title: Biomarkers, designs, and interpretations of resting-state fMRI in translational pharmacological research: A review of state-of-the-Art, challenges, and opportunities for studying brain chemistry.
abstract: A decade of research and development in resting-state functional MRI (RSfMRI) has opened new translational and clinical research frontiers. This review aims to bridge between technical and clinical researchers who seek reliable neuroimaging biomarkers for studying drug interactions with the brain. About 85 pharma-RSfMRI studies using BOLD signal (75% of all) or arterial spin labeling (ASL) were surveyed to investigate the acute effects of psychoactive drugs. Experimental designs and objectives include drug fingerprinting dose-response evaluation, biomarker validation and calibration, and translational studies. Common biomarkers in these studies include functional connectivity, graph metrics, cerebral blood flow and the amplitude and spectrum of BOLD fluctuations. Overall, RSfMRI-derived biomarkers seem to be sensitive to spatiotemporal dynamics of drug interactions with the brain. However, drugs cause both central and peripheral effects, thus exacerbate difficulties related to biological confounds, structured noise from motion and physiological confounds, as well as modeling and inference testing. Currently, these issues are not well explored, and heterogeneities in experimental design, data acquisition and preprocessing make comparative or meta-analysis of existing reports impossible. A unifying collaborative framework for data-sharing and data-mining is thus necessary for investigating the commonalities and differences in biomarker sensitivity and specificity, and establishing guidelines. Multimodal datasets including sham-placebo or active control sessions and repeated measurements of various psychometric, physiological, metabolic and neuroimaging phenotypes are essential for pharmacokinetic/pharmacodynamic modeling and interpretation of the findings. We provide a list of basic minimum and advanced options that can be considered in design and analyses of future pharma-RSfMRI studies. Hum Brain Mapp 38:2276-2325, 2017. © 2017 Wiley Periodicals, Inc.
authors.affiliation: McGill Centre for Integrative Neuroscience, Montreal Neurological Institute, McGill University, Montreal, Canada.|PERFORM Centre, Concordia University, Montreal, Canada.
authors.forename: Najmeh
authors.identifier: 0000-0002-5248-2609
authors.initials: N
authors.lastname: Khalili-Mahani
authors.affiliation: Department of Radiology, Leiden University Medical Centre, Leiden, The Netherlands.|Institute of Psychology and Leiden Institute for Brain and Cognition, Leiden University, Leiden, The Netherlands.
authors.forename: Serge A R B
authors.initials: SA
authors.lastname: Rombouts
authors.affiliation: Department of Radiology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Matthias J P
authors.initials: MJ
authors.lastname: van Osch
authors.affiliation: Institute of Psychology and Leiden Institute for Brain and Cognition, Leiden University, Leiden, The Netherlands.|Oxford Centre for Functional MRI of the Brain, Oxford University, Oxford, United Kingdom.
authors.forename: Eugene P
authors.initials: EP
authors.lastname: Duff
authors.affiliation: Biospective Inc, Montreal, Quebec, Canada.
authors.forename: Felix
authors.initials: F
authors.lastname: Carbonell
authors.affiliation: McLean Hospital, Belmont, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Nickerson
authors.affiliation: Center for Pain and the Brain, Harvard Medical School & Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Lino
authors.initials: L
authors.lastname: Becerra
authors.affiliation: Department of Anesthesiology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Dahan
authors.affiliation: McGill Centre for Integrative Neuroscience, Montreal Neurological Institute, McGill University, Montreal, Canada.|McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Evans
authors.affiliation: PERFORM Centre, Concordia University, Montreal, Canada.|McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Soucy
authors.affiliation: Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Cardiff, United Kingdom.
authors.forename: Richard
authors.identifier: 0000-0003-1700-2144
authors.initials: R
authors.lastname: Wise
authors.affiliation: McGill Centre for Integrative Neuroscience, Montreal Neurological Institute, McGill University, Montreal, Canada.|Biospective Inc, Montreal, Quebec, Canada.
authors.forename: Alex P
authors.initials: AP
authors.lastname: Zijdenbos
authors.affiliation: Centre for Human Drug Research, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Joop M
authors.initials: JM
authors.lastname: van Gerven
mesh_terms: D000818:Animals; D035843:Biomedical Research; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000502:physiology; D001923:Brain Chemistry; D001931:Brain Mapping; D002560:Cerebrovascular Circulation / Q000187:drug effects; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D012146:Rest; D013113:Spin Labels; D057170:Translational Research, Biomedical
chemical_list: D013113:Spin Labels
keywords: PK/PD modeling; arterial spin labeling; biomarkers; brain chemistry; drug; functional connectivity; pharma-fMRI; pharmacological neuroimaging; resting state fMRI; translational research