To increase the clinical utility of the functional imaging modalities fMRI and diffuse optical imaging (DOI), we need to determine the relationship between the hemodynamic changes they measure and the underlying neural activity that causes these changes. During our last grant cycle we used DOI in combination with EEG/MEG to study neurovascular coupling. The results of these measurements have provided new insight into the role of different synaptic activity components in the hemodynamic response revealing a higher correlation of the hemodynamic response to the late superficial cortico-cortical transmissions than to the principal synaptic activity in layer IV. These results are provocative considering that most invasive animal studies to date have not looked at the late synaptic activity. In light of our results, it is necessary to revisit the invasive studies and include the late synaptic activity in the modeling of the neurovascular coupling. In this new project, following our preliminary macroscopic EEG/DOI measurements in rats, we propose to use a broad range of microscopic techniques to validate our overall hypothesis that: The hemodynamic response is not driven by the afferent inputs in layer IV, but by the late cortico-cortical transmission in more superficial layers. The key feature of our proposal is the multimodal approach that will allow us to interrogate the neurovascular coupling from a microscopic to a macroscopic level in the same animal model and translate the results to human functional neuroimaging.
In Aim 1 we will determine the role of the individual SEP components in the hemodynamic response at a microscopic level, addressing our overall hypothesis and several open questions in neuroscience: (1a) Is the neurovascular relationship linear or non-linear? (1b) Does the hemodynamic response start in superficial or middle layers? (1c) Does superficial secondary or late synaptic activity correlate better with the hemodynamic response? (1d) Does hyperpolarization cause vasoconstriction? In Aim 2 we will link our microscopic findings with the macroscopic noninvasive results in humans. The necessary steps are: (2a) Evaluate the correspondence between microscopic and macroscopic findings in the same small animal model. (2b) Validate the neurovascular coupling model in awake rats. (2c) Evaluate the effect of baseline blood flow. (2d) Validate the neurovascular coupling model in human subjects during EEG/DOI and MEG/DOI experiments. From a clinical perspective, determining whether the hemodynamic response is driven by late cortico- cortico transmission rather than by afferent inputs to layer IV would have a profound effect on the clinical role of BOLD fMRI and DOI. In fact the development and validation of such a model would allow expansion of the use of neurovascular responses from localization of function to fundamental assessment of regional functional integrity, involvement in network processing and character of modulation.

Public Health Relevance

We will determine the relationship between electrical and vascular functional imaging signals during neuronal activity and their link with the underlying microscopic neurovascular physiology. This knowledge will benefit basic and clinical neuroscience applications of fMRI and DOI.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
Project #
Application #
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Conroy, Richard
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Selb, Juliette; Boas, David A; Chan, Suk-Tak et al. (2014) Sensitivity of near-infrared spectroscopy and diffuse correlation spectroscopy to brain hemodynamics: simulations and experimental findings during hypercapnia. Neurophotonics 1:
Chan, Aaron C; Srinivasan, Vivek J; Lam, Edmund Y (2014) Maximum likelihood Doppler frequency estimation under decorrelation noise for quantifying flow in optical coherence tomography. IEEE Trans Med Imaging 33:1313-23
Roche-Labarbe, Nadege; Fenoglio, Angela; Radhakrishnan, Harsha et al. (2014) Somatosensory evoked changes in cerebral oxygen consumption measured non-invasively in premature neonates. Neuroimage 85 Pt 1:279-86
Radhakrishnan, Harsha; Srinivasan, Vivek J (2013) Multiparametric optical coherence tomography imaging of the inner retinal hemodynamic response to visual stimulation. J Biomed Opt 18:86010
Srinivasan, Vivek J; Radhakrishnan, Harsha (2013) Total average blood flow and angiography in the rat retina. J Biomed Opt 18:76025
Srinivasan, Vivek J; Mandeville, Emiri T; Can, Anil et al. (2013) Multiparametric, longitudinal optical coherence tomography imaging reveals acute injury and chronic recovery in experimental ischemic stroke. PLoS One 8:e71478
Srinivasan, Vivek J; Radhakrishnan, Harsha; Jiang, James Y et al. (2012) Optical coherence microscopy for deep tissue imaging of the cerebral cortex with intrinsic contrast. Opt Express 20:2220-39
Srinivasan, Vivek J; Radhakrishnan, Harsha; Lo, Eng H et al. (2012) OCT methods for capillary velocimetry. Biomed Opt Express 3:612-29
Devor, Anna; Sakadzic, Sava; Srinivasan, Vivek J et al. (2012) Frontiers in optical imaging of cerebral blood flow and metabolism. J Cereb Blood Flow Metab 32:1259-76
Lee, Jonghwan; Srinivasan, Vivek; Radhakrishnan, Harsha et al. (2011) Motion correction for phase-resolved dynamic optical coherence tomography imaging of rodent cerebral cortex. Opt Express 19:21258-70

Showing the most recent 10 out of 26 publications