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J Neurosci. 2019 Jun 3. pii: 2043-18. doi: 10.1523/JNEUROSCI.2043-18.2019. [Epub ahead of print]

Functional involvement of human periaqueductal gray and other midbrain nuclei in cognitive control.

Author information

1
Department of Psychology and Neuroscience and the Institute of Cognitive Science, University of Colorado, Boulder, USA philip.kragel@colorado.edu a.satpute@northeastern.edu.
2
Institute for Behavioral Genetics, University of Colorado, Boulder, USA.
3
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
4
Department of Psychology, Northeastern University, Boston, MA, USA.
5
Department of Psychology and Neuroscience and the Institute of Cognitive Science, University of Colorado, Boulder, USA.
6
Center for Healthcare Organization and Implementation Research (CHOIR) & the Social and Community Reintegration Research Program (SoCRR), Edith Nourse Rogers Memorial VA Hospital, Bedford, MA, USA.
7
Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

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) functional magnetic resonance imaging 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, e.g., 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 vs. 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.SIGNIFICANCE STATEMENTFunctional neuroimaging in humans has shown that cognitive control engages multiple cortico-striatal networks and brainstem nuclei, but theoretical advances suggest that the periaqueductal gray (PAG) should also be engaged during cognitively demanding tasks. Recent advances in ultra-high-field fMRI provided an opportunity to obtain the first evidence that increased activation of intermediate and rostral portions of lateral and ventrolateral PAG columns in humans is modulated by cognitive load. These findings suggest that cognitive control is not solely mediated by activity in the cortex, but that midbrain structures important for autonomic regulation also play a crucial role in higher-order cognition.

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