How does obstructive sleep apnea alter cerebral hemodynamics?

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.

Influence of chain length and branching on poly(ADP-ribose)-protein interactions.

Hundreds of proteins interact with poly(ADP-ribose) (PAR) via multiple PAR interaction motifs, thereby regulating their physico-chemical properties, sub-cellular localizations, enzymatic activities, or protein stability. Here, we present a targeted approach based on fluorescence correlation spectroscopy (FCS) to characterize potential structure-specific interactions of PAR molecules of defined chain length and branching with three prime PAR-binding proteins, the tumor suppressor protein p53, histone H1, and the histone chaperone APLF. Our study reveals complex and structure-specific PAR-protein interactions. Quantitative Kd values were determined and binding affinities for all three proteins were shown to be in the nanomolar range. We report PAR chain length dependent binding of p53 and H1, yet chain length independent binding of APLF. For all three PAR binders, we found a preference for linear over hyperbranched PAR. Importantly, protein- and PAR-structure-specific binding modes were revealed. Thus, while the H1-PAR interaction occurred largely on a bi-molecular 1:1 basis, p53-and potentially also APLF-can form complex multivalent PAR-protein structures. In conclusion, our study gives detailed and quantitative insight into PAR-protein interactions in a solution-based setting at near physiological buffer conditions. The results support the notion of protein and PAR-structure-specific binding modes that have evolved to fit the purpose of the respective biochemical functions and biological contexts.

Blood flow response to orthostatic challenge identifies signatures of the failure of static cerebral autoregulation in patients with cerebrovascular disease.

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.

Early microvascular cerebral blood flow response to head-of-bed elevation is related to outcome in acute ischemic stroke.

BACKGROUND AND AIMS: 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. METHODS: Patients with a non-lacunar AIS in the anterior circulation were monitored by DCS to measure relative CBF (ΔrCBF) on the frontal lobes bilaterally during a 0°-30° HOB elevation at early (≤ 12) or late (> 12) hours from symptom onset. National Institutes of Health Stroke Scale (NIHSS) scores were recorded at baseline at 24 and at 48 h. Functional outcome was measured by the modified Rankin Scale (mRS) at 3 months. RESULTS: Thirty-eight (n = 38) AIS patients [baseline NIHSS = 19 (interquartile range: 16, 21)] were studied. ΔrCBF decreased similarly in both hemispheres (p = 0.4) when HOB was elevated and was not associated with baseline and follow-up NIHSS scores or patient demographics. At the early phase (n = 17), a lower or paradoxical ΔrCBF response to HOB elevation was associated with an unfavorable functional outcome (mRS > 2) in the ipsilesional (but not in the contralesional) hemisphere (p = 0.010). ΔrCBF response in the late acute phase was not related to mRS. CONCLUSIONS: Early CBF response to mild HOB elevation in the ipsilesional hemisphere is related to functional outcome. Further studies may enable optical monitoring at the bedside to individualize management strategies in the early phase of AIS.

Cerebral vasoreactivity in response to a head-of-bed position change is altered in patients with moderate and severe obstructive sleep apnea.

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.

Transcranial diffuse optical assessment of the microvascular reperfusion after thrombolysis for acute ischemic stroke.

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.

Characterization of the microvascular cerebral blood flow response to obstructive apneic events during night sleep.

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.

Longitudinal, transcranial measurement of functional activation in the rat brain by diffuse correlation spectroscopy.

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.

Stimulated Raman scattering microscopy by Nyquist modulation of a two-branch ultrafast fiber source.

A highly stable setup for stimulated Raman scattering (SRS) microscopy is presented. It is based on a two-branch femtosecond Er:fiber laser operating at a 40 MHz repetition rate. One of the outputs is directly modulated at the Nyquist frequency with an integrated electro-optic modulator (EOM). This compact source combines a jitter-free pulse synchronization with a broad tunability and allows for shot-noise limited SRS detection. The performance of the SRS microscope is illustrated with measurements on samples from material science and cell biology.

Transcranial diffuse optical monitoring of microvascular cerebral hemodynamics after thrombolysis in ischemic stroke.

The ultimate goal of therapeutic strategies for ischemic stroke is to reestablish the blood flow to the ischemic region of the brain. However, currently, the local cerebral hemodynamics (microvascular) is almost entirely inaccessible for stroke clinicians at the patient bed-side, and the recanalization of the major cerebral arteries (macrovascular) is the only available measure to evaluate the therapy, which does not always reflect the local conditions. Here we report the case of an ischemic stroke patient whose microvascular cerebral blood flow and oxygenation were monitored by a compact hybrid diffuse optical monitor during thrombolytic therapy. This monitor combined diffuse correlation spectroscopy and near-infrared spectroscopy. The reperfusion assessed by hybrid diffuse optics temporally correlated with the recanalization of the middle cerebral artery (assessed by transcranial-Doppler) and was in agreement with the patient outcome. This study suggests that upon further investigation, diffuse optics might have a potential for bed-side acute stroke monitoring and therapy guidance by providing hemodynamics information at the microvascular level.

Microvascular versus macrovascular cerebral vasomotor reactivity in patients with severe internal carotid artery stenosis or occlusion.

RATIONALE AND OBJECTIVES: In patients with severe internal carotid artery steno-occlusive lesions (ISOL), impaired cerebrovascular reactivity (CVR) is predictive of future ischemic stroke (IS) or transient ischemic attack (TIA). Therefore, the evaluation of CVR in ISOL patients may be a means to evaluate the risk for IS/TIA and decide on an intervention. Our aim was (1) to explore the feasibility of concurrent near-infrared spectroscopy (NIRS-DOS), diffuse correlation spectroscopy, and transcranial Doppler for CVR assessment in ISOL patients, and (2) to compare macrovascular and microvascular CVR in ISOL patients and explore its potential for IS/TIA risk stratification. MATERIALS AND METHODS: Twenty-seven ISOL patients were recruited. The changes in continuous microvascular and macrovascular hemodynamics upon acetazolamide injection were used to determine CVR. RESULTS: Oxyhemoglobin (HbO2, by near-infrared spectroscopy), microvascular cerebral blood flow (CBF, by diffuse correlation spectroscopy) and CBF velocity (by transcranial Doppler) showed significant increases upon acetazolamide injection in all subjects (P < .03). Only macrovascular CVR (P = .024) and none of the microvascular measures were significantly dependent on the presence of ISOL. In addition, while CBF was significantly correlated with HbO2, neither of these microvascular measures correlated with macrovascular CBF velocity. CONCLUSIONS: We demonstrated the simultaneous, continuous, and noninvasive evaluation of CVR at both the microvasculature and macrovasculature. We found that macrovascular CVR response depends on the presence of ISOL, whereas the microvascular CVR did not significantly depend on the ISOL presence, possibly due to the role of collaterals other than those of the circle of Willis. The concurrent microvascular and macrovascular CVR measurement in the ISOL patients might improve future IS/TIA risk assessment.

Pulsatile and steady-state hemodynamics of the human patella bone by diffuse optical spectroscopy.

The cardiac cycle related pulsatile behavior of the absorption and scattering coefficients of diffuse light and the corresponding alterations in hemoglobin concentrations in the human patella was studied. The pulsations in scattering is considerably smaller than absorption. The difference in amplitude of absorption coefficient pulsations for different wavelengths was translated to pulsations in oxygenated and deoxygenated hemoglobin, which leads to strong pulsations in the total hemoglobin concentration and oxygen saturation. The physiological origin of the observed signals was confirmed by applying a thigh-cuff. Moreover, we have investigated the optical and physiological properties of the patella bone and their changes in response to arterial cuff occlusion.

Effects of acetazolamide on the micro- and macro-vascular cerebral hemodynamics: a diffuse optical and transcranial doppler ultrasound study.

Acetazolamide (ACZ) was used to stimulate the cerebral vasculature on ten healthy volunteers to assess the cerebral vasomotor reactivity (CVR). We have combined near infrared spectroscopy (NIRS), diffuse correlation spectroscopy (DCS) and transcranial Doppler (TCD) technologies to non-invasively assess CVR in real-time by measuring oxy- and deoxy-hemoglobin concentrations, using NIRS, local cerebral blood flow (CBF), using DCS, and blood flow velocity (CBFV) in the middle cerebral artery, using TCD. Robust and persistent increases in oxy-hemoglobin concentration, CBF and CBFV were observed. A significant agreement was found between macro-vascular (TCD) and micro-vascular (DCS) hemodynamics, between the NIRS and TCD data, and also within NIRS and DCS results. The relative cerebral metabolic rate of oxygen, rCMRO(2), was also determined, and no significant change was observed. Our results showed that the combined diffuse optics-ultrasound technique is viable to follow (CVR) and rCMRO(2) changes in adults, continuously, at the bed-side and in real time.