Focal acetylcholinergic modulation of the human midcingulo‐insular network during attention: Meta‐analytic neuroimaging and behavioral evidence

• Published in: Journal of neurochemistry 2024-04, Vol.168 (4), p.397-413
• Main Authors: Chakraborty, Sudesna, Lee, Sun Kyun, Arnold, Sarah M., Haast, Roy A. M., Khan, Ali R., Schmitz, Taylor W.
• Format: Article
• Language: English
• Subjects: Acetylcholine; Attention; Basal forebrain; Cholinergic Agents - pharmacology; Cholinergics; Cognition; Cognition - physiology; Cognitive science; connectivity; Cortex (insular); Emission analysis; Forebrain; Humans; imaging; Innervation; Magnetic resonance imaging; Mathematical analysis; Medical imaging; meta‐analysis; Modulation; Neuroimaging; Neuroscience; Pharmacology; Positron emission; Positron emission tomography
• ISSN: 0022-3042; 1471-4159; 1471-4159
• DOI: 10.1111/jnc.15990

The basal forebrain cholinergic neurons provide acetylcholine to the cortex via large projections. Recent molecular imaging work in humans indicates that the cortical cholinergic innervation is not uniformly distributed, but rather may disproportionately innervate cortical areas relevant to supervisory attention. In this study, we therefore reexamined the spatial relationship between acetylcholinergic modulation and attention in the human cortex using meta‐analytic strategies targeting both pharmacological and non‐pharmacological neuroimaging studies. We found that pharmaco‐modulation of acetylcholine evoked both increased activity in the anterior cingulate and decreased activity in the opercular and insular cortex. In large independent meta‐analyses of non‐pharmacological neuroimaging research, we demonstrate that during attentional engagement these cortical areas exhibit (1) task‐related co‐activation with the basal forebrain, (2) task‐related co‐activation with one another, and (3) spatial overlap with dense cholinergic innervations originating from the basal forebrain, as estimated by multimodal positron emission tomography and magnetic resonance imaging. Finally, we provide meta‐analytic evidence that pharmaco‐modulation of acetylcholine also induces a speeding of responses to targets with no apparent tradeoff in accuracy. In sum, we demonstrate in humans that acetylcholinergic modulation of midcingulo‐insular hubs of the ventral attention/salience network via basal forebrain afferents may coordinate selection of task relevant information, thereby facilitating cognition and behavior. Chakraborty and colleagues performed meta‐analyses of non‐pharmacological task functional magnetic resonance imaging (fMRI) studies (>1000 individuals) which reported brain activity in the cholinergic basal forebrain (left) and in a separate sample of placebo‐controlled pharmacological task fMRI studies (>400 individuals) which reported changes in brain activity under a cholinergic agonist (right). They then examined which brain regions tend to co‐activate with either the basal forebrain or the cortical areas most strongly modulated by cholinergic agonists. These analyses revealed strikingly similar cortical patterns emphasizing the midcingulo‐insular network. They further confirmed that these midcingulo‐insular hotspots spatially overlap a third independently derived brain map reflecting the basal forebrain's functional, structural, and molecular connectivity. Analysis o