Despite extensive neuroimaging research of primary sensory cortices involved in auditory and visual functions, subcortical structures within these domains, such as the inferior and superior colliculi, the medial and lateral geniculate nuclei and the superior olivary complex, are currently understudied with magnetic resonance imaging (MRI) in living humans. This is because a precise localization of these nuclei is hampered by the limited contrast and sensitivity of conventional neuroimaging methods for deep brain nuclei. In this work, we used 7 Tesla multi-modal (T 2 -weighted and diffusion fractional anisotropy) 1.1 mm isotropic resolution MRI to achieve high sensitivity and contrast for single-subject brainstem and thalamic nuclei delineation. After precise coregistration to stereotactic space, we generated an in vivo human probabilistic atlas of auditory (medial geniculate nucleus, inferior colliculus, and superior olivary complex) and visual (lateral geniculate nucleus and superior colliculus) subcortical nuclei. We foresee the use of this atlas as a tool to precisely identify the location and shape of auditory/visual deep nuclei in research as well as clinical human studies.

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Introduction: The mesencephalic reticular formation, isthmic reticular formation, microcellular tegmental nucleus, ventral tegmental area-parabrachial pigmented nucleus complex, and caudal-rostral linear nucleus of the raphe are small brainstem regions crucially involved in arousal, sleep, and reward. Yet, these nuclei are difficult to identify with magnetic resonance imaging (MRI) of living humans. In the current work, we developed a probabilistic atlas of these brainstem nuclei in living humans, using noninvasive ultra-high-field MRI. Methods: We acquired single-subject, multicontrast (diffusion and T 2 -weighted), 1.1-mm isotropic resolution, 7 Tesla MRI images of 12 healthy subjects. After preprocessing and alignment to the stereotactic space, these images were used to delineate (in each subject) the nuclei of interest based on the image contrast as well as on neighboring nuclei and landmarks. Nucleus labels were averaged across subjects to yield probabilistic labels. The latter were further validated by assessment of the label inter-rater agreement, internal consistency, and volume. Results: Labels were delineated for each nucleus with good overlap across subjects. The inter-rater agreement and internal consistency were below ( p < 10 À8 ) the linear spatial imaging resolution (1.1 mm), thus validating the generated probabilistic atlas labels. The volumes of our labels did not differ from literature volumes ( p < 0.05), further validating our atlas. Discussion and Conclusion: The probabilistic atlas of these five mesopontine nuclei expands current in vivo brainstem nuclei atlases and can be used as a tool to identify the location of these areas in conventional (e.g., 3 Tesla) images. This might serve to unravel the brainstem structure-to-function link and thus improve clinical outcomes.Keywords: brainstem nuclei atlas; caudal-rostral linear nucleus of the raphe; isthmic reticular formation; mesencephalic reticular formation; microcellular tegmental nucleus; ventral tegmental area-parabrachial pigmented nucleus complex Impact StatementThe mesencephalic reticular formation, isthmic reticular formation, microcellular tegmental nucleus, ventral tegmental areaparabrachial pigmented nucleus complex, and caudal-rostral linear nucleus of the raphe are small brainstem regions crucially involved in arousal, sleep, and reward. In the current work, we developed a probabilistic atlas of these brainstem nuclei in living humans, using noninvasive, ultra-high-field magnetic resonance imaging. The probabilistic atlas of these five mesopontine nuclei expands current in vivo brainstem nuclei atlases and can be used as a tool to identify the location of these areas in conventional (e.g., 3 Tesla) images. This might serve to unravel the brainstem structure-to-function link and thus improve clinical outcomes.

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Background: Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is one of the earliest manifestations of α synucleinopathies. Brainstem pathophysiology underlying REM sleep behavior disorder has been described in animal models, yet it is understudied in living humans because of the lack of an in vivo brainstem nuclei atlas and to the limited magnetic resonance imaging (MRI) sensitivity. Objective: To investigate brainstem structural connectivity changes in iRBD patients by using an in vivo probabilistic brainstem nuclei atlas and 7 Tesla MRI. Methods: Structural connectivity of 12 iRBD patients and 12 controls was evaluated by probabilistic tractography. Two-sided Wilcoxon rank-sum test was used to compare the structural connectivity indices across groups. Results: In iRBD, we found impaired (Z = 2.6, P < 0.01) structural connectivity in 14 brainstem nuclei, including the connectivity between REM-on (eg, subcoeruleus [SubC]) and REM sleep muscle atonia (eg, medullary reticular formation) areas. Conclusions: The brainstem nuclei diagram of impaired connectivity in human iRBD expands animal models and is a promising tool to study and possibly assess prodromal synucleinopathy stages.

To characterize the anatomical connectivity of the prelemniscal radiations (Raprl), a white matter region within the posterior subthalamic area (PSA) that is an effective neurosurgical target for treating motor symptoms of Parkinson's disease (PD). Diffusion-weighted images were acquired from twelve healthy subjects using a 3T scanner. Constrained spherical deconvolution, a method that allows the distinction of crossing fibers within a voxel, was used to compute track-density images with sufficient resolution to accurately delineate distinct PSA regions and probabilistic tractography of Raprl in both hemispheres. Raprl connectivity was reproducible across all subjects and showed fibers traversing through this region towards primary and supplementary motor cortices, the orbitofrontal cortex, ventrolateral thalamus, and the globus pallidus, cerebellum and dorsal brainstem. All brain regions reached by Raprl fibers are part of motor circuits involved in the pathophysiology of PD; while these fiber systems converge at the level of the PSA, they can be spatially segregated. Fibers of distinct and specific motor control networks are identified within Raprl. The description of this anatomical crossroad suggests that, in the future, tractography could allow deep brain stimulation or lesional therapies in white matter targets according to individual patient's symptoms.

Autonomic, pain, limbic, and sensory processes are mainly governed by the central nervous system, with brainstem nuclei as relay centers for these crucial functions.Yet, the structural connectivity of brainstem nuclei in living humans remains understudied. These tiny structures are difficult to locate using conventional in vivo MRI, and ex vivo brainstem nuclei atlases lack precise and automatic transformability to in vivo images. To fill this gap, we mapped our recently developed probabilistic brainstem nuclei atlas developed in living humans to high-spatial resolution (1.7 mm isotropic) and diffusion weighted imaging (DWI) at 7 Tesla in 20 healthy participants.To demonstrate clinical translatability, we also acquired 3 Tesla DWI with conventional resolution (2.5 mm isotropic) in the same participants. Results showed the structural connectome of 15 autonomic, pain, limbic, and sensory (including vestibular) brainstem nuclei/nuclei complex (superior/inferior colliculi, ventral tegmental area-parabrachial pigmented, microcellular tegmental-parabigeminal, lateral/medial parabrachial, vestibular, superior olivary, superior/inferior medullary reticular formation, viscerosensory motor, raphe magnus/pallidus/obscurus, parvicellular reticular nucleus-alpha part), derived from probabilistic tractography computation. Through Kavita Singh and María Guadalupe García-Gomar equally contributed to this work and share first authorship.