory neurons with cortical areas. However, the olfactory bulb does not appear to play a simple relay role and is subject instead to extensive local and extrinsic synaptic influences. Prime among the external, or centrifugal, inputs is the dense cholinergic innervation from the basal forebrain, which terminates in both the granule cell and plexiform layers. Cholinergic inputs to the bulb have been implicated in olfactory working memory tasks in rodents and may be related to olfactory deficits reported in people with neurodegenerative disorders that involve basal forebrain neurons. In this study, we use whole-cell recordings from acute rat slices to demonstrate that one function of this input is to potentiate the excitability of GABAergic granule cells and thereby modulate inhibitory drive onto mitral cells. This increase in granule cell excitability is mediated by a concomitant decrease in the normal afterhyperpolarization response and augmentation of an afterdepolarization, both triggered by pirenzepine-sensitive M1 receptors. The afterdepolarization was dependent on elevations in intracellular calcium and appeared to be mediated by a calcium-activated nonselective cation current (I(CAN)). Near firing threshold, depolarizing inputs could evoke quasipersistent firing characterized by irregular discharges that lasted, on average, for 2 min. In addition to regulating the excitability of the primary interneuronal subtype in the bulb, M1 receptors regulate the degree of adaptation that occurs during repetitive sniffing-like inputs and may therefore play a critical role in regulating short-term plasticity in the olfactory system.

Multiple modes of synaptic excitation of olfactory bulb granule cells.

Inhibition generated by granule cells, the most common GABAergic cell type in the olfactory bulb, plays a critical role in shaping the output of the olfactory bulb. However, relatively little is known about the synaptic mechanisms responsible for activating these interneurons in addition to the specialized dendrodendritic synapses located on distal dendrites. Using two-photon guided minimal stimulation in acute rat brain slices, we found that distal and proximal excitatory synapses onto granule cells are functionally distinct. Proximal synapses arise from piriform cortical neurons and facilitate with paired-pulse stimulation, whereas distal dendrodendritic synapses generate EPSCs with slower kinetics that depress with paired stimulation. Proximal cortical feedback inputs can relieve the tonic Mg block of NMDA receptors (NMDARs) at distal synapses and gate dendrodendritic inhibition onto mitral cells. Most excitatory synapses we examined onto granule cells activated both NMDARs and AMPA receptors, whereas a subpopulation appeared to be NMDAR silent. The convergence of two types of excitatory inputs onto GABAergic granule cells provides a novel mechanism for regulating the degree of interglomerular processing of sensory input in the olfactory bulb through piriform cortex/olfactory bulb synaptic interactions.

Effect of lamotrigine on cognition in children with epilepsy.

BACKGROUND: Lamotrigine does not affect cognition in healthy adult volunteers or adult patients with epilepsy, but its effect on cognition in children is uncertain. OBJECTIVE: To compare the effect of lamotrigine and placebo on cognition in children with well-controlled or mild epilepsy. METHOD: In a double-blind, placebo-controlled, crossover study, 61 children with well-controlled or mild epilepsy were randomly assigned to add-on therapy with either lamotrigine followed by placebo or placebo followed by lamotrigine. Each treatment phase was 9 weeks, the crossover period 5 weeks. A neuropsychological test battery was performed during EEG monitoring at baseline and at the end of placebo and drug phases. The paired Student' t test was used for statistical analysis for neuropsychological data (two tailed) with a p value of 0.01 considered significant. Carryover and period effect were analyzed with generalized linear modeling (SPSS 10). RESULTS: Forty-eight children completed the study. Seizure frequency was similar during both treatment phases. No significant difference was found in continuous performance, binary choice reaction time, verbal and nonverbal recognition, computerized visual searching task, verbal and spatial delayed recognition, and verbal and nonverbal working memory between placebo and lamotrigine treatment phase. There was no significant carryover and period effect when corrected for randomization. CONCLUSION: Lamotrigine exhibits no clinically significant cognitive effects in adjunctive therapy for children with epilepsy.

Blanes cells mediate persistent feedforward inhibition onto granule cells in the olfactory bulb.

Inhibitory local circuits in the olfactory bulb play a critical role in determining the firing patterns of output neurons. However, little is known about the circuitry in the major plexiform layers of the olfactory bulb that regulate this output. Here we report the first electrophysiological recordings from Blanes cells, large stellate-shaped interneurons located in the granule cell layer. We find that Blanes cells are GABAergic and generate large I(CAN)-mediated afterdepolarizations following bursts of action potentials. Using paired two-photon guided intracellular recordings, we show that Blanes cells have a presumptive axon and monosynaptically inhibit granule cells. Sensory axon stimulation evokes barrages of EPSPs in Blanes cells that trigger long epochs of persistent spiking; this firing mode was reset by hyperpolarizing membrane potential steps. Persistent firing in Blanes cells may represent a novel mechanism for encoding short-term olfactory information through modulation of tonic inhibitory synaptic input onto bulbar neurons.

The relationship between the onset of electrographic seizure activity after birth and the time of cerebral injury in utero.

In the fetal lamb model of hypoxic-ischaemic injury, the insult is followed by EEG depression, after which seizures emerge at 7-13 hours. We explored the relationship between the emergence of electrographic seizures and our estimate of the time of the cerebral injury in nine babies who underwent continuous video-EEG monitoring from soon after birth. Babies with prelabour insults had their first seizures before 12 hours of age, whereas those whose insult was peripartum had seizure onset at 18-20 hours of age. EEG seizure onset time could have important clinical and medico-legal applications, and be related to the time or severity of the insult, or both.

Second-line anticonvulsant treatment of neonatal seizures: a video-EEG monitoring study.

The authors conducted a randomized trial of second-line anticonvulsant treatments for neonates. The response to treatment was assessed using continuous video-EEG because the clinical diagnosis of seizure in neonates is known to be unreliable. Of 27 neonates with EEG-confirmed seizures, 5 were excluded because of protocol violations, and 11 responded to phenobarbitone in a dose of 40 mg/kg as first line. Three of five neonates treated with lignocaine responded. Six neonates were treated with benzodiazepines as second line: None responded, and their neurodevelopmental outcome was poor.

Non-expert use of the cerebral function monitor for neonatal seizure detection.

BACKGROUND: The cerebral function monitor (CFM) is widely used to detect neonatal seizures, but there are very few studies comparing it with simultaneous electroencephalography (EEG). OBJECTIVE: To determine the accuracy of non-expert use of the CFM and to assess interobserver agreement of CFM seizure detection. PATIENTS: Babies admitted to the neonatal intensive care unit at King's College Hospital who were at high risk of seizure and had video-EEG monitoring. METHODS: Video-EEG was used to detect seizures. Each baby had CFM recordings at speeds of 6, 15, and 30 cm/h during the EEG. Four neonatologists, trained in CFM seizure recognition, independently rated one hour CFM samples at three speeds from each baby. Interobserver agreement was quantified using Cohen's kappa. RESULTS: CFM traces from 19 babies with EEG seizures and 21 babies without EEG seizures were analysed. Overall non-expert interpretation of the CFM performed poorly as a seizure detector compared with simultaneous EEG (sensitivities 38% at 6 cm/h; 54% at 15 cm/h; 55% at 30 cm/h). Although babies with seizures were more likely to be correctly classified at higher speeds (p = 0.02), babies without seizures were also more likely to be misclassified (p < 0.001). Agreement between observers was not good at any speed (kappa values from 0.01 to 0.39). The observers usually detected generalised seizures but often missed seizures that were focal, low amplitude, or lasted less than one minute. CONCLUSION: Approximately half of all neonatal seizures may be missed using CFM alone. Neonatal seizures need to be diagnosed, characterised, and quantified first using EEG. The CFM may then be useful for long term monitoring.

Phenobarbitone, neonatal seizures, and video-EEG.

AIMS: To evaluate the effectiveness of phenobarbitone as an anticonvulsant in neonates. METHODS: An observational study using video-EEG telemetry. Video-EEG was obtained before treatment was started, for an hour after treatment was given, two hours after treatment was given, and again between 12 and 24 hours after treatment was given. Patients were recruited from all babies who required phenobarbitone (20-40 mg/kg intravenously over 20 minutes) for suspected clinical seizures and had EEG monitoring one hour before and up to 24 hours after the initial dose. An EEG seizure discharge was defined as a sudden repetitive stereotyped discharge lasting for at least 10 seconds. Neonatal status epilepticus was defined as continuous seizure activity for at least 30 minutes. Seizures were categorised as EEG seizure discharges only (electrographic), or as EEG seizure discharges with accompanying clinical manifestations (electroclinical). Surviving babies were assessed at one year using the Griffiths neurodevelopmental score. RESULTS: Fourteen babies were studied. Four responded to phenobarbitone; these had normal or moderately abnormal EEG background abnormalities and outcome was good. In the other 10 babies electrographic seizures increased after treatment, whereas electroclinical seizures reduced. Three babies were treated with second line anticonvulsants, of whom two responded. One of these had a normal neurodevelopmental score at one year, but the outcome for the remainder of the whole group was poor. CONCLUSION: Phenobarbitone is often ineffective as a first line anticonvulsant in neonates with seizures in whom the background EEG is significantly abnormal.