Mapping the structural connectivity between the periaqueductal gray and the cerebellum in humans

Alberto Cacciola,Salvatore Bertino,Alessandro Calamuneri,Gaetana Chillemi,Gianpaolo Antonio Basile,Rocco Salvatore Calabrò,Paolo Flace,Daniele Bruschetta,Debora Di Mauro,Angelo Favaloro,Giuseppe Anastasi,Antonio Duca,Demetrio Milardi

doi:10.1007/s00429-019-01893-x

Abstract

The periaqueductal gray is a mesencephalic structure involved in modulation of responses to stressful stimuli. Structural connections between the periaqueductal gray and the cerebellum have been described in animals and in a few diffusion tensor imaging studies. Nevertheless, these periaqueductal gray–cerebellum connectivity patterns have yet to be fully investigated in humans. The objective of this study was to qualitatively and quantitatively characterize such pathways using high-resolution, multi-shell data of 100 healthy subjects from the open-access Human Connectome Project repository combined with constrained spherical deconvolution probabilistic tractography. Our analysis revealed robust connectivity density profiles between the periaqueductal gray and cerebellar nuclei, especially with the fastigial nucleus, followed by the interposed and dentate nuclei. High-connectivity densities have been observed between vermal (Vermis IX, Vermis VIIIa, Vermis VIIIb, Vermis VI, Vermis X) and hemispheric cerebellar regions (Lobule IX). Our in vivo study provides for the first time insights on the organization of periaqueductal gray–cerebellar pathways thus opening new perspectives on cognitive, visceral and motor responses to threatening stimuli in humans.

Highlights

The periaqueductal gray (PAG) is an important neuronal station situated in the mesencephalon, surrounding the Sylvian aqueduct
With some limitations (Smith et al 2013), such numbers are used as markers of connectivity density, both in healthy and pathological conditions (Behrens and Sporns 2012; Bijttebier et al 2015; Guo et al 2016; Zhang et al 2017)
Since connectivity between seed region and regions of interest (ROI) is subjected to volume biases (Cheng et al 2012), we extracted seed and target Region of interest (ROI) volumes to scale the number of streamlines (NOS) by the mean volume of the two ROI involving each pathway computing a normalized connectivity density not affected from the volume bias

Summary

Introduction

The periaqueductal gray (PAG) is an important neuronal station situated in the mesencephalon, surrounding the Sylvian aqueduct. According to the present knowledge, it probably works as a main control station for innate and acquired responses to stressful stimuli such as fear, anxiety and pain, by coordinating and integrating appropriate vegetative and behavioral responses (Carrive 1993; Fanselow et al 1991; Tovote et al 2016; Walker and Carrive 2003). Anatomical connectivity between PAG with the cerebellum has been subject of interest in the past decades and has been investigated by means of tract-tracing techniques (Chan-Palay 1977; Dietrichs 1983). Connections joining the cerebellar cortex and nuclei with PAG were first described in monkeys (Chan-Palay 1977).

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