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While several studies have attributed the development of tumour-associated seizures to an excitatory-inhibitory imbalance, we have yet to resolve the spatiotemporal interplay between different types of neuron in glioma-infiltrated cortex. Herein, we combined methods for single unit analysis of microelectrode array recordings with wide-field optical mapping of Thy1-GCaMP pyramidal cells in an ex vivo acute slice model of diffusely infiltrating glioma. This enabled simultaneous tracking of individual neurons from both excitatory and inhibitory populations throughout seizure-like events. Moreover, our approach allowed for observation of how the crosstalk between these neurons varied spatially, as we recorded across an extended region of glioma-infiltrated cortex. In tumour-bearing slices, we observed marked alterations in single units classified as putative fast-spiking interneurons, including reduced firing, activity concentrated within excitatory bursts and deficits in local inhibition. These results were correlated with increases in overall excitability. Mechanistic perturbation of this system with the mTOR inhibitor AZD8055 revealed increased firing of putative fast-spiking interneurons and restoration of local inhibition, with concomitant decreases in overall excitability. Altogether, our findings suggest that diffusely infiltrating glioma affect the interplay between excitatory and inhibitory neuronal populations in a reversible manner, highlighting a prominent role for functional mechanisms linked to mTOR activation.

Interictal epileptiform discharges (IEDs), also known as interictal spikes, are large intermittent electrophysiological events observed between seizures in patients with epilepsy. While seizures are infrequent and unpredictable, IEDs are far more common, often occurring several times per minute. Yet despite the abundance of IEDs, it remains unknown how they relate to seizures. To better understand this relationship, we examined multi-day recordings of 96-channel microelectrode arrays implanted in human epilepsy patients. These recordings (spanning single cell action potentials to population field potentials) allowed us to study the microscale spatiotemporal organization of over 45,000 IEDs across 10 participants from 2 surgical centers. These recordings showed that the majority of IEDs propagate across neocortex as traveling waves. While all of these traveling wave distributions exhibited a predominant, consistent direction, the majority also exhibited a second, auxiliary, direction. Clustering the IED distributions revealed that their predominant and auxiliary distributions were antipodal, mimicking the spatial microstructure of seizure discharges (SDs) that we have previously reported. We thus compared spatial features of IED sub-distributions to those for SDs, showing a correspondence between ictal and interictal spatial properties in participants whose microelectrode arrays were recruited into the seizure from adjacent cortical tissue. These results reveal fundamental relationships between IEDs and seizures and suggest how IEDs could be used to infer spatial features of seizures.

Burst suppression is an electroencephalogram pattern of globally symmetric alternating high amplitude activity and isoelectricity that can be induced by general anaesthetics. There is scattered evidence that burst suppression may become spatially non-uniform in the setting of underlying pathology. Here, we induced burst suppression with isoflurane in rodents and then created a neocortical acute seizure focus with injection of 4-aminopyridine (4-AP) in somatosensory cortex. Burst suppression events were recorded before and after creation of the focus using bihemispheric wide-field calcium imaging and multielectrode arrays. We find that the seizure focus elicits a rapid alteration in triggering, initiation, and propagation of burst suppression events. Compared with the non-seizing brain, bursts are triggered from the thalamus, initiate in regions uniquely outside the epileptic focus, elicit marked increases of multiunit activity and propagate towards the seizure focus. These findings support the rapid, widespread impact of focal epilepsy on the extended brain network.

OBJECTIVE The dynamics of the postictal period, which may demonstrate such dramatic clinical phenomena as focal neurological deficits, prolonged coma and immobility, and even sudden death, are poorly understood. We sought to classify and characterize postictal phases of bilateral tonic-clonic seizures based on electroencephalographic (EEG) criteria and associated clinical features. METHODS We performed a detailed electroclinical evaluation of the postictal period in a series of 31 bilateral tonic-clonic seizures in 16 patients undergoing epilepsy surgery evaluations for focal pharmacoresistant epilepsy with intracranial electrodes and time-locked video. RESULTS The postictal EEG demonstrated three clearly differentiated phases as follows: attenuation, a burst-attenuation pattern, and a return to continuous background, with abrupt, synchronized transitions between phases. Postictal attenuation was common, occurring in 84% of seizures in 94% of patients in this study. There was increased power in gamma frequencies (>25 Hz) during postictal attenuation periods relative to preictal baseline in 88% of seizures demonstrating the attenuation pattern (n = 25 seizures, P 90% of channels in 13 seizures (52%) and

Several studies have attributed the development of tumor-associated seizures to an excitatory-inhibitory imbalance, highlighting the importance of resolving the spatiotemporal interplay of different neuronal populations within the peritumoral microenvironment. We combined methods for microelectrode array recordings and single unit analysis during ictal events with wide-field optical mapping of pyramidal neurons in an ex vivo acute slice model of diffusely infiltrating glioma in Thy1-GCaMP6f mice. This approach allowed for characterization of excitatory and inhibitory populations across an extended peritumoral cortical region. As expected, measures of excitability were increased in tumor-bearing slices compared to control. This was accompanied by marked functional alterations in single units classified as fast-spiking interneurons, including reduced firing, altered timing with respect to excitatory firing, and deficits in surround inhibition. Inhibiting mTOR with AZD8055 reversed these glioma-induced changes to excitatory and inhibitory neuronal populations, suggesting a prominent role for functional mechanisms linked to mTOR activation.

Background: Inhalational anesthetic-induced burst suppression (BS) is classically considered a bilaterally synchronous rhythm. However, local asynchrony has been predicted in theoretical studies and reported in patients with pre-existing focal pathology.Method: We used high-speed widefield calcium imaging to study the spatiotemporal dynamics of isoflurane-induced BS in rats.Results: We found that isoflurane-induced BS is not a globally synchronous rhythm. In the neocortex, neural activity first emerged in a spatially shifting, variably localized focus. Subsequent propagation across the whole cortex was rapid, typically within Conclusion: The classical impression that anesthetics-induced BS is a state of global brain synchrony is inaccurate. Bursts are a series of shifting local cortical events facilitated by thalamic projection that unfold as rapid, bilaterally asynchronous propagating waves.

We developed a neural network model that can account for major elements common to human focal seizures. These include the tonic-clonic transition, slow advance of clinical semiology and corresponding seizure territory expansion, widespread EEG synchronization, and slowing of the ictal rhythm as the seizure approaches termination. These were reproduced by incorporating usage-dependent exhaustion of inhibition in an adaptive neural network that receives global feedback inhibition in addition to local recurrent projections. Our model proposes mechanisms that may underline common EEG seizure onset patterns and status epilepticus, and postulates a role for synaptic plasticity in the emergence of epileptic foci. Complex patterns of seizure activity and bi-stable seizure end-points arise when stochastic noise is included. With the rapid advancement of clinical and experimental tools, we believe that this model can provide a roadmap and potentially an in silico testbed for future explorations of seizure mechanisms and clinical therapies.

ObjectiveHigh frequency oscillations (HFOs) recorded from intracranial electrodes during epileptiform discharges have been proposed as a biomarker of epileptic brain sites and may also be a useful feature for seizure forecasting, with mixed results. Currently, pathological subclasses of HFOs have been defined primarily by frequency characteristics. Despite this, there has been limited investigation into the spatial context of HFOs with recruitment of local cortex into seizure discharging. We sought to further understand the biophysical underpinnings of ictal HFOs.MethodsHere we examine ictal HFOs from multi-scale electrophysiological recordings during spontaneous human rhythmic onset seizures. We compare features of ictal discharges in both the seizure core and penumbra, as defined by multiunit activity patterns.ResultsWe show marked differences in spectral features, unit coupling, and information theoretic characteristics of HFOs during ictal discharges before and after local seizure invasion. Furthermore, we tie these timing-related differences to different spatial domains of seizures, showing that eccentric, penumbral discharges are widely distributed and less useful for seizure localization, which may explain the variable utility of HFOs in seizure localization and forecasting.InterpretationWe thus identify two distinct classes of ictal HFOs, implying two different mechanisms underlying pathological HFOs with contrasting significance for seizure localization.

It has been postulated that glia play a critical role in modifying neuronal activity, mediating neurovascular coupling, and in seizure initiation. We investigated the role of glia in ictogenesis and neurovascular coupling through wide-field multicell and 2-photon single cell imaging of calcium and intrinsic signal imaging of cerebral blood volume in an in vivo rat model of focal neocortical seizures. Ictal events triggered a slowly propagating glial calcium wave that was markedly delayed after both neuronal and hemodynamic onset. Glial calcium waves exhibited a stereotypical spread that terminated prior to seizure offset and propagated to an area ~60% greater than the propagation area of neural and vascular signals. Complete blockage of glial activity with fluoroacetate resulted in no change in either neuronal or hemodynamic activity. These ictal glial waves were blocked by carbenoxolone, a gap junction blocker. Our in vivo data reveal that ictal events trigger a slowly propagating, stereotypical glial calcium wave, mediated by gap junctions, that is spatially and temporally independent of neuronal and hemodynamic activities. We introduce a novel ictally triggered propagating glial calcium wave calling into question the criticality of glial calcium wave in both ictal onset and neurovascular coupling.

Neuronal oscillations at beta frequencies (20-50 Hz) in the cortico-basal ganglia circuits have long been the leading theory for bradykinesia, the slow movements that are cardinal symptoms in Parkinson's disease (PD). The beta oscillation theory helped to drive a frequency-based design in the development of deep brain stimulation therapy for PD. However, in contrast to this theory, here we have found that bradykinesia can be completely dissociated from beta oscillations in rodent models. Instead, we observed that bradykinesia is causatively regulated by the burst-firing pattern of the subthalamic nucleus (STN) in a feed-forward, or efferent-only, mechanism. Furthermore, STN burst-firing and beta oscillations are two independent mechanisms that are regulated by different NMDA receptors in STN. Our results shift the understanding of bradykinesia pathophysiology from an interactive oscillatory theory toward a feed-forward mechanism that is coded by firing patterns. This distinct mechanism may improve understanding of the fundamental concepts of motor control and enable more selective targeting of bradykinesia-specific mechanisms to improve PD therapy.

We developed a neural network model that can account for the major elements common to human focal seizures. These include the tonic-clonic transition, slow advance of clinical semiology and corresponding seizure territory expansion, widespread EEG synchronization, and slowing of the ictal rhythm as the seizure approaches termination. These were reproduced by incorporating usage-dependent exhaustion of inhibition in an adaptive neural network that receives global feedback inhibition in addition to local recurrent projections. Our model proposes mechanisms that may underline common EEG seizure onset patterns and status epilepticus and postulates a role for synaptic plasticity in emergence of epileptic foci. Complex patterns of seizure activity and bi-stable seizure evolution end-points arise when stochastic noise is included. With the rapid advancement of clinical and experimental tools, we believe that this can provide a roadmap and potentially a testbed for future explorations of seizure mechanisms and clinical therapies.

Background Chylothorax is a rare condition among neonates, although it is considered clinically significant, as it is difficult to manage in these patients. In addition, the course of chylothorax varies widely. Therefore, we aimed to elucidate the clinical features and effect of prenatal therapy on the prognosis of congenital chylothorax in neonates. Methods We retrospectively reviewed the medical records of all infants with congenital chylothorax who were admitted to National Taiwan University Hospital, Taipei, Taiwan between January 2000 and December 2012. Their demographic characteristics, as well as their antenatal, perinatal, and postnatal information, were collected for our analysis of the mortality risk. Results We found 29 infants who were diagnosed with congenital chylothorax during the study period. The median gestational age at birth was 34 weeks (range, 28–41 weeks), and 71% of the infants presented with hydrops fetalis. Most cases of congenital chylothorax were bilateral (bilateral: 86.2%, unilateral: 13.79%), and the overall survival rate was 59.6%. Among the cases with a prenatal diagnosis at ≤ 34 weeks of gestation, infants who received prenatal therapy had a significantly higher survival rate, compared to infants who did not receive prenatal therapy (76.9% vs. 11%, respectively; p = 0.008). Conclusion We found that infants whose chylothorax was diagnosed ≤ 34 weeks of gestation, and who subsequently received prenatal therapy, experienced a better perinatal condition and exhibited improved postnatal outcomes.

The extensive distribution and simultaneous termination of seizures across cortical areas has led to the hypothesis that seizures are caused by large-scale coordinated networks spanning these areas. This view, however, is difficult to reconcile with most proposed mechanisms of seizure spread and termination, which operate on a cellular scale. We hypothesize that seizures evolve into self-organized structures wherein a small seizing territory projects high-intensity electrical signals over a broad cortical area. Here we investigate human seizures on both small and large electrophysiological scales. We show that the migrating edge of the seizing territory is the source of travelling waves of synaptic activity into adjacent cortical areas. As the seizure progresses, slow dynamics in induced activity from these waves indicate a weakening and eventual failure of their source. These observations support a parsimonious theory for how large-scale evolution and termination of seizures are driven from a small, migrating cortical area., Epileptic brains display inhibitory restraint as manifested by the spread of synchronized activities being delayed in timing. Here, Elliot Smith and colleagues show fast-moving traveling wave that originates from the edge of ictal wavefront with subsequent depolarization and multiunit firing in the seizing brain regions in epileptic patients.

The purpose of this study is to develop a platform in which the cellular and molecular underpinnings of chronic focal neocortical lesional epilepsy can be explored and use it to characterize seizure-like events (SLEs) in an ex vivo model of infiltrating high-grade glioma. Microelectrode arrays were used to study electrophysiologic changes in ex vivo acute brain slices from a PTEN/p53 deleted, PDGF-B driven mouse model of high-grade glioma. Electrode locations were co-registered to the underlying histology to ascertain the influence of the varying histologic landscape on the observed electrophysiologic changes. Peritumoral, infiltrated, and tumor sites were sampled in tumor-bearing slices. Following the addition of zero Mg2+ solution, all three histologic regions in tumor-bearing slices showed significantly greater increases in firing rates when compared to the control sites. Tumor-bearing slices demonstrated increased proclivity for SLEs, with 40 events in tumor-bearing slices and 5 events in control slices (p-value = .0105). Observed SLEs were characterized by either low voltage fast (LVF) onset patterns or short bursts of repetitive widespread, high amplitude low frequency discharges. Seizure foci comprised areas from all three histologic regions. The onset electrode was found to be at the infiltrated margin in 50% of cases and in the peritumoral region in 36.9% of cases. These findings reveal a landscape of histopathologic and electrophysiologic alterations associated with ictogenesis and spread of tumor-associated seizures.

Focal seizure propagation is classically thought to be spatially contiguous. However, distribution of seizures through a large-scale epileptic network has been theorized. Here, we used a multielectrode array, wide field calcium imaging, and two-photon calcium imaging to study focal seizure propagation pathways in an acute rodent neocortical 4-aminopyridine model. Although ictal neuronal bursts did not propagate beyond a 2-3 mm region, they were associated with hemisphere-wide field potential fluctuations and parvalbumin-positive interneuron activity outside the seizure focus. While bicuculline surface application enhanced contiguous seizure propagation, focal bicuculline microinjection at sites distant to the 4-aminopyridine focus resulted in epileptic network formation with maximal activity at the two foci. Our study suggests that both classical and epileptic network propagation can arise from localized inhibition defects, and that the network appearance can arise in the context of normal brain structure without requirement for pathological connectivity changes between sites.

Changes in climbing fiber-Purkinje cell (CF-PC) synaptic connections have been found in the essential tremor (ET) cerebellum, and these changes are correlated with tremor severity. Whether these postmortem changes are specific to ET remains to be investigated. We assessed CF-PC synaptic pathology in the postmortem cerebellum across a range of degenerative movement disorders [10 Parkinson's disease (PD) cases, 10 multiple system atrophy (MSA) cases, 10 spinocerebellar ataxia type 1 (SCA1) cases, and 20 ET cases] and 25 controls. We observed differences in terms of CF pathological features across these disorders. Specifically, PD cases and ET cases both had more CFs extending into the parallel fiber (PF) territory, but ET cases had more complex branching and increased length of CFs in the PF territory along with decreased CF synaptic density compared to PD cases. MSA cases and SCA1 cases had the most severely reduced CF synaptic density and a marked paucity of CFs extending into the PF territory. Furthermore, CFs in a subset of MSA cases formed collateral branches parallel to the PC layer, a feature not seen in other diagnostic groups. Using unsupervised cluster analysis, the cases and controls could all be categorized into four clusters based on the CF pathology and features of PC pathology, including counts of PCs and their axonal torpedoes. ET cases and PD cases co-segregated into two clusters, whereas SCA1 cases and MSA cases formed another cluster, separate from the control cluster. Interestingly, the presence of resting tremor seemed to be the clinical feature that separated the cases into the two ET-PD clusters. In conclusion, our study demonstrates that these degenerative movement disorders seem to differ with respect to the pattern of CF synaptic pathology they exhibit. It remains to be determined how these differences contribute to the clinical presentations of these diseases.

Essential tremor (ET) patients have abnormal climbing fiber (CF) synapses in the parallel fiber territory in the cerebellum, and these abnormal CF synapses are inversely correlated with tremor severity. We therefore examined CF synaptic pathology in ET cases with and without thalamic deep brain stimulation (DBS) and assessed the association with tremor severity. We found that CF synaptic pathology was inversely correlated with tremor severity in ET cases without DBS, and this correlation disappeared in ET cases with DBS. Our data suggest that DBS might have effects in modulating excitatory synapses in ET cerebellum, in addition to its symptomatic effects on tremor. Ann Neurol 2016;80:461-465.

In this issue of Neurology ®, Jung et al.1 present the results of a thoughtful prospective study examining the neuropsychological findings in children treated with 2 medications commonly used for the treatment of focal seizures, levetiracetam and carbamazepine. Their study followed 81 children with focal epilepsy, randomized to either treatment, for 1 year. They found levetiracetam is non-inferior in efficacy and tolerability compared to carbamazepine. In addition, there was no difference in neuropsychological testing performed at baseline and at the end of the study. Both aspects of this study are noteworthy.

BackgroundAlthough antenatal steroids and early use nasal continuous positive airway pressure (NCPAP) have significantly improved outcomes of neonatal respiratory distress syndrome, intubation with ventilator support is still commonly required in extremely low birth weight (ELBW) infants. The optimal timing of extubation in ELBW infants remains unclear.MethodsWe retrospectively analyzed all ELBW preterm infants who were admitted to our neonatal intensive care unit (NICU) from January 2009 to December 2013. Demographic, ventilation, and arterial blood gas analysis results prior to and 2 hours after extubation were collected. Extubation failure was defined as reintubation due to deterioration of respiratory condition within 7 days after extubation. Risk factors for extubation failure were analyzed.ResultsIn total, 173 ELBW infants were born and admitted to our NICU during these 5 years. Among these 173 infants, 77 (44.5%) used NCPAP only during their hospitalization (20 diagnosed with chronic lung disease (CLD), 25.9%). Among the 95 patients that required intubation, 27 patients expired so extubation was not attempted. Sixteen of 68 (23.5%) survival cases required reintubation within 7 days after extubation. We found that gestational age, birth body weight, and sex ratio did not differ between the successful extubation group and the failed extubation group. Univariate analysis showed that the failed extubation group had a lower arterial pH right before and 2 hours after extubation, with a lower bicarbonate level after extubation. Further multivariate logistic regression analysis revealed an association between poor acid-base homeostasis 2 hours after extubation (pH