Functional PET Evaluation of the Photosensitive Baboon

The baboon provides a unique, natural model of epilepsy in nonhuman primates. Additionally, photosensitivity of the epileptic baboon provides an important window into the mechanism of human idiopathic generalized epilepsies. In order to better understand the networks underlying this model, our group utilized functional positron emission tomography (PET) to compare cerebral blood flow (CBF) changes occurring during intermittent light stimulation (ILS) and rest between baboons photosensitive, epileptic (PS) and asymptomatic, control (CTL) animals. Our studies utilized subtraction and covariance analyses to evaluate CBF changes occurring during ILS across activation and resting states, but also evaluated CBF correlations with ketamine doses and interictal epileptic discharge (IED) rate during the resting state. Furthermore, our group also assessed the CBF responses related to variation of ILS in PS and CTL animals. CBF changes in the subtraction and covariance analyses reveal the physiological response and visual connectivity in CTL animals and pathophysiological networks underlying responses associated with the activation of ictal and interictal epileptic discharges in PS animals. The correlation with ketamine dose is essential to understanding differences in CBF responses between both groups, and correlations with IED rate provides an insight into an epileptic network independent of visual activation. Finally, the ILS frequency dependent changes can help develop a framework to study not only spatial connectivity but also the temporal sequence of regional activations and deactivations related to ILS. The maps generated by the CBF analyses will be used to target specific nodes in the epileptic network for electrophysiological evaluation using intracranial electrodes

Neuronal networks underlying Jeavons-syndrome and eye closure sensitivity by using EEG source analysis methods

Eyelid myoclonia with absences (EMA) or Jeavons syndrome (JS) is considered to be the type of idiopathic generalized epilepsy, clinically characterized by eyelid myoclonia (EM) with or without absences, eye closure-induced electroencephalography (EEG) paroxysms, and photosensitivity. Interictal and ictal EEG mostly shows high amplitude discharges of generalised irregular spike/polyspike and waves (GSW) at 3-6 Hz often appearing immediately after closing the eyes (eye closure sensitivity). The mechanism underling eye closure sensitivity (ECS) and Jeavons syndrome is not well understood. The clinical and neuroimaging studies suggest that the occipital visual cortex and thalamus play the main role in the generation of EMA in the presence of light and eye closure. In our study, we attempted to estimate functional connectivity (FC) during ictal myoclonus and interictal generalized epileptic discharges using the imaginary part of coherency (iCoh) at the sensory and source level to find out what changes underlie JS and to find out whether there is a network-level difference between ictal and interictal discharges.The EEG data of 11 pediatric patients with the diagnosis of Jeavons syndrome were retrospectively collected and analyzed. In our FC study, we found a complex involvement of different brain networks. We saw the thalamus connection to the brain regions, which participate in state of consciousness, oculomotor control, myoclonus, eye closure sensitivity and photosensitivity. Our result complies with the previous results of fMRI studies performed in JS and IGEs Patients. However, when we compared the FC of ictal and interictal EEG paroxysms we could not find any significant differences. This could be due to the fact that we only selected one seizure type, myoclonus and excluded epochs with absences. We speculate that the reason we did not see any group differences is DM network is that the state of consciousness was not altered in the selected segmen

Netzwerke der photoparoxysmalen Reaktion (Eine funktionelle Magnetresonanztomographie-Studie)

Ziel der Arbeit war es, mit Hilfe der fMRT und synchroner EEG-Aufzeichnung neuronale Netzwerke zu erfassen, die an der Entstehung einer PPR beteiligt sind. Zu diesem Zwecke wurden Probanden mit bekannter PPR in einem Magnetresonanztomographen mit Lichtblitzen stimuliert. Synchron zu dieser Stimulation wurde die Aktivität der Neuronen im Gehirn mit Hilfe eines EEG aufgezeichnet. Nach Erhebung der Daten, wurden diese mit Hilfe von SPM 5 ausgewertet und die Ergebnisse graphisch dargestellt. Mit Hilfe der graphischen Darstellung wurden Regionen im Gehirn identifiziert, die an der Entstehung von PPRs beteiligt bzw. dafür verantwortlich sind

Multifokale Epilepsie ist mit einer gesteigerten funktionellen Konnektivität assoziiert: eine kombinierte EEG-fMRT-Studie

Multifokale epileptische Aktivität ist ein ungünstiges Merkmal einer Vielzahl von epileptischen Syndromen (Lennox-Gastaut-Syndrom, West Syndrom und schwere fokale Epilepsien) und geht mit einer generellen Vulnerabilität des Gehirns für pathologische Synchronisation einher. Die zu Grunde liegenden Mechanismen der multifokalen Aktivität sind bisher noch ungenügend erforscht. In dieser Arbeit sollte untersucht werden, ob pathologische Konnektivität innerhalb der Hirnregionen des Default mode Netzwerkes sowie Thalamus, Hirnstamm und retrosplenialer Cortex Individuen für multifokale epileptische Aktivität prädisponiert. Hierfür wurden insgesamt 33 Kinder mit multifokaler und monofokaler (Kontrollgruppe) Epilepsie mittels kombiniertem EEG-fMRT während des Schlafs untersucht. Patienten mit monofokaler Epilepsie waren charakterisiert durch starke Korrelationen zwischen den korrespondierenden interhemisphärischen homotopen Regionen. Dieses Muster mit ausgeprägter Kurzdistanz- und schwacher Langdistanz-Konnektivität ähnelt dem Konnektivitätsmuster, welches für gesunde Kinder beschrieben ist. Patienten mit multifokaler epileptischer Aktivität zeigten hingegen erheblich stärkere Korrelationen zwischen einer Vielzahl von Regionen des DMN sowie dem Thalamus und Hirnstamm mit signifikantem Anstieg der langstreckigen Konnektivität im Vergleich zu den Kindern mit monofokaler epileptischer Aktivität. Innerhalb der Gruppe der Patienten mit multifokaler Epilepsie gab es keine Unterschiede hinsichtlich der funktionellen Konnektivität zwischen Patienten mit oder ohne Lennox-Gastaut-Syndrom. Diese Studie zeigt, dass multifokale Aktivität mit einer gesteigerten funktionellen Konnektivität des Hirns auf den langen Distanzen assoziiert ist. Daraus lässt sich schlussfolgern, dass diese ausgeprägte funktionelle Konnektivität die generelle Vulnerabilität des Hirns für pathologische Synchronisation darstellt

Mechanisms of altered cortical excitability in photosensitive epilepsy

Despite the multiplicity of approaches and techniques so far applied for identifying the pathophysiological mechanisms of photosensitive epilepsy, a generally agreed explanation of the phenomenon is still lacking. The present thesis reports on three interlinked original experimental studies conducted to explore the neurophysiological correlates and the phatophysiological mechanism of photosensitive epilepsy. In the first study I assessed the role of the habituation of the Visual Evoked Response test as a possible biomarker of epileptic visual sensitivity. The two subsequent studies were designed to address specific research questions emerging from the results of the first study. The findings of the three intertwined studies performed provide experimental evidence that photosensitivity is associated with changes in a number of electrophysiological measures suggestive of altered balance between excitatory and inhibitory cortical processes. Although a strong clinical association does exist between specific epileptic syndromes and visual sensitivity, results from this research indicate that photosensitivity trait seems to be the expression of specific pathophysiological mechanisms quite distinct from the “epileptic” phenotype. The habituation of Pattern Reversal Visual Evoked Potential (PR-VEP) appears as a reliable candidate endo-phenotype of visual sensitivity. Interpreting the findings of this study in the context of the broader literature on visual habituation we can hypothesise the existence of a shared neurophysiological background between photosensitive epilepsy and migraine. Future studies to elucidate the relationship between the proposed indices of cortical excitability and specific polymorphisms of excitatroy and inhibitory neurotransmission will need to be conducted to assess their potential role as biomarkers of photosensitivity

Fisiopatologia della risposta fotoparossistica nella Epilessia Mioclonica Giovanile: studio EEG e Risonanza Magnetica funzionale

L'Epilessia Mioclonica Giovanile (JME) è una sindrome elettro-clinica, classificata tra le epilessie generalizzate genetiche, che presenta esordio tipicamente in età giovanile ed è caratterizzata da crisi miocloniche, tonico-cloniche e talora assenze tipiche. Le anomalie elettroencefalografiche di più frequente riscontro sono rappresentate da complessi punta/polipunta-onda a 3-6 Hz. La fotosensibilità è un fenotipo particolarmente frequente nei pazienti JME, con prevalenza variabile fra il 30% e il 90% a seconda delle casistiche (Wolf & Goosses, 1986; Appleton et al. 2000). Con approcci neurofisiologici classici, la fisiopatologia della fotosensibilità nella JME non è ancora stata chiarita. L’utilizzo di un approccio innovativo e multimodale, quale l’associazione di EEG e Risonanza Magnetica funzionale (EEG-fMRI) consente di mappare l’attivazione funzionale (tramite misura del c.d. segnale blood-oxygen-level-dependent- BOLD) specifica di aree cerebrali in concomitanza temporale con anomalie elettroencefalografiche selezionate dallo sperimentatore: un’analisi del pattern di attivazioni/deattivazioni in relazione allo stimolo luminoso e alle anomalie epilettiformi foto-indotte può aiutare a chiarire i networks coinvolti nella generazione della scarica epilettiforme. Per il presente studio sono stati reclutati venti soggetti, dieci pazienti JME e dieci controlli sani. Gli obiettivi sono rappresentati da: (1) caratterizzazione delle mappe fMRI in pazienti e controlli in risposta a un protocollo di stimolazione luminosa intermittente (SLI) a bassa luminanza; (2) identificazione dell’andamento temporale del segnale BOLD, nel sottogruppo di pazienti foto-sensibili, in relazione alla comparsa di risposta fotoparossistica nel tracciato EEG. Come ulteriore sotto-analisi, abbiamo validato il nostro metodo di SLI a bassa luminanza e luce rossa (lunghezza d’onda = 680 nm), effettuata durante la risonanza tramite occhialini LCD RM-compatibili, rispetto al protocollo di stimolazione con luce stroboscopica convenzionalmente utilizzato durante EEG di routine. Nei controlli sani abbiamo rilevato, in corrispondenza della stimolazione luminosa, l’attivazione delle aree visive striate ed extrastriate e del putamen, e la deattivazione di aree cerebrali deputate alla preparazione ed attuazione del movimento. Nei pazienti si è identificato l’attivazione della aree visive, in maniera meno marcata rispetto ai controlli, e la deattivazione delle aree costituenti il c.d. default mode network. Il task di stimolazione luminosa a bassa luminanza ha determinato la comparsa di risposta fotoparossistica (PPR) nel tracciato EEG nel 70% dei pazienti. In tali soggetti, l’analisi temporale del segnale BOLD in intervalli antecedenti e successivi alla risposta fotoparossistica (PPR) ha mostrato l’attivazione del putamen prima della PPR, seguita dall’attivazione di aree motorie e del talamo poco dopo l’anomalia; successivamente, sono stati osservati soprattutto fenomeni di deattivazione a carico di aree motorie, caudato-putamen bilateralmente e default mode network nella sua componente anteriore. Nella sotto-analisi comparativa delle metodiche di stimolazione luminosa, la tecnica a bassa luminanza con luce rossa è risultata più provocativa della metodica SLI convenzionale, confermando l’utilità di tale approccio per questa categoria di pazienti. I risultati da noi ottenuti suggeriscono che, nel contesto dell’alterazione della connettività funzionale tra aree visive e aree motorie, recentemente identificata nella JME, un ruolo significativo possa essere svolto dai circuiti dei nuclei dalla base. La complessa sequenza di attivazioni e deattivazioni, riscontrata in corrispondenza delle risposte fotoparossistiche, potrebbe rappresentare la manifestazione dell’alterazione della connettività del sistema striato-talamo-corticale, verosimile base fisiopatologica della JME

Mechanisms of altered cortical excitability in photosensitive epilepsy

Despite the multiplicity of approaches and techniques so far applied for identifying the pathophysiological mechanisms of photosensitive epilepsy, a generally agreed explanation of the phenomenon is still lacking. The present thesis reports on three interlinked original experimental studies conducted to explore the neurophysiological correlates and the phatophysiological mechanism of photosensitive epilepsy. In the first study I assessed the role of the habituation of the Visual Evoked Response test as a possible biomarker of epileptic visual sensitivity. The two subsequent studies were designed to address specific research questions emerging from the results of the first study. The findings of the three intertwined studies performed provide experimental evidence that photosensitivity is associated with changes in a number of electrophysiological measures suggestive of altered balance between excitatory and inhibitory cortical processes. Although a strong clinical association does exist between specific epileptic syndromes and visual sensitivity, results from this research indicate that photosensitivity trait seems to be the expression of specific pathophysiological mechanisms quite distinct from the “epileptic” phenotype. The habituation of Pattern Reversal Visual Evoked Potential (PR-VEP) appears as a reliable candidate endo-phenotype of visual sensitivity. Interpreting the findings of this study in the context of the broader literature on visual habituation we can hypothesise the existence of a shared neurophysiological background between photosensitive epilepsy and migraine. Future studies to elucidate the relationship between the proposed indices of cortical excitability and specific polymorphisms of excitatroy and inhibitory neurotransmission will need to be conducted to assess their potential role as biomarkers of photosensitivity.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

A Prospective Advanced Magnetic Resonance Imaging Study of Newly Diagnosed Epilepsy

According to the World Health Organization (WHO), approximately 50 million people in the world have active epilepsy. Epilepsy is the most common neurological disorder after migraine, stroke and Alzheimer’s disease. Epilepsy disorder affects men and women of all ages, races and social classes. There is an extensive neuroimaging literature describing patients with chronic epilepsy. However, few studies have investigated brain structural changes in patients with newly diagnosed epilepsy (NDE) using quantitative magnetic resonance imaging (MRI). The main goal of this thesis was to determine the nature and extent of brain structural and functional differences in patients with NDE using different MRI techniques compared with healthy controls. The first study was to determine the morphometric changes in patients with NDE compared to healthy controls using quantitative MRI analysis. The second study was to identify functional connectivity differences (in the whole brain and regions of interest) in patients with NDE and healthy controls using resting state functional magnetic resonance imaging (RS-fMRI). All study participants were recruited from the Walton Centre NHS Foundation Trust, Liverpool. All had been diagnosed with focal epilepsy by a consultant neurologist and recruited for MRI scanning within 12 months of diagnosis. Twenty-seven patients with NDE were recruited (14 male, 13 female, with mean age (M)=33.2) and 32 healthy matched controls (14 male, 18 female, M=33.07).Control and NDE study participants were matched for age, handedness and gender. All participants were scanned using a Siemens 3T Trio whole-body scanner (Siemens, Erlangen, Germany) with eight-channel radiofrequency (RF) head coil together with foam padding to comfortably restrict head motion at the Magnetic Resonance and Image Analysis Research Centre (MARIARC), University of Liverpool. Various MRI sequences were conducted including: 3D MPRAGE T1-weighted anatomical data, and RS-fMRI In the first study, shape, surface based, and voxel based morphometry analysis were applied, and the results suggested differences to the morphology of the brain stem and both the right and left thalami in patients with NDE. The independent component analysis of RS-fMRI showed abnormal different functional connectivity in visual and attention networks in patients with NDE relative to healthy controls while ROI-ROI demonstrated increased functional connectivity between the subcallosal cortex and both thalami in NDE patients. This is the first extensive programme of research to employ various analysis techniques and advanced MRI sequences to study structural and functional differences in patients with NDE compared to healthy controls. The results of this thesis show that structural and functional differences occur in both thalami in patients with NDE. These findings suggest that the thalamus plays a very important role in epilepsy pathophysiology. The results of this thesis offer further understanding regarding the role of structural and functional differences in NDE. They highlight the need for future quantitative MRI analysis studies of NDE to help patients avoid the chronic stage of the disorder and improve their quality of life