Multimodal gradients of human basal forebrain connectivity

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, [(18)F] 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.