Research ArticleDISEASES AND DISORDERS

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

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Science Advances  18 Nov 2020:
Vol. 6, no. 47, eabc6457
DOI: 10.1126/sciadv.abc6457
  • Fig. 1 Cortical thickness and subcortical volume in TLE and IGE.

    (A) Cortical thickness and subcortical volume reductions in TLE (n = 732), compared to healthy controls (n = 1418), spanned bilateral precuneus (PFDR < 4 × 10−36), precentral (PFDR < 8 × 10−36), paracentral (PFDR < 6 × 10−29), and superior temporal (PFDR < 3 × 10−14) cortices and ipsilateral hippocampus (PFDR < 2 × 10−199) and thalamus (PFDR < 5 × 10−64). (B) In contrast, gray matter cortical and subcortical atrophy in IGE (n = 289), relative to controls (n = 1075), was more subtle and affected predominantly bilateral precentral cortical regions (PFDR < 9 × 10−10) and the thalamus (PFDR < 3 × 10−6). Negative log10-transformed FDR-corrected P values are shown.

  • Fig. 2 Epilepsy-related atrophy correlates with hub organization.

    (A) Normative functional and structural network organization, derived from the HCP dataset, was used to identify hubs (i.e., regions with greater degree centrality). (B) Schematic of the figure layout is pictured in the middle. Gray matter atrophy related to node-level functional (left) and structural (right) maps of degree centrality, with greater atrophy in hub compared to nonhub regions. Stratifying findings across TLE and IGE, we observed stronger associations between cortico-cortical functional hubs and cortical atrophy patterns in TLE (Pspin < 0.0001) and between subcortical volume loss and subcortico-cortical structural hubs in IGE (Pshuf < 0.01).

  • Fig. 3 Syndrome-specific disease epicenters.

    (A) Disease epicenter mapping schema. Spatial correlations between cortical atrophy patterns and seed-based cortico- and subcortico-cortical connectivity were used to identify disease epicenters in TLE and IGE. Epicenters are regions whose connectivity profiles significantly correlated with the syndrome-specific atrophy map; statistical significance was assessed using spin permutation tests. This procedure was repeated systematically to assess the epicenter value of every cortical and subcortical region, as well as in both functional and structural connectivity matrices. (B and C) Correlation coefficients indexing spatial similarity between TLE- and IGE-specific atrophy and seed-based functional (left) and structural (right) connectivity measures for every cortical and subcortical region. Regions with significant associations were ranked in descending order based on their correlation coefficients, with the first five regions identified as disease epicenters (white outline). In TLE, ipsilateral temporo-limbic cortices (functional: Pspin < 0.05, structural: Pspin < 0.1) and subcortical areas—including ipsilateral amygdala (functional: Pspin < 0.05), thalamus (functional: Pspin < 0.05, structural: Pspin < 0.01), pallidum (functional: Pspin < 0.05), putamen (functional: Pspin < 0.05), and hippocampus (functional: Pspin < 0.1)—emerged as disease epicenters. In IGE, the highest ranked disease epicenters were located in bilateral fronto-central cortices, including postcentral gyri (functional: Pspin < 0.05, structural: Pspin < 0.05), left (functional: Pspin < 0.005, structural: Pspin < 0.1) and right amygdala (functional: Pspin < 0.005), and left pallidum (structural: Pspin < 0.1). *Pspin < 0.1, n.s., nonsignificant.

  • Fig. 4 Negative effects of age on cortical thickness and subcortical volume in TLE.

    (A) Significant age-related differences on gray matter atrophy between individuals with TLE and healthy controls for all cortical and subcortical regions. Patients with TLE showed a negative effect of age on cortical thickness in bilateral temporo-parietal (PFDR < 0.005) and sensorimotor (PFDR < 0.01) cortices and on subcortical volume in ipsilateral hippocampus (PFDR < 5 × 10−7) and bilateral thalamus (PFDR < 0.05). Negative log10-transformed FDR-corrected P values are shown. (B) Schematic of the figure layout is provided in the middle. Scatterplots depict relationships between the age-related effects and functional (red) and structural (blue) maps of degree centrality (left) and disease epicenter (right). Significant associations were observed between age-related effects and every hub and epicenter measures, with the exception of structural subcortical degree centrality, suggesting a role of connectome organization on age-related effects in TLE.

  • Fig. 5 Patient-tailored atrophy modeling.

    (A) Patient-specific associations between degree centrality (denoting hub distribution) and individualized atrophy maps showed high stability between functional cortico-cortical hubs and cortical atrophy in TLE (Pspin < 0.05 in 22.4% of patients) and high stability between structural cortico-cortical hubs and cortical atrophy in IGE (Pspin < 0.05 in 15.2% of patients). (B) We identified patient-specific structural and functional disease epicenters by keeping brain regions whose connectivity profiles significantly correlated with the patient’s atrophy map (Pspin < 0.05). In TLE, ipsilateral temporo-limbic regions and subcortical areas (including the hippocampus) were most often identified as epicenters of gray matter atrophy, whereas in IGE, bilateral fronto-central (including sensorimotor cortices) and subcortical areas most often emerged as disease epicenters. Disease epicenters in individual patients strongly resembled those seen across the group as a whole.

  • Table 1 ENIGMA Epilepsy Working Group demographics.

    Demographic breakdown of patient-specific subcohorts with site-matched controls, including age (in years), age at onset of epilepsy (in years), sex, side of seizure focus (patients with TLE only), and mean duration of illness (in years). Healthy controls from sites that did not have TLE (or IGE) patients were excluded from analyses comparing TLE (or IGE) to controls.

    Case-control
    subcohorts
    Age (means ± SD)Age at onset
    (means ± SD)
    Sex (male/female)Side of focus (L/R)Duration of illness
    (means ± SD)
    TLE (n = 732)38.56 ± 10.6116.07 ± 12.27329/403391/34122.74 ± 14.06*
    HC (n = 1418)33.76 ± 10.54643/775
    IGE (n = 289)32.06 ± 10.8516.84 ± 11.25111/17815.09 ± 11.70*
    HC (n = 1075)31.41 ± 9.59454/621

    *Information available in 695 of 732 patients with TLE and 250 of 289 patients with IGE.

    Supplementary Materials

    • Supplementary Materials

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

      Sara Larivière, Raúl Rodríguez-Cruces, Jessica Royer, Maria Eugenia Caligiuri, Antonio Gambardella, Luis Concha, Simon S. Keller, Fernando Cendes, Clarissa Yasuda, Leonardo Bonilha, Ezequiel Gleichgerrcht, Niels K. Focke, Martin Domin, Felix von Podewills, Soenke Langner, Christian Rummel, Roland Wiest, Pascal Martin, Raviteja Kotikalapudi, Terence J. O’Brien, Benjamin Sinclair, Lucy Vivash, Patricia M. Desmond, Saud Alhusaini, Colin P. Doherty, Gianpiero L. Cavalleri, Norman Delanty, Reetta Kälviäinen, Graeme D. Jackson, Magdalena Kowalczyk, Mario Mascalchi, Mira Semmelroch, Rhys H. Thomas, Hamid Soltanian-Zadeh, Esmaeil Davoodi-Bojd, Junsong Zhang, Matteo Lenge, Renzo Guerrini, Emanuele Bartolini, Khalid Hamandi, Sonya Foley, Bernd Weber, Chantal Depondt, Julie Absil, Sarah J. A. Carr, Eugenio Abela, Mark P. Richardson, Orrin Devinsky, Mariasavina Severino, Pasquale Striano, Domenico Tortora, Sean N. Hatton, Sjoerd B. Vos, John S. Duncan, Christopher D. Whelan, Paul M. Thompson, Sanjay M. Sisodiya, Andrea Bernasconi, Angelo Labate, Carrie R. McDonald, Neda Bernasconi, Boris C. Bernhardt

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