An In Vivo Assay of Synaptic Function Mediating Human Cognition

The contribution of dopamine to working memory has been studied extensively [1Gao W.J. Goldman-Rakic P.S. Selective modulation of excitatory and inhibitory microcircuits by dopamine.Proc. Natl. Acad. Sci. USA. 2003; 100: 2836-2841Crossref PubMed Scopus (127) Google Scholar, 2Goldman-Rakic P.S. Regional and cellular fractionation of working memory.Proc. Natl. Acad. Sci. USA. 1996; 93: 13473-13480Crossref PubMed Scopus (681) Google Scholar, 3Robbins T.W. Chemical neuromodulation of frontal-executive functions in humans and other animals.Exp. Brain Res. 2000; 133: 130-138Crossref PubMed Scopus (338) Google Scholar]. Here, we exploited its well characterized effects [1Gao W.J. Goldman-Rakic P.S. Selective modulation of excitatory and inhibitory microcircuits by dopamine.Proc. Natl. Acad. Sci. USA. 2003; 100: 2836-2841Crossref PubMed Scopus (127) Google Scholar, 2Goldman-Rakic P.S. Regional and cellular fractionation of working memory.Proc. Natl. Acad. Sci. USA. 1996; 93: 13473-13480Crossref PubMed Scopus (681) Google Scholar, 3Robbins T.W. Chemical neuromodulation of frontal-executive functions in humans and other animals.Exp. Brain Res. 2000; 133: 130-138Crossref PubMed Scopus (338) Google Scholar] to validate a novel human in vivo assay of ongoing synaptic [4Kiebel S.J. David O. Friston K.J. Dynamic causal modelling of evoked responses in EEG/MEG with lead field parameterization.Neuroimage. 2006; 30: 1273-1284Crossref PubMed Scopus (181) Google Scholar, 5David O. Kiebel S.J. Harrison L.M. Mattout J. Kilner J.M. Friston K.J. Dynamic causal modeling of evoked responses in EEG and MEG.Neuroimage. 2006; 30: 1255-1272Crossref PubMed Scopus (464) Google Scholar] processing. We obtained magnetoencephalographic (MEG) measurements from subjects performing a working memory (WM) task during a within-subject, placebo-controlled, pharmacological (dopaminergic) challenge. By applying dynamic causal modeling (DCM), a Bayesian technique for neuronal system identification [6Moran R.J. Stephan K.E. Seidenbecher T. Pape H.C. Dolan R.J. Friston K.J. Dynamic causal models of steady-state responses.Neuroimage. 2009; 44: 796-811Crossref PubMed Scopus (129) Google Scholar], to MEG signals from prefrontal cortex, we demonstrate that it is possible to infer synaptic signaling by specific ion channels in behaving humans. Dopamine-induced enhancement of WM performance was accompanied by significant changes in MEG signal power, and a DCM assay disclosed related changes in synaptic signaling. By estimating the contribution of ionotropic receptors (AMPA, NMDA, and GABAA) to the observed spectral response, we demonstrate changes in their function commensurate with the synaptic effects of dopamine. The validity of our model is reinforced by a striking quantitative effect on NMDA and AMPA receptor signaling that predicted behavioral improvement over subjects. Our results provide a proof-of-principle demonstration of a novel framework for inferring, noninvasively, neuromodulatory influences on ion channel signaling via specific ionotropic receptors, providing a window on the hidden synaptic events mediating discrete psychological processes in humans.