National Institute of Clinical Neuroscience

Budapest, Hungary

National Institute of Clinical Neuroscience

Budapest, Hungary
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Keller C.J.,Feinstein Institute for Medical Research | Keller C.J.,Yeshiva University | Honey C.J.,Princeton University | Honey C.J.,University of Toronto | And 7 more authors.
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2014

The cerebral cortex forms a sheet of neurons organized into a network of interconnected modules that is highly expanded in humans and presumably enables our most refined sensory and cognitive abilities. The links of this network form a fundamental aspect of its organization, and a great deal of research is focusing on understanding how information flows within and between different regions. However, an often-overlooked element of this connectivity regards a causal, hierarchical structure of regions, whereby certain nodes of the cortical network may exert greater influence over the others. While this is difficult to ascertain non-invasively, patients undergoing invasive electrode monitoring for epilepsy provide a unique window into this aspect of cortical organization. In this review, we highlight the potential for corticocortical evoked potential (CCEP) mapping to directly measure neuronal propagation across large-scale brain networks with spatio-temporal resolution that is superior to traditional neuroimaging methods.We first introduce effective connectivity and discuss the mechanisms underlying CCEP generation. Next, we highlight how CCEP mapping has begun to provide insight into the neural basis of non-invasive imaging signals. Finally, we present a novel approach to perturbing and measuring brain network function during cognitive processing. The direct measurement of CCEPs in response to electrical stimulation represents a potentially powerful clinical and basic science tool for probing the large-scale networks of the human cerebral cortex. © 2014 The Author(s) Published by the Royal Society. All rights reserved.


Karlocai M.R.,Hungarian Academy of Sciences | Wittner L.,Hungarian Academy of Sciences | Wittner L.,National Institute of Clinical Neuroscience | Toth K.,Hungarian Academy of Sciences | And 10 more authors.
Brain Structure and Function | Year: 2015

Synaptic reorganization in the epileptic hippocampus involves altered excitatory and inhibitory transmission besides the rearrangement of dendritic spines, resulting in altered excitability, ion homeostasis, and cell swelling. The potassium-chloride cotransporter-2 (KCC2) is the main chloride extruder in neurons and hence will play a prominent role in determining the polarity of GABAA receptor-mediated chloride currents. In addition, KCC2 also interacts with the actin cytoskeleton which is critical for dendritic spine morphogenesis, and for the maintenance of glutamatergic synapses and cell volume. Using immunocytochemistry, we examined the cellular and subcellular levels of KCC2 in surgically removed hippocampi of temporal lobe epilepsy (TLE) patients and compared them to control human tissue. We also studied the distribution of KCC2 in a pilocarpine mouse model of epilepsy. An overall increase in KCC2-expression was found in epilepsy and confirmed by Western blots. The cellular and subcellular distributions in control mouse and human samples were largely similar; moreover, changes affecting KCC2-expression were also alike in chronic epileptic human and mouse hippocampi. At the subcellular level, we determined the neuronal elements exhibiting enhanced KCC2 expression. In epileptic tissue, staining became more intense in the immunopositive elements detected in control tissue, and profiles with subthreshold expression of KCC2 in control samples became labelled. Positive interneuron somata and dendrites were more numerous in epileptic hippocampi, despite severe interneuron loss. Whether the elevation of KCC2-expression is ultimately a pro- or anticonvulsive change, or both—behaving differently during ictal and interictal states in a context-dependent manner—remains to be established. © 2015 Springer-Verlag Berlin Heidelberg


Entz L.,Feinstein Institute for Medical Research | Entz L.,Hungarian Academy of Sciences | Entz L.,National Institute of Clinical Neuroscience | Entz L.,Pázmány Péter Catholic University | And 17 more authors.
Human Brain Mapping | Year: 2014

The role of cortical connectivity in brain function and pathology is increasingly being recognized. While in vivo magnetic resonance imaging studies have provided important insights into anatomical and functional connectivity, these methodologies are limited in their ability to detect electrophysiological activity and the causal relationships that underlie effective connectivity. Here, we describe results of cortico-cortical evoked potential (CCEP) mapping using single pulse electrical stimulation in 25 patients undergoing seizure monitoring with subdural electrode arrays. Mapping was performed by stimulating adjacent electrode pairs and recording CCEPs from the remainder of the electrode array. CCEPs reliably revealed functional networks and showed an inverse relationship to distance between sites. Coregistration to Brodmann areas (BA) permitted group analysis. Connections were frequently directional with 43% of early responses and 50% of late responses of connections reflecting relative dominance of incoming or outgoing connections. The most consistent connections were seen as outgoing from motor cortex, BA6-BA9, somatosensory (SS) cortex, anterior cingulate cortex, and Broca's area. Network topology revealed motor, SS, and premotor cortices along with BA9 and BA10 and language areas to serve as hubs for cortical connections. BA20 and BA39 demonstrated the most consistent dominance of outdegree connections, while BA5, BA7, auditory cortex, and anterior cingulum demonstrated relatively greater indegree. This multicenter, large-scale, directional study of local and long-range cortical connectivity using direct recordings from awake, humans will aid the interpretation of noninvasive functional connectome studies. © 2014 Wiley Periodicals, Inc.


PubMed | National Institute of Clinical Neuroscience, University of Helsinki, Hungarian Academy of Sciences and University of California at Davis
Type: Journal Article | Journal: Brain structure & function | Year: 2016

Synaptic reorganization in the epileptic hippocampus involves altered excitatory and inhibitory transmission besides the rearrangement of dendritic spines, resulting in altered excitability, ion homeostasis, and cell swelling. The potassium-chloride cotransporter-2 (KCC2) is the main chloride extruder in neurons and hence will play a prominent role in determining the polarity of GABAA receptor-mediated chloride currents. In addition, KCC2 also interacts with the actin cytoskeleton which is critical for dendritic spine morphogenesis, and for the maintenance of glutamatergic synapses and cell volume. Using immunocytochemistry, we examined the cellular and subcellular levels of KCC2 in surgically removed hippocampi of temporal lobe epilepsy (TLE) patients and compared them to control human tissue. We also studied the distribution of KCC2 in a pilocarpine mouse model of epilepsy. An overall increase in KCC2-expression was found in epilepsy and confirmed by Western blots. The cellular and subcellular distributions in control mouse and human samples were largely similar; moreover, changes affecting KCC2-expression were also alike in chronic epileptic human and mouse hippocampi. At the subcellular level, we determined the neuronal elements exhibiting enhanced KCC2 expression. In epileptic tissue, staining became more intense in the immunopositive elements detected in control tissue, and profiles with subthreshold expression of KCC2 in control samples became labelled. Positive interneuron somata and dendrites were more numerous in epileptic hippocampi, despite severe interneuron loss. Whether the elevation of KCC2-expression is ultimately a pro- or anticonvulsive change, or both-behaving differently during ictal and interictal states in a context-dependent manner-remains to be established.


Hegyi M.,Bethesda Childrens Hospital | Siegler Z.,Bethesda Childrens Hospital | Fogarasi A.,Bethesda Childrens Hospital | Barsi P.,Research Center | Halasz P.,National Institute of Clinical Neuroscience
Ideggyogyaszati Szemle | Year: 2016

Objectives - A retrospective study has been done at the Bethesda Children's Hospital Epilepsy Center with those patients whose EEG records fulfilled in one or more records the criteria of electrical status epilepticus in slow wave sleep (ESES) pattern, occupying at least 75% of NREM sleep with bilateral discharges, and had detailed disease history and long term follow-up data, between 2000 and 2012. Patients and methods - Thirty-three patients (mean 11.1 ±4.2 years of age) were studied by 171 sleep EEG records. Sleep was recorded after sleep deprivation or during spontaneous sleep at least for one hour length of NREM. From the 492 EEGs, 171 sleep records were performed (average five/patient). Average follow-up time was 7.5 years. Eighty-two ESES records have been analyzed in 15 non-lesional and 18 lesional (11 with dysgenetic and seven with perinatal - asphyxic or vascular origin) patients. Variability of seizure types, seizure frequency and frequency of status epilepticus was higher in the iesional group. Impairment of the cognitive functions was moderate and partial in the non-lesional, while severely damaged in the lesional group. Results - EEG records of 29 patients showed unihemispherial spike fields with a perpendicular axis (in anterior, medial and posterior variants) to the Sylvian fissure, regardless their lesional or non-lesional origin. Only three (lone non-lesional and two lesional) patients had bilateral synchronous spike-wave discharges with bilateral symmetric frontocentral spike fields. The individual discharges of the sleep EEG pattern were very similar to the awake interictal records except their extension in time and field, their increased number, amplitude, and continuity of them and furthermore in the increased trans-hemispheral propagation and their synchronity. Conclusions - Assumed circuits involved in the pathome-chanism of discharges during NREM sleep in ESES are discussed based on our findings.


Halasz P.,National Institute of Clinical Neuroscience
Behavioural Neurology | Year: 2015

System epilepsy is an emerging concept interpreting major nonlesional epilepsies as epileptic dysfunctions of physiological systems. I extend here the concept of reflex epilepsy to epilepsies linked to input dependent physiological systems. Experimental and clinical reseach data were collected to create a coherent explanation of underlying pathomechanism in AE and NFLE. We propose that AE should be interpreted as epilepsy linked to the corticothalamic burst-firing mode of NREM sleep, released by evoked vigilance level oscillations characterized by reactive slow wave response. In the genetic variation of NFLE the ascending cholinergic arousal system plays an essential role being in strong relationship with a gain mutation of the nicotinic acethylcholin receptors, rendering the arousal system hyperexcitable. I try to provide a more unitary interpretation for the variable seizure manifestation integrating them as different degree of pathological arosuals and alarm reactions. As a supporting hypothesis the similarity between arousal parasomnias and FNLE is shown, underpinned by overlaping pathomechanism and shared familiarity, but without epileptic features. Lastly we propose that both AE and NFLE are system epilepsies of the sleep-wake system representing epileptic disorders of the antagonistic sleep/arousal network. This interpretation may throw new light on the pathomechanism of AE and NFLE. © 2015 Péter Halász.


Halasz P.,National Institute of Clinical Neuroscience | Kelemen A.,National Institute of Clinical Neuroscience | Szucs A.,National Institute of Clinical Neuroscience
Epilepsy Research | Year: 2013

The article summarises the role of input and consequent phasic events in the dynamism of non-rapid eye movement (NREM) sleep and in homeostatic slow-wave economy during sleep.Then, an overview of the mechanism of how micro-arousals in NREM sleep gate epileptic events in absence epilepsy (AE) and in sporadic and autosomal dominant nocturnal frontal lobe epilepsy (NFLE/ADNFLE) is presented.The ictal type of generalised spike-wave discharges (SWDs) are associated with a special vigilance level in between NREM, rapid-eye movement (REM) and wake state. This transitional state is characterised by input-driven bidirectional fluctuations. Among them, SWDs are linked to A1 type A phases of CAP and therefore seem to be associated with shifts towards NREM sleep (sleep induction).In ADNFLE (and presumably in NFLE), micro-arousals release epileptic events in NREM sleep probably due to epileptic sensitisation of the cholinergic arousal system by the known acetylcholine (ACh) receptor mutations affecting the arousal system, giving rise to the epileptic (and also parasomniac) episodes.In both kinds of these system epilepsies (AE and NFLE), epileptic events can be released by phasic events during NREM sleep.The difference is that absences are activated in reactive states with a sleep-promoting, antiarousal effect, while in NFLE the epileptic disorder is interwoven with the cholinergic arousal function.The role of arousal/antiarousal in NFLE and AE fits nicely with the hypothesis that these epilepsies are disorders of two antagonistic thalamo-frontal systems involved in functions NREM sleep and wakefulness. © 2013 Elsevier B.V.


Papp Z.,National Institute of Clinical Neuroscience | Marosfoi M.,National Institute of Clinical Neuroscience | Szikora I.,National Institute of Clinical Neuroscience | Banczerowski P.,National Institute of Clinical Neuroscience | Banczerowski P.,Semmelweis University
Journal of Neurosurgery: Spine | Year: 2014

Object: Metastatic spinal tumors of the atlantoaxial region are quite uncommon, and surgery is challenging. The aim in this study was to evaluate the safety and efficacy of transoral or transpedicular vertebroplasty combined with posterior fixation in C-2 metastatic disease. Methods: The authors collected from a hospital database all cases of C-2 metastatic tumor treated in the period from January 2009 to December 2012. Cases with histologically confirmed metastatic disease were included, but those with epidural tumorous propagation and signs of spinal cord compression were excluded. Results: Five patients (3 females, 2 males) with osteolytic C-2 metastasis were eligible for this study. In 3 cases a purely posterior approach was taken to perform a dorsal open C-2 biopsy and transpedicular vertebroplasty followed by posterior occipitocervical fixation. In the other 2 cases a transoral C-2 biopsy and vertebroplasty were performed in combination with dorsal occipitocervical fixation during the same operative session. Patients were followed up with regular fluoroscopy, MRI, and CT studies as well as neurological examinations. During an average follow-up of 13 months (range 8-19 months), no surgical or neurological complications were associated with this combined approach. In all cases spinal stability and pain reduction were detected. The average pain score according to the visual analog scale was 3.5 after surgery (range 2-5); before surgery, the average score was 7 (range 6-8). The average volume of polymethylmethacrylate injected was 4 ml. The body and dens of the C-2 vertebra was filled more than 60% for each patient. Conclusions: In this small series, simultaneous intraoperative transoral or transpedicular vertebroplasty and dorsal occipitocervical fixation proved to be a safe and effective treatment for patients with osteolytic C-2 metastatic tumors. These techniques may provide excellent pain relief and improvements in quality of life. The true value of these combined techniques should be evaluated in larger series. © AANS, 2014.


PubMed | National Institute of Clinical Neuroscience
Type: Journal Article | Journal: Epilepsy research | Year: 2013

The article summarises the role of input and consequent phasic events in the dynamism of non-rapid eye movement (NREM) sleep and in homeostatic slow-wave economy during sleep. Then, an overview of the mechanism of how micro-arousals in NREM sleep gate epileptic events in absence epilepsy (AE) and in sporadic and autosomal dominant nocturnal frontal lobe epilepsy (NFLE/ADNFLE) is presented. The ictal type of generalised spike-wave discharges (SWDs) are associated with a special vigilance level in between NREM, rapid-eye movement (REM) and wake state. This transitional state is characterised by input-driven bidirectional fluctuations. Among them, SWDs are linked to A1 type A phases of CAP and therefore seem to be associated with shifts towards NREM sleep (sleep induction). In ADNFLE (and presumably in NFLE), micro-arousals release epileptic events in NREM sleep probably due to epileptic sensitisation of the cholinergic arousal system by the known acetylcholine (ACh) receptor mutations affecting the arousal system, giving rise to the epileptic (and also parasomniac) episodes. In both kinds of these system epilepsies (AE and NFLE), epileptic events can be released by phasic events during NREM sleep. The difference is that absences are activated in reactive states with a sleep-promoting, antiarousal effect, while in NFLE the epileptic disorder is interwoven with the cholinergic arousal function. The role of arousal/antiarousal in NFLE and AE fits nicely with the hypothesis that these epilepsies are disorders of two antagonistic thalamo-frontal systems involved in functions NREM sleep and wakefulness.


PubMed | National Institute of Clinical Neuroscience, University of Szeged, Semmelweis University, Nyiro Gyula Hospital National Institute of Psychiatry and Addictology and 6 more.
Type: | Journal: Parkinson's disease | Year: 2014

Movement Disorder Society-sponsored Unified Parkinsons Disease Rating Scale (MDS-UPDRS) has separate items for measuring sleep problems (item 1.7) and daytime sleepiness (1.8). The aim of our study was to evaluate the screening sensitivity and specificity of these items to the PD Sleep Scale 2nd version (PDSS-2) and Epworth Sleepiness Scale (ESS). In this nationwide, cross-sectional study 460 PD patients were enrolled. Spearmans rank correlation coefficients were calculated between the individual items, domains, and the total score of PDSS-2 and item 1.7 of MDS-UPDRS. Similarly, the items and the total score of ESS were contrasted to item 1.8 of MDS-UPDRS. After developing generalized ordinal logistic regression models, the transformed and observed scores were compared by Lins Concordance Correlation Coefficient. Only item 3 difficulties staying asleep and the disturbed sleep domain of PDSS-2 showed high correlation with sleep problems item 1.7 of the MDS-UPDRS. Total score of PDSS-2 had moderate correlation with this MDS-UPRDS item. The total score of ESS showed the strongest, but still moderate, correlation with daytime sleepiness item 1.8 of MDS-UPDRS. As intended, the MDS-UPDRS serves as an effective screening tool for both sleep problems and daytime sleepiness and identifies subjects whose disabilities need further investigation.

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