J Physiol 591.20 (2013) pp 4959–4960 4959

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The cerebovasculature: a smooth(muscle) operator?

David A. Low1,2

1Research Institute of Sport and ExerciseSciences, Faculty of Science, Liverpool JohnMoores University, UK2Autonomic and Neurovascular MedicineUnit, Department of Medicine, Faculty ofMedicine, Imperial College London at StMary’s Hospital, London, UK

Email: d.a.low@ljmu.ac.uk

The maintenance of cerebral perfusionis critical for optimal cognitive function,and its autoregulation is vital forthe maintenance of blood flow andoxygenation during changes in arterialblood pressure. The mechanisms ofcerebral autoregulation are thought toinvolve neurogenic, metabolic and intrinsicmyogenic processes (Peterson et al.2011). The myogenic process involves acalcium-dependent pathway in smoothmuscle that responds to changes inperfusion pressure and vascular wall tension(Potocnik et al. 2000). Previous studies haveprovided equivocal data on whether themyogenic response actually does modulatecerebral autoregulation, probably due todifficulties in blocking and separating thevarious mechanisms.

A study by Tan and colleagues (2013)in this issue of The Journal of Physiologyprovides compelling evidence for therole of myogenic mechanisms in cerebralautoregulation in humans. Furthermore,most previous studies have adopted linearinput–output models, e.g. cross-spectralanalysis, for the analyses of arterialblood pressure and cerebral blood flowfluctuations. Cerebral autoregulation isinherently non-linear, however, particularlyat slower frequencies. In their study,Tan and colleagues (2013) have alsointroduced a novel assessment approachthat takes into account the non-linearityof cerebral autoregulation. These authorsexamined cerebral blood flow responses(using transcranial Doppler ultrasoundof the middle cerebral artery) to arterialpressure oscillations (∼15–20 mmHg;similar to changes that occur when movingfrom sitting to a standing position) thatwere provoked by oscillatory lower body

negative pressure (−30 mmHg) acrossa range of frequencies (0.03–0.08 Hz).These experiments were conductedwith and without nicardipine hydro-chloride administration, which blocksL-type calcium channels on vascularsmooth muscle and thus the myogenicresponse. Tan and colleagues (2013)used a novel approach called projectionpursuit regression for the analysis ofthe relationship between fluctuations inarterial pressure and cerebral blood flow.This is a non-linear, non-parametric,atheoretical method wherein a model isnot posited a priori, but derived directlyfrom the variables of interest, allowingnon-linearities in the input–output relationto be revealed. Projection pursuit regressionmodifies the usual linear regression byallowing more than one function, orrelationship, of input to output. Each ofthese functions is analysed and points wherethe relationship between arterial pressureand cerebral blood flow fluctuations changeand the range within which the relation isapproximately linear (the ‘autoregulatory’slope) are identified.

There were two novel findings of thestudy. Firstly, projection pursuit regressionexplained more than half the variationbetween arterial pressure and cerebralblood flow fluctuations and revealedthe characteristic non-linear relationshipbetween pressure and flow fluctuations,namely two relatively passive regionswherein changes in arterial pressure aretransmitted into cerebral blood flow almostlinearly, and an autoregulatory regionwithin which slow (∼30 s) changes in bloodpressure were buffered against. The secondmain finding of the study was that calciumchannel blockade significantly altered thenon-linearity between pressure and flow,particularly at the slowest fluctuations, e.g.at 0.03 Hz oscillatory lower body negativepressure, halving the range of pressurefluctuations that could be effectivelybuffered against by the cerebrovasculatureand increased the autoregulatory slopealmost 5-fold. These findings indicate thatwhen myogenic mechanisms are blocked areduced cerebral autoregulation is evident –for the same change in pressure a greaterchange in flow occurs. These results werestill evident after changes in arterial CO2,a key modulator of cerebral blood flow,

were accounted for. Interestingly, Tanet al. also conducted linear input–outputcross-spectral analysis of the pressure andflow data and found no changes in thecross-spectral gain (the relative amplitudeof the relationship between pressure andflow) and coherence (the linear relationshipbetween pressure and flow) functions ofthe pressure and flow fluctuations aftercalcium channel blockade. According to thistechnique, these results suggest that cerebralautoregulation was not affected by calciumchannel blockade, as previously reported(Tzeng et al. 2011). Tan and colleaguessuggested that the contrasting results ofthe linear cross-spectral analysis and theprojection pursuit regression in their studycould be due to the effective buffering ofpressure fluctuations, i.e. the autoregulationitself, affecting the linear cross-spectralindices of autoregulation, namely gainand coherence, and furthermore, althoughlinear approaches may indicate the pre-sence or absence of cerebral autoregulation,they are unable to describe the non-linearcharacteristics of cerebral autoregulation.

Overall, the study by Tan et al. (2013)provides valuable new information on thephysiology and assessment of cerebral auto-regulation and suggests several avenues forfurther investigation in this growing field.The evidence for myogenic mechanismsplaying a role in cerebrovascular regulationhas implications for disease such as strokeor traumatic brain injury, and for situationswhere cerebral perfusion is challengedor impaired (e.g. orthostasis or exercise).Furthermore, examining the extent of myo-genic control of the cerebrovasculaturein regional vascular beds in addition toutilising other methods for investigatingthe cerebral circulation (e.g. carotidand vertebral artery ultrasonography,the transcerebral exchange approach)could provide further characterisation ofcerebrovascular control. Cerebral auto-regulation is influenced by metabolic andneurogenic factors and further studies ofinteractions with these processes wouldallow an integrated approach to the studyof the cerebrovasculature. Moreover, theability of projection pursuit regression todetermine the non-linear characteristicsof cerebral autoregulation may afford anadvantage over linear analysis methods inthe investigation of cerebral autoregulation

C© 2013 The Author. The Journal of Physiology C© 2013 The Physiological Society DOI: 10.1113/jphysiol.2013.264291

4960 Perspectives J Physiol 591.20

and physiology, as well as providing aninstrument for assessing and monitoringcerebrovascular disease.

References

Peterson EC, Wang Z & Britz G (2011). Int J ofVasc Med 2011, 823525.

Potocnik SJ, Murphy TV, Kotecha N & Hill MA(2000). Brit J Pharmacol 131, 1065–1072.

Tan CO (2012). J Appl Physiol 113,1194–1200.

Tan CO, Hamner JW & Taylor JA (2013).J Physiol 591, 5095–5105.

Tzeng YC, Chan GS, Willie CK & Ainslie PN(2011). J Physiol 589, 3263–3274.

Additional information

Competing interests

None declared.

Funding

None

C© 2013 The Authors. The Journal of Physiology C© 2013 The Physiological Society