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1. Clinical outcomes among initial survivors of cryptogenic new-onset refractory status epilepsy (NORSE)

Author: Costello, Daniel, Matthews, Elizabeth, Aurangzeb, Sidra, Doran, Elisabeth, Stack, Jessica, Wesselingh, Robb, Dugan, Patricia, Choi, Hyunmi, Depondt, Chantal, Devinsky, Orrin In, Doherty, Colin P, Kwan, Patrick, Monif, Mastura, O'Brien, Terence John, Sen, Arjune, Gaspard, Nicolas, Costello, Daniel, Matthews, Elizabeth, Aurangzeb, Sidra, Doran, Elisabeth, Stack, Jessica, Wesselingh, Robb, Dugan, Patricia, Choi, Hyunmi, Depondt, Chantal, Devinsky, Orrin In, Doherty, Colin P, Kwan, Patrick, Monif, Mastura, O'Brien, Terence John, Sen, Arjune, and Gaspard, Nicolas
Abstract: Objective: New-onset refractory status epilepticus (NORSE) is a rare but severe clinical syndrome. Despite rigorous evaluation, the underlying cause is unknown in 30%–50% of patients and treatment strategies are largely empirical. The aim of this study was to describe clinical outcomes in a cohort of well-phenotyped, thoroughly investigated patients who survived the initial phase of cryptogenic NORSE managed in specialist centers. Methods: Well-characterized cases of cryptogenic NORSE were identified through the EPIGEN and Critical Care EEG Monitoring Research Consortia (CCEMRC) during the period 2005–2019. Treating epileptologists reported on post-NORSE survival rates and sequelae in patients after discharge from hospital. Among survivors >6 months post-discharge, we report the rates and severity of active epilepsy, global disability, vocational, and global cognitive and mental health outcomes. We attempt to identify determinants of outcome. Results: Among 48 patients who survived the acute phase of NORSE to the point of discharge from hospital, 9 had died at last follow-up, of whom 7 died within 6 months of discharge from the tertiary care center. The remaining 39 patients had high rates of active epilepsy as well as vocational, cognitive, and psychiatric comorbidities. The epilepsy was usually multifocal and typically drug resistant. Only a minority of patients had a good functional outcome. Therapeutic interventions were heterogenous during the acute phase of the illness. There was no clear relationship between the nature of treatment and clinical outcomes. Significance: Among survivors of cryptogenic NORSE, longer-term outcomes in most patients were life altering and often catastrophic. Treatment remains empirical and variable. There is a pressing need to understand the etiology of cryptogenic NORSE and to develop tailored treatment strategies., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2024

2. Microvascular stabilization via blood-brain barrier regulation prevents seizure activity

Author: Greene, Chris, Hanley, Nicole, Reschke, Cristina R., Reddy, Avril, Andaloussi Mäe, Maarja, Connolly, Ruairi, Behan, Claire, O'Keeffe, Eoin, Bolger, Isobel, Hudson, Natalie, Delaney, Conor, Farrell, Michael A., O'Brien, Donncha F., Cryan, Jane, Brett, Francesca M., Beausang, Alan, Betsholtz, Christer, Henshall, David C., Doherty, Colin P., Campbell, Matthew, Greene, Chris, Hanley, Nicole, Reschke, Cristina R., Reddy, Avril, Andaloussi Mäe, Maarja, Connolly, Ruairi, Behan, Claire, O'Keeffe, Eoin, Bolger, Isobel, Hudson, Natalie, Delaney, Conor, Farrell, Michael A., O'Brien, Donncha F., Cryan, Jane, Brett, Francesca M., Beausang, Alan, Betsholtz, Christer, Henshall, David C., Doherty, Colin P., and Campbell, Matthew
Abstract: Blood-brain barrier (BBB) dysfunction is associated with worse epilepsy outcomes however the underlying molecular mechanisms of BBB dysfunction remain to be elucidated. Tight junction proteins are important regulators of BBB integrity and in particular, the tight junction protein claudin-5 is the most enriched in brain endothelial cells and regulates size-selectivity at the BBB. Additionally, disruption of claudin-5 expression has been implicated in numerous disorders including schizophrenia, depression and traumatic brain injury, yet its role in epilepsy has not been fully deciphered. Here we report that claudin-5 protein levels are significantly diminished in surgically resected brain tissue from patients with treatment-resistant epilepsy. Concomitantly, dynamic contrast-enhanced MRI in these patients showed widespread BBB disruption. We show that targeted disruption of claudin-5 in the hippocampus or genetic heterozygosity of claudin-5 in mice exacerbates kainic acid-induced seizures and BBB disruption. Additionally, inducible knockdown of claudin-5 in mice leads to spontaneous recurrent seizures, severe neuroinflammation, and mortality. Finally, we identify that RepSox, a regulator of claudin-5 expression, can prevent seizure activity in experimental epilepsy. Altogether, we propose that BBB stabilizing drugs could represent a new generation of agents to prevent seizure activity in epilepsy patients.
Published: 2022
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3. Microvascular stabilization via blood-brain barrier regulation prevents seizure activity

Author: Greene, Chris, Hanley, Nicole, Reschke, Cristina R., Reddy, Avril, Andaloussi Mäe, Maarja, Connolly, Ruairi, Behan, Claire, O'Keeffe, Eoin, Bolger, Isobel, Hudson, Natalie, Delaney, Conor, Farrell, Michael A., O'Brien, Donncha F., Cryan, Jane, Brett, Francesca M., Beausang, Alan, Betsholtz, Christer, Henshall, David C., Doherty, Colin P., Campbell, Matthew, Greene, Chris, Hanley, Nicole, Reschke, Cristina R., Reddy, Avril, Andaloussi Mäe, Maarja, Connolly, Ruairi, Behan, Claire, O'Keeffe, Eoin, Bolger, Isobel, Hudson, Natalie, Delaney, Conor, Farrell, Michael A., O'Brien, Donncha F., Cryan, Jane, Brett, Francesca M., Beausang, Alan, Betsholtz, Christer, Henshall, David C., Doherty, Colin P., and Campbell, Matthew
Abstract: Blood-brain barrier (BBB) dysfunction is associated with worse epilepsy outcomes however the underlying molecular mechanisms of BBB dysfunction remain to be elucidated. Tight junction proteins are important regulators of BBB integrity and in particular, the tight junction protein claudin-5 is the most enriched in brain endothelial cells and regulates size-selectivity at the BBB. Additionally, disruption of claudin-5 expression has been implicated in numerous disorders including schizophrenia, depression and traumatic brain injury, yet its role in epilepsy has not been fully deciphered. Here we report that claudin-5 protein levels are significantly diminished in surgically resected brain tissue from patients with treatment-resistant epilepsy. Concomitantly, dynamic contrast-enhanced MRI in these patients showed widespread BBB disruption. We show that targeted disruption of claudin-5 in the hippocampus or genetic heterozygosity of claudin-5 in mice exacerbates kainic acid-induced seizures and BBB disruption. Additionally, inducible knockdown of claudin-5 in mice leads to spontaneous recurrent seizures, severe neuroinflammation, and mortality. Finally, we identify that RepSox, a regulator of claudin-5 expression, can prevent seizure activity in experimental epilepsy. Altogether, we propose that BBB stabilizing drugs could represent a new generation of agents to prevent seizure activity in epilepsy patients.
Published: 2022
Full Text: View/download PDF

4. Microvascular stabilization via blood-brain barrier regulation prevents seizure activity

Author: Greene, Chris, Hanley, Nicole, Reschke, Cristina R., Reddy, Avril, Andaloussi Mäe, Maarja, Connolly, Ruairi, Behan, Claire, O'Keeffe, Eoin, Bolger, Isobel, Hudson, Natalie, Delaney, Conor, Farrell, Michael A., O'Brien, Donncha F., Cryan, Jane, Brett, Francesca M., Beausang, Alan, Betsholtz, Christer, Henshall, David C., Doherty, Colin P., Campbell, Matthew, Greene, Chris, Hanley, Nicole, Reschke, Cristina R., Reddy, Avril, Andaloussi Mäe, Maarja, Connolly, Ruairi, Behan, Claire, O'Keeffe, Eoin, Bolger, Isobel, Hudson, Natalie, Delaney, Conor, Farrell, Michael A., O'Brien, Donncha F., Cryan, Jane, Brett, Francesca M., Beausang, Alan, Betsholtz, Christer, Henshall, David C., Doherty, Colin P., and Campbell, Matthew
Abstract: Blood-brain barrier (BBB) dysfunction is associated with worse epilepsy outcomes however the underlying molecular mechanisms of BBB dysfunction remain to be elucidated. Tight junction proteins are important regulators of BBB integrity and in particular, the tight junction protein claudin-5 is the most enriched in brain endothelial cells and regulates size-selectivity at the BBB. Additionally, disruption of claudin-5 expression has been implicated in numerous disorders including schizophrenia, depression and traumatic brain injury, yet its role in epilepsy has not been fully deciphered. Here we report that claudin-5 protein levels are significantly diminished in surgically resected brain tissue from patients with treatment-resistant epilepsy. Concomitantly, dynamic contrast-enhanced MRI in these patients showed widespread BBB disruption. We show that targeted disruption of claudin-5 in the hippocampus or genetic heterozygosity of claudin-5 in mice exacerbates kainic acid-induced seizures and BBB disruption. Additionally, inducible knockdown of claudin-5 in mice leads to spontaneous recurrent seizures, severe neuroinflammation, and mortality. Finally, we identify that RepSox, a regulator of claudin-5 expression, can prevent seizure activity in experimental epilepsy. Altogether, we propose that BBB stabilizing drugs could represent a new generation of agents to prevent seizure activity in epilepsy patients.
Published: 2022
Full Text: View/download PDF

5. Structural network alterations in focal and generalized epilepsy assessed in a worldwide ENIGMA study follow axes of epilepsy risk gene expression.

Author: Larivière, Sara, Larivière, Sara, Royer, Jessica, Rodríguez-Cruces, Raúl, Paquola, Casey, Caligiuri, Maria Eugenia, Gambardella, Antonio, Concha, Luis, Keller, Simon S, Cendes, Fernando, Yasuda, Clarissa L, Bonilha, Leonardo, Gleichgerrcht, Ezequiel, Focke, Niels K, Domin, Martin, von Podewills, Felix, Langner, Soenke, Rummel, Christian, Wiest, Roland, Martin, Pascal, Kotikalapudi, Raviteja, O'Brien, Terence J, Sinclair, Benjamin, Vivash, Lucy, Desmond, Patricia M, Lui, Elaine, Vaudano, Anna Elisabetta, Meletti, Stefano, Tondelli, Manuela, Alhusaini, Saud, Doherty, Colin P, Cavalleri, Gianpiero L, Delanty, Norman, Kälviäinen, Reetta, Jackson, Graeme D, Kowalczyk, Magdalena, Mascalchi, Mario, Semmelroch, Mira, Thomas, Rhys H, Soltanian-Zadeh, Hamid, Davoodi-Bojd, Esmaeil, Zhang, Junsong, Winston, Gavin P, Griffin, Aoife, Singh, Aditi, Tiwari, Vijay K, Kreilkamp, Barbara AK, Lenge, Matteo, Guerrini, Renzo, Hamandi, Khalid, Foley, Sonya, Rüber, Theodor, Weber, Bernd, Depondt, Chantal, Absil, Julie, Carr, Sarah JA, Abela, Eugenio, Richardson, Mark P, Devinsky, Orrin, Severino, Mariasavina, Striano, Pasquale, Tortora, Domenico, Kaestner, Erik, Hatton, Sean N, Vos, Sjoerd B, Caciagli, Lorenzo, Duncan, John S, Whelan, Christopher D, Thompson, Paul M, Sisodiya, Sanjay M, Bernasconi, Andrea, Labate, Angelo, McDonald, Carrie R, Bernasconi, Neda, Bernhardt, Boris C, Larivière, Sara, Larivière, Sara, Royer, Jessica, Rodríguez-Cruces, Raúl, Paquola, Casey, Caligiuri, Maria Eugenia, Gambardella, Antonio, Concha, Luis, Keller, Simon S, Cendes, Fernando, Yasuda, Clarissa L, Bonilha, Leonardo, Gleichgerrcht, Ezequiel, Focke, Niels K, Domin, Martin, von Podewills, Felix, Langner, Soenke, Rummel, Christian, Wiest, Roland, Martin, Pascal, Kotikalapudi, Raviteja, O'Brien, Terence J, Sinclair, Benjamin, Vivash, Lucy, Desmond, Patricia M, Lui, Elaine, Vaudano, Anna Elisabetta, Meletti, Stefano, Tondelli, Manuela, Alhusaini, Saud, Doherty, Colin P, Cavalleri, Gianpiero L, Delanty, Norman, Kälviäinen, Reetta, Jackson, Graeme D, Kowalczyk, Magdalena, Mascalchi, Mario, Semmelroch, Mira, Thomas, Rhys H, Soltanian-Zadeh, Hamid, Davoodi-Bojd, Esmaeil, Zhang, Junsong, Winston, Gavin P, Griffin, Aoife, Singh, Aditi, Tiwari, Vijay K, Kreilkamp, Barbara AK, Lenge, Matteo, Guerrini, Renzo, Hamandi, Khalid, Foley, Sonya, Rüber, Theodor, Weber, Bernd, Depondt, Chantal, Absil, Julie, Carr, Sarah JA, Abela, Eugenio, Richardson, Mark P, Devinsky, Orrin, Severino, Mariasavina, Striano, Pasquale, Tortora, Domenico, Kaestner, Erik, Hatton, Sean N, Vos, Sjoerd B, Caciagli, Lorenzo, Duncan, John S, Whelan, Christopher D, Thompson, Paul M, Sisodiya, Sanjay M, Bernasconi, Andrea, Labate, Angelo, McDonald, Carrie R, Bernasconi, Neda, and Bernhardt, Boris C
Abstract: Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem epilepsy risk gene expression patterns. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE showed decreased clustering and path length in fronto-temporo-parietal cortices, indicating a random network configuration. Syndrome-specific topological alterations reflected expression patterns of risk genes for hippocampal sclerosis in TLE and for generalized epilepsy in IGE. These imaging-transcriptomic signatures could potentially guide diagnosis or tailor therapeutic approaches to specific epilepsy syndromes.
Published: 2022

6. A pharmacogenomic assessment of psychiatric adverse drug reactions to levetiracetam.

Author: Campbell, Ciarán, McCormack, Mark, Patel, Sonn, Stapleton, Caragh, Bobbili, Dheeraj Reddy, Krause, Roland, Depondt, Chantal, Sills, Graeme J., Koeleman, Bobby P., Striano, Pasquale, Zara, Federico, Sander, Josemir W., Lerche, Holger, Kunz, Wolfram S., Stefansson, Kari, Stefansson, Hreinn, Doherty, Colin P., Heinzen, Erin L., Scheffer, Ingrid E., Goldstein, David B., O'Brien, Terence, Cotter, David, Berkovic, Samuel F., Sisodiya, Sanjay M., Delanty, Norman, Cavalleri, Gianpiero L., Campbell, Ciarán, McCormack, Mark, Patel, Sonn, Stapleton, Caragh, Bobbili, Dheeraj Reddy, Krause, Roland, Depondt, Chantal, Sills, Graeme J., Koeleman, Bobby P., Striano, Pasquale, Zara, Federico, Sander, Josemir W., Lerche, Holger, Kunz, Wolfram S., Stefansson, Kari, Stefansson, Hreinn, Doherty, Colin P., Heinzen, Erin L., Scheffer, Ingrid E., Goldstein, David B., O'Brien, Terence, Cotter, David, Berkovic, Samuel F., Sisodiya, Sanjay M., Delanty, Norman, and Cavalleri, Gianpiero L.
Abstract: OBJECTIVE: Levetiracetam (LEV) is an effective antiseizure medicine, but 10%-20% of people treated with LEV report psychiatric side-effects, and up to 1% may have psychotic episodes. Pharmacogenomic predictors of these adverse drug reactions (ADRs) have yet to be identified. We sought to determine the contribution of both common and rare genetic variation to psychiatric and behavioral ADRs associated with LEV. METHODS: This case-control study compared cases of LEV-associated behavioral disorder (n = 149) or psychotic reaction (n = 37) to LEV-exposed people with no history of psychiatric ADRs (n = 920). All samples were of European ancestry. We performed genome-wide association study (GWAS) analysis comparing those with LEV ADRs to controls. We estimated the polygenic risk scores (PRS) for schizophrenia and compared cases with LEV-associated psychotic reaction to controls. Rare variant burden analysis was performed using exome sequence data of cases with psychotic reactions (n = 18) and controls (n = 122). RESULTS: Univariate GWAS found no significant associations with either LEV-associated behavioural disorder or LEV-psychotic reaction. PRS analysis showed that cases of LEV-associated psychotic reaction had an increased PRS for schizophrenia relative to contr ols (p = .0097, estimate = .4886). The rare-variant analysis found no evidence of an increased burden of rare genetic variants in people who had experienced LEV-associated psychotic reaction relative to controls. SIGNIFICANCE: The polygenic burden for schizophrenia is a risk factor for LEV-associated psychotic reaction. To assess the clinical utility of PRS as a predictor, it should be tested in an independent and ideally prospective cohort. Larger sample sizes are required for the identification of significant univariate common genetic signals or rare genetic signals associated with psychiatric LEV ADRs.
Published: 2022

7. Topographic divergence of atypical cortical asymmetry and atrophy patterns in temporal lobe epilepsy.

Author: Park, Bo-Yong, Park, Bo-Yong, Larivière, Sara, Rodríguez-Cruces, Raul, Royer, Jessica, Tavakol, Shahin, Wang, Yezhou, Caciagli, Lorenzo, Caligiuri, Maria Eugenia, Gambardella, Antonio, Concha, Luis, Keller, Simon S, Cendes, Fernando, Alvim, Marina KM, Yasuda, Clarissa, Bonilha, Leonardo, Gleichgerrcht, Ezequiel, Focke, Niels K, Kreilkamp, Barbara AK, Domin, Martin, von Podewils, Felix, Langner, Soenke, Rummel, Christian, Rebsamen, Michael, Wiest, Roland, Martin, Pascal, Kotikalapudi, Raviteja, Bender, Benjamin, O'Brien, Terence J, Law, Meng, Sinclair, Benjamin, Vivash, Lucy, Kwan, Patrick, Desmond, Patricia M, Malpas, Charles B, Lui, Elaine, Alhusaini, Saud, Doherty, Colin P, Cavalleri, Gianpiero L, Delanty, Norman, Kälviäinen, Reetta, Jackson, Graeme D, Kowalczyk, Magdalena, Mascalchi, Mario, Semmelroch, Mira, Thomas, Rhys H, Soltanian-Zadeh, Hamid, Davoodi-Bojd, Esmaeil, Zhang, Junsong, Lenge, Matteo, Guerrini, Renzo, Bartolini, Emanuele, Hamandi, Khalid, Foley, Sonya, Weber, Bernd, Depondt, Chantal, Absil, Julie, Carr, Sarah JA, Abela, Eugenio, Richardson, Mark P, Devinsky, Orrin, Severino, Mariasavina, Striano, Pasquale, Parodi, Costanza, Tortora, Domenico, Hatton, Sean N, Vos, Sjoerd B, Duncan, John S, Galovic, Marian, Whelan, Christopher D, Bargalló, Núria, Pariente, Jose, Conde-Blanco, Estefania, Vaudano, Anna Elisabetta, Tondelli, Manuela, Meletti, Stefano, Kong, Xiang-Zhen, Francks, Clyde, Fisher, Simon E, Caldairou, Benoit, Ryten, Mina, Labate, Angelo, Sisodiya, Sanjay M, Thompson, Paul M, McDonald, Carrie R, Bernasconi, Andrea, Bernasconi, Neda, Bernhardt, Boris C, Park, Bo-Yong, Park, Bo-Yong, Larivière, Sara, Rodríguez-Cruces, Raul, Royer, Jessica, Tavakol, Shahin, Wang, Yezhou, Caciagli, Lorenzo, Caligiuri, Maria Eugenia, Gambardella, Antonio, Concha, Luis, Keller, Simon S, Cendes, Fernando, Alvim, Marina KM, Yasuda, Clarissa, Bonilha, Leonardo, Gleichgerrcht, Ezequiel, Focke, Niels K, Kreilkamp, Barbara AK, Domin, Martin, von Podewils, Felix, Langner, Soenke, Rummel, Christian, Rebsamen, Michael, Wiest, Roland, Martin, Pascal, Kotikalapudi, Raviteja, Bender, Benjamin, O'Brien, Terence J, Law, Meng, Sinclair, Benjamin, Vivash, Lucy, Kwan, Patrick, Desmond, Patricia M, Malpas, Charles B, Lui, Elaine, Alhusaini, Saud, Doherty, Colin P, Cavalleri, Gianpiero L, Delanty, Norman, Kälviäinen, Reetta, Jackson, Graeme D, Kowalczyk, Magdalena, Mascalchi, Mario, Semmelroch, Mira, Thomas, Rhys H, Soltanian-Zadeh, Hamid, Davoodi-Bojd, Esmaeil, Zhang, Junsong, Lenge, Matteo, Guerrini, Renzo, Bartolini, Emanuele, Hamandi, Khalid, Foley, Sonya, Weber, Bernd, Depondt, Chantal, Absil, Julie, Carr, Sarah JA, Abela, Eugenio, Richardson, Mark P, Devinsky, Orrin, Severino, Mariasavina, Striano, Pasquale, Parodi, Costanza, Tortora, Domenico, Hatton, Sean N, Vos, Sjoerd B, Duncan, John S, Galovic, Marian, Whelan, Christopher D, Bargalló, Núria, Pariente, Jose, Conde-Blanco, Estefania, Vaudano, Anna Elisabetta, Tondelli, Manuela, Meletti, Stefano, Kong, Xiang-Zhen, Francks, Clyde, Fisher, Simon E, Caldairou, Benoit, Ryten, Mina, Labate, Angelo, Sisodiya, Sanjay M, Thompson, Paul M, McDonald, Carrie R, Bernasconi, Andrea, Bernasconi, Neda, and Bernhardt, Boris C
Abstract: Temporal lobe epilepsy, a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter structural alterations in temporal lobe epilepsy relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry; or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multisite ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 temporal lobe epilepsy patients and 1418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in temporal lobe epilepsy, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity calculated using 207 healthy controls obtained from Human Connectome Project and an independent dataset containing 23 temporal lobe epilepsy patients and 53 healthy controls and examined clinical associations using machine learning. We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables. Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of temporal lobe epilepsy-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine ou
Published: 2022

8. Microvascular stabilization via blood-brain barrier regulation prevents seizure activity

Author: Greene, Chris, Hanley, Nicole, Reschke, Cristina R., Reddy, Avril, Andaloussi Mäe, Maarja, Connolly, Ruairi, Behan, Claire, O'Keeffe, Eoin, Bolger, Isobel, Hudson, Natalie, Delaney, Conor, Farrell, Michael A., O'Brien, Donncha F., Cryan, Jane, Brett, Francesca M., Beausang, Alan, Betsholtz, Christer, Henshall, David C., Doherty, Colin P., Campbell, Matthew, Greene, Chris, Hanley, Nicole, Reschke, Cristina R., Reddy, Avril, Andaloussi Mäe, Maarja, Connolly, Ruairi, Behan, Claire, O'Keeffe, Eoin, Bolger, Isobel, Hudson, Natalie, Delaney, Conor, Farrell, Michael A., O'Brien, Donncha F., Cryan, Jane, Brett, Francesca M., Beausang, Alan, Betsholtz, Christer, Henshall, David C., Doherty, Colin P., and Campbell, Matthew
Abstract: Blood-brain barrier (BBB) dysfunction is associated with worse epilepsy outcomes however the underlying molecular mechanisms of BBB dysfunction remain to be elucidated. Tight junction proteins are important regulators of BBB integrity and in particular, the tight junction protein claudin-5 is the most enriched in brain endothelial cells and regulates size-selectivity at the BBB. Additionally, disruption of claudin-5 expression has been implicated in numerous disorders including schizophrenia, depression and traumatic brain injury, yet its role in epilepsy has not been fully deciphered. Here we report that claudin-5 protein levels are significantly diminished in surgically resected brain tissue from patients with treatment-resistant epilepsy. Concomitantly, dynamic contrast-enhanced MRI in these patients showed widespread BBB disruption. We show that targeted disruption of claudin-5 in the hippocampus or genetic heterozygosity of claudin-5 in mice exacerbates kainic acid-induced seizures and BBB disruption. Additionally, inducible knockdown of claudin-5 in mice leads to spontaneous recurrent seizures, severe neuroinflammation, and mortality. Finally, we identify that RepSox, a regulator of claudin-5 expression, can prevent seizure activity in experimental epilepsy. Altogether, we propose that BBB stabilizing drugs could represent a new generation of agents to prevent seizure activity in epilepsy patients.
Published: 2022
Full Text: View/download PDF

9. Structural network alterations in focal and generalized epilepsy assessed in a worldwide ENIGMA study follow axes of epilepsy risk gene expression

Author: Larivière, Sara, Royer, Jessica, Rodríguez-Cruces, Raul, Paquola, Casey, Caligiuri, Maria Eugenia, Gambardella, Antonio, Concha, Luis, Keller, Simone, Cendes, Fernando, Yasuda, Clarissa L., Bonilha, Leonardo, Gleichgerrcht, Ezequiel, Focke, Niels K., Domin, Martin, von Podewills, Felix, Langner, Soenke, Rummel, Christian, Wiest, Roland, Martin, Pascale, Kotikalapudi, Raviteja, O’Brien, Terence J., Sinclair, Benjamin, Vivash, Lucy, Desmond, Patricia M., Lui, Elaine, Vaudano, Anna Elisabetta, Meletti, Stefano, Tondelli, Manuela, Alhusaini, Saud, Doherty, Colin P, Cavalleri, Gianpiero L, Delanty, Norman, Kälviäinen, Reetta, Jackson, Graeme D, Kowalczyk, Magdalena, Mascalchi, Mario, Semmelroch, Mira, Thomas, Rhys H, Soltanian-Zadeh, Hamid, Davoodi-Bojd, Esmaeil, Zhang, Junsong, Winston, Gavin, Griffin, Aoife, Singh, Aditi, Tiwari, Vijay K., Kreilkamp, Barbara A. K., Lenge, Matteo, Guerrini, Renzo, Hamandi, Khalid, Foley, Sonya, Rüber, Theodor, Weber, Bernd, Depondt, Chantal, Absil, Julie, Carr, Sarah J A, Abela, Eugenio, Richardson, Mark P, Devinsky, Orrin In, Severino, Mariasavina, Striano, Pasquale, Tortora, Domenico, Kaestner, Erik, Hatton, Sean N., Vos, Sjoerd B, Caciagli, Lorenzo, Duncan, John S, Whelan, Christopher D, Thompson, Paul M, Sisodiya, Sanjay M, Bernasconi, Andrea, Labate, Angelo, McDonald, Carrie R, Bernasconi, Neda, Bernhardt, Boris C, Larivière, Sara, Royer, Jessica, Rodríguez-Cruces, Raul, Paquola, Casey, Caligiuri, Maria Eugenia, Gambardella, Antonio, Concha, Luis, Keller, Simone, Cendes, Fernando, Yasuda, Clarissa L., Bonilha, Leonardo, Gleichgerrcht, Ezequiel, Focke, Niels K., Domin, Martin, von Podewills, Felix, Langner, Soenke, Rummel, Christian, Wiest, Roland, Martin, Pascale, Kotikalapudi, Raviteja, O’Brien, Terence J., Sinclair, Benjamin, Vivash, Lucy, Desmond, Patricia M., Lui, Elaine, Vaudano, Anna Elisabetta, Meletti, Stefano, Tondelli, Manuela, Alhusaini, Saud, Doherty, Colin P, Cavalleri, Gianpiero L, Delanty, Norman, Kälviäinen, Reetta, Jackson, Graeme D, Kowalczyk, Magdalena, Mascalchi, Mario, Semmelroch, Mira, Thomas, Rhys H, Soltanian-Zadeh, Hamid, Davoodi-Bojd, Esmaeil, Zhang, Junsong, Winston, Gavin, Griffin, Aoife, Singh, Aditi, Tiwari, Vijay K., Kreilkamp, Barbara A. K., Lenge, Matteo, Guerrini, Renzo, Hamandi, Khalid, Foley, Sonya, Rüber, Theodor, Weber, Bernd, Depondt, Chantal, Absil, Julie, Carr, Sarah J A, Abela, Eugenio, Richardson, Mark P, Devinsky, Orrin In, Severino, Mariasavina, Striano, Pasquale, Tortora, Domenico, Kaestner, Erik, Hatton, Sean N., Vos, Sjoerd B, Caciagli, Lorenzo, Duncan, John S, Whelan, Christopher D, Thompson, Paul M, Sisodiya, Sanjay M, Bernasconi, Andrea, Labate, Angelo, McDonald, Carrie R, Bernasconi, Neda, and Bernhardt, Boris C
Abstract: Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem epilepsy risk gene expression patterns. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE showed decreased clustering and path length in fronto-temporo-parietal cortices, indicating a random network configuration. Syndrome-specific topological alterations reflected expression patterns of risk genes for hippocampal sclerosis in TLE and for generalized epilepsy in IGE. These imaging-transcriptomic signatures could potentially guide diagnosis or tailor therapeutic approaches to specific epilepsy syndromes., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2022

10. Topographic divergence of atypical cortical asymmetry and atrophy patterns in temporal lobe epilepsy

Author: Park, Bo Yong, Larivière, Sara, Rodríguez-Cruces, Raul, Royer, Jessica, Tavakol, Shahin, Wang, Yezhou, Caciagli, Lorenzo, Caligiuri, Maria Eugenia, Gambardella, Antonio, Concha, Luis, Keller, Simone, Cendes, Fernando, Alvim, Marina, Yasuda, Clarissa, Bonilha, Leonardo, Gleichgerrcht, Ezequiel, Focke, Niels, Kreilkamp, Barbara, Domin, Martin, von Podewils, Felix, Langner, Soenke, Rummel, Christian, Rebsamen, Michael, Wiest, Roland, Martin, Pascale, Kotikalapudi, Raviteja, Bender, Benjamin, O’Brien, Terence J, Law, Meng, Sinclair, Benjamin, Vivash, Lucy, Kwan, Patrick, Desmond, Patricia, Malpas, Charles, Lui, Elaine, Alhusaini, Saud, Doherty, Colin P, Cavalleri, Gianpiero L, Delanty, Norman, Kälviäinen, Reetta, Jackson, Graeme D, Kowalczyk, Magdalena, Mascalchi, Mario, Semmelroch, Mira, Thomas, Rhys H, Soltanian-Zadeh, Hamid, Davoodi-Bojd, Esmaeil, Zhang, Junsong, Lenge, Matteo, Guerrini, Renzo, Bartolini, Emanuele, Hamandi, Khalid, Foley, Sonya, Weber, Bernd, Depondt, Chantal, Absil, Julie, Carr, Sarah J A, Abela, Eugenio, Richardson, Mark P, Devinsky, Orrin In, Severino, Mariasavina, Striano, Pasquale, Parodi, Costanza, Tortora, Domenico, Hatton, Sean, Vos, Sjoerd B, Duncan, John S, Galovic, Marian, Whelan, Christopher D, Bargalló, Núria, Pariente, Jose, Conde-Blanco, Estefania, Vaudano, Anna Elisabetta, Tondelli, Manuela, Meletti, Stefano, Kong, Xiang-Zhen, Francks, Clyde, Fisher, Simon E, Caldairou, Benoit, Ryten, Mina, Labate, Angelo, Sisodiya, Sanjay M, Thompson, Paul M, McDonald, Carrie R, Bernasconi, Andrea, Bernasconi, Neda, Bernhardt, Boris C, Park, Bo Yong, Larivière, Sara, Rodríguez-Cruces, Raul, Royer, Jessica, Tavakol, Shahin, Wang, Yezhou, Caciagli, Lorenzo, Caligiuri, Maria Eugenia, Gambardella, Antonio, Concha, Luis, Keller, Simone, Cendes, Fernando, Alvim, Marina, Yasuda, Clarissa, Bonilha, Leonardo, Gleichgerrcht, Ezequiel, Focke, Niels, Kreilkamp, Barbara, Domin, Martin, von Podewils, Felix, Langner, Soenke, Rummel, Christian, Rebsamen, Michael, Wiest, Roland, Martin, Pascale, Kotikalapudi, Raviteja, Bender, Benjamin, O’Brien, Terence J, Law, Meng, Sinclair, Benjamin, Vivash, Lucy, Kwan, Patrick, Desmond, Patricia, Malpas, Charles, Lui, Elaine, Alhusaini, Saud, Doherty, Colin P, Cavalleri, Gianpiero L, Delanty, Norman, Kälviäinen, Reetta, Jackson, Graeme D, Kowalczyk, Magdalena, Mascalchi, Mario, Semmelroch, Mira, Thomas, Rhys H, Soltanian-Zadeh, Hamid, Davoodi-Bojd, Esmaeil, Zhang, Junsong, Lenge, Matteo, Guerrini, Renzo, Bartolini, Emanuele, Hamandi, Khalid, Foley, Sonya, Weber, Bernd, Depondt, Chantal, Absil, Julie, Carr, Sarah J A, Abela, Eugenio, Richardson, Mark P, Devinsky, Orrin In, Severino, Mariasavina, Striano, Pasquale, Parodi, Costanza, Tortora, Domenico, Hatton, Sean, Vos, Sjoerd B, Duncan, John S, Galovic, Marian, Whelan, Christopher D, Bargalló, Núria, Pariente, Jose, Conde-Blanco, Estefania, Vaudano, Anna Elisabetta, Tondelli, Manuela, Meletti, Stefano, Kong, Xiang-Zhen, Francks, Clyde, Fisher, Simon E, Caldairou, Benoit, Ryten, Mina, Labate, Angelo, Sisodiya, Sanjay M, Thompson, Paul M, McDonald, Carrie R, Bernasconi, Andrea, Bernasconi, Neda, and Bernhardt, Boris C
Abstract: Temporal lobe epilepsy, a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter structural alterations in temporal lobe epilepsy relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry; or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multisite ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 temporal lobe epilepsy patients and 1418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in temporal lobe epilepsy, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity calculated using 207 healthy controls obtained from Human Connectome Project and an independent dataset containing 23 temporal lobe epilepsy patients and 53 healthy controls and examined clinical associations using machine learning. We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables. Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of temporal lobe epilepsy-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings, SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2022

11. Microvascular stabilization via blood-brain barrier regulation prevents seizure activity

Author: Greene, Chris, Hanley, Nicole, Reschke, Cristina R., Reddy, Avril, Andaloussi Mäe, Maarja, Connolly, Ruairi, Behan, Claire, O'Keeffe, Eoin, Bolger, Isobel, Hudson, Natalie, Delaney, Conor, Farrell, Michael A., O'Brien, Donncha F., Cryan, Jane, Brett, Francesca M., Beausang, Alan, Betsholtz, Christer, Henshall, David C., Doherty, Colin P., Campbell, Matthew, Greene, Chris, Hanley, Nicole, Reschke, Cristina R., Reddy, Avril, Andaloussi Mäe, Maarja, Connolly, Ruairi, Behan, Claire, O'Keeffe, Eoin, Bolger, Isobel, Hudson, Natalie, Delaney, Conor, Farrell, Michael A., O'Brien, Donncha F., Cryan, Jane, Brett, Francesca M., Beausang, Alan, Betsholtz, Christer, Henshall, David C., Doherty, Colin P., and Campbell, Matthew
Abstract: Blood-brain barrier (BBB) dysfunction is associated with worse epilepsy outcomes however the underlying molecular mechanisms of BBB dysfunction remain to be elucidated. Tight junction proteins are important regulators of BBB integrity and in particular, the tight junction protein claudin-5 is the most enriched in brain endothelial cells and regulates size-selectivity at the BBB. Additionally, disruption of claudin-5 expression has been implicated in numerous disorders including schizophrenia, depression and traumatic brain injury, yet its role in epilepsy has not been fully deciphered. Here we report that claudin-5 protein levels are significantly diminished in surgically resected brain tissue from patients with treatment-resistant epilepsy. Concomitantly, dynamic contrast-enhanced MRI in these patients showed widespread BBB disruption. We show that targeted disruption of claudin-5 in the hippocampus or genetic heterozygosity of claudin-5 in mice exacerbates kainic acid-induced seizures and BBB disruption. Additionally, inducible knockdown of claudin-5 in mice leads to spontaneous recurrent seizures, severe neuroinflammation, and mortality. Finally, we identify that RepSox, a regulator of claudin-5 expression, can prevent seizure activity in experimental epilepsy. Altogether, we propose that BBB stabilizing drugs could represent a new generation of agents to prevent seizure activity in epilepsy patients.
Published: 2022
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12. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Motelow, Joshua E., Povysil, Gundula, Dhindsa, Ryan S., Stanley, Kate E., Allen, Andrew S., Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Cusick, Caroline, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea E., Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Gupta, Namrata, Neale, Benjamin M., Cavalleri, Gianpiero L., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, Dixon-Salazar, Tracy, Guerrini, Renzo, Hakonarson, Hakon, Heinzen, Erin L., Helbig, Ingo, Kwan, Patrick, Marson, Anthony G., Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Stewart, Randy, Weckhuysen, Sarah, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, Krause, Roland, May, Patrick, McKenna, Kevin, Regan, Brigid M., Bennett, Caitlin A., Leu, Costin, Leech, Stephanie L., O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Ali, Quratulain Zulfiqar, Sadoway, Tara R., Krestel, Heinz, Schaller, André, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Christou, Yiolanda, Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Neubauer, Bernd A., Zimprich, Friedrich, Feucht, Martha, Reinthaler, Eva M., Kunz, Wolfram S., Zsurka, Gábor, Surges, Rainer, Baumgartner, Tobias, Wrede, Randi Von, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, Baalen, Andreas Van, Spiczak, Sarah Von, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Lauxmann, Stephan, Boßelmann, Christian, Kegele, Josua, Hengsbach, Christian, Rau, Sarah, Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Borggräfe, Ingo, Schankin, Christoph J., Schubert-Bast, Susanne, Schreiber, Herbert, Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Wolff, Markus, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Saarela, Anni, Timonen, Oskari, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rheims, Sylvain, Lesca, Gaetan, Ryvlin, Philippe, Maillard, Louis, Valton, Luc, Derambure, Philippe, Bartolomei, Fabrice, Hirsch, Edouard, Michel, Véronique, Chassoux, Francine, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Baker, Mark D., Fonferko-Shadrach, Beata, Lawthom, Charlotte, Anderson, Joseph, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Delanty, Norman, Doherty, Colin P., Shukralla, Arif, El-Naggar, Hany, Widdess-Walsh, Peter, Barišić, Nina, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Ragona, Francesca, Zara, Federico, Iacomino, Michele, Riva, Antonella, Madia, Francesca, Vari, Maria Stella, Salpietro, Vincenzo, Scala, Marcello, Mancardi, Maria Margherita, Nobili, Lino, Amadori, Elisabetta, Giacomini, Thea, Bisulli, Francesca, Pippucci, Tommaso, Licchetta, Laura, Minardi, Raffaella, Tinuper, Paolo, Muccioli, Lorenzo, Mostacci, Barbara, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Barba, Carmen, Hirose, Shinichi, Ishii, Atsushi, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Beydoun, Ahmad, Nasreddine, Wassim, Zgheib, Nathalie Khoueiry, Tumiene, Birute, Utkus, Algirdas, Sadleir, Lynette G., King, Chontelle, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Topaloglu, Pınar, Kara, Bulent, Yis, Uluc, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Tsai, Meng-Han, Ho, Chen-Jui, Lin, Chih-Hsiang, Lin, Kuang-Lin, Chou, I.-Jun, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Noebels, Jeffrey L., Goldman, Alicia, Busch, Robyn M., Jehi, Lara, Najm, Imad M., Ferguson, Lisa, Khoury, Jean, Glauser, Tracy A., Clark, Peggy O., Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Greenberg, David A., Ellis, Colin A., Goldberg, Ethan, Helbig, Katherine L., Cosico, Mahgenn, Vaidiswaran, Priya, Fitch, Eryn, Berkovic, Samuel F., Lerche, Holger, Lowenstein, Daniel H., Goldstein, David B., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Motelow, Joshua E., Povysil, Gundula, Dhindsa, Ryan S., Stanley, Kate E., Allen, Andrew S., Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Cusick, Caroline, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea E., Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Gupta, Namrata, Neale, Benjamin M., Cavalleri, Gianpiero L., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, Dixon-Salazar, Tracy, Guerrini, Renzo, Hakonarson, Hakon, Heinzen, Erin L., Helbig, Ingo, Kwan, Patrick, Marson, Anthony G., Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Stewart, Randy, Weckhuysen, Sarah, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, Krause, Roland, May, Patrick, McKenna, Kevin, Regan, Brigid M., Bennett, Caitlin A., Leu, Costin, Leech, Stephanie L., O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Ali, Quratulain Zulfiqar, Sadoway, Tara R., Krestel, Heinz, Schaller, André, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Christou, Yiolanda, Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Neubauer, Bernd A., Zimprich, Friedrich, Feucht, Martha, Reinthaler, Eva M., Kunz, Wolfram S., Zsurka, Gábor, Surges, Rainer, Baumgartner, Tobias, Wrede, Randi Von, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, Baalen, Andreas Van, Spiczak, Sarah Von, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Lauxmann, Stephan, Boßelmann, Christian, Kegele, Josua, Hengsbach, Christian, Rau, Sarah, Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Borggräfe, Ingo, Schankin, Christoph J., Schubert-Bast, Susanne, Schreiber, Herbert, Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Wolff, Markus, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Saarela, Anni, Timonen, Oskari, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rheims, Sylvain, Lesca, Gaetan, Ryvlin, Philippe, Maillard, Louis, Valton, Luc, Derambure, Philippe, Bartolomei, Fabrice, Hirsch, Edouard, Michel, Véronique, Chassoux, Francine, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Baker, Mark D., Fonferko-Shadrach, Beata, Lawthom, Charlotte, Anderson, Joseph, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Delanty, Norman, Doherty, Colin P., Shukralla, Arif, El-Naggar, Hany, Widdess-Walsh, Peter, Barišić, Nina, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Ragona, Francesca, Zara, Federico, Iacomino, Michele, Riva, Antonella, Madia, Francesca, Vari, Maria Stella, Salpietro, Vincenzo, Scala, Marcello, Mancardi, Maria Margherita, Nobili, Lino, Amadori, Elisabetta, Giacomini, Thea, Bisulli, Francesca, Pippucci, Tommaso, Licchetta, Laura, Minardi, Raffaella, Tinuper, Paolo, Muccioli, Lorenzo, Mostacci, Barbara, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Barba, Carmen, Hirose, Shinichi, Ishii, Atsushi, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Beydoun, Ahmad, Nasreddine, Wassim, Zgheib, Nathalie Khoueiry, Tumiene, Birute, Utkus, Algirdas, Sadleir, Lynette G., King, Chontelle, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Topaloglu, Pınar, Kara, Bulent, Yis, Uluc, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Tsai, Meng-Han, Ho, Chen-Jui, Lin, Chih-Hsiang, Lin, Kuang-Lin, Chou, I.-Jun, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Noebels, Jeffrey L., Goldman, Alicia, Busch, Robyn M., Jehi, Lara, Najm, Imad M., Ferguson, Lisa, Khoury, Jean, Glauser, Tracy A., Clark, Peggy O., Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Greenberg, David A., Ellis, Colin A., Goldberg, Ethan, Helbig, Katherine L., Cosico, Mahgenn, Vaidiswaran, Priya, Fitch, Eryn, Berkovic, Samuel F., Lerche, Holger, Lowenstein, Daniel H., and Goldstein, David B.
Abstract: Summary Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.
Published: 2021

13. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Motelow, Joshua E., Povysil, Gundula, Dhindsa, Ryan S., Stanley, Kate E., Allen, Andrew S., Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Cusick, Caroline, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea E., Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Gupta, Namrata, Neale, Benjamin M., Cavalleri, Gianpiero L., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, Dixon-Salazar, Tracy, Guerrini, Renzo, Hakonarson, Hakon, Heinzen, Erin L., Helbig, Ingo, Kwan, Patrick, Marson, Anthony G., Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Stewart, Randy, Weckhuysen, Sarah, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, Krause, Roland, May, Patrick, McKenna, Kevin, Regan, Brigid M., Bennett, Caitlin A., Leu, Costin, Leech, Stephanie L., O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Ali, Quratulain Zulfiqar, Sadoway, Tara R., Krestel, Heinz, Schaller, André, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Christou, Yiolanda, Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Neubauer, Bernd A., Zimprich, Friedrich, Feucht, Martha, Reinthaler, Eva M., Kunz, Wolfram S., Zsurka, Gábor, Surges, Rainer, Baumgartner, Tobias, Wrede, Randi Von, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, Baalen, Andreas Van, Spiczak, Sarah Von, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Lauxmann, Stephan, Boßelmann, Christian, Kegele, Josua, Hengsbach, Christian, Rau, Sarah, Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Borggräfe, Ingo, Schankin, Christoph J., Schubert-Bast, Susanne, Schreiber, Herbert, Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Wolff, Markus, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Saarela, Anni, Timonen, Oskari, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rheims, Sylvain, Lesca, Gaetan, Ryvlin, Philippe, Maillard, Louis, Valton, Luc, Derambure, Philippe, Bartolomei, Fabrice, Hirsch, Edouard, Michel, Véronique, Chassoux, Francine, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Baker, Mark D., Fonferko-Shadrach, Beata, Lawthom, Charlotte, Anderson, Joseph, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Delanty, Norman, Doherty, Colin P., Shukralla, Arif, El-Naggar, Hany, Widdess-Walsh, Peter, Barišić, Nina, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Ragona, Francesca, Zara, Federico, Iacomino, Michele, Riva, Antonella, Madia, Francesca, Vari, Maria Stella, Salpietro, Vincenzo, Scala, Marcello, Mancardi, Maria Margherita, Nobili, Lino, Amadori, Elisabetta, Giacomini, Thea, Bisulli, Francesca, Pippucci, Tommaso, Licchetta, Laura, Minardi, Raffaella, Tinuper, Paolo, Muccioli, Lorenzo, Mostacci, Barbara, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Barba, Carmen, Hirose, Shinichi, Ishii, Atsushi, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Beydoun, Ahmad, Nasreddine, Wassim, Zgheib, Nathalie Khoueiry, Tumiene, Birute, Utkus, Algirdas, Sadleir, Lynette G., King, Chontelle, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Topaloglu, Pınar, Kara, Bulent, Yis, Uluc, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Tsai, Meng-Han, Ho, Chen-Jui, Lin, Chih-Hsiang, Lin, Kuang-Lin, Chou, I.-Jun, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Noebels, Jeffrey L., Goldman, Alicia, Busch, Robyn M., Jehi, Lara, Najm, Imad M., Ferguson, Lisa, Khoury, Jean, Glauser, Tracy A., Clark, Peggy O., Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Greenberg, David A., Ellis, Colin A., Goldberg, Ethan, Helbig, Katherine L., Cosico, Mahgenn, Vaidiswaran, Priya, Fitch, Eryn, Berkovic, Samuel F., Lerche, Holger, Lowenstein, Daniel H., Goldstein, David B., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Motelow, Joshua E., Povysil, Gundula, Dhindsa, Ryan S., Stanley, Kate E., Allen, Andrew S., Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Cusick, Caroline, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea E., Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Gupta, Namrata, Neale, Benjamin M., Cavalleri, Gianpiero L., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, Dixon-Salazar, Tracy, Guerrini, Renzo, Hakonarson, Hakon, Heinzen, Erin L., Helbig, Ingo, Kwan, Patrick, Marson, Anthony G., Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Stewart, Randy, Weckhuysen, Sarah, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, Krause, Roland, May, Patrick, McKenna, Kevin, Regan, Brigid M., Bennett, Caitlin A., Leu, Costin, Leech, Stephanie L., O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Ali, Quratulain Zulfiqar, Sadoway, Tara R., Krestel, Heinz, Schaller, André, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Christou, Yiolanda, Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Neubauer, Bernd A., Zimprich, Friedrich, Feucht, Martha, Reinthaler, Eva M., Kunz, Wolfram S., Zsurka, Gábor, Surges, Rainer, Baumgartner, Tobias, Wrede, Randi Von, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, Baalen, Andreas Van, Spiczak, Sarah Von, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Lauxmann, Stephan, Boßelmann, Christian, Kegele, Josua, Hengsbach, Christian, Rau, Sarah, Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Borggräfe, Ingo, Schankin, Christoph J., Schubert-Bast, Susanne, Schreiber, Herbert, Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Wolff, Markus, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Saarela, Anni, Timonen, Oskari, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rheims, Sylvain, Lesca, Gaetan, Ryvlin, Philippe, Maillard, Louis, Valton, Luc, Derambure, Philippe, Bartolomei, Fabrice, Hirsch, Edouard, Michel, Véronique, Chassoux, Francine, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Baker, Mark D., Fonferko-Shadrach, Beata, Lawthom, Charlotte, Anderson, Joseph, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Delanty, Norman, Doherty, Colin P., Shukralla, Arif, El-Naggar, Hany, Widdess-Walsh, Peter, Barišić, Nina, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Ragona, Francesca, Zara, Federico, Iacomino, Michele, Riva, Antonella, Madia, Francesca, Vari, Maria Stella, Salpietro, Vincenzo, Scala, Marcello, Mancardi, Maria Margherita, Nobili, Lino, Amadori, Elisabetta, Giacomini, Thea, Bisulli, Francesca, Pippucci, Tommaso, Licchetta, Laura, Minardi, Raffaella, Tinuper, Paolo, Muccioli, Lorenzo, Mostacci, Barbara, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Barba, Carmen, Hirose, Shinichi, Ishii, Atsushi, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Beydoun, Ahmad, Nasreddine, Wassim, Zgheib, Nathalie Khoueiry, Tumiene, Birute, Utkus, Algirdas, Sadleir, Lynette G., King, Chontelle, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Topaloglu, Pınar, Kara, Bulent, Yis, Uluc, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Tsai, Meng-Han, Ho, Chen-Jui, Lin, Chih-Hsiang, Lin, Kuang-Lin, Chou, I.-Jun, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Noebels, Jeffrey L., Goldman, Alicia, Busch, Robyn M., Jehi, Lara, Najm, Imad M., Ferguson, Lisa, Khoury, Jean, Glauser, Tracy A., Clark, Peggy O., Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Greenberg, David A., Ellis, Colin A., Goldberg, Ethan, Helbig, Katherine L., Cosico, Mahgenn, Vaidiswaran, Priya, Fitch, Eryn, Berkovic, Samuel F., Lerche, Holger, Lowenstein, Daniel H., and Goldstein, David B.
Abstract: Summary Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.
Published: 2021

14. Artificial intelligence for classification of temporal lobe epilepsy with ROI-level MRI data: A worldwide ENIGMA-Epilepsy study.

Author: Gleichgerrcht, Ezequiel, Gleichgerrcht, Ezequiel, Munsell, Brent C, Alhusaini, Saud, Alvim, Marina KM, Bargalló, Núria, Bender, Benjamin, Bernasconi, Andrea, Bernasconi, Neda, Bernhardt, Boris, Blackmon, Karen, Caligiuri, Maria Eugenia, Cendes, Fernando, Concha, Luis, Desmond, Patricia M, Devinsky, Orrin, Doherty, Colin P, Domin, Martin, Duncan, John S, Focke, Niels K, Gambardella, Antonio, Gong, Bo, Guerrini, Renzo, Hatton, Sean N, Kälviäinen, Reetta, Keller, Simon S, Kochunov, Peter, Kotikalapudi, Raviteja, Kreilkamp, Barbara AK, Labate, Angelo, Langner, Soenke, Larivière, Sara, Lenge, Matteo, Lui, Elaine, Martin, Pascal, Mascalchi, Mario, Meletti, Stefano, O'Brien, Terence J, Pardoe, Heath R, Pariente, Jose C, Xian Rao, Jun, Richardson, Mark P, Rodríguez-Cruces, Raúl, Rüber, Theodor, Sinclair, Ben, Soltanian-Zadeh, Hamid, Stein, Dan J, Striano, Pasquale, Taylor, Peter N, Thomas, Rhys H, Elisabetta Vaudano, Anna, Vivash, Lucy, von Podewills, Felix, Vos, Sjoerd B, Weber, Bernd, Yao, Yi, Lin Yasuda, Clarissa, Zhang, Junsong, Thompson, Paul M, Sisodiya, Sanjay M, McDonald, Carrie R, Bonilha, Leonardo, ENIGMA-Epilepsy Working Group, Gleichgerrcht, Ezequiel, Gleichgerrcht, Ezequiel, Munsell, Brent C, Alhusaini, Saud, Alvim, Marina KM, Bargalló, Núria, Bender, Benjamin, Bernasconi, Andrea, Bernasconi, Neda, Bernhardt, Boris, Blackmon, Karen, Caligiuri, Maria Eugenia, Cendes, Fernando, Concha, Luis, Desmond, Patricia M, Devinsky, Orrin, Doherty, Colin P, Domin, Martin, Duncan, John S, Focke, Niels K, Gambardella, Antonio, Gong, Bo, Guerrini, Renzo, Hatton, Sean N, Kälviäinen, Reetta, Keller, Simon S, Kochunov, Peter, Kotikalapudi, Raviteja, Kreilkamp, Barbara AK, Labate, Angelo, Langner, Soenke, Larivière, Sara, Lenge, Matteo, Lui, Elaine, Martin, Pascal, Mascalchi, Mario, Meletti, Stefano, O'Brien, Terence J, Pardoe, Heath R, Pariente, Jose C, Xian Rao, Jun, Richardson, Mark P, Rodríguez-Cruces, Raúl, Rüber, Theodor, Sinclair, Ben, Soltanian-Zadeh, Hamid, Stein, Dan J, Striano, Pasquale, Taylor, Peter N, Thomas, Rhys H, Elisabetta Vaudano, Anna, Vivash, Lucy, von Podewills, Felix, Vos, Sjoerd B, Weber, Bernd, Yao, Yi, Lin Yasuda, Clarissa, Zhang, Junsong, Thompson, Paul M, Sisodiya, Sanjay M, McDonald, Carrie R, Bonilha, Leonardo, and ENIGMA-Epilepsy Working Group
Abstract: Artificial intelligence has recently gained popularity across different medical fields to aid in the detection of diseases based on pathology samples or medical imaging findings. Brain magnetic resonance imaging (MRI) is a key assessment tool for patients with temporal lobe epilepsy (TLE). The role of machine learning and artificial intelligence to increase detection of brain abnormalities in TLE remains inconclusive. We used support vector machine (SV) and deep learning (DL) models based on region of interest (ROI-based) structural (n = 336) and diffusion (n = 863) brain MRI data from patients with TLE with ("lesional") and without ("non-lesional") radiographic features suggestive of underlying hippocampal sclerosis from the multinational (multi-center) ENIGMA-Epilepsy consortium. Our data showed that models to identify TLE performed better or similar (68-75%) compared to models to lateralize the side of TLE (56-73%, except structural-based) based on diffusion data with the opposite pattern seen for structural data (67-75% to diagnose vs. 83% to lateralize). In other aspects, structural and diffusion-based models showed similar classification accuracies. Our classification models for patients with hippocampal sclerosis were more accurate (68-76%) than models that stratified non-lesional patients (53-62%). Overall, SV and DL models performed similarly with several instances in which SV mildly outperformed DL. We discuss the relative performance of these models with ROI-level data and the implications for future applications of machine learning and artificial intelligence in epilepsy care.
Published: 2021

15. A pharmacogenomic assessment of psychiatric adverse drug reactions to levetiracetam

Author: Campbell, Ciarán, McCormack, Mark, Patel, Sonn, Stapleton, Caragh, Bobbili, Dheeraj, Krause, Roland, Depondt, Chantal, Sills, Graeme, Koeleman, B.P.C., Striano, Pasquale, Zara, Federico, Sander, Josemir W, Lerche, Holger, Kunz, Wolfram W.S., Stefansson, Kari, Stefansson, Hreinn, Doherty, Colin P, Heinzen, Erin E.L., Scheffer, Ingrid E, Goldstein, David B, O'Brien, Terence John, Cotter, David, Berkovic, Samuel F, Sisodiya, Sanjay, Delanty, Norman, Cavalleri, Gianpiero, Campbell, Ciarán, McCormack, Mark, Patel, Sonn, Stapleton, Caragh, Bobbili, Dheeraj, Krause, Roland, Depondt, Chantal, Sills, Graeme, Koeleman, B.P.C., Striano, Pasquale, Zara, Federico, Sander, Josemir W, Lerche, Holger, Kunz, Wolfram W.S., Stefansson, Kari, Stefansson, Hreinn, Doherty, Colin P, Heinzen, Erin E.L., Scheffer, Ingrid E, Goldstein, David B, O'Brien, Terence John, Cotter, David, Berkovic, Samuel F, Sisodiya, Sanjay, Delanty, Norman, and Cavalleri, Gianpiero
Abstract: Objective: Levetiracetam (LEV) is an effective antiseizure medicine, but 10%–20% of people treated with LEV report psychiatric side-effects, and up to 1% may have psychotic episodes. Pharmacogenomic predictors of these adverse drug reactions (ADRs) have yet to be identified. We sought to determine the contribution of both common and rare genetic variation to psychiatric and behavioral ADRs associated with LEV. Methods: This case-control study compared cases of LEV-associated behavioral disorder (n = 149) or psychotic reaction (n = 37) to LEV-exposed people with no history of psychiatric ADRs (n = 920). All samples were of European ancestry. We performed genome-wide association study (GWAS) analysis comparing those with LEV ADRs to controls. We estimated the polygenic risk scores (PRS) for schizophrenia and compared cases with LEV-associated psychotic reaction to controls. Rare variant burden analysis was performed using exome sequence data of cases with psychotic reactions (n = 18) and controls (n = 122). Results: Univariate GWAS found no significant associations with either LEV-associated behavioural disorder or LEV-psychotic reaction. PRS analysis showed that cases of LEV-associated psychotic reaction had an increased PRS for schizophrenia relative to contr ols (p =.0097, estimate =.4886). The rare-variant analysis found no evidence of an increased burden of rare genetic variants in people who had experienced LEV-associated psychotic reaction relative to controls. Significance: The polygenic burden for schizophrenia is a risk factor for LEV-associated psychotic reaction. To assess the clinical utility of PRS as a predictor, it should be tested in an independent and ideally prospective cohort. Larger sample sizes are required for the identification of significant univariate common genetic signals or rare genetic signals associated with psychiatric LEV ADRs., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2021

16. The genetic architecture of the human cerebral cortex

Author: Grasby, Katrina L., Jahanshad, Neda, Painter, Jodie N., Colodro-Conde, Lucia, Bralten, Janita, Hibar, Derrek P., Lind, Penelope A., Pizzagalli, Fabrizio, Ching, Christopher R. K., McMahon, Mary Agnes B., Shatokhina, Natalia, Zsembik, Leo C. P., Thomopoulos, Sophia I., Zhu, Alyssa H., Strike, Lachlan T., Agartz, Ingrid, Alhusaini, Saud, Almeida, Marcio A. A., Alnaes, Dag, Amlien, Inge K., Andersson, Micael, Ard, Tyler, Armstrong, Nicola J., Ashley-Koch, Allison, Atkins, Joshua R., Bernard, Manon, Brouwer, Rachel M., Buimer, Elizabeth E. L., Bulow, Robin, Burger, Christian, Cannon, Dara M., Chakravarty, Mallar, Chen, Qiang, Cheung, Joshua W., Couvy-Duchesne, Baptiste, Dale, Anders M., Dalvie, Shareefa, de Araujo, Tania K., de Zubicaray, Greig I., de Zwarte, Sonja M. C., den Braber, Anouk, Doan, Nhat Trung, Dohm, Katharina, Ehrlich, Stefan, Engelbrecht, Hannah-Ruth, Erk, Susanne, Fan, Chun Chieh, Fedko, Iryna O., Foley, Sonya F., Ford, Judith M., Fukunaga, Masaki, Garrett, Melanie E., Ge, Tian, Giddaluru, Sudheer, Goldman, Aaron L., Green, Melissa J., Groenewold, Nynke A., Grotegerd, Dominik, Gurholt, Tiril P., Gutman, Boris A., Hansell, Narelle K., Harris, Mathew A., Harrison, Marc B., Haswell, Courtney C., Hauser, Michael, Herms, Stefan, Heslenfeld, Dirk J., Ho, New Fei, Hoehn, David, Hoffmann, Per, Holleran, Laurena, Hoogman, Martine, Hottenga, Jouke-Jan, Ikeda, Masashi, Janowitz, Deborah, Jansen, Iris E., Jia, Tianye, Jockwitz, Christiane, Kanai, Ryota, Karama, Sherif, Kasperaviciute, Dalia, Kaufmann, Tobias, Kelly, Sinead, Kikuchi, Masataka, Klein, Marieke, Knapp, Michael, Knodt, Annchen R., Kramer, Bernd, Lam, Max, Lancaster, Thomas M., Lee, Phil H., Lett, Tristram A., Lewis, Lindsay B., Lopes-Cendes, Iscia, Luciano, Michelle, Macciardi, Fabio, Marquand, Andre F., Mathias, Samuel R., Melzer, Tracy R., Milaneschi, Yuri, Mirza-Schreiber, Nazanin, Moreira, Jose C. V., Muhleisen, Thomas W., Mueller-Myhsok, Bertram, Najt, Pablo, Nakahara, Soichiro, Nho, Kwangsik, Loohuis, Loes M. Olde, Orfanos, Dimitri Papadopoulos, Pearson, John F., Pitcher, Toni L., Putz, Benno, Quide, Yann, Ragothaman, Anjanibhargavi, Rashid, Faisal M., Reay, William R., Redlich, Ronny, Reinbold, Celine S., Repple, Jonathan, Richard, Genevieve, Riedel, Brandalyn C., Risacher, Shannon L., Rocha, Cristiane S., Mota, Nina R., Salminen, Lauren, Saremi, Arvin, Saykin, Andrew J., Schlag, Fenja, Schmaal, Lianne, Schofield, Peter R., Secolin, Rodrigo, Shapland, Chin Yang, Shen, Li, Shin, Jean, Shumskaya, Elena, Sonderby, Ida E., Sprooten, Emma, Tansey, Katherine E., Teumer, Alexander, Thalamuthu, Anbupalam, Tordesillas-Gutierrez, Diana, Turner, Jessica A., Uhlmann, Anne, Vallerga, Costanza L., van der Meer, Dennis, van Donkelaar, Marjolein M. J., van Eijk, Liza, van Erp, Theo G. M., van Haren, Neeltje E. M., van Rooij, Daan, van Tol, Marie-Jose, Veldink, Jan H., Verhoef, Ellen, Walton, Esther, Wang, Mingyuan, Wang, Yunpeng, Wardlaw, Joanna M., Wen, Wei, Westlye, Lars T., Whelan, Christopher D., Witt, Stephanie H., Wittfeld, Katharina, Wolf, Christiane, Wolfers, Thomas, Wu, Jing Qin, Yasuda, Clarissa L., Zaremba, Dario, Zhang, Zuo, Zwiers, Marcel P., Artiges, Eric, Assareh, Amelia A., Ayesa-Arriola, Rosa, Belger, Aysenil, Brandt, Christine L., Brown, Gregory G., Cichon, Sven, Curran, Joanne E., Davies, Gareth E., Degenhardt, Franziska, Dennis, Michelle F., Dietsche, Bruno, Djurovic, Srdjan, Doherty, Colin P., Espiritu, Ryan, Garijo, Daniel, Gil, Yolanda, Gowland, Penny A., Green, Robert C., Hausler, Alexander N., Heindel, Walter, Ho, Beng-Choon, Hoffmann, Wolfgang U., Holsboer, Florian, Homuth, Georg, Hosten, Norbert, Jack, Clifford R., Jr., Jang, MiHyun, Jansen, Andreas, Kimbrel, Nathan A., Kolskar, Knut, Koops, Sanne, Krug, Axel, Lim, Kelvin O., Luykx, Jurjen J., Mathalon, Daniel H., Mather, Karen A., Mattay, Venkata S., Matthews, Sarah, Van Son, Jaqueline Mayoral, McEwen, Sarah C., Melle, Ingrid, Morris, Derek W., Mueller, Bryon A., Nauck, Matthias, Nordvik, Jan E., Noethen, Markus M., O'Leary, Daniel S., Opel, Nils, Martinot, Marie-Laure Paillere, Pike, G. Bruce, Preda, Adrian, Quinlan, Erin B., Rasser, Paul E., Ratnakar, Varun, Reppermund, Simone, Steen, Vidar M., Tooney, Paul A., Torres, Fabio R., Veltman, Dick J., Voyvodic, James T., Whelan, Robert, White, Tonya, Yamamori, Hidenaga, Adams, Hieab H. H., Bis, Joshua C., Debette, Stephanie, Decarli, Charles, Fornage, Myriam, Gudnason, Vilmundur, Hofer, Edith, Ikram, M. Arfan, Launer, Lenore, Longstreth, W. T., Lopez, Oscar L., Mazoyer, Bernard, Mosley, Thomas H., Roshchupkin, Gennady V., Satizabal, Claudia L., Schmidt, Reinhold, Seshadri, Sudha, Yang, Qiong, Alvim, Marina K. M., Ames, David, Anderson, Tim J., Andreassen, Ole A., Arias-Vasquez, Alejandro, Bastin, Mark E., Baune, Bernhard T., Beckham, Jean C., Blangero, John, Boomsma, Dorret I., Brodaty, Henry, Brunner, Han G., Buckner, Randy L., Buitelaar, Jan K., Bustillo, Juan R., Cahn, Wiepke, Cairns, Murray J., Calhoun, Vince, Carr, Vaughan J., Caseras, Xavier, Caspers, Svenja, Cavalleri, Gianpiero L., Cendes, Fernando, Corvin, Aiden, Crespo-Facorro, Benedicto, Dalrymple-Alford, John C., Dannlowski, Udo, de Geus, Eco J. C., Deary, Ian J., Delanty, Norman, Depondt, Chantal, Desrivieres, Sylvane, Donohoe, Gary, Espeseth, Thomas, Fernandez, Guillen, Fisher, Simon E., Flor, Herta, Forstner, Andreas J., Francks, Clyde, Franke, Barbara, Glahn, David C., Gollub, Randy L., Grabe, Hans J., Gruber, Oliver, Haberg, Asta K., Hariri, Ahmad R., Hartman, Catharina A., Hashimoto, Ryota, Heinz, Andreas, Henskens, Frans A., Hillegers, Manon H. J., Hoekstra, Pieter J., Holmes, Avram J., Hong, L. Elliot, Hopkins, William D., Pol, Hilleke E. Hulshoff, Jernigan, Terry L., Jonsson, Erik G., Kahn, Rene S., Kennedy, Martin A., Kircher, Tilo T. J., Kochunov, Peter, Kwok, John B. J., Le Hellard, Stephanie, Loughland, Carmel M., Martin, Nicholas G., Martinot, Jean-Luc, McDonald, Colm, McMahon, Katie L., Meyer-Lindenberg, Andreas, Michie, Patricia T., Morey, Rajendra A., Mowry, Bryan, Nyberg, Lars, Oosterlaan, Jaap, Ophoff, Roel A., Pantelis, Christos, Paus, Tomas, Pausova, Zdenka, Penninx, Brenda W. J. H., Polderman, Tinca J. C., Posthuma, Danielle, Rietschel, Marcella, Roffman, Joshua L., Rowland, Laura M., Sachdev, Perminder S., Samann, Philipp G., Schall, Ulrich, Schumann, Gunter, Scott, Rodney J., Sim, Kang, Sisodiya, Sanjay M., Smoller, Jordan W., Sommer, Iris E., St Pourcain, Beate, Stein, Dan J., Toga, Arthur W., Trollor, Julian N., Van der Wee, Nic J. A., van't Ent, Dennis, Volzke, Henry, Walter, Henrik, Weber, Bernd, Weinberger, Daniel R., Wright, Margaret J., Zhou, Juan, Stein, Jason L., Thompson, Paul M., Medland, Sarah E., Grasby, Katrina L., Jahanshad, Neda, Painter, Jodie N., Colodro-Conde, Lucia, Bralten, Janita, Hibar, Derrek P., Lind, Penelope A., Pizzagalli, Fabrizio, Ching, Christopher R. K., McMahon, Mary Agnes B., Shatokhina, Natalia, Zsembik, Leo C. P., Thomopoulos, Sophia I., Zhu, Alyssa H., Strike, Lachlan T., Agartz, Ingrid, Alhusaini, Saud, Almeida, Marcio A. A., Alnaes, Dag, Amlien, Inge K., Andersson, Micael, Ard, Tyler, Armstrong, Nicola J., Ashley-Koch, Allison, Atkins, Joshua R., Bernard, Manon, Brouwer, Rachel M., Buimer, Elizabeth E. L., Bulow, Robin, Burger, Christian, Cannon, Dara M., Chakravarty, Mallar, Chen, Qiang, Cheung, Joshua W., Couvy-Duchesne, Baptiste, Dale, Anders M., Dalvie, Shareefa, de Araujo, Tania K., de Zubicaray, Greig I., de Zwarte, Sonja M. C., den Braber, Anouk, Doan, Nhat Trung, Dohm, Katharina, Ehrlich, Stefan, Engelbrecht, Hannah-Ruth, Erk, Susanne, Fan, Chun Chieh, Fedko, Iryna O., Foley, Sonya F., Ford, Judith M., Fukunaga, Masaki, Garrett, Melanie E., Ge, Tian, Giddaluru, Sudheer, Goldman, Aaron L., Green, Melissa J., Groenewold, Nynke A., Grotegerd, Dominik, Gurholt, Tiril P., Gutman, Boris A., Hansell, Narelle K., Harris, Mathew A., Harrison, Marc B., Haswell, Courtney C., Hauser, Michael, Herms, Stefan, Heslenfeld, Dirk J., Ho, New Fei, Hoehn, David, Hoffmann, Per, Holleran, Laurena, Hoogman, Martine, Hottenga, Jouke-Jan, Ikeda, Masashi, Janowitz, Deborah, Jansen, Iris E., Jia, Tianye, Jockwitz, Christiane, Kanai, Ryota, Karama, Sherif, Kasperaviciute, Dalia, Kaufmann, Tobias, Kelly, Sinead, Kikuchi, Masataka, Klein, Marieke, Knapp, Michael, Knodt, Annchen R., Kramer, Bernd, Lam, Max, Lancaster, Thomas M., Lee, Phil H., Lett, Tristram A., Lewis, Lindsay B., Lopes-Cendes, Iscia, Luciano, Michelle, Macciardi, Fabio, Marquand, Andre F., Mathias, Samuel R., Melzer, Tracy R., Milaneschi, Yuri, Mirza-Schreiber, Nazanin, Moreira, Jose C. V., Muhleisen, Thomas W., Mueller-Myhsok, Bertram, Najt, Pablo, Nakahara, Soichiro, Nho, Kwangsik, Loohuis, Loes M. Olde, Orfanos, Dimitri Papadopoulos, Pearson, John F., Pitcher, Toni L., Putz, Benno, Quide, Yann, Ragothaman, Anjanibhargavi, Rashid, Faisal M., Reay, William R., Redlich, Ronny, Reinbold, Celine S., Repple, Jonathan, Richard, Genevieve, Riedel, Brandalyn C., Risacher, Shannon L., Rocha, Cristiane S., Mota, Nina R., Salminen, Lauren, Saremi, Arvin, Saykin, Andrew J., Schlag, Fenja, Schmaal, Lianne, Schofield, Peter R., Secolin, Rodrigo, Shapland, Chin Yang, Shen, Li, Shin, Jean, Shumskaya, Elena, Sonderby, Ida E., Sprooten, Emma, Tansey, Katherine E., Teumer, Alexander, Thalamuthu, Anbupalam, Tordesillas-Gutierrez, Diana, Turner, Jessica A., Uhlmann, Anne, Vallerga, Costanza L., van der Meer, Dennis, van Donkelaar, Marjolein M. J., van Eijk, Liza, van Erp, Theo G. M., van Haren, Neeltje E. M., van Rooij, Daan, van Tol, Marie-Jose, Veldink, Jan H., Verhoef, Ellen, Walton, Esther, Wang, Mingyuan, Wang, Yunpeng, Wardlaw, Joanna M., Wen, Wei, Westlye, Lars T., Whelan, Christopher D., Witt, Stephanie H., Wittfeld, Katharina, Wolf, Christiane, Wolfers, Thomas, Wu, Jing Qin, Yasuda, Clarissa L., Zaremba, Dario, Zhang, Zuo, Zwiers, Marcel P., Artiges, Eric, Assareh, Amelia A., Ayesa-Arriola, Rosa, Belger, Aysenil, Brandt, Christine L., Brown, Gregory G., Cichon, Sven, Curran, Joanne E., Davies, Gareth E., Degenhardt, Franziska, Dennis, Michelle F., Dietsche, Bruno, Djurovic, Srdjan, Doherty, Colin P., Espiritu, Ryan, Garijo, Daniel, Gil, Yolanda, Gowland, Penny A., Green, Robert C., Hausler, Alexander N., Heindel, Walter, Ho, Beng-Choon, Hoffmann, Wolfgang U., Holsboer, Florian, Homuth, Georg, Hosten, Norbert, Jack, Clifford R., Jr., Jang, MiHyun, Jansen, Andreas, Kimbrel, Nathan A., Kolskar, Knut, Koops, Sanne, Krug, Axel, Lim, Kelvin O., Luykx, Jurjen J., Mathalon, Daniel H., Mather, Karen A., Mattay, Venkata S., Matthews, Sarah, Van Son, Jaqueline Mayoral, McEwen, Sarah C., Melle, Ingrid, Morris, Derek W., Mueller, Bryon A., Nauck, Matthias, Nordvik, Jan E., Noethen, Markus M., O'Leary, Daniel S., Opel, Nils, Martinot, Marie-Laure Paillere, Pike, G. Bruce, Preda, Adrian, Quinlan, Erin B., Rasser, Paul E., Ratnakar, Varun, Reppermund, Simone, Steen, Vidar M., Tooney, Paul A., Torres, Fabio R., Veltman, Dick J., Voyvodic, James T., Whelan, Robert, White, Tonya, Yamamori, Hidenaga, Adams, Hieab H. H., Bis, Joshua C., Debette, Stephanie, Decarli, Charles, Fornage, Myriam, Gudnason, Vilmundur, Hofer, Edith, Ikram, M. Arfan, Launer, Lenore, Longstreth, W. T., Lopez, Oscar L., Mazoyer, Bernard, Mosley, Thomas H., Roshchupkin, Gennady V., Satizabal, Claudia L., Schmidt, Reinhold, Seshadri, Sudha, Yang, Qiong, Alvim, Marina K. M., Ames, David, Anderson, Tim J., Andreassen, Ole A., Arias-Vasquez, Alejandro, Bastin, Mark E., Baune, Bernhard T., Beckham, Jean C., Blangero, John, Boomsma, Dorret I., Brodaty, Henry, Brunner, Han G., Buckner, Randy L., Buitelaar, Jan K., Bustillo, Juan R., Cahn, Wiepke, Cairns, Murray J., Calhoun, Vince, Carr, Vaughan J., Caseras, Xavier, Caspers, Svenja, Cavalleri, Gianpiero L., Cendes, Fernando, Corvin, Aiden, Crespo-Facorro, Benedicto, Dalrymple-Alford, John C., Dannlowski, Udo, de Geus, Eco J. C., Deary, Ian J., Delanty, Norman, Depondt, Chantal, Desrivieres, Sylvane, Donohoe, Gary, Espeseth, Thomas, Fernandez, Guillen, Fisher, Simon E., Flor, Herta, Forstner, Andreas J., Francks, Clyde, Franke, Barbara, Glahn, David C., Gollub, Randy L., Grabe, Hans J., Gruber, Oliver, Haberg, Asta K., Hariri, Ahmad R., Hartman, Catharina A., Hashimoto, Ryota, Heinz, Andreas, Henskens, Frans A., Hillegers, Manon H. J., Hoekstra, Pieter J., Holmes, Avram J., Hong, L. Elliot, Hopkins, William D., Pol, Hilleke E. Hulshoff, Jernigan, Terry L., Jonsson, Erik G., Kahn, Rene S., Kennedy, Martin A., Kircher, Tilo T. J., Kochunov, Peter, Kwok, John B. J., Le Hellard, Stephanie, Loughland, Carmel M., Martin, Nicholas G., Martinot, Jean-Luc, McDonald, Colm, McMahon, Katie L., Meyer-Lindenberg, Andreas, Michie, Patricia T., Morey, Rajendra A., Mowry, Bryan, Nyberg, Lars, Oosterlaan, Jaap, Ophoff, Roel A., Pantelis, Christos, Paus, Tomas, Pausova, Zdenka, Penninx, Brenda W. J. H., Polderman, Tinca J. C., Posthuma, Danielle, Rietschel, Marcella, Roffman, Joshua L., Rowland, Laura M., Sachdev, Perminder S., Samann, Philipp G., Schall, Ulrich, Schumann, Gunter, Scott, Rodney J., Sim, Kang, Sisodiya, Sanjay M., Smoller, Jordan W., Sommer, Iris E., St Pourcain, Beate, Stein, Dan J., Toga, Arthur W., Trollor, Julian N., Van der Wee, Nic J. A., van't Ent, Dennis, Volzke, Henry, Walter, Henrik, Weber, Bernd, Weinberger, Daniel R., Wright, Margaret J., Zhou, Juan, Stein, Jason L., Thompson, Paul M., and Medland, Sarah E.
Abstract: The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
Published: 2020
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17. The genetic architecture of the human cerebral cortex

Author: Grasby, Katrina L., Jahanshad, Neda, Painter, Jodie N., Colodro-Conde, Lucía, Bralten, Janita, Hibar, Derrek P., Lind, Penelope A., Pizzagalli, Fabrizio, Ching, Christopher R.K., McMahon, Mary Agnes B., Shatokhina, Natalia, Zsembik, Leo C.P., Thomopoulos, Sophia I., Zhu, Alyssa H., Strike, Lachlan T., Agartz, Ingrid, Alhusaini, Saud, Almeida, Marcio A.A., Alnæs, Dag, Amlien, Inge K., Andersson, Micael, Ard, Tyler, Armstrong, Nicola J., Ashley-Koch, Allison, Atkins, Joshua R., Bernard, Manon, Brouwer, Rachel M., Buimer, Elizabeth E.L., Bülow, Robin, Bürger, Christian, Cannon, Dara M., Chakravarty, Mallar, Chen, Qiang, Cheung, Joshua W., Couvy-Duchesne, Baptiste, Dale, Anders M., Dalvie, Shareefa, de Araujo, Tânia K., de Zubicaray, Greig I., de Zwarte, Sonja M.C., den Braber, Anouk, Doan, Nhat Trung, Dohm, Katharina, Ehrlich, Stefan, Engelbrecht, Hannah Ruth, Erk, Susanne, Fan, Chun Chieh, Fedko, Iryna O., Foley, Sonya F., Ford, Judith M., Fukunaga, Masaki, Garrett, Melanie E., Ge, Tian, Giddaluru, Sudheer, Goldman, Aaron L., Green, Melissa J., Groenewold, Nynke A., Grotegerd, Dominik, Gurholt, Tiril P., Gutman, Boris A., Hansell, Narelle K., Harris, Mathew A., Harrison, Marc B., Haswell, Courtney C., Hauser, Michael, Herms, Stefan, Heslenfeld, Dirk J., Ho, New Fei, Hoehn, David, Hoffmann, Per, Holleran, Laurena, Hoogman, Martine, Hottenga, Jouke Jan, Ikeda, Masashi, Janowitz, Deborah, Jansen, Iris E., Jia, Tianye, Jockwitz, Christiane, Kanai, Ryota, Karama, Sherif, Kasperaviciute, Dalia, Kaufmann, Tobias, Kelly, Sinead, Kikuchi, Masataka, Klein, Marieke, Knapp, Michael, Knodt, Annchen R., Krämer, Bernd, Lam, Max, Lancaster, Thomas M., Lee, Phil H., Lett, Tristram A., Lewis, Lindsay B., Lopes-Cendes, Iscia, Luciano, Michelle, Macciardi, Fabio, Marquand, Andre F., Mathias, Samuel R., Melzer, Tracy R., Milaneschi, Yuri, Mirza-Schreiber, Nazanin, Moreira, Jose C.V., Mühleisen, Thomas W., Müller-Myhsok, Bertram, Najt, Pablo, Nakahara, Soichiro, Nho, Kwangsik, Olde Loohuis, Loes M., Orfanos, Dimitri Papadopoulos, Pearson, John F., Pitcher, Toni L., Pütz, Benno, Quidé, Yann, Ragothaman, Anjanibhargavi, Rashid, Faisal M., Reay, William R., Redlich, Ronny, Reinbold, Céline S., Repple, Jonathan, Richard, Geneviève, Riedel, Brandalyn C., Risacher, Shannon L., Rocha, Cristiane S., Mota, Nina R., Salminen, Lauren, Saremi, Arvin, Saykin, Andrew J., Schlag, Fenja, Schmaal, Lianne, Schofield, Peter R., Secolin, Rodrigo, Shapland, Chin Yang, Shen, Li, Shin, Jean, Shumskaya, Elena, Sønderby, Ida E., Sprooten, Emma, Tansey, Katherine E., Teumer, Alexander, Thalamuthu, Anbupalam, Tordesillas-Gutiérrez, Diana, Turner, Jessica A., Uhlmann, Anne, Vallerga, Costanza L., van der Meer, Dennis, van Donkelaar, Marjolein M.J., van Eijk, Liza, van Erp, Theo G.M., van Haren, Neeltje E.M., van Rooij, Daan, van Tol, Marie José, Veldink, Jan H., Verhoef, Ellen, Walton, Esther, Wang, Mingyuan, Wang, Yunpeng, Wardlaw, Joanna M., Wen, Wei, Westlye, Lars T., Whelan, Christopher D., Witt, Stephanie H., Wittfeld, Katharina, Wolf, Christiane, Wolfers, Thomas, Wu, Jing Qin, Yasuda, Clarissa L., Zaremba, Dario, Zhang, Zuo, Zwiers, Marcel P., Artiges, Eric, Assareh, Amelia A., Ayesa-Arriola, Rosa, Belger, Aysenil, Brandt, Christine L., Brown, Gregory G., Cichon, Sven, Curran, Joanne E., Davies, Gareth E., Degenhardt, Franziska, Dennis, Michelle F., Dietsche, Bruno, Djurovic, Srdjan, Doherty, Colin P., Espiritu, Ryan, Garijo, Daniel, Gil, Yolanda, Gowland, Penny A., Green, Robert C., Häusler, Alexander N., Heindel, Walter, Ho, Beng Choon, Hoffmann, Wolfgang U., Holsboer, Florian, Homuth, Georg, Hosten, Norbert, Jack, Clifford R., Jang, Mi Hyun, Jansen, Andreas, Kimbrel, Nathan A., Kolskår, Knut, Koops, Sanne, Krug, Axel, Lim, Kelvin O., Luykx, Jurjen J., Mathalon, Daniel H., Mather, Karen A., Mattay, Venkata S., Matthews, Sarah, van Son, Jaqueline Mayoral, McEwen, Sarah C., Melle, Ingrid, Morris, Derek W., Mueller, Bryon A., Nauck, Matthias, Nordvik, Jan E., Nöthen, Markus M., O'Leary, Daniel S., Opel, Nils, Martinot, Marie Laure Paillère, Bruce Pike, G., Preda, Adrian, Quinlan, Erin B., Rasser, Paul E., Ratnakar, Varun, Reppermund, Simone, Steen, Vidar M., Tooney, Paul A., Torres, Fábio R., Veltman, Dick J., Voyvodic, James T., Whelan, Robert, White, Tonya, Yamamori, Hidenaga, Adams, Hieab H.H., Bis, Joshua C., Debette, Stephanie, Decarli, Charles, Fornage, Myriam, Gudnason, Vilmundur, Hofer, Edith, Arfan Ikram, M., Launer, Lenore, Longstreth, W. T., Lopez, Oscar L., Fisher, Simon E., Martin, Nicholas G., McMahon, Katie L., Wright, Margaret J., Thompson, Paul M., Medland, Sarah E., Grasby, Katrina L., Jahanshad, Neda, Painter, Jodie N., Colodro-Conde, Lucía, Bralten, Janita, Hibar, Derrek P., Lind, Penelope A., Pizzagalli, Fabrizio, Ching, Christopher R.K., McMahon, Mary Agnes B., Shatokhina, Natalia, Zsembik, Leo C.P., Thomopoulos, Sophia I., Zhu, Alyssa H., Strike, Lachlan T., Agartz, Ingrid, Alhusaini, Saud, Almeida, Marcio A.A., Alnæs, Dag, Amlien, Inge K., Andersson, Micael, Ard, Tyler, Armstrong, Nicola J., Ashley-Koch, Allison, Atkins, Joshua R., Bernard, Manon, Brouwer, Rachel M., Buimer, Elizabeth E.L., Bülow, Robin, Bürger, Christian, Cannon, Dara M., Chakravarty, Mallar, Chen, Qiang, Cheung, Joshua W., Couvy-Duchesne, Baptiste, Dale, Anders M., Dalvie, Shareefa, de Araujo, Tânia K., de Zubicaray, Greig I., de Zwarte, Sonja M.C., den Braber, Anouk, Doan, Nhat Trung, Dohm, Katharina, Ehrlich, Stefan, Engelbrecht, Hannah Ruth, Erk, Susanne, Fan, Chun Chieh, Fedko, Iryna O., Foley, Sonya F., Ford, Judith M., Fukunaga, Masaki, Garrett, Melanie E., Ge, Tian, Giddaluru, Sudheer, Goldman, Aaron L., Green, Melissa J., Groenewold, Nynke A., Grotegerd, Dominik, Gurholt, Tiril P., Gutman, Boris A., Hansell, Narelle K., Harris, Mathew A., Harrison, Marc B., Haswell, Courtney C., Hauser, Michael, Herms, Stefan, Heslenfeld, Dirk J., Ho, New Fei, Hoehn, David, Hoffmann, Per, Holleran, Laurena, Hoogman, Martine, Hottenga, Jouke Jan, Ikeda, Masashi, Janowitz, Deborah, Jansen, Iris E., Jia, Tianye, Jockwitz, Christiane, Kanai, Ryota, Karama, Sherif, Kasperaviciute, Dalia, Kaufmann, Tobias, Kelly, Sinead, Kikuchi, Masataka, Klein, Marieke, Knapp, Michael, Knodt, Annchen R., Krämer, Bernd, Lam, Max, Lancaster, Thomas M., Lee, Phil H., Lett, Tristram A., Lewis, Lindsay B., Lopes-Cendes, Iscia, Luciano, Michelle, Macciardi, Fabio, Marquand, Andre F., Mathias, Samuel R., Melzer, Tracy R., Milaneschi, Yuri, Mirza-Schreiber, Nazanin, Moreira, Jose C.V., Mühleisen, Thomas W., Müller-Myhsok, Bertram, Najt, Pablo, Nakahara, Soichiro, Nho, Kwangsik, Olde Loohuis, Loes M., Orfanos, Dimitri Papadopoulos, Pearson, John F., Pitcher, Toni L., Pütz, Benno, Quidé, Yann, Ragothaman, Anjanibhargavi, Rashid, Faisal M., Reay, William R., Redlich, Ronny, Reinbold, Céline S., Repple, Jonathan, Richard, Geneviève, Riedel, Brandalyn C., Risacher, Shannon L., Rocha, Cristiane S., Mota, Nina R., Salminen, Lauren, Saremi, Arvin, Saykin, Andrew J., Schlag, Fenja, Schmaal, Lianne, Schofield, Peter R., Secolin, Rodrigo, Shapland, Chin Yang, Shen, Li, Shin, Jean, Shumskaya, Elena, Sønderby, Ida E., Sprooten, Emma, Tansey, Katherine E., Teumer, Alexander, Thalamuthu, Anbupalam, Tordesillas-Gutiérrez, Diana, Turner, Jessica A., Uhlmann, Anne, Vallerga, Costanza L., van der Meer, Dennis, van Donkelaar, Marjolein M.J., van Eijk, Liza, van Erp, Theo G.M., van Haren, Neeltje E.M., van Rooij, Daan, van Tol, Marie José, Veldink, Jan H., Verhoef, Ellen, Walton, Esther, Wang, Mingyuan, Wang, Yunpeng, Wardlaw, Joanna M., Wen, Wei, Westlye, Lars T., Whelan, Christopher D., Witt, Stephanie H., Wittfeld, Katharina, Wolf, Christiane, Wolfers, Thomas, Wu, Jing Qin, Yasuda, Clarissa L., Zaremba, Dario, Zhang, Zuo, Zwiers, Marcel P., Artiges, Eric, Assareh, Amelia A., Ayesa-Arriola, Rosa, Belger, Aysenil, Brandt, Christine L., Brown, Gregory G., Cichon, Sven, Curran, Joanne E., Davies, Gareth E., Degenhardt, Franziska, Dennis, Michelle F., Dietsche, Bruno, Djurovic, Srdjan, Doherty, Colin P., Espiritu, Ryan, Garijo, Daniel, Gil, Yolanda, Gowland, Penny A., Green, Robert C., Häusler, Alexander N., Heindel, Walter, Ho, Beng Choon, Hoffmann, Wolfgang U., Holsboer, Florian, Homuth, Georg, Hosten, Norbert, Jack, Clifford R., Jang, Mi Hyun, Jansen, Andreas, Kimbrel, Nathan A., Kolskår, Knut, Koops, Sanne, Krug, Axel, Lim, Kelvin O., Luykx, Jurjen J., Mathalon, Daniel H., Mather, Karen A., Mattay, Venkata S., Matthews, Sarah, van Son, Jaqueline Mayoral, McEwen, Sarah C., Melle, Ingrid, Morris, Derek W., Mueller, Bryon A., Nauck, Matthias, Nordvik, Jan E., Nöthen, Markus M., O'Leary, Daniel S., Opel, Nils, Martinot, Marie Laure Paillère, Bruce Pike, G., Preda, Adrian, Quinlan, Erin B., Rasser, Paul E., Ratnakar, Varun, Reppermund, Simone, Steen, Vidar M., Tooney, Paul A., Torres, Fábio R., Veltman, Dick J., Voyvodic, James T., Whelan, Robert, White, Tonya, Yamamori, Hidenaga, Adams, Hieab H.H., Bis, Joshua C., Debette, Stephanie, Decarli, Charles, Fornage, Myriam, Gudnason, Vilmundur, Hofer, Edith, Arfan Ikram, M., Launer, Lenore, Longstreth, W. T., Lopez, Oscar L., Fisher, Simon E., Martin, Nicholas G., McMahon, Katie L., Wright, Margaret J., Thompson, Paul M., and Medland, Sarah E.
Abstract: The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
Published: 2020

18. White matter abnormalities across different epilepsy syndromes in adults: an ENIGMA-Epilepsy study.

Author: Hatton, Sean N, Hatton, Sean N, Huynh, Khoa H, Bonilha, Leonardo, Abela, Eugenio, Alhusaini, Saud, Altmann, Andre, Alvim, Marina KM, Balachandra, Akshara R, Bartolini, Emanuele, Bender, Benjamin, Bernasconi, Neda, Bernasconi, Andrea, Bernhardt, Boris, Bargallo, Núria, Caldairou, Benoit, Caligiuri, Maria E, Carr, Sarah JA, Cavalleri, Gianpiero L, Cendes, Fernando, Concha, Luis, Davoodi-Bojd, Esmaeil, Desmond, Patricia M, Devinsky, Orrin, Doherty, Colin P, Domin, Martin, Duncan, John S, Focke, Niels K, Foley, Sonya F, Gambardella, Antonio, Gleichgerrcht, Ezequiel, Guerrini, Renzo, Hamandi, Khalid, Ishikawa, Akari, Keller, Simon S, Kochunov, Peter V, Kotikalapudi, Raviteja, Kreilkamp, Barbara AK, Kwan, Patrick, Labate, Angelo, Langner, Soenke, Lenge, Matteo, Liu, Min, Lui, Elaine, Martin, Pascal, Mascalchi, Mario, Moreira, José CV, Morita-Sherman, Marcia E, O'Brien, Terence J, Pardoe, Heath R, Pariente, José C, Ribeiro, Letícia F, Richardson, Mark P, Rocha, Cristiane S, Rodríguez-Cruces, Raúl, Rosenow, Felix, Severino, Mariasavina, Sinclair, Benjamin, Soltanian-Zadeh, Hamid, Striano, Pasquale, Taylor, Peter N, Thomas, Rhys H, Tortora, Domenico, Velakoulis, Dennis, Vezzani, Annamaria, Vivash, Lucy, von Podewils, Felix, Vos, Sjoerd B, Weber, Bernd, Winston, Gavin P, Yasuda, Clarissa L, Zhu, Alyssa H, Thompson, Paul M, Whelan, Christopher D, Jahanshad, Neda, Sisodiya, Sanjay M, McDonald, Carrie R, Hatton, Sean N, Hatton, Sean N, Huynh, Khoa H, Bonilha, Leonardo, Abela, Eugenio, Alhusaini, Saud, Altmann, Andre, Alvim, Marina KM, Balachandra, Akshara R, Bartolini, Emanuele, Bender, Benjamin, Bernasconi, Neda, Bernasconi, Andrea, Bernhardt, Boris, Bargallo, Núria, Caldairou, Benoit, Caligiuri, Maria E, Carr, Sarah JA, Cavalleri, Gianpiero L, Cendes, Fernando, Concha, Luis, Davoodi-Bojd, Esmaeil, Desmond, Patricia M, Devinsky, Orrin, Doherty, Colin P, Domin, Martin, Duncan, John S, Focke, Niels K, Foley, Sonya F, Gambardella, Antonio, Gleichgerrcht, Ezequiel, Guerrini, Renzo, Hamandi, Khalid, Ishikawa, Akari, Keller, Simon S, Kochunov, Peter V, Kotikalapudi, Raviteja, Kreilkamp, Barbara AK, Kwan, Patrick, Labate, Angelo, Langner, Soenke, Lenge, Matteo, Liu, Min, Lui, Elaine, Martin, Pascal, Mascalchi, Mario, Moreira, José CV, Morita-Sherman, Marcia E, O'Brien, Terence J, Pardoe, Heath R, Pariente, José C, Ribeiro, Letícia F, Richardson, Mark P, Rocha, Cristiane S, Rodríguez-Cruces, Raúl, Rosenow, Felix, Severino, Mariasavina, Sinclair, Benjamin, Soltanian-Zadeh, Hamid, Striano, Pasquale, Taylor, Peter N, Thomas, Rhys H, Tortora, Domenico, Velakoulis, Dennis, Vezzani, Annamaria, Vivash, Lucy, von Podewils, Felix, Vos, Sjoerd B, Weber, Bernd, Winston, Gavin P, Yasuda, Clarissa L, Zhu, Alyssa H, Thompson, Paul M, Whelan, Christopher D, Jahanshad, Neda, Sisodiya, Sanjay M, and McDonald, Carrie R
Abstract: The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analysed from 1069 healthy controls and 1249 patients: temporal lobe epilepsy with hippocampal sclerosis (n = 599), temporal lobe epilepsy with normal MRI (n = 275), genetic generalized epilepsy (n = 182) and non-lesional extratemporal epilepsy (n = 193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fibre tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at P < 0.001). Across 'all epilepsies' lower fractional anisotropy was observed in most fibre tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. There were also less robust increases in mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippocampal sclerosis in the ipsilateral parahippocampal cingulum and external capsule, with smaller effects across most other tracts. Individuals with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in
Published: 2020

19. Network-based atrophy modeling in the common epilepsies: A worldwide ENIGMA study.

Author: Larivière, Sara, Larivière, Sara, Rodríguez-Cruces, Raúl, Royer, Jessica, Caligiuri, Maria Eugenia, Gambardella, Antonio, Concha, Luis, Keller, Simon S, Cendes, Fernando, Yasuda, Clarissa, Bonilha, Leonardo, Gleichgerrcht, Ezequiel, Focke, Niels K, Domin, Martin, von Podewills, Felix, Langner, Soenke, Rummel, Christian, Wiest, Roland, Martin, Pascal, Kotikalapudi, Raviteja, O'Brien, Terence J, Sinclair, Benjamin, Vivash, Lucy, Desmond, Patricia M, Alhusaini, Saud, Doherty, Colin P, Cavalleri, Gianpiero L, Delanty, Norman, Kälviäinen, Reetta, Jackson, Graeme D, Kowalczyk, Magdalena, Mascalchi, Mario, Semmelroch, Mira, Thomas, Rhys H, Soltanian-Zadeh, Hamid, Davoodi-Bojd, Esmaeil, Zhang, Junsong, Lenge, Matteo, Guerrini, Renzo, Bartolini, Emanuele, Hamandi, Khalid, Foley, Sonya, Weber, Bernd, Depondt, Chantal, Absil, Julie, Carr, Sarah JA, Abela, Eugenio, Richardson, Mark P, Devinsky, Orrin, Severino, Mariasavina, Striano, Pasquale, Tortora, Domenico, Hatton, Sean N, Vos, Sjoerd B, Duncan, John S, Whelan, Christopher D, Thompson, Paul M, Sisodiya, Sanjay M, Bernasconi, Andrea, Labate, Angelo, McDonald, Carrie R, Bernasconi, Neda, Bernhardt, Boris C, Larivière, Sara, Larivière, Sara, Rodríguez-Cruces, Raúl, Royer, Jessica, Caligiuri, Maria Eugenia, Gambardella, Antonio, Concha, Luis, Keller, Simon S, Cendes, Fernando, Yasuda, Clarissa, Bonilha, Leonardo, Gleichgerrcht, Ezequiel, Focke, Niels K, Domin, Martin, von Podewills, Felix, Langner, Soenke, Rummel, Christian, Wiest, Roland, Martin, Pascal, Kotikalapudi, Raviteja, O'Brien, Terence J, Sinclair, Benjamin, Vivash, Lucy, Desmond, Patricia M, Alhusaini, Saud, Doherty, Colin P, Cavalleri, Gianpiero L, Delanty, Norman, Kälviäinen, Reetta, Jackson, Graeme D, Kowalczyk, Magdalena, Mascalchi, Mario, Semmelroch, Mira, Thomas, Rhys H, Soltanian-Zadeh, Hamid, Davoodi-Bojd, Esmaeil, Zhang, Junsong, Lenge, Matteo, Guerrini, Renzo, Bartolini, Emanuele, Hamandi, Khalid, Foley, Sonya, Weber, Bernd, Depondt, Chantal, Absil, Julie, Carr, Sarah JA, Abela, Eugenio, Richardson, Mark P, Devinsky, Orrin, Severino, Mariasavina, Striano, Pasquale, Tortora, Domenico, Hatton, Sean N, Vos, Sjoerd B, Duncan, John S, Whelan, Christopher D, Thompson, Paul M, Sisodiya, Sanjay M, Bernasconi, Andrea, Labate, Angelo, McDonald, Carrie R, Bernasconi, Neda, and Bernhardt, Boris C
Abstract: Epilepsy is increasingly conceptualized as a network disorder. In this cross-sectional mega-analysis, we integrated neuroimaging and connectome analysis to identify network associations with atrophy patterns in 1021 adults with epilepsy compared to 1564 healthy controls from 19 international sites. In temporal lobe epilepsy, areas of atrophy colocalized with highly interconnected cortical hub regions, whereas idiopathic generalized epilepsy showed preferential subcortical hub involvement. These morphological abnormalities were anchored to the connectivity profiles of distinct disease epicenters, pointing to temporo-limbic cortices in temporal lobe epilepsy and fronto-central cortices in idiopathic generalized epilepsy. Negative effects of age on atrophy further revealed a strong influence of connectome architecture in temporal lobe, but not idiopathic generalized, epilepsy. Our findings were reproduced across individual sites and single patients and were robust across different analytical methods. Through worldwide collaboration in ENIGMA-Epilepsy, we provided deeper insights into the macroscale features that shape the pathophysiology of common epilepsies.
Published: 2020

20. Are patients ready for integrated person-centered care? A qualitative study of people with epilepsy in Ireland

Author: Power, Robert, Byrne, John-Paul, Kiersey, Rache, Varley, Jarlath, Doherty, Colin P., Lambert, Veronica, Heffernan, Emma, Saris, A. Jamie, Fitzsimons, Mary, Power, Robert, Byrne, John-Paul, Kiersey, Rache, Varley, Jarlath, Doherty, Colin P., Lambert, Veronica, Heffernan, Emma, Saris, A. Jamie, and Fitzsimons, Mary
Abstract: The National Clinical Programme for Epilepsy (NCPE) in Ireland aims to deliver a holistic model of integrated person-centered care (PCC) that addresses the full spectrum of biomedical and psychosocial needs of people with epilepsy (PwE). However, like all strategic plans, the model encompasses an inherent set of assumptions about the readiness of the environment to implement and sustain the actions required to realize its goals. In this study, through the lens of PwE, the Irish epilepsy care setting was explored to understand its capacity to adopt a new paradigm of integrated PCC. Focus groups and semi-structured one-to-one interviews were employed to capture the qualitative experiences of a sample of Irish PwE (n = 27) in the context of the care that they receive. Participants were from different regions of the country and were aged between 18 and 55 years with 1 to 42 years since diagnosis (YSD). Highlighting a gap between policy intent and action on the ground, findings suggest that patient readiness to adopt a new model of care cannot be assumed. Expectations, preferences, behaviors, and values of PwE may sustain the more traditional constructions of healthcare delivery rather than the integrated PCC goals of reform. These culturally constituted perceptions illustrate that PwE do not instinctively appreciate the goals of healthcare reform nor the different behavior expected from them within a reformed healthcare system. Recalibrating deep-rooted patient views is necessary to accomplish the aspirations of integrated PCC. Patient engagement emphasizing the meaningful role that they can play in shaping their healthcare services is vital.
Published: 2020

21. Are patients ready for integrated person-centered care? A qualitative study of people with epilepsy in Ireland

Author: Power, Robert, Byrne, John-Paul, Kiersey, Rache, Varley, Jarlath, Doherty, Colin P., Lambert, Veronica, Heffernan, Emma, Saris, A. Jamie, Fitzsimons, Mary, Power, Robert, Byrne, John-Paul, Kiersey, Rache, Varley, Jarlath, Doherty, Colin P., Lambert, Veronica, Heffernan, Emma, Saris, A. Jamie, and Fitzsimons, Mary
Abstract: The National Clinical Programme for Epilepsy (NCPE) in Ireland aims to deliver a holistic model of integrated person-centered care (PCC) that addresses the full spectrum of biomedical and psychosocial needs of people with epilepsy (PwE). However, like all strategic plans, the model encompasses an inherent set of assumptions about the readiness of the environment to implement and sustain the actions required to realize its goals. In this study, through the lens of PwE, the Irish epilepsy care setting was explored to understand its capacity to adopt a new paradigm of integrated PCC. Focus groups and semi-structured one-to-one interviews were employed to capture the qualitative experiences of a sample of Irish PwE (n = 27) in the context of the care that they receive. Participants were from different regions of the country and were aged between 18 and 55 years with 1 to 42 years since diagnosis (YSD). Highlighting a gap between policy intent and action on the ground, findings suggest that patient readiness to adopt a new model of care cannot be assumed. Expectations, preferences, behaviors, and values of PwE may sustain the more traditional constructions of healthcare delivery rather than the integrated PCC goals of reform. These culturally constituted perceptions illustrate that PwE do not instinctively appreciate the goals of healthcare reform nor the different behavior expected from them within a reformed healthcare system. Recalibrating deep-rooted patient views is necessary to accomplish the aspirations of integrated PCC. Patient engagement emphasizing the meaningful role that they can play in shaping their healthcare services is vital.
Published: 2020

22. Network-based atrophy modeling in the common epilepsies: A worldwide ENIGMA study.

Author: Larivière, Sara, Rodríguez-Cruces, Raul, Royer, Jessica, Caligiuri, Maria Eugenia, Gambardella, Antonio, Concha, Luis, Keller, Simone, Cendes, Fernando, Yasuda, Clarissa, Bonilha, Leonardo, Gleichgerrcht, Ezequiel, Focke, Niels K., Domin, Martin, von Podewills, Felix, Langner, Soenke, Rummel, Christian, Wiest, Roland, Martin, Pascale, Kotikalapudi, Raviteja, O'Brien, Terence, Sinclair, Benjamin, Vivash, Lucy, Desmond, Patricia M., Alhusaini, Saud, Doherty, Colin P, Cavalleri, Gianpiero L, Delanty, Norman, Kalviainen, Reetta, Jackson, Graeme D, Kowalczyk, Magdalena, Mascalchi, Mario, Semmelroch, Mira, Thomas, Rhys H, Soltanian-Zadeh, Hamid, Davoodi-Bojd, Esmaeil, Zhang, Junsong, Lenge, Matteo, Guerrini, Renzo, Bartolini, Emanuele, Hamandi, Khalid, Foley, Sonya, Weber, Bernd, Depondt, Chantal, Absil, Julie, Carr, Sarah J A, Abela, Eugenio, Richardson, Mark P, Devinsky, Orrin In, Severino, Mariasavina, Striano, Pasquale, Tortora, Domenico, Hatton, Sean N., Vos, Sjoerd B, Duncan, John S, Whelan, Christopher D, Thompson, Paul M, Sisodiya, Sanjay M, Bernasconi, Andrea, Labate, Angelo, McDonald, Carrie R, Bernasconi, Neda, Bernhardt, Boris C, Larivière, Sara, Rodríguez-Cruces, Raul, Royer, Jessica, Caligiuri, Maria Eugenia, Gambardella, Antonio, Concha, Luis, Keller, Simone, Cendes, Fernando, Yasuda, Clarissa, Bonilha, Leonardo, Gleichgerrcht, Ezequiel, Focke, Niels K., Domin, Martin, von Podewills, Felix, Langner, Soenke, Rummel, Christian, Wiest, Roland, Martin, Pascale, Kotikalapudi, Raviteja, O'Brien, Terence, Sinclair, Benjamin, Vivash, Lucy, Desmond, Patricia M., Alhusaini, Saud, Doherty, Colin P, Cavalleri, Gianpiero L, Delanty, Norman, Kalviainen, Reetta, Jackson, Graeme D, Kowalczyk, Magdalena, Mascalchi, Mario, Semmelroch, Mira, Thomas, Rhys H, Soltanian-Zadeh, Hamid, Davoodi-Bojd, Esmaeil, Zhang, Junsong, Lenge, Matteo, Guerrini, Renzo, Bartolini, Emanuele, Hamandi, Khalid, Foley, Sonya, Weber, Bernd, Depondt, Chantal, Absil, Julie, Carr, Sarah J A, Abela, Eugenio, Richardson, Mark P, Devinsky, Orrin In, Severino, Mariasavina, Striano, Pasquale, Tortora, Domenico, Hatton, Sean N., Vos, Sjoerd B, Duncan, John S, Whelan, Christopher D, Thompson, Paul M, Sisodiya, Sanjay M, Bernasconi, Andrea, Labate, Angelo, McDonald, Carrie R, Bernasconi, Neda, and Bernhardt, Boris C
Abstract: Epilepsy is increasingly conceptualized as a network disorder. In this cross-sectional mega-analysis, we integrated neuroimaging and connectome analysis to identify network associations with atrophy patterns in 1021 adults with epilepsy compared to 1564 healthy controls from 19 international sites. In temporal lobe epilepsy, areas of atrophy colocalized with highly interconnected cortical hub regions, whereas idiopathic generalized epilepsy showed preferential subcortical hub involvement. These morphological abnormalities were anchored to the connectivity profiles of distinct disease epicenters, pointing to temporo-limbic cortices in temporal lobe epilepsy and fronto-central cortices in idiopathic generalized epilepsy. Negative effects of age on atrophy further revealed a strong influence of connectome architecture in temporal lobe, but not idiopathic generalized, epilepsy. Our findings were reproduced across individual sites and single patients and were robust across different analytical methods. Through worldwide collaboration in ENIGMA-Epilepsy, we provided deeper insights into the macroscale features that shape the pathophysiology of common epilepsies., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2020

23. Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea, Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Heinzen, Erin L., Dhindsa, Ryan S., Stanley, Kate E., Cavalleri, Gianpiero L., Hakonarson, Hakon, Helbig, Ingo, Krause, Roland, May, Patrick, Weckhuysen, Sarah, Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, Dixon-Salazar, Tracy, Guerrini, Renzo, Kwan, Patrick, Marson, Anthony G., Stewart, Randy, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, McKenna, Kevin, Regan, Brigid M., Bellows, Susannah T., Leu, Costin, Bennett, Caitlin A., Johns, Esther M. C., Macdonald, Alexandra, Shilling, Hannah, Burgess, Rosemary, Weckhuysen, Dorien, Bahlo, Melanie, O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Sadoway, Tara R., Mo, Kelly, Krestel, Heinz, Gallati, Sabina, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Kunz, Wolfram S., Zsurka, Gábor, Elger, Christian E., Bauer, Jürgen, Rademacher, Michael, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, Baalen, Andreas Van, Spiczak, Sarah Von, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Hengsbach, Christian, Rau, Sarah, Maisch, Ana F., Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Schubert-Bast, Susanne, Schreiber, Herbert, Borggräfe, Ingo, Schankin, Christoph J., Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Auvinen, Pia, Saarela, Anni, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Barišić, Nina, Delanty, Norman, Doherty, Colin P., Shukralla, Arif, McCormack, Mark, El-Naggar, Hany, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Zara, Federico, Iacomino, Michele, Madia, Francesca, Vari, Maria Stella, Mancardi, Maria Margherita, Salpietro, Vincenzo, Bisulli, Francesca, Tinuper, Paolo, Licchetta, Laura, Pippucci, Tommaso, Stipa, Carlotta, Minardi, Raffaella, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Marini, Carla, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Tumiene, Birute, Sadleir, Lynette G., King, Chontelle, Mountier, Emily, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Yis, Uluc, Topaloglu, Pınar, Kara, Bulent, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Uğur-İşeri, Sibel, Baykan, Betül, Salman, Barış, Haryanyan, Garen, Yücesan, Emrah, Kesim, Yeşim, Özkara, Çiğdem, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Khankhanian, Pouya, Helbig, Katherine L., Ellis, Colin A., Spalletta, Gianfranco, Piras, Fabrizio, Piras, Federica, Gili, Tommaso, Ciullo, Valentina, Reif, Andreas, McQuillin, Andrew, Bass, Nick, McIntosh, Andrew, Blackwood, Douglas, Johnstone, Mandy, Palotie, Aarno, Pato, Michele T., Pato, Carlos N., Bromet, Evelyn J., Carvalho, Celia Barreto, Achtyes, Eric D., Azevedo, Maria Helena, Kotov, Roman, Lehrer, Douglas S., Malaspina, Dolores, Marder, Stephen R., Medeiros, Helena, Morley, Christopher P., Perkins, Diana O., Sobell, Janet L., Buckley, Peter F., Macciardi, Fabio, Rapaport, Mark H., Knowles, James A., Fanous, Ayman H., McCarroll, Steven A., Gupta, Namrata, Gabriel, Stacey B., Daly, Mark J., Lander, Eric S., Lowenstein, Daniel H., Goldstein, David B., Lerche, Holger, Berkovic, Samuel F., Neale, Benjamin M., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea, Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Heinzen, Erin L., Dhindsa, Ryan S., Stanley, Kate E., Cavalleri, Gianpiero L., Hakonarson, Hakon, Helbig, Ingo, Krause, Roland, May, Patrick, Weckhuysen, Sarah, Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, Dixon-Salazar, Tracy, Guerrini, Renzo, Kwan, Patrick, Marson, Anthony G., Stewart, Randy, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, McKenna, Kevin, Regan, Brigid M., Bellows, Susannah T., Leu, Costin, Bennett, Caitlin A., Johns, Esther M. C., Macdonald, Alexandra, Shilling, Hannah, Burgess, Rosemary, Weckhuysen, Dorien, Bahlo, Melanie, O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Sadoway, Tara R., Mo, Kelly, Krestel, Heinz, Gallati, Sabina, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Kunz, Wolfram S., Zsurka, Gábor, Elger, Christian E., Bauer, Jürgen, Rademacher, Michael, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, Baalen, Andreas Van, Spiczak, Sarah Von, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Hengsbach, Christian, Rau, Sarah, Maisch, Ana F., Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Schubert-Bast, Susanne, Schreiber, Herbert, Borggräfe, Ingo, Schankin, Christoph J., Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Auvinen, Pia, Saarela, Anni, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Barišić, Nina, Delanty, Norman, Doherty, Colin P., Shukralla, Arif, McCormack, Mark, El-Naggar, Hany, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Zara, Federico, Iacomino, Michele, Madia, Francesca, Vari, Maria Stella, Mancardi, Maria Margherita, Salpietro, Vincenzo, Bisulli, Francesca, Tinuper, Paolo, Licchetta, Laura, Pippucci, Tommaso, Stipa, Carlotta, Minardi, Raffaella, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Marini, Carla, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Tumiene, Birute, Sadleir, Lynette G., King, Chontelle, Mountier, Emily, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Yis, Uluc, Topaloglu, Pınar, Kara, Bulent, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Uğur-İşeri, Sibel, Baykan, Betül, Salman, Barış, Haryanyan, Garen, Yücesan, Emrah, Kesim, Yeşim, Özkara, Çiğdem, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Khankhanian, Pouya, Helbig, Katherine L., Ellis, Colin A., Spalletta, Gianfranco, Piras, Fabrizio, Piras, Federica, Gili, Tommaso, Ciullo, Valentina, Reif, Andreas, McQuillin, Andrew, Bass, Nick, McIntosh, Andrew, Blackwood, Douglas, Johnstone, Mandy, Palotie, Aarno, Pato, Michele T., Pato, Carlos N., Bromet, Evelyn J., Carvalho, Celia Barreto, Achtyes, Eric D., Azevedo, Maria Helena, Kotov, Roman, Lehrer, Douglas S., Malaspina, Dolores, Marder, Stephen R., Medeiros, Helena, Morley, Christopher P., Perkins, Diana O., Sobell, Janet L., Buckley, Peter F., Macciardi, Fabio, Rapaport, Mark H., Knowles, James A., Fanous, Ayman H., McCarroll, Steven A., Gupta, Namrata, Gabriel, Stacey B., Daly, Mark J., Lander, Eric S., Lowenstein, Daniel H., Goldstein, David B., Lerche, Holger, Berkovic, Samuel F., and Neale, Benjamin M.
Abstract: Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.
Published: 2019

24. Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea, Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Heinzen, Erin L., Dhindsa, Ryan S., Stanley, Kate E., Cavalleri, Gianpiero L., Hakonarson, Hakon, Helbig, Ingo, Krause, Roland, May, Patrick, Weckhuysen, Sarah, Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, Dixon-Salazar, Tracy, Guerrini, Renzo, Kwan, Patrick, Marson, Anthony G., Stewart, Randy, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, McKenna, Kevin, Regan, Brigid M., Bellows, Susannah T., Leu, Costin, Bennett, Caitlin A., Johns, Esther M. C., Macdonald, Alexandra, Shilling, Hannah, Burgess, Rosemary, Weckhuysen, Dorien, Bahlo, Melanie, O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Sadoway, Tara R., Mo, Kelly, Krestel, Heinz, Gallati, Sabina, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Kunz, Wolfram S., Zsurka, Gábor, Elger, Christian E., Bauer, Jürgen, Rademacher, Michael, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, Baalen, Andreas Van, Spiczak, Sarah Von, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Hengsbach, Christian, Rau, Sarah, Maisch, Ana F., Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Schubert-Bast, Susanne, Schreiber, Herbert, Borggräfe, Ingo, Schankin, Christoph J., Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Auvinen, Pia, Saarela, Anni, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Barišić, Nina, Delanty, Norman, Doherty, Colin P., Shukralla, Arif, McCormack, Mark, El-Naggar, Hany, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Zara, Federico, Iacomino, Michele, Madia, Francesca, Vari, Maria Stella, Mancardi, Maria Margherita, Salpietro, Vincenzo, Bisulli, Francesca, Tinuper, Paolo, Licchetta, Laura, Pippucci, Tommaso, Stipa, Carlotta, Minardi, Raffaella, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Marini, Carla, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Tumiene, Birute, Sadleir, Lynette G., King, Chontelle, Mountier, Emily, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Yis, Uluc, Topaloglu, Pınar, Kara, Bulent, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Uğur-İşeri, Sibel, Baykan, Betül, Salman, Barış, Haryanyan, Garen, Yücesan, Emrah, Kesim, Yeşim, Özkara, Çiğdem, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Khankhanian, Pouya, Helbig, Katherine L., Ellis, Colin A., Spalletta, Gianfranco, Piras, Fabrizio, Piras, Federica, Gili, Tommaso, Ciullo, Valentina, Reif, Andreas, McQuillin, Andrew, Bass, Nick, McIntosh, Andrew, Blackwood, Douglas, Johnstone, Mandy, Palotie, Aarno, Pato, Michele T., Pato, Carlos N., Bromet, Evelyn J., Carvalho, Celia Barreto, Achtyes, Eric D., Azevedo, Maria Helena, Kotov, Roman, Lehrer, Douglas S., Malaspina, Dolores, Marder, Stephen R., Medeiros, Helena, Morley, Christopher P., Perkins, Diana O., Sobell, Janet L., Buckley, Peter F., Macciardi, Fabio, Rapaport, Mark H., Knowles, James A., Fanous, Ayman H., McCarroll, Steven A., Gupta, Namrata, Gabriel, Stacey B., Daly, Mark J., Lander, Eric S., Lowenstein, Daniel H., Goldstein, David B., Lerche, Holger, Berkovic, Samuel F., Neale, Benjamin M., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea, Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Heinzen, Erin L., Dhindsa, Ryan S., Stanley, Kate E., Cavalleri, Gianpiero L., Hakonarson, Hakon, Helbig, Ingo, Krause, Roland, May, Patrick, Weckhuysen, Sarah, Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, Dixon-Salazar, Tracy, Guerrini, Renzo, Kwan, Patrick, Marson, Anthony G., Stewart, Randy, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, McKenna, Kevin, Regan, Brigid M., Bellows, Susannah T., Leu, Costin, Bennett, Caitlin A., Johns, Esther M. C., Macdonald, Alexandra, Shilling, Hannah, Burgess, Rosemary, Weckhuysen, Dorien, Bahlo, Melanie, O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Sadoway, Tara R., Mo, Kelly, Krestel, Heinz, Gallati, Sabina, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Kunz, Wolfram S., Zsurka, Gábor, Elger, Christian E., Bauer, Jürgen, Rademacher, Michael, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, Baalen, Andreas Van, Spiczak, Sarah Von, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Hengsbach, Christian, Rau, Sarah, Maisch, Ana F., Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Schubert-Bast, Susanne, Schreiber, Herbert, Borggräfe, Ingo, Schankin, Christoph J., Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Auvinen, Pia, Saarela, Anni, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Barišić, Nina, Delanty, Norman, Doherty, Colin P., Shukralla, Arif, McCormack, Mark, El-Naggar, Hany, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Zara, Federico, Iacomino, Michele, Madia, Francesca, Vari, Maria Stella, Mancardi, Maria Margherita, Salpietro, Vincenzo, Bisulli, Francesca, Tinuper, Paolo, Licchetta, Laura, Pippucci, Tommaso, Stipa, Carlotta, Minardi, Raffaella, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Marini, Carla, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Tumiene, Birute, Sadleir, Lynette G., King, Chontelle, Mountier, Emily, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Yis, Uluc, Topaloglu, Pınar, Kara, Bulent, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Uğur-İşeri, Sibel, Baykan, Betül, Salman, Barış, Haryanyan, Garen, Yücesan, Emrah, Kesim, Yeşim, Özkara, Çiğdem, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Khankhanian, Pouya, Helbig, Katherine L., Ellis, Colin A., Spalletta, Gianfranco, Piras, Fabrizio, Piras, Federica, Gili, Tommaso, Ciullo, Valentina, Reif, Andreas, McQuillin, Andrew, Bass, Nick, McIntosh, Andrew, Blackwood, Douglas, Johnstone, Mandy, Palotie, Aarno, Pato, Michele T., Pato, Carlos N., Bromet, Evelyn J., Carvalho, Celia Barreto, Achtyes, Eric D., Azevedo, Maria Helena, Kotov, Roman, Lehrer, Douglas S., Malaspina, Dolores, Marder, Stephen R., Medeiros, Helena, Morley, Christopher P., Perkins, Diana O., Sobell, Janet L., Buckley, Peter F., Macciardi, Fabio, Rapaport, Mark H., Knowles, James A., Fanous, Ayman H., McCarroll, Steven A., Gupta, Namrata, Gabriel, Stacey B., Daly, Mark J., Lander, Eric S., Lowenstein, Daniel H., Goldstein, David B., Lerche, Holger, Berkovic, Samuel F., and Neale, Benjamin M.
Abstract: Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.
Published: 2019

25. The rhetoric and reality of integrated patient-centered care for healthcare providers: An ethnographic exploration of epilepsy care in Ireland

Author: Byrne, John-Paul, Power, Robert, Kiersey, Rachel, Varley, Jarlath, Doherty, Colin P., Saris, A. Jamie, Lambert, Veronica, Fitzsimons, Mary, Byrne, John-Paul, Power, Robert, Kiersey, Rachel, Varley, Jarlath, Doherty, Colin P., Saris, A. Jamie, Lambert, Veronica, and Fitzsimons, Mary
Abstract: In line with healthcare reform across the world, the National Clinical Programme for Epilepsy (NCPE) in Ireland describes a model that aims to achieve holistic integrated person (patient)-centered care (PCC). While generally welcomed by stakeholders, the steps required to realize the NCPE ambition and the preparedness of those involved to make the journey are not clear. This study explored the perceptions of healthcare providers in the Irish epilepsy care ecosystem to understand their level of readiness to realize the benefits of an integrated PCC model. Ethnographic fieldwork including observations of different clinical settings across three regions in Ireland and one-to-one interviews with consultant epileptologists (n = 3), epilepsy specialist nurses (n = 5), general practitioners (n = 4), and senior healthcare managers (n = 3) were conducted. While there is a person-centered ambiance and a disposition toward advancing integrated PCC, there are limits to the readiness of the epilepsy care environment to fully meet the aspirations of healthcare reform. These are the following: underdeveloped healthcare partnerships;, poor care coordination;, unintended consequences of innovation;, and tension between pace and productivity. In the journey from policy to practice, the following multiple tensions collide: policy aims to improve services for all patients while simultaneously individualizing care; demands for productivity limit the time and space required to engage in incremental and iterative improvement initiatives. Understanding these tensions is an essential first step on the pathway to integrated PCC implementation.
Published: 2019

26. The rhetoric and reality of integrated patient-centered care for healthcare providers: An ethnographic exploration of epilepsy care in Ireland

Author: Byrne, John-Paul, Power, Robert, Kiersey, Rachel, Varley, Jarlath, Doherty, Colin P., Saris, A. Jamie, Lambert, Veronica, Fitzsimons, Mary, Byrne, John-Paul, Power, Robert, Kiersey, Rachel, Varley, Jarlath, Doherty, Colin P., Saris, A. Jamie, Lambert, Veronica, and Fitzsimons, Mary
Abstract: In line with healthcare reform across the world, the National Clinical Programme for Epilepsy (NCPE) in Ireland describes a model that aims to achieve holistic integrated person (patient)-centered care (PCC). While generally welcomed by stakeholders, the steps required to realize the NCPE ambition and the preparedness of those involved to make the journey are not clear. This study explored the perceptions of healthcare providers in the Irish epilepsy care ecosystem to understand their level of readiness to realize the benefits of an integrated PCC model. Ethnographic fieldwork including observations of different clinical settings across three regions in Ireland and one-to-one interviews with consultant epileptologists (n = 3), epilepsy specialist nurses (n = 5), general practitioners (n = 4), and senior healthcare managers (n = 3) were conducted. While there is a person-centered ambiance and a disposition toward advancing integrated PCC, there are limits to the readiness of the epilepsy care environment to fully meet the aspirations of healthcare reform. These are the following: underdeveloped healthcare partnerships;, poor care coordination;, unintended consequences of innovation;, and tension between pace and productivity. In the journey from policy to practice, the following multiple tensions collide: policy aims to improve services for all patients while simultaneously individualizing care; demands for productivity limit the time and space required to engage in incremental and iterative improvement initiatives. Understanding these tensions is an essential first step on the pathway to integrated PCC implementation.
Published: 2019

27. White matter abnormalities across different epilepsy syndromes in adults: an ENIGMA Epilepsy study

Author: Hatton, Sean N., Huynh, Khoa H., Bonilha, Leonardo, Abela, Eugenio Cecilio, Alhusaini, Saud, Altmann, André, Alvim, Marina K. M., Balachandra, Akshara R., Bartolini, Emanuele, Bender, Benjamin, Bernasconi, Neda, Bernasconi, Andrea, Bernhardt, Boris, Bargallo, Núria, Caldairou, Benoit, Caligiuri, Maria Eugenia, Carr, Sarah J. A., Cavalleri, Gianpiero L., Cendes, Fernando, Concha, Luis, Davoodi-Bojd, Esmaeil, Desmond, Patricia M., Devinsky, Orrin, Doherty, Colin P., Domin, Martin, Duncan, John S., Focke, Niels K., Foley, Sonya F., Gambardella, Antonio, Gleichgerrcht, Ezequiel, Guerrini, Renzo, Hamandi, Khalid, Ishikawa, Akari, Keller, Simon S., Kochunov, Peter V., Kotikalapudi, Raviteja, Kreilkamp, Barbara A. K., Kwan, Patrick, Labate, Angelo, Langner, Sönke, Lenge, Matteo, Liu, Min, Lui, Elaine, Martin, Pascal, Mascalchi, Mario, Moreira, José Carlos Vasques, Morita-Sherman, Marcia Elisabete, O’Brien, Terence J., Pardoe, Heath R., Pariente Zorrilla, José Carlos, Ribeiro, Letı́cia F., Richardson, Mark Philip, Rocha, Cristiane S., Rodrı́guez-Cruces, Raúl, Rosenow, Felix, Severino, Mariasavina, Sinclair, Benjamin, Soltanian-Zadeh, Hamid, Striano, Pasquale, Taylor, Peter N., Thomas, Rhys H., Tortora, Domenico, Velakoulis, Dennis, Vezzani, Annamaria, Vivash, Lucy, Podewils, Felix von, Vos, Sjoerd B., Weber, Bernd, Winston, Gavin P., Yasuda, Clarissa L., Thompson, Paul M., Jahanshad, Neda, Sisodiya, Sanjay M., McDonald, Carrie R., Hatton, Sean N., Huynh, Khoa H., Bonilha, Leonardo, Abela, Eugenio Cecilio, Alhusaini, Saud, Altmann, André, Alvim, Marina K. M., Balachandra, Akshara R., Bartolini, Emanuele, Bender, Benjamin, Bernasconi, Neda, Bernasconi, Andrea, Bernhardt, Boris, Bargallo, Núria, Caldairou, Benoit, Caligiuri, Maria Eugenia, Carr, Sarah J. A., Cavalleri, Gianpiero L., Cendes, Fernando, Concha, Luis, Davoodi-Bojd, Esmaeil, Desmond, Patricia M., Devinsky, Orrin, Doherty, Colin P., Domin, Martin, Duncan, John S., Focke, Niels K., Foley, Sonya F., Gambardella, Antonio, Gleichgerrcht, Ezequiel, Guerrini, Renzo, Hamandi, Khalid, Ishikawa, Akari, Keller, Simon S., Kochunov, Peter V., Kotikalapudi, Raviteja, Kreilkamp, Barbara A. K., Kwan, Patrick, Labate, Angelo, Langner, Sönke, Lenge, Matteo, Liu, Min, Lui, Elaine, Martin, Pascal, Mascalchi, Mario, Moreira, José Carlos Vasques, Morita-Sherman, Marcia Elisabete, O’Brien, Terence J., Pardoe, Heath R., Pariente Zorrilla, José Carlos, Ribeiro, Letı́cia F., Richardson, Mark Philip, Rocha, Cristiane S., Rodrı́guez-Cruces, Raúl, Rosenow, Felix, Severino, Mariasavina, Sinclair, Benjamin, Soltanian-Zadeh, Hamid, Striano, Pasquale, Taylor, Peter N., Thomas, Rhys H., Tortora, Domenico, Velakoulis, Dennis, Vezzani, Annamaria, Vivash, Lucy, Podewils, Felix von, Vos, Sjoerd B., Weber, Bernd, Winston, Gavin P., Yasuda, Clarissa L., Thompson, Paul M., Jahanshad, Neda, Sisodiya, Sanjay M., and McDonald, Carrie R.
Abstract: The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analyzed from 1,069 non-epileptic controls and 1,249 patients: temporal lobe epilepsy with hippocampal sclerosis (N=599), temporal lobe epilepsy with normal MRI (N=275), genetic generalized epilepsy (N=182) and nonlesional extratemporal epilepsy (N=193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fiber tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at p<0.001). Across “all epilepsies” lower fractional anisotropy was observed in most fiber tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. Less robust effects were seen with mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippocampal sclerosis in the ipsilateral parahippocampal cingulum and external capsule, with smaller effects across most other tracts. Those with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hip
Published: 2019

28. Comparative effectiveness of antiepileptic drugs in juvenile myoclonic epilepsy

Author: Silvennoinen, Katri, Depondt, Chantal, Brodie, M J, Chinthapalli, Krishna, de Haan, Gerrit Jan, Doherty, Colin P, Heavin, Sinead, McCormack, Mark, Petrovski, Slave, Sargsyan, Narek, Slattery, Lisa, Willis, Joseph, Silvennoinen, Katri, Depondt, Chantal, Brodie, M J, Chinthapalli, Krishna, de Haan, Gerrit Jan, Doherty, Colin P, Heavin, Sinead, McCormack, Mark, Petrovski, Slave, Sargsyan, Narek, Slattery, Lisa, and Willis, Joseph
Abstract: Objective: To study the effectiveness and tolerability of antiepileptic drugs (AEDs) commonly used in juvenile myoclonic epilepsy (JME). Methods: People with JME were identified from a large database of individuals with epilepsy, which includes detailed retrospective information on AED use. We assessed secular changes in AED use and calculated rates of response (12-month seizure freedom) and adverse drug reactions (ADRs) for the five most common AEDs. Retention was modeled with a Cox proportional hazards model. We compared valproate use between males and females. Results: We included 305 people with 688 AED trials of valproate, lamotrigine, levetiracetam, carbamazepine, and topiramate. Valproate and carbamazepine were most often prescribed as the first AED. The response rate to valproate was highest among the five AEDs (42.7%), and significantly higher than response rates for lamotrigine, carbamazepine, and topiramate; the difference to the response rate to levetiracetam (37.1%) was not significant. The rates of ADRs were highest for topiramate (45.5%) and valproate (37.5%). Commonest ADRs included weight change, lethargy, and tremor. In the Cox proportional hazards model, later start year (1.10 [1.08-1.13], P < 0.001) and female sex (1.41 [1.07-1.85], P = 0.02) were associated with shorter trial duration. Valproate was associated with the longest treatment duration; trials with carbamazepine and topiramate were significantly shorter (HR [CI]: 3.29 [2.15-5.02], P < 0.001 and 1.93 [1.31-2.86], P < 0.001). The relative frequency of valproate trials shows a decreasing trend since 2003 while there is an increasing trend for levetiracetam. Fewer females than males received valproate (76.2% vs 92.6%, P = 0.001). Significance: In people with JME, valproate is an effective AED; levetiracetam emerged as an alternative. Valproate is now contraindicated in women of childbearing potential without special precautions. With appropriate selection and safeguards in place, valproate, SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2019

29. Genomic and clinical predictors of lacosamide response in refractory epilepsies

Author: Heavin, Sinead, McCormack, Mark, Wolking, Stefan, Slattery, Lisa, Walley, Nicole, Avbersek, Andreja, Novy, Jan, Sinha, Saurabh S.R., Radtke, Rodney, Doherty, Colin P, Auce, Pauls, Craig, John, Johnson, Margaret, Koeleman, B.P.C., Krause, Roland, Kunz, Wolfram W.S., Marson, Anthony Guy, O'Brien, Terence John, Sander, Josemir W, Sills, Graeme, Stefansson, Hreinn, Striano, Pasquale, Zara, Federico, Depondt, Chantal, Sisodiya, Sanjay, Goldstein, David, Lerche, Holger, Cavalleri, Gianpiero, Delanty, Norman, Heavin, Sinead, McCormack, Mark, Wolking, Stefan, Slattery, Lisa, Walley, Nicole, Avbersek, Andreja, Novy, Jan, Sinha, Saurabh S.R., Radtke, Rodney, Doherty, Colin P, Auce, Pauls, Craig, John, Johnson, Margaret, Koeleman, B.P.C., Krause, Roland, Kunz, Wolfram W.S., Marson, Anthony Guy, O'Brien, Terence John, Sander, Josemir W, Sills, Graeme, Stefansson, Hreinn, Striano, Pasquale, Zara, Federico, Depondt, Chantal, Sisodiya, Sanjay, Goldstein, David, Lerche, Holger, Cavalleri, Gianpiero, and Delanty, Norman
Abstract: Objective: Clinical and genetic predictors of response to antiepileptic drugs (AEDs) are largely unknown. We examined predictors of lacosamide response in a real-world clinical setting. Methods: We tested the association of clinical predictors with treatment response using regression modeling in a cohort of people with refractory epilepsy. Genetic assessment for lacosamide response was conducted via genome-wide association studies and exome studies, comprising 281 candidate genes. Results: Most patients (479/483) were treated with LCM in addition to other AEDs. Our results corroborate previous findings that patients with refractory genetic generalized epilepsy (GGE) may respond to treatment with LCM. No clear clinical predictors were identified. We then compared 73 lacosamide responders, defined as those experiencing greater than 75% seizure reduction or seizure freedom, to 495 nonresponders (<25% seizure reduction). No variants reached the genome-wide significance threshold in our case-control analysis. Significance: No genetic predictor of lacosamide response was identified. Patients with refractory GGE might benefit from treatment with lacosamide., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2019

30. Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies

Author: Abou-Khalil, Bassel, Auce, Pauls, Avbersek, Andreja, Bahlo, Melanie, Balding, David J., Bast, Thomas, Baum, Larry, Becker, Albert J., Becker, Felicitas, Berghuis, Bianca, Berkovic, Samuel F., Boysen, Katja E., Bradfield, Jonathan P., Brody, Lawrence C., Buono, Russell J., Campbell, Ellen, Cascino, Gregory D., Catarino, Claudia B., Cavalleri, Gianpiero L., Cherny, Stacey S., Chinthapalli, Krishna, Coffey, Alison J., Compston, Alastair, Coppola, Antonietta, Cossette, Patrick, Craig, John J., de Haan, Gerrit-Jan, De Jonghe, Peter, de Kovel, Carolien G. F., Delanty, Norman, Depondt, Chantal, Devinsky, Orrin, Dlugos, Dennis J., Doherty, Colin P., Elger, Christian E., Eriksson, Johan G., Ferraro, Thomas N., Feucht, Martha, Francis, Ben, Franke, Andre, French, Jacqueline A., Freytag, Saskia, Gaus, Verena, Geller, Eric B., Gieger, Christian, Glauser, Tracy, Glynn, Simon, Goldstein, David B., Gui, Hongsheng, Guo, Youling, Haas, Kevin F., Hakonarson, Hakon, Hallmann, Kerstin, Haut, Sheryl, Heinzen, Erin L., Helbig, Ingo, Hengsbach, Christian, Hjalgrim, Helle, Iacomino, Michele, Ingason, Andres, Jamnadas-Khoda, Jennifer, Johnson, Michael R., Kalviainen, Reetta, Kantanen, Anne-Mari, Kasperaviciute, Dalia, Trenite, Dorothee Kasteleijn-Nolst, Kirsch, Heidi E., Knowlton, Robert C., Koeleman, Bobby P. C., Krause, Roland, Krenn, Martin, Kunz, Wolfram S., Kuzniecky, Ruben, Kwan, Patrick, Lal, Dennis, Lau, Yu-Lung, Lehesjoki, Anna-Elina, Lerche, Holger, Leu, Costin, Lieb, Wolfgang, Lindhout, Dick, Lo, Warren D., Lopes-Cendes, Iscia, Lowenstein, Daniel H., Malovini, Alberto, Marson, Anthony G., Mayer, Thomas, McCormack, Mark, Mills, James L., Mirza, Nasir, Moerzinger, Martina, Moller, Rikke S., Molloy, Anne M., Muhle, Hiltrud, Newton, Mark, Ng, Ping-Wing, Noethen, Markus M., Nuernberg, Peter, O'Brien, Terence J., Oliver, Karen L., Palotie, Aarno, Pangilinan, Faith, Peter, Sarah, Petrovski, Slave, Poduri, Annapurna, Privitera, Michael, Radtke, Rodney, Rau, Sarah, Reif, Philipp S., Reinthaler, Eva M., Rosenow, Felix, Sander, Josemir W., Sander, Thomas, Scattergood, Theresa, Schachter, Steven C., Schankin, Christoph J., Scheffer, Ingrid E., Schmitz, Bettina, Schoch, Susanne, Sham, Pak C., Shih, Jerry J., Sills, Graeme J., Sisodiya, Sanjay M., Slattery, Lisa, Smith, Alexander, Smith, David F., Smith, Michael C., Smith, Philip E., Sonsma, Anja C. M., Speed, Doug, Sperling, Michael R., Steinhoff, Bernhard J., Stephani, Ulrich, Stevelink, Remi, Strauch, Konstantin, Striano, Pasquale, Stroink, Hans, Surges, Rainer, Tan, K. Meng, Thio, Liu Lin, Thomas, G. Neil, Todaro, Marian, Tozzi, Rossana, Vari, Maria S., Vining, Eileen P. G., Visscher, Frank, von Spiczak, Sarah, Walley, Nicole M., Weber, Yvonne G., Wei, Zhi, Weisenberg, Judith, Whelan, Christopher D., Widdess-Walsh, Peter, Wolff, Markus, Wolking, Stefan, Yang, Wanling, Zara, Federico, Zimprich, Fritz, Abou-Khalil, Bassel, Auce, Pauls, Avbersek, Andreja, Bahlo, Melanie, Balding, David J., Bast, Thomas, Baum, Larry, Becker, Albert J., Becker, Felicitas, Berghuis, Bianca, Berkovic, Samuel F., Boysen, Katja E., Bradfield, Jonathan P., Brody, Lawrence C., Buono, Russell J., Campbell, Ellen, Cascino, Gregory D., Catarino, Claudia B., Cavalleri, Gianpiero L., Cherny, Stacey S., Chinthapalli, Krishna, Coffey, Alison J., Compston, Alastair, Coppola, Antonietta, Cossette, Patrick, Craig, John J., de Haan, Gerrit-Jan, De Jonghe, Peter, de Kovel, Carolien G. F., Delanty, Norman, Depondt, Chantal, Devinsky, Orrin, Dlugos, Dennis J., Doherty, Colin P., Elger, Christian E., Eriksson, Johan G., Ferraro, Thomas N., Feucht, Martha, Francis, Ben, Franke, Andre, French, Jacqueline A., Freytag, Saskia, Gaus, Verena, Geller, Eric B., Gieger, Christian, Glauser, Tracy, Glynn, Simon, Goldstein, David B., Gui, Hongsheng, Guo, Youling, Haas, Kevin F., Hakonarson, Hakon, Hallmann, Kerstin, Haut, Sheryl, Heinzen, Erin L., Helbig, Ingo, Hengsbach, Christian, Hjalgrim, Helle, Iacomino, Michele, Ingason, Andres, Jamnadas-Khoda, Jennifer, Johnson, Michael R., Kalviainen, Reetta, Kantanen, Anne-Mari, Kasperaviciute, Dalia, Trenite, Dorothee Kasteleijn-Nolst, Kirsch, Heidi E., Knowlton, Robert C., Koeleman, Bobby P. C., Krause, Roland, Krenn, Martin, Kunz, Wolfram S., Kuzniecky, Ruben, Kwan, Patrick, Lal, Dennis, Lau, Yu-Lung, Lehesjoki, Anna-Elina, Lerche, Holger, Leu, Costin, Lieb, Wolfgang, Lindhout, Dick, Lo, Warren D., Lopes-Cendes, Iscia, Lowenstein, Daniel H., Malovini, Alberto, Marson, Anthony G., Mayer, Thomas, McCormack, Mark, Mills, James L., Mirza, Nasir, Moerzinger, Martina, Moller, Rikke S., Molloy, Anne M., Muhle, Hiltrud, Newton, Mark, Ng, Ping-Wing, Noethen, Markus M., Nuernberg, Peter, O'Brien, Terence J., Oliver, Karen L., Palotie, Aarno, Pangilinan, Faith, Peter, Sarah, Petrovski, Slave, Poduri, Annapurna, Privitera, Michael, Radtke, Rodney, Rau, Sarah, Reif, Philipp S., Reinthaler, Eva M., Rosenow, Felix, Sander, Josemir W., Sander, Thomas, Scattergood, Theresa, Schachter, Steven C., Schankin, Christoph J., Scheffer, Ingrid E., Schmitz, Bettina, Schoch, Susanne, Sham, Pak C., Shih, Jerry J., Sills, Graeme J., Sisodiya, Sanjay M., Slattery, Lisa, Smith, Alexander, Smith, David F., Smith, Michael C., Smith, Philip E., Sonsma, Anja C. M., Speed, Doug, Sperling, Michael R., Steinhoff, Bernhard J., Stephani, Ulrich, Stevelink, Remi, Strauch, Konstantin, Striano, Pasquale, Stroink, Hans, Surges, Rainer, Tan, K. Meng, Thio, Liu Lin, Thomas, G. Neil, Todaro, Marian, Tozzi, Rossana, Vari, Maria S., Vining, Eileen P. G., Visscher, Frank, von Spiczak, Sarah, Walley, Nicole M., Weber, Yvonne G., Wei, Zhi, Weisenberg, Judith, Whelan, Christopher D., Widdess-Walsh, Peter, Wolff, Markus, Wolking, Stefan, Yang, Wanling, Zara, Federico, and Zimprich, Fritz
Abstract: The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.
Published: 2018

31. Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies

Author: Abou-Khalil, Bassel, Auce, Pauls, Avbersek, Andreja, Bahlo, Melanie, Balding, David J., Bast, Thomas, Baum, Larry, Becker, Albert J., Becker, Felicitas, Berghuis, Bianca, Berkovic, Samuel F., Boysen, Katja E., Bradfield, Jonathan P., Brody, Lawrence C., Buono, Russell J., Campbell, Ellen, Cascino, Gregory D., Catarino, Claudia B., Cavalleri, Gianpiero L., Cherny, Stacey S., Chinthapalli, Krishna, Coffey, Alison J., Compston, Alastair, Coppola, Antonietta, Cossette, Patrick, Craig, John J., de Haan, Gerrit-Jan, De Jonghe, Peter, de Kovel, Carolien G. F., Delanty, Norman, Depondt, Chantal, Devinsky, Orrin, Dlugos, Dennis J., Doherty, Colin P., Elger, Christian E., Eriksson, Johan G., Ferraro, Thomas N., Feucht, Martha, Francis, Ben, Franke, Andre, French, Jacqueline A., Freytag, Saskia, Gaus, Verena, Geller, Eric B., Gieger, Christian, Glauser, Tracy, Glynn, Simon, Goldstein, David B., Gui, Hongsheng, Guo, Youling, Haas, Kevin F., Hakonarson, Hakon, Hallmann, Kerstin, Haut, Sheryl, Heinzen, Erin L., Helbig, Ingo, Hengsbach, Christian, Hjalgrim, Helle, Iacomino, Michele, Ingason, Andres, Jamnadas-Khoda, Jennifer, Johnson, Michael R., Kalviainen, Reetta, Kantanen, Anne-Mari, Kasperaviciute, Dalia, Trenite, Dorothee Kasteleijn-Nolst, Kirsch, Heidi E., Knowlton, Robert C., Koeleman, Bobby P. C., Krause, Roland, Krenn, Martin, Kunz, Wolfram S., Kuzniecky, Ruben, Kwan, Patrick, Lal, Dennis, Lau, Yu-Lung, Lehesjoki, Anna-Elina, Lerche, Holger, Leu, Costin, Lieb, Wolfgang, Lindhout, Dick, Lo, Warren D., Lopes-Cendes, Iscia, Lowenstein, Daniel H., Malovini, Alberto, Marson, Anthony G., Mayer, Thomas, McCormack, Mark, Mills, James L., Mirza, Nasir, Moerzinger, Martina, Moller, Rikke S., Molloy, Anne M., Muhle, Hiltrud, Newton, Mark, Ng, Ping-Wing, Noethen, Markus M., Nuernberg, Peter, O'Brien, Terence J., Oliver, Karen L., Palotie, Aarno, Pangilinan, Faith, Peter, Sarah, Petrovski, Slave, Poduri, Annapurna, Privitera, Michael, Radtke, Rodney, Rau, Sarah, Reif, Philipp S., Reinthaler, Eva M., Rosenow, Felix, Sander, Josemir W., Sander, Thomas, Scattergood, Theresa, Schachter, Steven C., Schankin, Christoph J., Scheffer, Ingrid E., Schmitz, Bettina, Schoch, Susanne, Sham, Pak C., Shih, Jerry J., Sills, Graeme J., Sisodiya, Sanjay M., Slattery, Lisa, Smith, Alexander, Smith, David F., Smith, Michael C., Smith, Philip E., Sonsma, Anja C. M., Speed, Doug, Sperling, Michael R., Steinhoff, Bernhard J., Stephani, Ulrich, Stevelink, Remi, Strauch, Konstantin, Striano, Pasquale, Stroink, Hans, Surges, Rainer, Tan, K. Meng, Thio, Liu Lin, Thomas, G. Neil, Todaro, Marian, Tozzi, Rossana, Vari, Maria S., Vining, Eileen P. G., Visscher, Frank, von Spiczak, Sarah, Walley, Nicole M., Weber, Yvonne G., Wei, Zhi, Weisenberg, Judith, Whelan, Christopher D., Widdess-Walsh, Peter, Wolff, Markus, Wolking, Stefan, Yang, Wanling, Zara, Federico, Zimprich, Fritz, Abou-Khalil, Bassel, Auce, Pauls, Avbersek, Andreja, Bahlo, Melanie, Balding, David J., Bast, Thomas, Baum, Larry, Becker, Albert J., Becker, Felicitas, Berghuis, Bianca, Berkovic, Samuel F., Boysen, Katja E., Bradfield, Jonathan P., Brody, Lawrence C., Buono, Russell J., Campbell, Ellen, Cascino, Gregory D., Catarino, Claudia B., Cavalleri, Gianpiero L., Cherny, Stacey S., Chinthapalli, Krishna, Coffey, Alison J., Compston, Alastair, Coppola, Antonietta, Cossette, Patrick, Craig, John J., de Haan, Gerrit-Jan, De Jonghe, Peter, de Kovel, Carolien G. F., Delanty, Norman, Depondt, Chantal, Devinsky, Orrin, Dlugos, Dennis J., Doherty, Colin P., Elger, Christian E., Eriksson, Johan G., Ferraro, Thomas N., Feucht, Martha, Francis, Ben, Franke, Andre, French, Jacqueline A., Freytag, Saskia, Gaus, Verena, Geller, Eric B., Gieger, Christian, Glauser, Tracy, Glynn, Simon, Goldstein, David B., Gui, Hongsheng, Guo, Youling, Haas, Kevin F., Hakonarson, Hakon, Hallmann, Kerstin, Haut, Sheryl, Heinzen, Erin L., Helbig, Ingo, Hengsbach, Christian, Hjalgrim, Helle, Iacomino, Michele, Ingason, Andres, Jamnadas-Khoda, Jennifer, Johnson, Michael R., Kalviainen, Reetta, Kantanen, Anne-Mari, Kasperaviciute, Dalia, Trenite, Dorothee Kasteleijn-Nolst, Kirsch, Heidi E., Knowlton, Robert C., Koeleman, Bobby P. C., Krause, Roland, Krenn, Martin, Kunz, Wolfram S., Kuzniecky, Ruben, Kwan, Patrick, Lal, Dennis, Lau, Yu-Lung, Lehesjoki, Anna-Elina, Lerche, Holger, Leu, Costin, Lieb, Wolfgang, Lindhout, Dick, Lo, Warren D., Lopes-Cendes, Iscia, Lowenstein, Daniel H., Malovini, Alberto, Marson, Anthony G., Mayer, Thomas, McCormack, Mark, Mills, James L., Mirza, Nasir, Moerzinger, Martina, Moller, Rikke S., Molloy, Anne M., Muhle, Hiltrud, Newton, Mark, Ng, Ping-Wing, Noethen, Markus M., Nuernberg, Peter, O'Brien, Terence J., Oliver, Karen L., Palotie, Aarno, Pangilinan, Faith, Peter, Sarah, Petrovski, Slave, Poduri, Annapurna, Privitera, Michael, Radtke, Rodney, Rau, Sarah, Reif, Philipp S., Reinthaler, Eva M., Rosenow, Felix, Sander, Josemir W., Sander, Thomas, Scattergood, Theresa, Schachter, Steven C., Schankin, Christoph J., Scheffer, Ingrid E., Schmitz, Bettina, Schoch, Susanne, Sham, Pak C., Shih, Jerry J., Sills, Graeme J., Sisodiya, Sanjay M., Slattery, Lisa, Smith, Alexander, Smith, David F., Smith, Michael C., Smith, Philip E., Sonsma, Anja C. M., Speed, Doug, Sperling, Michael R., Steinhoff, Bernhard J., Stephani, Ulrich, Stevelink, Remi, Strauch, Konstantin, Striano, Pasquale, Stroink, Hans, Surges, Rainer, Tan, K. Meng, Thio, Liu Lin, Thomas, G. Neil, Todaro, Marian, Tozzi, Rossana, Vari, Maria S., Vining, Eileen P. G., Visscher, Frank, von Spiczak, Sarah, Walley, Nicole M., Weber, Yvonne G., Wei, Zhi, Weisenberg, Judith, Whelan, Christopher D., Widdess-Walsh, Peter, Wolff, Markus, Wolking, Stefan, Yang, Wanling, Zara, Federico, and Zimprich, Fritz
Abstract: The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.
Published: 2018

32. Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies.

Author: Abou-Khalil, Bassel, Auce, Pauls, Avbersek, Andreja, Bahlo, Melanie, Balding, David J., Bast, Thomas, Baum, Larry, Becker, Albert J., Becker, Felicitas, Berghuis, Bianca, Berkovic, Samuel F., Boysen, Katja E., Bradfield, Jonathan P., Brody, Lawrence C., Buono, Russell J., Campbell, Ellen, Cascino, Gregory D., Catarino, Claudia B., Cavalleri, Gianpiero L., Cherny, Stacey S., Chinthapalli, Krishna, Coffey, Alison J., Compston, Alastair, Coppola, Antonietta, Cossette, Patrick, Craig, John J., de Haan, Gerrit-Jan, De Jonghe, Peter, de Kovel, Carolien G.F., Delanty, Norman, Depondt, Chantal, Devinsky, Orrin, Dlugos, Dennis J., Doherty, Colin P., Elger, Christian E., Eriksson, Johan G., Ferraro, Thomas N., Feuch, Martha, Francis, Ben, Franke, Andre, French, Jacqueline A., Freytag, Saskia, Gaus, Verena, Geller, Eric B., Gieger, Christian, Glauser, Tracy, Glynn, Simon, Goldstein, David B., Gui, Hongsheng, Guo, Youling, Haas, Kevin F., Hakonarson, Hakon, Hallmann, Kerstin, Haut, Sheryl, Heinzen, Erin L., Helbig, Ingo, Hengsbach, Christian, Hjalgrim, Helle, Iacomino, Michele, Ingason, Andrés, Jamnadas-Khoda, Jennifer, Johnson, Michael R., Kälviäinen, Reetta, Kantanen, Anne-Mari, Kasperavičiūte, Dalia, Kasteleijn-Nolst Trenite, Dorothee, Kirsch, Heidi E., Knowlton, Robert C., Koeleman, Bobby P.C., Krause, Roland, Krenn, Martin, Kunz, Wolfram S., Kuzniecky, Ruben, Kwan, Patrick, Lal, Dennis, Lau, Yu-Lung, Lehesjoki, Anna-Elina, Lerche, Holger, Leu, Costin, Lieb, Wolfgang, Lindhout, Dick, Lo, Warren D., Lopes-Cendes, Iscia, Lowenstein, Daniel H., Malovini, Alberto, Marson, Anthony G., Mayer, Thomas, McCormack, Mark, Mills, James L., Mirza, Nasir, Moerzinger, Martina, Møller, Rikke S., Molloy, Anne M., Muhle, Hiltrud, Newton, Mark, Ng, Ping-Wing, Nöthen, Markus M., Nürnberg, Peter, O’Brien, Terence J., Oliver, Karen L., Palotie, Palotie, Pangilinan, Faith, Peter, Sarah, Petrovski, Slavé, Poduri, Annapurna, Privitera, Michael, Radtke, Rodney, Rau, Sarah, Reif, Philipp S., Reinthaler, Eva M., Rosenow, Felix, Sander, Josemir W., Sander, Thomas, Scattergood, Theresa, Schachter, Steven C., Schankin, Christoph J., Scheffer, Ingrid E., Schmitz, Bettina, Schoch, Susanne, Sham, Pak C., Shih, Jerry J., Sills, Graeme J., Sisodiya, Sanjay M., Slattery, Lisa, Smith, Alexander, Smith, David F., Smith, Michael C., Smith, Philip E., Sonsma, Anja C.M., Speed, Doug, Sperling, Michael R., Steinhoff, Bernhard J., Stephani, Ulrich, Stevelink, Remi, Strauch, Konstantin, Striano, Pasquale, Stroink, Hans, Surges, Rainer, Tan, K. Meng, Thio, Liu Lin, Thomas, G. Neil, Todaro, Marian, Tozzi, Rossana, Vari, Maria S., Vining, Ellen P.G., Visscher, Frank, von Spiczak, Sarah, Walley, Nicole M., Weber, Yvonne G., Wei, Zhi, Weisenberg, Judith, Whelan, Christopher D., Widdess-Walsh, Peter, Wolff, Markus, Wolking, Wolking, Yang, Wanling, Zara, Federico, Zimprich, Fritz, Abou-Khalil, Bassel, Auce, Pauls, Avbersek, Andreja, Bahlo, Melanie, Balding, David J., Bast, Thomas, Baum, Larry, Becker, Albert J., Becker, Felicitas, Berghuis, Bianca, Berkovic, Samuel F., Boysen, Katja E., Bradfield, Jonathan P., Brody, Lawrence C., Buono, Russell J., Campbell, Ellen, Cascino, Gregory D., Catarino, Claudia B., Cavalleri, Gianpiero L., Cherny, Stacey S., Chinthapalli, Krishna, Coffey, Alison J., Compston, Alastair, Coppola, Antonietta, Cossette, Patrick, Craig, John J., de Haan, Gerrit-Jan, De Jonghe, Peter, de Kovel, Carolien G.F., Delanty, Norman, Depondt, Chantal, Devinsky, Orrin, Dlugos, Dennis J., Doherty, Colin P., Elger, Christian E., Eriksson, Johan G., Ferraro, Thomas N., Feuch, Martha, Francis, Ben, Franke, Andre, French, Jacqueline A., Freytag, Saskia, Gaus, Verena, Geller, Eric B., Gieger, Christian, Glauser, Tracy, Glynn, Simon, Goldstein, David B., Gui, Hongsheng, Guo, Youling, Haas, Kevin F., Hakonarson, Hakon, Hallmann, Kerstin, Haut, Sheryl, Heinzen, Erin L., Helbig, Ingo, Hengsbach, Christian, Hjalgrim, Helle, Iacomino, Michele, Ingason, Andrés, Jamnadas-Khoda, Jennifer, Johnson, Michael R., Kälviäinen, Reetta, Kantanen, Anne-Mari, Kasperavičiūte, Dalia, Kasteleijn-Nolst Trenite, Dorothee, Kirsch, Heidi E., Knowlton, Robert C., Koeleman, Bobby P.C., Krause, Roland, Krenn, Martin, Kunz, Wolfram S., Kuzniecky, Ruben, Kwan, Patrick, Lal, Dennis, Lau, Yu-Lung, Lehesjoki, Anna-Elina, Lerche, Holger, Leu, Costin, Lieb, Wolfgang, Lindhout, Dick, Lo, Warren D., Lopes-Cendes, Iscia, Lowenstein, Daniel H., Malovini, Alberto, Marson, Anthony G., Mayer, Thomas, McCormack, Mark, Mills, James L., Mirza, Nasir, Moerzinger, Martina, Møller, Rikke S., Molloy, Anne M., Muhle, Hiltrud, Newton, Mark, Ng, Ping-Wing, Nöthen, Markus M., Nürnberg, Peter, O’Brien, Terence J., Oliver, Karen L., Palotie, Palotie, Pangilinan, Faith, Peter, Sarah, Petrovski, Slavé, Poduri, Annapurna, Privitera, Michael, Radtke, Rodney, Rau, Sarah, Reif, Philipp S., Reinthaler, Eva M., Rosenow, Felix, Sander, Josemir W., Sander, Thomas, Scattergood, Theresa, Schachter, Steven C., Schankin, Christoph J., Scheffer, Ingrid E., Schmitz, Bettina, Schoch, Susanne, Sham, Pak C., Shih, Jerry J., Sills, Graeme J., Sisodiya, Sanjay M., Slattery, Lisa, Smith, Alexander, Smith, David F., Smith, Michael C., Smith, Philip E., Sonsma, Anja C.M., Speed, Doug, Sperling, Michael R., Steinhoff, Bernhard J., Stephani, Ulrich, Stevelink, Remi, Strauch, Konstantin, Striano, Pasquale, Stroink, Hans, Surges, Rainer, Tan, K. Meng, Thio, Liu Lin, Thomas, G. Neil, Todaro, Marian, Tozzi, Rossana, Vari, Maria S., Vining, Ellen P.G., Visscher, Frank, von Spiczak, Sarah, Walley, Nicole M., Weber, Yvonne G., Wei, Zhi, Weisenberg, Judith, Whelan, Christopher D., Widdess-Walsh, Peter, Wolff, Markus, Wolking, Wolking, Yang, Wanling, Zara, Federico, and Zimprich, Fritz
Abstract: The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.
Published: 2018

33. Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A

Author: Kasperavičiūtė, Dalia, Catarino, Claudia B., Matarin, Mar, Leu, Costin, Novy, Jan, Tostevin, Anna, Leal, Bárbara, Hessel, Ellen V. S., Hallmann, Kerstin, Hildebrand, Michael S., Dahl, Hans-Henrik M., Ryten, Mina, Trabzuni, Daniah, Ramasamy, Adaikalavan, Alhusaini, Saud, Doherty, Colin P., Dorn, Thomas, Hansen, Jörg, Krämer, Günter, Steinhoff, Bernhard J., Zumsteg, Dominik, Duncan, Susan, Kälviäinen, Reetta K., Eriksson, Kai J., Kantanen, Anne-Mari, Pandolfo, Massimo, Gruber-Sedlmayr, Ursula, Schlachter, Kurt, Reinthaler, Eva M., Stogmann, Elisabeth, Zimprich, Fritz, Théâtre, Emilie, Smith, Colin, O'Brien, Terence J., Meng Tan, K., Petrovski, Slave, Robbiano, Angela, Paravidino, Roberta, Zara, Federico, Striano, Pasquale, Sperling, Michael R., Buono, Russell J., Hakonarson, Hakon, Chaves, João, Costa, Paulo P., Silva, Berta M., da Silva, António M., de Graan, Pierre N. E., Koeleman, Bobby P. C., Becker, Albert, Schoch, Susanne, von Lehe, Marec, Reif, Philipp S., Rosenow, Felix, Becker, Felicitas, Weber, Yvonne, Lerche, Holger, Rössler, Karl, Buchfelder, Michael, Hamer, Hajo M., Kobow, Katja, Coras, Roland, Blumcke, Ingmar, Scheffer, Ingrid E., Berkovic, Samuel F., Weale, Michael E., Delanty, Norman, Depondt, Chantal, Cavalleri, Gianpiero L., Kunz, Wolfram S., Sisodiya, Sanjay M., Kasperavičiūtė, Dalia, Catarino, Claudia B., Matarin, Mar, Leu, Costin, Novy, Jan, Tostevin, Anna, Leal, Bárbara, Hessel, Ellen V. S., Hallmann, Kerstin, Hildebrand, Michael S., Dahl, Hans-Henrik M., Ryten, Mina, Trabzuni, Daniah, Ramasamy, Adaikalavan, Alhusaini, Saud, Doherty, Colin P., Dorn, Thomas, Hansen, Jörg, Krämer, Günter, Steinhoff, Bernhard J., Zumsteg, Dominik, Duncan, Susan, Kälviäinen, Reetta K., Eriksson, Kai J., Kantanen, Anne-Mari, Pandolfo, Massimo, Gruber-Sedlmayr, Ursula, Schlachter, Kurt, Reinthaler, Eva M., Stogmann, Elisabeth, Zimprich, Fritz, Théâtre, Emilie, Smith, Colin, O'Brien, Terence J., Meng Tan, K., Petrovski, Slave, Robbiano, Angela, Paravidino, Roberta, Zara, Federico, Striano, Pasquale, Sperling, Michael R., Buono, Russell J., Hakonarson, Hakon, Chaves, João, Costa, Paulo P., Silva, Berta M., da Silva, António M., de Graan, Pierre N. E., Koeleman, Bobby P. C., Becker, Albert, Schoch, Susanne, von Lehe, Marec, Reif, Philipp S., Rosenow, Felix, Becker, Felicitas, Weber, Yvonne, Lerche, Holger, Rössler, Karl, Buchfelder, Michael, Hamer, Hajo M., Kobow, Katja, Coras, Roland, Blumcke, Ingmar, Scheffer, Ingrid E., Berkovic, Samuel F., Weale, Michael E., Delanty, Norman, Depondt, Chantal, Cavalleri, Gianpiero L., Kunz, Wolfram S., and Sisodiya, Sanjay M.
Abstract: Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10−9, odds ratio (A) = 1.42, 95% confidence interval: 1.26-1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and o
Published: 2017

34. Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study

Author: Kasperavičiūtė, Dalia, Catarino, Claudia B., Heinzen, Erin L., Depondt, Chantal, Cavalleri, Gianpiero L., Caboclo, Luis O., Tate, Sarah K., Jamnadas-Khoda, Jenny, Chinthapalli, Krishna, Clayton, Lisa M.S., Shianna, Kevin V., Radtke, Rodney A., Mikati, Mohamad A., Gallentine, William B., Husain, Aatif M., Alhusaini, Saud, Leppert, David, Middleton, Lefkos T., Gibson, Rachel A., Johnson, Michael R., Matthews, Paul M., Hosford, David, Heuser, Kjell, Amos, Leslie, Ortega, Marcos, Zumsteg, Dominik, Wieser, Heinz-Gregor, Steinhoff, Bernhard J., Krämer, Günter, Hansen, Jörg, Dorn, Thomas, Kantanen, Anne-Mari, Gjerstad, Leif, Peuralinna, Terhi, Hernandez, Dena G., Eriksson, Kai J., Kälviäinen, Reetta K., Doherty, Colin P., Wood, Nicholas W., Pandolfo, Massimo, Duncan, John S., Sander, Josemir W., Delanty, Norman, Goldstein, David B., Sisodiya, Sanjay M., Kasperavičiūtė, Dalia, Catarino, Claudia B., Heinzen, Erin L., Depondt, Chantal, Cavalleri, Gianpiero L., Caboclo, Luis O., Tate, Sarah K., Jamnadas-Khoda, Jenny, Chinthapalli, Krishna, Clayton, Lisa M.S., Shianna, Kevin V., Radtke, Rodney A., Mikati, Mohamad A., Gallentine, William B., Husain, Aatif M., Alhusaini, Saud, Leppert, David, Middleton, Lefkos T., Gibson, Rachel A., Johnson, Michael R., Matthews, Paul M., Hosford, David, Heuser, Kjell, Amos, Leslie, Ortega, Marcos, Zumsteg, Dominik, Wieser, Heinz-Gregor, Steinhoff, Bernhard J., Krämer, Günter, Hansen, Jörg, Dorn, Thomas, Kantanen, Anne-Mari, Gjerstad, Leif, Peuralinna, Terhi, Hernandez, Dena G., Eriksson, Kai J., Kälviäinen, Reetta K., Doherty, Colin P., Wood, Nicholas W., Pandolfo, Massimo, Duncan, John S., Sander, Josemir W., Delanty, Norman, Goldstein, David B., and Sisodiya, Sanjay M.
Abstract: Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio <1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies
Published: 2017

35. Comparative effectiveness of antiepileptic drugs in patients with mesial temporal lobe epilepsy with hippocampal sclerosis

Author: Androsova, Ganna, Borghei, Mojgansadat, Depondt, Chantal, Brodie, M J, Chinthapalli, Krishna, de Haan, Gerrit Jan, Doherty, Colin P, Gudmundsson, Lárus L.J., Heavin, Sinead, Ingason, Andres, Johnson, Michael, Kennedy, Clare, Krenn, Martin, McCormack, Mark, O'Brien, Terence John, Pandolfo, Massimo, Pataraia, Ekaterina, Petrovski, Slave, Rau, Sarah, Sargsyan, Narek, Slattery, Lisa, Stefánsson, Kári, Stern, William, Tostevin, Anna, Willis, Joseph, Zimprich, Fritz, Androsova, Ganna, Borghei, Mojgansadat, Depondt, Chantal, Brodie, M J, Chinthapalli, Krishna, de Haan, Gerrit Jan, Doherty, Colin P, Gudmundsson, Lárus L.J., Heavin, Sinead, Ingason, Andres, Johnson, Michael, Kennedy, Clare, Krenn, Martin, McCormack, Mark, O'Brien, Terence John, Pandolfo, Massimo, Pataraia, Ekaterina, Petrovski, Slave, Rau, Sarah, Sargsyan, Narek, Slattery, Lisa, Stefánsson, Kári, Stern, William, Tostevin, Anna, Willis, Joseph, and Zimprich, Fritz
Abstract: Objective: Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is a common epilepsy syndrome that is often poorly controlled by antiepileptic drug (AED) treatment. Comparative AED effectiveness studies in this condition are lacking. We report retention, efficacy, and tolerability in a cohort of patients with MTLE-HS. Methods: Clinical data were collected from a European database of patients with epilepsy. We estimated retention, 12-month seizure freedom, and adverse drug reaction (ADR) rates for the 10 most commonly used AEDs in patients with MTLE-HS. Results: Seven hundred sixty-seven patients with a total of 3,249 AED trials were included. The highest 12-month retention rates were observed with carbamazepine (85.9%), valproate (85%), and clobazam (79%). Twelve-month seizure freedom rates varied from 1.2% for gabapentin and vigabatrin to 11% for carbamazepine. Response rates were highest for AEDs that were prescribed as initial treatment and lowest for AEDs that were used in a third or higher instance. ADRs were reported in 47.6% of patients, with the highest rates observed with oxcarbazepine (35.7%), topiramate (30.9%), and pregabalin (27.4%), and the lowest rates with clobazam (6.5%), gabapentin (8.9%), and lamotrigine (16.6%). The most commonly reported ADRs were lethargy and drowsiness, dizziness, vertigo and ataxia, and blurred vision and diplopia. Significance: Our results did not demonstrate any clear advantage of newer versus older AEDs. Our results provide useful insights into AED retention, efficacy, and ADR rates in patients with MTLE-HS., 0, SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2017

36. Neurodegenerative Disorders : A Clinical Guide / edited by Orla Hardiman, Colin P. Doherty, Marwa Elamin, Peter Bede.

Author: Hardiman, Orla. editor., Doherty, Colin P. editor., Elamin, Marwa. editor., Bede, Peter. editor., SpringerLink (Online service), Hardiman, Orla. editor., Doherty, Colin P. editor., Elamin, Marwa. editor., Bede, Peter. editor., and SpringerLink (Online service)
Abstract: This new edition provides an accessible guide to the commonest neurodegenerative diseases, outlining the main clinical features, treatment options and outcomes of the conditions most frequently encountered in clinical practice. Beginning with an overview of the general principles that underlie degeneration, and the contribution of established and new diagnostics techniques, the book goes on to describe the most common neurodegenerative conditions and, new for the second edition, also HIV dementia and multiple sclerosis. Final chapters cover important management issues including the use of palliative care strategies, biomarkers and neuropsychology. Written by experts in the field internationally Neurodegenerative Disorders, Second Edition is a practical guide for clinicians that will be indispensable for the management of these conditions.
Published: 2016

37. Neurodegenerative Disorders : A Clinical Guide / edited by Orla Hardiman, Colin P. Doherty, Marwa Elamin, Peter Bede.

Author: Hardiman, Orla. editor., Doherty, Colin P. editor., Elamin, Marwa. editor., Bede, Peter. editor., SpringerLink (Online service), Hardiman, Orla. editor., Doherty, Colin P. editor., Elamin, Marwa. editor., Bede, Peter. editor., and SpringerLink (Online service)
Abstract: This new edition provides an accessible guide to the commonest neurodegenerative diseases, outlining the main clinical features, treatment options and outcomes of the conditions most frequently encountered in clinical practice. Beginning with an overview of the general principles that underlie degeneration, and the contribution of established and new diagnostics techniques, the book goes on to describe the most common neurodegenerative conditions and, new for the second edition, also HIV dementia and multiple sclerosis. Final chapters cover important management issues including the use of palliative care strategies, biomarkers and neuropsychology. Written by experts in the field internationally Neurodegenerative Disorders, Second Edition is a practical guide for clinicians that will be indispensable for the management of these conditions.
Published: 2016

38. Neurodegenerative Disorders: A Clinical Guide

Author: Hardiman, Orla., Doherty, Colin P., Elamin, Marwa., Bede, Peter., Hardiman, Orla., Doherty, Colin P., Elamin, Marwa., and Bede, Peter.
Published: 2016

39. Neurodegenerative Disorders: A Clinical Guide

Author: Hardiman, Orla., Doherty, Colin P., Elamin, Marwa., Bede, Peter., Hardiman, Orla., Doherty, Colin P., Elamin, Marwa., and Bede, Peter.
Published: 2016

40. Neurodegenerative Disorders: A Clinical Guide

Author: Hardiman, Orla., Doherty, Colin P., Elamin, Marwa., Bede, Peter., Hardiman, Orla., Doherty, Colin P., Elamin, Marwa., and Bede, Peter.
Published: 2016

41. Neurodegenerative Disorders: A Clinical Guide

Author: Hardiman, Orla., Doherty, Colin P., Elamin, Marwa., Bede, Peter., Hardiman, Orla., Doherty, Colin P., Elamin, Marwa., and Bede, Peter.
Published: 2016

42. Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A

Author: Kasperavičiūtė, Dalia, Catarino, Claudia B, Matarin, Mar, Leu, Costin, Novy, Jan, Tostevin, Anna, Leal, Bárbara, Hessel, Ellen V S, Hallmann, Kerstin, Hildebrand, Michael S, Dahl, Hans-Henrik M, Ryten, Mina, Trabzuni, Daniah, Ramasamy, Adaikalavan, Alhusaini, Saud, Doherty, Colin P, Dorn, Thomas, Hansen, Jörg, Krämer, Günter, Steinhoff, Bernhard J, Zumsteg, Dominik, Duncan, Susan, Kälviäinen, Reetta K, Eriksson, Kai J, Kantanen, Anne-Mari, Pandolfo, Massimo, Gruber-Sedlmayr, Ursula, Schlachter, Kurt, Reinthaler, Eva M, Stogmann, Elisabeth, et al, Kasperavičiūtė, Dalia, Catarino, Claudia B, Matarin, Mar, Leu, Costin, Novy, Jan, Tostevin, Anna, Leal, Bárbara, Hessel, Ellen V S, Hallmann, Kerstin, Hildebrand, Michael S, Dahl, Hans-Henrik M, Ryten, Mina, Trabzuni, Daniah, Ramasamy, Adaikalavan, Alhusaini, Saud, Doherty, Colin P, Dorn, Thomas, Hansen, Jörg, Krämer, Günter, Steinhoff, Bernhard J, Zumsteg, Dominik, Duncan, Susan, Kälviäinen, Reetta K, Eriksson, Kai J, Kantanen, Anne-Mari, Pandolfo, Massimo, Gruber-Sedlmayr, Ursula, Schlachter, Kurt, Reinthaler, Eva M, Stogmann, Elisabeth, and et al
Abstract: Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10−9, odds ratio (A) = 1.42, 95% confidence interval: 1.26-1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and o
Published: 2013

43. Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A.

Author: Kasperaviciute, Dalia, Catarino, Claudia B, Matarin, Mar, Leu, Costin, Novy, Jan, Tostevin, Anna, Leal, Bárbara, Hessel, Ellen V S, Hallmann, Kerstin, Hildebrand, Michael S, Dahl, Hans-Henrik M, Ryten, Mina, Trabzuni, Daniah, Ramasamy, Adaikalavan, Alhusaini, Saud, Doherty, Colin P, Dorn, Thomas, Hansen, Jörg, Krämer, Günter, Steinhoff, Bernhard J, Zumsteg, Dominik, Duncan, Susan, Kälviäinen, Reetta K, Eriksson, Kai J, Kantanen, Anne-Mari, Pandolfo, Massimo, Gruber-Sedlmayr, Ursula, Schlachter, Kurt, Reinthaler, Eva M, Stogmann, Elisabeth, Zimprich, Fritz, Théâtre, Emilie, Smith, Colin, O'Brien, Terence J, Meng Tan, K, Petrovski, Slave, Robbiano, Angela, Paravidino, Roberta, Zara, Federico, Striano, Pasquale, Sperling, Michael R, Buono, Russell J, Hakonarson, Hakon, Chaves, João, Costa, Paulo P, Silva, Berta M, da Silva, António M, de Graan, Pierre N E, Koeleman, Bobby P C, Becker, Albert, Schoch, Susanne, von Lehe, Marec, Reif, Philipp S, Rosenow, Felix, Becker, Felicitas, Weber, Yvonne, Lerche, Holger, Rössler, Karl, Buchfelder, Michael, Hamer, Hajo M, Kobow, Katja, Coras, Roland, Blumcke, Ingmar, Scheffer, Ingrid E, Berkovic, Samuel F, Weale, Michael E., UK Brain Expression Consortium, Delanty, Norman, Depondt, Chantal, Cavalleri, Gianpiero L, Kunz, Wolfram S, Sisodiya, Sanjay M, Kasperaviciute, Dalia, Catarino, Claudia B, Matarin, Mar, Leu, Costin, Novy, Jan, Tostevin, Anna, Leal, Bárbara, Hessel, Ellen V S, Hallmann, Kerstin, Hildebrand, Michael S, Dahl, Hans-Henrik M, Ryten, Mina, Trabzuni, Daniah, Ramasamy, Adaikalavan, Alhusaini, Saud, Doherty, Colin P, Dorn, Thomas, Hansen, Jörg, Krämer, Günter, Steinhoff, Bernhard J, Zumsteg, Dominik, Duncan, Susan, Kälviäinen, Reetta K, Eriksson, Kai J, Kantanen, Anne-Mari, Pandolfo, Massimo, Gruber-Sedlmayr, Ursula, Schlachter, Kurt, Reinthaler, Eva M, Stogmann, Elisabeth, Zimprich, Fritz, Théâtre, Emilie, Smith, Colin, O'Brien, Terence J, Meng Tan, K, Petrovski, Slave, Robbiano, Angela, Paravidino, Roberta, Zara, Federico, Striano, Pasquale, Sperling, Michael R, Buono, Russell J, Hakonarson, Hakon, Chaves, João, Costa, Paulo P, Silva, Berta M, da Silva, António M, de Graan, Pierre N E, Koeleman, Bobby P C, Becker, Albert, Schoch, Susanne, von Lehe, Marec, Reif, Philipp S, Rosenow, Felix, Becker, Felicitas, Weber, Yvonne, Lerche, Holger, Rössler, Karl, Buchfelder, Michael, Hamer, Hajo M, Kobow, Katja, Coras, Roland, Blumcke, Ingmar, Scheffer, Ingrid E, Berkovic, Samuel F, Weale, Michael E., UK Brain Expression Consortium, Delanty, Norman, Depondt, Chantal, Cavalleri, Gianpiero L, Kunz, Wolfram S, and Sisodiya, Sanjay M
Abstract: Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10(-9), odds ratio (A) = 1.42, 95% confidence interval: 1.26-1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and
Published: 2013

44. Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study.

Author: Kasperavičiūtė, Dalia, Catarino, Claudia B, Heinzen, Erin, Depondt, Chantal, Cavalleri, Gianpiero L, Caboclo, Luis O, Tate, Sarah K, Jamnadas-Khoda, Jenny, Chinthapalli, Krishna, Clayton, Lisa M S, Shianna, Kevin V, Radtke, Rodney A, Mikati, Mohamad A, Gallentine, William B, Husain, Aatif M, Alhusaini, Saud, Leppert, David, Middleton, Lefkos T, Gibson, Rachel A, Johnson, Michael R, Matthews, Paul M, Hosford, David, Heuser, Kjell, Amos, Leslie, Ortega, Marcos, Zumsteg, Dominik, Wieser, Heinz-Gregor, Steinhoff, Bernhard J, Kramer, G, Hansen, Jörg, Dorn, Thomas, Kantanen, Anne-Mari, Gjerstad, Leif, Peuralinna, Terhi, Hernandez, Dena G, Eriksson, Kai, Kalviainen, Reetta, Doherty, Colin P, Wood, Nicholas W, Pandolfo, Massimo, Duncan, John S, Sander, Josemir W, Delanty, Norman, Goldstein, David B, Sisodiya, Sanjay M, Kasperavičiūtė, Dalia, Catarino, Claudia B, Heinzen, Erin, Depondt, Chantal, Cavalleri, Gianpiero L, Caboclo, Luis O, Tate, Sarah K, Jamnadas-Khoda, Jenny, Chinthapalli, Krishna, Clayton, Lisa M S, Shianna, Kevin V, Radtke, Rodney A, Mikati, Mohamad A, Gallentine, William B, Husain, Aatif M, Alhusaini, Saud, Leppert, David, Middleton, Lefkos T, Gibson, Rachel A, Johnson, Michael R, Matthews, Paul M, Hosford, David, Heuser, Kjell, Amos, Leslie, Ortega, Marcos, Zumsteg, Dominik, Wieser, Heinz-Gregor, Steinhoff, Bernhard J, Kramer, G, Hansen, Jörg, Dorn, Thomas, Kantanen, Anne-Mari, Gjerstad, Leif, Peuralinna, Terhi, Hernandez, Dena G, Eriksson, Kai, Kalviainen, Reetta, Doherty, Colin P, Wood, Nicholas W, Pandolfo, Massimo, Duncan, John S, Sander, Josemir W, Delanty, Norman, Goldstein, David B, and Sisodiya, Sanjay M
Abstract: Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio <1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies., JOURNAL ARTICLE, SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2010

45. Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes.

Author: Heinzen, Erin, Radtke, Rodney A, Urban, Thomas J, Cavalleri, Gianpiero L, Depondt, Chantal, Need, Anna C, Walley, Nicole, Nicoletti, Paola, Ge, Dongliang, Catarino, Claudia B, Duncan, John S, Kasperavičiūtė, Dalia, Tate, Sarah K, Caboclo, Luis O, Sander, Josemir W, Clayton, Lisa M S, Linney, Kristen N, Shianna, Kevin V, Gumbs, Curtis, Smith, Jason, Cronin, Kenneth D, Maia, Jessica M, Doherty, Colin P, Pandolfo, Massimo, Leppert, David, Middleton, Lefkos T, Gibson, Rachel A, Johnson, Michael R, Matthews, Paul M, Hosford, David, Kalviainen, Reetta, Eriksson, Kai, Kantanen, Anne-Mari, Dorn, Thomas, Hansen, Jörg, Kramer, G, Steinhoff, Bernhard J, Wieser, Heinz-Gregor, Zumsteg, Dominik, Ortega, Marcos, Wood, Nicholas W, Huxley-Jones, Julie, Mikati, Mohamad A, Gallentine, William B, Husain, Aatif M, Buckley, Patrick G, Stallings, Ray L, Podgoreanu, Mihai V, Delanty, Norman, Sisodiya, Sanjay M, Goldstein, David B, Heinzen, Erin, Radtke, Rodney A, Urban, Thomas J, Cavalleri, Gianpiero L, Depondt, Chantal, Need, Anna C, Walley, Nicole, Nicoletti, Paola, Ge, Dongliang, Catarino, Claudia B, Duncan, John S, Kasperavičiūtė, Dalia, Tate, Sarah K, Caboclo, Luis O, Sander, Josemir W, Clayton, Lisa M S, Linney, Kristen N, Shianna, Kevin V, Gumbs, Curtis, Smith, Jason, Cronin, Kenneth D, Maia, Jessica M, Doherty, Colin P, Pandolfo, Massimo, Leppert, David, Middleton, Lefkos T, Gibson, Rachel A, Johnson, Michael R, Matthews, Paul M, Hosford, David, Kalviainen, Reetta, Eriksson, Kai, Kantanen, Anne-Mari, Dorn, Thomas, Hansen, Jörg, Kramer, G, Steinhoff, Bernhard J, Wieser, Heinz-Gregor, Zumsteg, Dominik, Ortega, Marcos, Wood, Nicholas W, Huxley-Jones, Julie, Mikati, Mohamad A, Gallentine, William B, Husain, Aatif M, Buckley, Patrick G, Stallings, Ray L, Podgoreanu, Mihai V, Delanty, Norman, Sisodiya, Sanjay M, and Goldstein, David B
Abstract: Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy syndromes and in 1299 neurologically-normal controls. Large deletions (> 100 kb) at 16p13.11 were observed in 23 patients, whereas no control had a deletion greater than 16 kb. Patients, even those with identically sized 16p13.11 deletions, presented with highly variable epilepsy phenotypes. For a subset of patients with a 16p13.11 deletion, we show a consistent reduction of expression for included genes, suggesting that haploinsufficiency might contribute to pathogenicity. We also investigated another possible mechanism of pathogenicity by using hybridization-based capture and next-generation sequencing of the homologous chromosome for ten 16p13.11-deletion patients to look for unmasked recessive mutations. Follow-up genotyping of suggestive polymorphisms failed to identify any convincing recessive-acting mutations in the homologous interval corresponding to the deletion. The observation that two of the 16p13.11 deletions were larger than 2 Mb in size led us to screen for other large deletions. We found 12 additional genomic regions harboring deletions > 2 Mb in epilepsy patients, and none in controls. Additional evaluation is needed to characterize the role of these exceedingly large, non-locus-specific deletions in epilepsy. Collectively, these data implicate 16p13.11 and possibly other large deletions as risk factors for a wide range of epilepsy disorders, and they appear to point toward haploinsufficiency as a contributor to the pathogenicity of deletions., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2010

46. Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study.

Author: Kasperavičiūtė, Dalia, Catarino, Claudia B, Heinzen, Erin, Depondt, Chantal, Cavalleri, Gianpiero L, Caboclo, Luis O, Tate, Sarah K, Jamnadas-Khoda, Jenny, Chinthapalli, Krishna, Clayton, Lisa M S, Shianna, Kevin V, Radtke, Rodney A, Mikati, Mohamad A, Gallentine, William B, Husain, Aatif M, Alhusaini, Saud, Leppert, David, Middleton, Lefkos T, Gibson, Rachel A, Johnson, Michael R, Matthews, Paul M, Hosford, David, Heuser, Kjell, Amos, Leslie, Ortega, Marcos, Zumsteg, Dominik, Wieser, Heinz-Gregor, Steinhoff, Bernhard J, Kramer, G, Hansen, Jörg, Dorn, Thomas, Kantanen, Anne-Mari, Gjerstad, Leif, Peuralinna, Terhi, Hernandez, Dena G, Eriksson, Kai, Kalviainen, Reetta, Doherty, Colin P, Wood, Nicholas W, Pandolfo, Massimo, Duncan, John S, Sander, Josemir W, Delanty, Norman, Goldstein, David B, Sisodiya, Sanjay M, Kasperavičiūtė, Dalia, Catarino, Claudia B, Heinzen, Erin, Depondt, Chantal, Cavalleri, Gianpiero L, Caboclo, Luis O, Tate, Sarah K, Jamnadas-Khoda, Jenny, Chinthapalli, Krishna, Clayton, Lisa M S, Shianna, Kevin V, Radtke, Rodney A, Mikati, Mohamad A, Gallentine, William B, Husain, Aatif M, Alhusaini, Saud, Leppert, David, Middleton, Lefkos T, Gibson, Rachel A, Johnson, Michael R, Matthews, Paul M, Hosford, David, Heuser, Kjell, Amos, Leslie, Ortega, Marcos, Zumsteg, Dominik, Wieser, Heinz-Gregor, Steinhoff, Bernhard J, Kramer, G, Hansen, Jörg, Dorn, Thomas, Kantanen, Anne-Mari, Gjerstad, Leif, Peuralinna, Terhi, Hernandez, Dena G, Eriksson, Kai, Kalviainen, Reetta, Doherty, Colin P, Wood, Nicholas W, Pandolfo, Massimo, Duncan, John S, Sander, Josemir W, Delanty, Norman, Goldstein, David B, and Sisodiya, Sanjay M
Abstract: Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio <1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies., JOURNAL ARTICLE, SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2010

47. Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes.

Author: Heinzen, Erin, Radtke, Rodney A, Urban, Thomas J, Cavalleri, Gianpiero L, Depondt, Chantal, Need, Anna C, Walley, Nicole, Nicoletti, Paola, Ge, Dongliang, Catarino, Claudia B, Duncan, John S, Kasperavičiūtė, Dalia, Tate, Sarah K, Caboclo, Luis O, Sander, Josemir W, Clayton, Lisa M S, Linney, Kristen N, Shianna, Kevin V, Gumbs, Curtis, Smith, Jason, Cronin, Kenneth D, Maia, Jessica M, Doherty, Colin P, Pandolfo, Massimo, Leppert, David, Middleton, Lefkos T, Gibson, Rachel A, Johnson, Michael R, Matthews, Paul M, Hosford, David, Kalviainen, Reetta, Eriksson, Kai, Kantanen, Anne-Mari, Dorn, Thomas, Hansen, Jörg, Kramer, G, Steinhoff, Bernhard J, Wieser, Heinz-Gregor, Zumsteg, Dominik, Ortega, Marcos, Wood, Nicholas W, Huxley-Jones, Julie, Mikati, Mohamad A, Gallentine, William B, Husain, Aatif M, Buckley, Patrick G, Stallings, Ray L, Podgoreanu, Mihai V, Delanty, Norman, Sisodiya, Sanjay M, Goldstein, David B, Heinzen, Erin, Radtke, Rodney A, Urban, Thomas J, Cavalleri, Gianpiero L, Depondt, Chantal, Need, Anna C, Walley, Nicole, Nicoletti, Paola, Ge, Dongliang, Catarino, Claudia B, Duncan, John S, Kasperavičiūtė, Dalia, Tate, Sarah K, Caboclo, Luis O, Sander, Josemir W, Clayton, Lisa M S, Linney, Kristen N, Shianna, Kevin V, Gumbs, Curtis, Smith, Jason, Cronin, Kenneth D, Maia, Jessica M, Doherty, Colin P, Pandolfo, Massimo, Leppert, David, Middleton, Lefkos T, Gibson, Rachel A, Johnson, Michael R, Matthews, Paul M, Hosford, David, Kalviainen, Reetta, Eriksson, Kai, Kantanen, Anne-Mari, Dorn, Thomas, Hansen, Jörg, Kramer, G, Steinhoff, Bernhard J, Wieser, Heinz-Gregor, Zumsteg, Dominik, Ortega, Marcos, Wood, Nicholas W, Huxley-Jones, Julie, Mikati, Mohamad A, Gallentine, William B, Husain, Aatif M, Buckley, Patrick G, Stallings, Ray L, Podgoreanu, Mihai V, Delanty, Norman, Sisodiya, Sanjay M, and Goldstein, David B
Abstract: Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy syndromes and in 1299 neurologically-normal controls. Large deletions (> 100 kb) at 16p13.11 were observed in 23 patients, whereas no control had a deletion greater than 16 kb. Patients, even those with identically sized 16p13.11 deletions, presented with highly variable epilepsy phenotypes. For a subset of patients with a 16p13.11 deletion, we show a consistent reduction of expression for included genes, suggesting that haploinsufficiency might contribute to pathogenicity. We also investigated another possible mechanism of pathogenicity by using hybridization-based capture and next-generation sequencing of the homologous chromosome for ten 16p13.11-deletion patients to look for unmasked recessive mutations. Follow-up genotyping of suggestive polymorphisms failed to identify any convincing recessive-acting mutations in the homologous interval corresponding to the deletion. The observation that two of the 16p13.11 deletions were larger than 2 Mb in size led us to screen for other large deletions. We found 12 additional genomic regions harboring deletions > 2 Mb in epilepsy patients, and none in controls. Additional evaluation is needed to characterize the role of these exceedingly large, non-locus-specific deletions in epilepsy. Collectively, these data implicate 16p13.11 and possibly other large deletions as risk factors for a wide range of epilepsy disorders, and they appear to point toward haploinsufficiency as a contributor to the pathogenicity of deletions., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2010

48. No major role of common SV2A variation for predisposition or levetiracetam response in epilepsy.

Author: Lynch, John M, Tate, Sarah K, Kinirons, Peter, Weale, Michael E, Cavalleri, Gianpiero L, Depondt, Chantal, Murphy, Kevin, O'Rourke, Deirdre, Doherty, Colin P, Shianna, Kevin V, Wood, Nicholas W, Sander, Josemir W, Delanty, Norman, Goldstein, David B, Sisodiya, Sanjay M, Lynch, John M, Tate, Sarah K, Kinirons, Peter, Weale, Michael E, Cavalleri, Gianpiero L, Depondt, Chantal, Murphy, Kevin, O'Rourke, Deirdre, Doherty, Colin P, Shianna, Kevin V, Wood, Nicholas W, Sander, Josemir W, Delanty, Norman, Goldstein, David B, and Sisodiya, Sanjay M
Abstract: Levetiracetam (LEV), a newer antiepileptic drug (AED) useful for several epilepsy syndromes, binds to SV2A. Identifying genetic variants that influence response to LEV may allow more tailored use of LEV. Obvious candidate genes are SV2A, SV2B and SV2C, which encode the only known binding site, synaptic vesicle protein 2 (SV2), with LEV binding to the SV2A isoform. SV2A is an essential protein as homozygous SV2A knockout mice appear normal at birth but fail to grow, experience severe seizures and die by 3 weeks. We addressed characterising AED response issues in pharmacogenetics and whether variation in these genes associates with response to LEV in two independent cohorts with epilepsy. We also investigated whether variation in these three genes associated with epilepsy predisposition in two larger cohorts of patients with various epilepsy phenotypes. Common genetic variation in SV2A, encoding the actual binding site of LEV, was fully represented in this study whereas SV2B and SV2C were not fully covered. None of the polymorphisms tested in SV2A, SV2B or SV2C influence LEV response or predisposition to epilepsy. We found no association between genetic variation in SV2A, SV2B or SV2C and response to LEV or epilepsy predisposition. We suggest this study design may be used in future pharmacogenetic work examining AED or LEV efficacy. However, different study designs would be needed to examine common variation with minor effect sizes, or rare variation, influencing AED or LEV response or epilepsy predisposition., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published
Published: 2009

49. Prolonged rote learning produces delayed memory facilitation and metabolic changes in the hippocampus of the ageing human brain

Author: Roche, Richard, Mullally, Sinéad L., McNulty, Jonathan P., Hayden, Judy, Brennan, Paul, Doherty, Colin P., Fitzsimons, Mary, McMackin, Deirdre, Prendergast, Julie, Sukumaran, Sunita, Mangaoang, Maeve A., Robertson, Ian H., O'Mara, Shane, Roche, Richard, Mullally, Sinéad L., McNulty, Jonathan P., Hayden, Judy, Brennan, Paul, Doherty, Colin P., Fitzsimons, Mary, McMackin, Deirdre, Prendergast, Julie, Sukumaran, Sunita, Mangaoang, Maeve A., Robertson, Ian H., and O'Mara, Shane
Abstract: Repeated rehearsal is one method by which verbal material may be transferred from short-to long-term memory. We hypothesised that extended engagement of memory structures through prolonged rehearsal would result in enhanced efficacy of recall and also of brain structures implicated in new learning. Twenty-four normal participants aged 55-70 (mean = 60.1) engaged in six weeks of rote learning, during which they learned 500 words per week every week (prose, poetry etc.). An extensive battery of memory tests was administered on three occasions, each six weeks apart. In addition, proton magnetic resonance spectroscopy (1H-MRS) was used to measure metabolite levels in seven voxels of interest (VOIs) (including hippocampus) before and after learning.
Published: 2009

50. Prolonged rote learning produces delayed memory facilitation and metabolic changes in the hippocampus of the ageing human brain

Author: Roche, Richard, Mullally, Sinéad L., McNulty, Jonathan P., Hayden, Judy, Brennan, Paul, Doherty, Colin P., Fitzsimons, Mary, McMackin, Deirdre, Prendergast, Julie, Sukumaran, Sunita, Mangaoang, Maeve A., Robertson, Ian H., O'Mara, Shane, Roche, Richard, Mullally, Sinéad L., McNulty, Jonathan P., Hayden, Judy, Brennan, Paul, Doherty, Colin P., Fitzsimons, Mary, McMackin, Deirdre, Prendergast, Julie, Sukumaran, Sunita, Mangaoang, Maeve A., Robertson, Ian H., and O'Mara, Shane
Abstract: Repeated rehearsal is one method by which verbal material may be transferred from short-to long-term memory. We hypothesised that extended engagement of memory structures through prolonged rehearsal would result in enhanced efficacy of recall and also of brain structures implicated in new learning. Twenty-four normal participants aged 55-70 (mean = 60.1) engaged in six weeks of rote learning, during which they learned 500 words per week every week (prose, poetry etc.). An extensive battery of memory tests was administered on three occasions, each six weeks apart. In addition, proton magnetic resonance spectroscopy (1H-MRS) was used to measure metabolite levels in seven voxels of interest (VOIs) (including hippocampus) before and after learning.
Published: 2009

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