Exploring the relation between BOLD fMRI and cognitive performance using a computer-based quantitative systems pharmacology model: Applications to the COMTVAL158MET genotype and ketamine.

BOLD fMRI is increasingly used mostly in an observational way to probe the effect of genotypes or therapeutic intervention in normal and diseased subjects. We use a mechanism-based quantitative systems pharmacology computer model of a human cortical microcircuit, previously calibrated for the 2-back working memory paradigm, adding established biophysical principles, of glucose metabolism, oxygen consumption, neurovascular effects and the paramagnetic impact on blood oxygen levels to calculate a readout for the voxel-based BOLD fMRI signal. The objective was to study the effect of the Catechol-O-methyl Transferase Val158Met (COMT) genotype on performance and BOLD fMRI. While the simulation suggests that on average virtual COMTVV genotype subjects perform worse, subjects with lower GABA, lower 5-HT and higher 5-HT activation can improve cognitive performance to the level of COMTMM subjects but at the expense of higher BOLD fMRI signal. In a schizophrenia condition, increased NMDA, GABA tone and noise levels, and lower DR activity can improve cognitive outcome with greater BOLD fMRI signal in COMT Val-carriers. We further generate hypotheses about why ketamine in healthy controls increases the BOLD fMRI signal but reduces cognitive performance. These simulations suggest a strong non-linear relationship between BOLD fMRI signal and cognitive performance. When validated, this mechanistic approach can be useful for moving beyond the descriptive nature of BOLD fMRI imaging and supporting the proper interpretation of imaging biomarkers in CNS disorders.