7-Tesla evidence for columnar and rostral–caudal organization of the human periaqueductal gray response in the absence of threat: a working memory study. (2024)

Abstract

The periaqueductal gray (PAG) is a small midbrain structure that surrounds the cerebral aqueduct, regulates brain–body communication, and is often studied for its role in “fight-or-flight” and “freezing” responses to threat. We used ultra-high field 7-Tesla fMRI to resolve the PAG in humans and distinguish it from the cerebral aqueduct, examining its in vivo function in humans during a working memory task (N = 87). Both mild and moderate cognitive demand elicited spatially similar patterns of whole brain BOLD response, and moderate cognitive demand elicited widespread BOLD increases above baseline in the brainstem. Notably, these brainstem increases were not significantly greater than those in the mild demand condition, suggesting that a subthreshold brainstem BOLD increase occurred for mild cognitive demand as well. PAG response was group-aligned and examined with subject-specific masks. In PAG, both mild and moderate demand elicited a well-defined response in ventrolateral PAG (vlPAG), a region thought to be functionally related to anticipated painful threat in humans and non-human animals—yet, the present task posed only the most minimal (if any) “threat”, with the cognitive tasks used being approximately equivalent to remembering a phone number. These findings suggest that the PAG may play a more general role in visceromotor regulation, even in the absence of threat.

Significance statement The periaqueductal gray (PAG) is thought to control survival-related behavior, and is typically studied using experiments that manipulate threat. Others have proposed that the PAG plays a more general role in bodily regulation, but studies examining PAG function outside of threat-based experimental contexts are rare. We used high-resolution fMRI to examine PAG response in humans during a working memory task, which involves minimal threat. Moderate cognitive demands elicited a well-defined response in ventrolateral PAG, a functional subregion thought to coordinate a “freezing” response to threat. A task where threat is minimal elicited a clear fMRI response in one of the most well-known survival circuits in the brain, which suggests the PAG supports a more general function in brain­–body coordination.

Footnotes

• This work was supported by grants from the National Institutes of Health (U01 CA193632; R01 AG071173; R01 MH113234; R21 MH129902), the National Science Foundation (BCS 1947972), the U.S. Army Research Institute for the Behavioral and Social Sciences (W911NF-16-1-019), and the Unlikely Collaborators Foundation. The views, opinions, and/or findings contained in this manuscript are those of the authors and shall not be construed as an official Department of the Army position, policy, or decision, unless so designated by other documents, nor do they necessarily reflect the views of the Unlikely Collaborators Foundation.

• ↵^**Shared senior authorship