Monkey in the middle: why non-human primates are needed to bridge the gap in resting-state investigations

Resting-state investigations based on the evaluation of intrinsic low-frequency fluctuations of the BOLD fMRI signal have been extensively utilized to map the structure and dynamics of large-scale functional network organization in humans. In addition to increasing our knowledge of normal brain connectivity, disruptions of the spontaneous hemodynamic fluctuations have been suggested as possible diagnostic indicators of neurological and psychiatric disease states. Though the non-invasive technique has been received with much acclamation, open questions remain regarding the origin, organization, phylogenesis, as well as the basis of disease-related alterations underlying the signal patterns. Experimental work utilizing animal models, including the use of neurophysiological recordings and pharmacological manipulations, therefore, represents a critical component in the understanding and successful application of resting-state analysis, as it affords a range of experimental manipulations not possible in human subjects. In this article, we review recent rodent and non-human primate studies and based on the examination of the homologous brain architecture propose the latter to be the best-suited model for exploring these unresolved resting-state concerns. Ongoing work examining the correspondence of functional and structural connectivity, state-dependency and the neuronal correlates of the hemodynamic oscillations are discussed. We then consider the potential experiments that will allow insight into different brain states and disease-related network disruptions that can extend the clinical applications of resting-state fMRI (RS-fMRI).