Intrinsic Functional Connectivity As a Tool For Human Connectomics: Theory, Properties, and Optimization

1 Department of Psychology, Center for Brain Science, Harvard University, Cambridge, Massachusetts; 2 Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology and 5 Department of Psychiatry, Massachusetts General Hospital, Charlestown, Massachusetts; 3 Department of Neuropsychology and Psychopharmacology, Faculty of Psychology, Maastricht University, Netherlands; 4 Computer Science and Artificial Intelligence Laboratory (CSAIL), Massachusetts Institute of Technology, Cambridge, Massachusetts; and 6 Howard Hughes Medical Institute, Cambridge, Massachusetts Submitted 24 August 2009; accepted in final form 26 October 2009 ABSTRACT Resting state functional connectivity MRI (fcMRI) is widely used to investigate brain networks that exhibit correlated fluctuations. While fcMRI does not provide direct measurement of anatomic connectivity, accumulating evidence suggests it is sufficiently constrained by anatomy to allow the architecture of distinct brain systems to be characterized. fcMRI is particularly useful for characterizing large-scale systems that span distributed areas (e.g., polysynaptic cortical pathways, cerebro-cerebellar circuits, cortical-thalamic circuits) and has complementary strengths when contrasted with the other major tool available for human connectomics—high angular resolution diffusion imaging (HARDI). We review what is known about fcMRI and then explore fcMRI data reliability, effects of preprocessing, analysis procedures, and effects of different acquisition parameters across six studies ( n = 98) to provide recommendations for optimization. Run length (2–12 min), run structure (1 12-min run or 2 6-min runs), temporal resolution (2.5 or 5.0 s), spatial resolution (2 or 3 mm), and the task (fixation, eyes closed rest, eyes open rest, continuous word-classification) were varied. Results revealed moderate to high test-retest reliability. Run structure, temporal resolution, and spatial resolution minimally influenced fcMRI results while fixation and eyes open rest yielded stronger correlations as contrasted to other task conditions. Commonly used preprocessing steps involving regression of nuisance signals minimized nonspecific (noise) correlations including those associated with respiration. The most surprising finding was that estimates of correlation strengths stabilized with acquisition times as brief as 5 min. The brevity and robustness of fcMRI positions it as a powerful tool for large-scale explorations of genetic in