Development of a novel diffuse correlation spectroscopy platform for monitoring cerebral blood flow and oxygen metabolism: from novel concepts and devices to preclinical live animal studies
New optical technologies were developed to continuously measure cerebral blood flow (CBF) and oxygen metabolism (CMRO2) non-invasively through the skull. Methods and devices were created to improve the performance of near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS) for use in experimental animals and humans. These were employed to investigate cerebral metabolism and cerebrovascular reactivity under different states of anesthesia and during models of pathological states. Burst suppression is a brain state arising naturally in pathological conditions or under deep general anesthesia, but its mechanism and consequences are not well understood. Electroencephalography (EEG) and cortical hemodynamics were simultaneously measured in rats to evaluate the coupling between cerebral oxygen metabolism and neuronal activity in the burst suppressed state. EEG bursts were used to deconvolve NIRS and DCS signals into the hemodynamic and metabolic response function for an individual burst. This response was found to be similar to the stereotypical functional hyperemia evoked by normal brain activation. Thus, spontaneous burst activity does not cause metabolic or hemodynamic dysfunction in the cortex. Furthermore, cortical metabolic activity was not associated with the initiation or termination of a burst. A novel technique, time-domain DCS (TD-DCS), was introduced to significantly increase the sensitivity of transcranial CBF measurements to the brain. A new time-correlated single photon counting (TCSPC) instrument with a custom high coherence pulsed laser source was engineered for the first-ever simultaneous measurement of photon time of flight and DCS autocorrelation decays. In this new approach, photon time tags are exploited to determine path-length-dependent autocorrelation functions. By correlating photons according to time of flight, CBF is distinguished from superficial blood flow. Experiments in phantoms and animals demonstrate TD-DCS has significantly greater sensitivity to the brain than existing transcranial techniques. Intracranial pressure (ICP) modulates both steady-state and pulsatile CBF, making CBF a potential marker for ICP. In particular, the critical closing pressure (CrCP) has been proposed as a surrogate measure of ICP. A new DCS device was developed to measure pulsatile CBF non-invasively. A novel method for estimating CrCP and ICP from DCS measurement of pulsatile microvascular blood flow in the cerebral cortex was demonstrated in rats.