J. W. Hamner

Spectral indices of human cerebral blood flow control: responses to augmented blood pressure oscillations

We set out to fully examine the frequency domain relationship between arterial pressure and cerebral blood flow. Oscillatory lower body negative pressure (OLBNP) was used to create consistent blood pressure oscillations of varying frequency and amplitude to rigorously test for a frequency‐ and/or amplitude‐dependent relationship between arterial pressure and cerebral flow. We also examined the predictions from OLBNP data for the cerebral flow response to the stepwise drop in pressure subsequent to deflation of ischaemic thigh cuffs. We measured spectral powers, cross‐spectral coherence, and transfer function gains and phases in arterial pressure and cerebral flow during three amplitudes (0, 20, and 40 mmHg) and three frequencies (0.10, 0.05, and 0.03 Hz) of OLBNP in nine healthy young volunteers. Pressure fluctuations were directly related to OLBNP amplitude and inversely to OLBNP frequency. Although cerebral flow oscillations were increased, they did not demonstrate the same frequency dependence seen in pressure oscillations. The overall pattern of the pressure–flow relation was of decreasing coherence and gain and increasing phase with decreasing frequency, characteristic of a high‐pass filter. Coherence between pressure and flow was increased at all frequencies by OLBNP, but was still significantly lower at frequencies below 0.07 Hz despite the augmented pressure input. In addition, predictions of thigh cuff data from spectral estimates were extremely inconsistent and highly variable, suggesting that cerebral autoregulation is a frequency‐dependent mechanism that may not be fully characterized by linear methods.

Cholinergic control of the cerebral vasculature in humans

•  Cerebral autoregulation maintains cerebral perfusion relatively constant in the face of slow changes in arterial pressure, but is less effective against more rapid changes (i.e. functions as a ‘high‐pass’ filter). •  While thought to be maintained mainly through myogenic adjustments to changes in transmural pressure, recent work has highlighted a possibility of active autonomic involvement in cerebral autoregulation. •  In this study we examined the cerebrovascular effects of cholinergic blockade on nine healthy volunteers during the application of oscillatory lower body pressure at six frequencies from 0.03 to 0.08 Hz. •  Cholinergic blockade impaired autoregulation at frequencies above 0.04 Hz, suggesting a role for active cholinergic vasodilatation in the maintenance of cerebral perfusion.

Relative Contributions of Sympathetic, Cholinergic, and Myogenic Mechanisms to Cerebral Autoregulation

Background and Purpose— Prior work aimed at improving our understanding of human cerebral autoregulation has explored individual physiological mechanisms of autoregulation in isolation, but none has attempted to consolidate the individual roles of these mechanisms into a comprehensive model of the overall cerebral pressure–flow relationship. Methods— We retrospectively analyzed this relationship before and after pharmacological blockade of &agr;-adrenergic–, muscarinic-, and calcium channel–mediated mechanisms in 43 healthy volunteers to determine the relative contributions of the sympathetic, cholinergic, and myogenic controllers to cerebral autoregulation. Projection pursuit regression was used to assess the effect of pharmacological blockade on the cerebral pressure–flow relationship. Subsequently, ANCOVA decomposition was used to determine the cumulative effect of these 3 mechanisms on cerebral autoregulation and whether they can fully explain it. Results— Sympathetic, cholinergic, and myogenic mechanisms together accounted for 62% of the cerebral pressure–flow relationship (P<0.05), with significant and distinct contributions from each of the 3 effectors. ANCOVA decomposition demonstrated that myogenic effectors were the largest determinant of the cerebral pressure–flow relationship, but their effect was outside of the autoregulatory region where neurogenic control appeared prepotent. Conclusions— Our results suggest that myogenic effects occur outside the active region of autoregulation, whereas neurogenic influences are largely responsible for cerebral blood flow control within it. However, our model of cerebral autoregulation left 38% of the cerebral pressure–flow relationship unexplained, suggesting that there are other physiological mechanisms that contribute to cerebral autoregulation.

The role of myogenic mechanisms in human cerebrovascular regulation

•  The autoregulatory capacity of the cerebral vasculature allows for maintenance of relatively stable blood flow in the face of fluctuating arterial pressure to protect neural tissue from wide swings in oxygen and nutrient delivery. •  We recently found that neurogenic control plays an active role in autoregulation. Although myogenic pathways have also been hypothesized to play a role, previous data have not provided an unequivocal answer. •  We examined cerebral blood flow responses to augmented arterial pressure oscillations with and without calcium channel blockade, and characterized autoregulation via a robust non‐linear method. •  Blockade significantly altered the non‐linearity between pressure and flow, particularly at the slowest fluctuations, and the same rate of change in pressure elicited a larger change in flow than at baseline. •  These results show that myogenic mechanisms also play a significant role in cerebrovascular regulation, and help us better understand physiological mechanisms that underlie cerebral autoregulation in humans.

Characterizing Sympathetic Neurovascular Transduction in Humans

Despite its critical role for cardiovascular homeostasis in humans, only a few studies have directly probed the transduction of sympathetic nerve activity to regional vascular responses – sympathetic neurovascular transduction. Those that have variably relied on either vascular resistance or vascular conductance to quantify the responses. However, it remains unclear which approach would better reflect the physiology. We assessed the utility of both of these as well as an alternative approach in 21 healthy men. We recorded arterial pressure (Finapres), peroneal sympathetic nerve activity (microneurography), and popliteal blood flow (Doppler) during isometric handgrip exercise to fatigue. We quantified and compared transduction via the relation of sympathetic activity to resistance and to conductance and via an adaptation of Poiseuille’s relation including pressure, sympathetic activity, and flow. The average relationship between sympathetic activity and resistance (or conductance) was good when assessed over 30-second averages (mean R2 = 0.49±0.07) but lesser when incorporating beat-by-beat time lags (R2 = 0.37±0.06). However, in a third of the subjects, these relations provided relatively weak estimates (R2<0.33). In contrast, the Poiseuille relation reflected vascular responses more accurately (R2 = 0.77±0.03, >0.50 in 20 of 21 individuals), and provided reproducible estimates of transduction. The gain derived from the relation of resistance (but not conductance) was inversely related to transduction (R2 = 0.37, p<0.05), but with a proportional bias. Thus, vascular resistance and conductance may not always be reliable surrogates for regional sympathetic neurovascular transduction, and assessment from a Poiseuille relation between pressure, sympathetic nerve activity, and flow may provide a better foundation to further explore differences in transduction in humans.

Transcranial direct current stimulation (tDCS) and the cardiovascular responses to acute pain in humans.

OBJECTIVE To determine if transcranial direct current stimulation (tDCS) reduces both acute pain perception and the resultant cardiovascular responses. METHODS Data were acquired on 15 healthy subjects at rest and in response to three cold pressor tests: 0, 7, and 14 °C. Subsequently, single sessions of sham and active anodal tDCS (2.0 mA for 40 min) were delivered to the left primary motor cortex (M1). RESULTS Perceived pain was reduced only after active tDCS with the 14 °C cold pressor test. This was accompanied by tendency for lesser increases in heart rate (~2 beats/min, p=0.09) and blood pressure (~3 mmHg, p=0.06). The effect size of tDCS on peak heart rate and blood pressure responses at 14 °C was 0.47 and 0.54, respectively. On the other hand, baseline heart rate, blood pressure, leg blood flow, and leg vascular resistance were unaffected by tDCS. No other responses were affected. CONCLUSIONS Our results demonstrate that M1 anodal tDCS has no effect on basal hemodynamics or cardiovascular autonomic outflow and has only modest effects on the responses to acute pain in healthy humans. SIGNIFICANCE Application of tDCS shifts the pain perception threshold in healthy individuals but does not significantly modulate efferent cardiovascular control at rest or in response to pain.

Alterations in sympathetic neurovascular transduction during acute hypoxia in humans

Resting vascular sympathetic outflow is significantly increased during and beyond exposure to acute hypoxia without a parallel increase in either resistance or pressure. This uncoupling may indicate a reduction in the ability of sympathetic outflow to effect vascular responses (sympathetic transduction). However, the effect of hypoxia on sympathetic transduction has not been explored. We hypothesized that transduction would either remain unchanged or be reduced by isocapnic hypoxia. In 11 young healthy individuals, we measured beat-by-beat pressure, multiunit sympathetic nerve activity, and popliteal blood flow velocity at rest and during isometric handgrip exercise to fatigue, before and during isocapnic hypoxia (~80% SpO₂), and derived sympathetic transduction for each subject via a transfer function that reflects Poiseuilles law of flow. During hypoxia, heart rate and sympathetic nerve activity increased, whereas pressure and flow remained unchanged. Both normoxic and hypoxic exercise elicited significant increases in heart rate, pressure, and sympathetic activity, although sympathetic responses to hypoxic exercise were blunted. Hypoxia slightly increased the gain relation between pressure and flow (0.062 ± 0.006 vs. 0.074 ± 0.004 cm·s(-1)·mmHg(-1); P = 0.04), but markedly increased sympathetic transduction (-0.024 ± 0.005 vs. -0.042 ± 0.007 cm·s(-1)·spike(-1); P < 0.01). The pressor response to isometric handgrip was similar during normoxic and hypoxic exercise due to the balance of interactions among the tachycardia, sympathoexcitation, and transduction. This indicates that the ability of sympathetic activity to affect vasoconstriction is enhanced during brief exposure to isocapnic hypoxia, and this appears to offset the potent vasodilatory stimulus of hypoxia.

Relative Contributions of Systemic Hemodynamic Variables to Cerebral Autoregulation during Orthostatic Stress

Postural changes impair the ability of the cerebrovasculature to buffer against dynamic pressure fluctuations, but the mechanisms underlying this impairment have not been elucidated. We hypothesized that autoregulatory impairment may reflect the impact of static central volume shifts on hemodynamic factors other than arterial pressure (AP). In 14 young volunteers, we assessed the relation of fluctuations in cerebral blood flow (CBF) to those in AP, cardiac output, and CO2, during oscillatory lower body pressure (LBP) (±20 mmHg at 0.01 and 0.06 Hz) at three static levels (-20, 0, and +20 mmHg). Static and dynamic changes in AP, cardiac output, and CO2 explained over 70% of the variation in CBF fluctuations. However, their contributions were different across frequencies and levels: dynamic AP changes explained a substantial proportion of the variation in faster CBF fluctuations (partial R2 = 0.75, standardized β = 0.83, P < 0.01), whereas those in CO2 explained the largest portion of the variation in slow fluctuations (partial R2 = 0.43, β = 0.51, P < 0.01). There was, however, a major contribution of slow dynamic AP changes during negative (β = 0.43) but not neutral (β = 0.05) or positive (β = -0.07) LBP. This highlights the differences in contributions of systemic variables to dynamic and static autoregulation and has important implications for understanding orthostatic intolerance. NEW & NOTEWORTHY While fluctuations in blood pressure drive faster fluctuations in cerebral blood flow, overall level of CO2 and the magnitude of its fluctuations, along with cardiac output, determine the magnitude of slow ones. The effect of slow blood pressure fluctuations on cerebrovascular responses becomes apparent only during pronounced central volume shifts (such as when standing). This underlines distinct but interacting contributions of static and dynamic changes in systemic hemodynamic variables to the cerebrovascular regulation.

Assessing Cerebral Autoregulation via Oscillatory Lower Body Negative Pressure and Projection Pursuit Regression

The process by which cerebral perfusion is maintained constant over a wide range of systemic pressures is known as “cerebral autoregulation.” Effective dampening of flow against pressure changes occurs over periods as short as ~15 sec and becomes progressively greater over longer time periods. Thus, slower changes in blood pressure are effectively blunted and faster changes or fluctuations pass through to cerebral blood flow relatively unaffected. The primary difficulty in characterizing the frequency dependence of cerebral autoregulation is the lack of prominent spontaneous fluctuations in arterial pressure around the frequencies of interest (less than ~0.07 Hz or ~15 sec). Oscillatory lower body negative pressure (OLBNP) can be employed to generate oscillations in central venous return that result in arterial pressure fluctuations at the frequency of OLBNP. Moreover, Projection Pursuit Regression (PPR) provides a nonparametric method to characterize nonlinear relations inherent in the system without a priori assumptions and reveals the characteristic non-linearity of cerebral autoregulation. OLBNP generates larger fluctuations in arterial pressure as the frequency of negative pressure oscillations become slower; however, fluctuations in cerebral blood flow become progressively lesser. Hence, the PPR shows an increasingly more prominent autoregulatory region at OLBNP frequencies of 0.05 Hz and below (20 sec cycles). The goal of this approach it to allow laboratory-based determination of the characteristic nonlinear relationship between pressure and cerebral flow and could provide unique insight to integrated cerebrovascular control as well as to physiological alterations underlying impaired cerebral autoregulation (e.g., after traumatic brain injury, stroke, etc.).

Response to Letter Regarding Article, “Relative Contributions of Sympathetic, Cholinergic, and Myogenic Mechanisms to Cerebral Autoregulation”

We thank Dr Shang1 for his interest in our study.2 We assessed cerebral autoregulation based on the relation between fluctuations in arterial pressure and those in middle cerebral artery blood flow before and after pharmacological blockade of 3 proposed mechanisms. The data suggested that α-adrenergic, cholinergic, and myogenic mechanisms collectively accounted for 62% of the relation between pressure and cerebral blood flow. However, implicit in our approach was the assumption that middle cerebral artery blood flow responses encompass the entirety of autoregulation across the cerebrovascular bed within the middle cerebral artery territory. In his letter, Dr Shang suggests that this assumption may be in error. In particular, he points out that regulation of the cerebral vasculature is segmental. First, there are fundamental …