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Outcomes following endovascular thrombectomy (EVT) for large vessel occlusion stroke remain variable. Clinical predictors include presenting NIHSS and age, surrogate metrics of stroke severity and pre-stroke brain health, respectively. Imaging biomarkers can also predict outcome, but prognostic models typically only include biomarkers of acute stroke severity. This study aimed at exploring how incorporating both imaging biomarkers of stroke severity and brain frailty, automatically derived from routine imaging, impacts outcome prediction following successful EVT. In this single-center retrospective study of 215 patients presenting with anterior circulation stroke, we evaluated prognostic significance of automated analysis outputs from e-Stroke. Acute ischemic volume (AIV) and e-ASPECTS were used to define stroke severity. Cerebral atrophy was used as a marker of brain frailty. Models incorporating imaging biomarkers, clinical features, procedural factors, and combinations of these were evaluated using multivariate regression models predicting mRS 0-2 at 30 and 90-days, NIHSS improvement, mortality and sICH. Incorporation of brain atrophy into models negated the effect of age on patient outcome. The interaction of stroke severity with age was similar to that of infarct volume and brain atrophy. Models incorporating age, presenting NIHSS, AIV, atrophy, reperfusion status and time to recanalization outperformed clinical models at predicting NIHSS improvement (ROC AUC 0.81 and 0.57, respectively) and 90-day mRS. Combinations of imaging and clinical features were superior for predicting any outcome compared with clinical or imaging features in isolation. Models incorporating automated image analysis of acute infarct volume and atrophy outperform models based solely on clinical characteristics for predicting short- and long-term outcome following EVT. Atrophy as a marker of brain frailty is associated with poorer long-term outcomes and negates the effect of age in multivariate models. AIV tempers the effect of intervention on early neurological improvement. Better understanding the relationship between stroke severity and baseline health status may improve patient selection strategies for reperfusion therapies.

Sleep EEG reflects instantaneous voltage differences relative to a reference, while its spectrum reflects the degree to which it is comprised of oscillations at various frequencies. In contrast, the envelope of the sleep EEG reflects the instantaneous amplitude of oscillations at specific frequencies, and its spectrum reflects the rhythmicity of the occurrence of these oscillations. The ordinary sleep EEG and its spectrum have been extensively studied and its individual stability and relationship to various demographic characteristics, psychological traits and pathologies is well known. In contrast, the envelope spectrum has not been extensively studied before. In two studies, we explored the generating mechanisms and utility of studying the envelope of the sleep EEG. First, we used human invasive data from cortex-penetrating microelectrodes and subdural grids to demonstrate that the sleep EEG envelope spectrum reflects local neuronal firing. Second, we used a large database of healthy volunteers to demonstrate that the scalp EEG envelope spectrum is highly stable within individuals, especially in NREM sleep, and that it is affected by age and sex. Multivariate models based on a learning algorithm could predict both age (r=0.6) and sex (r=0.5) with considerable accuracy from the EEG envelope spectrum. With age, oscillations characteristically shifted from a 4-5 second rhythm to higher rhythms. The envelope spectrum was not associated with general cognitive ability (IQ). Our results demonstrate that the sleep envelope spectrum is a promising, neuronal firing-based biomarker of various demographic and disease-related phenotypes.

Slow waves are major pacemakers of NREM sleep oscillations. While slow waves themselves are mainly generated by cortical neurons, it is not clear what role thalamic activity plays in the generation of some oscillations grouped by slow waves, and to what extent thalamic activity during slow waves is itself driven by corticothalamic inputs. To address this question, we simultaneously recorded both scalp EEG and local field potentials from six thalamic nuclei (bilateral anterior, mediodorsal and ventral anterior) in fifteen epileptic patients (age-range: 17-64 years, 7 females) undergoing Deep Brain Stimulation Protocol and assessed the temporal evolution of thalamic activity relative to scalp slow waves using time-frequency analysis. We found that thalamic activity in all six nuclei during scalp slow waves is highly similar to what is observed on the scalp itself. Slow wave downstates are characterized by delta, theta and alpha activity and followed by beta, high sigma and low sigma activity during subsequent upstates. Gamma activity in the thalamus is not significantly grouped by slow waves. Theta and alpha activity appeared first on the scalp, but sigma activity appeared first in the thalamus. These effects were largely independent from the scalp region in which SWs were detected and the precise identity of thalamic nuclei. Our results indicate that while small thalamocortical neuron assemblies may initiate cortical oscillations, especially in the sleep spindle range, the large-scale neuronal activity in the thalamus which is detected by field potentials is principally driven by global cortical activity, and thus it is highly similar to what is observed on the scalp.

International audience; Recently, a series of historical reports portrayed the first women neurosurgeons in various countries. One such woman, a pioneer on many levels, remained unrecognized: Judith Balkányi-Lepintre. She was the first woman neurosurgeon in France, the first woman war neurosurgeon for the French Army, and the first woman pediatric neurosurgeon in France. Born in 1912 to a Hungarian Jewish family, she graduated with honors from medical school in Budapest in 1935, then moved to Paris where she started neurosurgical training in 1937 at L'Hôpital de la Pitié under the mentorship of Clovis Vincent, the founder of French neurosurgery. Shortly after marrying a French colleague in 1940, she had to escape the Geheime Staatspolizei (Gestapo) in Paris and ended up in Algeria, where she joined the French Army of De Gaulle. As a neurosurgeon, she participated in the campaigns of Italy and France between 1943 and 1945. After the war, she returned to work at La Pitié Hospital. In 1947, she defended her doctoral thesis, "Treatment of cranio-cerebral wounds by projectiles and their early complications." Soon thereafter, she joined Europe's first dedicated children's hospital, Hôpital Necker-Enfants Malades in Paris, and contributed to the establishment of pediatric neurosurgery in France. She remained clinically and academically active at Necker until her death in 1982 but was never promoted.

The alpha rhythm is the longest-studied brain oscillation and has been theorized to play a key role in cognition. Still, its physiology is poorly understood. In this study, we used microelectrodes and macroelectrodes in surgical epilepsy patients to measure the intracortical and thalamic generators of the alpha rhythm during quiet wakefulness. We first found that alpha in both visual and somatosensory cortex propagates from higher-order to lower-order areas. In posterior cortex, alpha propagates from higher-order anterosuperior areas toward the occipital pole, whereas alpha in somatosensory cortex propagates from associative regions toward primary cortex. Several analyses suggest that this cortical alpha leads pulvinar alpha, complicating prevailing theories of a thalamic pacemaker. Finally, alpha is dominated by currents and firing in supragranular cortical layers. Together, these results suggest that the alpha rhythm likely reflects short-range supragranular feedback, which propagates from higher- to lower-order cortex and cortex to thalamus. These physiological insights suggest how alpha could mediate feedback throughout the thalamocortical system.

Sleep spindles are major oscillatory components of Non-Rapid Eye Movement (NREM) sleep, reflecting hyperpolarization-rebound sequences of thalamocortical neurons, the inhibition of which is caused by the NREM-dependent activation of GABAergic neurons in the reticular thalamic nucleus. Reports suggest a link between sleep spindles and several forms of interictal epileptic discharges (IEDs) which are considered as expressions of pathological off-line neural plasticity in the central nervous system. Here we investigated the relationship between thalamic sleep spindles, IEDs and ripples in the anterior and mediodorsal nuclei (ANT and MD) of epilepsy patients. Whole-night LFP from the ANT and MD were co-registered with scalp EEG/polysomnography by using externalized leads in 15 epilepsy patients undergoing Deep Brain Stimulation protocol. Slow (∼12 Hz) and fast (∼14 Hz) sleep spindles were present in the human ANT and MD. Roughly, one third of thalamic sleep spindles were associated with IEDs or ripples. Both IED- and ripple-associated spindles were longer than pure spindles. IED-associated thalamic sleep spindles were characterized by broadband increase in thalamic and cortical activity, both below and above the spindle frequency range, whereas ripple-associated thalamic spindles exceeded pure spindles in terms of 80–200 Hz thalamic, but not cortical activity as indicated by time-frequency analysis. These result show that thalamic spindles coupled with IEDs are reflected at the scalp slow and beta-gamma oscillation as well. IED density during sleep spindles in the MD, but not in the ANT was identified as correlates of years spent with epilepsy, whereas no signs of pathological processes were correlated with measures of ripple and spindle association. Furthermore, the density of ripple-associated sleep spindles in the ANT showed a positive correlation with general intelligence. Our findings indicate the complex and multifaceted role of the human thalamus in sleep spindle-related physiological and pathological neural plasticity.

Cortical dynamics obey a 1/f power law, exhibiting an exponential decay of spectral power with increasing frequency. The slope and offset of this 1/f decay reflect the timescale and magnitude of aperiodic neural activity, respectively. These properties are tightly linked to cellular and circuit mechanisms (e.g. excitation:inhibition balance and firing rates) as well as cognitive processes (e.g. perception, memory, and state). However, the physiology underlying the 1/f power law in cortical dynamics is not well understood. Here, we compared laminar recordings from human, macaque and mouse cortex to evaluate how 1/f aperiodic dynamics vary across cortical layers and species. We report that 1/f slope is steepest in superficial layers and flattest in deep layers in each species. Additionally, the magnitude of this 1/f decay is greatest in superficial cortex and decreases with depth. We could account for both of these findings with a simple model in which superficial cortical transmembrane currents had longer time constants and greater densities than those in deeper layers. Together, our results provide novel insight into the organization of cortical dynamics, suggesting that the amplitude and time constant of local currents control circuit processing as a function of laminar depth. This may represent a general mechanism to facilitate appropriate integration of fast sensory inputs (infragranular) with slow feedback-type inputs (supragranular) across cortical areas and species.

Sleep spindles are a cardinal feature in human slow wave sleep and may be important for memory consolidation. We studied the intracortical organization of spindles in humans by recording spontaneous sleep spindles from different cortical layers using linear microelectrode arrays. Two patterns of spindle generation were identified using visual inspection, and confirmed with factor analysis. Spindles were largest and most common in upper and middle channels, with limited involvement of deep channels. Many spindles were observed in only upper or only middle channels, but about half occurred in both. In spindles involving both middle and upper channels, the spindle envelope onset in middle channels led upper by ∼25-50ms on average. The phase relationship between spindle waves in upper and middle channels varied dynamically within spindle epochs, and across individuals. Current source density analysis demonstrated that upper and middle channel spindles were both generated by an excitatory supragranular current sink while an additional deep source was present for middle channel spindles only. Only middle channel spindles were accompanied by deep gamma activity. These results suggest that upper channel spindles are generated by supragranular pyramids, and middle channel by infragranular. Possibly, middle channel spindles are generated by core thalamocortical afferents, and upper channel by matrix. The concurrence of these patterns could reflect engagement of cortical circuits in the integration of more focal (core) and distributed (matrix) aspects of memory. These results demonstrate that at least two distinct intracortical systems generate human sleep spindles.Significance StatementBursts of ∼14Hz oscillations, lasting about a second, have been recognized for over 80 years as cardinal features of mammalian sleep. Recent findings suggest that they play a key role in organizing cortical activity during memory consolidation. We used linear microelectrode arrays to study their intracortical organization in humans. We found that spindles could be divided into two types. One mainly engages upper layers of the cortex, which are considered to be specialized for associative activity. The other engages both upper and middle layers, including those devoted to sensory input. The interaction of these two spindle types may help organize the interaction of sensory and associative aspects of memory consolidation.

INTRODUCTION: Although deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) represents an established third-line therapy for patients with drug-resistant focal epilepsy, guiding reports on practical treatment principles remain scarce. METHODS: An Expert Panel (EP) of 10 European neurologists and 4 neurosurgeons was assembled to share their experience with ANT-DBS therapy. The process included a review of the current literature, which served as a basis for an online survey completed by the EP prior to and following a face-to-face meeting (Delphi method). An agreement level of ≥71 % was considered as consensus. RESULTS: Out of 86 reviewed studies, 46 (53 %) were selected to extract information on the most reported criteria for patient selection, management, and outcome. The Delphi process yielded EP consensus on 4 parameters for selection of good candidates and patient management as well as 7 reasons of concern for this therapy. Since it was not possible to give strict device programming advice due to low levels of evidence, the experts shared their clinical practice: all of them start with monopolar stimulation, 79 % using the cycling mode. Most (93 %) EP members set the initial stimulation frequency and pulse width according to the SANTE parameters, while there is more variability in the amplitudes used. Further agreement was achieved on a list of 7 patient outcome parameters to be monitored during the follow-up. CONCLUSIONS: Although current evidence is too low for definite practical guidelines, this EP report could support the selection and management of patients with ANT-DBS. ispartof: SEIZURE-EUROPEAN JOURNAL OF EPILEPSY vol:81 pages:201-209 ispartof: location:England status: published

BackgroundAlthough they form a unitary phenomenon, the relationship between extracranial M/EEG and transmembrane ion flows is understood only as a general principle rather than as a well-articulated and quantified causal chain.MethodWe present an integrated multiscale model, consisting of a neural simulation of thalamus and cortex during stage N2 sleep and a biophysical model projecting cortical current densities to M/EEG fields. Sleep spindles were generated through the interactions of local and distant network connections and intrinsic currents within thalamocortical circuits. 32,652 cortical neurons were mapped onto the cortical surface reconstructed from subjects’ MRI, interconnected based on geodesic distances, and scaled-up to current dipole densities based on laminar recordings in humans. MRIs were used to generate a quasi-static electromagnetic model enabling simulated cortical activity to be projected to the M/EEG sensors.ResultsThe simulated M/EEG spindles were similar in amplitude and topography to empirical examples in the same subjects. Simulated spindles with more core-dominant activity were more MEG weighted.Comparison with Existing MethodsPrevious models lacked either spindle-generating thalamic neural dynamics or whole head biophysical modeling; the framework presented here is the first to simultaneously capture these disparate scales simultaneously.ConclusionsThis multiscale model provides a platform for the principled quantitative integration of existing information relevant to the generation of sleep spindles, and allows the implications of future findings to be explored. It provides a proof of principle for a methodological framework allowing large-scale integrative brain oscillations to be understood in terms of their underlying channels and synapses.

The neocortex is composed of six anatomically and physiologically specialized layers. It has been proposed that integration of activity across cortical areas is mediated anatomically by associative connections terminating in superficial layers, and physiologically by slow cortical rhythms. However, the means through which neocortical anatomy and physiology interact to coordinate neural activity remains obscure. Using laminar microelectrode arrays in 19 human participants, we found that most EEG activity is below 10-Hz (delta/theta) and generated by superficial cortical layers during both wakefulness and sleep. Cortical surface grid, grid-laminar, and dual-laminar recordings demonstrate that these slow rhythms are synchronous within upper layers across broad cortical areas. The phase of this superficial slow activity is reset by infrequent stimuli and coupled to the amplitude of faster oscillations and neuronal firing across all layers. These findings support a primary role of superficial slow rhythms in generating the EEG and integrating cortical activity.

Vagus nerve stimulation (VNS) is a nonpharmacologic therapeutic option for patients with intractable epilepsy. Better clinical outcomes were recorded in nonfocal and Lennox-Gastaut syndrome (LGS). We conducted a 2-year, open label, prospective study to measure the seizure outcome of 26 VNS patients. The seizure numbers were assessed using clinician's global impression scale (CGI) and patient diaries. The average seizure reduction was 23% at the first year and 22% at the second year. Seizure reduction was more pronounced among patients with nonfocal than with focal epilepsy. The response rate was 50% at first year and 30% at the second year. The best CGI record for clinically significant improvement was 15% in the LGS group. The only statistically significant result was the reduction of the generalized tonic-clonic seizures (GTCS). The side-effect profile was good; however, the large number of mild and reversible effects influenced the stimulation parameters and thus probably the effectiveness of the therapy. We suggest that VNS is an optional treatment mostly in cases of therapy-resistant Lennox-Gastaut syndrome. Patients with GTCS may experience improvement such as reduction of seizure severity. We conclude that VNS is a safe neuromodulatory treatment, but future developments of neuromodulatory approaches are needed.

Calretinin is expressed mainly in interneurons that specialize to innervate either principal cell dendrites or other interneurons in the human hippocampus. Calretinin-containing cells were shown to be vulnerable in animal models of ischaemia and epilepsy. In the human hippocampus, controversial data were published regarding their sensitivity in epilepsy. Therefore we aimed to reveal the fate of this cell type in human epileptic hippocampi. Surgically removed hippocampi of patients with drug-resistant temporal lobe epileptic (n = 44) were examined and compared to control (n = 8) samples with different post-mortem delays. The samples were immunostained for calretinin and the changes in the distribution, density and synaptic target selectivity of calretinin-positive cells were analysed. Control samples with post-mortem delays longer than 8 h resulted in a reduced number of immunolabelled cells compared to controls with short post-mortem delay. The number of calretinin-positive cells in the epileptic tissue was considerably decreased in correlation with the severity of principal cell loss. Preserved cells had segmented and shortened dendrites. Electron microscopic examination revealed that in controls, 23% of the calretinin-positive interneuronal terminals targeted calretinin-positive dendrites, whereas in the epileptic samples it was reduced to 3-5%. The number of contacts between calretinin-positive dendrites also dropped. The present quantitative data suggest that calretinin-containing cells in the human hippocampus are highly vulnerable, thus inhibition mediated by dendritic inhibitory cells and their synchronization by interneuron-specific interneurons may be impaired in epilepsy. We hypothesize that reorganization of the interneuron-selective cells may be implicated in the occurrence of seizures in non-sclerotic patients, where the majority of principal and non-principal cells are preserved.

A large proportion of hippocampal afferents and efferents are relayed through the subiculum. It is also thought to be a key structure in the generation and maintenance of epileptic activity; rhythmic interictal-like discharges were recorded in previous studies of subicular slices excised from temporal lobe epilepsy patients. In order to investigate if and how the subiculum is involved in the generation of epileptic discharges in vivo, subicular and lateral temporal lobe electrical activity were recorded under anesthesia in 11 drug-resistant epilepsy patients undergoing temporal lobectomy. Based on laminar field potential gradient, current source density, multiple unit activity (MUA) and spectral analyses, two types of interictal spikes were distinguished in the subiculum. The more frequently occurring spike started with an initial excitatory current (current source density sink) in the pyramidal cell layer associated with increased MUA in the same location, followed by later inhibitory currents (current source density source) and decreased MUA. In the other spike type, the initial excitation was confined to the apical dendritic region and it was associated with a less-prominent increase in MUA. Interictal spikes were highly synchronized at spatially distinct locations of the subiculum. Laminar data showed that the peak of the initial excitation occurred within 0-4 ms at subicular sites separated by 6 mm at the anterior-posterior axis. In addition, initial spike peak amplitudes were highly correlated in most recordings. A subset of subicular and temporal lobe spikes were also highly synchronous, in one case the subicular spikes reliably preceded the temporal lobe discharges. Our results indicate that multiple spike generator mechanisms exist in the human epileptic subiculum suggesting a complex network interplay between medial and lateral temporal structures during interictal epileptic activity. The observed widespread intra-subicular synchrony may reflect both of its intrinsic and extrinsically triggered activity supporting the hypothesis that subiculum may also play an active role in the distribution of epileptiform activity to other brain regions. Limited data suggest that subiculum might even play a pacemaker role in the generation of paroxysmal discharges.

Temporal lobe epilepsy (TLE) is known to be linked to an impaired balance of excitation and inhibition. Whether inhibition is decreased or preserved in the human epileptic hippocampus, beside the excess excitation, is still a debated question. In the present study, quantitative light and electron microscopy has been performed to analyse the distribution, morphology and input-output connections of parvalbumin (PV)-immunopositive interneurons, together with the entire perisomatic input of pyramidal cells, in the human control and epileptic CA1 region. Based on the degree of cell loss, the patients with therapy-resistant TLE formed four pathological groups. In the non-sclerotic CA1 region of TLE patients, where large numbers of pyramidal cells are preserved, the number of PV-immunopositive cell bodies decreased, whereas axon terminal staining, and the distribution of their postsynaptic targets was not altered. The synaptic coverage of CA1 pyramidal cell axon initial segments (AISs) remained unchanged in the epileptic tissue. The somatic inhibitory input is also preserved; it has been decreased only in the cases with patchy pyramidal cell loss in the CA1 region (control, 0.637; epileptic with mild cell loss, 0.642; epileptic with patchy cell loss, 0.424 microm synaptic length/100 microm soma perimeter). The strongly sclerotic epileptic CA1 region, where pyramidal cells can hardly be seen, contains a very small number of PV-immunopositive elements. Our results suggest that perisomatic inhibitory input is preserved in the epileptic CA1 region as long as pyramidal cells are present. Basket and axo-axonic cells survive in epilepsy if their original targets are present, although many of them lose their PV content or PV immunoreactivity. An efficient perisomatic inhibition is likely to take part in the generation of abnormal synchrony in the non-sclerotic epileptic CA1 region, and thus participate in the maintenance of epileptic seizures driven, for example, by hyperactive afferent input.

Laminar multiple microelectrodes have been developed to sample cortical and hippocampal activity in animals. If these measurements are adequately co-registered with the anatomy of the region, they can yield important information about its function and structure. In vivo laminar electrophysiological recordings from the human epileptic hippocampus are rare. However, histological and immunohistochemical analyses are widely used to determine the structural changes associated with temporal lobe epilepsy (TLE). Here we present data obtained by a combined approach: intraoperative recording of laminar field potentials, single and multiple unit activity under anesthesia, accompanied by histology and immunohistochemistry from the same hippocampal region of epileptic patients undergoing temporal lobectomy for drug-resistant TLE. The stability of the electrophysiology and the accuracy of its co-registration with histology were tested successfully. We have found large field potential spikes associated with bursting single units in CA1. Intracortical and subdural strip recordings from the lateral temporal cortex showed similar field potential activation patterns. A prominent oscillatory activity was present in the dentate gyrus with highly localized field potential gradient and multiple unit activity. This pattern could be used as a landmark defining the position of the electrode in the hippocampus. Our findings indicate that some aspects of the local and network epileptiform activity in the hippocampal formation are likely preserved under anesthesia. Electrophysiological identification of the functional state of the hippocampus together with its local structural correlates could further enhance our understanding of this disease.

Introduction The brain process of short term storage of multimodal information is called generally as working memory. This is thought to be located in the frontal and parietal lobes, however recent evidences show that the temporal lobe has important function in maintaining short-term and spatial information. Among multiple neuropsychological tests used for short term memory, the N-back test (NBT) has the advantage, that higher values of memory load can be set by increasing the recall distance (value n ). Methods We involved therapy resistant epilepsy patients undergoing video-EEG with scalp and invasive intracranial electrodes for visual and verbal NBT. The stimuli were presented gradually from 0 to 2 backs. The EEG graphs were filtered and averaged, and time-frequency analysis was performed (EEGLAB). Results Verbal NBT showed significant left-sided increase in gamma power, while during visual NBT right-sided gamma power increase was observed. The power correlated with the elevation of memory load. Intracranial data showed less increase in frontal regions compared to temporal. Conclusions Increase of gamma power seemed to be a good psychoneural correlate of memory processes during verbal and visual NBT. It showed appropriate lateralization and correlation with memory load. Based on our preliminary data the role of temporal lobe in short term memory can be hypothesized. We plan to include more patients.

Introduction Sleep spindles are generated in thalamo-cortical networks. Thalamo-cortical projections include core projections to middle and matrix projections to superficial cortical layers. It has been proposed that sleep spindles can be generated in either of these networks. Materials and methods We used electrophysiological data recorded with subdural grid and intracortical multielectrodes in five therapy-resistant epileptic patients undergoing invasive monitoring. Spindles were detected automatically in electrocorticography channels and detection-triggered laminar microelectrode recordings were analyzed. The second spatial derivative of spindle-band filtered (band pass 10–16 Hz, 96 dB) local field potential data allowed to approximate the laminar distribution of the transmembrane generators (current source density, CSD) of spindles. The information regarding the concurrent population cellular activity was obtained by applying a high frequency band filter (500–5000 Hz, 48 dB) on epoched data. Based on the histological reconstructions of laminar electrode tracks, we could identify the precise laminar localization of current sources and sinks. Results Results indicate highly heterogeneous intracortical local field potentials during sleep spindles, and maximum CSD in layer I, II and IV. Multi-unit activity was increased in spindle troughs as it was identified based on the spindle band filtered local field potentials. The single unit analyis revealed preferential firing of most neurons during the positive-negative phase transition of spindles. Conclusions The results confirm that both core and matrix thalamocortical projections contribute to spindle generation, but most spindles appear to be generated by a combination of the two and only a small minority by only one or the other. Neuronal firing tracks the phase of spindles in corticographic channels. Supported by KTIA_NAP_13-1-2013-0001.

Introduction Deep brain stimulation of anterior nucleus of the thalamus (ANT-DBS) is an approved therapeutic approach for drug resistant epilepsy. Little is known about the participation of ANT in epileptic and sleep EEG processes. The appearance of the sleep spindles (SS) is related to interictal discharges (IID), and thalamus is considered as the generator of SSs, however, according to animal data, ANT do not participate in the genesis of sleep spindles. Methods In this present study we included 10 ANT-DBS bitemporal epilepsy patients with externalised leads and surface electrodes undergoing 2 days video-EEG monitoring (VEM). We investigated IIDs, ictal events (IE) and SSs in ANT and also in surface EEG recordings. IIDs and IEs were analysed by visual inspection, SSs were detected according to the patient own special spindle frequency, separately on the scalp (Fp1-2, F3-4, F7-8) and thalamus both sides. SS spectral peak frequency and synchronization between scalp and ANT was measured. Results IIDs appeared in the thalamus and on the scalp both dependent and independent manner. Three patients had seizures during VEM. Seizures did not start but start spread to the ANT electrodes. The slow, frontal type of SSs were prevailing in the ANT. Conclusion ANT participates in both sleep and epileptogenic processes. It seems that IIDs and IE spread to the ANT. Frontal, slow frequency SSs has local sources int he ANT indication its participation in sleep processes. Further evaluation for seizure outcome of ANT-DBS therapy and correlation with ANT recordings are underway.

Central neurocytoma is a benign neuronal tumor of young adults in the lateral cerebral ventricles with characteristic X ray and light microscopic findings. In many respects typical central neurocytoma is reported below, with recurrence in the third month requiring reoperation. Death ensued in the fifth postoperative month. Subsequent histology proved progressive vascular proliferation and increasing, unusual glial differentiation of the neuronal tumor. At autopsy tumorous seeding blocked the liquor circulation. A thin tumorous layer covered the surface of all ventricles, the cerebellum and medulla oblongata. The GFAP positive cells out-numbered the synaptophysin positive ones. Increase of GFAP positivity and vascular proliferation of the central neurocytoma may be alarming signs suggesting a malignant course in addition to the other atypical features.

In advanced Parkinson's disease, medically refractory motor fluctuation or medically resistant tremor considerably affects quality of life. However, these symptoms can be mostly successfully treated by deep brain stimulation. We analyzed the efficacy of bilateral subthalamic stimulation in our patients with Parkinson's disease.We assessed the clinical data of ten patients who have been treated in the Department of Neurology, Semmelweis University and have been operated in the National Institute of Neurosciences between 2008 and 2011. The Hoehn-Yahr scale score, the Unified Parkinson's Disease Rating Scale score and the Parkinson's Disease Questionnaire 39, as well as the dose of antiparkinson medication were documented prior to and one year after surgery.Patient condition improved according to the Hoehn-Yahr scale, approximately by two stages. The dose of antiparkinson medication could be reduced by 63.4% (p = 0.005) post operation. Unified Parkinson's Disease Rating Scale scores decreased by 70.9% (p = 0.005). 12 hours after medication withdrawal, execution of daily activity improved by 57.1% (p0.01) and motor functions developed by 79.1% (p0.01). Duration of dyskinesias decreased by 62.5% (p = 0.018), duration of akinesia diminished by 87.5% (p = 0.005). Quality of life rose by 41.6% (p0.01). Neuropsychological tests detected improvement in verbal memory.With deep brain stimulation, the dosage of antiparkinson medication could be significantly reduced, with considerable improvements in motor function and quality of life. Although the number of patients is still low, good results have been established by careful patient selection, precise neurosurgical procedure and by appropriate programming and patient care.

Introduction In collaboration of the Department of Neurology at Semmelweis University, and the National Institute of Clinical Neurosciences, we have performed 59 DBS implantations in movement disorders since 2009. Thirty-four patients have been operated with Parkinson's disease (PD). Objectives In our Centre, we calculated the overall motor outcome of the bilateral subthalamic DBS therapy in PD during a one-year follow-up. Patients & methods Twenty-eight patients with Parkinson's disease (18 females, 10 males), who had a follow-up visit one year after the operation, were enrolled to the study. Each patient underwent a bilateral DBS lead and pulse generator implantation simultaneously. For individual anatomical planning, stereotactic contrast-enhanced CT sequences, contrast-enhanced 3D T1 weighted images and T2 weighted MRI (3T) images were merged. The individual anatomical target in the STN was selected according to standard stereotactic principles. Dopaminergic medication was withdrawn 12h before the operation. Electrophysiological mapping was executed with five microelectrodes; clinical symptoms were controlled through macrostimulation. Lead implantation was carried out using local anesthetics, and was assisted by fluoroscopy, while the implantation of the pulse generator was carried out under general anesthesia. The UPDRS (Unified Parkinson's Disease Rating Scale) total score, the subscores, and the Hoehn–Yahr stage were all measured preoperatively and at a postoperative control for 12–18months. For statistical analysis, we used the Wilcoxon signed-rank test. Results At the time of operation, the mean age of the patients was 60±8.8years (mean±standard deviation) with the disease duration of 12±5.3years. Before the operation, the patients had been under levodopa therapy for 9±5.4years. The levodopa equivalent dose was 1000±480mg before and 491±329.4mg after the operation ( p p =0.34); UPDRS II in OFF state: 18(12)/8(6) points ( p p =0.06); UPDRS III in OFF state: 35(30)/10(7) points ( p p p p p =0.045). The difference of the pre- and postoperative points in the modified Hoehn–Yahr scale was 1.5(1.5). Conclusion Similarly to international results, the bilateral subthalamic stimulation has markedly improved the motor function of our patients. Furthermore, the postural instability score has also significantly decreased after the operation.

To summarize the results gained with awake craniotomies, which were performed in either low grade glioma patients or epilepsy surgical patients whose tumor or epileptogenic zone, was in the vicinity of eloquent, mostly language, cortices. PATIENT SELECTION AND METHODS: In our retrospective study we selected 16 patients who were operated awake between 1999-2011 at the Neurosurgical Department of MAV Kórház Budapest, or at the National Institute of Neurosciences in Budapest, or at the Neurosurgical Department of the University of Debrecen in Debrecen. In the presurgical evaluation if it was possible we performed functional magnetic resonance imaging, tractography and detailed neuropsychological testing. At the National Institute of Neurosciences all patients were operated with the aid of MR guided neuronavigation.Anesthesia was carried out without complications in all of the 16 cases. Monitoring of sleep deepness has significantly contributed to the safety of anesthesia during the superficial anesthezied states of the operation. The intraoperative neuropsychological tasks used for testing language were sensitive enough to judge the little disturbances in speech during stimulation. Stimulation evoked seizures could be adequately managed during surgery and did not influence the outcome of the procedures. The use of neuronavigation helped significantly by planning the optimal place for the craniotomy and by intraoperative orientation.Awake craniotomies require well practiced surgical teams, which requires the cooperation of neuro-anesthesiologits, neurosurgeons, neuropsychologist and electrophysiologists. It has two goals, first to reduce the time of surgery to minimize surgical complications, secondly the detailed intraoperative mapping of cognitive and motor functions to avoid any neurological deficit. The intraoperative anatomical data provided by the neuronavigation and the functional data provided by awake intraoperative stimulation of the patient together serve the safety of the patient which is essential in the neurologically minimal invasive neurosurgical approach of the 21st century.

For localizing the epileptogenic zone in cases of focal epilepsies detailed clinical investigations, imaging studies and electrophysiological methods are in use. In lesional epilepsies the intrapreoperative localization of the lesion and it's location to the eloquent cortex is essential for the neurosurgeon. The development in image guided neurosurgery lead us to use neuronavigation systems to localize intracerebral lesions or functionally eloquent cortical areas or subcortical pathways during surgery. Neuronavigation brought changes in preoperative evaluation and in resective surgery in epilepsy as well. In this article we describe the basics of neuronavigation and enhance the advantages of the technique in epilepsy surgery during the presurgical evaluation with invasive electrodes, in resective surgery and DBS for epilepsy.

Sleep-associated memory consolidation is thought to rely on coordinated information transfer between the hippocampus and neocortex brought about during slow wave sleep (SWS) by distinct local field potential oscillations. Specifically, findings in animals have led to the concept that ripples originating from hippocampus combine with spindles to provide a fine-tuned temporal frame for a persistent transfer of memory-related information to the neocortex. The present study focused on characterizing the temporal relationship between parahippocampal ripple activity (80-140 Hz) and spindles recorded from frontal, parietal and parahippocampal cortices in 12 epilepsy patients implanted with parahippocampal foramen ovale electrodes. Overall, parietal and parahippocampal spindles showed closer relationships to parahippocampal ripple activity than frontal spindles, with the latter following parietal and parahippocampal spindles at a variable delay of up to 0.5 s. On a timescale of seconds, ripple activity showed a continuous increase before the peak of parietal and parahippocampal spindles, and decreased thereafter. At a fine timescale of milliseconds, parahippocampal ripple activity was tightly phase-locked to the troughs of these spindles. The demonstration of spindle phase-locked ripple activity in humans is consistent with the idea of a temporally fine-tuned hippocampus-to-neocortex transfer of information taking place during SWS.

Brain electrical activity is largely composed of oscillations at characteristic frequencies. These rhythms are hierarchically organized and are thought to perform important pathological and physiological functions. The slow wave is a fundamental cortical rhythm that emerges in deep non-rapid eye movement sleep. In animals, the slow wave modulates delta, theta, spindle, alpha, beta, gamma and ripple oscillations, thus orchestrating brain electrical rhythms in sleep. While slow wave activity can enhance epileptic manifestations, it is also thought to underlie essential restorative processes and facilitate the consolidation of declarative memories. Animal studies show that slow wave activity is composed of rhythmically recurring phases of widespread, increased cortical cellular and synaptic activity, referred to as active- or up-state, followed by cellular and synaptic inactivation, referred to as silent- or down-state. However, its neural mechanisms in humans are poorly understood, since the traditional intracellular techniques used in animals are inappropriate for investigating the cellular and synaptic/transmembrane events in humans. To elucidate the intracortical neuronal mechanisms of slow wave activity in humans, novel, laminar multichannel microelectrodes were chronically implanted into the cortex of patients with drug-resistant focal epilepsy undergoing cortical mapping for seizure focus localization. Intracortical laminar local field potential gradient, multiple-unit and single-unit activities were recorded during slow wave sleep, related to simultaneous electrocorticography, and analysed with current source density and spectral methods. We found that slow wave activity in humans reflects a rhythmic oscillation between widespread cortical activation and silence. Cortical activation was demonstrated as increased wideband (0.3-200 Hz) spectral power including virtually all bands of cortical oscillations, increased multiple- and single-unit activity and powerful inward transmembrane currents, mainly localized to the supragranular layers. Neuronal firing in the up-state was sparse and the average discharge rate of single cells was less than expected from animal studies. Action potentials at up-state onset were synchronized within +/-10 ms across all cortical layers, suggesting that any layer could initiate firing at up-state onset. These findings provide strong direct experimental evidence that slow wave activity in humans is characterized by hyperpolarizing currents associated with suppressed cell firing, alternating with high levels of oscillatory synaptic/transmembrane activity associated with increased cell firing. Our results emphasize the major involvement of supragranular layers in the genesis of slow wave activity.

Vagus nerve stimulation (VNS) is a nonpharmacologic therapeutic option for patients with intractable epilepsy. Better clinical outcomes were recorded in nonfocal and Lennox-Gastaut syndrome (LGS). We conducted a 2-year, open label, prospective study to measure the seizure outcome of 26 VNS patients. The seizure numbers were assessed using clinician's global impression scale (CGI) and patient diaries. The average seizure reduction was 23% at the first year and 22% at the second year. Seizure reduction was more pronounced among patients with nonfocal than with focal epilepsy. The response rate was 50% at first year and 30% at the second year. The best CGI record for clinically significant improvement was 15% in the LGS group. The only statistically significant result was the reduction of the generalized tonic-clonic seizures (GTCS). The side-effect profile was good; however, the large number of mild and reversible effects influenced the stimulation parameters and thus probably the effectiveness of the therapy. We suggest that VNS is an optional treatment mostly in cases of therapy-resistant Lennox-Gastaut syndrome. Patients with GTCS may experience improvement such as reduction of seizure severity. We conclude that VNS is a safe neuromodulatory treatment, but future developments of neuromodulatory approaches are needed.

The endocannabinoid system plays a central role in retrograde synaptic communication, and controls both glutamatergic and gamma-aminobutyric acid (GABA)ergic transmission via type 1 cannabinoid (CB1) receptor. Both in sclerotic human hippocampi and in the chronic phase of pilocarpine-induced epilepsy in mice with sclerosis, CB1-receptor-positive interneuron somata were preserved both in the dentate gyrus and in the CA1 area, and the density of CB1-immunostained fibers increased considerably in the dentate molecular layer. This suggests that, although CB1 receptors are known to be reduced in density on glutamatergic axons, the CB1-receptor-expressing GABAergic axons sprout, or there is an increase of CB1-receptor levels on these fibers. The changes of CB1 immunostaining in association with the GABAergic inhibitory system appear to correlate with the severity of pyramidal cell loss in the CA1 subfield. These results confirm the involvement of the endocannabinoid system associated with GABAergic transmission in human temporal lobe epilepsy (TLE), as well as in the chronic phase of the pilocarpine model in mice. Pharmacotherapy aimed at the modulation of endocannabinoid-mediated retrograde synaptic signaling should take into account the opposite change in CB1-receptor expression observed on glutamatergic versus GABAergic axon terminals.

To investigate interhemispheric propagation of mesial temporal lobe epilepsy seizures in patients undergoing long-term video-EEG monitoring with combined scalp and foramen ovale electrodes.To reveal possible interhemispheric propagation patterns in mesial temporal lobe epilepsy, to improve presurgical evaluation of temporal epileptic patients.Sixty-five seizures from 20 patients were analyzed. We defined two contralateral seizure propagation patterns: Type I for those seizures that spread to the contralateral foramen ovale electrodes earlier than to the contralateral scalp electrodes, and type II for the opposite.Twenty drug resistant epileptic patients were investigated in frame of their presurgical evaluation.The majority of seizures (80%) were classified as type I. Inter-foramen ovale electrode propagation time was significantly shorter for type I compared to type II seizures. Ninety percent of patients had either type I or type II seizures only. Patients with type I seizures significantly more often had mesiotemporal structural alterations evident on magnetic resonance imaging scans, and became more often seizure-free after surgery compared to patients with type II seizures whose surgical outcome was less favorable or surgery could not be indicated because of independent bilateral ictal seizure-onset.The two types of contralateral propagation patterns we are describing seem to represent two subtypes of mesial temporal lobe epilepsy with different morphological and prognostic features. The predominance of type I over type II seizures together with shorter propagation times for type I seizures indicate a role of a more direct and dominant interhemispheric pathway in mesial temporal lobe epilepsy.

The dentate gyrus, the cornu ammonis 2 region and the subiculum of the human hippocampal formation are resistant to the cell loss associated with temporal lobe epilepsy. The subiculum, but not the dentate gyrus, generates interictal-like activity in tissue slices from epileptic patients. In this study, we asked whether a similar population activity is generated in the cornu ammonis 2 region and examined the electrophysiological and neuroanatomical characteristics of human epileptic cornu ammonis 2 neurons that may be involved. Hippocampal slices were prepared from postoperative temporal lobe tissue derived from epileptic patients. Field potentials and multi-unit activity were recorded in vitro using multiple extracellular microelectrodes. Pyramidal cells were characterized in intra-cellular records and were filled with biocytin for subsequent anatomy. Fluorescent immunostaining was made on fixed tissue against the chloride-cation cotransporters sodium-potassium-chloride cotransporter-1 and potassium-chloride cotransporter-2. Light and electron microscopy were used to examine the parvalbumin-positive perisomatic inhibitory network. In 15 of 20 slices, the hippocampal cornu ammonis 2 region generated a spontaneous interictal-like activity, independently of population events in the subiculum. Most cornu ammonis 2 pyramidal cells fired spontaneously. All cells fired single action potentials and burst firing was evoked in three cells. Spontaneous excitatory postsynaptic potentials were recorded in all cells, but hyperpolarizing inhibitory postsynaptic potentials were detected in only 27% of the cells. Two-thirds of cornu ammonis 2 neurons showed depolarizing responses during interictal-like events, while the others were inhibited, according to the current sink in the cell body layer. Two biocytin-filled cells both showed a pyramidal-like morphology with axons projecting to the cornu ammonis 2 and cornu ammonis 3 regions. Expression of sodium-potassium-chloride cotransporter-1 and potassium-chloride cotransporter-2 was reduced in some cells of the epileptic cornu ammonis 2 region, but not to an extent corresponding to the proportion of cells in which hyperpolarizing postsynaptic potentials were absent. Numbers of parvalbumin-positive inhibitory cells and axons were shown to be decreased in the epileptic tissue. Electron microscopy showed the preservation of somatic inhibitory input of cornu ammonis 2 cells, and confirmed the loss of parvalbumin from the interneurons rather than their death. An extra excitatory input (partly coming from sprouted mossy fibres) was demonstrated to innervate cornu ammonis 2 cell bodies. Our results show that the cornu ammonis 2 region of the sclerotic human hippocampus can generate an independent epileptiform activity. Inhibitory and excitatory signalling were functional but modified in epileptic cornu ammonis 2 pyramidal cells. Overexcitation and the altered functional properties of perisomatic inhibitory network, rather than a modified chloride homeostasis, may account for the perturbed gamma-aminobutyric acid-ergic signalling and the generation of interictal-like activity in the human epileptic cornu ammonis 2 region.

In this study we analyzed monofractal and multifractal properties of epileptic local field potentials recorded from different layers of the frontal cortex. Seven seizures of two patients suffering from drug resistant frontal lobe epilepsy were assessed. We found drastic changes of fractal properties during the seizures. Distinct gradual changes of these properties were present before and after the ictal states. Moreover, laminar characteristics of the estimated measures were observed. Our results might be used to reveal the mechanisms related to the dynamics of epileptic seizures and perhaps to develop a seizure detection/prediction algorithm.

For localization of the epileptogenic zone in cases of focal epilepsy, detailed clinical investigations, imaging studies, and electrophysiological methods are used. If the noninvasive presurgical evaluation provides insufficient data, intracranial electrodes are necessary. Computed tomography and MR imaging techniques are the gold standard for localization of the postoperative position of the implanted intracranial electrode contacts. If the electrode strips are inserted through a bur hole, however, the exact localization of the electrode contacts on the patient's brain remains uncertain for the surgeon during insertion. Therefore, the authors developed a simple method to visualize the electrodes during the procedure. In this method they combine neuronavigation and intraoperative fluoroscopy for parallel visualization of the cortex, electrodes, and the navigation probe. The target region is searched with neuronavigation, a bur hole is made over the optimal entry point, and using real-time fluoroscopy the strip electrode is slid to the tip of the navigation probe, which was kept over the area of interest. At the authors' institution 26 strips in 8 patients have been inserted with this technique, and none of the strips had to be repositioned. There were no complications with this procedure and the prolongation of surgery time is acceptable. Compared to previously published electrode placement methods, this one enhances the accuracy of electrode placement at occipital, parietal, frontal, or interhemispheric regions as well. Intraoperative visualization of the electrodes with fluoroscopy combined with neuronavigation during positioning through a bur hole gives the neurosurgeon the ability to control the real position of the electrode over the gyri during the procedure.

Endocannabinoid signaling is a key regulator of synaptic neurotransmission throughout the brain. Compelling evidence shows that its perturbation leads to development of epileptic seizures, thus indicating that endocannabinoids play an intrinsic protective role in suppressing pathologic neuronal excitability. To elucidate whether long-term reorganization of endocannabinoid signaling occurs in epileptic patients, we performed comparative expression profiling along with quantitative electron microscopic analysis in control (postmortem samples from subjects with no signs of neurological disorders) and epileptic (surgically removed from patients with intractable temporal lobe epilepsy) hippocampal tissue. Quantitative PCR measurements revealed that CB1cannabinoid receptor mRNA was downregulated to one-third of its control value in epileptic hippocampus. Likewise, the cannabinoid receptor-interacting protein-1a mRNA was decreased, whereas 1b isoform levels were unaltered. Expression of diacylglycerol lipase-α, an enzyme responsible for 2-arachidonoylglycerol synthesis, was also reduced by ∼60%, whereas its related β isoform levels were unchanged. Expression level ofN-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D and fatty acid amide hydrolase, metabolic enzymes of anandamide, and 2-arachidonoylglycerol's degrading enzyme monoacylglycerol lipase did not change. The density of CB1immunolabeling was also decreased in epileptic hippocampus, predominantly in the dentate gyrus, where quantitative electron microscopic analysis did not reveal changes in the ratio of CB1-positive GABAergic boutons, but uncovered robust reduction in the fraction of CB1-positive glutamatergic axon terminals. These findings show that a neuroprotective machinery involving endocannabinoids is impaired in epileptic human hippocampus and imply that downregulation of CB1receptors and related molecular components of the endocannabinoid system may facilitate the deleterious effects of increased network excitability.

Ripples are high-frequency oscillation bursts in the mammalian hippocampus mainly present during Non-REM sleep. In rodents they occur in association with sharp waves and are grouped by the cortical slow oscillation such that, in parallel with sleep spindles, ripple activity is suppressed during the hyperpolarized down-state and enhanced during the depolarized up-state. The temporal coupling between slow oscillations, spindles and ripples has been suggested to serve a hippocampo-neocortical dialogue underlying memory consolidation during sleep. Here, we examined whether a similar coupling exists between these oscillatory phenomena in humans. In sleep recordings from seven epileptic patients, scalp-recorded slow oscillations and spindles as well as parahippocampal ripples recorded from foramen ovale electrodes were identified by automatic algorithms. Additionally, ripple and spindle root mean square activity was determined for relevant frequency bands. Ripple density was higher during Non-REM than REM sleep (P < 0.001). Ripple activity distinctly decreased time-locked to slow oscillation negative half-waves in the three patients without temporal structural alterations (P < 0.001), whereas in the four patients with severe mesiotemporal structural alterations this coupling was obscure. Generally, in the patients ripple activity was increased before spindle peaks and distinctly decreased after the peak (P < 0.001). Ripples were consistently associated with interictal spikes suggesting that spike-ripple complexes represent an epileptic transformation of sharp wave-ripple complexes in the epileptic hippocampus. Our findings are consistent with the notion of a hippocampo-to-neocortical information transfer during sleep that is linked to coordinate ripple and spindle activity, and that in the intact temporal lobe is synchronized to cortical slow oscillations.