Can Ozan Tan

Sympathetic Control of the Cerebral Vasculature in Humans

Background and Purpose— The role of the sympathetic nervous system in cerebral autoregulation remains poorly characterized. We examined cerebral blood flow responses to augmented arterial pressure oscillations with and without sympathetic blockade and compared them with responses in the forearm circulation. Methods— An oscillatory lower body negative pressure of 40 mm Hg was used at 6 frequencies from 0.03 to 0.08 Hz in 11 healthy subjects with and without &agr;-adrenergic blockade by phentolamine. Results— Sympathetic blockade resulted in unchanged mean pressure and cerebral flow. The transfer function relationship to arterial pressure at frequencies >0.05 Hz was significantly increased in both the cerebral and brachial circulations, but the coherence of the relation remained weak at the lowest frequencies in the cerebral circulation. Conclusion— Our data demonstrate a strong, frequency-dependent role for sympathetic regulation of blood flow in both cerebral and brachial circulations. However, marked differences in the response to blockade suggest the control of the cerebral circulation at longer time scales is characterized by important nonlinearities and relies on regulatory mechanisms other than the sympathetic system.

Fractal properties of human heart period variability: physiological and methodological implications

Fractal frequency scaling of heart period variability is used as a concise index of overall cardiac control. However, no prior study has assessed within‐individual reproducibility of fractal indices of heart period, or reported how the estimated indices respond to autonomic blockade. Therefore, we examined fractal properties of the heart period from ten young, healthy individuals during three separate experimental sessions under control (saline) conditions and twice under combined autonomic blockade (atenolol and atropine sulfate) conditions. Under each condition, R‐R intervals were recorded with the subject in the supine and the 40 deg upright tilt positions during 20 min of controlled breathing in each position. We calculated the fractal scaling exponent using detrended fluctuation analysis and estimated confidence intervals of the scaling exponents for each R‐R interval time series within each individual. In the control condition, upright tilt significantly increased the scaling exponents (from 0.73 ± 0.11 (±s.d., session 1), 0.72 ± 0.10 (session 2) and 0.75 ± 0.13 (session 3) to 0.82 ± 0.12, 0.82 ± 0.11 and 0.84 ± 0.10; Students paired t‐test, t= 2.79, P= 0.02; t= 2.80, P= 0.02; and t= 2.07, P= 0.07). However, neither the absolute scaling exponents nor their change in response to upright tilt were reproducible (Lins concordance coefficient less than 0.9, P > 0.1 for all comparisons). Following autonomic blockade, the scaling exponents were significantly increased (supine: 1.08 ± 0.13 and 1.08 ± 0.14; tilt: 1.07 ± 0.21 and 1.08 ± 0.14) for both experimental sessions (two‐way repeated‐measures ANOVA; F17,1= 40.89, P < 0.001 and F17,1= 42.72, P < 0.001) regardless of position. However, within individuals, the scaling exponents failed to distinguish between control and blockade for half of the subjects in at least one experimental session. Thus, fractal scaling exponents are not reproducible within individuals and do not reliably reflect the autonomic mechanisms responsible for heart period variability. In fact, data from combined blockade suggest that physiological effects of autonomic outflow may mask intrinsic fractal behaviour of the sinoatrial node.

Impaired Cerebral Autoregulation Is Associated With Vasospasm and Delayed Cerebral Ischemia in Subarachnoid Hemorrhage

Background and Purpose— Cerebral autoregulation may be impaired in the early days after subarachnoid hemorrhage (SAH). The purpose of this study was to examine the relationship between cerebral autoregulation and angiographic vasospasm (aVSP) and radiographic delayed cerebral ischemia (DCI) in patients with SAH. Methods— Sixty-eight patients (54±13 years) with a diagnosis of nontraumatic SAH were studied. Dynamic cerebral autoregulation was assessed using transfer function analysis (phase and gain) of the spontaneous blood pressure and blood flow velocity oscillations on days 2 to 4 post-SAH. aVSP was diagnosed using a 4-vessel conventional angiogram. DCI was diagnosed from CT. Decision tree models were used to identify optimal cut-off points for clinical and physiological predictors of aVSP and DCI. Multivariate logistic regression models were used to develop and validate a risk scoring tool for each outcome. Results— Sixty-two percent of patients developed aVSP, and 19% developed DCI. Patients with aVSP had higher transfer function gain (1.06±0.33 versus 0.89±0.30; P=0.04) and patients with DCI had lower transfer function phase (17.5±39.6 versus 38.3±18.2; P=0.03) compared with those who did not develop either. Multivariable scoring tools using transfer function gain >0.98 and phase <12.5 were strongly predictive of aVSP (92% positive predictive value; 77% negative predictive value; area under the receiver operating characteristic curve, 0.92) and DCI (80% positive predictive value; 91% negative predictive value; area under the curve, 0.94), respectively. Conclusions— Dynamic cerebral autoregulation is impaired in the early days after SAH. Including autoregulation as part of the initial clinical and radiographic assessment may enhance our ability to identify patients at a high risk for developing secondary complications after SAH.

Defining the characteristic relationship between arterial pressure and cerebral flow

Reliable assessment of cerebrovascular effectiveness in buffering against pressure fluctuations may have important implications for the timing and the outcome of therapy after adverse cerebrovascular events. Although linear approaches may indicate the presence or absence of cerebral autoregulation, they are inadequate to describe its characteristics and its effectiveness. Establishing a simple yet robust methodology to reliably measure the effectiveness of cerebral autoregulation could provide a tool to guide screening and clinical options to characterize and treat adverse cerebrovascular events associated with alterations in cerebral perfusion. To test the utility of one such methodology, an oscillatory lower body negative pressure of 30-40 mmHg was used at six frequencies from 0.03 to 0.08 Hz in 43 healthy volunteers, and the pressure-flow relation and the effectiveness of autoregulation was quantified using projection pursuit regression. Projection pursuit regression explained the majority of the relationship between pressure and cerebral blood flow fluctuations and revealed its nature consistently across individuals and across separate study days. The nature of this relationship entailed an autoregulatory region wherein slow arterial pressure fluctuations are effectively counterregulated and two passive regions wherein pressure fluctuations resulted in parallel changes in flow. The effectiveness of autoregulation was significantly reduced as pressure fluctuations became faster. These results demonstrate the characteristic relationship between arterial pressure and cerebral blood flow. Furthermore, the methodology utilized in this study provides a tool that can provide unique insight to integrated cerebrovascular control and may allow diagnosis of physiological alterations underlying impaired cerebral autoregulation.

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.

Attenuated inspiratory muscle metaboreflex in endurance-trained individuals

The inspiratory metaboreflex is activated during loaded breathing to task failure and induces sympathetic activation and peripheral vasoconstriction that may limit exercise performance. Inspiratory muscle training appears to attenuate the inspiratory metaboreflex in healthy subjects. Since whole body aerobic exercise training improves breathing endurance and inspiratory muscle strength, we hypothesized that endurance-trained individuals would demonstrate a blunted inspiratory muscle metaboreflex in comparison to sedentary individuals. We studied 9 runners (23±0.7 years; maximal oxygen uptake [VO2 max] = 53 ± 4 ml kg(-1) min(-1)) and 9 sedentary healthy volunteers (24±0.7 years; VO2 max = 37 ±2 ml kg(-1) min(-1)). The inspiratory muscle metaboreflex was induced by breathing against an inspiratory load of 60% of maximal inspiratory pressure (MIP), with prolonged duty cycle. Arterial pressure, popliteal blood flow, and heart rate were measured throughout the protocol. Loaded breathing to task failure increased mean arterial pressure in both sedentary and endurance-trained individuals (96±3 to 100±4 mmHg and 101±3 to 110±5 mmHg). Popliteal blood flow decreased in sedentary but not in trained individuals (0.179±0.01 to 0.141±0.01 cm/s, and 0.211±0.02 to 0.214±0.02 cm/s). Similarly, popliteal vascular resistance increased in sedentary but not in trained individuals (559±35 to 757±56 mmHg s/cm, and 528±69 to 558±64 mmHg s/cm). These data demonstrate that endurance-trained individuals have an attenuated inspiratory muscle metaboreflex.

Cerebrovascular regulation, exercise, and mild traumatic brain injury

A substantial number of people who sustain a mild traumatic brain injury report persistent symptoms. Most common among these symptoms are headache, dizziness, and cognitive difficulties. One possible contributor to sustained symptoms may be compromised cerebrovascular regulation. In addition to injury-related cerebrovascular dysfunction, it is possible that prolonged rest after mild traumatic brain injury leads to deconditioning that may induce physiologic changes in cerebral blood flow control that contributes to persistent symptoms in some people. There is some evidence that exercise training may reduce symptoms perhaps because it engages an array of cerebrovascular regulatory mechanisms. Unfortunately, there is very little work on the degree of impairment in cerebrovascular control that may exist in patients with mild traumatic brain injury, and there are no published studies on the subacute phase of recovery from this injury. This review aims to integrate the current knowledge of cerebrovascular mechanisms that might underlie persistent symptoms and seeks to synthesize these data in the context of exploring aerobic exercise as a feasible intervention to treat the underlying pathophysiology.

Integrative physiological and computational approaches to understand autonomic control of cerebral autoregulation

•  What is the topic of this review? This review focuses on the autonomic control of the cerebral vasculature in health and disease from an integrative physiological and computational perspective. •  What advances does it highlight? This review highlights recent studies exploring autonomic effectors of cerebral autoregulation as well as recent advances in experimental and analytical approaches to understand cerebral autoregulation.