New perspectives on the multimodal validation of the human brain white matter anatomy.

For much of history, the brain has fascinated scholars as the seat of thought, sensation, and behavior. Early theories of brain functioning focused on the cortical surface, seeking to localize cognition within discrete gray matter regions. Today, it is clear that the richness of human behavior cannot be explained based on the activity of isolated cortical modules alone, but rather emerges from the communication between them, supported by networks of white matter connections. Diffusion MRI-based tractography has transformed neuroscience by enabling non-invasive mapping of these white matter connections in the living human brain, fueling both basic research and clinical practices. Yet, tractography remains an indirect measure, prone to artefactual reconstructions and fragmented by inconsistent nomenclatures. Remarkably, many of the most reliable anatomical insights still derive from the work of early white matter dissectionists, whose methods continue to provide the ground truth against which modern digital reconstructions are evaluated. This thesis builds on this dual legacy of innovation and tradition through three main contributions, towards a comprehensive and anatomically reliable characterization of the white matter pathways of the human brain. First, I validated a streamline-based tractography segmentation approach that improves anatomical reliability over classical ROI-based methods, even under routine clinical imaging conditions. This approach allows to directly identify, select and discard streamlines with an anatomically implausible course, improving the accuracy of virtual bundle segmentations with significant implication for both research and clinical practice. Second, I developed BraDiPho, a multimodal framework that integrates ex-vivo Klingler dissections with in-vivo tractography through photogrammetry and spatial alignment of anatomical evidence across modalities. This contribution resulted in the production of an open resource for anatomically grounded multimodal investigations of white matter connections. Third, I combined these advances with a theorethical framework that considers white matter connections as systems defined by macroanatomical landmarks to deliver an unbiased, data-driven and anatomically evaluated reconstruction of the Superior Longitudinal System. This revealed a layered dorso-ventral and latero-medial organization that captures the architecture of white matter fiber pathways beyond classical bundle definitions, thus reinforcing a distributed model of cognitive processes. Together, these contributions provide a framework for anatomically grounded and multimodal investigations of the human white matter, deepening the understanding of the structural basis of cognitive function and dysfunction, informing models of disease progression, and opening new opportunities in the prediction of outcome for neurological and neurosurgical diseases.