The influence of voxelotor on cerebral blood flow and oxygen extraction in pediatric sickle cell disease.

ABSTRACT: Voxelotor is an inhibitor of sickle hemoglobin polymerization that is used to treat sickle cell disease. Although voxelotor has been shown to improve anemia, the clinical benefit on the brain remains to be determined. This study quantified the cerebral hemodynamic effects of voxelotor in children with sickle cell anemia (SCA) using noninvasive diffuse optical spectroscopies. Specifically, frequency-domain near-infrared spectroscopy combined with diffuse correlation spectroscopy were used to noninvasively assess regional oxygen extraction fraction (OEF), cerebral blood volume, and an index of cerebral blood flow (CBFi). Estimates of CBFi were first validated against arterial spin-labeled magnetic resonance imaging (ASL-MRI) in 8 children with SCA aged 8 to 18 years. CBFi was significantly positively correlated with ASL-MRI-measured blood flow (R2 = 0.651; P = .015). Next, a single-center, open-label pilot study was completed in 8 children with SCA aged 4 to 17 years on voxelotor, monitored before treatment initiation and at 4, 8, and 12 weeks (NCT05018728). By 4 weeks, both OEF and CBFi significantly decreased, and these decreases persisted to 12 weeks (both P < .05). Decreases in CBFi were significantly correlated with increases in blood hemoglobin (Hb) concentration (P = .025), whereas the correlation between decreases in OEF and increases in Hb trended toward significance (P = .12). Given that previous work has shown that oxygen extraction and blood flow are elevated in pediatric SCA compared with controls, these results suggest that voxelotor may reduce cerebral hemodynamic impairments. This trial was registered at www.ClinicalTrials.gov as #NCT05018728.

Profiling the neuroimmune cascade in 3xTg-AD mice exposed to successive mild traumatic brain injuries.

Repetitive mild traumatic brain injuries (rmTBI) sustained within a window of vulnerability can result in long term cognitive deficits, depression, and eventual neurodegeneration associated with tau pathology, amyloid beta (Aß) plaques, gliosis, and neuronal and functional loss. However, a comprehensive study relating acute changes in immune signaling and glial reactivity to neuronal changes and pathological markers after single and repetitive mTBIs is currently lacking. In the current study, we addressed the question of how repeated injuries affect the brain neuroimmune response in the acute phase of injury (< 24 h) by exposing the 3xTg-AD mouse model of tau and Aß pathology to successive (1x-5x) once-daily weight drop closed-head injuries and quantifying immune markers, pathological markers, and transcriptional profiles at 30 min, 4 h, and 24 h after each injury. We used young adult 2-4 month old 3xTg-AD mice to model the effects of rmTBI in the absence of significant tau and Aß pathology. We identified pronounced sexual dimorphism in this model, with females eliciting more diverse changes after injury compared to males. Specifically, females showed: (1) a single injury caused a decrease in neuron-enriched genes inversely correlated with inflammatory protein expression and an increase in AD-related genes within 24 h, (2) each injury significantly increased a group of cortical cytokines (IL-1α, IL-1ß, IL-2, IL-9, IL-13, IL-17, KC) and MAPK phospho-proteins (phospho-Atf2, phospho-Mek1), several of which co-labeled with neurons and correlated with phospho-tau, and (3) repetitive injury caused increased expression of genes associated with astrocyte reactivity and macrophage-associated immune function. Collectively our data suggest that neurons respond to a single injury within 24 h, while other cell types, including astrocytes, transition to inflammatory phenotypes within days of repetitive injury.

Noninvasive optical measurement of microvascular cerebral hemodynamics and autoregulation in the neonatal ECMO patient.

BACKGROUND: Extra-corporeal membrane oxygenation (ECMO) is a life-saving intervention for severe respiratory and cardiac diseases. However, 50% of survivors have abnormal neurologic exams. Current ECMO management is guided by systemic metrics, which may poorly predict cerebral perfusion. Continuous optical monitoring of cerebral hemodynamics during ECMO holds potential to detect risk factors of brain injury such as impaired cerebrovascular autoregulation (CA). METHODS: We conducted daily measurements of microvascular cerebral blood flow (CBF), oxygen saturation, and total hemoglobin concentration using diffuse correlation spectroscopy (DCS) and frequency-domain diffuse optical spectroscopy in nine neonates. We characterize CA utilizing the correlation coefficient (DCSx) between CBF and mean arterial blood pressure (MAP) during ECMO pump flow changes. RESULTS: Average MAP and pump flow levels were weakly correlated with CBF and were not correlated with cerebral oxygen saturation. CA integrity varied between individuals and with time. Systemic measurements of MAP, pulse pressure, and left cardiac dysfunction were not predictive of impaired CA. CONCLUSIONS: Our pilot results suggest that systemic measures alone cannot distinguish impaired CA from intact CA during ECMO. Furthermore, optical neuromonitoring could help determine patient-specific ECMO pump flows for optimal CA integrity, thereby reducing risk of secondary brain injury. IMPACT: Cerebral blood flow and oxygenation are not well predicted by systemic proxies such as ECMO pump flow or blood pressure. Continuous, quantitative, bedside monitoring of cerebral blood flow and oxygenation with optical tools enables new insight into the adequacy of cerebral perfusion during ECMO. A demonstration of hybrid diffuse optical and correlation spectroscopies to continuously measure cerebral blood oxygen saturation and flow in patients on ECMO, enabling assessment of cerebral autoregulation. An observation of poor correlation of cerebral blood flow and oxygenation with systemic mean arterial pressure and ECMO pump flow, suggesting that clinical decision making guided by target values for these surrogates may not be neuroprotective. ~50% of ECMO survivors have long-term neurological deficiencies; continuous monitoring of brain health throughout therapy may reduce these tragically common sequelae through brain-focused adjustment of ECMO parameters.

Low cerebral blood flow is a non-invasive biomarker of neuroinflammation after repetitive mild traumatic brain injury.

Previous work has shown that non-invasive optical measurement of low cerebral blood flow (CBF) is an acute biomarker of poor long-term cognitive outcome after repetitive mild traumatic brain injury (rmTBI). Herein, we explore the relationship between acute cerebral blood flow and underlying neuroinflammation. Specifically, because neuroinflammation is a driver of secondary injury after TBI, we hypothesized that both glial activation and inflammatory signaling are associated with acute CBF and, by extension, with long-term cognitive outcome after rmTBI. To test this hypothesis, cortical CBF was non-invasively measured in anesthetized mice 4 h after 3 repetitive closed head injuries spaced once-daily, at which time brains were collected. Right hemispheres were fixed for immunohistochemical staining for glial activation markers Iba1 and GFAP while left hemispheres were used to quantify Iba1 and GFAP expression via Western blot as well as 32 cytokines and 21 phospho-proteins in the MAPK, PI3K/Akt, and NF-κB pathways using a Luminex multiplexed immunoassay. N = 8/7 injured/sham C57/black-6 adult male mice were studied. Within the injured group, CBF inversely correlated with Iba1 expression (R = -0.86, p < .01). Further, partial least squares regression analysis revealed significant correlations between CBF and expression of multiple pro-inflammatory cytokines, including RANTES and IL-17. Finally, within the injured group, phosphorylation of specific signals in the MAPK and NF-κB intracellular signaling pathways (e.g., p38 MAPK and NF-κB) were significantly positively correlated with Iba1. In total, our data indicate that acute cerebral blood flow after rmTBI is a biomarker of underlying neuroinflammatory pathology.

In vivo Monitoring of Cerebral Hemodynamics in the Immature Rat: Effects of Hypoxia-Ischemia and Hypothermia.

BACKGROUND: Neonatal hypoxic-ischemic (HI) encephalopathy occurs in 1-4 per 1,000 live term births and can cause devastating neurodevelopmental disabilities. Currently, therapeutic hypothermia (TH) is the only treatment with proven efficacy. Since TH is associated with decreased cerebral metabolism and cerebral blood flow (CBF), it is important to assess CBF at the bedside. Diffuse correlation spectroscopy (DCS) has emerged as a promising optical modality to noninvasively assess an index of CBF (CBFi) in both humans and animals. In this initial descriptive study, we employ DCS to monitor the evolution of CBFi following HI with or without TH in immature rats. We investigate potential relationships between CBF and subsequent cerebral damage. METHODS: HI was induced on postnatal day 10 or 11 rat pups by right common carotid artery ligation followed by 60-70 min hypoxia (8% oxygen). After HI, the pups recovered for 4 h under hypothermia (HI-TH group, n = 23) or normothermia (HI-N group, n = 23). Bilateral measurements of hemispheric CBFi were made with DCS in unanesthetized animals at baseline, before HI, and 0, 1, 2, 3, 4, 5, and 24 h after HI. The animals were sacrificed at either 1 or 4 weeks, and brain injury was scored on an ordinal scale of 0-5 (0 = no injury). RESULTS: Carotid ligation caused moderate bilateral decreases in CBFi. Following HI, an initial hyperemia was observed that was more prominent in the contralateral hemisphere. After initiation of TH, CBFi dropped significantly below baseline levels and remained reduced for the duration of TH. In contrast, CBFi in the HI-N group was not significantly decreased from baseline levels. Reductions in CBFi after 4 h of TH were not associated with reduced damage at 1 or 4 weeks. However, elevated ipsilateral CBFi and ipsilateral-to-contralateral CBFi ratios at 24 h were associated with worse outcome at 1 week after HI. CONCLUSIONS: Both HI and TH alter CBFi, with significant differences in CBFi between hypothermic and normothermic groups after HI. CBFi may be a useful biomarker of subsequent cerebral damage.

Scoring system for periventricular leukomalacia in infants with congenital heart disease.

BACKGROUND: Currently two magnetic resonance imaging (MRI) methods have been used to assess periventricular leukomalacia (PVL) severity in infants with congenital heart disease: manual volumetric lesion segmentation and an observational categorical scale. Volumetric classification is labor intensive and the categorical scale is quick but unreliable. We propose the quartered point system (QPS) as a novel, intuitive, time-efficient metric with high interrater agreement. METHODS: QPS is an observational scale that asks the rater to score MRIs on the basis of lesion size, number, and distribution. Pre- and postoperative brain MRIs were obtained on term congenital heart disease infants. Three independent observers scored PVL severity using all three methods: volumetric segmentation, categorical scale, and QPS. RESULTS: One-hundred and thirty-five MRIs were obtained from 72 infants; PVL was seen in 48 MRIs. Volumetric measurements among the three raters were highly concordant (ρc = 0.94-0.96). Categorical scale severity scores were in poor agreement between observers (κ = 0.17) and fair agreement with volumetrically determined severity (κ = 0.26). QPS scores were in very good agreement between observers (κ = 0.82) and with volumetric severity (κ = 0.81). CONCLUSION: QPS minimizes training and sophisticated radiologic analysis and increases interrater reliability. QPS offers greater sensitivity to stratify PVL severity and has the potential to more accurately correlate with neurodevelopmental outcomes.

DCS blood flow index underestimates skeletal muscle perfusion in vivo: rationale and early evidence for the NIRS-DCS perfusion index.

Significance: Diffuse correlation spectroscopy (DCS) permits non-invasive assessment of skeletal muscle blood flow but may misestimate changes in muscle perfusion. Aim: We aimed to highlight recent evidence that DCS blood flow index (BFI) misestimates changes in muscle blood flow during physiological perturbation and to introduce a novel approach that adjusts BFI for estimated changes in vasodilation. Approach: We measured changes in muscle BFI during quadriceps and forearm exercises using DCS, the latter of which were adjusted for estimated changes in microvascular flow area and then compared to Doppler ultrasound in the brachial artery. Then, we compared adjusted BFI- and arterial spin labeling (ASL) MRI measures of gastrocnemius blood flow during reactive hyperemia and plantar flexion exercise. Results: We observed little-to-no change in quadriceps BFI during maximal-effort exercise. Similarly, forearm BFI was modestly increased during handgrip exercise, but the magnitude was significantly lower than measured by Doppler ultrasound in the brachial artery. However, this difference was ameliorated after adjusting BFI for estimated changes in microvascular flow area. Similar observations were also observed in the gastrocnemius when directly comparing the adjusted BFI values to ASL-MRI. Conclusions: Adjusting BFI for estimated changes in microvascular flow area may improve DCS estimates of muscle blood flow, but further study is needed to validate these methods moving forward.

Cerebrospinal Fluid Pharmacokinetics of Nicardipine Following Intrathecal Administration in Subarachnoid Hemorrhage Patients.

Subarachnoid hemorrhage (SAH) is a devastating type of stroke, leading to high mortality and morbidity rates. Cerebral vasospasm and delayed cerebral ischemia (DCI) are common complications following SAH that contribute significantly to the poor outcomes observed in these patients. Intrathecal (IT) nicardipine delivered via an existing external ventricular drain is an off-label intervention that has been shown to be correlated with reduced DCI and improved patient outcomes. The current study aims to characterize the population pharmacokinetic (popPK) properties of intermittent IT nicardipine. Following informed consent, serial cerebrospinal fluid (CSF) samples were obtained from 16 SAH patients (50.4 ± 9.3 years old; 13 females) treated with IT nicardipine every 6 h (q6h, n = 8) or every 8 h (q8h, n = 8) for an average of 72 ± 21 doses. High-performance liquid chromatography was used to quantify CSF concentration from each sample. Our popPK analysis showed that the CSF pharmacokinetics of IT nicardipine in the cohort was adequately described by a two-compartment model with a lag time. Model parameter estimates were reliable (relative standard error <50%). Intracranial pressure influenced both the total clearance and the central volume of nicardipine (i.e., negative correlation, P <-.001). Calculated PK parameters were similar between q6h and q8h dosing regimens. Despite a small cohort of SAH patients, we successfully developed a popPK model to describe the nicardipine disposition kinetics in the CSF following IT administration. These findings may help inform future clinical trials designed to examine the optimal dosing of IT nicardipine.

Sodium bicarbonate causes dose-dependent increases in cerebral blood flow in infants and children with single-ventricle physiology.

BACKGROUND: Sodium bicarbonate (NaHCO3) is a common treatment for metabolic acidemia; however, little definitive information exists regarding its treatment efficacy and cerebral hemodynamic effects. This pilot observational study quantifies relative changes in cerebral blood flow (ΔrCBF) and oxy- and deoxyhemoglobin concentrations (ΔHbO2 and ΔHb) due to bolus administration of NaHCO3 in patients with mild base deficits. METHODS: Infants and children with hypoplastic left heart syndrome (HLHS) were enrolled before cardiac surgery. NaHCO3 was given as needed for treatment of base deficit. Diffuse optical spectroscopies were used for 15 min postinjection to noninvasively monitor ΔHb, ΔHbO2, and ΔrCBF relative to baseline before NaHCO3 administration. RESULTS: Twenty-two anesthetized and mechanically ventilated patients with HLHS (aged 1 d to 4 y) received a median (interquartile range) dose of 1.1 (0.8, 1.8) mEq/kg NaHCO3 administered intravenously over 10-20 s to treat a median (interquartile range) base deficit of -4 (-6, -3) mEq/l. NaHCO3 caused significant dose-dependent increases in ΔrCBF; however, population-averaged ΔHb and ΔHbO2 as compared with those of controls were not significant. CONCLUSIONS: Dose-dependent increases in cerebral blood flow (CBF) caused by bolus administration of NaHCO3 are an important consideration in vulnerable populations wherein risk of rapid CBF fluctuations does not outweigh the benefit of treating a base deficit.

Rebellion, curiosity, and perseverance: a conversation with Maria Angela Franceschini.

Neurophotonics Associate Editor Erin M. Buckley (Georgia Institute of Technology and Emory University) interviewed her colleague Maria Angela Franceschini, professor at the Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, and recognized leader in the field of diffuse optical imaging in both neuroscience and clinical neuro-monitoring applications.

Influence of oversimplifying the head anatomy on cerebral blood flow measurements with diffuse correlation spectroscopy.

Significance: Diffuse correlation spectroscopy (DCS) is an emerging optical modality for non-invasive assessment of an index of regional cerebral blood flow. By the nature of this noninvasive measurement, light must pass through extracerebral layers (i.e., skull, scalp, and cerebral spinal fluid) before detection at the tissue surface. To minimize the contribution of these extracerebral layers to the measured signal, an analytical model has been developed that treats the head as a series of three parallel and infinitely extending slabs (mimicking scalp, skull, and brain). The three-layer model has been shown to provide a significant improvement in cerebral blood flow estimation over the typically used model that treats the head as a bulk homogenous medium. However, the three-layer model is still a gross oversimplification of the head geometry that ignores head curvature, the presence of cerebrospinal fluid (CSF), and heterogeneity in layer thickness. Aim: Determine the influence of oversimplifying the head geometry on cerebral blood flow estimated with the three-layer model. Approach: Data were simulated with Monte Carlo in a four-layer slab medium and a three-layer sphere medium to isolate the influence of CSF and curvature, respectively. Additionally, simulations were performed on magnetic resonance imaging (MRI) head templates spanning a wide-range of ages. Simulated data were fit to both the homogenous and three-layer model for CBF. Finally, to mitigate the errors in potential CBF estimation due to the difficulty in defining layer thickness, we investigated an approach to identify an equivalent, "optimized" thickness via a pressure modulation. Results: Both head curvature and failing to account for CSF lead to significant errors in the estimation of CBF. However, the effect of curvature and CSF on relative changes in CBF is minimal. Further, we found that CBF was underestimated in all MRI-templates, although the magnitude of these underestimations was highly influenced by small variations in the source and detector optode positioning. The optimized thickness obtained from pressure modulation did not improve estimation accuracy of CBF, although it did significantly improve the estimation accuracy of relative changes in CBF. Conclusions: In sum, these findings suggest that the three-layer model holds promise for improving estimation of relative changes in cerebral blood flow; however, estimations of absolute cerebral blood flow with the approach should be viewed with caution given that it is difficult to account for appreciable sources of error, such as curvature and CSF.

Agreement in cerebrovascular reactivity assessed with diffuse correlation spectroscopy across experimental paradigms improves with short separation regression.

Significance: Cerebrovascular reactivity (CVR), i.e., the ability of cerebral vasculature to dilate or constrict in response to vasoactive stimuli, is a biomarker of vascular health. Exogenous administration of inhaled carbon dioxide, i.e., hypercapnia (HC), remains the "gold-standard" intervention to assess CVR. More tolerable paradigms that enable CVR quantification when HC is difficult/contraindicated have been proposed. However, because these paradigms feature mechanistic differences in action, an assessment of agreement of these more tolerable paradigms to HC is needed. Aim: We aim to determine the agreement of CVR assessed during HC, breath-hold (BH), and resting state (RS) paradigms. Approach: Healthy adults were subject to HC, BH, and RS paradigms. End tidal carbon dioxide (EtCO2) and cerebral blood flow (CBF, assessed with diffuse correlation spectroscopy) were monitored continuously. CVR (%/mmHg) was quantified via linear regression of CBF versus EtCO2 or via a general linear model (GLM) that was used to minimize the influence of systemic and extracerebral signal contributions. Results: Strong agreement ( CCC ≥ 0.69 ; R ≥ 0.76 ) among CVR paradigms was demonstrated when utilizing a GLM to regress out systemic/extracerebral signal contributions. Linear regression alone showed poor agreement across paradigms ( CCC ≤ 0.35 ; R ≤ 0.45 ). Conclusions: More tolerable experimental paradigms coupled with regression of systemic/extracerebral signal contributions may offer a viable alternative to HC for assessing CVR.

Profiling the neuroimmune cascade in 3xTg mice exposed to successive mild traumatic brain injuries.

Repetitive mild traumatic brain injuries (rmTBI) sustained within a window of vulnerability can result in long term cognitive deficits, depression, and eventual neurodegeneration associated with tau pathology, amyloid beta (Aß) plaques, gliosis, and neuronal and functional loss. However, we have limited understanding of how successive injuries acutely affect the brain to result in these devastating long-term consequences. In the current study, we addressed the question of how repeated injuries affect the brain in the acute phase of injury (<24hr) by exposing the 3xTg-AD mouse model of tau and Aß pathology to successive (1x, 3x, 5x) once-daily weight drop closed-head injuries and quantifying immune markers, pathological markers, and transcriptional profiles at 30min, 4hr, and 24hr after each injury. We used young adult mice (2-4 months old) to model the effects of rmTBI relevant to young adult athletes, and in the absence of significant tau and Aß pathology. Importantly, we identified pronounced sexual dimorphism, with females eliciting more differentially expressed proteins after injury compared to males. Specifically, females showed: 1) a single injury caused a decrease in neuron-enriched genes inversely correlated with inflammatory protein expression as well as an increase in AD-related genes within 24hr, 2) each injury significantly increased expression of a group of cortical cytokines (IL-1α, IL-1ß, IL-2, IL-9, IL-13, IL-17, KC) and MAPK phospho-proteins (phospho-Atf2, phospho-Mek1), several of which were co-labeled with neurons and correlated with phospho-tau, and 3) repetitive injury caused increased expression of genes associated with astrocyte reactivity and immune function. Collectively our data suggest that neurons respond to a single injury within 24h, while other cell types including astrocytes transition to inflammatory phenotypes within days of repetitive injury.

Normative cerebral microvascular blood flow waveform morphology assessed with diffuse correlation spectroscopy.

Microvascular cerebral blood flow exhibits pulsatility at the cardiac frequency that carries valuable information about cerebrovascular health. This study used diffuse correlation spectroscopy to quantify normative features of these waveforms in a cohort of thirty healthy adults. We demonstrate they are sensitive to changes in vascular tone, as indicated by pronounced morphological changes with hypercapnia. Further, we observe significant sex-based differences in waveform morphology, with females exhibiting higher flow, greater area-under-the-curve, and lower pulsatility. Finally, we quantify normative values for cerebral critical closing pressure, i.e., the minimum pressure required to maintain flow in a given vascular region.

Microvascular cerebral blood flow response to intrathecal nicardipine is associated with delayed cerebral ischemia.

One of the common complications of non-traumatic subarachnoid hemorrhage (SAH) is delayed cerebral ischemia (DCI). Intrathecal (IT) administration of nicardipine, a calcium channel blocker (CCB), upon detection of large-artery cerebral vasospasm holds promise as a treatment that reduces the incidence of DCI. In this observational study, we prospectively employed a non-invasive optical modality called diffuse correlation spectroscopy (DCS) to quantify the acute microvascular cerebral blood flow (CBF) response to IT nicardipine (up to 90 min) in 20 patients with medium-high grade non-traumatic SAH. On average, CBF increased significantly with time post-administration. However, the CBF response was heterogeneous across subjects. A latent class mixture model was able to classify 19 out of 20 patients into two distinct classes of CBF response: patients in Class 1 (n = 6) showed no significant change in CBF, while patients in Class 2 (n = 13) showed a pronounced increase in CBF in response to nicardipine. The incidence of DCI was 5 out of 6 in Class 1 and 1 out of 13 in Class 2 (p < 0.001). These results suggest that the acute (<90 min) DCS-measured CBF response to IT nicardipine is associated with intermediate-term (up to 3 weeks) development of DCI.

Impaired cerebrovascular reactivity in pediatric sickle cell disease using diffuse correlation spectroscopy.

Cerebrovascular reactivity (CVR), defined as the ability of cerebral vasculature to dilate in response to a vasodilatory stimulus, is an integral mechanism in brain homeostasis that is thought to be impaired in sickle cell disease (SCD). This study used diffuse correlation spectroscopy and a simple breath-hold stimulus to quantify CVR non-invasively in a cohort of 12 children with SCD and 14 controls. Median [interquartile range] CVR was significantly decreased in SCD compared to controls (2.03 [1.31, 2.44] versus 3.49 [3.00, 4.11] %/mmHg, p = 0.028). These results suggest DCS may provide a feasible means to routinely monitor CVR impairments in pediatric SCD.

Cerebrospinal Fluid Pharmacokinetics of Nicardipine Following Intrathecal Administration in Subarachnoid Hemorrhage Patients.

Subarachnoid hemorrhage (SAH) is a devastating type of stroke, leading to high mortality and morbidity rates. Cerebral vasospasm and delayed cerebral ischemia (DCI) are common complications following SAH and contribute significantly to the poor outcomes observed in these patients. Intrathecal (IT) nicardipine delivered via an existing external ventricular drain has been shown to be correlated with reduced DCI and improved patient outcomes. The current study aims to characterize population pharmacokinetic (popPK) properties of intermittent IT nicardipine. Following informed consent, serial cerebrospinal fluid (CSF) samples were obtained from 16 SAH patients (50.4 ± 9.3 years old; 12 females) treated with IT nicardipine every 6 hours (n=8) or every 8 hours (n=8), which were subject to high-performance liquid chromatography for measurement of its CSF concentration. Our popPK analysis showed that the CSF PK of IT nicardipine in the cohort was adequately described by a two-compartment model with a lag time, with reliable parameter estimates (relative standard error < 50%). The intracranial pressure influenced both the total clearance and the central volume. Calculated PK parameters were similar between q6h and q8h dosing regimens. Despite a small cohort of SAH patients, we successfully developed a popPK model to describe the nicardipine disposition kinetics in the CSF following IT administration. These findings may help inform future clinical trials designed to examine the optimal dosing of IT nicardipine.

Comparison of diffuse correlation spectroscopy analytical models for measuring cerebral blood flow in adults.

Significance: Although multilayer analytical models have been proposed to enhance brain sensitivity of diffuse correlation spectroscopy (DCS) measurements of cerebral blood flow, the traditional homogeneous model remains dominant in clinical applications. Rigorous in vivo comparison of these analytical models is lacking. Aim: We compare the performance of different analytical models to estimate a cerebral blood flow index (CBFi) with DCS in adults. Approach: Resting-state data were obtained on a cohort of 20 adult patients with subarachnoid hemorrhage. Data at 1 and 2.5 cm source-detector separations were analyzed with the homogenous, two-layer, and three-layer models to estimate scalp blood flow index and CBFi. The performance of each model was quantified via fitting convergence, fit stability, brain-to-scalp flow ratio (BSR), and correlation with transcranial Doppler ultrasound (TCD) measurements of cerebral blood flow velocity in the middle cerebral artery (MCA). Results: The homogeneous model has the highest pass rate (100%), lowest coefficient of variation (CV) at rest (median [IQR] at 1 Hz of 0.18 [0.13, 0.22]), and most significant correlation with MCA blood flow velocities (Rs=0.59, p=0.010) compared with both the two- and three-layer models. The multilayer model pass rate was significantly correlated with extracerebral layer thicknesses. Discarding datasets with non-physiological BSRs increased the correlation between DCS measured CBFi and TCD measured MCA velocities for all models. Conclusions: We found that the homogeneous model has the highest pass rate, lowest CV at rest, and most significant correlation with MCA blood flow velocities. Results from the multilayer models should be taken with caution because they suffer from lower pass rates and higher coefficients of variation at rest and can converge to non-physiological values for CBFi. Future work is needed to validate these models in vivo, and novel approaches are merited to improve the performance of the multimodel models.

Influence of source-detector separation on diffuse correlation spectroscopy measurements of cerebral blood flow with a multilayered analytical model.

Significance: Diffuse correlation spectroscopy (DCS) is an emerging noninvasive optical technology for bedside monitoring of cerebral blood flow. However, extracerebral hemodynamics can significantly influence DCS estimations of cerebral perfusion. Advanced analytical models can be used to remove the contribution of extracerebral hemodynamics; however, these models are highly sensitive to measurement noise. There is a need for an empirical determination of the optimal source-detector separation(s) (SDS) that improves the accuracy and reduces sensitivity to noise in the estimation of cerebral blood flow with these models. Aim: To determine the influence of SDS on solution uniqueness, measurement accuracy, and sensitivity to inaccuracies in model parameters when using the three-layer model to estimate cerebral blood flow with DCS. Approach: We performed a series of in silico simulations on samples spanning a wide range of physiologically-relevant layer optical properties, thicknesses, and flow. Data were simulated at SDS ranging from 0.5 to 3.0 cm using the three-layer solution to the correlation diffusion equation (with and without noise added) and using three-layer slab Monte Carlo simulations. We quantified the influence of SDS on uniqueness, accuracy, and sensitivity to inaccuracies in model parameters using the three-layer inverse model. Results: Two SDS are required to ensure a unique solution of cerebral blood flow index (CBFi). Combinations of 0.5/1.0/1.5 and 2.5 cm provide the optimal choice for balancing the depth penetration with signal-to-noise ratio to minimize the error in CBFi across a wide range of samples with varying optical properties, thicknesses, and dynamics. Conclusions: These results suggest that the choice of SDS is critical for minimizing the estimated error of cerebral blood flow when using the three-layer model to analyze DCS data.