Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article


Doctor of Philosophy




Khan, Ali R.

2nd Supervisor

Schmitz, Taylor W.


The cholinergic innervation of the cortex originates from neurons in the basal forebrain (BF) and plays a crucial role in cognitive processing. However, it is unclear how the organization of BF cholinergic neurons in the human brain is related to their functional and structural integration with the cortex. To address this, we have used high-resolution 7 Tesla diffusion and resting-state functional MRI to examine multimodal forebrain cholinergic connectivity with the neocortex in humans. Discrete parcellation analyses revealed that structural and functional parcellation broadly differentiated the anteromedial from posterolateral nuclei of BF. Next, we used gradient estimation to capture more fine-grained connectivity profile of the BF-cortical projectome and found 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). Additionally, 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. Moreover, [18F] FEOBV PET imaging was used to demonstrate that these transmodal cortical areas are also among the most densely innervated regions. This intrinsic BF cholinergic connectivity map of cortex was compared with meta-analytic connectivity map of cholinergic modulation on attention, demonstrating that patterns of brain activity evoked by directed attention are altered by pharmacological activation of acetylcholine (ACh) compared to placebo and these patterns spatially overlap with the intrinsic BF cholinergic connectivity map. Altogether, our findings provide new insights into how cholinergic signaling is organized in the human brain.

Summary for Lay Audience

Cholinergic signaling is an essential process for how our brain thinks and processes information. If this signaling doesn't work properly, it can lead to cognitive issues. Cholinergic connections in the brain mostly come from specific neurons in a region called the basal forebrain (BF). However, we don't fully understand how these neurons are organized in the human brain and how they interact with the other areas of the brain.

To study this, we used high-resolution MRI images to examine the structural and functional connections of cholinergic BF with other areas, neocortex (the outer layer) of human brains. We discovered that the organization of these connections is similar to what is observed in mice, and monkeys and there are distinct differences between subregions of the BF. We found that the organization of the cholinergic projections can be broadly differentiated between anteromedial and posterolateral nuclei of the BF.

We used a technique called "gradients" to study these connections in more detail. As we moved from one part, anteromedial of the BF to posterolateral, we found that the structural and functional connection differences became more noticeable, especially in a specific subregion called nucleus basalis of Meynert. On the neocortex side, this dissimilarity in connection was most evident in the area called transmodal cortex, which is closely associated with the ventral attention network. Also, areas of the brain closer to the BF that receive dense cholinergic connections showed higher levels of divergence.

Additionally, we conducted a meta-analysis to study the relationship with the cognitive process of attention. We discovered that when acetylcholine (the neurotransmitter released by BF) is activated by certain drugs, it leads to diverse but functionally integrated patterns of brain activation that overlap with the ventral attention network.

In conclusion, this research sheds new light on how cholinergic signaling is organized in the human brain. It will be valuable for researchers studying the brain's connections and could potentially help in developing imaging-based methods for early detection of neurodegenerative diseases such as Alzheimer's disease before cognitive decline begins.