Mapping Lesion-Related Epilepsy to a Human Brain Network

Frederic L.W.V.J. Schaper; Janne Nordberg; Alexander L. Cohen; Christopher Lin; Joey Hsu; Andreas Horn; Michael A. Ferguson; Shan H. Siddiqi; William Drew; Louis Soussand; Anderson M. Winkler; Marta Simó; Jordi Bruna; Sylvain Rheims; Marc Guenot; Marco Bucci; Lauri Nummenmaa; Julie Staals; Albert J. Colon; Linda Ackermans; Ellen J. Bubrick; Jurriaan M. Peters; Ona Wu; Natalia S. Rost; Jordan Grafman; Hal Blumenfeld; Yasin Temel; Rob P.W. Rouhl; Juho Joutsa; Michael D. Fox

doi:10.1001/jamaneurol.2023.1988

Mapping Lesion-Related Epilepsy to a Human Brain Network

Frederic L.W.V.J. Schaper^*, Janne Nordberg, Alexander L. Cohen, Christopher Lin, Joey Hsu, Andreas Horn, Michael A. Ferguson, Shan H. Siddiqi, William Drew, Louis Soussand, Anderson M. Winkler, Marta Simó, Jordi Bruna, Sylvain Rheims, Marc Guenot, Marco Bucci, Lauri Nummenmaa, Julie Staals, Albert J. Colon, Linda AckermansEllen J. Bubrick, Jurriaan M. Peters, Ona Wu, Natalia S. Rost, Jordan Grafman, Hal Blumenfeld, Yasin Temel, Rob P.W. Rouhl, Juho Joutsa, Michael D. Fox^*

^*Corresponding author for this work

Physical Medicine and Rehabilitation

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

Abstract

Importance: It remains unclear why lesions in some locations cause epilepsy while others do not. Identifying the brain regions or networks associated with epilepsy by mapping these lesions could inform prognosis and guide interventions. Objective: To assess whether lesion locations associated with epilepsy map to specific brain regions and networks. Design, Setting, and Participants: This case-control study used lesion location and lesion network mapping to identify the brain regions and networks associated with epilepsy in a discovery data set of patients with poststroke epilepsy and control patients with stroke. Patients with stroke lesions and epilepsy (n = 76) or no epilepsy (n = 625) were included. Generalizability to other lesion types was assessed using 4 independent cohorts as validation data sets. The total numbers of patients across all datasets (both discovery and validation datasets) were 347 with epilepsy and 1126 without. Therapeutic relevance was assessed using deep brain stimulation sites that improve seizure control. Data were analyzed from September 2018 through December 2022. All shared patient data were analyzed and included; no patients were excluded. Main Outcomes and Measures: Epilepsy or no epilepsy. Results: Lesion locations from 76 patients with poststroke epilepsy (39 [51%] male; mean [SD] age, 61.0 [14.6] years; mean [SD] follow-up, 6.7 [2.0] years) and 625 control patients with stroke (366 [59%] male; mean [SD] age, 62.0 [14.1] years; follow-up range, 3-12 months) were included in the discovery data set. Lesions associated with epilepsy occurred in multiple heterogenous locations spanning different lobes and vascular territories. However, these same lesion locations were part of a specific brain network defined by functional connectivity to the basal ganglia and cerebellum. Findings were validated in 4 independent cohorts including 772 patients with brain lesions (271 [35%] with epilepsy; 515 [67%] male; median [IQR] age, 60 [50-70] years; follow-up range, 3-35 years). Lesion connectivity to this brain network was associated with increased risk of epilepsy after stroke (odds ratio [OR], 2.82; 95% CI, 2.02-4.10; P <.001) and across different lesion types (OR, 2.85; 95% CI, 2.23-3.69; P <.001). Deep brain stimulation site connectivity to this same network was associated with improved seizure control (r, 0.63; P <.001) in 30 patients with drug-resistant epilepsy (21 [70%] male; median [IQR] age, 39 [32-46] years; median [IQR] follow-up, 24 [16-30] months). Conclusions and Relevance: The findings in this study indicate that lesion-related epilepsy mapped to a human brain network, which could help identify patients at risk of epilepsy after a brain lesion and guide brain stimulation therapies..

Original language	English (US)
Pages (from-to)	891-902
Number of pages	12
Journal	JAMA Neurology
Volume	80
Issue number	9
DOIs	https://doi.org/10.1001/jamaneurol.2023.1988
State	Published - Sep 11 2023

Funding

Funding/Support: Dr Schaper was supported by grants from the American Epilepsy Society (846534), National Institutes of Health (R01NS127892), Royal Netherlands Academy of Arts and Sciences , Dr Jan Meerwaldt Stichting , and Stichting De Drie Lichten . Dr Cohen was supported by grants from the Child Neurology Foundation and the National Institutes of Health (K23MH120510). Dr Horn was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, 424778381–TRR 295), Deutsches Zentrum für Luft- und Raumfahrt (DynaSti grant within the EU Joint Programme Neurodegenerative Disease Research, JPND), the National Institutes of Health (R01 13478451, 1R01NS127892-01 & 2R01 MH113929), and the New Venture Fund (FFOR seed grant). Dr Winkler was supported through the National Institutes of Health Intramural Research Program (ZIA-MH002781 and ZIA-MH002782). Dr Nummenmaa was supported by Academy of Finland grant 332225 and Sigrid Juselius Stiftelse . Dr Joutsa was supported by grants from the Finnish Medical Foundation , Finnish Foundation for Alcohol Studies , Finnish Parkinson Foundation , Sigrid Juselius Foundation , and Turku University Hospital (ERVA funds). Dr Fox was supported by grants from the Sidney R. Baer Jr Foundation , the National Institutes of Health (R01NS127892, R01MH113929, R21MH126271, R56AG069086, R21NS123813), the Nancy Lurie Marks Foundation , the Kaye Family Research Fund , the Ellison-Baszucki Foundation , and the Mather’s Foundation .

ASJC Scopus subject areas

Clinical Neurology

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10.1001/jamaneurol.2023.1988

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Schaper, F. L. W. V. J., Nordberg, J., Cohen, A. L., Lin, C., Hsu, J., Horn, A., Ferguson, M. A., Siddiqi, S. H., Drew, W., Soussand, L., Winkler, A. M., Simó, M., Bruna, J., Rheims, S., Guenot, M., Bucci, M., Nummenmaa, L., Staals, J., Colon, A. J., ... Fox, M. D. (2023). Mapping Lesion-Related Epilepsy to a Human Brain Network. JAMA Neurology, 80(9), 891-902. https://doi.org/10.1001/jamaneurol.2023.1988

@article{359ec351da734df085327e3124f0e58c,

title = "Mapping Lesion-Related Epilepsy to a Human Brain Network",

abstract = "Importance: It remains unclear why lesions in some locations cause epilepsy while others do not. Identifying the brain regions or networks associated with epilepsy by mapping these lesions could inform prognosis and guide interventions. Objective: To assess whether lesion locations associated with epilepsy map to specific brain regions and networks. Design, Setting, and Participants: This case-control study used lesion location and lesion network mapping to identify the brain regions and networks associated with epilepsy in a discovery data set of patients with poststroke epilepsy and control patients with stroke. Patients with stroke lesions and epilepsy (n = 76) or no epilepsy (n = 625) were included. Generalizability to other lesion types was assessed using 4 independent cohorts as validation data sets. The total numbers of patients across all datasets (both discovery and validation datasets) were 347 with epilepsy and 1126 without. Therapeutic relevance was assessed using deep brain stimulation sites that improve seizure control. Data were analyzed from September 2018 through December 2022. All shared patient data were analyzed and included; no patients were excluded. Main Outcomes and Measures: Epilepsy or no epilepsy. Results: Lesion locations from 76 patients with poststroke epilepsy (39 [51%] male; mean [SD] age, 61.0 [14.6] years; mean [SD] follow-up, 6.7 [2.0] years) and 625 control patients with stroke (366 [59%] male; mean [SD] age, 62.0 [14.1] years; follow-up range, 3-12 months) were included in the discovery data set. Lesions associated with epilepsy occurred in multiple heterogenous locations spanning different lobes and vascular territories. However, these same lesion locations were part of a specific brain network defined by functional connectivity to the basal ganglia and cerebellum. Findings were validated in 4 independent cohorts including 772 patients with brain lesions (271 [35%] with epilepsy; 515 [67%] male; median [IQR] age, 60 [50-70] years; follow-up range, 3-35 years). Lesion connectivity to this brain network was associated with increased risk of epilepsy after stroke (odds ratio [OR], 2.82; 95% CI, 2.02-4.10; P <.001) and across different lesion types (OR, 2.85; 95% CI, 2.23-3.69; P <.001). Deep brain stimulation site connectivity to this same network was associated with improved seizure control (r, 0.63; P <.001) in 30 patients with drug-resistant epilepsy (21 [70%] male; median [IQR] age, 39 [32-46] years; median [IQR] follow-up, 24 [16-30] months). Conclusions and Relevance: The findings in this study indicate that lesion-related epilepsy mapped to a human brain network, which could help identify patients at risk of epilepsy after a brain lesion and guide brain stimulation therapies..",

author = "Schaper, {Frederic L.W.V.J.} and Janne Nordberg and Cohen, {Alexander L.} and Christopher Lin and Joey Hsu and Andreas Horn and Ferguson, {Michael A.} and Siddiqi, {Shan H.} and William Drew and Louis Soussand and Winkler, {Anderson M.} and Marta Sim{\'o} and Jordi Bruna and Sylvain Rheims and Marc Guenot and Marco Bucci and Lauri Nummenmaa and Julie Staals and Colon, {Albert J.} and Linda Ackermans and Bubrick, {Ellen J.} and Peters, {Jurriaan M.} and Ona Wu and Rost, {Natalia S.} and Jordan Grafman and Hal Blumenfeld and Yasin Temel and Rouhl, {Rob P.W.} and Juho Joutsa and Fox, {Michael D.}",

year = "2023",

month = sep,

day = "11",

doi = "10.1001/jamaneurol.2023.1988",

language = "English (US)",

volume = "80",

pages = "891--902",

journal = "JAMA Neurology",

issn = "2168-6149",

publisher = "American Medical Association",

number = "9",

}

Schaper, FLWVJ, Nordberg, J, Cohen, AL, Lin, C, Hsu, J, Horn, A, Ferguson, MA, Siddiqi, SH, Drew, W, Soussand, L, Winkler, AM, Simó, M, Bruna, J, Rheims, S, Guenot, M, Bucci, M, Nummenmaa, L, Staals, J, Colon, AJ, Ackermans, L, Bubrick, EJ, Peters, JM, Wu, O, Rost, NS, Grafman, J, Blumenfeld, H, Temel, Y, Rouhl, RPW, Joutsa, J & Fox, MD 2023, 'Mapping Lesion-Related Epilepsy to a Human Brain Network', JAMA Neurology, vol. 80, no. 9, pp. 891-902. https://doi.org/10.1001/jamaneurol.2023.1988

TY - JOUR

T1 - Mapping Lesion-Related Epilepsy to a Human Brain Network

AU - Schaper, Frederic L.W.V.J.

AU - Nordberg, Janne

AU - Cohen, Alexander L.

AU - Lin, Christopher

AU - Hsu, Joey

AU - Horn, Andreas

AU - Ferguson, Michael A.

AU - Siddiqi, Shan H.

AU - Drew, William

AU - Soussand, Louis

AU - Winkler, Anderson M.

AU - Simó, Marta

AU - Bruna, Jordi

AU - Rheims, Sylvain

AU - Guenot, Marc

AU - Bucci, Marco

AU - Nummenmaa, Lauri

AU - Staals, Julie

AU - Colon, Albert J.

AU - Ackermans, Linda

AU - Bubrick, Ellen J.

AU - Peters, Jurriaan M.

AU - Wu, Ona

AU - Rost, Natalia S.

AU - Grafman, Jordan

AU - Blumenfeld, Hal

AU - Temel, Yasin

AU - Rouhl, Rob P.W.

AU - Joutsa, Juho

AU - Fox, Michael D.

PY - 2023/9/11

Y1 - 2023/9/11

N2 - Importance: It remains unclear why lesions in some locations cause epilepsy while others do not. Identifying the brain regions or networks associated with epilepsy by mapping these lesions could inform prognosis and guide interventions. Objective: To assess whether lesion locations associated with epilepsy map to specific brain regions and networks. Design, Setting, and Participants: This case-control study used lesion location and lesion network mapping to identify the brain regions and networks associated with epilepsy in a discovery data set of patients with poststroke epilepsy and control patients with stroke. Patients with stroke lesions and epilepsy (n = 76) or no epilepsy (n = 625) were included. Generalizability to other lesion types was assessed using 4 independent cohorts as validation data sets. The total numbers of patients across all datasets (both discovery and validation datasets) were 347 with epilepsy and 1126 without. Therapeutic relevance was assessed using deep brain stimulation sites that improve seizure control. Data were analyzed from September 2018 through December 2022. All shared patient data were analyzed and included; no patients were excluded. Main Outcomes and Measures: Epilepsy or no epilepsy. Results: Lesion locations from 76 patients with poststroke epilepsy (39 [51%] male; mean [SD] age, 61.0 [14.6] years; mean [SD] follow-up, 6.7 [2.0] years) and 625 control patients with stroke (366 [59%] male; mean [SD] age, 62.0 [14.1] years; follow-up range, 3-12 months) were included in the discovery data set. Lesions associated with epilepsy occurred in multiple heterogenous locations spanning different lobes and vascular territories. However, these same lesion locations were part of a specific brain network defined by functional connectivity to the basal ganglia and cerebellum. Findings were validated in 4 independent cohorts including 772 patients with brain lesions (271 [35%] with epilepsy; 515 [67%] male; median [IQR] age, 60 [50-70] years; follow-up range, 3-35 years). Lesion connectivity to this brain network was associated with increased risk of epilepsy after stroke (odds ratio [OR], 2.82; 95% CI, 2.02-4.10; P <.001) and across different lesion types (OR, 2.85; 95% CI, 2.23-3.69; P <.001). Deep brain stimulation site connectivity to this same network was associated with improved seizure control (r, 0.63; P <.001) in 30 patients with drug-resistant epilepsy (21 [70%] male; median [IQR] age, 39 [32-46] years; median [IQR] follow-up, 24 [16-30] months). Conclusions and Relevance: The findings in this study indicate that lesion-related epilepsy mapped to a human brain network, which could help identify patients at risk of epilepsy after a brain lesion and guide brain stimulation therapies..

AB - Importance: It remains unclear why lesions in some locations cause epilepsy while others do not. Identifying the brain regions or networks associated with epilepsy by mapping these lesions could inform prognosis and guide interventions. Objective: To assess whether lesion locations associated with epilepsy map to specific brain regions and networks. Design, Setting, and Participants: This case-control study used lesion location and lesion network mapping to identify the brain regions and networks associated with epilepsy in a discovery data set of patients with poststroke epilepsy and control patients with stroke. Patients with stroke lesions and epilepsy (n = 76) or no epilepsy (n = 625) were included. Generalizability to other lesion types was assessed using 4 independent cohorts as validation data sets. The total numbers of patients across all datasets (both discovery and validation datasets) were 347 with epilepsy and 1126 without. Therapeutic relevance was assessed using deep brain stimulation sites that improve seizure control. Data were analyzed from September 2018 through December 2022. All shared patient data were analyzed and included; no patients were excluded. Main Outcomes and Measures: Epilepsy or no epilepsy. Results: Lesion locations from 76 patients with poststroke epilepsy (39 [51%] male; mean [SD] age, 61.0 [14.6] years; mean [SD] follow-up, 6.7 [2.0] years) and 625 control patients with stroke (366 [59%] male; mean [SD] age, 62.0 [14.1] years; follow-up range, 3-12 months) were included in the discovery data set. Lesions associated with epilepsy occurred in multiple heterogenous locations spanning different lobes and vascular territories. However, these same lesion locations were part of a specific brain network defined by functional connectivity to the basal ganglia and cerebellum. Findings were validated in 4 independent cohorts including 772 patients with brain lesions (271 [35%] with epilepsy; 515 [67%] male; median [IQR] age, 60 [50-70] years; follow-up range, 3-35 years). Lesion connectivity to this brain network was associated with increased risk of epilepsy after stroke (odds ratio [OR], 2.82; 95% CI, 2.02-4.10; P <.001) and across different lesion types (OR, 2.85; 95% CI, 2.23-3.69; P <.001). Deep brain stimulation site connectivity to this same network was associated with improved seizure control (r, 0.63; P <.001) in 30 patients with drug-resistant epilepsy (21 [70%] male; median [IQR] age, 39 [32-46] years; median [IQR] follow-up, 24 [16-30] months). Conclusions and Relevance: The findings in this study indicate that lesion-related epilepsy mapped to a human brain network, which could help identify patients at risk of epilepsy after a brain lesion and guide brain stimulation therapies..

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Mapping Lesion-Related Epilepsy to a Human Brain Network

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