multi-electrode-array-recordings-human-epileptic-postoperative

Multi-electrode Array Recordings of Human Epileptic Postoperative Cortical Tissue

Epilepsy, affecting about 1% of the population, comprises a group of neurological disorders characterized by the periodic occurrence of seizures, which ...

Paris Descartes University, Sorbonne Paris Cité, CEA

La Pitié-Salpêtrière Hospital, AP-HP, Sorbonne and Pierre and Marie Curie University

About 13% of patients with epilepsy have a history of febrile seizures (FS). Studies of familial forms suggest a genetic component to the epidemiological link. Indeed, in certain monogenic forms of FS, for which several loci have been reported, some patients develop epilepsy with a higher risk than in the general population. Patients with generalised epilepsy with febrile seizures plus (GEFS+) can have typical and isolated FS, FS lasting more beyond age 6 years, and subsequent afebrile (typically generalised) seizures. Mutations associated with GEFS+ were identified in genes for subunits of the voltage-gated sodium channel and the gamma2 subunit of the ligand-gated GABAA receptor. Screening for these genes in patients with severe myoclonic epilepsy in infancy showed de novo mutations of the alpha1 subunit of the voltage-gated sodium channel. Antecedent FS are commonly observed in temporal-lobe epilepsy (TLE). In sporadic mesial TLE-characterised by the sequence of complex FS in childhood, hippocampal sclerosis, and refractory temporal-lobe seizures-association studies suggested the role of several susceptibility genes. Work on some large pedigrees also suggests that FS and temporal-lobe seizures may have a common genetic basis, whether hippocampus sclerosis is present or not. The molecular defects identified in the genetic associations of FS and epileptic seizures are very attractive models to aid our understanding of epileptogenesis and susceptibility to seizure-provoking factors, especially fever.

Fever, genes, and epilepsy.

Suppressing inhibition mediated by GABAA receptors induces rhythmic bursts of synchronous firing in the CA3 region of the hippocampus. Extracellular and intracellular records were made from guinea pig hippocampal slices to examine the emergence of this synchrony. We found that application of GABAA receptor antagonists initiated a sequence of changes in the activity of the CA3 neuronal population. First, the frequency of firing detected in multiunit records increased. Then, firing began to oscillate with increases followed by decreases in firing that occurred at intervals of 0.5-2 s. The coherence of the rhythmic activity at a single site increased with time, and discharges at distant sites in the CA3 region became correlated. Fluctuations in firing were associated with extracellular field potentials. Finally, epileptiform events associated with large field potentials began to recur at intervals of 5-10 s. The onset of fully synchronous events was sudden and correlated with a large increase in the amplitude of the field potential. Thus the CA3 population can express states of partial population synchrony preceding the onset of epileptiform discharges. A similar activity was induced and maintained by applying low doses of GABAA receptor antagonists. Intracellular records suggest that inhibitory signalling mediated by GABAB receptors contributes to the emergence of this activity. States of partial synchrony in the CA3 region exposed to GABAA receptor antagonists therefore depend on alternating periods of firing, presumably dependent on excitatory synaptic mechanisms, and silence, mediated in part by the activation of GABAB receptors.

Emergence of disinhibition-induced synchrony in the CA3 region of the guinea pig hippocampus in vitro.

Hippocampal population discharges such as sharp waves, epileptiform firing, and GDPs recur at long and variable intervals. The mechanisms for their precise timing are not well understood. Here, we show that population bursts in the disinhibited CA3 region are initiated at a threshold level of population firing after recovery from a previous event. Each population discharge follows an active buildup period when synaptic traffic and cell firing increase to threshold levels. Single-cell firing can advance burst onset by increasing population firing to suprathreshold values. Population synchrony is suppressed when threshold frequencies cannot be reached due to reduced cellular excitability or synaptic efficacy. Reducing synaptic strength reveals partially synchronous population bursts that are curtailed by GABA(B)-mediated conductances. Excitatory glutamatergic transmission and delayed GABA(B)-mediated signals have opposing feedback effects on CA3 cell firing and so determine threshold behavior for population synchrony.

Threshold behavior in the initiation of hippocampal population bursts.

Ictal single-photon emission computed tomography (SPECT) may help localize the seizure-onset zone (SOZ) by detecting changes in regional cerebral blood flow induced by epileptic discharges. This imaging method also reveals hyperperfusions in areas of seizure propagation, including the hemisphere contralateral to the SOZ. We have studied the occurrence, the topography, and the clinical value of such contralateral ictal hyperperfusion areas (HPAs).

Ictal brain hyperperfusion contralateral to seizure onset: the SPECT mirror image.

&#x6C2F;&#x79BB;&#x5B50; (Cl-) &#x7A33;&#x6001;&#x7684;&#x53D8;&#x5316;&#x53EF;&#x80FD;&#x4F1A;&#x6D89;&#x53CA;&#x4E00;&#x4E9B;&#x766B;&#x75EB;&#x6D3B;&#x52A8;&#x7684;&#x4EE3;&#x4E2D;&#x3002;&#x5728;&#x6B64;&#x7814;&#x7A76;&#x4E2D;&#xFF0C;&#x6211;&#x4EEC;&#x95EE;&#x662F;&#x5426; Cl-&#x7A33;&#x6001;&#xFF0C;&#x5E76;&#x56E0;&#x6B64;&#x5B89;&#x57FA;&#x4FE1;&#x53F7;&#xFF0C;&#x6539;&#x53D8;&#x60A3;&#x8005;&#x7EC4;&#x7EC7;&#x4E2D;&#x989E;&#x53F6;&#x766B;&#x75EB;&#x6D77;&#x9A6C;&#x786C;&#x5316;&#x4E0E;&#x76F8;&#x5173;&#x8054;&#x3002;&#x51C6;&#x5907;&#x4ECE;&#x8FD9;&#x4EBA;&#x7684;&#x7EC4;&#x7EC7;&#x5207;&#x7247;&#x4E2D; subiculum &#x751F;&#x6210;&#x53D1;&#x8D77;&#x4E86;&#x81EA;&#x53D1;&#x53D1;&#x4F5C;&#x95F4;&#x671F;&#x7C7B;&#x4F3C;&#x6D3B;&#x52A8;&#x3002;&#x4ECE; subicular &#x9525;&#x4F53;&#x7EC6;&#x80DE;&#x5C11;&#x6570;&#x8BB0;&#x5F55;&#x663E;&#x793A;&#x9664; GABA(A) &#x53D7;&#x4F53;&#x4ECB;&#x5BFC;&#x7A81;&#x89E6;&#x540E;&#xFF0C;&#x8868;&#x660E;&#x4E8B;&#x4EF6;&#x6444;&#x52A8;&#x7684; Cl &#x7A33;&#x6001;&#x3002;&#x6211;&#x4EEC;&#x53EF;&#x80FD;&#x644A;&#x4E2D;&#x67B8;&#x6A7C;&#x9178; KCC2-&#x6C2F;&#x5316;&#x94BE;&#x8F6C;&#x8FD0;&#x86CB;&#x767D;&#x57FA;&#x56E0;&#x8868;&#x8FBE;&#x7684;&#x53D8;&#x5316;&#x3002;&#x53CC;&#x539F;&#x4F4D;&#x6742;&#x4EA4;&#x663E;&#x793A;&#x4E3A; KCC2 mRNA &#x662F;&#x7F3A;&#x5E2D;&#x4ECE;&#x7EA6; 30%&#x7684; CaMKIIalpha (&#x9499;&#x9499;&#x8C03;&#x7D20;&#x4F9D;&#x8D56;&#x6027;&#x86CB;&#x767D;&#x6FC0;&#x9176; IIalpha)-&#x79EF;&#x6781; subicular &#x9525;&#x4F53;&#x7EC6;&#x80DE;&#x3002;&#x80DE;&#x5185;&#x5F55;&#x5236;&#x7ED3;&#x5408; biocytin &#x586B;&#x5145;&#x7535;&#x6781;&#x548C; KCC2 &#x514D;&#x75AB;&#x5316;&#x5B66;&#xFF0C;&#x6211;&#x4EEC;&#x6307;&#x51FA;&#x5728;&#x53D1;&#x4F5C;&#x95F4;&#x671F;&#x4E8B;&#x4EF6;&#x671F;&#x95F4;&#x88AB;&#x8D85;&#x6781;&#x5316;&#x7684;&#x6240;&#x6709;&#x5355;&#x5143;&#x683C;&#x662F;&#x9633;&#x6027;&#x4E3A; KCC2&#xFF0C;&#x800C;&#x6D88;&#x504F;&#x578B;&#x7EC6;&#x80DE;&#x5927;&#x90E8;&#x5206;&#x4E3A; immunonegative&#x3002;&#x5C3C;&#x7247;&#xFF0C;&#x6709;&#x9009;&#x62E9;&#x5730;&#x963B;&#x6B62;&#x67B8;&#x6A7C;&#x9178;&#x8F6C;&#x8FD0;&#x86CB;&#x767D;&#x6C2F;&#x5316;&#x8FDB;&#x53E3;&#x6C2F;&#x5316;&#x94BE;&#x94A0;&#x57FA;&#x56E0; NKCC1&#xFF0C;&#x5242;&#x91CF;&#x4E0A;&#x7684;&#x5236;&#x4F5C; GABA(A) &#x9006;&#x8F6C;&#x7535;&#x4F4D;&#x8D85;&#x6781;&#x5316;&#x8F6C;&#x79FB;&#x548C;&#x6291;&#x5236;&#x53D1;&#x4F5C;&#x95F4;&#x671F;&#x7684;&#x6D3B;&#x52A8;&#x3002;&#x4E2D; Cl-&#x8F6C;&#x8FD0;&#x4F53;&#x8868;&#x8FBE;&#x7684;&#x53D8;&#x5316;&#xFF0C;&#x4ECE;&#x800C;&#x6709;&#x52A9;&#x4E8E;&#x4EBA;&#x7C7B;&#x766B;&#x75EB;&#x6837;&#x7684;&#x6D3B;&#x52A8;&#xFF0C;&#x548C;&#x6839;&#x636E;&#x8FD9;&#x4E9B;&#x8F6C;&#x8FD0;&#x86CB;&#x767D;&#x7684;&#x5206;&#x5B50;&#x53EF;&#x80FD;&#x662F;&#x6709;&#x7528;&#x7684;&#x6297;&#x766B;&#x75EB;&#x836F;&#x7269;&#x3002;

&#x6444;&#x52A8;&#x6C2F;&#x7A33;&#x6001;&#x548C;&#x4FE1;&#x53F7;&#x5728;&#x4EBA;&#x7C7B;&#x989E;&#x53F6;&#x766B;&#x75EB;&#x4E2D;&#x7684;&#x4E01;&#x9178;&#x3002;

Changes in chloride (Cl-) homeostasis may be involved in the generation of some epileptic activities. In this study, we asked whether Cl- homeostasis, and thus GABAergic signaling, is altered in tissue from patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis. Slices prepared from this human tissue generated a spontaneous interictal-like activity that was initiated in the subiculum. Records from a minority of subicular pyramidal cells revealed depolarizing GABA(A) receptor-mediated postsynaptic events, indicating a perturbed Cl- homeostasis. We assessed possible contributions of changes in expression of the potassium-chloride cotransporter KCC2. Double in situ hybridization showed that mRNA for KCC2 was absent from approximately 30% of CaMKIIalpha (calcium/calmodulin-dependent protein kinase IIalpha)-positive subicular pyramidal cells. Combining intracellular recordings with biocytin-filled electrodes and KCC2 immunochemistry, we observed that all cells that were hyperpolarized during interictal events were immunopositive for KCC2, whereas the majority of depolarized cells were immunonegative. Bumetanide, at doses that selectively block the chloride-importing potassium-sodium-chloride cotransporter NKCC1, produced a hyperpolarizing shift in GABA(A) reversal potentials and suppressed interictal activity. Changes in Cl- transporter expression thus contribute to human epileptiform activity, and molecules acting on these transporters may be useful antiepileptic drugs.

Perturbed chloride homeostasis and GABAergic signaling in human temporal lobe epilepsy.

Changements dans l&#39;hom&eacute;ostasie de chlorure (Cl-) pourraient &ecirc;tre impliqu&eacute;s dans la g&eacute;n&eacute;ration de certaines activit&eacute;s &eacute;pileptiques. Dans cette &eacute;tude, nous avons demand&eacute; si Cl-hom&eacute;ostasie et donc GABAergique, signalisation, est alt&eacute;r&eacute; dans les tissus de patients atteints d&#39;&eacute;pilepsie m&eacute;sio-temporale associ&eacute;e &agrave; la scl&eacute;rose hippocampique. Tranches, pr&eacute;par&eacute;s &agrave; partir de ce tissu humain a g&eacute;n&eacute;r&eacute; une activit&eacute; spontan&eacute;e d&#39;intercritiques semblable qui a &eacute;t&eacute; lanc&eacute;e dans le subiculum. Chronogramme d&#39;une minorit&eacute; de cellules pyramidales de subicular a r&eacute;v&eacute;l&eacute; d&eacute;polarisants GABA m&eacute;di&eacute;e par les r&eacute;cepteurs postsynaptiques &eacute;v&eacute;nements, indiquant une hom&eacute;ostasie-Cl perturb&eacute;e. Nous avons &eacute;valu&eacute; les contributions possibles de changements dans l&#39;expression du cotransporteur de chlorure de potassium KCC2. Double hybridation in situ ont montr&eacute; que les ARNm de KCC2 &eacute;tait absente d&#39;environ 30 % de CaMKIIalpha (calcium/calmoduline-d&eacute;pendante prot&eacute;ine kinase IIalpha)-cellules pyramidales de subicular positif. Combinant des enregistrements intracellulaires avec &eacute;lectrodes remplis de la biocytine et immunochimie KCC2, nous avons observ&eacute; que toutes les cellules qui &eacute;taient hyperpolaris&eacute;s lors d&#39;&eacute;v&eacute;nements intercritiques &eacute;taient immunopositifs pour KCC2, alors que la majorit&eacute; des cellules d&eacute;polaris&eacute;es &eacute;tait immunonegative. Bum&eacute;tanide, &agrave; des doses qui bloquer de fa&ccedil;on s&eacute;lective le cotransporteur importateurs de chlorure de potassium-sodium-chlorure NKCC1, produit un glissement hyperpolarisant potentiels d&#39;inversion de GABA et supprim&eacute;e interictal activit&eacute;. Changements dans l&#39;expression de Cl-transporteur ainsi contribuent &agrave; l&#39;activit&eacute; &eacute;pileptiforme humaine et mol&eacute;cules agissant sur ces transporteurs peuvent &ecirc;tre utiles de m&eacute;dicaments anti&eacute;pileptiques.

Perturb&eacute; l&#39;hom&eacute;ostasie du chlorure et GABAergiques signalisation dans l&#39;&eacute;pilepsie humaine lobe temporal.

&Auml;nderungen in Chlorid (CL-) Hom&ouml;ostase k&ouml;nnen bei der Generierung von einige epileptischen Aktivit&auml;ten einbezogen werden. In dieser Studie fragten wir ob Cl-Hom&ouml;ostase und damit GABAergic signalisieren, wird im Gewebe von Patienten mit mesiale Temporallappen-Epilepsie, die zugeordnete hippocampale Sklerose ver&auml;ndert. Scheiben aus diesem menschlichen Gewebe vorbereitet erstellt eine spontane interiktale Aktivit&auml;ten der Initiierung in das Subiculum. Datens&auml;tze aus einer Minderheit von Subicular Pyramidenzellen offenbart depolarisierende GABA(A) Rezeptor-vermittelte postsynaptisches Ereignisse, in denen ein Cl-Hom&ouml;ostase gest&ouml;rt. Wir pr&uuml;fen m&ouml;gliche Beitr&auml;ge der &Auml;nderungen im Ausdruck der Kalium-Chlorid-Kotransporter KCC2. Doppel-in situ-Hybridisierung zeigte, dass mRNA f&uuml;r KCC2 abwesend war von etwa 30 % der CaMKIIalpha (Calcium/Calmodulin-abh&auml;ngigen Proteinkinase IIalpha)-positive Subicular Pyramidenzellen. Intrazellul&auml;re Aufnahmen mit Biocytin gef&uuml;llten Elektroden und KCC2 Immunchemie kombinierend beobachteten wir, dass alle Zellen, die bei interiktale Veranstaltungen hyperpolarized wurden Immunopositive f&uuml;r KCC2, waren die meisten depolarisiert Zellen Immunonegative waren. Bumetanid, bei Dosen, die selektiv-die Chlorid-Importieren von Kalium-Natrium-Chlorid Kotransporter NKCC1 blockieren, produziert eine hyperpolarizing Verschiebung GABA(A) Umkehr Potenziale und interiktaler Aktivit&auml;t unterdr&uuml;ckt. &Auml;nderungen in Cl-Transporter Ausdruck tragen so zur menschlichen Epileptiform T&auml;tigkeit und Molek&uuml;le, die auf diese Transporter k&ouml;nnen auch n&uuml;tzliche antiepileptische Medikamente.

Umwerfen, Chlorid-Hom&ouml;ostase und GABAergic signalisieren in menschlichen Temporallappen-Epilepsie.

Cambiamenti nell&#39;omeostasi del cloruro (Cl-) possono essere coinvolti nella generazione di alcune attivit&agrave; epilettica. In questo studio, abbiamo chiesto se Cl-omeostasi e quindi GABAergico segnalazione, viene alterata in tessuto da pazienti con epilessia del lobo temporale mesiale associato con Sclerosi ippocampale. Fette preparate da questo tessuto umano generato una spontanea attivit&agrave; interittale-come che &egrave; stata avviata nel subiculum. Record da una minoranza di cellule piramidali subicular rivelato depolarizing GABA(A) mediata dal recettore postsinaptici eventi, che indica un perturbato Cl-omeostasi. Abbiamo valutato i possibili contributi di cambiamenti nell&#39;espressione dei che di cloruro di potassio KCC2. Doppia ibridazione in situ ha mostrato che il mRNA per KCC2 era assente da circa il 30% di CaMKIIalpha (chinasi di proteina calcio/calmodulina-dipendente IIalpha)-le cellule piramidali subicular positivo. Combinando le registrazioni intracellulari con elettrodi pieni di biocytin e KCC2 immunochimica, abbiamo osservato che tutte le cellule che erano hyperpolarized durante manifestazioni interictali immunopositive per KCC2, considerando che la maggior parte delle cellule depolarizzate era immunonegative. Bumetanide, a dosi che bloccano selettivamente l&#39;importazione di cloruro di potassio-sodio-cloruro che NKCC1, prodotto un cambiamento hyperpolarizing in potenziali di inversione GABA(A) e soppressa attivit&agrave; interictali. Cambiamenti nell&#39;espressione di Cl-trasportatore cos&igrave; contribuiscono all&#39;attivit&agrave; epileptiform umana, e molecole che agiscono su questi trasportatori possono essere utili farmaci antiepilettici.

Turbare l&#39;omeostasi cloruro e GABAergico segnalazione nell&#39;epilessia del lobo temporale umana.

&#x5869;&#x5316;&#x7269; (Cl-) &#x6052;&#x5E38;&#x6027;&#x306E;&#x5909;&#x5316;&#x306F;&#x3001;&#x3066;&#x3093;&#x304B;&#x3093;&#x306E;&#x6D3B;&#x52D5;&#x306F;&#x3044;&#x304F;&#x3064;&#x304B;&#x306E;&#x4E16;&#x4EE3;&#x306E;&#x95A2;&#x4E0E;&#x53EF;&#x80FD;&#x6027;&#x304C;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002;&#x672C;&#x7814;&#x7A76;&#x3067;&#x306F;&#x3001;Cl &#x306E;&#x6052;&#x5E38;&#x6027;&#x3068;&#x3053;&#x3046;&#x3057;&#x3066; gaba &#x4F5C;&#x52D5;&#x6027;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x3001;&#x3067;&#x3059;&#x5909;&#x66F4;&#x304B;&#x3069;&#x3046;&#x304B;&#x60A3;&#x8005;&#x304B;&#x3089;&#x7D44;&#x7E54;&#x306B;&#x304A;&#x3051;&#x308B;&#x6D77;&#x99AC;&#x786C;&#x5316;&#x75C7;&#x3092;&#x4F34;&#x3046;&#x5074;&#x982D;&#x8449;&#x3066;&#x3093;&#x304B;&#x3093;&#x3092;&#x5C0B;&#x306D;&#x305F;&#x3002;&#x3053;&#x306E;&#x4EBA;&#x9593;&#x306E;&#x30C6;&#x30A3;&#x30C3;&#x30B7;&#x30E5;&#x304B;&#x3089;&#x6E96;&#x5099;&#x30B9;&#x30E9;&#x30A4;&#x30B9;&#x958B;&#x59CB;&#x3055;&#x308C;&#x305F;&#x81EA;&#x767A;&#x306E;&#x767A;&#x4F5C;&#x9593;&#x6B20;&#x671F;&#x306E;&#x3088;&#x3046;&#x306A;&#x6D3B;&#x52D5;&#x3067; subiculum &#x3092;&#x751F;&#x6210;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x30EC;&#x30B3;&#x30FC;&#x30C9;&#x304B;&#x3089;&#x306E;&#x5C11;&#x6570;&#x6C11;&#x65CF; subicular &#x9310;&#x4F53;&#x7D30;&#x80DE;&#x306E;&#x6442;&#x52D5;&#x306E; Cl &#x6052;&#x5E38;&#x6027;&#x3092;&#x793A;&#x3059;&#x8131;&#x5206;&#x6975; GABA(A) &#x53D7;&#x5BB9;&#x4F53;&#x3092;&#x4ECB;&#x3059;&#x308B;&#x5F8C;&#x30B7;&#x30CA;&#x30D7;&#x30B9; &#x30A4;&#x30D9;&#x30F3;&#x30C8;&#x3001;&#x660E;&#x3089;&#x304B;&#x306B;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x5869;&#x5316;&#x30AB;&#x30EA;&#x30A6;&#x30E0;&#x5171; KCC2 &#x306E;&#x767A;&#x73FE;&#x306E;&#x5909;&#x5316;&#x306E;&#x53EF;&#x80FD;&#x306A;&#x8CA2;&#x732E;&#x3092;&#x8A55;&#x4FA1;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x4E8C;&#x91CD;&#x306E; in situ &#x30CF;&#x30A4;&#x30D6;&#x30EA;&#x30C0;&#x30A4;&#x30BC;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#x3092;&#x793A;&#x3057;&#x305F; KCC2 &#x306E; mRNA &#x304C;&#x4F11;&#x3093;&#x3060;&#x304B;&#x3089; CaMKIIalpha &#xFF08;&#x30AB;&#x30EB;&#x30B7;&#x30A6;&#x30E0;/&#x30AB;&#x30EB;&#x30E2;&#x30C7;&#x30E5;&#x30EA;&#x30F3;&#x4F9D;&#x5B58;&#x6027;&#x30D7;&#x30ED;&#x30C6;&#x30A4;&#x30F3;&#x30AD;&#x30CA;&#x30FC;&#x30BC; IIalpha&#xFF09; &#x306E;&#x7D04; 30 &#xFF05;-&#x6B63; subicular &#x9310;&#x4F53;&#x7D30;&#x80DE;&#x3002;Immunonegative &#x7121;&#x504F;&#x5149;&#x7D30;&#x80DE;&#x3092;&#x5360;&#x3081;&#x305F;&#x306B;&#x5BFE;&#x3057;&#x7D30;&#x80DE;&#x5185;&#x8A18;&#x9332;&#x306F;&#x3001;biocytin &#x3067;&#x6E80;&#x305F;&#x3055;&#x308C;&#x305F;&#x96FB;&#x6975;&#x3068; KCC2 &#x514D;&#x75AB;&#x3068;&#x7D44;&#x307F;&#x5408;&#x308F;&#x305B;&#x3066;&#x3001;&#x6211;&#x3005; &#x767A;&#x4F5C;&#x9593;&#x6B20;&#x671F;&#x306E;&#x30A4;&#x30D9;&#x30F3;&#x30C8;&#x4E2D;&#x306B;&#x9AD8;&#x504F;&#x6975;&#x3057;&#x305F;&#x3059;&#x3079;&#x3066;&#x306E;&#x30BB;&#x30EB; KCC2 &#x306E;&#x305F;&#x3081;&#x306E;&#x967D;&#x6027;&#x304C;&#x8A8D;&#x3081;&#x3089;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x30D6;&#x30E1;&#x30BF;&#x30CB;&#x30C9;&#x5869;&#x5316;&#x30A4;&#x30F3;&#x30DD;&#x30FC;&#x30C8;&#x5869;&#x5316;&#x30AB;&#x30EA;&#x30A6;&#x30E0; &#x30CA;&#x30C8;&#x30EA;&#x30A6;&#x30E0;&#x5171; NKCC1&#x3001;&#x9078;&#x629E;&#x7684;&#x306B;&#x30D6;&#x30ED;&#x30C3;&#x30AF;&#x3059;&#x308B;&#x7528;&#x91CF;&#x3067; GABA(A) &#x53CD;&#x8EE2;&#x96FB;&#x4F4D;&#x306E;&#x904E;&#x5206;&#x6975;&#x30B7;&#x30D5;&#x30C8;&#x3092;&#x751F;&#x7523;&#x3001;&#x767A;&#x4F5C;&#x9593;&#x6B20;&#x671F;&#x306E;&#x6D3B;&#x52D5;&#x3092;&#x6291;&#x5236;&#x3057;&#x307E;&#x3059;&#x3002;Cl &#x30C8;&#x30E9;&#x30F3;&#x30B9;&#x30DD;&#x30FC;&#x30BF;&#x30FC;&#x767A;&#x73FE;&#x5909;&#x5316;&#x3072;&#x3068;&#x3066;&#x3093;&#x304B;&#x3093;&#x6D3B;&#x52D5;&#x306B;&#x8CA2;&#x732E;&#x3059;&#x308B;&#x305F;&#x3081;&#x3001;&#x3053;&#x308C;&#x3089;&#x306E;&#x904B;&#x9001;&#x8005;&#x306B;&#x4F5C;&#x7528;&#x3059;&#x308B;&#x5206;&#x5B50;&#x304C;&#x6709;&#x7528;&#x306A;&#x6297;&#x3066;&#x3093;&#x304B;&#x3093;&#x85AC;&#x304C;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002;

&#x5869;&#x5316;&#x30DB;&#x30E1;&#x30AA;&#x30B9;&#x30BF;&#x30B7;&#x30B9;&#x3068;&#x3072;&#x3068;&#x5074;&#x982D;&#x8449;&#x3066;&#x3093;&#x304B;&#x3093;&#x3067;&#x30B7;&#x30B0;&#x30CA;&#x30EA;&#x30F3;&#x30B0; gaba &#x4F5C;&#x52D5;&#x6027;&#x6442;&#x52D5;&#x3002;

&#xC5FC;&#xD654; &#xBB3C; (Cl-) &#xD56D;&#xC0C1;&#xC131; &#xBCC0;&#xD654; &#xC77C;&#xBD80; &#xAC04; &#xC9C8; &#xD65C;&#xB3D9;&#xC758; &#xC0DD;&#xC131;&#xC5D0; &#xCC38;&#xC5EC; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC774; &#xC5F0;&#xAD6C;&#xC5D0;&#xC11C; &#xC6B0;&#xB9AC;&#xB294; &#xC5EC;&#xBD80; Cl &#xD56D;&#xC0C1;&#xC131; &#xADF8;&#xB9AC;&#xACE0; &#xB530;&#xB77C;&#xC11C; GABAergic &#xC2E0;&#xD638;, hippocampal sclerosis &#xC5F0;&#xAD00; mesial &#xCE21; &#xB450; &#xC5FD; &#xAC04; &#xC9C8; &#xD658;&#xC790;&#xC5D0;&#xC11C; &#xC870;&#xC9C1;&#xC5D0;&#xC11C; &#xBCC0;&#xACBD; &#xB429;&#xB2C8;&#xB2E4; &#xBB3C;&#xC5C8;&#xB2E4;. &#xC2AC;&#xB77C;&#xC774;&#xC2A4;&#xAC00; &#xC778;&#xCCB4; &#xC870;&#xC9C1;&#xC5D0;&#xC11C; &#xC900;&#xBE44;&#xB294; subiculum &#xC2DC;&#xC791; &#xB41C; &#xC790;&#xBC1C;&#xC801;&#xC778; interictal &#xAC19;&#xC740; &#xD65C;&#xB3D9;&#xC744; &#xC0DD;&#xC131; &#xD569;&#xB2C8;&#xB2E4;. Subicular &#xD53C;&#xB77C;&#xBBF8;&#xB4DC; &#xC138;&#xD3EC;&#xC758; &#xC18C;&#xC218;&#xC5D0;&#xC11C; &#xB808;&#xCF54;&#xB4DC; depolarizing GABA(A) &#xC218;&#xC6A9; &#xCCB4;-&#xC911;&#xC7AC; postsynaptic &#xC774;&#xBCA4;&#xD2B8;, &#xAD50;&#xB780;&#xB41C; Cl &#xD56D;&#xC0C1;&#xC131; &#xB098;&#xD0C0;&#xB0B4;&#xB294; &#xBC1D;&#xD600;. &#xC6B0;&#xB9AC; &#xC5FC;&#xD654; &#xCE7C;&#xB968; cotransporter kcc2&#xC758; &#xD45C;&#xD604;&#xC5D0; &#xBCC0;&#xD654; &#xAC00;&#xB2A5;&#xD55C; &#xAE30;&#xC5EC;&#xB97C; &#xD3C9;&#xAC00;. &#xC774;&#xC911; &#xC81C;&#xC790;&#xB9AC; &#xAD50; &#xC7A1; &#xBCF4;&#xC600;&#xB2E4; kcc2&#xC5D0; &#xB300; &#xD55C; mRNA &#xACB0; &#xC11D; &#xD588;&#xB2E4; CaMKIIalpha (&#xCE7C;&#xC298;/calmodulin &#xC885;&#xC18D; &#xB2E8;&#xBC31;&#xC9C8; &#xD0A4; &#xB2C8; &#xC544; IIalpha)&#xC758; &#xC57D; 30%&#xC5D0;&#xC11C;-&#xC591;&#xC218; subicular &#xD53C;&#xB77C;&#xBBF8;&#xB4DC; &#xC138;&#xD3EC;. &#xC138;&#xD3EC;&#xB0B4; &#xB179;&#xC74C; biocytin &#xAC00;&#xB4DD; &#xC804;&#xADF9; &#xBC0F; KCC2 immunochemistry &#xACB0;&#xD569; &#xAD00;&#xCC30; interictal &#xC774;&#xBCA4;&#xD2B8; &#xAE30;&#xAC04; &#xB3D9;&#xC548; hyperpolarized &#xD588;&#xB2E4; &#xBAA8;&#xB4E0; &#xC140;&#xC5D0; &#xB300; &#xD55C; KCC2, immunopositive &#xD588;&#xB2E4; &#xBC18;&#xBA74; depolarized &#xC138;&#xD3EC;&#xC758; &#xB300;&#xBD80;&#xBD84;&#xC740; immunonegative. &#xC120;&#xD0DD;&#xC801;&#xC73C;&#xB85C; NKCC1, &#xCE7C;&#xB968;-&#xB098;&#xD2B8;&#xB968;-&#xC5FC;&#xD654; &#xBB3C; &#xC5FC;&#xD654;&#xB97C; &#xAC00;&#xC838;&#xC624;&#xB294; cotransporter&#xB97C; &#xCC28;&#xB2E8; &#xD558;&#xB294; &#xBCF5;&#xC6A9;&#xB7C9;&#xC5D0; Bumetanide hyperpolarizing GABA(A) &#xBC18;&#xC804; &#xC804;&#xC704; &#xBCC0;&#xD654;&#xB97C; &#xC0DD;&#xC0B0; &#xD558; &#xACE0; interictal &#xD65C;&#xB3D9;&#xC744; &#xC5B5;&#xC81C;. Cl-&#xC804;&#xC1A1; &#xC2DD;&#xC758; &#xBCC0;&#xD654;&#xB294; &#xB530;&#xB77C;&#xC11C; &#xC778;&#xAC04;&#xC758; epileptiform &#xD65C;&#xB3D9;&#xC5D0; &#xAE30;&#xC5EC; &#xD558; &#xACE0; &#xBD84;&#xC790;&#xAC00;&#xC774; &#xC804;&#xC1A1;&#xAE30;&#xC5D0; &#xC720;&#xC6A9;&#xD55C; &#xD56D; &#xC804; &#xAC04; &#xC57D;&#xBB3C;&#xC744; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;.

&#xC5FC;&#xD654; &#xD56D;&#xC0C1;&#xC131; &#xBC0F; GABAergic &#xC778;&#xAC04;&#xC758; &#xCE21; &#xB450; &#xC5FD; &#xAC04; &#xC9C8;&#xC5D0;&#xC11C; &#xC2E0;&#xD638; &#xAD50;&#xB780;.

La generaci&oacute;n de algunas actividades de epil&eacute;pticos conllevan cambios en la homeostasis de cloruro (Cl-). En este estudio, preguntamos si Cl-homeostasis y as&iacute; GABA&eacute;rgico se&ntilde;alizaci&oacute;n, est&aacute; alterado en tejido de pacientes con epilepsia del l&oacute;bulo temporal medial asociada con esclerosis del hipocampo. Rodajas preparadas a partir de este tejido humano generan una interictal-como la actividad espont&aacute;nea que se inici&oacute; en el sub&iacute;culo. Registros de una minor&iacute;a de las c&eacute;lulas piramidales subicular revelaron despolarizantes GABA(A) mediada por receptor postsin&aacute;pticos eventos, indicando una Cl-homeostasis perturbada. Se evaluaron las posibles contribuciones de cambios en la expresi&oacute;n de la cotransporter KCC2 de cloruro de potasio. Hibridaci&oacute;n in situ doble demostr&oacute; que el mRNA para KCC2 estaba ausente de aproximadamente el 30% de CaMKIIalpha (dependiente de Calcio/calmodulina quinasa IIalpha)-c&eacute;lulas piramidales subicular positivo. Combinando grabaciones intracelulares con electrodos biocitina lleno y KCC2 inmunoqu&iacute;mica, observamos que todas las c&eacute;lulas que fueron hyperpolarized durante eventos interictales eran immunopositive para KCC2, mientras que la mayor&iacute;a de c&eacute;lulas despolarizadas era immunonegative. Bumetanida, en dosis que bloquean selectivamente los importadores de cloruro de potasio-Sodio-cloruro cotransporter NKCC1, produjo un cambio hiperpolarizador en GABA(A) potenciales de inversi&oacute;n y suprimi&oacute; la actividad interictal. Cambios en la expresi&oacute;n de Cl-transportador as&iacute; contribuyan a la actividad epileptiforme humana y mol&eacute;culas act&uacute;an sobre estos transportadores pueden ser &uacute;tiles los f&aacute;rmacos antiepil&eacute;pticos.

Perturbado cloruro homeostasis y GABA&eacute;rgico en epilepsia temporal humana.

Hippocampal seizures.

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.

The epileptic human hippocampal cornu ammonis 2 region generates spontaneous interictal-like activity in vitro.

The mechanisms involved in the transition to an epileptic seizure remain unclear. To examine them, we used tissue slices from human subjects with mesial temporal lobe epilepsies. Ictal-like discharges were induced in the subiculum by increasing excitability along with alkalinization or low Mg(2+). During the transition, distinct pre-ictal discharges emerged concurrently with interictal events. Intracranial recordings from the mesial temporal cortex of subjects with epilepsy revealed that similar discharges before seizures were restricted to seizure onset sites. In vitro, pre-ictal events spread faster and had larger amplitudes than interictal discharges and had a distinct initiation site. These events depended on glutamatergic mechanisms and were preceded by pyramidal cell firing, whereas interneuron firing preceded interictal events that depended on both glutamatergic and depolarizing GABAergic transmission. Once established, recurrence of these pre-ictal discharges triggered seizures. Thus, the subiculum supports seizure generation, and the transition to seizure involves an emergent glutamatergic population activity.

Glutamatergic pre-ictal discharges emerge at the transition to seizure in human epilepsy.

Synchronous activation of neural networks is an important physiological mechanism, and dysregulation of synchrony forms the basis of epilepsy. We analyzed the propagation of synchronous activity through chronically epileptic neural networks. Electrocorticographic recordings from epileptic patients demonstrate remarkable variance in the pathways of propagation between sequential interictal spikes (IISs). Calcium imaging in chronically epileptic slice cultures demonstrates that pathway variance depends on the presence of GABAergic inhibition and that spike propagation becomes stereotyped following GABA receptor blockade. Computer modeling suggests that GABAergic quenching of local network activations leaves behind regions of refractory neurons, whose late recruitment forms the anatomical basis of variability during subsequent network activation. Targeted path scanning of slice cultures confirmed local activations, while ex vivo recordings of human epileptic tissue confirmed the dependence of interspike variance on GABA-mediated inhibition. These data support the hypothesis that the paths by which synchronous activity spreads through an epileptic network change with each activation, based on the recent history of localized activity that has been successfully inhibited.

A candidate mechanism underlying the variance of interictal spike propagation.

Portosystemic shunts (PSS) remain an unrecognized cause of neurological or psychiatric disorders. Here we report 5 patients with neuropsychiatric presentations of PSS. Main presentations encompassed progressive Parkinsonism, organic psychosis, recurrent coma, recurrent delusion, cognitive decline and posterior cortical atrophy. None of our patients had a known history of liver disease and laboratory analyses of liver function were normal or only slightly perturbed. Only 16 similar cases of PSS revealed by neurological or psychiatric symptoms were found in the English literature. Clinical presentations were similar to our patients but asterixis, cerebellar symptoms and spastic paraparesis were noticed in some cases. EEG could be normal or could show non specific slow waves or even, rarely, triphasic slow waves. The most frequent and specific diagnostic features included hyperammonemia, abnormal brain magnetic resonance spectroscopy and visualization of the shunts by ultrasonography or abdominal imaging techniques. Therefore, in otherwise unexplained neuropsychiatric disturbances, ammonia should be routinely measured and, if elevated, a dedicated gastroenterologist or an expert radiologist should be consulted for potential PSS examination. Treatment of the shunts or of the hyperammonemia resulted in marked neurological or psychiatric improvement in all cases.

Portosystemic shunts: an underdiagnosed but treatable cause of neurological and psychiatric disorders.

An epileptic brain is permanently in a diseased state, but seizures occur rarely and without warning. Here we examine this paradox, common to paroxysmal diseases. We review the problem in the context of the prototypic acquired epilepsies of the medial temporal lobe. We ask how an epileptic temporal lobe differs from a healthy one and examine biological mechanisms that may explain the transition to seizure. Attempts to predict seizure timing from analyses of brain electrical activity suggest that the neurological processes involved may be initiated significantly before a seizure. Furthermore, whereas seizures are said to occur without warning, some patients say they know when a seizure is imminent. Several factors, including sleep deprivation, oscillations in hormonal levels, or withdrawal from drugs, increase the probability of a seizure. We ask whether these seizure precipitants might act through common neuronal mechanisms. Several precipitating factors seem to involve relief from a neurosteroid modulation of gamma-amino butyric acid receptor type A (GABAA) receptors. We propose tests of this hypothesis.

The paradox of the paroxysm: can seizure precipitants help explain human ictogenesis?

Gliomas are the most frequent primary brain tumors and most glioma patients have seizures. The origin and mechanisms of human glioma-related epilepsy are multifactorial and an intermix of oncologic and neuronal processes. In this brief review, we show that the infiltrated peritumoral neocortex appears to be the key structure for glioma-related epileptic activity, which depends on the interactions between the tumor per se and the surrounding brain. We shed light on the underlying mechanisms from two different "tumorocentric" and "epileptocentric" approaches, with a special emphasis on the glioma-related glutamatergic and γ-aminobutyric acid (GABA)ergic changes leading to epileptogenicity. Because gliomas use the neurotransmitter glutamate as a "tumor growth factor" to enhance glioma cell proliferation and invasion with neurotoxic, proinvasive, and proliferative effects, glutamate homeostasis is impaired, with elevated extracellular glutamate concentrations. Such excitatory effects contribute to the generation of epileptic activity in the peritumoral neocortex. GABAergic signaling is also involved both in tumor growth and in paradoxical excitatory effects mediated by alterations in neuronal and tumor cell Cl(-) homeostasis related to cotransporter changes. Local excitability may also be affected by an increase in extracellular K(+) concentration, the alkalization of peritumoral neocortex, and alterations of gap-junction functioning. Finally, the tumor itself may mechanically affect locally neuronal behavior, connections, and networks. Better understanding of glioma-related oncologic and epileptologic processes are crucial for development of combined therapeutic strategies, but so far, the surgical management of gliomas should comprise a maximally safe surgical resection encompassing peritumoral neocortex.

Tumoral epileptogenicity: how does it happen?

Diffuse low-grade gliomas are highly epileptogenic brain tumours. We aimed to explore the natural course of epileptic seizures, their predictors and the prognostic significance of their occurrence in adult patients harbouring a diffuse low-grade glioma. An observational retrospective multicentre study examined 1509 patients with diffuse low-grade gliomas to identify mutual interactions between tumour characteristics, tumour course and epileptic seizures. At diagnosis, 89.9% of patients had epileptic seizures. Male gender (P = 0.003) and tumour location within functional areas (P = 0.001) were independent predictors of a history of epileptic seizures at diagnosis. Tumour volume, growth velocity, cortical location, histopathological subtype or molecular markers did not significantly affect epileptic seizure occurrence probability. Prolonged history of epileptic seizures (P < 0.001), insular location (P = 0.003) and tumour location close to functional areas (P = 0.038) were independent predictors of uncontrolled epileptic seizures at diagnosis. Occurrence of epileptic seizures (P < 0.001), parietal (P = 0.029) and insular (P = 0.002) locations were independent predictors of uncontrolled epileptic seizures after oncological treatment. Patient age (P < 0.001), subtotal (P = 0.007) and total (P < 0.001) resections were independent predictors of total epileptic seizure control after oncological treatment. History of epileptic seizures at diagnosis and total surgical resection were independently associated with increased malignant progression-free (P < 0.001 and P < 0.001) and overall (P < 0.001 and P = 0.016) survivals. Epileptic seizures are independently associated with diffuse low-grade glioma prognosis. Patients diagnosed with epileptic seizures and those with complete and early surgical resections have better oncological outcomes. Early and maximal surgical resection is thus required for diffuse low-grade gliomas, both for oncological and epileptological purposes.

Epileptic seizures in diffuse low-grade gliomas in adults.

Commentary: Morris-Coole/Epilepsia prize.

Brain gliomas are highly epileptogenic. Excitatory glutamatergic mechanisms are involved in the generation of epileptic activities in the neocortex surrounding gliomas. However, chloride homeostasis is known to be perturbed in glioma cells. Thus, the contribution of γ-aminobutyric acidergic (GABAergic) mechanisms that depend on intracellular chloride merits closer study. We studied the occurrence, networks, cells, and signaling basis of epileptic activities in neocortical slices from the peritumoral surgical margin resected around human brain gliomas. Postoperative glioma tissue from 69% of patients spontaneously generated interictal-like discharges, synchronized, with a high-frequency oscillation signature, in superficial layers of neocortex around areas of glioma infiltration. Interictal-like events depended both on glutamatergic AMPA receptor-mediated transmission and on depolarizing GABAergic signaling. GABA released by interneurons depolarized 65% of pyramidal cells, in which chloride homeostasis was perturbed because of changes in expression of neuronal chloride cotransporters: KCC2 (K-Cl cotransporter 2) was reduced by 42% and expression of NKCC1 (Na-K-2Cl cotransporter 1) increased by 144%. Ictal-like activities were initiated by convulsant stimuli exclusively in these epileptogenic areas. This study shows that epileptic activities are sustained by excitatory effects of GABA in human peritumoral neocortex, as reported in temporal lobe epilepsies, suggesting that both glutamate and GABA signaling and cellular chloride regulation processes, all also involved in oncogenesis as already shown, induce an imbalance between synaptic excitation and inhibition underlying epileptic discharges in glioma patients. Thus, the control of chloride in neurons and glioma cells may provide a therapeutic target for patients with epileptogenic gliomas.

Cortical GABAergic excitation contributes to epileptic activities around human glioma.

Epilepsy is a paroxysmal condition characterized by repeated transient seizures separated by longer interictal periods. Ictogenesis describes the processes of transition from the interictal state to a seizure. The processes include a preictal state, with specific clinical signs and a distinct electrophysiology which may provide opportunities to anticipate, or even prevent, seizures. Biological mechanisms of ictogenesis remain poorly understood and may vary between conditions/syndromes. We review here ictogenic processes including the involvement of pyramidal cells, interneurons and astrocytes, GABAergic and glutamatergic signaling, and ionic perturbations. Our review suggests that specific excitatory influences at the transition to an ictal event include (1) GABA receptor activation with a neuronal Cl(-) load and (2) a transient increase in external K(+).

Article	Year
Fever, genes, and epilepsy. The Lancet. Neurology\| PubMed ID: 15207799	2004
Emergence of disinhibition-induced synchrony in the CA3 region of the guinea pig hippocampus in vitro. The Journal of physiology\| PubMed ID: 16322056	2006
Threshold behavior in the initiation of hippocampal population bursts. Neuron\| PubMed ID: 16387645	2006
Ictal brain hyperperfusion contralateral to seizure onset: the SPECT mirror image. Epilepsia\| PubMed ID: 16417540	2006
Perturbed chloride homeostasis and GABAergic signaling in human temporal lobe epilepsy. The Journal of neuroscience : the official journal of the Society for Neuroscience\| PubMed ID: 17855601	2007
Hippocampal seizures. Journal of neurosurgery\| PubMed ID: 19245292	2009
The epileptic human hippocampal cornu ammonis 2 region generates spontaneous interictal-like activity in vitro. Brain : a journal of neurology\| PubMed ID: 19767413	2009
Glutamatergic pre-ictal discharges emerge at the transition to seizure in human epilepsy. Nature neuroscience\| PubMed ID: 21460834	2011
A candidate mechanism underlying the variance of interictal spike propagation. The Journal of neuroscience : the official journal of the Society for Neuroscience\| PubMed ID: 22378874	2012
Portosystemic shunts: an underdiagnosed but treatable cause of neurological and psychiatric disorders. Journal of the neurological sciences\| PubMed ID: 22906583	2012
The paradox of the paroxysm: can seizure precipitants help explain human ictogenesis? The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry\| PubMed ID: 23881918	2013
Tumoral epileptogenicity: how does it happen? Epilepsia\| PubMed ID: 24328869	2013
Epileptic seizures in diffuse low-grade gliomas in adults. Brain : a journal of neurology\| PubMed ID: 24374407	2014
Commentary: Morris-Coole/Epilepsia prize. Epilepsia\| PubMed ID: 24836167	2014
Cortical GABAergic excitation contributes to epileptic activities around human glioma. Science translational medicine\| PubMed ID: 25009229	2014
Mechanisms of ictogenesis. International review of neurobiology\| PubMed ID: 25078502	2014

Gilles Huberfeld

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