Table 1.

Methodologies incorporating molecular information into the analysis of fMRI data. PET: Positron Emission Tomography; AHBA: Allen Human Brain Atlas; PLS: Partial Least Squares regression.

Method	Summary	Types of molecular information	Advantages	Disadvantages	Key applications
Spatial correlation (Section 3)	Conventional analysis of fMRI data is undertaken and then resulting un-thresholded maps are correlated with the spatial distribution of molecular information	•Receptor/transporter density (PET) •Transcriptomics (AHBA) •Cytoarchitectonics	•Simple •Flexible •Easily interpretable •Opportunity to scale up (PLS)	•Less insight into spatiotemporal dynamics •Less amenable to providing subject-specific information •Less clear spatial localisation	•Adding as secondary outcome to provide biological specificity •Large scale mapping of molecular-functional relationships (PLS)
Molecular-enriched networks (Section 4)	A multiple regression framework creates functional networks capturing relationships between BOLD signal and spatial distribution of molecular information	•Receptor/transporter density (PET) •Transcriptomics (AHBA)	•Spatiotemporal insight •Can apply conventional higher level analyses	•Interpretation of negative functional connectivity can be challenging •Collinearity across PET templates requires careful consideration	•Disentangling pharmacodynamics •Novel biomarkers
Computational modelling (Section 5)	Creation of whole brain models that attempt to recapitulate experimental data from functional imaging, within which molecular information can be used to regionally modulate different aspects of neuronal micro-circuitry and examine the counterfactual consequences	•Receptor/transporter density (PET) •Transcriptomics (AHBA)	•Requires careful hypotheses •Allows for manipulation and mechanistic insight not possible experimentally	•Technically challenging •Resource intensive •Modelling multiple receptor systems and their interactions is currently difficult	•Testing hypotheses regarding the role molecular mechanisms play in shaping network dynamics •Characterising contribution of different receptor mechanisms to drug pharmacodynamics