Revealing the ventral amygdalofugal pathway of the human limbic system using high spatial resolution diffusion tensor tractography

Abstract

The amygdala is known to have a role in core processes regulated by the limbic system such as motivation, memory, emotion, social behavior, self-awareness as well as certain primitive instincts. Several functional studies have investigated some of these brain tasks of the human limbic system. However, the underlying neuronal fiber connectivity of the amygdalo-diencephalon, as part of the limbic system, has not been delineated separately by prior diffusion-weighted imaging studies. The ability to trace the underlying fiber connections individually will be helpful in understanding the neurophysiology of these tracts in different functions. To date, few diffusion-weighted studies have focused on the amygdala, yet the fine connections of the amygdala, hypothalamus, septum or other adjacent limbic structures have yet to be elucidated by diffusion-weighted tractography studies. We therefore aimed to further investigate these fine neuronal connections using fiber tractography and high spatial resolution diffusion tensor imaging on 3T on 15 healthy right-handed male human subjects (age range 24-37 years). The ventral amygdalofugal pathway, anterior commissure and stria terminalis are the three main efferent pathways of the amygdala. We delineated the detailed trajectories of the ventral amygdalofugal tract, anterior commissure and their connections bilaterally in 15 normal adult human brains. Using a high-resolution diffusion tensor tractography technique, for the first time, we were able to demonstrate the trajectory of amygdalofugal tract and its connections to the hypothalamic and septal nuclei. We further revealed, for the first time, the close relationship of the amygdalofugal tract and anterior commissure with the fornix, stria terminalis and uncinate fasciculus bilaterally in 15 healthy adult human brains.

Elucidation of White Matter Tracts of the Human Amygdala by Detailed Comparison between High-Resolution Postmortem Magnetic Resonance Imaging and Histology

“…In previous reports based on histology, these fibers had been collectively called the amygdalofugal pathway. This tract was also recently revealed using in vivo DTI (Kamali et al, 2016). Several bundles could be differentiated as they entered the amygdala, forming clearly identifiable branches (Figures 2C–I, colored arrows).…”

“…This area had been reproducibly recognized in previous in vivo DTI data, with a very strong structural alignment with the medial-lateral (red) orientation and intermediate FA values (0.4–0.6). In a recent study using in vivo DTI (Kamali et al, 2016) suggested that this area represented the amygdalofugal pathway. Our results confirm that claim, but it should be noted that the amygdalofugal pathway was only one of the constituents of this area, as annotated in the panels in Figure 2.…”

“…For MRI-based anatomical analysis of the amygdala, T1-weighted images have been used most frequently and anatomical protocols for structural delineation have been proposed (Watson et al, 1992; Achten et al, 1998; Makris et al, 1999; Pruessner et al, 2000; Bonilha et al, 2004; Entis et al, 2012). In recent years, in vivo DTI has also been used in an attempt to delineate white matter tracts related to the amygdala (Wakana et al, 2004; Mori et al, 2005, 2008; Kamali et al, 2015, 2016) or its connectivity (Solano-Castiella et al, 2010, 2011; Bach et al, 2011; Saygin et al, 2011; Kamali et al, 2015, 2016; Rafal et al, 2015). However, these small white matter tracts are intricately linked with the target structures, requiring high-resolution observation that is often beyond the resolution achievable in in vivo imaging.…”

Intrinsic functional connectivity of the central extended amygdala

“…The EAc encompasses a collection of subcortical regions with similar cellular compositions, neurochemistry, gene expression, and structural connectivity and it encompasses the bed nucleus of the stria terminalis (BST), the central nucleus of the amygdala (Ce), the sublenticular extended amygdala (SLEA), and portions of the accumbens shell (Alheid & Heimer, ; Fox, Oler, Tromp, Fudge, & Kalin, a; Oler et al, ; Yilmazer‐Hanke, ). It has long been recognized that the amygdala is connected to the BST via two major fiber bundles—the ventral amygdalofugal pathway (VA) and the stria terminalis (ST) (Avery et al, ; Kamali et al, ; Nauta, ) (Figure c)—and more recent tracing studies have identified a third, indirect pathway centered on the SLEA (Ce ↔ SLEA ↔ BSTL) (deCampo & Fudge, ; Fudge et al, ; Oler et al, ). Anatomically, the Ce and the BST are both poised to trigger or orchestrate key signs of fear and anxiety—including alterations in arousal, behavioral inhibition, and neuroendocrine activity—via dense mono‐ and polysynaptic projections to brainstem and subcortical effector regions (Fox et al, a; Freese & Amaral, ; Fudge et al, ).…”

“…Abbreviations: BL 5 basolateral nucleus of the amygdala; BM 5 basomedial nucleus of the amygdala; BST 5 bed nucleus of the stria terminalis; Ce 5 central nucleus of the amygdala; EAc 5 central division of the extended amygdala; La 5 lateral nucleus of the amygdala; Me 5 medial nucleus of the amygdala; SLEA 5 sublenticular extended amygdala [Color figure can be viewed at wileyonlinelibrary.com] the accumbens shell (Alheid & Heimer, 1988;Fox, Oler, Tromp, Fudge, & Kalin, 2015a;Oler et al, 2017;Yilmazer-Hanke, 2012). It has long been recognized that the amygdala is connected to the BST via two major fiber bundles-the ventral amygdalofugal pathway (VA) and the stria terminalis (ST) (Avery et al, 2014;Kamali et al, 2015Kamali et al, , 2016Nauta, 1961) (Figure 1c)-and more recent tracing studies have identified a third, indirect pathway centered on the SLEA (Ce $ SLEA $ BSTL) (deCampo & Fudge, 2013;Fudge et al, 2017;Oler et al, 2017).…”