Monoaminergic circuits in brainstem and hypothalamus using structural multimodal imaging in humans
Poster No:
1703
Submission Type:
Abstract Submission
Authors:
Poliana hartung toppa1, Richard Rushmore2, Kayley Haggerty1, George Papadimitriou1, Darin Dougherty1, Edward Yeterian3, Nikos Makris1
Institutions:
1Harvard Medical School, Boston, MA, 2Boston University School of Medicine, Boston, MA, 3Colby College, Waterville, ME
First Author:
Co-Author(s):
Introduction:
Monoaminergic systems, including serotonin (5-HT), and catecholamines, such as dopamine (DA), norepinephrine (NE), and epinephrine (E) play critical roles in regulating autonomic functions, cognitive-emotional behaviors, and stress responses. Monoaminergic neurons are primarily located in the brainstem and hypothalamus, regions characterized by small structures with complex anatomical organization. Historically, these features have made the brainstem and hypothalamus particularly challenging to study using traditional neuroimaging techniques. However, current advances in multimodal neuroimaging allow for the delineation and mapping of these monoaminergic pathways, offering valuable insights into their structural connectivity, functional significance, and clinical implications.
Methods:
We applied a multimodal neuroimaging approach combining T1-weighted morphometric magnetic resonance imaging (MRI) and diffusion MRI (dMRI)-based tractography to identify brainstem-originating monoaminergic pathways. This study was carried out in one ultra-high-resolution post-mortem human brainstem/diencephalon dataset (Calabrese et al., 2015) and in five healthy human subject datasets obtained from the publicly available Human Connectome Project (HCP) repository (Makris et al., 2024; Van Essen et al., 2013). It should be noted that the human post-mortem brainstem/diencephalon dataset has been sampled at 200-micron isotropic voxel resolution for dMRI, which can be considered as ground truth in the field of diffusion MRI. Therefore, the delineation of monoaminergic circuits in our ultra-high-resolution post-mortem human dataset may serve as a ground truth comparator for the HCP datasets, which are commonly used.
Results:
We successfully delineated 28 bilateral (14 on the left side and 14 on the right side) brainstem-originating distinct fiber tracts associated with monoaminergic circuitries. To our knowledge, this is the first study reporting the delineation and mapping of the distinct fiber tracts constituting the monoaminergic neurochemical systems in the human brainstem and hypothalamus using neuroimaging. The fiber tracts of the post-mortem dataset and those of the HCP datasets were comparable. An example of these findings is illustrated in Figures 1 and 2. The tractographic results of all datasets analyzed herein matched the hodological knowledge of the monoaminergic circuitries derived from experimental animal research.
Conclusions:
Our findings demonstrate the efficacy of multimodal neuroimaging for mapping the structural connectivity of small, complex brainstem and hypothalamic structures. Herein we demonstrate for the first time that specific neurochemical circuitries in the human brainstem and diencephalon can be delineated with accuracy comparable to the neuroanatomy reported from experimental animal material. Furthermore, as has been emphasized by pioneers in chemical neuroanatomy (e.g., Nieuwenhuys, 1985), the integration of traditional brain structural connectivity, and chemical neuroanatomy, is of great clinical relevance. Moreover, the present results lay the foundation for future research into brain-immune interactions and clinical conditions associated with monoaminergic dysfunction, including major depression, anxiety disorders, cardiovascular disease, chronic stress-related disorders, and COVID-19 (Kikinis et al., 2024), which are matters of great importance in public health. Last but not least, the precise localization of the nuclei or cell groups of origin and termination as well as the fiber tracts of the brainstem and hypothalamus monoaminergic circuits using multimodal neuroimaging is expected to have significant implications in current neuromodulation therapeutic approaches in neuropsychiatry such as deep brain stimulation (DBS) and transcranial magnetic stimulation (TMS).
Brain Stimulation:
TMS
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s)
Psychiatric (eg. Depression, Anxiety, Schizophrenia)
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Anatomy and Functional Systems 1
Novel Imaging Acquisition Methods:
Multi-Modal Imaging 2
Keywords:
Brainstem
DISORDERS
Dopamine
Epinephrine
MRI
Norpinephrine
Seretonin
Transcranial Magnetic Stimulation (TMS)
Other - COVID-19
1|2Indicates the priority used for review
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Were any human subjects research approved by the relevant Institutional Review Board or ethics panel? NOTE: Any human subjects studies without IRB approval will be automatically rejected.
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Provide references using APA citation style.
Kikinis, Z., Castañeyra-Perdomo, A., González-Mora, J. L., Rushmore, R. J., Toppa, P. H., Haggerty, K., Papadimitriou, G., Rathi, Y., Kubicki, M., Kikinis, R., Heller, C., Yeterian, E., Besteher, B., Pallanti, S., & Makris, N. (2024). Investigating the structural network underlying brain-immune interactions using combined histopathology and neuroimaging: a critical review for its relevance in acute and long COVID-19. Frontiers in Psychiatry / Frontiers Research Foundation, 15, 1337888.
Makris, N., Hartung Toppa, P., Rushmore, R. J., Haggerty, K., Papadimitriou, G., Tobet, S., Rathi, Y., Kubicki, M., Yeterian, E., Castañeyra-Perdomo, A., & Goldstein, J. M. (2024). A combined structural T1-weighted MRI morphometric and diffusion MRI tractographic study of paraventricular (PVN), coerulean (LC), dorsal vagal complex (DVC) brainstem-hypothalamic nuclear connectivity. Journal of Biological Methods, 11. https://doi.org/10.14440/jbm.2024.0043
Nieuwenhuys, R. (1985). Survey of Chemically Defined Cell Groups and Pathways. In R. Nieuwenhuys (Ed.), Chemoarchitecture of the Brain (pp. 7–113). Springer Berlin Heidelberg.
Van Essen, D. C., Smith, S. M., Barch, D. M., Behrens, T. E. J., Yacoub, E., Ugurbil, K., & WU-Minn HCP Consortium. (2013). The WU-Minn Human Connectome Project: an overview. NeuroImage, 80, 62–79.