Microvascular cerebral blood flow fluctuations in association with apneas and hypopneas in acute ischemic stroke Clara Gregori-Pla Raquel Delgado-Mederos Gianluca Cotta Giacomo Giacalone Federica Maruccia Stella Avtzi Luís Prats-Sánchez Alejandro Martínez-Domeño Pol Camps-Renom Joan Martí-Fàbregas Turgut Durduran Mercedes Mayos Clara Gregori-Pla, Raquel Delgado-Mederos, Gianluca Cotta, Giacomo Giacalone, Federica Maruccia, Stella Avtzi, Luís Prats-Sánchez, Alejandro Martínez-Domeño, Pol Camps-Renom, Joan Martí-Fàbregas, Turgut Durduran, Mercedes Mayos, “Microvascular cerebral blood flow fluctuations in association with apneas and hypopneas in acute ischemic stroke,” Neurophoton. 6(2), 025004 (2019), doi: 10.1117/1.NPh.6.2.025004. Neurophotonics 6(2), 025004 (Apr–Jun 2019) Microvascular cerebral blood flow fluctuations in association with apneas and hypopneas in acute ischemic stroke Clara Gregori-Pla,a,* Raquel Delgado-Mederos,b Gianluca Cotta,a Giacomo Giacalone,a,c Federica Maruccia,a,d Stella Avtzi,a Luís Prats-Sánchez,b Alejandro Martínez-Domeño,b Pol Camps-Renom,b Joan Martí-Fàbregas,b Turgut Durduran,a,e and Mercedes Mayosf,g a ICFO-Institut de Ciències Fotòniques, The Barcelona Institute of Science and Technology, Castelldefels (Barcelona), Spain b Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Department of Neurology (Stroke Unit), Barcelona, Spain c San Raffaele Scientific Institute, Milan, Italy d Universitat Autònoma de Barcelona, Neurotraumatology and Neurosurgery Research Unit, Vall d’Hebron University Research Institute, Barcelona, Spain e Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain f Hospital de la Santa Creu i Sant Pau, Sleep Unit, Department of Respiratory Medicine, Barcelona, Spain g CIBER Enfermedades Respiratorias (CB06/06), Madrid, Spain Abstract. In a pilot study on acute ischemic stroke (AIS) patients, unexpected periodic fluctuations in micro- vascular cerebral blood flow (CBF) had been observed. Motivated by the relative lack of information about the impact of the emergence of breathing disorders in association with stroke on cerebral hemodynamics, we hypothesized that these fluctuations are due to apneic and hypopneic events. A total of 28 patients were screened within the first week after stroke with a pulse oximeter. Five (18%) showed fluctuations of arterial blood oxygen saturation (≥3%) and were included in the study. Near-infrared diffuse correlation spectroscopy (DCS) was utilized bilaterally to measure the frontal lobe CBF alongside respiratory polygraphy. Biphasic CBF fluctuations were observed with a bilateral increase of 27.1%  17.7% and 29.0%  17.4% for the ipsilesional and contralesional hemispheres, respectively, and a decrease of −19.3%  9.1% and −21.0%  8.9% for the ipsilesional and contralesional hemispheres, respectively. The polygraph revealed that, in general, the fluctua- tions were associated with apneic and hypopneic events. This study motivates us to investigate whether the impact of altered respiratory patterns on cerebral hemodynamics can be detrimental in AIS patients. © The Authors. Published by SPIE under a Creative Commons Attribution 4.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI. [DOI: 10.1117/1.NPh.6.2.025004] Keywords: diffuse optics; diffuse correlation spectroscopy; stroke; sleep disorders. Paper 18058RR received Oct. 5, 2018; accepted for publication Apr. 4, 2019; published online Apr. 23, 2019. 1 Introduction brain)17 but also the possible, variable amount of detrimental Most interventions during the early hours after ischemic stroke impact of these events on the cerebral hemodynamics. Thus, onset aim to maximize and stabilize cerebral blood perfusion to the diagnosis, the quantification of these respiratory events, diminish the neurological damage and improve the long-term and the characterization of their effect on the cerebral hemo- outcome.1 Furthermore, these patients could be at risk of pos- dynamics may be relevant for the management of the ischemic sible detrimental cerebral blood flow (CBF) fluctuations in the stroke patients. case, for instance, of undiagnosed breathing disorders (BDs). The dynamics of local, microvascular CBF are particularly Disordered breathing includes a range of respiratory disorders,2 interesting as, hypothetically, they could reveal that large, often during sleep, characterized by repetitive reduction (hypo- repeated changes in the cerebral perfusion could be detrimental pneas) or cessation (apneas) of airflow. when cerebral autoregulation is damaged in the acute stages of Different types of BDs with different physiological origins stroke.18 This is relevant during these acute stages as ischemia in have been reported in association with stroke in 10% to 70% the brain is a potentially reversible process dependent on the of the patients.3–12 However, it is not yet clear if the presence restoration of the microvascular CBF in the penumbra within of a BD is associated with the long-term outcome. Although a time window of cellular viability that varies on duration some works support the idea that BDs are associated with and severity of CBF cessation.19 However, if cerebral autoregu- poor recovery from stroke,10,13–16 one study has reported that lation is damaged, CBF can abruptly increase or decrease with- BDs in stroke patients are associated with early neurological out following the needs of the brain and without restoring the worsening but not with long-term outcome at 6 months.4 The needed CBF in the penumbra. If so, BD treatment could be used reason for the divergence of the results of these studies could to avoid these unwanted changes. However, there are no estab- be not only the physiological origin of BDs (upper airway lished methods to monitor microvascular CBF at the bedside. obstruction, heart failure, disease, or injury involving the In non-stroke subjects, cerebral hemodynamic fluctuations due to apneas or hypopneas have been extensively studied and characterized previously by several groups by measuring *Address all correspondence to Clara Gregori-Pla, E-mail: clara.gregori@ the cerebral blood flow velocity (CBFV) in the middle cerebral alumni.icfo.eu artery by transcranial Doppler ultrasound (TCD).20–24 However, Neurophotonics 025004-1 Apr–Jun 2019 • Vol. 6(2) Gregori-Pla et al.: Microvascular cerebral blood flow fluctuations in association. . . macrovascular CBFV is only an indirect measurement of what of 4 h between 8 am and 2 pm. Afterward, if the pulse oximeter happens in the distal microcirculation. showed periodic decreases of ≥3% in SpO2 , the patients were Fluctuations of cerebral hemodynamics have previously been measured in the afternoon with DCS and also with a respiratory observed in acute stroke patients. A study of nine patients with polygraphy device simultaneously for 1 h in the most comfort- acute stroke25 reported arterial desaturations from unknown ori- able head-of-bed position for the patients. gin that correlated with cerebral hemodynamics measured with near-infrared diffuse optical spectroscopy (NIRS-DOS), and 2.1 Neurological Evaluation showed an asymmetry of the changes in the two cerebral hemi- spheres. Pizza et al.26 observed in seven patients with acute/sub- Baseline examinations included the collection of a summary of acute middle cerebral artery stroke that obstructive and central the medical history from patient records (demographics and vas- apneas were linked to cerebral oxygenation changes by NIRS- cular risk factors) and a clinical examination. The stroke severity DOS. Asymmetrical patterns of cerebral hemodynamic changes was assessed with the National Institutes of Health Stroke Scale were again found with significantly larger changes on the unaf- (NIHSS)32 on admission and right after the measurement. fected hemisphere compared to the affected one. However, Indirect ischemic signs were evaluated by the Alberta Stroke neither NIRS-DOS nor TCD provide a direct measure of micro- Program Early Computed Tomography Score (ASPECTS).33 vascular CBF. Long-term outcome was evaluated at 3 months by means of In this pilot study, we have utilized diffuse correlation spec- the modified Rankin Scale (mRS)34 where a score of >2 was troscopy (DCS), which uses the speckle statistics of near-infra- considered indicative of an unfavorable outcome. red diffuse light to noninvasively monitor local, microvascular The extent and location of the ischemic area along with the CBF.27–29 DCS does not need any exogenous tracers and has site of arterial occlusion were evaluated on admission by a cranial been validated against different modalities.29,30 In previous stud- computed tomography scan and vascular imaging either by ies,31 we have observed unexpected fluctuations of microvascu- angio-computed tomography or by TCD. If patients were eligible, lar CBF, heart rate (HR), arterial oxygen saturation (SpO2 ), and reperfusion therapy (thrombolysis or thrombectomy) was end-tidal carbon dioxide in three (18%) of the seventeen acute applied.35 Recanalization (either by spontaneous or by revascula- ischemic stroke (AIS) patients during the first week from stroke rization treatment) was assessed with TCD within 24 to 48 h. onset, which has motivated the design of this study to investigate The neurological scales were scored by a neurologist or the origin of these fluctuations. Here, we have aimed to test the a senior neurology resident blinded to the optical information. hypothesis that these cerebral and systemic fluctuations were associated with apneic and hypopneic events after stroke. 2.2 Optical Methods and Instrumentation We have used a custom-built DCS,27 which was previously 2 Methods described in other protocols within the same collaboration.36–39 This study was conducted at the Stroke Unit of Hospital de la Two optical probes were placed on the forehead bilaterally on Santa Creu i Sant Pau, in Barcelona, Spain, from August 2016 both hemispheres as lateral as possible, avoiding the sinuses. to March 2017. The study protocol was approved by the local These probes consisted of a bundle of four detector fiber set at ethical committee (EC/15/130). Either the patients or their rel- 2.5 cm from a source fiber. We have measured the blood flow atives gave their informed written consent. index (BFI) continuously with a 2.5-s temporal resolution. The The inclusion criteria were being older than 18 years, con- relative CBF changes were obtained by normalizing the calcu- firmed ischemic stroke in the anterior circulation, measurement lated continuous BFI with the mean BFI of the first 5 min (base- time ≤7 days from the stroke onset and written informed con- line) of the measurement. Also, the CBF changes per event were sent. The exclusion criteria were resting HR <40 or >110 beats calculated, as explained in Sec. 2.3. per minute (bmp), SpO2 <92%, use of oxygen therapy, sympto- matic lacunar stroke, previous diagnosis of BDs, previous tran- 2.2.1 Pulse oximetry and respiratory polygraphy sient ischemic attack, minor stroke, or intracranial hemorrhage. The study included two different parts (see Fig. 1, for a flow A standard pulse oximeter (CMS-50D Plus, CONTEC Medical chart of the procedure). First, patients who fit the clinical inclu- Systems CO, Qinhuangdao, China) was used for the screening sion criteria were screened with a pulse oximeter for a minimum of the stroke patients. If these patients were eligible, then they Fig. 1 Methodology of the two parts of the study. The subjects included in each part are depicted in gray. SpO2 , arterial oxygen saturation. Neurophotonics 025004-2 Apr–Jun 2019 • Vol. 6(2) Gregori-Pla et al.: Microvascular cerebral blood flow fluctuations in association. . . were enrolled for the full study which, in addition to DCS, Averages and standard deviations have been performed con- included a respiratory polygraphy monitoring (Embletta MPR sidering all apneic and hypopneic events for each patient and PG, Natus Medical, Middleton, Wisconsin). also for the population. The Wilcoxon signed-rank test was The respiratory polygraphy included the recording of the used to assess the difference between ipsilesional and contrale- oronasal flow (by a thermistor and a nasal cannula), the thoracic sional ΔrCBF responses. The same test was used to assess if the and the abdominal movements (by a respiratory inductance apneic/hypopneic response of different variables was signifi- plethysmography band), the SpO2 and the HR (both by pulse cantly different from zero. All analyses were performed with oximetry), among others. The respiratory polygraphy data MATLAB (Mathworks, Natick, Massachusetts). A p-value were further postprocessed by a pulmonologist to determine <0.05 was considered to be statistically significant. the following variables: the start and end time points of each event, the event type (obstructive apnea, hypopnea, mixed apnea, or central apnea), the 3% oxygen desaturation index 3 Results (ODI3), and the number of apneic and hypopneic events per During the 8-month period, we have screened 28 ischemic hour of study (AHI).40 stroke patients with pulse oximetry, of whom 5 (n ¼ 5, 18%) presented fluctuations (≥3%) in SpO2 and were then included 2.3 Statistical Analysis in the second part of the study. Table 1 shows the clinical char- acteristics of these five patients. Four were male, had an age of To calculate the percentage of CBF change (ΔrCBF) due to each 81  6 years (mean  standard deviation), an admission apneic or hypopneic event, we have estimated a basal BFI NIHSS of 8 (2, 16) [median (first quartile, third quartile)], (BFIbl ) as the average of the cerebral BFI from 30 s before and a time from stroke onset to measurement of 4 (3, 5) days. the apnea/hypopnea start up to 30 s after the event end. This Table 2 shows the results of the DCS and the respiratory was considered to correct for slight changes in the probe posi- polygraphy measurements. In all five patients, the respiratory tion during the measurement. Afterward, the CBF changes were polygraphy confirmed the presence of altered breathing pat- calculated as ΔrCBF ¼ ðBFI BFI bl − 1Þ × 100. Similarly, ΔHR was terns; two presented periodic breathing [cases 1 and 3; clusters defined as ΔHR ¼ HR − HRbl and ΔSpO2 was defined as of breaths separated by intervals of apnea (no breathing) or ΔSpO2 ¼ SpO2 − SpO2bl . In all cases, the subscriptbl indicates hypopnea], two presented a predominance of obstructive and an average over the same period. hypopneic events (cases 2 and 4; the airflow ceased or partially Afterward, the events were parametrized for the characteri- ceased due to upper airway obstruction), and one presented cen- zation of the induced ΔrCBF, ΔHR, or ΔSpO2 for each event. tral apneas (case 5; the airflow ceased or partially ceased due to The goal was to study if individual apneic or hypopneic events diminished or absent effort to breath). were associated with significant increases or decreases in these Figure 3 shows a representative trace (from case 4) of 10 min variables as it was hypothesized. This step consisted in consid- of continuous oronasal flow, abdominal and thoracic move- ering each event as a function dependent on time [ΔrCBFðtÞ, ments, HR, SpO2 , and CBF changes. This specific interval ΔHRðtÞ, and ΔSpO2 ðtÞ], and then, the extrema of these func- shows two types of events with good signal-to-noise ratio in tions along a specific time interval were calculated. The refer- the optical data and a “close-up” revealing details. Both apneic ence time (time zero) was considered as the end of each event. (four obstructive apneas, green shading) and hypopneic (three, The time windows to find these extrema were considered from yellow shading) events are visible and the simultaneous moni- −5 to 15 s for the first extremum on ΔrCBF (see Fig. 2, as an toring shows time correlated variation of microvascular CBF, example), from 0 to 15 s for the ΔHR, and from 5 to 35 s for the HR, and respiratory variables. From the polygraphy recording, ΔSpO2 . These time windows were chosen by visual observation oronasal flow appears to be reduced during the hypopneas and of all the apneas and hypopneas plotted together from −30 to ceases during the obstructive apneas, whereas abdominal and 60 s and according to the literature.20,41 These analysis methods thoracic movements are reduced during these events. HR does have previously been verified in nocturnal measurements of not follow a general pattern for this trace. SpO2 shows a drop chronic obstructive sleep apnea patients.42 with a delay relative to the apneic/hypopneic event. In this time period with frequent events, as commonly observed, the SpO2 drop of the previous event is overlapped with the next event. It can also be observed that the CBF reaches its maximum at the end of an event. Finally, for this specific interval, periodic breathing is diagnosed but the rest of the acquisition is domi- nated by obstructive apneic events, as shown in Table 2. On the contrary, Fig. 4 shows 10 min of similar traces where neither fluctuations nor apnea/hypopnea events are found. This patient (case 3) is the only one with no apneic/hypopneic events during those 10 min. For completeness, the full data set for the five patients can be found in Sec. 5 Appendix. From the five patients, 239 (n ¼ 239) apneic/hypopneic events were analyzed. In all patients, the CBF changes were biphasic. In other words, significant bilateral CBF increases Fig. 2 Cerebral blood flow characterization of individual sleep events, where the apnea end is considered as a pivot point. The light gray of 27.1%  17.7% (p < 0.001) for the ipsilesional and 29.0%  region indicates the sleep event. The dark gray region indicates 17.4% (p < 0.001) for the contralesional hemispheres were fol- the time window used for finding the first extremum value. The first lowed by decreases of −19.3%  9.1% (p < 0.001) for the ipsi- and second extrema are labeled in blue. lesional and −21.0%  8.9% (p < 0.001) for the contralesional Neurophotonics 025004-3 Apr–Jun 2019 • Vol. 6(2) Gregori-Pla et al.: Microvascular cerebral blood flow fluctuations in association. . . Table 1 Demographics and prestroke clinical characteristics (top) and poststroke clinical characteristics (bottom) of the five ischemic stroke patients. Case 1 2 3 4 5 Age (y), gender (M/F) 83, F 73, M 82, M 89, M 76, M Smoking Former Former Former Former Former Arterial hypertension Yes Yes No No No Dyslipidemia Yes Yes No No No Diabetes No No Yes No Yes Ipsilesional ICA stenosis >70% Yes No No — No Coronary disease No No Yes No Yes Atrial fibrillation No No No No No Left ventricular ejection fraction (%) >50 40 to 50 40 — 25 Arterial occlusion Left MCA Left MCA Right ACA Left MCA Right MCA NIHSS admission 7 7 3 20 21 NIHSS after the measurement 2 1 8 16 21 Reperfusion therapy Yes Yes No No No Recanalization Yes No Yes No No Infarct location Insular and frontal Insular and frontal Frontal Insular, temporal, Insular, temporal, and basal ganglia and parietal ASPECTS 8 8 10 6 6 Days from stroke to measurement 7 4 3 5 0 mRS 3 months 2 1 4 6 6 Note: M, male; F, female; ICA, internal carotid artery; MCA, middle cerebral artery; ACA, anterior cerebral artery; NIHSS, National Institutes of Health Stroke Scale; ASPECTS, Alberta Stroke Program Early Computed Tomography Score; and mRS, modified Rankin Scale. hemispheres were found due to each apneic/hypopneic event. obstructive and central apneas found in the two most severe There was no interhemispheric difference between the maxi- patients (cases 4 and 5). We note that, given the small popula- mum increases (p ¼ 0.189) or the maximum decreases tion, these were just anecdotal statements and should not be con- (p ¼ 0.053). However, this result suggested a trend toward a sidered generalizable. potential difference between hemispheres, as it has been previ- ously found by NIRS-DOS,25,26 as mentioned in Sec. 1. Also, as 4 Discussion expected, HR increased (p < 0.001) by 6.5  6.8 bpm and SpO2 In this study, we have followed up on our previous observation decreased (p < 0.001) by −4.9%  16.8%. of unexpected bilateral fluctuations in microvascular CBF in The two patients (cases 4 and 5) with the highest AHI, one patients with anterior, cerebral ischemic stroke that were with predominance of an obstructive apnea pattern and the other observed in different protocols with DCS measurements.31 with predominance of a central apnea pattern, had the two high- We have hypothesized that these fluctuations were due to est NIHSS both on admission and after the measurement and the BDs, in particular, due to apneic and hypopneic events. lowest ASPECTS. Unfortunately, both had a mRS of 6, i.e., they Therefore, a protocol based on prescreening for these events had died during the 3 months after stroke onset. Of these two with a pulse oximeter was introduced to enroll patients without patients, the one with the highest AHI (case 5) also presented the a previous diagnosis of BDs for follow-up study combining res- lowest left ventricular ejection fraction. However, neither of piratory polygraphy and DCS. A careful evaluation was carried these two patients presented the highest physiological or cer- out to identify the origin of these fluctuations and to characterize ebral hemodynamic changes in response to the respiratory their details by combining this recording of different respiratory events. One of the characteristics of the remaining three patients variables, SpO2 , and HR. Apneic and hypopneic events were (cases 1, 2, and 3) with lower stroke severity was that they determined to be associated with the effect of cerebral hemo- presented mainly hypopneic events, in comparison to the dynamics and this effect was characterized. Neurophotonics 025004-4 Apr–Jun 2019 • Vol. 6(2) Gregori-Pla et al.: Microvascular cerebral blood flow fluctuations in association. . . Table 2 Polygraphic characteristics (top) and maximum CBF, HR and SpO2 changes due to each apneic/hypopneic event (bottom) of each patient. Case 1 2 3 4 5 AHI (n∕hour) 45.6 13 24.8 45.8 63.8 ODI3 (%) 46.3 15.7 17.4 48.1 10 Obstructive apneas, n 0 0 1 31 1 Central apneas, n 1 0 2 0 82 Mixed apneas, n 0 0 1 0 0 Hypopneas, n 37 13 20 30 0 Event duration (s) 21  7 24  4 27  8 30  11 19  5 BD Periodic respiration Hypopneas Periodic respiration Obstructive events Central apneas Max. increase-induced ΔrCBFipsi (%) 30.0  12.7 37.4  13.0 22.4  8.9 31.0  10.1 21.9  23.9 Max. increase-induced ΔrCBFcontra (%) 32.9  21.4 27.6  11.0 29.7  15 36.1  11.2 21.7  18.3 Max. decrease-induced ΔrCBFipsi (%) −19.2  7.0 −33.3  12.1 −16.1  8.2 −24.2  6.6 −13.6  5.8 Max. decrease-induced ΔrCBFcontra (%) −17.8  7.4 −25.4  11.1 −19.9  8.1 −28.0  8.1 −16.3  5.3 Max. increase-induced ΔHR (bpm) 2.8  1.6 14.8  8.0 16.0  6.8 10.6  4.3 1.1  0.7 Max. decrease-induced ΔSpO2 (%) −2.2  1.0 −1.6  0.7 −1.5  9.3 −9.9  24.6 −0.9  0.8 Note: AHI, apnea–hypopnea index; ODI3, 3% oxygen desaturation index; ΔrCBF, relative cerebral blood flow changes; ΔHR, HR changes; ΔSpO2 , arterial oxygenation saturation changes; Max., maximum; ipsi., ipsilesional hemisphere; contra., contralesional hemisphere; and n, number of events detected; mean±standard deviation. As observed by the full data set in the Sec. 5 Appendix, the and 29.0%  17.4% for the ipsilesional and contralesional precise nature of the cause of the microvascular CBF changes is hemispheres, respectively, and a decrease of −19.3%  9.1% not absolutely clear from this study, i.e., some CBF fluctuations and −21.0%  8.9% for the ipsilesional and contralesional lead the apnea/hypopnea, whereas others follow it. This may be hemispheres, respectively, close to the end of the apneic/hypo- partially due to errors in the precise synchronization of the mea- pneic events. This increase is similar to the CBF increase of surements but it may also have further implications indicating 30%  17% and the decrease of −20%  12% described previ- secondary events that may have caused respiratory effects, such ously by us using DCS in obstructive sleep apneic events.42 It is as cortical spreading depression43–45 in the brain stem.46,47 also consistent with the CBFVof 22% to 42% increase found by However, our study did not gather definitive evidence (e.g., Alex et al.23 and also to the 14.6%  14% increase right after the recordings at multiple locations to demonstrate any spreading apnea end by Bålfors and Franklin.20 However, other authors activity and/or recordings of the electrical activity) to accept have found larger CBFV increases.21,24 or refute this possibility. These results have encouraged us to These results show that there is a decrease in cerebral perfu- look further and deeper into this issue in future studies by com- sion due to an apneic or hypopneic event. If these intermittent bining multimodal, precisely synchronized diffuse optical decreases lead to ischemia, they can cause hypoxic/ischemic recordings with polygraphy, capnography, and electroencepha- brain injury, especially if cerebrovascular reactivity and regula- lography, and a larger head coverage with multiple source and tion are impaired, which is often the case in ischemic stroke detector pairs. patients.51,52 Consequently, this could lead to a worsened progno- By the polygraphy, HR and SpO2 changes were found during sis, which may call for interventions such as continuous positive these events. These HR and SpO2 changes followed the apneic/ airway pressure (CPAP) therapy. We note that, to date, no direct hypopneic dynamics expected by the literature in patients with link among a degree of microvascular CBF changes, the long- BDs,20,24,41,48,49 showing an increase during the event or at the term outcome, and the use of CPAP therapy has been studied. end of it for the HR, and a decrease after the end of the event for Several works have studied the general effect of CPAP the SpO2 . No periodicity in the respiratory changes was found, therapy, mainly in obstructive disorders or adaptive servo-ven- as shown in the full data set in Sec. 5 Appendix, as the perio- tilation (ASV) treatment for central disorders to avoid apneas dicity depended on the pathogenic mechanism, on the sleep and hypopneas.53–55 In stroke patients, whereas some authors stage, and on the position, among others.50 support the benefits of the CPAP treatment on BDs,15,56–61 others In non-stroke patients with BDs, several studies have claim that these benefits are not clear62,63 or that there is no ben- reported CBFV changes measured by TCD as showing an efit at all.64 Nevertheless, as mentioned earlier, BDs diagnosis increase close to the end of the apnea.20,23,24 Our findings are and CPAP or ASV treatment are not the common practice in the similar; we have observed a CBF increase of 27.1%  17.7% stroke units. Neurophotonics 025004-5 Apr–Jun 2019 • Vol. 6(2) Gregori-Pla et al.: Microvascular cerebral blood flow fluctuations in association. . . Fig. 3 A 10-min trace of systemic fluctuations of physiological variables alongside the fluctuations of CBF. Red and black CBF traces correspond to the ipsilesional and contralesional hemispheres, respec- tively. Hypopneas (yellow) and obstructive apneas (green) are shown from the measurements of an 89- year-old male with a left middle cerebral artery ischemic stroke (case 4). The patient presented a left middle cerebral artery stroke with insular, temporal, and basal ganglia ischemic areas. The NIHSS score was 16 when measured. The patient died after 24 h of the measurement. Future work with a larger sample size to investigate if the Insular and frontal ischemic regions were present in our cohort CPAP or ASV could be effective in those patients who show and, interestingly, these regions have already been associated to the presence and/or large fluctuations in CBF (e.g., above a BDs of central origin.13,65,66 However, other works have sup- threshold) in relation to apneic/hypopneic events is warranted. ported the idea of the lack of an association between the pres- In addition, it would be of interest to study if all ischemic stroke ence of BDs of central origin and the location of stroke.5,9,11 patients with apneic/hypopneic events show similar CBF fluc- Nevertheless, more patients are needed to clearly identify clini- tuations, or if there is an interindividual variability in the cal associations. response to apneas or hypopneas, and, consequently, the Our proof-of-concept study has some limitations, including response to treatment may be different. the small number of patients included in the final analysis, the In our cohort, the two patients (cases 4 and 5) with the high- different types of possible BDs with different physiological ori- est AHI were those with the worse stroke severity (higher gins, and the short recording time of DCS simultaneously with NIHSS score) at the moment of the measurement. This has respiratory polygraphy. Future studies will add more subjects been previously reported in patients with stroke showing central and will measure these subjects during several hours continu- BDs.13 Similarly, the ASPECTS score of these two patients were ously in order to better identify the type of BD, and moreover, the lowest of the group, which was compatible with the idea that to link it to the degree of the cerebral hemodynamic responses, large acute cerebral hemispheric lesions were associated to among other previously mentioned goals. BDs.7,65 One of these two severe patients (case 5; case 4 had Another limitation is that only one measurement per no information available) presented heart failure [low left ven- patient has been performed for this study, so we could not tricular ejection fraction (<40%)] and mainly central events, as it track the start and cessation of the fluctuations together has been found in stroke patients in association with central with the clinical stroke evolution. Anecdotally, in our previous BDs.6 The BD present in this patient could be related to it. protocols,31,67 the physiological fluctuations observed have Neurophotonics 025004-6 Apr–Jun 2019 • Vol. 6(2) Gregori-Pla et al.: Microvascular cerebral blood flow fluctuations in association. . . Fig. 4 A 10-min trace with no typical fluctuations of cerebral blood and no apneas or hypopneas. Red and black CBF traces correspond to the ipsilesional and contralesional hemispheres, respectively. Measurements of an 82-year-old male with a right anterior cerebral artery ischemic stroke (case 3) are provided. The patient had a blockage of the right anterior cerebral artery with a frontal ischemic area. The NIHSS score was 8 when measured. prevailed in the different measurements performed in each to the changes in blood pressure. However, these studies only patient during the first week after stroke. Accordingly, it is focus on the macrocirculation level; on the microcirculation expected that BDs could be present during the first week level, these parameters may have a different influence on micro- after stroke in the case of patients with BDs of central origin, vascular CBF. Moreover, hypoxia has been found during apneic as BDs have been found to resolve after several weeks.66 events,70,71 which could also contribute to the local microvascu- Future studies should include daily measurements to track lar change. when these fluctuations cease and to relate it to clinical Finally, diffuse optical spectroscopy techniques not only pro- parameters. vide information from the brain but also contain scalp and skull Owing to the small number of subjects considered for this contributions.29,72 In this work, instead of including a small analysis, we have avoided a group analysis. Two important source–detector separation (1 cm) to study the superficial parameters to understand CBF changes are the blood pressure effects, we have kept all detectors for large separations to and the end-tidal carbon dioxide; future studies should include focus on improving the signal-to-noise ratio, as a source–detec- their simultaneous measurement with DCS. Different studies tor separation of 2.5 cm has been found to be a good compro- have suggested these two parameters as different primary drivers mise.29,30,73 Future implementations could utilize more source– to the CBFV changes during apneas. Przybylowski et al.68 sug- detector pairs as well as a pressure modulation protocol to min- gested that carbon dioxide is the primary regulator, and not the imize this effect.74 blood pressure, of the rise in CBFV (measured by TCD) during In conclusion, DCS has successfully revealed bilateral fluc- apnea and in the reduction of CBFV in the following apnea. On tuations in CBF of ischemic stroke patients with undiagnosed the contrary, Yaggi and Mohsenin69 suggested that if autoregu- BDs, in accordance with systemic fluctuations of physiological lation is impaired or the changes in blood pressure are suffi- variables. These cerebral hemodynamic fluctuations are related ciently rapid that an intact autoregulation does not have time to apneic and hypopneic events in the five patients tested. to adapt, then the changes in TCD velocity could be related Further studies are needed to study the possible detrimental Neurophotonics 025004-7 Apr–Jun 2019 • Vol. 6(2) Gregori-Pla et al.: Microvascular cerebral blood flow fluctuations in association. . . impact of the magnitude and presence of these cerebral hemo- 5 Appendix dynamic fluctuations, especially in the early hours after stroke The full data set for the five patients measured is shown in where the interventions are more relevant to the outcome, for the Figs. 5–9. recovery of stroke patients. Fig. 5 The full trace recording of case 1 showing periodic respiration, with mainly hypopneic events. Hypopneas are depicted in yellow and central apneas in light blue. Red and black CBF traces correspond to the ipsilesional and contralesional hemispheres, respectively. Neurophotonics 025004-8 Apr–Jun 2019 • Vol. 6(2) Neurophotonics 025004-9 Gregori-Pla et al.: Microvascular cerebral blood flow fluctuations in association. . . Fig. 6 The full trace recording of case 2 showing only hypopneic events (in yellow). Red and black CBF traces correspond to the ipsilesional and contralesional hemispheres, respectively. Apr–Jun 2019 • Vol. 6(2) Neurophotonics 025004-10 Gregori-Pla et al.: Microvascular cerebral blood flow fluctuations in association. . . Fig. 7 The full trace recording of case 3 showing periodic respiration, with mainly hypopneic events. Hypopneas are depicted in yellow, central apneas in light blue, obstructive apneas in green, and mixed apneas in magenta. Red and black CBF traces correspond to the ipsilesional and contralesional hemispheres, respectively. Apr–Jun 2019 • Vol. 6(2) Neurophotonics 025004-11 Gregori-Pla et al.: Microvascular cerebral blood flow fluctuations in association. . . Fig. 8 The full trace recording of case 4 showing both obstructive (in green) and hypopneic (in yellow) events. Red and black CBF traces correspond to the ipsilesional and contralesional hemispheres, respectively. Apr–Jun 2019 • Vol. 6(2) Neurophotonics 025004-12 Gregori-Pla et al.: Microvascular cerebral blood flow fluctuations in association. . . Fig. 9 The full trace recording of case 5 showing central apneic events (in light blue). Obstructive apneas are depicted in green. Red and black CBF traces correspond to the ipsilesional and contralesional hemispheres, respectively. Apr–Jun 2019 • Vol. 6(2) Gregori-Pla et al.: Microvascular cerebral blood flow fluctuations in association. . . Disclosures prognosis in conscious acute stroke patients,” Cerebrovasc. Dis. 21(5-6), 340–347 (2006). Herewith the following current or potential financial relation- 14. T. Cherkassky et al., “Sleep-related breathing disorders and rehabilita- ships are disclosed. ICFO has equity ownership in the spin- tion outcome of stroke patients: a prospective study,” Am. J. Phys. Med. off company HemoPhotonics S.L. Potential financial conflicts Rehabil./Assoc. Acad. Physiatr. 82(6), 452–455 (2003). of interest and objectivity of research have been monitored 15. M. Á. Martínez-García et al., “Continuous positive airway pressure by ICFO Knowledge & Technology Transfer Department. No treatment reduces mortality in patients with ischemic stroke and obstruc- tive sleep apnea,” Am. J. Respir. Crit. Care Med. 180(1), 36–41 (2009). financial conflicts of interest were identified. 16. P. M. Turkington et al., “Effect of upper airway obstruction in acute stroke on functional outcome at 6 months,” Thorax 59(5), 367–371 (2004). Acknowledgments 17. O. C. Ioachimescu and N. A. Collop, “Sleep-disordered breathing,” The authors thank Dr. Arjun Yodh, Dr. John A. Detre, Dr. Janos Neurol. Clin. 30, 1095–1136 (2012). 18. R. Aaslid et al., “Cerebral autoregulation dynamics in humans,” Stroke Lückl, and Rosa Maria Miralda for their useful discussions. 20(1), 45–52 (1989). They acknowledge the support from Redes Temáticas de 19. H. S. Markus, “Cerebral perfusion and stroke,” J. Neurol. Neurosurg. Investigación Cooperativa (RETICS-INVICTUS RD012/0014 Psychiatry 75(3), 353–361 (2004). and RETICS-INVICTUS PLUS RD16/0019/0010), Fundació 20. E. M. Bålfors and K. A. Franklin, “Impairment of cerebral perfusion CELLEX Barcelona, Ministerio de Economía y during obstructive sleep apneas,” Am. J. Respir. Crit. Care Med. Competitividad/FEDER (PHOTODEMENTIA, DPI2015- 150, 1587–1591 (1994). 21. J. Klingelhofer et al., “Assessment of intracranial hemodynamics in 64358-C2-1-R), Instituto de Salud Carlos III/FEDER sleep apnea syndrome,” Stroke 23, 1427–1433 (1992). (MEDPHOTAGE, DTS16/00087, FIS PI09/0557), the 22. G. Hajak et al., “Sleep apnea syndrome and cerebral hemodynamics,” “Severo Ochoa” Programme for Centres of Excellence in Chest 110(3), 670–679 (1996). R&D (SEV-2015-0522), the Obra Social “la Caixa” 23. R. Alex et al., “Effect of apnea duration on apnea induced variations in Foundation (LlumMedBcn), Institució CERCA, AGAUR- cerebral blood flow velocity and arterial blood pressure,” in 36th Annu. Generalitat (2017SGR-1555), LASERLAB-EUROPE IV (EU- Int. Conf. Eng. Med. Biol. Soc. (EMBC), IEEE, 270–273 (2014). 24. M. Siebler and A. Nachtmann, “Cerebral hemodynamics in obstructive H2020 654148), “Fundació La Marató TV3” (201709.31), sleep apnea,” Chest 103(4), 1118–1119 (1993). Marie Curie initial training network (OILTEBIA 317526), 25. M. J. Aries et al., “Near infrared spectroscopy for the detection of desa- Societat Catalana de Pneumologia (SOCAP), and Sociedad turations in vulnerable ischemic brain tissue,” Stroke 43(4), 1134–1136 Española de Neumología y Cirugía Torácica (SEPAR). (2012). 26. F. Pizza et al., “Cerebral hemodynamic changes in stroke during sleep- disordered breathing,” Stroke. 43, 1951–1953 (2012). References 27. T. Durduran et al., “Diffuse optics for tissue monitoring and tomogra- phy,” Rep. Prog. Phys. 73, 76701 (2010). 1. W. J. Powers et al., “2015 American Heart Association/American stroke 28. D. A. Boas, L. E. Campbell, and A. G. Yodh, “Scattering and imaging association focused update of the 2013 guidelines for the early manage- with diffusing temporal field correlations,” Phys. Rev. Lett. 75(9), 1855– ment of patients with acute ischemic stroke regarding endovascular 1858 (1995). treatment: a guideline for healthcare professionals from the 29. T. Durduran and A. G. Yodh, “Diffuse correlation spectroscopy for American Heart Association/American Stroke Association,” Stroke non-invasive, micro-vascular cerebral blood flow measurement,” 46(10), 3020–3035 (2015). NeuroImage 85, 51–63 (2014). 2. I. Darien, International Classification of Sleep Disorders, 3rd ed. 30. R. C. Mesquita et al., “Direct measurement of tissue blood flow and (ICSD-3), American Academy of Sleep Medicine (2014). metabolism with diffuse optics,” Philos. Trans. A. Math. Phys. Eng. 3. C. Bassetti and M. S. Aldrich, “Sleep apnea in acute cerebrovascular Sci. 369, 4390–4406 (2011). diseases: final report on 128 patients,” Sleep 22(0161-8105 (Print)), 31. C. Gregori-Pla et al., “Early microvascular cerebral blood flow response 217–223 (1999). to head-of-bed elevation is related to outcome in acute ischemic stroke: 4. A. Iranzo et al., “Prevalence and clinical importance of sleep apnea in a diffuse correlation spectroscopy study,” in Int. Stroke Conf. 2017, the first night after cerebral infarction,” Neurology 58(6), 911–916 American Heart Association, (Houston, USA) (2017). (2002). 32. T. Brott et al., “Measurements of acute cerebral infarction: a clinical 5. A. Nachtmann et al., “Cheyne-Stokes respiration in ischemic stroke,” examination scale,” Stroke 20(7), 864–870 (1989). Neurology 45(4), 820–821 (1995). 6. C. Nopmaneejumruslers et al., “Cheyne-stokes respiration in stroke: 33. P. A. Barber et al., “Validity and reliability of a quantitative computed relationship to hypocapnia and occult cardiac dysfunction,” Am. J. tomography score in predicting outcome of hyperacute stroke before Respir. Crit. Care Med. 171, 1048–1052 (2005). thrombolytic therapy,” Lancet 355, 1670–1674 (2000). 7. M. Siccoli et al., “Central periodic breathing in 74 patients with acute 34. J. C. Van Swieten et al., “Interobserver agreement for the assessment of ischemic stroke—neurogenic versus cardiogenic,” J. Neuroimaging handicap in stroke patients,” Stroke 19(5), 604–607 (1988). 255(11), 1687–1692 (2008). 35. E. C. Jauch et al., “Guidelines for the early management of patients with 8. D. L. Brown et al., “Brainstem infarction and sleep-disordered breathing acute ischemic stroke: a guideline for healthcare professionals from the in the BASIC Sleep Apnea Study,” Sleep Med. 15(8), 887–891 (2014). American Heart Association/American Stroke Association,” Stroke 9. C. Bassetti, M. S. Aldrich, and D. Quint, “Sleep-disordered breathing in 44(3), 870–947 (2013). patients with acute supra- and infratentorial strokes: a prospective study 36. P. Zirak et al., “Effects of acetazolamide on the micro- and macro-vas- of 39 patients,” Stroke 28(9), 1765–1772 (1997). cular cerebral hemodynamics: a diffuse optical and transcranial Doppler 10. D. C. Good et al., “Sleep-disordered breathing and poor functional out- ultrasound study,” Biomed. Opt. Express 1(5), 1443 (2010). come after stroke,” Stroke 27(2), 252–259 (1996). 37. P. Zirak et al., “Microvascular versus macrovascular cerebral vasomotor 11. O. Parra et al., “Time course of sleep-related breathing disorders in first- reactivity in patients with severe internal carotid artery stenosis or occlu- ever stroke or transient ischemic attack,” Am. J. Respir. Crit. Care Med. sion,” Acad. Radiol. 21, 168–174 (2014). 161(2 Pt 1), 375–380 (2000). 38. P. Zirak et al., “Transcranial diffuse optical monitoring of microvascular 12. K. G. Johnson and D. C. Johnson, “Frequency of sleep apnea in stroke cerebral hemodynamics after thrombolysis in ischemic stroke,” and TIA patients: a meta-analysis,” J. Clin. Sleep Med. 6(2), 131–137 J. Biomed. Opt. 19(1), 018002 (2014). (2010). 39. R. Delgado-Mederos et al., “Transcranial diffuse optical assessment of 13. A. M. Rowat, M. S. Dennis, and J. M. Wardlaw, “Central periodic the microvascular reperfusion after thrombolysis for acute ischemic breathing observed on hospital admission is associated with an adverse stroke,” Biomed. Opt. Express 9(3), 1262 (2018). Neurophotonics 025004-13 Apr–Jun 2019 • Vol. 6(2) Gregori-Pla et al.: Microvascular cerebral blood flow fluctuations in association. . . 40. R. B. Berry et al., “Rules for scoring respiratory events in sleep: Update 66. D. M. Hermann et al., “Central periodic breathing during sleep in acute of the 2007 AASM manual for the scoring of sleep and associated ischemic stroke,” Stroke 38(3), 1082–1084 (2007). events,” J. Clin. Sleep Med. 8(5), 597–619 (2012). 67. T. Durduran et al., “Transcranial optical monitoring of cerebrovascular 41. A. Roebuck et al., “A review of signals used in sleep analysis,” Physiol. hemodynamics in acute stroke patients,” Opt. Express 17(5), 3884– Meas. 35, R1–R57 (2014). 3902 (2009). 42. P. Zirak et al., “Characterization of the microvascular cerebral blood 68. T. Przybylowski et al., “Mechanisms of the cerebrovascular response to flow response to obstructive apneic events during night sleep,” apnoea in humans,” J. Physiol. 548(1), 323–332 (2003). Neurophotonics 5, 1 (2018). 69. H. Yaggi and V. Mohsenin, “Obstructive sleep apnoea and stroke,” 43. A. Leao, “Spreading depression of activity in cerebral cortex,” J Lancet Neurol. 3(June), 333–342 (2004). Neurophysiol 7, 359–390 (1944). 70. N. L. Chamberlin and L. Ling, “The effect of intermittent hypoxia on 44. J. P. Dreier et al., “Cortical spreading ischaemia is a novel process obstructive sleep apnea: beneficial or detrimental?” J. Appl. Physiol. involved in ischaemic damage in patients with aneurysmal subarachnoid 110, 9–10 (2011). haemorrhage,” Brain 132(7), 1866–1881 (2009). 71. E. C. Fletcher, “Effect of episodic hypoxia on sympathetic activity and 45. A. J. Strong, J. A. Hartings, and J. P. Dreier, “Cortical spreading depres- blood pressure,” Respir. Physiol. 119, 189–197 (2000). sion: an adverse but treatable factor in intensive care?” Curr. Opin. Crit. 72. A. Torricelli et al., “Time domain functional NIRS imaging for human Care 13(2), 126–133 (2007). brain mapping,” NeuroImage 85, 28–50 (2014). 46. H. Yanamoto et al., “Induced spreading depression activates persistent 73. J. Selb et al., “Sensitivity of near-infrared spectroscopy and diffuse cor- neurogenesis in the subventricular zone, generating cells with markers relation spectroscopy to brain hemodynamics: simulations and experi- for divided and early committed neurons in the caudate putamen and mental findings during hypercapnia,” Neurophotonics 1(1), 015005 cortex,” Stroke 36(7), 1544–1550 (2005). (2014). 47. I. Aiba and J. L. Noebels, “Spreading depolarization in the brainstem 74. W. B. Baker et al., “Pressure modulation algorithm to separate cerebral mediates sudden cardiorespiratory arrest in mouse SUDEP models,” Sci. hemodynamic signals from extracerebral artifacts,” Neurophotonics Transl. Med. 7(282), 282ra46–282ra46 (2015). 2(3), 035004 (2015). 48. A. D. Mcgown et al., “Measurement of changes in cytochrome oxidase redox state during obstructive sleep apnea using near-infrared spectros- Clara Gregori-Pla is a postdoctoral researcher in the group Medical copy,” Sleep 26(6), 710–716 (2003). Optics at ICFO—The Institute of Photonic Sciences, Spain. She 49. A. Valipour et al., “Some factors affecting cerebral tissue saturation dur- received her master’s degree in engineering physics in biomedical ing obstructive sleep apnoea,” Eur. Respir. J. 20(2), 444–450 (2002). physics at the Royal Institute of Technology, Sweden, and her 50. L. V. Pham and A. R. Schwartz, “The pathogenesis of obstructive sleep PhD in photonics at ICFO. Her research is focused on developing apnea,” J. Thorac. Dis. 7(8), 1358–1372 (2015). novel diffuse optical instrumentation, algorithms, and protocols and 51. D. J. Durgan and R. M. Bryan, “Cerebrovascular consequences of applying them for clinical studies. obstructive sleep apnea,” J. Am. Heart Assoc. 1, e000091 (2012). 52. O. B. Paulson, S. Strandgaard, and L. Edvinsson, “Cerebral autoregu- Raquel Delgado-Mederos is a specialist in stroke neurology. She lation,” Cerebrovasc. Brain Metab. Rev. 2, 161–192 (1990). obtained her PhD in medicine at the Universitat Autònoma de Barcelona, Spain, in 2008. She works at the Stroke Unit of a compre- 53. J. Wright et al., “Health effects of obstructive sleep apnoea and the hensive stroke center (Hospital de la Santa Creu i Sant Pau, effectiveness of continuous positive airways pressure: a systematic Barcelona, Spain), in which she has professional experience as a cli- review of the research evidence,” BMJ 314(7084), 851–860 (1997). nician and as a researcher. Her research interests include acute 54. M. T. Naughton et al., “Effect of continuous positive airway pressure on stroke management, neuromonitoring, multimodal neuroimaging, central sleep apnea and nocturnal PCO2 in heart failure,” Am. J. Respir. neurosonology, and rehabilitation. Crit. Care Med. 150(6 Pt 1), 1598–1604 (1994). 55. W. Randerath et al., “Definition, discrimination, diagnosis and treatment Gianluca Cotta is a medical doctor who obtained his training in pneu- of central breathing disturbances during sleep,” Eur. Respir. J. 49(1), mology at Hospital de la Santa Creu i Sant Pau in 2014. He studied 1600959 (2017). for his master’s degree in scientific research methodology at 56. C. M. Ryan et al., “Influence of continuous positive airway pressure on Universitat Autònoma de Barcelona. He is currently working in a hos- outcomes of rehabilitation in stroke patients with obstructive sleep pital as a pneumologist. apnea,” Stroke 42(4), 1062–1067 (2011). 57. O. Parra et al., “Early treatment of obstructive apnoea and stroke out- Giacomo Giacalone obtained his degree in medicine, the specialty in come: a randomised controlled trial,” Eur. Respir. J. Off. J. Eur. Soc. neurology and his PhD in experimental neurology from the San Clin. Respir. Physiol. 37(5), 1128–1136 (2011). Raffaele University in Milan, in 2008, 2014, and 2018, respectively. He works at the Stroke Unit of the Neurology Department of San 58. D. M. Bravata et al., “Continuous positive airway pressure: evaluation Raffaele Hospital in Milan as a clinician and researcher. In 2015, of a novel therapy for patients with acute ischemic stroke,” Sleep 34(9), he promoted the setup of a clinical research laboratory for the appli- 1271–1277 (2011). cation of advanced optical device in ischemic stroke and other neu- 59. O. Sandberg et al., “Nasal continuous positive airway pressure in stroke rological diseases. patients with sleep apnoea: a randomized treatment study,” Eur. Respir. J. 18, 630–634 (2001). Federica Maruccia is a doctoral student in Neurotraumatology and 60. A. Gupta et al., “Role of positive airway pressure therapy for obstructive Neurosurgery Research Unit (UNINN), Vall d’Hebron University sleep apnea in patients with stroke: A randomized controlled trial,” J. Research Institute, Spain. She received her master’s degree in reha- Clin. Sleep Med. 14(4), 511–521 (2018). bilitation therapy from the University of Pisa in 2013. The objective of 61. A.-K. Brill et al., “CPAP as treatment of sleep apnea after stroke,” her research is to evaluate the psychomotor development of babies Neurology 90(14), e1222–e1230 (2018). and children affected by neurological diseases and to collaborate in 62. L. M. Tomfohr et al., “Continuous positive airway pressure for treat- the application of noninvasive technologies in order to better under- ment of obstructive sleep apnea in stroke survivors: what do we really stand the pathological frame. know?” Stroke. 43(11), 3118–3123 (2012). 63. M. E. Dyken and K. B. Im, “Sleep-disordered breathing and stroke,” Stella Avtzi is a doctoral student in Medical Optics Group, at ICFO. Sleep Med. Clin. 3(3), 361–376 (2008). She received her master’s degree in optics and vision from the faculty of medicine at the University of Crete, Greece. Her research interests 64. C.-Y. Hsu, “Sleep-disordered breathing after stroke: a randomised con- are mainly focused on developing new, noninvasive methods based trolled trial of continuous positive airway pressure,” J. Neurol. on diffuse optics for their application in clinical studies. Neurosurg. Psychiatry 77(10), 1143–1149 (2006). 65. A. M. Rowat, J. M. Wardlaw, and M. S. Dennis, “Abnormal breathing Luís Prats-Sànchez is a neurologist in the Hospital de la Santa Creu i patterns in stroke: relationship with location of acute stroke lesion and Sant Pau. He works in the Unit of Stroke Medicine since 2013. He has prior cerebrovascular disease,” J. Neurol. Neurosurg. Psychiatry 78(3), professional experience as a clinician and as a researcher in stroke 277–279 (2007). medicine. In 2019, he will finish his doctoral thesis in medicine at the Neurophotonics 025004-14 Apr–Jun 2019 • Vol. 6(2) Gregori-Pla et al.: Microvascular cerebral blood flow fluctuations in association. . . Universitat Autònoma de Barcelona. He is member of the Spanish Santa Creu i Sant Pau). He has experience as a clinician and as a and Catalan Societies of Neurology. researcher. His research interests include acute stroke management, intracerebral hemorrhage, neurosonology, and stroke prevention. Alejandro Martínez-Domeño is a neurologist at the Hospital de la Santa Creu i Sant Pau. He works in the Unit of Stroke Medicine. Turgut Durduran was trained at the University of Pennsylvania, He has professional experience as a clinician and as a researcher Philadelphia. In 2009, he moved to ICFO, where he leads the medical in stroke medicine. optics group. His research interests revolve around the use of diffuse light to noninvasively probe tissue function. The group develops new Pol Camps-Renom is a specialist in stroke neurology. He was trained technologies and algorithms and routinely translates them to preclini- in the Calgary Stroke Program, Alberta, Canada. He is currently doing cal, clinical, and industrial applications. his PhD studies at the Universitat Autònoma de Barcelona, focusing on stroke prevention. Mercedes Mayos obtained her PhD in medicine from the Universitat Autònoma de Barcelona, where she is now an associate professor. Joan Martí-Fàbregas is a specialist in stroke neurology (1988). He She is a specialist in pneumology. She coordinates the Sleep was trained in the Department of Neurology (Hospital de la Santa Disorders Unit and leads the Pulmonary Function Unit in the Creu i Sant Pau, 1988). He obtained his PhD in medicine at the Hospital de la Santa Creu i Sant Pau. Her research and work interests Universitat Autònoma de Barcelona, in 1993. He is the director of are related to respiratory sleep disorders and new study methods and the Stroke Unit at the Department of Neurology (Hospital de la clinical impact of obstructive sleep apnea–hypopnea syndrome. Neurophotonics 025004-15 Apr–Jun 2019 • Vol. 6(2)