Mapping neurotransmitter systems to the structural and functional organization of the human neocortex

Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macro-scale neuroanatomy and how they shape emergent function remain poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from more than 1,200 healthy individuals to construct a whole-brain three-dimensional normative atlas of 19 receptors and transporters across nine different neurotransmitter systems. We found that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting-state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncovered a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we found both expected and novel associations between receptor distributions and cortical abnormality patterns across 13 disorders. We replicated all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization.


Statistics
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n/a Confirmed The exact sample size (n) for each experimental group/condition, given as a discrete number and unit of measurement A statement on whether measurements were taken from distinct samples or whether the same sample was measured repeatedly The statistical test(s) used AND whether they are one-or two-sided Only common tests should be described solely by name; describe more complex techniques in the Methods section.
A description of all covariates tested A description of any assumptions or corrections, such as tests of normality and adjustment for multiple comparisons A full description of the statistical parameters including central tendency (e.g. means) or other basic estimates (e.g. regression coefficient) AND variation (e.g. standard deviation) or associated estimates of uncertainty (e.g. confidence intervals) For null hypothesis testing, the test statistic (e.g. F, t, r) with confidence intervals, effect sizes, degrees of freedom and P value noted Give P values as exact values whenever suitable.
For Bayesian analysis, information on the choice of priors and Markov chain Monte Carlo settings For hierarchical and complex designs, identification of the appropriate level for tests and full reporting of outcomes Estimates of effect sizes (e.g. Cohen's d, Pearson's r), indicating how they were calculated Our web collection on statistics for biologists contains articles on many of the points above.

Software and code
Policy information about availability of computer code Data collection enigmatoolbox v1.1.1 (https://github.com/MICA-MNI/ENIGMA) was used for fetching ENIGMA data.
MEG data was processed using the open software toolbox Brainstorm v220420. HCP structural data was processed using MRtrix3 v3.0.0
For manuscripts utilizing custom algorithms or software that are central to the research but not yet described in published literature, software must be made available to editors and reviewers. We strongly encourage code deposition in a community repository (e.g. GitHub). See the Nature Portfolio guidelines for submitting code & software for further information.

Data
Policy information about availability of data All manuscripts must include a data availability statement. This statement should provide the following information, where applicable: -Accession codes, unique identifiers, or web links for publicly available datasets -A description of any restrictions on data availability -For clinical datasets or third party data, please ensure that the statement adheres to our policy All data used to perform the analyses can be found at https://github.com/netneurolab/hansen_receptors. Volumetric PET images, including receptor images and synaptic density, are included in neuromaps (https://github.com/netneurolab/neuromaps) where they can be easily converted between template spaces. Autoradiography data is available in Supplementary All studies must disclose on these points even when the disclosure is negative.

Sample size
No sample size calculations were performed. We collated as many PET tracer images as possible to construct a comprehensive (19-receptor/ transporter) atlas. HCP data was used because of the large number of subjects and the relatively equal male/female balance. For HCP data, only unrelated subjects were included. For PET data, only healthy subjects were included. The ENIGMA dataset was selected because of the large number of subjects in each meta-analysis and because it contains many brain maps for diseases/disorders/conditions that have been similarly processed such that comparison between datasets is possible.
Data exclusions No data was excluded.

Replication
The analysis pipeline was conducted and replicated: (1) at the Schaefer-100 parcellation resolution, (2) at the Schaefer-200 parcellation resolution, (3) at the Schaefer-400 parcellation resolution, (4) using the 68-node Desikan Killiany atlas alongside structural/functional connectomes from the Lausanne atlas. Furthermore, we recalculated the receptor similarity matrix in a leave-one-out fashion, and confirmed that no single receptor/transporter exerts undue influence on this similarity matrix (correlation between leave-one-out similarity matrix and original similarity matrix >0.98 for all receptors). Finally, analyses were repeated using autoradiography data for 15 receptors as opposed to PET data for 19 receptors/transporters.

Blinding
Blinding is not relevant to this study because it does not include experimental groups.

Reporting for specific materials, systems and methods
We require information from authors about some types of materials, experimental systems and methods used in many studies. Here, indicate whether each material, system or method listed is relevant to your study. If you are not sure if a list item applies to your research, read the appropriate section before selecting a response.

Recruitment
Only data from healthy control subjects were used in the analyses.

Ethics oversight
Each individual PET study was approved, details can be found in the references found in Table 1.
Note that full information on the approval of the study protocol must also be provided in the manuscript. . All four resting state fMRI scans (two scans (R/L and L/R phase encoding directions) on day 1 and two scans (R/L and L/R phase encoding directions) on day 2, each about 15 min long; TR=720 ms), as well as diffusion weighted imaging (DWI) data were available for all participants. All the structural and functional MRI data were pre-processed using HCP minimal pre-processing pipelines. Detailed information regarding data acquisition and pre-processing is available elsewhere (Van Essen et al., 2013, Glasser et al., 2013 Behavioral performance measures No behavioural measures were recorded during the fMRI runs.

Acquisition
Imaging type(s) Functional and diffusion-weighted MRI Field strength 3T Sequence & imaging parameters Multi-band sequence; functional images have a 2-mm isotropic signal resolution, structural modalities were acquired on a Siemens Skyra 3T scanner and included a T1-weighted MPRAGE sequence at an isotropic resolution of 0.7mm, and a T2-weighted SPACE at an isotropic resolution of 0.7mm. More details on imaging protocols and procedures are available at http://protocols.humanconnectome.org/HCP/3T/imaging-protocols.html.