Origins of BOLD - Neuroscience Perspectives
Anna Devor1,2

1Neurosciences and Radiology, UCSD, La Jolla, CA, United States, 2MGH/Harvard, Charlestown, MA, United States

Synopsis

Our ability to study human brain is limited by the necessity to use noninvasive technologies. This is in contrast to animal models where a detailed view of cellular-level brain function has become available due to recent advances in microscopic optical imaging and genetics. Thus, a central challenge facing neuroscience today is leveraging these mechanistic insights from animal studies to accurately draw physiological inferences from noninvasive signals in humans. On the essential path towards this goal is the development of a detailed “bottom-up” forward model bridging neuronal activity at the level of cell-type-specific populations to noninvasive imaging signals.

HIGHLIGHTS

  • Blood flow and energy metabolism are driven in parallel by neuronal activity
  • The “overshoot” prevents tissue oxygenation drop in between capillaries
  • GABAergic neurons play a key role in neurovascular coupling
  • Astrocytes may not drive CBF but contribute to BOLD by consuming O2
  • Macroscopic BOLD signal can be predicted by “bottom-up” modeling
  • Free parameters in the Davis model have no physiological meaning and should be treated simply as fitting parameters

TARGET AUDIENCE

MR physicists developing models of fMRI signals and MDs/neuroscientists using fMRI as a tool

OUTCOME/OBJECTIVES

  1. Learn about recent developments in microscopic imaging that have revealed the behavior of concrete physiological parameters underlying BOLD fMRI
  2. Learn how these data can be integrated to predict macroscopic BOLD signal

PURPOSE

Understanding how neuronal activity drives changes in cerebral blood flow (CBF) and cerebral metabolic rate of O2 (CMRO2) is critical for laying a solid physiological foundation for interpreting the BOLD signal. In this talk, we will review recent data on neurovascular and neurometabolic coupling that have become available due to advances in microscopic imaging technology. Further, we will introduce a theoretical framework to bridge between micro- and macroscopic level of description and will discuss our working hypotheses on CBF regulation and neurophysiological correlates of BOLD fMRI signals.

METHODS

We will review novel optical imaging methods with microscopic resolution that provide definitive and quantitative measures of concrete physiological parameters. These measures are used to predict macroscopic BOLD signal. The prediction is then tested against BOLD-fMRI data to ensure validity of the model.

RESULTS

We will provide examples of (1) how in vivo microscopic imaging technology can be used to test specific hypotheses on regulation of blood flow and identify cellular players and vasoactive messengers in neurovascular and neurometabolic coupling, and (2) how these microscopic data are integrated in a mechanistic framework to predict the BOLD signal.

DISCUSSION/CONCLUSION

Recent developments in optical microscopy now offer a versatile suite of tools for high-resolution, high-sensitivity measurements of vascular, metabolic, and neuronal parameters in deep tissue and local, cell-type specific manipulations of neuronal activity. These technological advances have challenged the “too hard to do” status quo for mechanistic studies in vivo and have defined a new standard for theoretical efforts that now can be rooted in microscopic reality of concrete physiological parameters’ behavior.

Acknowledgements

  • NIH BRAIN Initiative grants U01 NS094232 and R01MH111359
  • NIH Grants NS057198 and EB00790

References

  1. The roadmap for estimation of cell-type-specific neuronal activity from non-invasive measurements. Uhlirova H, Kılıç K, Tian P, Sakadžić S, Gagnon L, Thunemann M, Desjardins M, Saisan PA, Nizar K, Yaseen MA, Hagler DJ Jr, Vandenberghe M, Djurovic S, Andreassen OA, Silva GA, Masliah E, Kleinfeld D, Vinogradov S, Buxton RB, Einevoll GT, Boas DA, Dale AM, Devor A. Philos Trans R Soc Lond B Biol Sci. 2016 Oct 5;371(1705). PMID: 27574309
  2. Validation and optimization of hypercapnic-calibrated fMRI from oxygen-sensitive two-photon microscopy. Gagnon L, Sakadžić S, Lesage F, Pouliot P, Dale AM, Devor A, Buxton RB, Boas DA. Philos Trans R Soc Lond B Biol Sci. 2016 Oct 5;371(1705). PMID: 27574311
Proc. Intl. Soc. Mag. Reson. Med. 25 (2017)