Cerebral chemoarchitecture shares organizational traits with brain structure and function
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eLife assessment
This work provides a valuable structural and functional characterization of the neurotransmitter's spatial distribution heterogeneity in cortical and subcortical regions. The authors report a systematic description and annotation of a new "layer" of brain organization that has been relatively poorly integrated with the wider neuroimaging literature to date. In sum, this paper has the potential to be of great interest to a wide audience in neurosciences.
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Abstract
Chemoarchitecture, the heterogeneous distribution of neurotransmitter transporter and receptor molecules, is a relevant component of structure–function relationships in the human brain. Here, we studied the organization of the receptome, a measure of interareal chemoarchitectural similarity, derived from positron-emission tomography imaging studies of 19 different neurotransmitter transporters and receptors. Nonlinear dimensionality reduction revealed three main spatial gradients of cortical chemoarchitectural similarity – a centro-temporal gradient, an occipito-frontal gradient, and a temporo-occipital gradient. In subcortical nuclei, chemoarchitectural similarity distinguished functional communities and delineated a striato-thalamic axis. Overall, the cortical receptome shared key organizational traits with functional and structural brain anatomy, with node-level correspondence to functional, microstructural, and diffusion MRI-based measures decreasing along a primary-to-transmodal axis. Relative to primary and paralimbic regions, unimodal and heteromodal regions showed higher receptomic diversification, possibly supporting functional flexibility.
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eLife assessment
This work provides a valuable structural and functional characterization of the neurotransmitter's spatial distribution heterogeneity in cortical and subcortical regions. The authors report a systematic description and annotation of a new "layer" of brain organization that has been relatively poorly integrated with the wider neuroimaging literature to date. In sum, this paper has the potential to be of great interest to a wide audience in neurosciences.
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Reviewer #1 (Public Review):
The work presented here uses a large collection of PET data to discover the principle axes of neurotransmitter receptor/transporter molecule (NTRM) variation in the human cortex and subcortex. These spatial axes are then systematically annotated for their alignment with diverse other measures of brain organization. The work is valuable for providing a systematic description and annotation of a new "layer" of brain organization that has been relatively poorly integrated with the wider neuroimaging literature to date. The methods used are state-of-the-art and the findings generated by these methods are sound. The discovered NTRM gradients will allow others in the field to more easily incorporate information of neurotransmitter maps in their analyses - helping to advance integration between different views of …
Reviewer #1 (Public Review):
The work presented here uses a large collection of PET data to discover the principle axes of neurotransmitter receptor/transporter molecule (NTRM) variation in the human cortex and subcortex. These spatial axes are then systematically annotated for their alignment with diverse other measures of brain organization. The work is valuable for providing a systematic description and annotation of a new "layer" of brain organization that has been relatively poorly integrated with the wider neuroimaging literature to date. The methods used are state-of-the-art and the findings generated by these methods are sound. The discovered NTRM gradients will allow others in the field to more easily incorporate information of neurotransmitter maps in their analyses - helping to advance integration between different views of the human brain. A fundamental challenge to this goal of cross-modal integration, however - which doesn't just impact this work, but the field more broadly - is that we are often left to work with spatial correlations between modalities in humans. The lack of access to experimental methods means that the biological basis for observed spatial correlations between different brain features in humans is typically poorly understood. It is therefore hard to know what newly-reported spatial correlations are telling us about brain organization that was not already captured in prior work. Nevertheless, the new resources and results presented here are important because they can guide the future work needed to unpick the biology behind spatially correlated features of the human brain
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Reviewer #2 (Public Review):
In this work, Hänisch and colleagues investigate the relationship between neurotransmitter transporter and receptor's spatial heterogeneity and well-studied functional and structural brain gradients in the human brain. They calculate the spatial similarity between the distribution of the neurotransmitter transporters and receptors for each parcel, thus obtaining a new brain distribution comprising a similarity index of all neurotransmitters mapped to each brain area. They employ a nonlinear dimensionality reduction on this neurotransmitter similarity map to reveal three spatial gradients for cortical and subcortical levels, respectively. Based on this, they characterize their significance by comparing them with functional fMRI meta-analytic activations, MRI microstructure, architectural contextualization, …
Reviewer #2 (Public Review):
In this work, Hänisch and colleagues investigate the relationship between neurotransmitter transporter and receptor's spatial heterogeneity and well-studied functional and structural brain gradients in the human brain. They calculate the spatial similarity between the distribution of the neurotransmitter transporters and receptors for each parcel, thus obtaining a new brain distribution comprising a similarity index of all neurotransmitters mapped to each brain area. They employ a nonlinear dimensionality reduction on this neurotransmitter similarity map to reveal three spatial gradients for cortical and subcortical levels, respectively. Based on this, they characterize their significance by comparing them with functional fMRI meta-analytic activations, MRI microstructure, architectural contextualization, MRI-based structural and functional connectivity, and gray matter atrophy-derived disease maps.
The claim of the work is broad, and the motivation is general, but the data presented is specific and biologically diverse. The neurotransmitter system operates at different pre- and post-synaptic synaptic levels, and the general assumption that transporters are equivalent to receptors lacks appropriate discussion for supporting this claim. The motivations of the work are very broad, and the analysis used is sufficient for the general claims, but the data presented is specific and biologically diverse.
Besides these conceptual issues, I find this work interesting as it jointly characterizes the cortical and subcortical PET neurotransmitter's distribution maps and their structural and functional meaning for the first time. In essence, the study presents several arguments to consider the organization of the characterized maps as an additional layer of brain organization. The results are convincing and clearly presented. Although this is a correlative study using unconnected datasets, I appreciate the use of multiple brain maps. I also appreciate that the authors made the data and code available for reproducibility. The data and analysis used in the current draft enable a powerful set of tools for hypothesis testing in the human brain's natural distribution of neurotransmitters beyond the usual pharmacological intervention strategy traditionally used in neurotransmitters' brain mapping area.
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