Brainstem Modulation of Large-Scale Intrinsic Cortical Activity Correlations

Abstract

Brain activity fluctuates continuously, even in the absence of changes in sensory input or motor output. These intrinsic activity fluctuations are correlated across brain regions and are spatially organized in macroscale networks. Variations in the strength, topography, and topology of correlated activity occur over time, and unfold upon a backbone of long-range anatomical connections. Subcortical neuromodulatory systems send widespread ascending projections to the cortex, and are thus ideally situated to shape the temporal and spatial structure of intrinsic correlations. These systems are also the targets of the pharmacological treatment of major neurological and psychiatric disorders, such as Parkinson's disease, depression, and schizophrenia. Here, we review recent work that has investigated how neuromodulatory systems shape correlations of intrinsic fluctuations of large-scale cortical activity. We discuss studies in the human, monkey, and rodent brain, with a focus on non-invasive recordings of human brain activity. We provide a structured but selective overview of this work and distil a number of emerging principles. Future efforts to chart the effect of specific neuromodulators and, in particular, specific receptors, on intrinsic correlations may help identify shared or antagonistic principles between different neuromodulatory systems. Such principles can inform models of healthy brain function and may provide an important reference for understanding altered cortical dynamics that are evident in neurological and psychiatric disorders, potentially paving the way for mechanistically inspired biomarkers and individualized treatments of these disorders.

Keywords: acetycholine; brainstem; dopamine; functional connectivity; neuromodulation; norepinepherine; resting-state; serotonin.

FIGURE 1

Schematic of major neuromodulatory systems. Cerebellar, spinal, and temporal projections are omitted for brevity. The inset shows the approximate anatomical location of each nucleus that sends major afferents to the forebrain.

FIGURE 2

Overview of cortical distributions of genetic expression of neuromodulator receptors in the human brain. Receptor maps were taken from Gryglewski et al. (2018), projected onto the cortical surface, and Z-scored across space. Files and tool for plotting these maps can be found here: github.com/rudyvdbrink/receptormaps. Abbreviations: D: dopamine; ACh: acetylcholine; M: muscarinic; N: nicotinic; 5HT: serotonin; H: histamine.