Neurovascular Impulse Response Function (IRF) during spontaneous activity differentially reflects intrinsic neuromodulation across cortical regions

Ascending neuromodulatory projections from deep brain nuclei generate internal brain states that differentially engage specific neuronal cell types. Because neurovascular coupling is cell-type specific and neuromodulatory transmitters have vasoactive properties, we hypothesized that the impulse response function (IRF) linking spontaneous neuronal activity with hemodynamics would depend on neuromodulation. To test this hypothesis, we used optical imaging to measure (1) release of neuromodulatory transmitters norepinephrine (NE) or acetylcholine (ACh), (2) Ca ²⁺ activity of local cortical neurons, and (3) changes in hemoglobin concentration and oxygenation across the dorsal surface of cerebral cortex during spontaneous neuronal activity in awake mice. A canonical convolution model with a stationary IRF (e.g., the convolution kernel) describing evolution of total hemoglobin (HbT, reflective of dilation dynamics) with respect to Ca ²⁺ , resulted in a poor fit to the data. However, the HbT time-course was well predicted, pixel-by-pixel, by a weighted sum of Ca ²⁺ and NE time-courses. The weighting coefficients, calculated using linear regression, varied smoothly across the cortical space. Consistent with this result, modeling HbT as a weighted sum of stationary Ca ²⁺ - and NE-specific IRFs convolved with the respective time-courses dramatically improved the fit compared to the invariant IRF. In both the linear regression and the Double-IRF convolution models, Ca ²⁺ and NE weighting was positive and negative, respectively. In contrast to NE, ACh was largely redundant with Ca ²⁺ and therefore did not improve HbT estimation. Because NE covaried with arousal, we observed instances of the diminished hemodynamic coherence between cortical regions during high arousal despite coherent behavior of the underlying neuronal Ca ²⁺ activity. We conclude that while neurovascular coupling with respect to neuronal Ca ²⁺ is a dynamic and seemingly complex phenomenon, hemodynamic fluctuations can be captured by a simple linear model with stationary IRFs with respect to the underlying dilatory and constrictive forces. In the current study, these forces were captured by the positive Ca ²⁺ (dilation) and negative NE (constriction) coefficients. Without accounting for NE neuromodulation and the associated vasoconstriction, diminished hemodynamic coherence, commonly referred to as ″functional (dys)connectivity″ in BOLD fMRI studies, can be falsely interpreted as neuronal desynchronizations.