Review| Volume 245, 103069, March 2023

Cerebral blood flow response to cardiorespiratory oscillations in healthy humans

Published:December 22, 2022DOI:


      • The wavelet phase coherence and synchronization index were used to quantify cerebral autoregulation in healthy volunteers.
      • Sympathetic nervous activity may drive vasomotion at 0.1 Hz in both systemic and cerebral circulation.
      • Increased synchronization between arterial blood pressure and cerebral blood flow velocity was found around the respiratory frequency.
      • Low synchronization was found in the 0.05-0.15 Hz frequency interval.


      Dynamic cerebral autoregulation (CA) characterizes the cerebral blood flow (CBF) response to abrupt changes in arterial blood pressure (ABP). CA operates at frequencies below 0.15 Hz. ABP regulation and probably CA are modified by autonomic nervous activity. We investigated the CBF response and CA dynamics to mild increase in sympathetic activity.
      Twelve healthy volunteers underwent oscillatory lower body negative pressure (oLBNP), which induced respiratory-related ABP oscillations at an average of 0.22 Hz. We recorded blood velocity in the internal carotid artery (ICA) by Doppler ultrasound and ABP. We quantified variability and peak wavelet power of ABP and ICA blood velocity by wavelet analysis at low frequency (LF, 0.05–0.15 Hz) and Mayer waves (0.08–0.12 Hz), respectively. CA was quantified by calculation of the wavelet synchronization gamma index for the pair ABP–ICA blood velocity in the LF and Mayer wave band.
      oLBNP increased ABP peak wavelet power at the Mayer wave frequency. At the Mayer wave, ABP peak wavelet power increased by >70 % from rest to oLBNP (p < 0.05), while ICA blood flow velocity peak wavelet power was unchanged, and gamma index increased (from 0.49 to 0.69, p < 0.05). At LF, variability in both ABP and ICA blood velocity and gamma index were unchanged from rest to oLBNP.
      Despite an increased gamma index at Mayer wave, ICA blood flow variability was unchanged during increased ABP variability. The increased synchronization during oLBNP did not cause less stable CBF or less active CA. Sympathetic activation seems to improve the mechanisms of CA.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Autonomic Neuroscience: Basic and Clinical
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Addison P.S.
        A review of wavelet transform time-frequency methods for NIRS-based analysis of cerebral autoregulation.
        IEEE Rev. Biomed. Eng. 2015; 8: 78-85
        • Ainslie P.N.
        • Willie C.K.
        • Tzeng Y.C.
        Role of SNA in the pathophysiology of cardiovascular collapse during syncope: muscle vs. brain.
        J. Physiol. 2009; 587: 5795-5796
        • Akay M.
        Wavelet applications in medicine.
        IEEE Spectr. 1997; 34: 50-56
        • Bandrivskyy A.
        • Bernjak A.
        • McClintock P.
        • Stefanovska A.
        Wavelet phase coherence analysis: application to skin temperature and blood flow.
        Cardiovasc. Eng. 2004; 4: 89-93
        • Bernjak A.
        • Stefanovska A.
        • Mcclintock P.V.E.
        • Owen-Lynch P.J.
        • Clarkson P.B.M.
        Coherence between fluctuations in blood flow and oxygen saturation.
        Fluctuation Noise Lett. 2012; 111240013
        • Bracic M.
        • Stefanovska A.
        Wavelet-based analysis of human blood-flow dynamics.
        Bull. Math. Biol. 1998; 60: 919-935
        • Carter R.
        • Hinojosa-Laborde C.
        • Convertino V.
        Gender differences in muscle sympathetic nerve activity and arterial pressure oscillations during progressive central hypovolemia.
        FASEB J. 2014; 28
        • Cassaglia P.A.
        • Griffiths R.I.
        • Walker A.M.
        Comments on Point:Counterpoint: Sympathetic activity does/does not influence cerebral blood flow. Sympathetic nerves influence cerebral blood flow.
        J. Appl. Physiol. 2008; 105: 1372
        • Cassaglia P.A.
        • Griffiths R.I.
        • Walker A.M.
        Sympathetic nerve activity in the superior cervical ganglia increases in response to imposed increases in arterial pressure.
        Am. J. Physiol. Regul. Integr. Comp. Physiol. 2008; 294: 1255-1261
        • Cassaglia P.A.
        • Griffiths R.I.
        • Walker A.M.
        Cerebral sympathetic nerve activity has a major regulatory role in the cerebral circulation in REM sleep.
        J. Appl. Physiol. 2009; 106: 1050-1056
        • Claassen J.A.
        • Meel-van den Abeelen A.S.
        • Simpson D.M.
        • Panerai R.B.
        Transfer function analysis of dynamic cerebral autoregulation: a white paper from the international cerebral autoregulation research network.
        J. Cereb. Blood Flow Metab. 2016; 36: 665-680
        • Clemson P.
        • Lancaster G.
        • Stefanovska A.
        Reconstructing time-dependent dynamics.
        Proc. IEEE. 2016; 104: 223-241
        • Convertino V.A.
        Mechanisms of inspiration that modulate cardiovascular control: the other side of breathing.
        J. Appl. Physiol. 2019; 127: 1187-1196
        • Cooke W.H.
        • Ryan K.L.
        • Convertino V.A.
        Lower body negative pressure as a model to study progression to acute hemorrhagic shock in humans.
        J. Appl. Physiol. 2004; 96: 1249-1261
        • Eckberg D.L.
        The human respiratory gate.
        J. Physiol. 2003; 548: 339-352
        • Eckberg D.L.
        Point:counterpoint: respiratory sinus arrhythmia is due to a central mechanism vs. respiratory sinus arrhythmia is due to the baroreflex mechanism.
        J. Appl. Physiol. 2009; 106 (discussion 1744): 1740-1742
        • Elstad M.
        • Toska K.
        • Chon K.H.
        • Raeder E.A.
        • Cohen R.J.
        Respiratory sinus arrhythmia: opposite effects on systolic and mean arterial pressure in supine humans.
        J. Physiol. 2001; 536: 251-259
        • Faes L.
        • Pinna G.D.
        • Porta A.
        • Maestri R.
        • Nollo G.
        Surrogate data analysis for assessing the significance of the coherence function.
        IEEE Trans. Biomed. Eng. 2004; 51: 1156-1166
        • Fan J.L.
        • Nogueira R.C.
        • Brassard P.
        • Rickards C.A.
        • Page M.
        • Nasr N.
        • Tzeng Y.C.
        Integrative physiological assessment of cerebral hemodynamics and metabolism in acute ischemic stroke.
        J. Cereb. Blood Flow Metab. 2021; 42: 454-470
        • Franke W.D.
        • Johnson C.P.
        • Steinkamp J.A.
        • Wang R.
        • Halliwill J.R.
        Cardiovascular and autonomic responses to lower body negative pressure: do not explain gender differences in orthostatic tolerance.
        Clin. Auton. Res. 2003; 13: 36-44
        • Fu Q.
        • Arbab-Zadeh A.
        • Perhonen M.A.
        • Zhang R.
        • Zuckerman J.H.
        • Levine B.D.
        Hemodynamics of orthostatic intolerance: implications for gender differences.
        Am. J. Physiol. Heart Circ. Physiol. 2004; 286: H449-H457
        • Goswami N.
        • Blaber A.P.
        • Hinghofer-Szalkay H.
        • Convertino V.A.
        Lower body negative pressure: physiological effects, applications, and implementation.
        Physiol. Rev. 2019; 99: 807-851
        • Goupillaud P.
        • Grossmann A.
        • Morlet J.
        Cycle-octave and related transforms in seismic signal analysis.
        Geoexploration. 1984; 23: 85-102
        • Gruszecki M.
        • Lancaster G.
        • Stefanovska A.
        • Neary J.P.
        • Dech R.T.
        • Guminski W.
        • Winklewski P.J.
        Human subarachnoid space width oscillations in the resting state.
        Sci. Rep. 2018; 8: 3057
        • Hamner J.W.
        • Tan C.O.
        Relative contributions of sympathetic, cholinergic, and myogenic mechanisms to cerebral autoregulation.
        Stroke. 2014; 45: 1771-1777
        • Hamner J.W.
        • Cohen M.A.
        • Mukai S.
        • Lipsitz L.A.
        • Taylor J.A.
        Spectral indices of human cerebral blood flow control: responses to augmented blood pressure oscillations.
        J. Physiol. 2004; 559: 965-973
        • Hilz M.J.
        • Koehn J.
        • Tillmann A.
        • Riss S.
        • Marthol H.
        • Kohrmann M.
        • Stemper B.
        Autonomic blockade during sinusoidal baroreflex activation proves sympathetic modulation of cerebral blood flow velocity.
        Stroke. 2013; 44: 1062-1069
        • Hinojosa-Laborde C.
        • Ryan K.L.
        • Rickards C.A.
        • Convertino V.A.
        Resting sympathetic baroreflex sensitivity in subjects with low and high tolerance to central hypovolemia induced by lower body negative pressure.
        Front. Physiol. 2014; 5: 241
        • Hinojosa-Laborde C.
        • Shade R.E.
        • Muniz G.W.
        • Bauer C.
        • Goei K.A.
        • Pidcoke H.F.
        • Convertino V.A.
        Validation of lower body negative pressure as an experimental model of hemorrhage.
        J. Appl. Physiol. 2014; 116: 406-415
        • Hisdal J.
        • Toska K.
        • Walloe L.
        Beat-to-beat cardiovascular responses to rapid, low-level LBNP in humans.
        Am. J. Physiol. Regul. Integr. Comp. Physiol. 2001; 281: R213-R221
        • Horsman H.M.
        • Peebles K.C.
        • Tzeng Y.C.
        Interactions between breathing rate and low-frequency fluctuations in blood pressure and cardiac intervals.
        J. Appl. Physiol. 2015; 119: 793-798
        • Iatsenko D.
        • Bernjak A.
        • Stankovski T.
        • Shiogai Y.
        • Owen-Lynch P.J.
        • Clarkson P.B.
        • Stefanovska A.
        Evolution of cardiorespiratory interactions with age.
        Philos. Trans. A Math. Phys. Eng. Sci. 2013; 371: 20110622
        • Intharakham K.
        • Beishon L.
        • Panerai R.B.
        • Haunton V.J.
        • Robinson T.G.
        Assessment of cerebral autoregulation in stroke: a systematic review and meta-analysis of studies at rest.
        J. Cereb. Blood Flow Metab. 2019; 39: 2105-2116
        • Julien C.
        The enigma of Mayer waves: facts and models.
        Cardiovasc. Res. 2006; 70: 12-21
        • Keissar K.
        • Davrath L.R.
        • Akselrod S.
        Coherence analysis between respiration and heart rate variability using continuous wavelet transform.
        Philos. Trans. A Math. Phys. Eng. Sci. 2009; 367: 1393-1406
        • Keselbrener L.
        • Akselrod S.
        Selective discrete Fourier transform algorithm for time-frequency analysis: method and application on simulated and cardiovascular signals.
        IEEE Trans. Biomed. Eng. 1996; 43: 789-802
        • Kim D.I.
        • Tan C.O.
        Alterations in autonomic cerebrovascular control after spinal cord injury.
        Auton. Neurosci. 2018; 209: 43-50
        • Lancaster G.
        • Iatsenko D.
        • Pidde A.
        • Ticcinelli V.
        • Stefanovska A.
        Surrogate data for hypothesis testing of physical systems.
        Phys. Rep. 2018; 748: 1-60
        • Larsen P.D.
        • Tzeng Y.C.
        • Sin P.Y.
        • Galletly D.C.
        Respiratory sinus arrhythmia in conscious humans during spontaneous respiration.
        Respir. Physiol. Neurobiol. 2010; 174: 111-118
        • Latka M.
        • Turalska M.
        • Glaubic-Latka M.
        • Kolodziej W.
        • Latka D.
        • West B.J.
        Phase dynamics in cerebral autoregulation.
        Am. J. Physiol. Heart Circ. Physiol. 2005; 289: H2272-H2279
        • Lee Y.K.
        • Rothwell P.M.
        • Payne S.J.
        • Webb A.J.S.
        Reliability, reproducibility and validity of dynamic cerebral autoregulation in a large cohort with transient ischaemic attack or minor stroke.
        Physiol. Meas. 2020; 41095002
        • Levine B.D.
        • Giller C.A.
        • Lane L.D.
        • Buckey J.C.
        • Blomqvist C.G.
        Cerebral versus systemic hemodynamics during graded orthostatic stress in humans.
        Circulation. 1994; 90: 298-306
        • Maharatna K.
        • Bonfiglio S.
        Systems Design for Remote Healthcare.
        Springer, New York2013
        • Meel-van den Abeelen A.S.
        • van Beek A.H.
        • Slump C.H.
        • Panerai R.B.
        • Claassen J.A.
        Transfer function analysis for the assessment of cerebral autoregulation using spontaneous oscillations in blood pressure and cerebral blood flow.
        Med. Eng. Phys. 2014; 36: 563-575
        • Meng L.
        • Hou W.
        • Chui J.
        • Han R.
        • Gelb A.W.
        Cardiac output and cerebral blood flow: the integrated regulation of brain perfusion in adult humans.
        Anesthesiology. 2015; 123: 1198-1208
        • Mitsis G.D.
        • Poulin M.J.
        • Robbins P.A.
        • Marmarelis V.Z.
        Nonlinear modeling of the dynamic effects of arterial pressure and CO2 variations on cerebral blood flow in healthy humans.
        IEEE Trans. Biomed. Eng. 2004; 51: 1932-1943
        • Mitsis G.D.
        • Zhang R.
        • Levine B.D.
        • Marmarelis V.Z.
        Cerebral hemodynamics during orthostatic stress assessed by nonlinear modeling.
        J. Appl. Physiol. 2006; 101: 354-366
        • Morlet J.
        Sampling theory and wave propagation.
        in: Chen C.H. Issues in Acoustic Signal — Image Processing and Recognition. Springer, Berlin Heidelberg, Berlin, Heidelberg1983: 233-261
        • Ogoh S.
        • Tarumi T.
        Cerebral blood flow regulation and cognitive function: a role of arterial baroreflex function.
        J. Physiol. Sci. 2019; 69: 813-823
        • Ogoh S.
        • Brothers R.M.
        • Barnes Q.
        • Eubank W.L.
        • Hawkins M.N.
        • Purkayastha S.
        • Raven P.B.
        The effect of changes in cardiac output on middle cerebral artery mean blood velocity at rest and during exercise.
        J. Physiol. 2005; 569: 697-704
        • Panerai R.B.
        Nonstationarity of dynamic cerebral autoregulation.
        Med. Eng. Phys. 2014; 36: 576-584
        • Papademetriou M.D.
        • Tachtsidis I.
        • Elliot M.J.
        • Hoskote A.
        • Elwell C.E.
        Multichannel near infrared spectroscopy indicates regional variations in cerebral autoregulation in infants supported on extracorporeal membrane oxygenation.
        J. Biomed. Opt. 2012; 17067008
        • Peng T.
        • Rowley A.B.
        • Ainslie P.N.
        • Poulin M.J.
        • Payne S.J.
        Wavelet phase synchronization analysis of cerebral blood flow autoregulation.
        IEEE Trans. Biomed. Eng. 2010; 57: 960-968
        • Porta A.
        • Gelpi F.
        • Bari V.
        • Cairo B.
        • De Maria B.
        • Tonon D.
        • Faes L.
        Categorizing the role of respiration in cardiovascular and cerebrovascular variability interactions.
        IEEE Trans. Biomed. Eng. 2022; 69: 2065-2076
        • Purkayastha S.
        • Maffuid K.
        • Zhu X.
        • Zhang R.
        • Raven P.B.
        The influence of the carotid baroreflex on dynamic regulation of cerebral blood flow and cerebral tissue oxygenation in humans at rest and during exercise.
        Eur. J. Appl. Physiol. 2018; 118: 959-969
        • Robertson A.D.
        • Papadhima I.
        • Edgell H.
        Sex differences in the autonomic and cerebrovascular responses to upright tilt.
        Auton. Neurosci. 2020; 229102742
        • Schreiber T.
        • Schmitz A.
        Surrogate time series.
        Physica D. 2000; 142: 346-382
        • Sheppard L.W.
        • Stefanovska A.
        • McClintock P.V.
        Testing for time-localized coherence in bivariate data.
        Phys. Rev. E Stat. Nonlinear Soft Matter Phys. 2012; 85046205
        • Skytioti M.
        • Sovik S.
        • Elstad M.
        Internal carotid artery blood flow in healthy awake subjects is reduced by simulated hypovolemia and noninvasive mechanical ventilation.
        Physiol. Rep. 2016; 4
        • Skytioti M.
        • Sovik S.
        • Elstad M.
        Respiration-related cerebral blood flow variability increases during control-mode non-invasive ventilation in normovolemia and hypovolemia.
        Eur. J. Appl. Physiol. 2017; : 2237-2249
        • Skytioti M.
        • Sovik S.
        • Elstad M.
        Dynamic cerebral autoregulation is preserved during isometric handgrip and head-down tilt in healthy volunteers.
        Physiol. Rep. 2018; 6e13656
        • Stefanovska A.
        • Bracic M.
        • Kvernmo H.D.
        Wavelet analysis of oscillations in the peripheral blood circulation measured by laser Doppler technique.
        IEEE Trans. Biomed. Eng. 1999; 46: 1230-1239
        • Tan C.O.
        Defining the characteristic relationship between arterial pressure and cerebral flow.
        J. Appl. Physiol. 2012; : 1194-1200
        • Tan C.O.
        • Taylor J.A.
        Integrative physiological and computational approaches to understand autonomic control of cerebral autoregulation.
        Exp. Physiol. 2014; 99: 3-15
        • Theiler J.
        • Eubank S.
        • Longtin A.
        • Galdrikian B.
        • Doyne Farmer J.
        Testing for nonlinearity in time series: the method of surrogate data.
        Physica D. 1992; 58: 77-94
        • Tian F.
        • Tarumi T.
        • Liu H.
        • Zhang R.
        • Chalak L.
        Wavelet coherence analysis of dynamic cerebral autoregulation in neonatal hypoxic-ischemic encephalopathy.
        Neuroimage Clin. 2016; 11: 124-132
        • Toska K.
        • Eriksen M.
        Respiration-synchronous fluctuations in stroke volume, heart rate and arterial pressure in humans.
        J. Physiol. 1993; 472: 501-512
        • Tzeng Y.C.
        • Panerai R.B.
        CrossTalk proposal: dynamic cerebral autoregulation should be quantified using spontaneous blood pressure fluctuations.
        J. Physiol. 2018; 596: 3-5
        • Tzeng Y.C.
        • Lucas S.J.
        • Atkinson G.
        • Willie C.K.
        • Ainslie P.N.
        Fundamental relationships between arterial baroreflex sensitivity and dynamic cerebral autoregulation in humans.
        J. Appl. Physiol. 2010; 108: 1162-1168
        • Unser M.
        • Aldroubi A.
        A review of wavelets in biomedical applications.
        Proc. IEEE. 1996; 84: 626-638
        • Zhang R.
        • Zuckerman J.H.
        • Giller C.A.
        • Levine B.D.
        Transfer function analysis of dynamic cerebral autoregulation in humans.
        Am. J. Phys. 1998; 274: H233-H241
        • Zhang R.
        • Zuckerman J.H.
        • Iwasaki K.
        • Wilson T.E.
        • Crandall C.G.
        • Levine B.D.
        Autonomic neural control of dynamic cerebral autoregulation in humans.
        Circulation. 2002; 106: 1814-1820