This study addresses the pressing need for non-invasive, continuous monitoring of cerebral physiologic derangements following traumatic brain injury (TBI). We combine frequency-domain and broadband diffuse optical spectroscopy with diffuse correlation spectroscopy to monitor cerebral oxygen metabolism, cerebral blood volume, and cerebral water content in an established adult swine-model of focal TBI. Cerebral physiology is monitored before and after TBI (up to 14 days post injury). Overall, our results suggest that non-invasive optics can monitor cerebral physiology impairments such as reduced oxygen metabolism, hemorrhage, and edema formation post-TBI.
This report is the second part of a comprehensive two-part series aimed at reviewing an extensive and diverse toolkit of novel methods to explore brain health and function. While the first report focused on neurophotonic tools mostly applicable to animal studies, here, we highlight optical spectroscopy and imaging methods relevant to noninvasive human brain studies. We outline current state-of-the-art technologies and software advances, explore the most recent impact of these technologies on neuroscience and clinical applications, identify the areas where innovation is needed, and provide an outlook for the future directions.
Significance: The critical closing pressure (CrCP) of cerebral circulation, as measured by diffuse correlation spectroscopy (DCS), is a promising biomarker of intracranial hypertension. However, CrCP techniques using DCS have not been assessed in gold standard experiments.Aim: CrCP is typically calculated by examining the variation of cerebral blood flow (CBF) during the cardiac cycle (with normal sinus rhythm). We compare this typical CrCP measurement with a gold standard obtained during the drops in arterial blood pressure (ABP) caused by rapid ventricular pacing (RVP) in patients undergoing invasive electrophysiologic procedures.Approach: Adults receiving electrophysiology procedures with planned ablation were enrolled for DCS CBF monitoring. CrCP was calculated from CBF and ABP data by three methods: (1) linear extrapolation of data during RVP (CrCPRVP; the gold standard); (2) linear extrapolation of data during regular heartbeats (CrCPLinear); and (3) fundamental harmonic Fourier filtering of data during regular heartbeats (CrCPFourier).Results: CBF monitoring was performed prior to and during 55 episodes of RVP in five adults. CrCPRVP and CrCPFourier demonstrated agreement (R = 0.66, slope = 1.05 (95%CI, 0.72 to 1.38). Agreement between CrCPRVP and CrCPLinear was worse; CrCPLinear was 8.2 ± 5.9 mmHg higher than CrCPRVP (mean ± SD; p < 0.001).Conclusions: Our results suggest that DCS-measured CrCP can be accurately acquired during normal sinus rhythm.
Currently, no bedside tool measures placental hemoglobin properties. Thus, we developed a hybrid optical/ultrasound (US) system to measure and study placental oxygen dynamics noninvasively. The system combines a Frequency-Domain Diffuse Optical Spectroscopy (FD-DOS) instrument that is capable of probing tissue as deep as 5 cm below the surface, with a commercial US device to provide synchronized tissue morphological information. Multi-layer models of photon diffusion are then utilized to reconstruct placental hemoglobin properties from FD-DOS data with morphological constraints from US. Phantom experiments, simulations, and studies in human subjects demonstrate that this instrument quantifies in vivo placental hemodynamics non-invasively.
Hydrocephalus is a disorder of cerebral spinal fluid (CSF) physiology that results in increased intracranial pressure (ICP). It is commonly treated via surgical placement of a shunt in the ventricles to divert CSF. Diffuse optical measurements of cerebral perfusion and oxygen extraction were acquired before and after surgical shunt placement in neonates with hydrocephalus. An invasive ICP measurement was made at the time of shunt placement. Shunting increased cerebral perfusion and decreased oxygen extraction only in infants with elevated ICP. This suggests abnormally low perfusion in patients with elevated ICP, and normal perfusion in patients without elevated ICP.
Mild hypothermic cardiopulmonary bypass (CPB) is used during neonatal cardiac surgery. To elucidate potential risk factors for brain injury, diffuse optical spectroscopy, diffuse correlation spectroscopy, and cerebral microdialysis techniques were employed to monitor cerebral hemodynamics during mild hypothermic CPB in a swine model. Optical metrics were further compared with microdialysis metrics. Stable microdialysis metabolite levels, a significant decrease in CMRO2, and trending (but not significant) decreases in CBF and increases in OEF were observed. This suggests that the optical metrics may be more sensitive to neurologic injury during CPB than microdialysis.
Monitoring critical closing pressure (CrCP) can be a useful and noninvasive measure of intracranial pressure (ICP), especially in patients with high risk factors for brain injury. We monitored five patients undergoing cardiac ablation procedures using diffuse correlation spectroscopy (DCS). We utilized the prolonged diastolic events that occur during this procedure to validate non-invasive measurements of CrCP with DCS. to estimate the gold standard CrCP during long diastolic events induced during the procedure and compared them to estimations from normal pressure and flow waveforms prior to each event.
Extracorporeal membrane oxygenation (ECMO) is an important therapy for critically ill children but survivors have neurodevelopmental impairments. Cerebral inflammatory response resulting in brain edema is observed on ECMO. This pathologic response may adversely impact the quantitative accuracy of diffuse optical spectroscopy (DOS) neuromonitoring (including commercial NIRS) which commonly assumes a 75% water fraction. Using fresh brain tissue desiccation, we directly quantified the severity of cerebral edema in pediatric swine following cardiac arrest, CPR and 22-24 hours of ECMO therapy. The fractional error in DOS quantification of cerebral hemodynamics from assuming 75% water fraction was determined to be <5%.
Evaluation of the brain’s resting-state is an important window into neuronal function, connectivity, and health. Resting-state brain activity is reflected via neurovascular coupling in low frequency (0.01-0.1 Hz) hemodynamics, and low frequency power (LFP) can be a proxy for regional neuronal activity. In this exploratory study, we measured LFP in cerebral blood flow using diffuse correlation spectroscopy (LFP-DCS) during the course of an asphyxial cardiac arrest model in pediatric swine. The data demonstrate that LFP-DCS has distinct temporal information to blood flow index and may provide an additional biomarker to predict successful recovery after neurologic insults.
We examine the correlation of non-invasive, frequency-domain diffuse optical spectroscopy (FD-DOS) and diffuse correlation spectroscopy (DCS) measurements of cerebral tissue oxygen extraction fraction (OEF) and relative cerebral blood flow (rCBF) with invasive cerebral microdialysis measurement of the cerebral lactate-pyruvate ratio (LPR), a biomarker of metabolic stress, during extracorporeal membrane oxygenation (ECMO) in a pediatric swine model of ECMO assisted cardiopulmonary resuscitation (n=15). During 22-24 hours of ECMO, non-invasive FD-DOS/DCS neuromonitoring of OEF and rCBF demonstrated significant correlations with cerebral LPR. Non-invasive detection of critical neurometabolic stress at the bedside may facilitate brain-targeted ECMO management after cardiac arrest.
We investigate and assess the utility of a simple scheme for continuous absolute blood flow monitoring based on diffuse correlation spectroscopy (DCS). The scheme calibrates DCS using venous-occlusion diffuse optical spectroscopy (VO-DOS) measurements of arm muscle tissue at a single time-point. A calibration coefficient (γ) for the arm is determined, permitting conversion of DCS blood flow indices to absolute blood flow units, and a study of healthy adults (N=10) is carried out to ascertain the variability of γ. The average DCS calibration coefficient for the right (i.e., dominant) arm was γ=(1.24±0.15)×108 (mL·100 mL−1·min−1)/(cm2/s). However, variability can be significant and is apparent in our site-to-site and day-to-day repeated measurements. The peak hyperemic blood flow overshoot relative to baseline resting flow was also studied following arm-cuff ischemia; excellent agreement between VO-DOS and DCS was found (R2=0.95, slope=0.94±0.07, mean difference=−0.10±0.45). Finally, we show that incorporation of subject-specific absolute optical properties significantly improves blood flow calibration accuracy.
We introduce and validate a pressure measurement paradigm that reduces extracerebral contamination from superficial tissues in optical monitoring of cerebral blood flow with diffuse correlation spectroscopy (DCS). The scheme determines subject-specific contributions of extracerebral and cerebral tissues to the DCS signal by utilizing probe pressure modulation to induce variations in extracerebral blood flow. For analysis, the head is modeled as a two-layer medium and is probed with long and short source-detector separations. Then a combination of pressure modulation and a modified Beer-Lambert law for flow enables experimenters to linearly relate differential DCS signals to cerebral and extracerebral blood flow variation without a priori anatomical information. We demonstrate the algorithm’s ability to isolate cerebral blood flow during a finger-tapping task and during graded scalp ischemia in healthy adults. Finally, we adapt the pressure modulation algorithm to ameliorate extracerebral contamination in monitoring of cerebral blood oxygenation and blood volume by near-infrared spectroscopy.
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