Study of the Correlation Between Cortical Excitability and Cytoarchitectonics of Prefrontal Cortex in Healthy Adult Participants, Using Transcranial Magnetic Stimulation Coupled to EEG and High-field MRI

Repeated transcranial magnetic stimulation (rTMS) is mainly used to treat mood disorders by addressing differences in brain function, particularly in the dorsolateral prefrontal cortex (DLPFC), which affects emotions and executive functions. The therapy aims to enhance the left DLPFC or suppress the right. It has been approved for severe major depression in several countries (Canada and Israel since 2002, USA since 2008) and is in the process of being validated in Europe but is not yet reimbursed in France. due to variable results from one study to another and lack of standardization issues.

In a previous study, by recording electroencephalographic (EEG) rhythms before and after rTMS treatment of the DLPFC, the investigators showed on a small cohort of patients (n=17) with major or bipolar depression, that the responder patients showed higher EEG theta rhythms in the DLPFC but also and especially in parietal regions. This suggests that the DLPFC is part of the fronto-parietal central executive network (CEN), which is important for working memory and cognitive control. The CEN is not well connected in severe resistant depression, possibly leading to negative emotional bias. The rTMS cure of DLPFC can be interpreted as improving depressive symptoms through the normalization of the CEN by increasing DLPFC excitability and its downward connectivity. However experimental and clinical evidence for this mechanism, among others, is still to be demonstrated, and remission rates of rTMS from DLPFC in drug-resistant depression are still low (20-40%).

To improve these response rates to rTMS in DLPFC, it is essential to continue research aimed at improving clinical practices through a better knowledge of the functional neuroanatomy and mechanisms of action of rTMS. This will require the definition of biomarkers allowing in particular to better target the DLPFC, this structure beeing indeed relatively poorly defined on the neuroanatomical level (large portion of the medial frontal gyrus). To this end, the investigators have set up a collaborative research program with Dr. Corey Keller, psychiatrist at Stanford University USA, which was jointly funded in 2022 by the Agence Nationale pour la Recherche (ANR) and the National Institute of Health (NIH) - FrontalProbe project "Probing the dorsolateral prefrontal cortex and central executive network for improving neuromodulation in depression". The ultimate aim of this project is to develop and test different strategies for targeting the DLPFC in the rTMS treatment of pharmaco-resistant depressive patients, following the fundamental neuroanatomical and pathophysiological hypothesis that patients will respond better to therapy if their CEN network is better modulated. This clinical trial will take place in Stanford, USA, in the years 2025-2026. Previously, the investigators are working on the development of methodological strategies aimed at preferentially activating, in a personalized way, the part of the DLPFC that projects onto the PPC. This is the subject of the present protocol, which aims to identify this subpart of the DLPFC to be targeted as a priority for modulating the CEN, through neuroanatomical measurements with high-field MRI and cortical excitability by TMS-EEG in healthy subjects. To this end, the investigators will use a small cohort of healthy subjects who will have one multimodal MRI acquisition session of at 7T and one TMS-EEG session. The 7T MRI data, acquired at the Centre de Résonance Magnétique en Biologie et Médecine (CRMBM), will be used to obtain anatomical markers of the DLPFC. TMS-EEG data, acquired at the Institut de Neurosciences de Systèmes (INS), will be used for cortical excitability measurements of the DLPFC and its projection sites, notably the PPC. At this stage, no data exchange is planned with our American partners.

Firstly, the processing of MRI data will include segmentation of gray and white matter, reconstruction of the cortical surface and estimation of the different cortical layers, mainly by monitoring variations in the T1 parameter along the cortical mantle. Other MRI parameters will also be acquired to maximize the specificity of the segmentation of the DLPFC into sub-regions, firstly by identifying the part of the DLPFC that connects preferentially to the PPC using the reconstruction of fiber bundles from diffusion MRI and functional resting MRI. Secondly, during TMS-EEG acquisitions, participants will be stimulated in 3 sub-regions of the DLPFC. For each target, the analyses of the EEG data will focus on quantifying connectivity with the PPC as well as their spectral signature, which is possibly an indirect reflection of the neuronal composition of the stimulated regions.

Correlation of 7T MRI and TMS-EEG data will help set optimal DLPFC targeting criteria for PPC activation. The aim is to create an MRI-based targeting procedure for clinical practice. In this sense, TMS-EEG will serve as validation of MRI markers.