Gregori-Pla et al. BMC Neurology (2021) 21:154 https://doi.org/10.1186/s12883-021-02179-8 RESEARCH ARTICLE Open Access Blood flow response to orthostatic challenge identifies signatures of the failure of static cerebral autoregulation in patients with cerebrovascular disease Clara Gregori-Pla1* , Rickson C. Mesquita2, Christopher G. Favilla3, David R. Busch4, Igor Blanco1, Peyman Zirak1, Lisa Kobayashi Frisk1, Stella Avtzi1, Federica Maruccia1,5, Giacomo Giacalone1,6, Gianluca Cotta1, Pol Camps-Renom7, Michael T. Mullen3, Joan Martí-Fàbregas7, Luís Prats-Sánchez7, Alejandro Martínez-Domeño7, Scott E. Kasner3, Joel H. Greenberg3, Chao Zhou8, Brian L. Edlow9, Mary E. Putt10, John A. Detre3, Arjun G. Yodh11, Turgut Durduran1,12 and Raquel Delgado-Mederos7 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. Keywords: Cerebrovascular disease, Mean arterial pressure, Cerebral blood flow, Cerebral autoregulation, Diffuse correlation spectroscopy, Diffuse optics * Correspondence: clara.gregori@alumni.icfo.eu 1 ICFO-Institut de Ciències Fotòniques, The Barcelona Institute of Science and Technology, 08860 Castelldefels, Barcelona, Spain Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Gregori-Pla et al. BMC Neurology (2021) 21:154 Page 2 of 12 Background syndrome [14–17]. Moreover, we recently showed that Static cerebral autoregulation (CAR) maintains cerebral the CBF response to HOB elevation in patients with blood flow (CBF) during variations of the cerebral perfu- acute ischemic stroke (AIS) was related to functional sion pressure [1, 2] by modulating microvascular resist- outcome at 3 months after the onset [20]. ance. However, static CAR may be impaired due to Curiously, CBF does not always recover to baseline acute ischemic injury or in chronic disease states such as after HOB position changes. In patients with OSA - a carotid steno-occlusive disease. This, in turn, may in- highly prevalent disorder associated with cardiovascular crease the vulnerability of brain tissue to ischemia and and cerebrovascular disease [24–27] - the failure to re- further impairments [1, 3]. In fact, the presumed impair- cover to baseline CBF after a HOB manipulation of pos- ment in static CAR provides the rationale for interven- ition changes was correlated with severity and was tions such as volume repletion, permissive hypertension, reversed after long-term treatment [15]. To the best of and flat head-of-bed (HOB) positioning that are com- our knowledge, this lack of recovery has not been evalu- monly performed empirically for patients with acute ated in cerebrovascular disease. The assessment of CBF stroke [4, 5]. In chronic carotid steno-occlusive disease, recovery during HOB manipulation of position changes impaired static CAR has been associated with higher risk could reflect the functional capacity of static CAR of stroke [6, 7], cognitive decline and neurodegeneration mechanisms. [8–10]. There is an increasing awareness of the import- The association between CBF and MAP is considered ance of non-invasive bedside measurements of static to be an indicator of CAR status. Classically, impaired CAR as a biomarker to develop personalized manage- CAR is characterized by CBF passively following MAP ment strategies [11]. Unfortunately, the evaluation of fluctuations. However, a relative “pressure-passive” rela- static CAR at the bedside is difficult. tionship has been shown in healthy humans during In the past, CBF responses to the manipulation of pharmacological or orthostatic-induced changes in HOB position have been employed to monitor a surro- MAP. The relationship between CBF and systemic blood gate of static CAR impairment in patients with cerebro- pressure change within early hours after stroke during vascular disease [12–20]. The HOB manipulation is HOB manipulation of position changes has not yet been attractive because it is non-invasive, easy to perform, explored [28, 29]. and does not require patient cooperation. Previous stud- The assessment of CBF recovery during HOB manipu- ies in both brain-injured and healthy subjects [12–16] lation of position changes could reflect the functional showed that brief (≃minutes) HOB position changes are capacity of static CAR mechanisms. Acute CAR mea- well tolerated and do not cause pathological alterations. surements could identify patients at risk for recurrent is- On the contrary, other methods such as leg cuff occlu- chemic events and could also be used as a prognostic sion/release impose additional risks in this often elderly tool. This could also be applied to patients with chronic population, for example, due to the possibility of emboli internal carotid artery (ICA) stenosis, in which static release. Changes in HOB positioning have been found to CAR evaluation could be used to identify high-risk pa- evoke macrovascular and microvascular hemodynamic tients who may benefit from a prophylactic carotid inter- responses in cerebral vasculature as measured by trans- vention, or could have prognostic value for predicting cranial Doppler ultrasound (TCD) [12] and diffuse op- the future risk of stroke or cognitive decline of these tical spectroscopy (DCS) [13–17] respectively. patients. The mechanisms underlying these responses are com- Here, we investigate the recovery (supine-to-supine) of plex, reflecting a combination of factors including static CBF after repeated HOB manipulation of position CAR, venous blood return to the heart due to posture changes and test for associations in CBF changes with change, changes in intracranial pressure and blood vol- concurrent MAP changes. We aggregate DCS data [30– ume, mean arterial pressure (MAP), and other neurore- 32] acquired in patients with cerebrovascular disease flex mechanisms [18, 19, 21–23]. Typically, from four studies with similar HOB manipulation proto- microvascular CBF correlates inversely with increases in cols. We aimed to characterize the CBF response and its HOB angle in patients with cerebrovascular disease, but association to MAP changes. We hypothesize that DCS responses are heterogeneous across subjects and be- measurements of CBF provide a biomarker of autoregu- tween cerebral hemispheres [14–17]. latory impairment. Generally, the CBF changes measured from HOB an- gles of supine (0°) to 30° and from 30° to supine (0°) were Methods not associated with neurologic deterioration, although Study population paradoxical responses, i.e., CBF increase after HOB ele- The present work utilized data of four independent co- vation, were identified in approximately 20% of patients horts that included patients with cerebrovascular disease with brain-injury, and obstructive sleep apnea (OSA) on whom DCS monitoring was performed using similar Gregori-Pla et al. BMC Neurology (2021) 21:154 Page 3 of 12 HOB protocols. One cohort of patients had asymptom- intracranial stenosis in the anterior circulation. Neuro- atic severe (at least 70%) ICA stenosis or occlusion and logically healthy volunteers were also included in the healthy controls. The other three cohorts were com- study as controls. prised of patients with AIS. The specific inclusion and exclusion criteria for each Two of the AIS cohorts were studied at the Hos- study can be found on the corresponding publications pital of the University of Pennsylvania, USA: (1) from [16, 17, 20] and in Supplementary Material. 2005 to 2007 [17] (PENN05–07) and (2) from 2009 to 2011 [16] (PENN09–11). Two other studies were conducted at the Stroke Unit of Hospital de la Santa Head-of-bed manipulation protocol Creu i Sant Pau of Barcelona: (3) a study on AIS pa- Different HOB position alteration protocols are illus- tients from 2015 to 2017 [20] (BCN15–17), and (4) a trated in Fig. 1. All protocols involved orthostatic chal- study on ICA stenosis patients and healthy volunteers lenges at different HOB positions including repeated (BCN-study), both with the same HOB manipulation supine positions (highlighted with circles in Fig. 1). For protocol. All protocols were approved by local in- all studies, optical data was acquired for 5 min at each ternal review boards, and the participants or their position. The transition between HOB positions was legal proxies provided written consent to participate. noted as event markers in the data. All methods were performed in accordance with the AIS patients were placed flat with the HOB between 0° relevant guidelines and regulations. and 15° according to the local clinical practice guidelines PENN05–07, PENN09–11 and BCN15–17 studies in- during the first 24 h after the presumed stroke onset. cluded patients admitted to the stroke service with AIS Afterwards, mobilization was guided by the judgment of affecting the anterior circulation. The general exclusion the attending clinician. criteria were intracranial hemorrhage on initial neuroim- For the PENN05–07 and PENN09–11 studies [16, 17], aging, and inability to lie supine for 15 min. the study protocol was planned for three separate days The BCN-study included asymptomatic patients (de- and the first measurement was performed as soon as the fined as no stroke in the territory of the stenotic artery patient was available. For the BCN15–17 study [20], the in the preceding 6 months) with severe unilateral or bi- study protocol was initiated within the first 48 h after lateral extracranial ICA stenosis (at least 70%). The latter symptom onset. The protocol was repeated up-to four were referred to the neurosonology lab for cerebrovascu- times at intervals of 48 h during the first week of admis- lar reserve testing. The exclusion criteria were bilateral sion as long as the patient was stable. For the BCN- inadequate temporal acoustic windows for sufficient study (on patients with ICA stenosis and controls), the TCD examination or the evidence of an additional measurements were performed once. Fig. 1 Schematic illustrating the different protocols. The supine positions used for this analysis are indicated with a circle Gregori-Pla et al. BMC Neurology (2021) 21:154 Page 4 of 12 Optical methods and instrumentation measurements, the first and last minutes from the ana- The specific optical methods and instrumentation for lysis were discarded and the rest were used to calculate the measurement of CBF and MAP for each study can a mean of each head-of-bed (HOB) position. These data be found in previous publications [16, 17, 20] and in were obtained continuously by a non-invasive blood Supplementary Material. Here we briefly outline the sali- pressure monitor Finapres (Finapres Medical Systems, ent, common features. Arnhem, the Netherlands) device in a sub-set of pa- For all studies, two non-invasive, optical probes tients. The mean of the MAP changes is reported as were placed on the forehead bilaterally and as lat- ΔMAP = ðMAP supine2 ðtÞ− ðMAP  supine1 ÞÞ . ðMAP supine1 Þ is erally as possible to avoid the frontal sinuses. This se- the average of the MAP during the first supine position lection was guided by practical reasons (to avoid hair) and MAPsupine2(t) is the continuous MAP data during and also since previous studies by other methods [33] the measurement on the second supine position. and, by DCS [32], have shown that the frontal cortical When the measurements were performed at half-time area is a valid area of measurement when studying of each HOB position, a manual sphygmomanometer the global cerebral vasoreactivity (CVR) at the level of (Omron BP785 IntelliSense Automatic Blood Pressure individual cerebral hemispheres. The probes consisted Monitor, Omron, Osaka, Japan) was used to measure of detector fibers and a source fiber set at 2.5 cm the MAP at 2.5 min from each HOB position change. from the detector fibers. A 2.5 cm separation provides The changes are reported in the same manner as the information about the cortical cerebral continuous measurements. hemodynamics, as previously validated [32, 34, 35]. Diffuse correlation spectroscopy has been extensively validated for measuring relative microvascular cortical Clinical and imaging evaluation CBF against other modalities [32, 35]. Recently, Giovan- The baseline examinations included the collection of nella et al. [36] has paved the way to calibrate for accur- demographics and vascular risk factors and a physical ate absolute CBF measurements by DCS on neonates examination obtained by certified neurologists or senior which would be applicable for adult brain measurements residents under supervision who were blinded to the op- with appropriate means to account for the partial vol- tical information. Diabetes mellitus, arterial hypertension ume effects. Finally, we stress that, unlike near-infrared and dyslipidemia were obtained for all stroke studies. spectroscopy (NIRS), DCS is a direct measure of CBF. The etiologic stroke subtype was classified according NIRS, on the other hand, provides surrogate measures of to the modified Trial of Org 10,172 in Acute Stroke CBF by making assumptions about oxygen extraction Treatment (TOAST) [37] criteria in two stroke studies. and blood volume and their relationship to CBF. The extent of early ischemic changes was evaluated by The DCS system [31] employed a long coherence the Alberta Stroke Program Early Computed Tomog- length laser (785 nm) single photon avalanche photo- raphy Score (ASPECTS) [38] in two stroke studies. The diode detectors and a hardware auto-correlator. DCS specific clinical and imaging evaluations for each study evaluates the statistics of the diffuse laser speckles by can be found in previous publications [16, 17, 20] and in using the auto-correlation function of the detected light Supplementary Material. intensity fluctuations. The blood flow index (BFI) of the local microvasculature is then calculated by fitting the Statistical analysis appropriate solution of the correlation diffusion equation Quantitative clinical variables are described as a median to the intensity autocorrelation function as previously and an interquartile range (IQR) and categorical vari- described [30]. ables as number of cases and percentages of the total The changes in CBF at the second supine position (cases (percentages)). Demographic characteristics were were calculated by using the mean BFI at the first supine compared across groups using either the Kruskal-Wallis position as the baseline. The results are reported as test (for quantitative variables) or Fisher’s exact test (for BFI  ðtÞ  categorical variables). If the global test was statistically ΔrCBF = ðð supine2  −1Þx100Þ , where BFI supine1 is the BFI supine1 significant, multiple pairwise comparisons were made average of the cerebral BFI during the first supine pos- using the Wilcoxon rank-sum or Fisher’s exact test to ition and BFIsupine2(t) is the continuous BFI data dur- assess differences with adjustment using Holm- ing the measurement at the second supine position. Up- Bonferroni correction. to 1 min of the continuous BFI data was discarded for For the patient groups, each cerebral hemisphere was each HOB position in order to avoid bed movement tagged as being “ipsilesional” or “contralesional” based artifacts. on the presence of the pathology on that hemisphere. In MAP was measured continuously or at half-time of the case of AIS patients, “ipsilesional” refers to the cere- each HOB position. For the continuous MAP bral hemisphere where the hemisphere with cerebral Gregori-Pla et al. BMC Neurology (2021) 21:154 Page 5 of 12 ischemia was observed. In the case of ICA stenosis sub- Results jects, the categorization was by degree of the asymptom- Characteristics of the study population atic ICA stenosis as severe (≥70% or occlusion, Data from 114 subjects in four different studies, includ- “ipsilesional”) and non-severe (stenosis< 70% or absent, ing 99 patients (n = 72 AIS and n = 27 ICA stenosis) and “contralesional”). Only patients with unilateral ICA were 15 healthy controls was collected. In total, 117 repeated considered when evaluating the associations between DCS measurements during orthostatic challenges in dif- CBF and MAP. ferent HOB positions were analyzed. MAP was recorded There are no known pathological lesions present for in 55 subjects, including a total of 66 measurements in the healthy volunteers, we have thus randomly assigned 40 patients. MAP measurements were continuous in each hemisphere measured in the controls as “side 1” or nine and at half-time in 31 patients. The control group “side 2”. This was done to avoid any systematic bias by (n = 15) had half-time MAP measurements. This infor- using the left/right indication. mation is further detailed in Table 1 and we note that The AIS group involved repeated measurements. In the sample sizes for different variables varied because of this case, linear mixed-effect models (if lack of inde- incomplete data or artifacts. pendence in the response variable) were used for The clinical characteristics of the subjects are summa- checking if the mean response of ΔrCBF or ΔMAP rized in Table 2. For the AIS patients, the severity of differed from zero, where patient identifier, the study stroke upon arrival was not statistically significantly dif- name and the hemisphere were, if needed, the ran- ferent across the three cohorts (NIHSS =13.5 (IQR 6, dom factors for these analyses. Otherwise, simple lin- 20), p = 0.188). The median age of the AIS patients was ear models were used when the response variable was 74.5 (IQR 60, 85) years but patients from AIS BCN15– independent. Linear mixed-effect models (if there was 17 were older than the rest (p = 0.006 and p = 0.014, for a lack of independence in the response variable) were PENN05–07 and PENN09–11 studies, respectively). 53% also used to study the association between ΔrCBF of the subjects were female. The median time from the and ΔMAP, where patient identifier was the random stroke event to the HOB manipulation measurement factor. If needed in the specific model, the hemi- was 1 (IQR 0.5, 2) day but the PENN05–07 study pa- sphere and/or the study name were the covariables. tients were measured later from the stroke onset than Again, simple linear models were used when the re- the other studies (p = 0.044 and p < 0.001, for PENN09– sponse variable was independent. 11 and BCN15–17 studies, respectively). For the linear models we report estimates of the mean The ICA stenosis patients were 68 (IQR 64, 62) years effect along with 95% confidence intervals (95% CI). The old and 15% of them were female. All ICA stenosis pa- p-values are reported for the hypothesis test of whether tients were asymptomatic. ICA stenosis was unilateral in the effect is zero. Significance of specific terms was 16 (59%) subjects, and bilateral in 11 (41%). A prior is- assessed using a likelihood ratio test for the full versus chemic stroke event (more than 6 months before the reduced models. A type I error of 0.05 was used to measurement) was recorded in seven (35%) of the accept significance without adjustment for multiple patients. comparisons. The “nlme” software package was used for Both AIS and ICA stenosis patients were older than the linear mixed-effect models implemented in R [39]. the healthy controls (p < 0.001 and p < 0.001, respect- All statistical analyses were performed with R [39]. ively). Fewer female ICA stenosis subjects were included Table 1 Number of subjects and total number of measurements included in each analysis Subjects number Patients Controls Total (measurements number) Acute ischemic stroke ICA PENN05–07 PENN09–11 BCN15–17 BCN-study Total 17 (42) 17 (21) 38 (72) 27 (27) 15 (15) 114 (177) Supine1 to supine2 CBF data 15 (35) 14 (16) 38 (72) 27 (27) 15 (15) 109 (165) Supine1 to supine2 CBF 15 (35) 11 (13) 36 (65) 14 (14) – 76 (127) ipsilesional vs contralesional hemisphere analysis Mean arterial pressure data 0 9 (13) 17 (39) 14 (14) 15 (15) 55 (81) Ipsilesional CBF data + MAP data 0 6 (8) 14 (35) 14 (14) – 34 (57) Contralesional CBF data + MAP data 0 9 (11) 13 (31) 14 (14) – 36 (59) ICA internal carotid artery, CBF cerebral blood flow, MAP mean arterial pressure (−) indicates that there was no specific control subject data for a particular hemisphere and specific group Gregori-Pla et al. BMC Neurology (2021) 21:154 Page 6 of 12 Table 2 Demographic and clinical variables available for all groups Patients Controls (n = 15) Acute ischemic stroke ICA (n = 27) PENN05–07 (n = 17) PENN09–11 (n = 17) BCN15–17 BCN-study (n = 38) Age; 59 (53, 75) 62 (60, 64) 83 (69, 88) 68 (64, 72) 28 (28, 33) years median, (interquartile range) Females, n (%) 10 (59%) 7 (41%) 21 (55%) 4 (15%) 6 (40%) Diabetes mellitus, n (%) 8 (26.7) – 8 (26.7) 16 (59) 1 (7) Hypertension, n (%) 33 (86.8) 15 (88.2) 33 (86.8) 20 (74) 0 (0) Dyslipidemia, n (%) 19 (50) 14 (82.4) 19 (50) 26 (96) 0 (0) NIHSS on admission 15 (6, 20) 9 (5, 13) 18 (7, 20) – – Admission ASPECTS – 7 (4.3, 9.7) 9 (6, 10) – – Days from stroke onset 2 (2, 3) 1 (1, 1) 1 (0.5, 1) – – TOAST, n (%) LAA 3 (18) – 5 (13) – – CE 7 (41) – 13 (34) – – Other 7 (41) – 2 (5) – – Undef. 0 (0) – 18 (47) – – AIS acute ischemic stroke, ICA internal carotid artery, NIHSS National Institutes of Health Stroke Scale, ASPECTS Alberta Stroke Program Early Computed Tomography Score, TOAST Trial of ORG 10172 in Acute Stroke Treatment, LAA Large artery atherosclerosis, CE cardioembolism, Undef. undefined etiology (−) indicates that the data do not exist for a specific group. Values are median and interquartile range or the number and proportion compared to the AIS study (p < 0.001) and the controls Figure 2 shows representative results for CBF changes (p = 0.002). No other demographic differences were during the head-of-bed position challenge measured by observed. DCS from two ICA patients. CBF and MAP responses to HOB manipulation of As shown in Table 1, repeated measurements from the position changes from the first to second supine same subjects were also assessed. The complete optical position. data of n = 109 subjects and n = 165 repeated measure- ments were included for further analysis while some data Fig. 2 Representative microvascular CBF response to a head-of-bed position alteration. Representative microvascular CBF response (vertical axis) to a head-of-bed position alteration versus time of two different internal carotid artery stenosis patients. The periods in light gray are averaged for further analysis and dark gray shades show the transition periods. The subject on the left panel showed a CBF response that recovered back to the baseline levels whereas the other subject (right) did not Gregori-Pla et al. BMC Neurology (2021) 21:154 Page 7 of 12 was discarded due to incomplete collection or quality acute stroke (p = 0.588) or unilateral ICA stenosis (p = degradation due to excessive patient motion. 0.936). Only subjects with optical data available from In AIS patients (n = 67), ΔrCBF was 9.6% [6.0, 13.3] both hemispheres were included in this sub-analysis [mean, 95% confidence interval] and did not recover back (n = 62). to its baseline values (p < 0.001) as shown in Fig. 3. In con- A significant MAP increase of 2.6 mmHg [0.5, 4.7] was trast, in controls (n = 15), ΔrCBF was 0.3% [− 4.7, 5.4], and observed in AIS patients (n = 26, p = 0.018), and a non- it recovered back to baseline values (p = 0.890). We have significant change of 1.4 mmHg [− 2.3, 5.1] was observed compared the two groups using the data derived from the in ICA stenosis patients (n = 14, p = 0.431), and also in same protocol (BCN15–17 and the controls of the BCN- controls, − 1.9 mmHg [− 4.6, 0.9] (n = 15, p = 0.165), study) since the other protocols on ischemic stroke did Fig. 4. not have controls. The ΔrCBF was different between the AIS (n = 38) and control (n = 15) groups (p = 0.038). Correlation between relative cerebral blood flow changes In ICA stenosis patients (n = 27), ΔrCBF was 8.6% [3.1, and relative mean arterial pressure changes during HOB 14.0] and it did not recover back to its baseline values manipulation of position changes (p = 0.003) as shown in Fig. 3. Furthermore, we have In patients with AIS, ΔrCBF measured in the ipsilesional compared ΔrCBF between the ICA stenosis and control hemisphere was positively associated with ΔMAP as subjects (n = 15) (BCN-study protocol) and no difference 6.0%/mmHg [− 2.4, 14.3] (p = 0.038, n = 20) in the early was found (p = 0.082). hours (≤ 48 h) from the stroke onset, Fig. 5. By contrast, The observed ΔrCBF responses did not differ between the contralesional hemisphere did not exhibit a signifi- hemispheres, for example due to the presence of either cant association being 3.1%/mmHg [− 10.0, 16.2] (p = Fig. 3 Cerebral blood flow response to the transition from the first to second supine position for all cohorts. Cerebral blood flow response (ΔrCBF) to the transition from the first to second supine position for each hemisphere for all cohorts of patients and controls is shown. 67 patients and 123 measurements were included for the acute ischemic stroke group, 27 patients for the internal carotid artery stenosis group, and 15 healthy controls. Classic boxplots and the mean ΔrCBF data point color-coded for each cohort are shown. (*) indicates that the mean response differed from zero. Ipsi. hemisp. = ipsilesional hemisphere; Contra. hemisp. = contralesional hemisphere Gregori-Pla et al. BMC Neurology (2021) 21:154 Page 8 of 12 Fig. 4 Mean arterial pressure response to the transition from the first to second supine position for all cohorts. Mean arterial pressure response (ΔMAP) to the transition from the first to second supine position for all cohorts of patients and for controls is shown. 26 (52) -number of patients (total number of measurements performed)- were included for the acute ischemic stroke group, 14 (14) for the internal carotid artery stenosis group, and 15 (15) healthy controls. Classic boxplots and the mean ΔrCBF data point color-coded for each cohort group are shown. (*) indicates that the mean response differed from zero 0.600) between ΔrCBF and ΔMAP parameters. However, returning to the supine position after orthostatic there were no detectable differences in the MAP/CBF challenges. association between the two hemispheres of the same We have identified a significant increase in CBF from patients (p = 0.467, n = 22) possibly due to the high vari- the first supine position to the second supine position in ability in the measurement and limited sample size. AIS and ICA stenosis patient groups (p < 0.001 and p = In patients with ICA stenosis, the CBF changes that 0.003, respectively) but not in controls (p = 0.890). This were observed on the ipsilesional hemisphere were asso- finding is similar to prior observations in patients with ciated with ΔMAP as 11.0%/mmHg [2.4, 19.5] (p < 0.001, moderate and severe obstructive sleep apnea (OSA) [15]. n = 14). Again, the contralesional hemisphere did not ex- This is an encouraging finding for further study on these hibit a similar association being 8.6%/mmHg [− 5.9, populations since previous work [15] has shown that it 23.1] (p = 0.303, n = 14) between both parameters. This was related to disease severity and long-term effects. If did not imply that there were intra-subject differences validated in these populations, it could be a prognostic (p = 0.682). Similarly, there was no association between biomarker. CBF and MAP in control subjects (p = 0.605). A significant increase of ΔMAP was observed in AIS patients from the first supine position to the second su- Discussion pine position (p = 0.018) which was not observed in the We have aggregated ΔrCBF data that was acquired dur- ICA patients nor in the control group (p > 0.05). This ing HOB manipulation protocols from hundred and four raises the question of whether there is a significant im- patients with cerebrovascular disease to examine the pairment of the cerebral autoregulation which may variation and relationship of CBF and MAP upon imply a risk situation for the patient. We note that it is Gregori-Pla et al. BMC Neurology (2021) 21:154 Page 9 of 12 Fig. 5 Cerebral blood flow response versus relative mean arterial pressure change. Cerebral blood flow response (ΔrCBF) for the transition from the first to the second supine position versus relative mean arterial pressure change (ΔMAP) in the ipsilesional hemisphere (left), and in the contralesional hemisphere (right) for the measurements performed on AIS in the first 48 h after stroke, ICA stenosis patients and controls. For more details about the statistical results, see the text. Linear model fit and 95% confidence intervals (in grey) are plotted. (*) indicates a statistically significant linear model. Ipsi. = ipsilesional; contra. = contralesional also known that AIS itself affects the resting arterial orthostatic challenges in healthy subjects and patients blood pressure if the compensatory mechanisms are with compromised static CAR. damaged [2]. Detrimental conditions may occur even It is also interesting to compare our results with those without any challenges [40, 41], i.e. cerebral perfusion of Aries et al [12] from the AIS population. That study may passively follow the variations in MAP since normal employed TCD to measure CBF velocity changes in re- autoregulatory mechanisms are impaired [40, 41]. sponse to HOB position changes, and, also included The physiological basis underlying the lack of return concurrent MAP monitoring. Aries et al [12] found an to the baseline of CBF and MAP after a brief period of increase in MAP from the first to last (fourth) supine HOB position changes is unclear. One possible explan- position of the protocol; this MAP increase is similar to ation is that patients with cerebral pathology need more that of our work. Conversely, they did not observe an ac- than 5 min in each HOB position to stabilize their cere- companying increase in CBF velocity, which is consistent bral and systemic hemodynamics. This view is consistent with our prior findings in Favilla et al [16] (PENN09– with the TCD measurements by Urbano et al [42] who 11). This discrepancy may have arisen because TCD explored the effect of stronger orthostatic challenges measures velocity in large arteries rather than the micro- (standing to squatting position) in patients with moder- vascular perfusion measured in the current study. ate or severe OSA who also often have impaired static We have observed that the CBF changes in the ipsile- CAR [43]. Patients with OSA exhibited significantly sional hemisphere were associated with MAP changes in slower (~seconds) recovery rates for MAP, CBF velocity, subjects with AIS studied within 48 h after stroke onset and cerebrovascular conductance compared to the con- (p = 0.038), as well as with the group of subjects with trol group. More research is needed to understand the ICA stenosis (p < 0.001). Notably, this association was temporal dynamics (from seconds to hours) following not detected in the contralesional hemisphere of the AIS Gregori-Pla et al. BMC Neurology (2021) 21:154 Page 10 of 12 or ICA stenosis patients (p = 0.600 and p = 0.303, re- measurements. We include this study as it provides spectively), nor was there an association between CBF critical data for the first result in our present analysis: and MAP in control subjects (p = 0.605). The question the effect of return-to-supine on CBF. Furthermore, that arises is whether this implies that impaired static the studies cover a time period of 12 years with dif- CAR is hemispheric. Since the association between CBF ferent protocols. The clinical care and management and MAP are often considered to be an indication of im- has evolved during this period including changes in paired CAR [1, 2, 11, 29, 44], we suggest that our find- patient demographics. Furthermore, technology has ings imply that both ICA stenosis and AIS patients have developed and our methods have also changed in this hemispheric static CAR impairments [1]. 12 year period. Despite these differences, importantly, We note that in the case of AIS patients, the impair- similar results were found across studies which ment appears to diminish with time since the association strengthens the results reported in this work. There- between CBF and MAP was observed only during the fore, our results are encouraging to suggest future first 48 h after the stroke onset. Alternatively, this time- multi-center studies with common protocols and dependent result may be attributable to the increased similar clinical management at the point-of-care. heterogeneity of the patient population as the time after The ΔrCBF increase found in the contralesional stroke increased. This is expected since the evolution of hemisphere in our hypothesis generating study needs ischemic injury following AIS is heterogeneous. Ideally, further exploration. One of the reasons of this result the study should have been conducted at the hyper- could be caused by small number of subjects com- acute time period, e.g. during the first 6 to 8 h after the pared to the amount of heterogeneity in the results. stroke onset since the majority of the ischemic penum- It is important to note that the result is hemispheric bra is viable during that period. However, this finding which rules out that the optical data is dominated by may still be relevant since some studies using imaging systemic changes due to partial volume effects. Future techniques have identified viable penumbra up to 48 h studies could address these findings by relying on the post stroke onset [45, 46]. In addition, cerebrovascular utilizing more recent advances in technology, by com- auroregulation has been associated with other mecha- bination of DCS with near-infrared spectroscopy and nisms of secondary damage that occur later than the re- by the so called fast measurements evaluating beat-to- cruitment of ischemic penumbra, such as hemorrhagic beat hemodynamic changes [30, 32, 47, 48] which transformation and cerebral edema, which also have an should improve data fidelity, and help to answer these impact on the prognosis. and other questions in larger studies. Our study has several other limitations. Unfortu- Currently, a routine evaluation of static CAR is not nately, data of ASPECT and TOAST classification is utilized in clinical practice for several reasons. Among missing in one of the three cohorts. Final infarct vol- these are the lack of a gold-standard methodology and umes were calculated utilizing different imaging tech- the requirement to induce hemodynamic changes. The niques and at different time points, which precludes a stimuli utilized by many methods (e.g., rapid release of comparison among patients and cohorts. Even though thigh tourniquets or infusion of vasoactive drugs) have EtCO2 changes have not been measured in the stud- issues with safety and patient compliance. HOB manipu- ies, we point out that an extensive study on a healthy lations are simpler and safer compared to these population over a large age range has shown that methods, even in patients with acute brain injury. In this EtCO2 does not change significantly during this chal- contribution, we have shown that the increase in correl- lenge [13]. Our unpublished data (mean [range], ation between DCS-measured CBF and MAP during ser- supine-to-30: 0.046 [− 1.3,1.1] mmHg, p = 0.9; 30-to- ial HOB position changes is a promising protocol to supine: 0.26 [− 1.1,1.7], mmHg, p = 0.23) from an on- assess static CAR performance in patients with both going study (currently at n = 72 subjects) on a similar acute and chronic cerebrovascular disease. Further stud- population of acute ischemic stroke patients have ies are needed to ascertain whether this information can confirmed that this is true for the patient population be used to individualize management of patients with too. The minimal changes observed in some individ- cardiovascular disease. uals are not expected to correlate with MAP. More- over, the use of different protocols, from different centers, separated over time has increased the vari- Conclusions ability between studies. For example, the MAP assess- A brief and mild HOB challenge elicits evidence of cere- ment was continuous in a small subset but brovascular autoregulatory deficits. DCS can be used to intermittent in all the others and different instru- monitor these changes at the bed-side, and after further ments were used. One study (PENN05–07) had a fur- validation, may ultimately help to individualize clinical ther limitation in utility due to lack of blood pressure management in AIS. Gregori-Pla et al. BMC Neurology (2021) 21:154 Page 11 of 12 Supplementary Information Unit). Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant The online version contains supplementary material available at https://doi. Pau (IIB Sant Pau), Barcelona, Spain. 8McKelvey School of Engineering, org/10.1186/s12883-021-02179-8. Washington University in St. Louis, St. Louis, MO, USA. 9Center for Neurotechnology and Neurorecovery, Massachusetts General Hospital, Boston, MA, USA. 10Department of Biostatistics and Epidemiology, University Additional file 1. of Pennsylvania, Philadelphia, USA. 11Department of Physics and Astronomy, University of Pennsylvania, Philadelphia, USA. 12Institució Catalana de Recerca Authors’ contributions i Estudis Avançats (ICREA), 08015 Barcelona, Spain. All authors have read and approved the manuscript. CGP, SA, FM, GG, GC, IB, PZ, TD, RM and CF acquired the optical data. RDM, MM, PCR, AMD, LPS Received: 24 October 2020 Accepted: 23 March 2021 acquired the clinical data. CGP analyzed the data and wrote the manuscript. JD, JG, AY, RDM, TD and JMF supervised the study, contributed to the discussion, and reviewed and contributed to the manuscript. LKF, DB, S K, CZ References and BE contributed to the discussion. MP provided guidance for the 1. Payne S. Cerebral autoregulation. 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Monitoring of cerebral autoregulation. Neurocrit Care. of the University of Pennsylvania Ethics Committee and Ethics Committee of 2014;21(2):95–102. https://doi.org/10.1007/s12028-014-0046-0. the Hospital de la Santa Creu i Sant Pau. The participants or their legal 12. Aries MJ, Elting JW, Stewart R, De Keyser J, Kremer B, Vroomen P. Cerebral proxies gave written informed consent to participate. All methods were blood flow velocity changes during upright positioning in bed after acute carried out in accordance with national guidelines and regulations. stroke: an observational study. BMJ Open. 2013;3(8):1–8. 13. Edlow BL, Kim MN, Durduran T, Zhou C, Putt ME, Yodh AG, et al. The effects Competing interests of healthy aging on cerebral hemodynamic responses to posture change. Herewith the following current or potential financial relationships are Physiol Meas. 2010;31(4):477–95. https://doi.org/10.1088/0967-3334/31/4/ disclosed. ICFO has equity ownership in the spin-off company HemoPho- 002. tonics S.L., which commercializes relevant technologies. Potential financial 14. Kim MN, Edlow BL, Durduran T, Frangos S, Mesquita RC, Levine JM, et al. conflicts of interest and objectivity of research have been monitored by ICFO Continuous optical monitoring of cerebral hemodynamics during head-of- Knowledge & Technology Transfer Department. No financial conflicts of inter- bed manipulation in brain-injured adults. Neurocrit Care. 2014;20(3):443–53. est were identified. DRB, RCM, TD and AGY have several patents accepted https://doi.org/10.1007/s12028-013-9849-7. and under application related to DCS technologies and receive no revenue. 15. Gregori-Pla C, Cotta G, Blanco I, Zirak P, Giovannella M, Mola A, et al. The other authors have no conflicts of interest. Cerebral vasoreactivity in response to a head-of-bed position change is altered in patients with moderate and severe obstructive sleep apnea. 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