A Structural Connectivity Atlas of Limbic Brainstem Nuclei
Authors: Levinson Simon , Miller Michelle , Iftekhar Ahmed , Justo Monica , Arriola Daniel , Wei Wenxin , Hazany Saman , Avecillas-Chasin Josue , Kuhn Taylor , Horn Andreas , Bari Ausaf 
Published: August 2022

AbstractBackgroundUnderstanding the structural connectivity of key brainstem nuclei with limbic cortical regions is essential to the development of therapeutic neuromodulation for depression, chronic pain, addiction, anxiety and movement disorders. Several brainstem nuclei have been identified as the primary central nervous system (CNS) source of important monoaminergic ascending fibers including the noradrenergic locus coeruleus, serotonergic dorsal raphe nucleus, and dopaminergic ventral tegmental area. However, due to practical challenges to their study, there is limited data regarding theirin vivoanatomic connectivity in humans.ObjectiveTo evaluate the structural connectivity of the following brainstem nuclei with limbic cortical areas: locus coeruleus, ventral tegmental area, periaqueductal grey, dorsal raphe nucleus, and nucleus tractus solitarius. Additionally, to develop a group average atlas of these limbic brainstem structures to facilitate future analyses.MethodsEach nucleus was manually masked from 197 Human Connectome Project (HCP) structural MRI images using FSL software. Probabilistic tractography was performed using FSL’s FMRIB Diffusion Toolbox. Connectivity with limbic cortical regions was calculated and compared between brainstem nuclei. Results were aggregated to produce a freely available MNI structural atlas of limbic brainstem structures.ResultsA general trend was observed for a high probability of connectivity to the amygdala, hippocampus and DLPFC with relatively lower connectivity to the orbitofrontal cortex, nucleus accumbens, hippocampus and insula. The locus coeruleus and nucleus tractus solitarius demonstrated significantly greater connectivity to the DLPFC than amygdala while the periaqueductal grey, dorsal raphe nucleus, and ventral tegmental area did not demonstrate a significant difference between these two structures.ConclusionMonoaminergic and other modulatory nuclei in the brainstem project widely to cortical limbic regions. We describe the structural connectivity across the several key brainstem nuclei theorized to influence emotion, reward, and cognitive functions. An increased understanding of the anatomic basis of the brainstem’s role in emotion and other reward-related processing will support targeted neuromodulatary therapies aimed at alleviating the symptoms of neuropsychiatric disorders.HighlightsThe brainstem plays a key role in the processing of emotional stimuli and is intricately linked with the limbic system.Anatomic data for these connections is limited in humansWe describe the structural connectivity of five brain stem nuclei (locus coeruleus, ventral tegmental area, periaqueductal grey, dorsal raphe nucleus, and nucleus tractus solitarius) in relation to limbic circuitsOur results present a comprehensive delineation of the brainstem-limbic structural connectivity of these nuclei and are compiled into a freely available tractographic atlasApplications include future targeting of these structures for neuropsychiatric conditions