Functional Involvement of Human Periaqueductal Gray and Other Midbrain Nuclei in Cognitive Control

Abstract

Recent theoretical advances have motivated the hypothesis that the periaqueductal gray (PAG) participates in behaviors that involve changes in the autonomic control of visceromotor activity, including during cognitively demanding tasks. We used ultra-high-field (7 tesla) fMRI to measure human brain activity at 1.1 mm resolution while participants completed a working memory task. Consistent with prior work, participants were less accurate and responded more slowly with increasing memory load-signs of increasing task difficulty. Whole-brain fMRI analysis revealed increased activity in multiple cortical areas with increasing working memory load, including frontal and parietal cortex, dorsal cingulate, supplementary motor area, and anterior insula. Several dopamine-rich midbrain nuclei, such as the substantia nigra and ventral tegmental area, also exhibited load-dependent increases in activation. To investigate PAG involvement during cognitive engagement, we developed an automated method for segmenting and spatially normalizing the PAG. Analyses using cross-validated linear support vector machines showed that the PAG discriminated high versus low working memory load conditions with 95% accuracy in individual subjects based on activity increases in lateral and ventrolateral PAG. Effect sizes in the PAG were comparable in magnitude to those in many of the cortical areas. These findings suggest that cognitive control is not only associated with cortical activity in the frontal and parietal lobes, but also with increased activity in the subcortical PAG and other midbrain regions involved in the regulation of autonomic nervous system function.

A 7-Tesla MRI study of the periaqueductal gray: resting state and task activation under threat

“…Manual segmentation of the PAG was done in reference to Duvernoy’s Atlas of the Human Brain Stem and Cerebellum ( Duvernoy, 2009 ) and in accordance with previous human PAG segmentation protocols ( Satpute et al. , 2013 ; Kragel et al. , 2019 ).…”

“…Once the aqueduct was identified, its mask was used to create the PAG by dilating out two voxels in all directions: +0.86 × 0.86 × 1.60 mm ( Satpute et al. , 2013 ; Kragel et al. , 2019 ).…”

“…, 2013 ) and cold ( La Cesa et al. , 2014 ), working memory load ( Kragel et al. , 2019 ), virtual threat imminence ( Mobbs et al.…”

Identification of retinal ganglion cell types and brain nuclei expressing the transcription factor Brn3c/Pou4f3 using a Cre recombinase knock‐in allele

“…In mice, vPAG GABAergic projections to the VTA induce immobility (St Laurent, Martinez Damonte, Tsuda, & Kauer, 2020). A CeA to vlPAG pathway also produces freezing, by desinhibition of gutamatergic vlPAG neurons projecting to the motor column (Tovote et al, 2016), while in humans l/vlPAG may also participate in visual cognitive recognition/short memory task (Kragel et al, 2019).…”

Cue-elicited functional connectivity of the periaqueductal gray and tonic cocaine craving

“…With the new model, the IFG cluster was not significant at cluster-level p<0.05 FWE, while the vmPFC findings remain the same (Supplementary Figure 2). Finally, the PAG is known to harbor functional subdivisions (Coulombe et al, 2016;Kragl et al, 2019;Satpute et al, 2013), and more work is needed to understand how these functional subareas may be differentially involved in the clinical manifestations during cocaine withdrawal. In summary, we showed higher connectivity of the PAG with the vmPFC during exposure to cocaine as compared to neutral cues in abstinent patients with cocaine dependence.…”