Made available in DSpace on 2014-12-17T15:28:53Z (GMT). No. of bitstreams: 1 AndersonBS_DISSERT.pdf: 4240084 bytes, checksum: 0331343a1aab5e54d0d9cb6baeccb72d (MD5) Previous issue date: 2013-12-13 / Epilepsies are neurological disorders characterized by recurrent and spontaneous seizures due to an abnormal electric activity in a brain network. The mesial temporal lobe epilepsy (MTLE) is the most prevalent type of epilepsy in adulthood, and it occurs frequently in association with hippocampal sclerosis. Unfortunately, not all patients benefit from pharmacological treatment (drug-resistant patients), and therefore become candidates for surgery, a procedure of high complexity and cost. Nowadays, the most common surgery is the anterior temporal lobectomy with selective amygdalohippocampectomy, a procedure standardized by anatomical markers. However, part of patients still present seizure after the procedure. Then, to increase the efficiency of this kind of procedure, it is fundamental to know the epileptic human brain in order to create new tools for auxiliary an individualized surgery procedure. The aim of this work was to identify and quantify the occurrence of epilepticform activity -such as interictal spikes (IS) and high frequency oscillations (HFO) - in electrocorticographic (ECoG) signals acutely recorded during the surgery procedure in drug-resistant patients with MTLE. The ECoG recording (32 channels at sample rate of 1 kHz) was performed in the surface of temporal lobe in three moments: without any cortical resection, after anterior temporal lobectomy and after amygdalohippocampectomy (mean duration of each record: 10 min; N = 17 patients; ethic approval #1038/03 in Research Ethic Committee of Federal University of S?o Paulo). The occurrence of IS and HFO was quantified automatically by MATLAB routines and validated manually. The events rate (number of events/channels) in each recording time was correlated with seizure control outcome. In 8 hours and 40 minutes of record, we identified 36,858 IS and 1.756 HFO. We observed that seizure-free outcome patients had more HFO rate before the resection than non-seizure free, however do not differentiate in relation of frequency, morphology and distribution of IS. The HFO rate in the first record was better than IS rate on prediction of seizure-free patients (IS: AUC = 57%, Sens = 70%, Spec = 71% vs HFO: AUC = 77%, Sens = 100%, Spec = 70%). We observed the same for the difference of the rate of pre and post-resection (IS: AUC = 54%, Sens = 60%, Spec = 71%; vs HFO: AUC = 84%, Sens = 100%, Spec = 80%). In this case, the algorithm identifies all seizure-free patients (N = 7) with two false positives. To conclude, we observed that the IS and HFO can be found in intra-operative ECoG record, despite the anesthesia and the short time of record. The possibility to classify the patients before any cortical resection suggest that ECoG can be important to decide the use of adjuvant pharmacological treatment or to change for tailored resection procedure. The mechanism responsible for this effect is still unknown, thus more studies are necessary to clarify the processes related to it / As epilepsias s?o dist?rbios neurol?gicos caracterizados por crises espont?neas e recorrentes, resultantes de uma atividade el?trica anormal de uma rede neural. Dentre os diferentes tipos de epilepsia, a epilepsia mesial do lobo temporal (EMLT) ? a mais observada em adultos, sendo frequentemente associada ? esclerose hipocampal. Infelizmente, nem todos os pacientes s?o beneficiados pelo tratamento farmacol?gico (pacientes f?rmaco-resistentes). Para estes sujeitos, uma alternativa ? a realiza??o de cirurgia, um procedimento de alta complexidade e elevado custo. Atualmente, o procedimento mais realizado ? a lobectomia temporal anterior com amigdalo-hipocampectomia seletiva, uma cirurgia padronizada por marcos anat?micos. Entretanto, uma parcela dos pacientes continua a apresentar crises incapacitantes ap?s o tratamento cir?rgico. Desta forma, para aumentar a efici?ncia deste tipo de tratamento, ? fundamental a compreens?o do enc?falo humano epil?ptico com vistas a se criar ferramentas que auxiliem na realiza??o de procedimentos individualizados. O objetivo do presente trabalho foi identificar e quantificar a ocorr?ncia de atividade epileptiforme - esp?culas interictais (EI) e oscila??es de alta frequ?ncia (OAF) - em registros eletrocorticogr?ficos (ECoG) realizados durante procedimento cir?rgico em pacientes com EMLT refrat?ria ao tratamento farmacol?gico. Registros ECoG (32 canais a uma taxa de amostragem de 1 kHz) foram realizados na superf?cie do lobo temporal em 3 momentos cir?rgicos: no c?rtex intacto, ap?s lobectomia temporal anterior e ap?s amigdalo-hipocampectomia (dura??o m?dia de cada um desses registros: 10 min; N=17 pacientes). A ocorr?ncia de EI e OAF foi quantificada automatica-mente, por meio de rotinas em MATLAB, e validadas manualmente. A taxa de ocorr?ncia em cada um dos tempos cir?rgicos foi correlacionada com o resultado cir?rgico quanto ao controle das crises, num seguimento de 2 anos. De um total de 8 h e 40 min de registro, identificamos 36.858 EI e 1.756 OAF. Observamos que os pacientes que ficaram livres de crises no p?s-operat?rio apresentaram maior quanti-dade de OAF antes da cirurgia do que aqueles que continuaram a ter crises; por?m, n?o diferiram quanto a frequ?ncia, morfologia e distribui??o de EI. A ocorr?ncia de OAF no registro basal apresentou melhor desempenho que as EI na previs?o do controle total das crises no p?s-operat?rio (EI: AUC = 57%, S = 71% , E = 70% vs OAF: AUC = 77%, S = 100%, E=70%). O mesmo foi observado com a varia??o da ocorr?ncia entre os momentos pr?- e p?s-ressec??o (EI: AUC = 54%, S = 71%, E = 60% vs OAF: AUC = 84%, S = 100%, E = 80%). Nesse caso, o classificador foi capaz de identificar todos os pacientes livres de crises (N = 7) , apresentando apenas dois falsos positivos. Desta forma, podemos concluir que as OAF, juntamente com as EI, podem ser encontradas no registro ECoG intra-operat?rio, mesmo na presen?a de anest?sicos e em uma curta sess?o de registro. Al?m disso, a observa??o de que a ocorr?ncia desses eventos no in?cio da cirurgia permite classificar o paciente quanto ao progn?stico cir?rgico abre caminho para aplicar o ECoG intra-operat?rio, por exemplo, na decis?o sobre o uso de tratamento farmacol?gico adjuvante ou da convers?o para ressec??es individualizadas. No entanto, o mecanismo respons?vel por esse efeito ainda ? desconhecido, logo novos estudos s?o necess?rios para melhor esclarec?-lo

Indiana University-Purdue University Indianapolis (IUPUI) / Posttraumatic epilepsy, the development of temporal lobe epilepsy (TLE) following traumatic brain injury, accounts for 20% of symptomatic epilepsy. Reorganization of mossy fibers within the hippocampus is a common pathological finding of TLE. Normal mossy fibers project into the CA3 region of the hippocampus where they form synapses with pyramidal cells. During TLE, mossy fibers are observed to innervate the inner molecular layer where they synapse onto the dendrites of other dentate granule cells, leading to the formation of recurrent excitatory circuits. To date, the molecular mechanisms contributing to mossy fiber sprouting are relatively unknown. Recent focus has centered on the involvement of tropomycin-related kinase receptor B (TrkB), which culminates in glycogen synthase kinase 3β (GSK3β) inactivation. As the neurite outgrowth promoting collapsin response mediator protein 2 (CRMP2) is rendered inactive by GSK3β phosphorylation, events leading to inactivation of GSK3β should therefore increase CRMP2 activity. To determine the involvement of CRMP2 in mossy fiber sprouting, I developed a novel tool ((S)-LCM) for selectively targeting the ability of CRMP2 to enhance tubulin polymerization. Using (S)-LCM, it was demonstrated that increased neurite outgrowth following GSK3β inactivation is CRMP2 dependent. Importantly, TBI led to a decrease in GSK3β-phosphorylated CRMP2 within 24 hours which was secondary to the inactivation of GSK3β. The loss of GSK3β-phosphorylated CRMP2 was maintained even at 4 weeks post-injury, despite the transience of GSK3β-inactivation. Based on previous work, it was hypothesized that activity-dependent mechanisms may be responsible for the sustained loss of CRMP2 phosphorylation. Activity-dependent regulation of GSK3β-phosphorylated CRMP2 levels was observed that was attributed to a loss of priming by cyclin dependent kinase 5 (CDK5), which is required for subsequent phosphorylation by GSK3β. It was confirmed that the loss of GSK3β-phosphorylated CRMP2 at 4 weeks post-injury was likely due to decreased phosphorylation by CDK5. As TBI resulted in a sustained increase in CRMP2 activity, I attempted to prevent mossy fiber sprouting by targeting CRMP2 in vivo following TBI. While (S)-LCM treatment dramatically reduced mossy fiber sprouting following TBI, it did not differ significantly from vehicle-treated animals. Therefore, the necessity of CRMP2 in mossy fiber sprouting following TBI remains unknown.

Nach dem Prinzip synchronisierter Reimwörter wurde ein deutscher dichotischer Hörtest entwickelt und erprobt (Fused Words, FW10b). Die Reliabilitätskennwerte lagen für die innere Konsistenz bei alpha=0,89 und für die Re-Test-Reliabilität im Bereich von r-tt=0,67 bis r-tt=0,87. Der dichotische Test korrelierte hoch mit einem Paralleltest (r=.73, FW12k). In mehreren Untersuchungen fand sich keine Assoziation des dichotischen Lateralisationsergebnisses mit dem Hormonzyklus bei Frauen. Zwischen der Klassifikation im Wada-Test und der Klassifikation im dichotischen Test wurde eine hohe prozentuale Übereinstimmung beobachtet (91%). Auch in einer externen Studie wurde eine hohe Konkordanz mit einem fMRT Paradigma gefunden (97%, Hund-Georgiadis et al 2002). Unter Rechtshändern hatten 70% einen Rechts-Ohr-Vorteil, 23% einen Links-Ohr-Vorteil; bei 7% wurde kein Ohr-Vorteil beobachtet. Es bestand eine hohe Assoziation zwischen dem Lateralitätsquotient der Händigkeit und dem Lateralitätsindex Lambda aus dem dichotischen Test (R=0,76, r=0,72). Bei epilepsiechirurgischen Kandidaten mit links- oder rechtsseitigen Temporallappenläsionen, die alle durch einen Wada-Test als unilateral links-hemisphärisch sprachdominant kategorisiert worden waren, wurden Läsionseffekte analysiert (Hippocampus-Sklerose vs. extra-hippocampale Läsionen). Wie erwartet ergaben sich massive Läsionseffekte für die Patienten mit den Läsionen in der linken sprachdominanten Hemisphäre. In der linken extra-hippocampalen Untergruppe kam es zu einer signifikanten Abnahme der Rechts-Ohr-Punkte und gleichzeitig zu einem signifikanten Anstieg der Links-Ohr-Punkte. Die Einbeziehung von neokortikalen und anderen extra-hippocampalen Strukturen in die temporalen Läsionen war von entscheidender Bedeutung für die Unterdrückung der Antworten vom kontralateralen (rechtsseitigen) Ohr. Die Zunahme der Links-Ohr-Punkte in der Gruppe mit linksseitigen extra-hippocampalen Läsionen deutet eine kompensatorische Verlagerung von Sprachfunktionen auf die rechte Hemisphäre an, die durch den Wada Test nicht erfasst wurde. / Following the principle of synchronized rhyming words a German dichotic listening test was developed and tested (fused words, FW10b). Reliability coefficients for the inner consistency were at alpha=0,89 and for the re-test-reliability between r-tt=0,67 and r-tt=0,87. The dichotic test FW10b was highly correlated with a parallel test (r=.73, FW12k). None of several studies did show any association between the dichotic language lateralization and the hormonal cycle in women. A high percentage of agreement was observed between the Wada classification and the classification by the dichotic test (91%). Furthermore Hund-Georgiadis et al. (2002) found a high percentage of concordance with the lateralization by a fMRI paradigm in an external study (97%). Among right-handers 70% showed a right ear advantage, 23% had a left ear advantage, and 7% had no ear advantage. There was a high association between the laterality quotient of the handedness inventory and the laterality index Lambda of the dichotic listening test FW10b (R=0.76, r=0.72). Lesion effects were analyzed in epilepsy surgical candidates with left and right temporal lobe lesions (hippocampus sclerosis vs. extra-hippocampal lesions), who were all categorized as left-hemispheric language dominant by a Wada-test. As expected, massive lesion effects were apparent in those patients who had their lesions in the left language dominant hemisphere. In the subgroup with left extra-hippocampal lesions there was a significant decrease of right-ear-points and at the same time a significant increase of left-ear-points. The involvement of neocortex and other extra-hippocampal structures in temporal lobe lesions were of crucial importance for the suppression of contralateral (right) ear responses. The elevation of left-ear-points in the left-lateral group indicated a partial compensational shift of language functions to the right hemisphere, which was not detected by the Wada procedure.

Die flexible Anwendung von Wissen in neuen Alltagssituationen ist eine notwendige kognitive Fähigkeit. Bisherige Studien betonen die zentrale Rolle des Hippocampus beim Lernen und Verknüpfen neuer Informationen mit bereits vorhandenem Wissen. Die funktionelle Integrität des Hippocampus ändert sich jedoch im Laufe des Lebens bzw. wird durch neuropsychiatrische Erkrankungen häufig beeinflusst. Die betroffenen Personen müssen deswegen adaptive Strategien entwickeln, um behaviorale Ziele weiter zu erreichen. Daher befasst sich meine Doktorarbeit mit Adaptationsprozessen im sich entwickelnden Gehirn und im vollständig entwickelten Gehirn mit einer hippocampalen Dysfunktion. Diese Synopsis umfasst dazu drei Studien: (1) zu behavioralen Strategien im sich entwickelnden Gehirn, (2) zu behavioralen Strategien im vollständig entwickelten Gehirn nach einer Läsion und (3) zu strukturellen Veränderungen im vollständig entwickelten Gehirn nach einer Läsion. Studie 1 zeigt einen altersgebundenen Wechsel beim assoziativen Gedächtnis: Kinder, Jugendliche und junge Erwachsene benutzen verschiedene Gedächtnisstrategien beim Integrieren von Gedächtnisinhalten. Studie 2 zeigt, dass die beobachteten Gedächtnisbeeinträchtigungen bei Patienten mit rechtsseitigen hippocampalen Läsionen sich nicht alleine durch ein Defizit des assoziativen Gedächtnisses erklären lassen, sondern auf einen zusätzlichen hippocampalen Beitrag zur Gedächtnisintegration zurückzuführen sind. Studie 3 zeigt, dass sich postoperative Adaptationsprozesse auf struktureller Ebene in überraschend kurzer Zeit ereignen und dass die strukturelle Reorganisation nicht nur im Hippocampus, sondern auch in entfernteren Hirnregionen, die mit dem Hippocampus verbunden sind, stattfindet. Zusammenfassend zeigen die Ergebnisse der drei Studien, dass Adaptationsprozesse im sich entwickelnden Gehirn sowie bei Erwachsenen mit einer hippocampalen Dysfunktion sowohl auf der behavioralen als auch auf der strukturellen Ebene auftreten. / Applying knowledge flexibly to new situations is a cognitive faculty that is necessary in every-day life. Previous findings emphasise the crucial role the hippocampus plays in learning and linking new information with pre-existing knowledge. However, the functional integrity of the hippocampus changes over the lifespan and is frequently affected by neuropsychiatric disorders. The affected subjects must, therefore, develop adaptive strategies to achieve behavioural goals. Thus, my doctoral thesis deals with adaptation processes in the developing brain and in adult brains with a hippocampal dysfunction. This synopsis encompasses three studies on: (1) behavioural strategies in the developing brain, (2) behavioural strategies in the lesioned fully developed brain, and (3) structural changes in the lesioned fully developed brain. Study 1 suggests an age-related shift in the associative memory: Children, adolescents, and young adults use different memory strategies when integrating information. Study 2 suggests that the memory deficits observed in patients with right-sided hippocampal lesions are not merely a consequence of an impaired associative memory but rather result from an additional hippocampal contribution to the memory integration. Study 3 suggests that postoperative structural adaptation processes occur on a surprisingly short time-scale, and this structural reorganisation happens not only in the hippocampus but also in distant brain areas connected to the hippocampus. In conclusion, findings from these three studies show that adaptation processes in the developing brain and in adult brains with hippocampal dysfunction occur on both the behavioural and the structural level.