Brain Connectivity in PCDH19 Epilepsy

Autori

Darvin Shehu¹, Matteo Lenge², Simona Balestrini², Davide Mei², Valerio Conti², Marina Trivisano³, Simona Pellacani², Letizia Macconi⁴, Daniela Longo⁵, Maria Camilla Rossi Espagnet⁵, Simona Cappelletti³, Ludovico D’Incerti⁴, Carmen Barba², Nicola Specchio³, Renzo Guerrini⁶, Antonio Napolitano¹

¹Medical Physics Department, Bambino Gesù Children’s Hospital, 00165 Rome, Italy.

²Child Neurology Unit and Laboratories, Neuroscience Department, Meyer Children’s Hospital IRCCS, 50139, Florence, Italy.

³Neurology, Epilepsy and Movement Disorders, Bambino Gesù Children’s Hospital, IRCCS, Full Member of European Reference Network EpiCARE, 00165, Rome, Italy.

⁴Pediatric Radiology Unit, Meyer Children’s Hospital IRCCS, 50139, Florence, Italy.

⁵Functional and Interventional Neuroimaging Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165, Rome, Italy.

⁶Child Neurology Unit and Laboratories, Neuroscience Department, Meyer Children’s Hospital IRCCS, 50139, Florence

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Abstract

Introduction: Mutations in the PCDH19 gene cause EFMR (female-restricted epilepsy and mental retardation). This study explores brain connectivity alterations in EFMR patients to identify key affected regions.

Materials and Methods: A cohort of 17 patients (mean age: 14.13 ± 6.95 years, 15 females) and 25 healthy controls (HCs) (mean age: 13.97 ± 6.62 years, 20 females) was analyzed, representing one of the largest datasets available for this rare condition. Brain connectivity was assessed using diffusion tensor imaging (DTI), with connectome matrices extracted via the MICAPIPE[1] processing pipeline using the Desikan-Killiany atlas. Connectivity differences between patients and HCs were evaluated using a multiple hypothesis correction based on permutations[2] (Fig.1, Fig.2).

Results: Three brain regions exhibited the most significant connectivity alterations, ranking within the top 20% of the largest differences between groups. These differences surpassed the critical threshold (0.61) derived from the distribution of maximum differences. The latero-orbitofrontal cortex showed the greatest disparity in the right hemisphere and ranked 15th in the left. The parahippocampal cortex ranked 4th in the right and 24th in the left, while the isthmus of the cingulate cortex ranked 5th in the right and 19th in the left.

Conclusions: The latero-orbitofrontal, parahippocampal, and isthmus cingulate cortices are key regions of connectivity deficits in PCDH19-mutated patients. The findings also suggest a lateralization effect, with a greater impact on the right hemisphere, contributing to a deeper understanding of EFMR-related connectivity alterations and potential targets for future research.

[1] R. R. Cruces et al., “Micapipe: A pipeline for multimodal neuroimaging and connectome analysis,” Neuroimage, vol. 263, 2022, doi: 10.1016/j.neuroimage.2022.119612.

[2] G. A. Rempala and Y. Yang, “On permutation procedures for strong control in multiple testing with gene expression data,” Stat Interface, vol. 6, no. 1, 2013, doi: 10.4310/SII.2013.v6.n1.a8.

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