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The cortical angiome: an interconnected vascular network with noncolumnar patterns of blood flow

Abstract

What is the nature of the vascular architecture in the cortex that allows the brain to meet the energy demands of neuronal computations? We used high-throughput histology to reconstruct the complete angioarchitecture and the positions of all neuronal somata of multiple cubic millimeter regions of vibrissa primary sensory cortex in mouse. Vascular networks were derived from the reconstruction. In contrast with the standard model of cortical columns that are tightly linked with the vascular network, graph-theoretical analyses revealed that the subsurface microvasculature formed interconnected loops with a topology that was invariant to the position and boundary of columns. Furthermore, the calculated patterns of blood flow in the networks were unrelated to location of columns. Rather, blood sourced by penetrating arterioles was effectively drained by the penetrating venules to limit lateral perfusion. This analysis provides the underpinning to understand functional imaging and the effect of penetrating vessels strokes on brain viability.

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Figure 1: Examples of the vectorized data sets.
Figure 2: Analysis of the local geometry and topology of the microvasculature.
Figure 3: Community analysis of the global topology of the microvasculature.
Figure 4: Calculated fluid flow and domains of common input in complete vectorized networks.
Figure 5: Relation of penetrating vessels to cortical columns.
Figure 6: Relation of images of the intrinsic optical signal (IOS) to the centroids of the cortical columns.
Figure 7: Calculated loss of lateral flow under numerically imposed pathological conditions in comparison with experimental observations.
Figure 8: Lattice models of the angiome.

References

  1. Magistretti, P.J. & Pellerin, L. Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging. Philos. Trans. R. Soc. Lond. B Biol. Sci. 354, 1155–1163 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Attwell, D. & Laughlin, S.B. An energy budget for signaling in the grey matter of the brain. J. Cereb. Blood Flow Metab. 21, 1133–1145 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Mchedlishvili, G. Arterial Behavior and Blood Circulation in the Brain (Consultants Bureau, New York, 1963).

  4. Schaffer, C.B. et al. Two-photon imaging of cortical surface microvessels reveals a robust redistribution in blood flow after vascular occlusion. PLoS Biol. 4, 22 (2006).

    Article  CAS  Google Scholar 

  5. Blinder, P., Shih, A.Y., Rafie, C.A. & Kleinfeld, D. Topological basis for the robust distribution of blood to rodent neocortex. Proc. Natl. Acad. Sci. USA 107, 12670–12675 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Devor, A. et al. Suppressed neuronal activity and concurrent arteriolar vasoconstriction may explain negative blood oxygenation level–dependent signaling. J. Neurosci. 27, 4452–4459 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Derdikman, D., Hildesheim, R., Ahissar, E., Arieli, A. & Grinvald, A. Imaging spatiotemporal dynamics of surround inhibition in the barrels somatosensory cortex. J. Neurosci. 23, 3100–3105 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gorelick, P.B. et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 42, 2672–2713 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Iadecola, C. Neurovascular regulation in the normal brain and in Alzheimer's disease. Nat. Rev. Neurosci. 5, 347–360 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Cauli, B. et al. Cortical GABA interneurons in neurovascular coupling: relays for subcortical vasoactive pathways. J. Neurosci. 24, 8940–8949 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Attwell, D. & Iadecola, C. The neural basis of functional brain imaging signals. Trends Neurosci. 25, 621–625 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Weber, B., Keller, A.L., Reichold, J. & Logothetis, N.K. The microvascular system of the striate and extrastriate visual cortex of the macaque. Cereb. Cortex 18, 2318–2330 (2008).

    Article  PubMed  Google Scholar 

  13. Grinvald, A., Lieke, E.E., Frostig, R.D., Gilbert, C.D. & Wiesel, T.N. Functional architecture of cortex revealed by optical imaging of intrinsic signals. Nature 324, 361–364 (1986).

    Article  CAS  PubMed  Google Scholar 

  14. Woolsey, T.A. & Van Der Loos, H. The structural organization of layer IV in the somatosensory region (SI) of mouse cerebral cortex. Brain Res. 17, 205–242 (1970).

    Article  CAS  PubMed  Google Scholar 

  15. Woolsey, T.A. et al. Neuronal units linked to microvascular modules in cerebral cortex: response elements for imaging the brain. Cereb. Cortex 6, 647–660 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Nishimura, N., Schaffer, C.B., Friedman, B., Lyden, P.D. & Kleinfeld, D. Penetrating arterioles are a bottleneck in the perfusion of neocortex. Proc. Natl. Acad. Sci. USA 104, 365–370 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Nishimura, N., Rosidi, N.L., Iadecola, C. & Schaffer, C.B. Limitations of collateral flow after occlusion of a single cortical penetrating arteriole. J. Cereb. Blood Flow Metab. 30, 1914–1927 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Drew, P.J. et al. Chronic optical access through a polished and reinforced thinned skull. Nat. Methods 7, 981–984 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Tsai, P.S. et al. Correlations of neuronal and microvascular densities in murine cortex revealed by direct counting and colocalization of cell nuclei and microvessels. J. Neurosci. 29, 14553–14570 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tsai, P.S. et al. All-optical histology using ultrashort laser pulses. Neuron 39, 27–41 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Shih, A.Y. et al. The smallest stroke: occlusion of one penetrating vessel leads to infarction and a cognitive deficit. Nat. Neurosci. 16, 55–63 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Nguyen, J., Nishimura, N., Fetcho, R.N., Iadecola, C. & Schaffer, C.B. Occlusion of cortical ascending venules causes blood flow decreases, reversals in flow direction, and vessel dilation in upstream capillaries. J. Cereb. Blood Flow Metab. 31, 2243–2254 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Kim, T. & Kim, S.G. Temporal dynamics and spatial specificity of aterial and venous blood volume changes during visual stimulation: implication for BOLD quantification. J. Cereb. Blood Flow Metab. 31, 1211–1222 (2011).

    Article  PubMed  Google Scholar 

  24. Frostig, R.D., Lieke, E.E., Ts'o, D.Y. & Grinvald, A. Cortical functional architecture and local coupling between neuronal activity and the microcirculation revealed by in vivo high-resolution optical imaging of intrinsic signals. Proc. Natl. Acad. Sci. USA 87, 6082–6086 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kaufhold, J.P., Tsai, P.S., Blinder, P. & Kleinfeld, D. Vectorization of optically sectioned brain microvasculature: learning aids completion of vascular graphs by connecting gaps and deleting open-ended segments. Med. Image Anal. 16, 1241–1258 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Lauwers, F., Cassot, F., Lauwers-Cances, V., Puwanarajah, P. & Duvernoy, H. Morphometry of the human cerebral cortex microcirculation: general characteristics and space-related profiles. Neuroimage 39, 936–948 (2008).

    Article  PubMed  Google Scholar 

  27. Hirsch, S., Reichold, J., Schneider, M., Székely, G. & Weber, B. Topology and hemodynamics of the cortical cerebrovascular system. J. Cereb. Blood Flow Metab. 32, 952–967 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Duvernoy, H.M., Delon, S. & Vannson, J.L. Cortical blood vessels of the human brain. Brain Res. Bull. 7, 519–579 (1981).

    Article  CAS  PubMed  Google Scholar 

  29. Nishimura, N. et al. Targeted insult to individual subsurface cortical blood vessels using ultrashort laser pulses: three models of stroke. Nat. Methods 3, 99–108 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Shih, A.Y. et al. Active dilation of penetrating arterioles restores red blood cell flux to penumbral neocortex after focal stroke. J. Cereb. Blood Flow Metab. 29, 738–751 (2009).

    Article  PubMed  Google Scholar 

  31. Cserti, J. Application of the lattice Green's function for calculating the resistance of infinite networks of resistors. Am. J. Phys. 68, 896–913 (2000).

    Article  Google Scholar 

  32. Pries, A.R., Secomb, T.W., Gaehtgens, P. & Gross, J.F. Blood flow in microvascular networks. Experiments and simulation. Circ. Res. 67, 826–834 (1990).

    Article  CAS  PubMed  Google Scholar 

  33. Wu, F.Y. Theory of resistor networks: the two-point resistance. J. Phys. A Math. Gen. 37, 6653 (2004).

    Article  Google Scholar 

  34. Newman, M.E.J. Modularity and community structure in networks. Proc. Natl. Acad. Sci. USA 103, 8577–8582 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Mayhan, W.G. & Heistad, D.D. Role of veins and cerebral venous pressure in disruption of the blood-brain barrier. Circ. Res. 59, 216–220 (1986).

    Article  CAS  PubMed  Google Scholar 

  36. Grinvald, A., Frostig, R.D., Siegel, R.M. & Bartfeld, E. High-resolution optical imaging of functional brain architecture in the awake monkey. Proc. Natl. Acad. Sci. USA 88, 11559–11563 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bonhoeffer, T. & Grinvald, A. The layout of Iso-orientation domains in area 18 of cat visual cortex: optical imaging reveals a pinwheel-like organization. J. Neurosci. 13, 4157–4180 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Vazquez, A.L., Fukuda, M. & Kim, S.G. Evolution of the dynamic changes in functional cerebral oxidative metabolism from tissue mitochondria to blood oxygen. J. Cereb. Blood Flow Metab. 32, 745–758 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chen-Bee, C.H., Agoncillo, T., Xiong, Y. & Frostig, R.D. The triphasic intrinsic signal: implications for functional imaging. J. Neurosci. 27, 4572–4586 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sirotin, Y.B., Hillman, E.M., Bordier, C. & Das, A. Spatiotemporal precision and hemodynamic mechanism of optical point spreads in alert primates. Proc. Natl. Acad. Sci. USA 106, 18390–18395 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Eppihimer, M.J. & Lipowsky, H.H. Effects of leukocyte-capillary plugging on the resistance to flow in the microvasculature of cremaster muscle for normal and activated leukocytes. Microvasc. Res. 51, 187–201 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Nakai, K. et al. Microangioarchitecture of rat parietal cortex with special reference to vascular “sphincters”: scanning electron microscopic and dark field microscopic study. Stroke 12, 653–659 (1981).

    Article  CAS  PubMed  Google Scholar 

  43. Boas, D.A., Jones, S.R., Devor, A., Huppert, T.J. & Dale, A.M. A vascular anatomical network model of the spatio-temporal response to brain activation. Neuroimage 40, 1116–1129 (2008).

    Article  PubMed  Google Scholar 

  44. Guibert, R., Fonta, C. & Plouraboué, F. Cerebral blood flow modeling in primate cortex. J. Cereb. Blood Flow Metab. 30, 1860–1873 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Risser, L., Plouraboue, F., Cloetens, P. & Fonta, C. A 3D-investigation shows that angiogenesis in primate cerebral cortex mainly occurs at capillary level. Int. J. Dev. Neurosci. 27, 185–196 (2009).

    Article  PubMed  Google Scholar 

  46. Kleinfeld, D. et al. A guide to delineate the logic of neurovascular signaling in the brain. Front. Neuroenergetics 1, 1–9 (2011).

    Google Scholar 

  47. Attwell, D. et al. Glial and neuronal control of brain blood flow. Nature 468, 232–243 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhang, S. & Murphy, T.H. Imaging the impact of cortical microcirculation on synaptic structure and sensory-evoked hemodynamic responses in vivo. PLoS Biol. 5, e119 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Smith, E.E., Schneider, J.A., Wardlaw, J.M. & Greenberg, S.M. Cerebral microinfarcts: the invisible lesions. Lancet Neurol. 11, 272–282 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Brundel, M., de Bresser, J., van Dillen, J.J., Kappelle, L.J. & Biessels, G.J. Cerebral microinfarcts: a systematic review of neuropathological studies. J. Cereb. Blood Flow Metab. 32, 425–436 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Kohn, A., Metz, C., Quibrera, M., Tommerdahl, M.A. & Whitsel, B.L. Functional neocortical microcircuitry demonstrated with intrinsic signal optical imaging in vitro. Neuroscience 95, 51–62 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. Denk, W., Strickler, J.H. & Webb, W.W. Two-photon laser scanning fluorescence microscopy. Science 248, 73–76 (1990).

    Article  CAS  PubMed  Google Scholar 

  53. Oraevsky, A. et al. Plasma mediated ablation of biological tissues with nanosecond-to-femtosecond laser pulses: relative role of linear and nonlinear absorption. IEEE J. Sel. Top. Quantum Electron. 2, 801–809 (1996).

    Article  CAS  Google Scholar 

  54. Nguyen, Q.-T., Tsai, P.S. & Kleinfeld, D. MPScope: a versatile software suite for multiphoton microscopy. J. Neurosci. Methods 156, 351–359 (2006).

    Article  PubMed  Google Scholar 

  55. Emmenlauer, M. et al. XuvTools: free, fast and reliable stitching of large 3D datasets. J. Microsc. 233, 42–60 (2009).

    Article  CAS  PubMed  Google Scholar 

  56. Blondel, V.D., Guillaume, J.-L., Lambiotte, R. & Lefebvre, E. Fast unfolding of communities in large networks. J. Stat. Mech. published online, doi:10.1088/1742-5468/2008/10/P10008 (9 October 2008).

  57. Fortunat, S. Community detection in graphs. Phys. Rep. 486, 74–175 (2010).

    Google Scholar 

  58. Strehl, A. & Ghosh, J. Cluster ensembles: a knowledge reuse framework for combining multiple partitions. J. Mach. Learn. Res. 3, 583–617 (2001).

    Google Scholar 

  59. Watts, D.J. & Strogatz, S.H. Collective dynamics of 'small-world' networks. Nature 393, 440–442 (1998).

    Article  CAS  PubMed  Google Scholar 

  60. Newman, M. Networks: An Introduction (Oxford University Press, New York, 2010).

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Acknowledgements

We thank J. Lee for assistance in the analysis of the surface vasculature, J.D. Driscoll for assistance with the imaging acquisition software, N. Nishimura and C.B. Schaffer for sharing their data logs, S. Chien, W. Denk, P.J. Drew, A.L. Fairhall, B. Friedman, R.D. Frostig, H.J. Karten, H.S. Seung, T.W. Secomb, A.Y. Shih and B. Weber for critical discussions. This work was supported by the Israeli Science Foundation (Bikura fellowship to P.B.) and the US National Institutes of Health (grants EB003832, MH085499, MH072570 and OD006831).

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P.B., D.K. and P.S.T. designed the study. P.B., P.M.K. and P.S.T. carried out the experiments and analyzed and summarized the data with input from J.P.K., D.K. and H.S. D.K. wrote the manuscript.

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Correspondence to David Kleinfeld.

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Blinder, P., Tsai, P., Kaufhold, J. et al. The cortical angiome: an interconnected vascular network with noncolumnar patterns of blood flow. Nat Neurosci 16, 889–897 (2013). https://doi.org/10.1038/nn.3426

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