Disruption of Brainstem Structural Connectivity in REM Sleep Behavior Disorder Using 7 Tesla Magnetic Resonance Imaging

Abstract

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.

Structural connectivity of autonomic, pain, limbic, and sensory brainstem nuclei in living humans based on 7 Tesla and 3 Tesla MRI

“…For the 2D connectome generation described above, a probabilistic atlas of brainstem nuclei developed by our group (Bianciardi et al, 2018 , 2016 ; García‐Gomar, Singh, & Bianciardi, 2021 ; García‐Gomar et al, 2019 ; Singh et al, 2019 , 2021 ), recently released within the Brainstem Navigator toolkit ( https://www.nitrc.org/projects/brainstemnavig/ ), and FreeSurfer cortical and subcortical parcellation (Destrieux et al, 2010 ) were used to define seed and target regions. Specifically, we used as seed regions the probabilistic atlas labels (binarized by setting a threshold at 35%) of the following 15 brainstem nuclei ( https://www.nitrc.org/projects/brainstemnavig/ ; Bianciardi et al, 2018 , 2016 ; García‐Gomar et al, 2019 ; García‐Gomar, Videnovic, et al, 2021 ; Singh et al, 2021 , 2019 ; 12 bilateral and 3 midline nuclei, for a total of 27 nuclei) involved in autonomic, limbic, pain, and sensory processing: RMg, LPB, MPB, VTA‐PBP, RPa, ROb, VSM, sMRt, iMRt, PCRtA, Ve, SC, IC, SOC, and MiTg‐PBG.…”

“…Specifically, we used as seed regions the probabilistic atlas labels (binarized by setting a threshold at 35%) of the following 15 brainstem nuclei (https://www.nitrc.org/projects/brainstemnavig/; Bianciardi et al, 2018Bianciardi et al, , 2016García-Gomar et al, 2019;García-Gomar, Videnovic, et al, 2021;Singh et al, 2021Singh et al, , 2019 12 bilateral and 3 midline nuclei, for a total of 27 nuclei) involved in autonomic, limbic, pain, and sensory processing: RMg, LPB, MPB, VTA-PBP, RPa, ROb, VSM, sMRt, iMRt, PCRtA, Ve, SC, IC, SOC, and MiTg-PBG.…”

“…We defined as target regions the 27 autonomic/limbic/pain/sensory seed regions defined above, and 18 (31 counting bilateral nuclei) probabilistic atlas labels (binarized by setting a threshold at 35%) of brainstem nuclei (https://www.nitrc.org/projects/brainstemnavig/; Bianciardi et al, 2018Bianciardi et al, , 2016García-Gomar et al, 2019;García-Gomar, Videnovic, et al, 2021;Singh et al, 2021Singh et al, , 2019, involved in wakeful arousal and motor function (Datta, Curr o Dossi, Paré, Oakson, & Steriade, 1991;Lima, Andersen, Reksidler, Vital, & Tufik, 2007;Lima, Reksidler, & Vital, 2008;Merel, Botvinick, & Wayne, 2019;Moruzzi & Magoun, 1949;J. Olszewski & Baxter, 1954;Parvizi & Damasio, 2001;Saper, Chou, & Scammell, 2001;Saper, Fuller, Pedersen, Lu, & Scammell, 2010), namely, median raphe (MnR), paramedian raphe (PMnR), and dorsal raphe (DR); substantia nigra-subregion1 (SN1; compatible with pars reticulata), and substantia nigra-subregion2 (SN2; compatible with pars compacta), caudalrostral linear raphe (CLi-RLi), periaqueductal gray (PAG); mesopontine reticular formation nuclei: mesencephalic reticular formation (mRt), cuneiform nucleus (CnF), isthmic reticular formation (isRt), and pontine reticular formation oral and caudal part (PnO-PnC); noradrenergic nucleus of locus coeruleus (LC), and subcoeruleus (SubC), (J.…”

“…Autonomic, pain, limbic and sensory functions in the body are mainly governed by networks from the brainstem‐to‐cortex involving brainstem nuclei such as the ventral tegmental area‐parabrachial pigmented nucleus complex (VTA‐PBP; G. Holstege et al, 2003 ; Ikemoto & Wise, 2004 ), microcellular tegmental–parabigeminal nucleus (MiTg‐PBG; Usunoff, Schmitt, Itzev, Rolfs, & Wree, 2007 ), lateral parabrachial nucleus (LPB), medial parabrachial nucleus (MPB; Kaur et al, 2017 ; Veening, Swanson, & Sawchenko, 1984 ), parvicellular reticular nucleus‐alpha part (PCRtA; Dessem & Luo, 1999 ), superior medullary reticular formation (sMRt; Robinson, Phillips, & Fuchs, 1994 ), inferior medullary reticular formation (iMRt; García‐Gomar, Videnovic, et al, 2021 ), raphe magnus (RMg; Hornung, 2003 ), raphe obscurus (ROb; Nieuwenhuys, Voogd, & Van Huijzen, 2008 ), raphe pallidus (RPa; Hornung, 2003 ; Loewy & Neil, 1981 ), viscerosensory motor nuclei complex (VSM; Chamberlin & Saper, 1995 ; Nieuwenhuys et al, 2008 ), superior colliculus (SC; Lee & Groh, 2012 ; May, 2006 ), inferior colliculus (IC; Aitkin, 1979 ), vestibular nuclei complex (Ve; Goldberg et al, 2012 ), and superior olivary complex (SOC; Fay, Popper, & Webster, 1992 ). These nuclei with their overlapping functional domains provide a network of connectivity modulating respiration, cardiac function, initial processing of sensory stimuli including pain, metabolic control including thermoregulation, memory storage, and sexual arousal, integrated with reflexive emotional responses (Hermann, Luppi, Peyron, Hinckel, & Jouvet, 1997 ; Morgane, Galler, & Mokler, 2005 ; Schmidt, 1989 ; Uschakov, Gong, McGinty, & Szymusiak, 2007 ).…”

“…To this end we utilized our recently developed atlas of brainstem nuclei (Bianciardi et al, 2018 , 2016 ; García‐Gomar et al, 2019 ; García‐Gomar, Videnovic, et al, 2021 ; Singh, García‐Gomar, & Bianciardi, 2021 ; Singh et al, 2019 , 2021 ), released within the Brainstem Navigator toolkit ( https://www.nitrc.org/projects/brainstemnavig/ ) and achieved using multicontrast and high‐spatial resolution images at 7 Tesla in living humans, to generate a comprehensive structural connectome of autonomic, pain, limbic, and sensory nuclei. To do so, we mapped this atlas to high‐spatial resolution (1.7 mm isotropic) diffusion weighted imaging (DWI) at 7 Tesla on 20 healthy participants.…”