3. CAPÍTULO III: METODOLOGÍA
3.4. Desarrollo Metodológico
3.4.3.1 Una primera mirada del acceso a la LEBECS
3.4.3.1.3 Herramientas utilizadas para la garantía y democratización del acceso
Subjects at rest dedicate the largest amount of energy to the brain3. This fuels ongoing neuronal activity that is not random noise but is organized into large-‐scale networks of coherent low-‐frequency signal fluctuations in fMRI14. Organized intrinsic brain activity therefore is a fundamental and ubiquitous organizational principle of the brain yet its functional meaning is still largely unknown. Early work on the intrinsic functional architecture suggested that patterns of FC simply reflect underlying anatomical
connections, or SC, between brain regions36,48. This is supported by the fact that intrinsic brain activity forms patterns of ICNs robustly occurring in several species35,36, across time (test-‐retest reliability)66-‐68, and even in states of altered consciousness44. However, recent data clearly showed that only a certain amount (25%) of distinct brain regions is indeed coupled by FC when also strong SC is present49. As soon as polysynaptic
connections are assumed on the structural level, no correlation exists with FC patterns. Moreover, a prominent feature of certain ICNs is strong FC between contralateral
INTRINSIC FUNCTIONAL BRAIN NETWORKS IN HEALTH AND DISEASE Valentin Riedl, 2012
79
Furthermore, we have shown that consistent differences in subjective experiences of primary sensory processing can be predicted from an altered intrinsic brain architecture (Dovern et al, J Neurosci, under revision). But modulations of FC even occur on shorter time scale of days or seconds. We have shown that the repeated experience of an
identical painful stimulation leads to plasticity in the intrinsic functional architecture59. Fox and colleagues even showed immediate influence of the strength of FC in the motor system on the motor force a subject applied to a lever on a trial-‐by-‐trial basis97.
We therefore suggest two layers of processing inherited in ongoing brain activity of large scale brain networks. On the one hand, intrinsic brain activity forms a robust architecture of consistent ICNs reflecting mainly anatomical connections. On the other hand, immediate changes in the coherence of spontaneous activity relate to fluctuations in cognitive functions and motor behavior. This suggests a volatile layer of intrinsic brain fluctuations influencing behavior in the range of seconds. We hypothesize that with continuous experiences, coherent intrinsic activity might stabilize networks of brain regions that are commonly activated together during sensory or cognitive processing. These organized patterns of intrinsic activity continuously adapt with ongoing experiences to reflect past and anticipate future experiences. By this, the intrinsic architecture of ongoing brain activity continuously adapts and prepares the organism for what might happen. In conclusion, the intrinsic brain state might have more impact on human behavior than does the brain's immediate response to an event.
INTRINSIC FUNCTIONAL BRAIN NETWORKS IN HEALTH AND DISEASE Valentin Riedl, 2012
13 References
1. Friston, K. J. Modalities, modes, and models in functional neuroimaging. Science 326, 399– 403 (2009).
2. Raichle, M. E. A brief history of human brain mapping. Trends Neurosci 32, 118–126 (2009).
3. Raichle, M. E. & Mintun, M. A. Brain work and brain imaging. Annu Rev Neurosci 29, 449– 476 (2006).
4. Gusnard, D. A., Raichle, M. E. & Raichle, M. E. Searching for a baseline: functional imaging and the resting human brain. Nat Rev Neurosci 2, 685–694 (2001).
5. Raichle, M. E. Two views of brain function. Trends Cogn Sci (Regul Ed) 14, 180–190 (2010).
6. Belliveau, J. W. et al. Functional mapping of the human visual cortex by magnetic resonance imaging. Science 254, 716–719 (1991).
7. Friston, K. J. Imaging neuroscience: principles or maps? Proc Natl Acad Sci USA 95, 796– 802 (1998).
8. Logothetis, N. K. What we can do and what we cannot do with fMRI. Nature 453, 869–878 (2008).
9. Logothetis, N. K., Pauls, J., Augath, M., Trinath, T. & Oeltermann, A. Neurophysiological investigation of the basis of the fMRI signal. Nature 412, 150–157 (2001).
10. Ogawa, S., Lee, T. M., Nayak, A. S. & Glynn, P. Oxygenation-‐sensitive contrast in magnetic resonance image of rodent brain at high magnetic fields. Magn Reson Med 14, 68–78 (1990).
11. Bandettini, P., Wong, E. & Hinks, R. Time course EPI of human brain function during task activation. Magnetic … (1992).
12. Kwong, K. & Belliveau, J. Dynamic magnetic resonance imaging of human brain activity during primary sensory stimulation. Proceedings of the … (1992).
13. Ogawa, S., Tank, D. & Menon, R. Intrinsic signal changes accompanying sensory
stimulation: functional brain mapping with magnetic resonance imaging. Proceedings of the … (1992).
14. Fox, M. D. & Raichle, M. E. Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nat Rev Neurosci 8, 700–711 (2007).
15. Corbetta, M., Patel, G. & Shulman, G. L. The reorienting system of the human brain: from environment to theory of mind. Neuron 58, 306–324 (2008).
16. Shulman, R. G., Rothman, D. L., Behar, K. L. & Hyder, F. Energetic basis of brain activity: implications for neuroimaging. Trends Neurosci 27, 489–495 (2004).
INTRINSIC FUNCTIONAL BRAIN NETWORKS IN HEALTH AND DISEASE Valentin Riedl, 2012
81
22. Van Dijk, K. R. A. et al. Intrinsic functional connectivity as a tool for human connectomics: theory, properties, and optimization. J Neurophysiol 103, 297–321 (2010).
23. Sporns, O., Tononi, G. & Kötter, R. The human connectome: A structural description of the human brain. PLoS Comput Biol 1, e42 (2005).
24. Bressler, S. L. & Menon, V. Large-‐scale brain networks in cognition: emerging methods and principles. Trends Cogn Sci (Regul Ed) 14, 277–290 (2010).
25. 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).
26. 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).
27. 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).
28. Beckmann, C. F., DeLuca, M., Devlin, J. T. & Smith, S. M. Investigations into resting-‐state connectivity using independent component analysis. Philos Trans R Soc Lond, B, Biol Sci 360, 1001–1013 (2005).
29. 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).
30. Damoiseaux, J. S. et al. Consistent resting-‐state networks across healthy subjects. Proc Natl Acad Sci USA 103, 13848–13853 (2006).
31. Yeo, B. T. T. et al. The organization of the human cerebral cortex estimated by intrinsic functional connectivity. J Neurophysiol 106, 1125–1165 (2011).
32. Allen, E. A. et al. A baseline for the multivariate comparison of resting-‐state networks. Front Syst Neurosci 5, 2 (2011).
33. Doucet, G. et al. Brain activity at rest: A multi-‐scale hierarchical functional organization. J Neurophysiol (2011).doi:10.1152/jn.00895.2010
34. Abou-‐Elseoud, A. et al. Group-‐ICA Model Order Highlights Patterns of Functional Brain Connectivity. Front Syst Neurosci 5, 37 (2011).
35. Lu, Zuo, Gu & Waltz Synchronized delta oscillations correlate with the resting-‐state functional MRI signal. Proc Natl Acad Sci USA 104, 18265–18269 (2007).
36. Vincent, J. L. et al. Intrinsic functional architecture in the anaesthetized monkey brain. Nature 447, 83–86 (2007).
37. Biswal, B. B. et al. Toward discovery science of human brain function. Proc Natl Acad Sci U S A 107, 4734–4739 (2010).
38. Kelly, A. M. C. et al. Development of anterior cingulate functional connectivity from late childhood to early adulthood. Cereb Cortex 19, 640–657 (2009).
39. Supekar, K. et al. Development of functional and structural connectivity within the default mode network in young children. NeuroImage 52, 290–301 (2010).
40. Fair, D. A. et al. Functional brain networks develop from a “local to distributed” organization. PLoS Comput Biol 5, e1000381 (2009).
41. Andrews-‐Hanna, J. R. et al. Disruption of large-‐scale brain systems in advanced aging. Neuron 56, 924–935 (2007).
42. Fukunaga, M. et al. Large-‐amplitude, spatially correlated fluctuations in BOLD fMRI signals during extended rest and early sleep stages. Magn Reson Imaging 24, 979–992
INTRINSIC FUNCTIONAL BRAIN NETWORKS IN HEALTH AND DISEASE Valentin Riedl, 2012
(2006).
43. Larson-‐Prior, L. J. et al. Cortical network functional connectivity in the descent to sleep. Proc Natl Acad Sci USA 106, 4489–4494 (2009).
44. Greicius, M. D. et al. Persistent default-‐mode network connectivity during light sedation. Hum Brain Mapp 29, 839–847 (2008).
45. Boveroux, P. et al. Breakdown of within-‐ and between-‐network resting state functional magnetic resonance imaging connectivity during propofol-‐induced loss of consciousness. Anesthesiology 113, 1038–1053 (2010).
46. Achard, S. & Bullmore, E. Efficiency and cost of economical brain functional networks. PLoS Comput Biol 3, e17 (2007).
47. Kelly, C. et al. L-‐dopa modulates functional connectivity in striatal cognitive and motor networks: a double-‐blind placebo-‐controlled study. J Neurosci 29, 7364–7378 (2009). 48. Hagmann, P. et al. Mapping the structural core of human cerebral cortex. PLoS Biol 6,
e159 (2008).
49. Honey, C. J. et al. Predicting human resting-‐state functional connectivity from structural connectivity. Proc Natl Acad Sci USA 106, 2035–2040 (2009).
50. Leopold, D. A. & Maier, A. Ongoing physiological processes in the cerebral cortex. NeuroImage (2011).doi:10.1016/j.neuroimage.2011.10.059
51. Niazy, R. K., Xie, J., Miller, K., Beckmann, C. F. & Smith, S. M. Spectral characteristics of resting state networks. Prog Brain Res 193, 259–276 (2011).
52. Shmuel, A. & Leopold, D. Neuronal correlates of spontaneous fluctuations in fMRI signals in monkey visual cortex: Implications for functional connectivity at rest. Hum Brain Mapp 29, 751–761 (2008).
53. He, B., Snyder, A., Zempel, J., Smyth, M. & Raichle, M. Electrophysiological correlates of the brain's intrinsic large-‐scale functional architecture. Proc Natl Acad Sci USA
(2008).doi:10.1073/pnas.0807010105
54. Nir, Y. et al. Interhemispheric correlations of slow spontaneous neuronal fluctuations revealed in human sensory cortex. Nat Neurosci (2008).doi:10.1038/nn.2177
55. Keller, C. J. et al. Intrinsic functional architecture predicts electrically evoked responses in the human brain. Proc Natl Acad Sci U S A 108, 10308–10313 (2011).
56. Laufs, H. et al. Electroencephalographic signatures of attentional and cognitive default modes in spontaneous brain activity fluctuations at rest. Proc Natl Acad Sci USA 100, 11053–11058 (2003).
57. Albert, N., Robertson, E. & Miall, R. The Resting Human Brain and Motor Learning. Curr Biol (2009).doi:10.1016/j.cub.2009.04.028
INTRINSIC FUNCTIONAL BRAIN NETWORKS IN HEALTH AND DISEASE Valentin Riedl, 2012
83
63. Sorg, C. et al. Selective changes of resting-‐state networks in individuals at risk for Alzheimer's disease. Proc Natl Acad Sci U S A 104, 18760–18765 (2007).
64. Sorg, C. et al. Increased Intrinsic Brain Activity in the Striatum Reflects Symptom
Dimensions in Schizophrenia. Schizophrenia bulletin (2012).doi:10.1093/schbul/sbr184 65. Boly, M. et al. Functional connectivity in the default network during resting state is
preserved in a vegetative but not in a brain dead patient. Hum Brain Mapp (2009).doi:10.1002/hbm.20672
66. Meindl, T. et al. Test-‐retest reproducibility of the default-‐mode network in healthy individuals. Hum Brain Mapp (2009).doi:10.1002/hbm.20860
67. Shehzad, Z. et al. The Resting Brain: Unconstrained yet Reliable. Cereb Cortex (2009).doi:10.1093/cercor/bhn256
68. Zuo, X.-‐N. et al. Reliable intrinsic connectivity networks: test-‐retest evaluation using ICA and dual regression approach. NeuroImage 49, 2163–2177 (2010).
69. Ploghaus, A., Becerra, L., Borras, C. & Borsook, D. Neural circuitry underlying pain modulation: expectation, hypnosis, placebo. Trends Cogn Sci (Regul Ed) 7, 197–200 (2003).
70. Apkarian, A. V., Bushnell, M. C., Treede, R.-‐D. & Zubieta, J.-‐K. Human brain mechanisms of pain perception and regulation in health and disease. European journal of pain (London, England) 9, 463–484 (2005).
71. Bingel, U., Schoell, E., Herken, W., Büchel, C. & May, A. Habituation to painful stimulation involves the antinociceptive system. Pain 131, 21–30 (2007).
72. Apkarian, A., Baliki, M. & Geha, P. Towards a theory of chronic pain. Prog Neurobiol 87, 81–97 (2009).
73. Gündel, H. et al. Altered cerebral response to noxious heat stimulation in patients with somatoform pain disorder. Pain (2007).doi:10.1016/j.pain.2007.10.003
74. Tambini, A., Ketz, N. & Davachi, L. Enhanced brain correlations during rest are related to memory for recent experiences. Neuron 65, 280–290 (2010).
75. van Kesteren, M. T. R., Fernández, G., Norris, D. G. & Hermans, E. J. Persistent schema-‐ dependent hippocampal-‐neocortical connectivity during memory encoding and postencoding rest in humans. Proc Natl Acad Sci USA 107, 7550–7555 (2010). 76. Grossenbacher, P. G. & Lovelace, C. T. Mechanisms of synesthesia: cognitive and
physiological constraints. Trends Cogn Sci (Regul Ed) 5, 36–41 (2001).
77. Rouw, R. & Scholte, H. S. Increased structural connectivity in grapheme-‐color synesthesia. Nat Neurosci 10, 792–797 (2007).
78. Hänggi, J., Wotruba, D. & Jäncke, L. Globally altered structural brain network topology in grapheme-‐color synesthesia. J Neurosci 31, 5816–5828 (2011).
79. Hampson, M., Driesen, N. R., Skudlarski, P., Gore, J. C. & Constable, R. T. Brain connectivity related to working memory performance. J Neurosci 26, 13338–13343 (2006).
80. Adelstein, J. S. et al. Personality is reflected in the brain's intrinsic functional architecture. PLoS ONE 6, e27633 (2011).
81. Doria, V. et al. Emergence of resting state networks in the preterm human brain. Proc Natl Acad Sci USA 107, 20015–20020 (2010).
82. Fransson, P. et al. Resting-‐state networks in the infant brain. Proc Natl Acad Sci USA 104, 15531–15536 (2007).
83. Fair, D. A. et al. Maturing thalamocortical functional connectivity across development. Front Syst Neurosci 4, 10 (2010).
INTRINSIC FUNCTIONAL BRAIN NETWORKS IN HEALTH AND DISEASE Valentin Riedl, 2012
84. Zhang, D. & Raichle, M. E. Disease and the brain's dark energy. Nat Rev Neurol 6, 15–28 (2010).
85. Greicius, M. Resting-‐state functional connectivity in neuropsychiatric disorders. Curr Opin Neurol 21, 424–430 (2008).
86. Delbeuck, X., Van der Linden, M. & Collette, F. Alzheimer's disease as a disconnection syndrome? Neuropsychology review 13, 79–92 (2003).
87. Greicius, M. D., Srivastava, G., Reiss, A. L. & Menon, V. Default-‐mode network activity distinguishes Alzheimer's disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci USA 101, 4637–4642 (2004).
88. Wang, K. et al. Altered functional connectivity in early Alzheimer's disease: A resting-‐state fMRI study. Hum Brain Mapp 28, 967–978 (2007).
89. He, Y., Chen, Z. & Evans, A. Structural insights into aberrant topological patterns of large-‐ scale cortical networks in Alzheimer's disease. J Neurosci 28, 4756–4766 (2008).
90. Wang, Z. et al. Spatial patterns of intrinsic brain activity in mild cognitive impairment and alzheimer's disease: A resting-‐state functional MRI study. Hum Brain Mapp
(2010).doi:10.1002/hbm.21140
91. He, Y., Chen, Z., Gong, G. & Evans, A. Neuronal Networks in Alzheimer's Disease. Neuroscientist (2009).doi:10.1177/1073858409334423
92. Kegeles, L. S. et al. Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. Arch Gen Psychiatry 67, 231–239 (2010).
93. Garrity, A. G. et al. Aberrant “default mode” functional connectivity in schizophrenia. Am J Psychiatry 164, 450–457 (2007).
94. Bluhm, R. L. et al. Spontaneous low-‐frequency fluctuations in the BOLD signal in schizophrenic patients: anomalies in the default network. Schizophrenia bulletin 33, 1004–1012 (2007).
95. Lynall, M.-‐E. et al. Functional connectivity and brain networks in schizophrenia. J Neurosci 30, 9477–9487 (2010).
96. Liu, Y. et al. Disrupted small-‐world networks in schizophrenia. Brain (2008).doi:10.1093/brain/awn018
97. Fox, M. D., Snyder, A. Z., Vincent, J. L. & Raichle, M. E. Intrinsic fluctuations within cortical systems account for intertrial variability in human behavior. Neuron 56, 171–184 (2007).
INTRINSIC FUNCTIONAL BRAIN NETWORKS IN HEALTH AND DISEASE Valentin Riedl, 2012
85
14 Acknowledgments
I am deeply grateful for the love and support of Kathrin and my parents and I have been enjoying the hours of discussions and exchange on brain and other matters with Afra and Christian.
15 Statutory declaration and statement
Ich versichere hiermit eidesstattlich, dass die vorgelegte Dissertation von mir selbständig und