Focal acetylcholinergic modulation of the human midcingulo-insular network during attention

2481 

Abstract Submission 

Sudesna Chakraborty¹, Sun Kyun Lee², Sarah Arnold³, Roy Haast⁴, Ali Khan¹, Taylor Schmitz¹

¹University of Western Ontario, London, Ontario, ²University of Toronto, Toronto, Ontario, ³McMaster University, Hamilton, Ontario, ⁴Aix-Marseille University, Marseille, Provence

Sudesna Chakraborty  
University of Western Ontario
London, Ontario

Sun Kyun Lee  
University of Toronto
Toronto, Ontario

Sarah Arnold  
McMaster University
Hamilton, Ontario

Roy Haast  
Aix-Marseille University
Marseille, Provence

Ali Khan  
University of Western Ontario
London, Ontario

Taylor Schmitz  
University of Western Ontario
London, Ontario

The cholinergic basal forebrain neurons send large projections to the cortex which are involved in rapid and spatially precise coordination of neuronal activity and behavior. The relatively recent discovery of 'wired' cholinergic neurotransmission modes comes mostly from non-human animal research but implies a central role of acetylcholine (ACh) in attention. However, the direct link between ACh signaling and attention has proven challenging to study experimentally in humans. Here, we used meta-analytic strategies targeting both pharmacological and non-pharmacological neuroimaging studies to examine the relationship between ACh and attention in humans (Chakraborty, Lee, et al. 2023).

We performed several meta-analyses including (1) focused meta-analysis on a well curated sample of placebo-controlled neuroimaging studies examining attention under pharmacological modulation with an ACh agonist and (2) discovery and validation meta-analyses on larger independent samples of non-pharmacological neuroimaging studies (Fig.1). First, we conducted a literature search on the PubMed database (https://pubmed.ncbi.nlm.nih.gov) to identify pharmacological functional imaging studies of potential relevance up to April 2023 (N=32 experiments in total). Relevant coordinates from the selected studies were extracted and converted into MNI coordinates, using the Lancaster transform included in GingerALE v.3.0.2 (Lancaster et al. 2007) (http://www.brainmap.org/ale/) to perform Activation Likelihood Estimation (ALE). We also extracted measures of response accuracy and response latency from these studies for a behavioral meta-analysis examining if and how ACh affects attentional task performance. For the discovery and validation meta-analyses of non-pharmacological imaging studies, we used Sleuth (https://brainmap.org/sleuth/) to perform meta-analytic connectivity mapping (MACM) on two seed regions of interest (ROIs). For the discovery MACM, we used the a priori anatomically defined nuclei of the BF as our ROI (Fig.1AB). For the validation MACM, we used the suprathreshold clusters identified in the previous ALE analysis of ACh pharmacological imaging studies (Fig.1C). The binarized MNI space masks for each ROI were entered into the BrainMap database, along with two other search criteria specifying (1) normal mapping and (2) activations. Using the search criteria, MACM queries the database for imaging studies which report coordinates for brain areas that are co-activated with the seed ROI during a particular task or under specific conditions. The coordinates are then entered into an ALE to identify brain regions that are consistently activated across studies. Finally, we used our previously defined "multimodal cholinergic map" (Chakraborty, Haast, et al. 2023) to perform spin test (Alexander-Bloch et al. 2018) to assess the spatial correspondences between the meta-analytic findings and the BF cortical cholinergic projectome (Fig.2).

We found that pharmaco-modulation of ACh evoked both increased activity in the anterior cingulate and decreased activity in the opercular and insular cortex. Behaviorally, ACh evoked a significant speeding of responses compared to placebo, with negligible tradeoff in accuracy, consistent with attentional enhancement. In large independent meta-analyses of non-pharmacological neuroimaging research, we demonstrate that during attentional engagement these same 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 BF, as estimated by multimodal cholinergic map.

In sum, the present meta-analytic findings provide further evidence that acetylcholinergic modulation of midcingulo-insular network via basal forebrain afferents may coordinate selection of task relevant information, thereby facilitating cognition and behavior.

Connectivity (eg. functional, effective, structural)

Other Methods

Subcortical Structures ²

Perception and Attention Other ¹

Acetylcholine

Cognition

Meta- Analysis

Other - Basal Forebrain