Multimodal gradients of basal forebrain connectivity across the neocortex

Abstract

The cholinergic innervation of the cortex originates almost entirely from populations of neurons in the basal forebrain. Structurally, the ascending basal forebrain cholinergic projections are highly branched, with individual cells targeting multiple different cortical regions. However, it is not known whether the structural organization of basal forebrain projections reflects their functional integration with the cortex. We therefore used high resolution 7T diffusion and resting state functional MRI in humans to examine multimodal gradients of forebrain cholinergic connectivity with the neocortex. Moving from anteromedial to posterolateral BF, structural and functional gradients became progressively detethered, with the most pronounced dissimilarity localized in the nucleus basalis of Meynert (NbM). Structure-function tethering was shaped in part by the distance of cortical parcels from the BF and their myelin content. Functional but not structural connectivity with the BF grew stronger at shorter geodesic distances, with weakly myelinated transmodal cortical areas most strongly expressing this divergence. We then used an in vivo cell type-specific marker of the presynaptic cholinergic nerve terminals, [18F] FEOBV PET, to demonstrate that the transmodal cortical areas exhibiting highest structure-function detethering with BF gradients are also among the most densely innervated by its cholinergic projections. Altogether, multimodal gradients of basal forebrain connectivity reveal inhomogeneity in structure-function tethering which becomes most pronounced in the transition from anteromedial to posterolateral BF. Cortical cholinergic projections emanating from the NbM in particular may exhibit a broad repertoire of connections with key transmodal cortical areas associated with the ventral attention network.

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

“…We performed MACM analyses using Sleuth Spin tests assessing spatial correspondences among brain maps Brain maps encoding the ALE Z values were transformed from MNI volume-space to 10k_fsavg surface-space using neuromaps toolbox (Markello et al 2022) and parcellated using the HCP-MMP 1.0 atlas (Glasser et al 2016). We used a multimodal surface map of the BF connectome derived from (Chakraborty et al 2023); Figure 1A). In neuroimaging studies, spin tests evaluate the statistical significance of spatial relationships between different cortical surface features (Alexander-Bloch et al 2018).…”

“…Extending on our prior work examining the BF cholinergic connectome with multimodal imaging (Chakraborty et al 2023), we first examined which brain areas are consistently co-activated with the BF during attentional engagement. To do so, we employed meta-analytic connectivity mapping (MACM) of the BF (see Methods, Figure 2A).…”

“…Moreover, extending on the discovery ALE of BF co-activation (Figure 3B), this observed spatial pattern of cortical coactivations provides further validation that these clusters form hubs of the midcinguloinsular network. As with the discovery ALE of BF co-activation, we used spin tests to determine whether the continuous map of ALE Z values encoding the cortical ACh coactivation pattern was also spatially related to the multimodal gradient of cortical cholinergic innervation originating from BF (Chakraborty et al 2023) (Figure 1A). Consistent with a structure-function link between cortical cholinergic innervation and attention-related functional activations, the spin test yielded a significant positive correlation (r=0.31, p spin =0.009), indicating that cortical areas exhibiting the highest task-related co-activations under ACh also receive the densest BF cholinergic innervation (Figure 5B).…”

“…We recently demonstrated with multimodal MRI and PET data acquired from humans that cortical regions including the dorsal anterior cingulate, anterior insula and frontal operculum express molecular, structural and functional markers of BF cholinergic innervation which are disproportionately higher than other cortical regions (Chakraborty et al 2023) (Figure 1A). Further analysis revealed that these regions closely overlap with hubs of the ventral attention network (Yeo et al 2011;Alves et al 2022;Corbetta et al 2008;Vossel et al 2014) and salience network (Seeley et al 2007;Seeley 2019).…”

“…The phylogenetic cortical homologues of a midcinguloinsular network are also observed in the intrinsic cortical connectome of the mouse (Mandino et al 2022;Sforazzini et al 2014), suggesting evolutionary conservation of a core attention system for saliency, switching, and control (Figure 1B). In mouse and human, these systems receive dense inputs from highly branched BF cholinergic neurons (Chakraborty et al 2023;Li et al 2018). However, in humans the direct link between ACh signaling and attention has proven challenging to study experimentally.…”