Study Objectives We aimed to characterize the cerebral hemodynamic response to obstructive sleep apnea/hypopnea events, and evaluate their association to polysomnographic parameters. The characterization of the cerebral hemodynamics in obstructive sleep apnea (OSA) may add complementary information to further the understanding of the severity of the syndrome beyond the conventional polysomnography. Methods Severe OSA patients were studied during night sleep while monitored by polysomnography. Transcranial, bed-side diffuse correlation spectroscopy (DCS) and frequency-domain near-infrared diffuse correlation spectroscopy (NIRS-DOS) were used to follow microvascular cerebral hemodynamics in the frontal lobes of the cerebral cortex. Changes in cerebral blood flow (CBF), total hemoglobin concentration (THC), and cerebral blood oxygen saturation (StO2) were analyzed. Results We considered 3283 obstructive apnea/hypopnea events from sixteen OSA patients (Age (median, interquartile range) 57 (52-64.5); females 25%; AHI (apnea-hypopnea index) 84.4 (76.1-93.7)). A biphasic response (maximum/minimum followed by a minimum/maximum) was observed for each cerebral hemodynamic variable (CBF, THC, StO2), heart rate and peripheral arterial oxygen saturation (SpO2). Changes of the StO2 followed the dynamics of the SpO2, and were out of phase from the THC and CBF. Longer events were associated with larger CBF changes, faster responses and slower recoveries. Moreover, the extrema of the response to obstructive hypopneas were lower compared to apneas (p < .001). Conclusions Obstructive apneas/hypopneas cause profound, periodic changes in cerebral hemodynamics, including periods of hyper- and hypo-perfusion and intermittent cerebral hypoxia. The duration of the events is a strong determinant of the cerebral hemodynamic response, which is more pronounced in apnea than hypopnea events.

Abstract Background The cortical microvascular cerebral blood flow response (CBF) to different changes in head-of-bed (HOB) position has been shown to be altered in acute ischemic stroke (AIS) by diffuse correlation spectroscopy (DCS) technique. However, the relationship between these relative ΔCBF changes and associated systemic blood pressure changes has not been studied, even though blood pressure is a major driver of cerebral blood flow. Methods Transcranial DCS data from four studies measuring bilateral frontal microvascular cerebral blood flow in healthy controls (n = 15), patients with asymptomatic severe internal carotid artery stenosis (ICA, n = 27), and patients with acute ischemic stroke (AIS, n = 72) were aggregated. DCS-measured CBF was measured in response to a short head-of-bed (HOB) position manipulation protocol (supine/elevated/supine, 5 min at each position). In a sub-group (AIS, n = 26; ICA, n = 14; control, n = 15), mean arterial pressure (MAP) was measured dynamically during the protocol. Results After elevated positioning, DCS CBF returned to baseline supine values in controls (p = 0.890) but not in patients with AIS (9.6% [6.0,13.3], mean 95% CI, p < 0.001) or ICA stenosis (8.6% [3.1,14.0], p = 0.003)). MAP in AIS patients did not return to baseline values (2.6 mmHg [0.5, 4.7], p = 0.018), but in ICA stenosis patients and controls did. Instead ipsilesional but not contralesional CBF was correlated with MAP (AIS 6.0%/mmHg [− 2.4,14.3], p = 0.038; ICA stenosis 11.0%/mmHg [2.4,19.5], p < 0.001). Conclusions The observed associations between ipsilateral CBF and MAP suggest that short HOB position changes may elicit deficits in cerebral autoregulation in cerebrovascular disorders. Additional research is required to further characterize this phenomenon.

27 Obstructive apnea causes periodic changes in cerebral and systemic hemodynamics, which 28 may contribute to the increased risk of cerebrovascular disease of patients with obstructive 29 sleep apnea (OSA) syndrome. The improved understanding of the consequences of an apneic 30 event on the brain perfusion may improve our knowledge of these consequences and then 31 allow for the development of preventive strategies. Our aim was to characterize the typical 32 microvascular, cortical cerebral blood flow (CBF) changes in an OSA population during an 33 apneic event. 34 Sixteen patients (age 58 ± 8 years, 75% male) with a high risk of severe OSA were 35 measured with a polysomnography device and with di use correlation spectroscopy (DCS) 36 during one night of sleep with 1365 obstructive apneic events detected. All patients were 37 later confirmed to su er from severe OSA syndrome with a mean of 83 ± 15 apneas and 38 hypopneas per hour. 39 DCS has been shown to be able to characterize the microvascular CBF ::::::::: response ::: to ::::: each 40 ::::: event :::::: with :: a :::::::::: su cient :::::::::::::::::: contrast-to-noise :::::: ratio ::: to ::::::: reveal :::: its ::::::::::: dynamics. :: It has also revealed 41 that an apnea causes a peak increase of microvascular CBF (30 ± 17 %) at the end of the 42 event followed by a drop (-20 ± 12 %) similar to what was observed in macrovascular CBF 43 velocity of the middle cerebral artery. This study paves the way for the utilization of DCS 44 for further studies on these populations. 45

Previously, microvascular cerebral blood flow (CBF) response to a mild head-of-bed (HOB) elevation has been shown to be altered in acute ischemic stroke (AIS) by diffuse correlation spectroscopy (DCS). We have hypothesized that early CBF response is related to the functional outcome.

In this pilot study, we have evaluated bedside diffuse optical monitoring combining diffuse correlation spectroscopy and near-infrared diffuse optical spectroscopy to assess the effect of thrombolysis with an intravenous recombinant tissue plasminogen activator (rtPA) on cerebral hemodynamics in an acute ischemic stroke. Frontal lobes of five patients with an acute middle cerebral artery occlusion were measured bilaterally during rtPA treatment. Both ipsilesional and contralesional hemispheres showed significant increases in cerebral blood flow, total hemoglobin concentration and oxy-hemoglobin concentration during the first 2.5 hours after rtPA bolus. The increases were faster and higher in the ipsilesional hemisphere. The results show that bedside optical monitoring can detect the effect of reperfusion therapy for ischemic stroke in real-time.

Motivation Obstructive sleep apnea (OSA) can impair cerebral vasoreactivity and is associated with an increased risk of cerebrovascular disease. Unfortunately, an easy-to-use, non-invasive, portable monitor of cerebral vasoreactivity does not exist. Therefore, we have evaluated the use of near-infrared diffuse correlation spectroscopy to measure the microvascular cerebral blood flow (CBF) response to a mild head-of-bed position change as a biomarker for the evaluation of cerebral vasoreactivity alteration due to chronic OSA. Furthermore, we have monitored the effect of two years of continuous positive airway pressure (CPAP) treatment on the cerebral vasoreactivity. Methodology CBF was measured at different head-of-bed position changes (supine to 30° to supine) in sixty-eight patients with OSA grouped according to severity (forty moderate to severe, twenty-eight mild) and in fourteen control subjects without OSA. A subgroup (n = 13) with severe OSA was measured again after two years of CPAP treatment. Results All patients and controls showed a similar CBF response after changing position from supine to 30° (p = 0.819), with a median (confidence interval) change of -17.5 (-10.3, -22.9)%. However, when being tilted back to the supine position, while the control group (p = 0.091) and the mild patients with OSA (p = 0.227) recovered to the initial baseline, patients with moderate and severe OSA did not recover to the baseline (9.8 (0.8, 12.9)%, p < 0.001) suggesting altered cerebral vasoreactivity. This alteration was correlated with OSA severity defined by the apnea-hypopnea index, and with mean nocturnal arterial oxygen saturation. The CBF response was normalized after two years of CPAP treatment upon follow-up measurements. Conclusion In conclusion, microvascular CBF response to a head-of-bed challenge measured by diffuse correlation spectroscopy suggests that moderate and severe patients with OSA have altered cerebral vasoreactivity related to OSA severity. This may normalize after two years of CPAP treatment.

Obstructive apnea causes periodic changes in cerebral and systemic hemodynamics, which may contribute to the increased risk of cerebrovascular disease of patients with obstructive sleep apnea (OSA) syndrome. The improved understanding of the consequences of an apneic event on the brain perfusion may improve our knowledge of these consequences and then allow for the development of preventive strategies. Our aim was to characterize the typical microvascular, cortical cerebral blood flow (CBF) changes in an OSA population during an apneic event. Sixteen patients (age 58 +/- 8 years, 75% male) with a high risk of severe OSA were measured with a polysomnography device and with diffuse correlation spectroscopy (DCS) during one night of sleep with 1365 obstructive apneic events detected. All patients were later confirmed to suffer from severe OSA syndrome with a mean of 83 +/- 15 apneas and hypopneas per hour. DCS has been shown to be able to characterize the microvascular CBF response to each event with a sufficient contrast-to-noise ratio to reveal its dynamics. It has also revealed that an apnea causes a peak increase of microvascular CBF (30 +/- 17%) at the end of the event followed by a drop (-20 +/- 12%) similar to what was observed in macrovascular CBF velocity of the middle cerebral artery. This study paves the way for the utilization of DCS for further studies on these populations. (c) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.

Neural activity is an important biomarker for the presence of neurodegenerative diseases, cerebrovascular alterations, and brain trauma; furthermore, it is a surrogate marker for treatment effects. These pathologies may occur and evolve in a long time-period, thus, noninvasive, transcutaneous techniques are necessary to allow a longitudinal follow-up. In the present work, we have customized noninvasive, transcutaneous, diffuse correlation spectroscopy (DCS) to localize changes in cerebral blood flow (CBF) induced by neural activity. We were able to detect changes in CBF in the somatosensory cortex by using a model of electrical forepaw stimulation in rats. The suitability of DCS measurements for longitudinal monitoring was demonstrated by performing multiple sessions with the same animals at different ages (from 6 to 18 months). In addition, functional DCS has been cross-validated by comparison with functional magnetic resonance imaging (fMRI) in the same animals in a subset of the time-points. The overall results obtained with transcutaneous DCS demonstrates that it can be utilized in longitudinal studies safely and reproducibly to locate changes in CBF induced by neural activity in the small animal brain.

Introduction: The microvascular cerebral blood flow response (rCBF) to orthostatic stress has been shown to be altered in acute ischemic stroke (AIS) by diffuse correlation spectroscopy (DCS). However, its relevance to the outcome is unknown. Hypothesis: CBF response to head-of-the-bed (HOB) elevation within the first hours after AIS is related to outcome. Methods: Patients with a large anterior circulation stroke of less than 48h from the stroke onset were monitored with DCS to follow rCBF in the frontal lobes during a HOB elevation from supine to 30°. All patients were placed flat during the first 24 hours and later, mobilization was initiated depending on the clinical condition. We categorized measurements as early (<12h) or late (>12h) from stroke onset. NIHSS was recorded at baseline, during HOB, at 24h and 48h. The modified Rankin scale (mRS) score was utilized as the outcome measure (favorable when 0-2). Results: We studied 34 patients (age 78±13y, male 47%, median NIHSS 19 (14-21)) at 16±11 hours from stroke. Ipsilateral extracranial and/or intracranial occlusion was present in 61%. Frontal CBF decreased in both hemispheres after HOB (-5±14%). A paradoxical response (increase/no change) was observed in 18%. rCBF was not correlated to NIHSS and age. Unfavorable outcome was found in 85%. Only at early hours (<12h, n=16), rCBF to HOB elevation in the ipsilateral (not in contralateral) hemisphere (p=0.04, Figure 1) and NIHSS HOB (p=0.008) were associated with poor outcome. Conclusions: This result suggests that paradoxical CBF response to a mild HOB elevation in the early hours of stroke onset is associated with a poor outcome in patients with AIS. Optical continuous monitoring in the bedside may help to individualize management strategies in the early hours of AIS. Figure 1: rCBF due to HOB elevation versus mRS for the ipsi-lateral side in patients measured <12h after stroke.

Obstructive sleep apnea (OSA) impairs cerebral vasoreactivity (CVR). CVR was evaluated in severe OSA patients and a control group before and after two years of continuous positive air pressure treatment demonstrating improvements in vasoreactivity.

Background: In OSA patients the impairment of cerebrovascular reactivity (CVR) likely contributes to the increased incidence of stroke. The technique "Diffuse Correlation Spectroscopy" (DCS) allows non-invasive, continuous measurements of the microvascular cerebral 1,2, blood flow to evaluate CVR. Objective: The aim of the study was to evaluate the effect of orthostatic stress in relative cerebral blood flow (rCBF) measured by DCS in OSA patients. Method: We utilized a modified version of a protocol involving orthostatic stress induced by head-of-bed positioning, used in acute ischemic stroke patients 2 and a cohort of healthy subjects 1 . Cerebral hemodynamics were monitored by DCS for 5 min at the following postures: head-of-bed angle 0º to 30º to 0º to 20º to −8º to 0º. Results: 57 OSA patients were included: mean age: 55 (10) years; mean body mass index (BMI): 31 (6) kg/m 2 . The mean AHI was 39 (33) and the mean nighttime SpO 2 : 93(2,5) %. At 0º to 30º, mild OSA patients showed a similar rCBF response , -18 (9,5)%, as previous data published in healthy subjects 1 .Severe OSA presented lower but not significant rCBF (%) change, -15(10,8)%. There was a significant correlation between rCBF (%) change at 0º to 30ºwith mean SpO 2 % (r: 0,29; p=0,03) and with BMI (r:- 0,3; p=0,025). Conclusions: These preliminary results suggest an impairment cerebral vascular reactivity in severe OSA patients related with obesity and oxygen saturation. Diffuse optical techniques may allow noninvasive assessment of the involvement of the cerebral microvasculature. 1) B. L. Edlow et al, Physiological Meas 2010. 2) T. Durduran et al, Optics Express 2009. This work was funded by SOCAP ( 2011) and SEPAR (2012).

Changes in cerebral blood flow in response to orthostatic stress in obstructive sleep apnea patients were measured using diffuse correlation spectroscopy. Clinical indices derived from arterial oxygen saturation alter the cerebrovascular response.

Diffuse correlation spectroscopy is used to monitor cerebral blood flow changes at the hyper-acute phase of ischemic stroke (1) detecting local hemodynamic changes due to recanalization and (2) in cerebrovascular response to orthostatic challenges.

Comunicacion presentada en la European Conferences on Biomedical Optics (ECBO), celebrada del 12 al 16 de mayo de 2013 en Munchen (Alemania)