High-resolution tractography protocol to investigate the pathways between human mediodorsal thalamic nucleus and prefrontal cortex

Animal studies have established that the mediodorsal nucleus (MD) of the thalamus is heavily and reciprocally connected with all areas of the prefrontal cortex (PFC). In humans, however, these connections are difficult to investigate. High resolution imaging protocols capable of reliably tracing the axonal tracts linking the human MD with each of the PFC areas may thus be key to advance our understanding of variation, development and plastic changes of these important circuits, in health and disease. Here, we tested in adult female and male humans the reliability of a new reconstruction protocol based on in vivo diffusion MRI to trace, measure and characterize the fiber tracts interconnecting the MD with 39 human PFC areas per hemisphere. Our protocol comprised three components: a) defining regions-of-interest; b) preprocessing diffusion data; and, c) modeling white-matter tracts and tractometry. This analysis revealed largely separate PFC territories of reciprocal MD-PFC tracts bearing striking resemblance with the topographic layout observed in macaque connection-tracing studies. We then examined whether our protocol could reliably reconstruct each of these MD-PFC tracts and their profiles across test and retest sessions. Results revealed that this protocol was able to trace and measure, in both left and right hemispheres, the trajectories of these 39 area-specific axon bundles with good-to-excellent test-retest reproducibility. This protocol, which has been made publicly available, may be relevant for cognitive neuroscience and clinical studies of normal and abnormal PFC function, development and plasticity. Significance Statement Reciprocal MD-PFC interactions are critical for complex human cognition and learning. Reliably tracing, measuring and characterizing MD-PFC white-matter tracts using high-resolution non-invasive methods is key to assess individual variation of these systems in humans. Here, we propose a high-resolution tractography protocol that reliably reconstructs 39 area-specific MD-PFC white-matter tracts per hemisphere and quantifies structural information from diffusion MRI data. This protocol revealed a detailed mapping of thalamocortical and corticothalamic MD-PFC tracts in four different PFC territories (dorsal, medial, orbital/frontal pole, inferior frontal) showing structural connections resembling those observed in tracing studies with macaques. Furthermore, our automated protocol revealed high test-retest reproducibility and is made publicly available, constituting a step forward in mapping human MD-PFC circuits in clinical and academic research.