High-resolution electrophysiological mapping of effective connectivity of lateral prefrontal cortex

The lateral prefrontal cortex (LPFC) serves as a critical hub for higher-order cognitive and executive functions in the human brain, coordinating brain networks whose disruption has been implicated in many neurological and psychiatric disorders. While transcranial brain stimulation treatments often target the LPFC, our current understanding of connectivity profiles guiding these interventions based on electrophysiology remains limited. Here, we present a high-resolution probabilistic map of bidirectional effective connectivity between the LPFC and widespread cortical and subcortical regions. This map is derived from intracranial evoked potential analysis of 48 797 intracranial direct electrical stimulation runs across 759 implantations in 724 patients with refractory epilepsy (368 male, 354 female, two unspecified; mean age ± standard deviation: 24 ± 13.5 years). We mapped probabilistic connectivity between brain parcels with adaptive resolution-higher resolution in the LPFC in the hemisphere of interest and lower elsewhere-maintaining statistical power while achieving 95% average confidence interval of ∼0.03 for connectivity probability estimates. In addition, the significance threshold (P-value) for probabilistic connectivity was obtained from surrogate distributions. Overall, we observed remarkable symmetry between afferent and efferent connectivity patterns of the LPFC, with a slight preference for efferent connections (mean slope = 0.92 ± 0.09, mean R2 = 0.93 ± 0.025). For example, connections between the inferior frontal gyrus (IFG) and anterior cingulate showed notable directional asymmetry. The IFG strongly projected to most brain networks compared to other LPFC regions, with the strongest connectivity to the ventral attention network (0.26 ± 0.01 compared to values between 0.15 and 0.21 in other LPFC regions). Posterior dorso-lateral prefrontal cortex (DLPFC) demonstrated stronger connectivity to brain networks compared to anterior DLPFC regions (e.g. 0.21 ± 0.01 versus 0.15 ± 0.01 for connectivity to ventral attention network), with the exception of the limbic cortex. All LPFC subregions strongly projected to the fronto-parietal (greater than 0.17) and ventral attention (greater than 0.15) networks, with moderate connections to the default network (between 0.1 and 0.15, with the maximum corresponding to superior DLPFC). Finally, latency analysis suggested that the left LPFC's influence on ipsilateral emotion-related regions is primarily polysynaptic, with particularly strong pathways from IFG to amygdala (0.16 ± 0.02) and hippocampus (0.12 ± 0.01). Taken together, these comprehensive connectivity maps provide a new detailed electrophysiological foundation for understanding the functional anatomy of LPFC and guiding targeted brain stimulation protocols.

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Journal
Brain
Published
2025-08-30
DOI
https://doi.org/10.1093/brain/awaf317
Citations
3
Primary Topic
Functional Brain Connectivity Studies
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article
Field-Weighted Citation Impact
4.29

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article

High-resolution electrophysiological mapping of effective connectivity of lateral prefrontal cortex

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Functional Brain Connectivity Studies
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article

High-resolution electrophysiological mapping of effective connectivity of lateral prefrontal cortex

Anna Kamińska, Rodrigo Rocamora, Francine Chassoux, Hélène Catenoix, Alexandra Montavont, Lorella Minotti, William Szurhaj, Jean Gotman, Martin Pail, Sara Parmigiani, Rima Nabbout, Xi Mei, Matteo Lenge, Olivier David A, Agnès Trébuchon, Renzo Guerrini, Cristiana Pinheiro, Jean Isnard, Antonio Valentı́n, Aileen McGonigal, Thomas Blauwblomme, Sylvain Rheims, Maria Paola Valenti, Philippe Ryvlin, Ivana Sartori, Robert Kuba, Leena Lauronen, Liisa Metsähonkala, Ana Maria Roxana Petrescu, Mercedes Garcés, Marion Quirins, Wenjing Zhou, Alessandro Príncipe, Louise Tyvaert, Anthony Boyer, P. Masnou, Marie Denuelle, Anca Nica, Corey J. Keller, Sinclair Liu, Marie Bourgeois, Anne-Sophie Job, Elizabeth Landré, Jonathan Curot, Mathilde Chipaux, Lino Nobili, François Dubeau, Véronique Michel, Dan Zhu, Philippe Derambure, Christopher C. Cline, Luc Valton, Eija Gaily, Rinki Singh, Ioana Mı̂ndruță, Jérôme Aupy, Laura Tassi, Vincent Navarro, Yasser Alemán‐Gómez, Patric Hagmann, Yigang Feng, Carmen Barba, Delphine Taussig, Andrei Barborică, Claire Dussaule, Irena Doležalová, Blandine Chanteloup-Forêt, Jacques Jonas, Jitka Kočvarová, Philippe Kahane, Claude Adam, Édouard Hirsch, Stefano Francione, Milan Brázdil, Qiang Guo, Fabrice Bartoloméi, Wei Zhang, Wensheng Wang, Haixiang Wang, Maciej Jedynak, Hua Gang, Arnaud Biraben, Marie de Montaudoin, Maxime Chochois, Elisa Nacci, Hu Xiangshu, Louis Maillard, Roberto Mai, Julia Scholly, Li Hua, Miguel Ley, Maria Peltola, Dominique Ménard, Jean‐Pierre Vignal, Sofia Avalos-Alais, Viviane Bouilleret
article en
3 citations

Abstract

The lateral prefrontal cortex (LPFC) serves as a critical hub for higher-order cognitive and executive functions in the human brain, coordinating brain networks whose disruption has been implicated in many neurological and psychiatric disorders. While transcranial brain stimulation treatments often target the LPFC, our current understanding of connectivity profiles guiding these interventions based on electrophysiology remains limited. Here, we present a high-resolution probabilistic map of bidirectional effective connectivity between the LPFC and widespread cortical and subcortical regions. This map is derived from intracranial evoked potential analysis of 48 797 intracranial direct electrical stimulation runs across 759 implantations in 724 patients with refractory epilepsy (368 male, 354 female, two unspecified; mean age ± standard deviation: 24 ± 13.5 years). We mapped probabilistic connectivity between brain parcels with adaptive resolution-higher resolution in the LPFC in the hemisphere of interest and lower elsewhere-maintaining statistical power while achieving 95% average confidence interval of ∼0.03 for connectivity probability estimates. In addition, the significance threshold (P-value) for probabilistic connectivity was obtained from surrogate distributions. Overall, we observed remarkable symmetry between afferent and efferent connectivity patterns of the LPFC, with a slight preference for efferent connections (mean slope = 0.92 ± 0.09, mean R2 = 0.93 ± 0.025). For example, connections between the inferior frontal gyrus (IFG) and anterior cingulate showed notable directional asymmetry. The IFG strongly projected to most brain networks compared to other LPFC regions, with the strongest connectivity to the ventral attention network (0.26 ± 0.01 compared to values between 0.15 and 0.21 in other LPFC regions). Posterior dorso-lateral prefrontal cortex (DLPFC) demonstrated stronger connectivity to brain networks compared to anterior DLPFC regions (e.g. 0.21 ± 0.01 versus 0.15 ± 0.01 for connectivity to ventral attention network), with the exception of the limbic cortex. All LPFC subregions strongly projected to the fronto-parietal (greater than 0.17) and ventral attention (greater than 0.15) networks, with moderate connections to the default network (between 0.1 and 0.15, with the maximum corresponding to superior DLPFC). Finally, latency analysis suggested that the left LPFC's influence on ipsilateral emotion-related regions is primarily polysynaptic, with particularly strong pathways from IFG to amygdala (0.16 ± 0.02) and hippocampus (0.12 ± 0.01). Taken together, these comprehensive connectivity maps provide a new detailed electrophysiological foundation for understanding the functional anatomy of LPFC and guiding targeted brain stimulation protocols.

BrainVol. 149(3)
Inserm (FR), Neurosciences Institute (US), VA Palo Alto Health Care System (US), Aix-Marseille Université (FR), Institut de Neurosciences des Systèmes (FR), Mental Illness Research, Education and Clinical Centers (US), Fondation Lenval (FR), Stanford Medicine (US), Grenoble Institute of Neurosciences (FR), Université Grenoble Alpes (FR), Stanford University (US), University of Lausanne (CH)
National Science Foundation, European Commission, Agence Nationale de la Recherche, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, National Institutes of Health, Horizon 2020 Framework Programme
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Functional Brain Connectivity Studies
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