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Opportunities and limitations of intrinsic functional connectivity MRI

Abstract

Intrinsic functional connectivity magnetic resonance imaging (fcMRI) has emerged as a powerful tool for mapping large-scale networks in the human brain. Robust and reliable functionally coupled networks can be detected in individuals that echo many known features of anatomical organization. Features of brain organization have been discovered, including descriptions of distributed large-scale networks interwoven throughout association cortex, interactions (including anticorrelations) between brain networks and insights into the topography of subcortical structures. But interpreting fcMRI is complicated by several factors. Functional coupling changes dynamically, suggesting that it is constrained by, but not fully dictated by, anatomic connectivity. Critically to study of between-group differences, fcMRI is sensitive to head motion and to differences in the mental states of participants during the scans. We discuss the potential of fcMRI in the context of its limitations.

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Figure 1: The basic strategy of intrinsic functional connectivity MRI (fcMRI).
Figure 2: Large-scale cerebral networks identified by intrinsic functional connectivity.
Figure 3: Functional connectivity is sensitive to the task performed during data acquisition.
Figure 4: The organization of the human cerebellum.
Figure 5: Network interactions.

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References

  1. Ogawa, S. et al. Functional brain mapping by blood oxygenation level-dependent contrast magnetic resonance imaging: a comparison of signal characteristics with a biophysical model. Biophys. J. 64, 803–812 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Biswal, B., Yetkin, F.Z., Haughton, V.M. & Hyde, J.S. Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn. Reson. Med. 34, 537–541 (1995).

    Article  CAS  PubMed  Google Scholar 

  3. Greicius, M.D., Krasnow, B., Reiss, A.L. & Menon, V. Functional connectivity in the resting brain: a network analysis of the default mode hypothesis. Proc. Natl. Acad. Sci. USA 100, 253–258 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Fox, M.D., Corbetta, M., Snyder, A.Z., Vincent, J.L. & Raichle, M.E. Spontaneous neuronal activity distinguishes human dorsal and ventral attention systems. Proc. Natl. Acad. Sci. USA 103, 10046–10051 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. De Luca, M., Beckmann, C.F., De Stefano, N., Matthews, P.M. & Smith, S.M. fMRI resting state networks define distinct modes of long-distance interactions in the human brain. Neuroimage 29, 1359–1367 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Damoiseaux, J.S. et al. Consistent resting-state networks across healthy subjects. Proc. Natl. Acad. Sci. USA 103, 13848–13853 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Seeley, W.W. et al. Dissociable intrinsic connectivity networks for salience processing and executive control. J. Neurosci. 27, 2349–2356 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Margulies, D.S. et al. Mapping the functional connectivity of anterior cingulate cortex. Neuroimage 37, 579–588 (2007).

    Article  PubMed  Google Scholar 

  9. Dosenbach, N.U.F. et al. Distinct brain networks for adaptive and stable task control in humans. Proc. Natl. Acad. Sci. USA 104, 11073–11078 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Greicius, M. Resting-state functional connectivity in neuropsychiatric disorders. Curr. Opin. Neurol. 21, 424–430 (2008).

    Article  PubMed  Google Scholar 

  11. Zhang, D. & Raichle, M.E. Disease and the brain's dark energy. Nat. Rev. Neurol. 6, 15–28 (2010).

    Article  PubMed  Google Scholar 

  12. Buckner, R.L., Krienen, F.M., Castellanos, A., Diaz, J.C. & Yeo, B.T.T. The organization of the human cerebellum estimated by intrinsic functional connectivity. J. Neurophysiol. 106, 2322–2345 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Lu, J. et al. Focal pontine lesions provide evidence that intrinsic functional connectivity reflects polysynaptic anatomical pathways. J. Neurosci. 31, 15065–15071 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Johnston, J.M. et al. Loss of resting interhemispheric functional connectivity after complete section of the corpus callosum. J. Neurosci. 28, 6453–6458 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Damoiseaux, J.S. & Greicius, M.D. Greater than the sum of its parts: a review of studies combining structural connectivity and resting-state functional connectivity. Brain Struct. Funct. 213, 525–533 (2009).

    Article  PubMed  Google Scholar 

  16. Greicius, M.D., Supekar, K., Menon, V. & Dougherty, R.F. Resting-state functional connectivity reflects structural connectivity in the default mode network. Cereb. Cortex 19, 72–78 (2009).

    Article  PubMed  Google Scholar 

  17. Honey, C.J. et al. Predicting human resting-state functional connectivity from structural connectivity. Proc. Natl. Acad. Sci. USA 106, 2035–2040 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Vincent, J.L. et al. Intrinsic functional architecture in the anaesthetized monkey brain. Nature 447, 83–86 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Margulies, D.S. et al. Precuneus shares intrinsic functional architecture in humans and monkeys. Proc. Natl. Acad. Sci. USA 106, 20069–20074 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Mars, R.B. et al. Diffusion-weighted imaging tractography-based parcellation of the human parietal cortex and comparison with human and macaque resting-state functional connectivity. J. Neurosci. 31, 4087–4100 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hill, J. et al. Similar patterns of cortical expansion during human development and evolution. Proc. Natl. Acad. Sci. USA 107, 13135–13140 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Tyszka, J.M., Kennedy, D.P., Adolphs, R. & Paul, L.K. Intact bilateral resting-state networks in the absence of the corpus callosum. J. Neurosci. 31, 15154–15162 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Shirer, W.R., Ryali, S., Rykhlevskaia, E., Menon, V. & Greicius, M.D. Decoding subject-driven cognitive states with whole-brain connectivity patterns. Cereb. Cortex 22, 158–165 (2012).

    Article  CAS  PubMed  Google Scholar 

  24. Lewis, C.M., Baldassarre, A., Committeri, G., Romani, G.L. & Corbetta, M. Learning sculpts the spontaneous activity of the resting human brain. Proc. Natl. Acad. Sci. USA 106, 17558–17563 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Hutchison, R.M., Womelsdorf, T., Gati, J.S., Everling, S. & Menon, R.S. Resting-state networks show dynamic functional connectivity in awake humans and anesthetized macaques. Hum. Brain Mapp. doi:dx10.1002/hbm.22058 (2012).

  26. Handwerker, D.A., Gonzalez-Castillo, J., D'Esposito, M. & Bandettini, P.A. The continuing challenge of understanding and modeling hemodynamic variation in fMRI. Neuroimage 62, 1017–1023 (2012).

    Article  PubMed  Google Scholar 

  27. Van Dijk, K.R.A., Sabuncu, M.R. & Buckner, R.L. The influence of head motion on intrinsic functional connectivity MRI. Neuroimage 59, 431–438 (2012).

    Article  PubMed  Google Scholar 

  28. Power, J.D., Barnes, K.A., Snyder, A.Z., Schlaggar, B.L. & Petersen, S.E. Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion. Neuroimage 59, 2142–2154 (2012).

    Article  PubMed  Google Scholar 

  29. Birn, R.M., Smith, M.A., Jones, T.B. & Bandettini, P.A. The respiration response function: the temporal dynamics of fMRI signal fluctuations related to changes in respiration. Neuroimage 40, 644–654 (2008).

    Article  PubMed  Google Scholar 

  30. Deco, G. & Corbetta, M. The dynamical balance of the brain at rest. Neuroscientist 17, 107–123 (2011).

    Article  PubMed  Google Scholar 

  31. Andrews-Hanna, J.R. The brain's default network and its adaptive role in internal mentation. Neuroscientist 18, 251–270 (2012).

    Article  PubMed  Google Scholar 

  32. Spreng, R.N., Mar, R.A. & Kim, A.S.N. The common neural basis of autobiographical memory, prospection, navigation, theory of mind and the default mode: a quantitative meta-analysis. J. Cogn. Neurosci. 21, 489–510 (2009).

    Article  PubMed  Google Scholar 

  33. Smith, S.M. et al. Correspondence of the brain's functional architecture during activation and rest. Proc. Natl. Acad. Sci. USA 106, 13040–13045 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Bleuler, E. Dementia Praecox or the Group of Schizophrenias (ed. Zinkin, J.) (International Universities Press; New York, 1950).

  35. Nolen-Hoeksma, S. The role of rumination in depressive disorders and mixed anxiety/depressive symptoms. J. Abnorm. Psychol. 109, 504–511 (2000).

    Article  Google Scholar 

  36. Cohen, A.L. et al. Defining functional areas in individual human brains using resting functional connectivity MRI. Neuroimage 41, 45–57 (2008).

    Article  PubMed  Google Scholar 

  37. Yeo, B.T.T. et al. The organization of human cerebral cortex estimated by intrinsic functional connectivity. J. Neurophysiol. 106, 1125–1165 (2011).

    Article  PubMed  Google Scholar 

  38. Power, J.D. et al. Functional network organization of the human brain. Neuron 72, 665–678 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kaas, J.H. The organization of neocortex in mammals: implications for theories of brain function. Annu. Rev. Psychol. 38, 129–151 (1987).

    Article  CAS  PubMed  Google Scholar 

  40. Wig, G.S., Schlaggar, B.L. & Petersen, S.E. Concepts and principles in the analysis of brain networks. Ann. NY Acad. Sci. 1224, 126–146 (2011).

    Article  PubMed  Google Scholar 

  41. Maunsell, J.H.R. & Van Essen, D.C. The connections of the middle temporal visual area (MT) and their relationship to a cortical hierarchy in the macaque monkey. J. Neurosci. 3, 2563–2586 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Passingham, R.E., Stephan, K.E. & Kötter, R. The anatomical basis of functional localization in the cortex. Nat. Rev. Neurosci. 3, 606–616 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Rosa, M.G.P. & Tweedale, R. Brain maps, great and small: lessons from comparative studies of primate visual cortical organization. Phil. Trans. R. Soc. Lond. B. Biol. Sci. 360, 665–691 (2005).

    Article  Google Scholar 

  44. Rakic, P. Specification of cerebral cortical areas. Science 241, 170–176 (1988).

    Article  CAS  PubMed  Google Scholar 

  45. Mueller, S. et al. Individual variability in functional connectivity architecture of the human brain. Neuron 77, 586–595 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Goldman-Rakic, P.S. Topography of cognition: parallel distributed networks in primate association cortex. Annu. Rev. Neurosci. 11, 137–156 (1988).

    Article  CAS  PubMed  Google Scholar 

  47. Manni, E. & Petrosini, L. A century of cerebellar somatotopy: a debated representation. Nat. Rev. Neurosci. 5, 241–249 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Strick, P.L., Dum, R.P. & Fiez, J.A. Cerebellum and nonmotor function. Annu. Rev. Neurosci. 32, 413–434 (2009).

    Article  CAS  PubMed  Google Scholar 

  49. Habas, C. et al. Distinct cerebellar contributions to intrinsic connectivity networks. J. Neurosci. 29, 8586–8594 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. O'Reilly, J.X., Beckmann, C.F., Tomassini, V., Ramnani, N. & Johansen-Berg, H. Distinct and overlapping functional zones in the cerebellum defined by resting state functional connectivity. Cereb. Cortex 20, 953–965 (2010).

    Article  PubMed  Google Scholar 

  51. Mesulam, M. The evolving landscape of human cortical connectivity: facts and inferences. Neuroimage 62, 2182–2189 (2012).

    Article  PubMed  Google Scholar 

  52. Fransson, P. Spontaneous low-frequency bold signal fluctuations: an fMRI investigation of the resting-state default mode of brain function hypothesis. Hum. Brain Mapp. 26, 15–29 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Fox, M.D. et al. The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proc. Natl. Acad. Sci. USA 102, 9673–9678 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Whitfield-Gabrieli, S. & Ford, J.M. Default mode network activity and connectivity in psychopathology. Annu. Rev. Clin. Psychol. 8, 49–76 (2012).

    Article  PubMed  Google Scholar 

  55. Murphy, K., Birn, R., Handwerker, D., Jones, T.B. & Bandettini, P.A. The impact of global signal regression on resting state correlations: are anti-correlated networks introduced? Neuroimage 44, 893–905 (2009).

    Article  PubMed  Google Scholar 

  56. Chai, X.J., Castañón, A.N., Öngür, D. & Whitfield-Gabrieli, S. Anticorrelations in resting state networks without global signal regression. Neuroimage 59, 1420–1428 (2012).

    Article  PubMed  Google Scholar 

  57. He, B.J., Snyder, A.Z., Zempel, J.M., Smyth, M.D. & Raichle, M.E. Electrophysiological correlates of the brain's intrinsic large-scale functional architecture. Proc. Natl. Acad. Sci. USA 105, 16039–16044 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Wang, L., Saalmann, Y.B., Pinsk, M.A., Arcaro, M.J. & Kastner, S. Electrophysiological low-frequency coherence and cross-frequency coupling contribute to BOLD connectivity. Neuron 76, 1010–1020 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Correspondence to Randy L Buckner.

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Supplementary information

Supplementary Video 1

Resting-state functional connectivity of lateral parietal cortex. The intrinsic functional connectivity networks of human parietal cortex are displayed for a 4-mm seed region that is gradually moved along the cortical surface. The functional connectivity networks are estimated on the surface using resting-state functional MRI data from 1000 young adults. The seed region begins in a region at or near the human homologue of LIP and gradually moves through distinct parietal regions including those primarily coupled to limbic regions. Note that multiple interdigitated networks converge on contiguous regions of parietal cortex. Some of these regions are embedded in sensory-motor circuits; others lack coupling to sensory or motor regions and are embedded in networks comprising what has come to be known as the 'default network'. Thus, human parietal cortex represents a nexus of multiple, interdigitated association pathways. (AVI 8770 kb)

Supplementary Video 2

Resting-state functional connectivity of lateral parietal cortex. The left and right panels each show a 4-mm seed region that is gradually moved along identical trajectories through lateral temporal and parietal cortex. Left panel functional connectivity patterns are computed from a dataset of passive rest collected in 16 subjects. The right panel consists of data collected in the same participants during performance of a semantic classification task. (AVI 14645 kb)

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Buckner, R., Krienen, F. & Yeo, B. Opportunities and limitations of intrinsic functional connectivity MRI. Nat Neurosci 16, 832–837 (2013). https://doi.org/10.1038/nn.3423

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