Bernhard Rosengarten

Neurovascular coupling and cerebral autoregulation can be described in terms of a control system

Neurovascular coupling and cerebral autoregulation are important and fast mechanisms for maintaining an adequate blood supply to the brain. It was suggested that both mechanisms follow a common control system. The aim of our study was to describe neurovascular coupling and cerebral autoregulation in mathematical terms of a control system and to test the aforementioned hypothesis. We analyzed the input-output dynamics of neurovascular coupling (flicker light test) and cerebral autoregulation (leg cuff test) in terms of a control system, and compared both systems. A transcranial Doppler device was used to measure continuously the blood flow velocity changes in young healthy volunteers who lacked vascular risk factors. For both tests, a control system model with only four parameters was sufficient to allow the vascular reaction to be described in all (rate time, undamped natural angular frequency, attenuation, gain). All parameters were identical for both control systems, except for gain, which is not directly comparable because, in the flicker light test, input function was not measured but assumed as a unit step function in each volunteer. This new method permits description of the regulation of cerebral blood flow using a control loop with four parameters. For the first time, these parameters allowed a demonstration that cerebral autoregulation and neurovascular coupling could be governed by the same control system.

Acetylcholine esterase inhibitor donepezil improves dynamic cerebrovascular regulation in Alzheimer patients.

AbstractBackgroundAlzheimers disease (AD) leads to a degeneration of the nucleus basalis of Meynert and thus to decreased cholinergic tonus in the brain. The transcription of endothelial nitric oxide synthase depends on an adequate cholinergic innervation of microvessels and vasoregulative abnormalities have been reported in AD. We investigated activationflow coupling to study the role of acetylcholine esterase inhibition (AChEI) on vasoregulative function.MethodsA functional transcranial Doppler approach was used to measure the visually evoked flow velocity response in the posterior cerebral artery in AD patients who had no vascular risk factors. The diagnosis of AD was made according to the ICD10/DSMIIIR–criteria. After baseline recording the effect of four weeks 5mg donepezil and then four weeks 10 mg was investigated. Doppler data were evaluated with a control system approach to obtain dynamic properties of vasoregulation and were compared with a healthy control group.ResultsAD patients showed an increased damping (0.64 ± 0.2; p = 0.007 vs. control) in evoked responses and lower resting flow velocity levels (40 ± 13 cm/s; p = 0.06 vs. control), which were restored in a dose–dependent manner under AChEI (0.4 ± 0.2; 44 ± 11 cm/s).ConclusionsAD is associated with a functional vasoregulative deficit possibly due to decreased levels of the endothelial nitric oxide synthase. Augmenting levels with AChEI normalized flow regulation possibly leading to a better blood supply to active neurons.

Microcirculatory Dysfunction in the Brain Precedes Changes in Evoked Potentials in Endotoxin-Induced Sepsis Syndrome in Rats

Background: During sepsis progression microcirculatory dysfunction precedes macrocirculatory failure, partly explaining the occurrence of early organ dysfunction. The matter concerning microcirculatory dysfunction in the brain under septic conditions is less clear. We investigated the integrity of the activation flow coupling during sepsis progression in a rat model of septic shock. Methods: Chloralose-anesthetized rats (n = 30) were subjected to electric forepaw stimulation. Over the somatosensory cortex electrical activity and hemodynamic responses were recorded with surface electrodes and laser Doppler. After baseline recordings, vehicle, 1 or 5 mg/kg lipopolysaccharide (LPS) from Escherichia coli was given intravenously, and activation flow coupling, blood pressure and blood gases were investigated at regular time points up to 270 min. In the end lactate, glucose, neuron-specific enolase (NSE) and S-100B protein levels were measured. Results: Besides stable data from the control group, all LPS-treated rats developed signs of septic shock, which were more pronounced in the 5 mg/kg LPS group. Cerebral hyperemia occurred and was similar between the sepsis groups despite lower blood pressure levels in the 5 mg/kg LPS group. While the activation flow coupling remained intact in the 1 mg/kg LPS group, an uncoupling occurred in the 5 mg/kg group. First, the evoked flow velocity responses dropped 60 min after sepsis induction before the somatosensory amplitudes also decreased 120 min later. From similar NSE levels we suggest a functional rather than structural deficit explaining the difference in evoked potentials. Conclusions: For the first time we demonstrate microcirculatory dysfunction in the activation flow coupling of the brain. Inappropriate blood supply of neurons might explain the disturbance of neuronal function.

Neurovascular coupling remains unaffected during normal aging.

Background and Purpose. During normal aging, the cerebral autoregulation mechanism and the CO2‐induced cerebral reserve capacity remain unaffected. This led to the suggestion of a wide compensatory range of mechanisms responsible for the cerebral blood flow regulation. The authors investigated the neurovascular coupling mechanism for age‐related changes. Because several authors criticized the comparison between higher and younger age groups, the current authors restricted their study on volunteers between 10 and 60 years. Methods. Twenty healthy volunteers in the age group of 10 to 20, 20 to 40, and 40 to 60 each without cerebrovascular risk factors were enrolled in this study; they were aged 16.3 ± 3.4 SD years (9 boys), 32.7 ± 2.3 SD years (9 men), and 53.1 ± 5.3 SD years (10 men). A functional transcranial Doppler test was performed using a visual stimulation paradigm. The resultant flow velocity changes in the posterior cerebral artery were analyzed using a control system approach. Resting flow velocity and each of the control system parameters, which were time delay, attenuation, natural frequency, rate time, and gain, were compared between groups statistically. Results. Control system parameters remained statistically unchanged between groups, whereas the resting flow velocity decreased significantly by age. Conclusions. The neurovascular coupling mechanism seems to be unaffected by moderate aging as estimated by Doppler parameters. Vasoregulative dysfunction in patients at vascular risk is more likely to be caused by the risk factor rather than by age.

Sildenafil Improves Dynamic Vascular Function in the Brain: Studies in Patients with Pulmonary Hypertension

Background: Prostaglandins and nitric oxide play a pivotal role in the regulation of macro- and microcirculatory blood flow distribution. Interference with both mediator systems have been implicated in cerebrovascular dysfunction. Inhaled iloprost (long-acting prostacyclin analogue) and the phosphodiesterase-5 inhibitor sildenafil have recently shown efficacy in the treatment of chronic pulmonary hypertension. We investigated the impact of these agents on cerebral microcirculatory regulation in patients suffering from this disease. Methods: In 11 patients suffering from severe pulmonary hypertension, a functional transcranial Doppler test utilizing a visual stimulation paradigm was undertaken to measure the evoked flow velocity in the posterior cerebral artery. Measurements were performed in parallel to right heart catheterization and pharmacological testing of the pulmonary vasoreactivity. After assessment of baseline measurements, inhaled iloprost and oral sildenafil were given consecutively for testing of cerebral and pulmonary vascular function. The data gained from the Doppler measurements were compared to data from 22 healthy volunteers. Results: Both substances provoked a significant reduction of pulmonary arterial pressure and vascular resistance, accompanied by minor changes in systemic vascular resistance. In contrast to these superimposable hemodynamic profiles opposite effects were observed regarding cerebral vascular tone: cerebral microvascular reactivity, as assessed by attenuation and time rate parameters, was significantly improved by sildenafil, but slightly worsened by iloprost. Conclusions: Sildenafil has beneficial effects on cerebral vascular reactivity indicative of an improvement in neurovascular coupling in patients with pulmonary hypertension. These results warrant further investigations of the influence of sildenafil on dynamic vascular function in the brain independent of the underlying disease.

Neurovascular coupling in terms of a control system: validation of a second-order linear system model

Neurovascular coupling (NC) adapts cerebral blood flow to cortical activity. Functional transcranial Doppler (f-TCD) investigations revealed a typical time course of evoked blood flow responses with an initial overshoot and a stabilization at a lower, but stable, level. This blood flow reaction can be described in terms of a control-system model. We tested reliability and validity of this new approach using different stimulation paradigms. The P2 segment of the posterior cerebral artery was insonated in 14 healthy volunteers and, subsequently, NC was stimulated using two tests, a checkerboard stimulus of 1 s with different repetition rates and a reading test. Data were analyzed according to algorithms of control-system theory. The reading test was used to measure test reliability and side differences. A second-order linear system can describe blood flow regulation of NC. Different stimulation protocols of the checkerboard test and the related evoked blood flow curves could be described by the same control-system model. Further, there were no differences between the checkerboard and reading test nor between right and left side or test and retest of the reading test. NC can be described in a much more detailed manner using control-system analysis. We were able to show that blood flow response due to different visual stimuli follow one common control-system model. Unlike quantification of NC using overshoot, parameters of the control system have smaller SDs, increasing the statistical power and, thereby, usefulness of f-TCD as a diagnostic instrument.

Interplay of cerebral autoregulation and neurovascular coupling evaluated by functional TCD in different orthostatic conditions

BackgroundAdequate cerebral blood flow (CBF) is mainly governed by neurovascular coupling (NC) which adapts local CBF to underlying cortical activity, and cerebral autoregulation (CA) that tends to maintain constant CBF despite changes in arterial blood pressure (BP). Since it was suggested that resistance vessels play an important role in both mechanisms, we investigated their regulative interplay by performing a functional transcranial Doppler (f-TCD) test under different orthostatic conditions.MethodsFifteen healthy volunteers performed a visual reading test stimulation task after stabilized in sitting, supine and upright position on a tilt table. Simultaneously, BP and heart rate (HR) were recorded by a photoplethysmographic method and CBF velocity was measured with TCD in left posterior cerebral artery, and, as a reference, also in right middle cerebral artery. Evoked flow velocity (FV) responses were evaluated by a control system approach for systolic and diastolic data. Parameters studied were baseline FV with eyes closed, stable FV under stimulation (gain), oscillatory feature (natural frequency) and damping (attenuation) of the control system model, rate time, and also systolic and diastolic BP and HR. ANOVA test was used for comparing the values of variables in different postural settings, inferring statistical significance at a p < 0,05 level.ResultsAlthough there was a significant variation on the different orthostatic conditions in systolic (p = 0,027) and diastolic (p = 0,001) BP and HR (p = 0,0001), there was no significant change in the basal or evoked CBF velocities.ConclusionsAn intact CA compensates the different orthostatic conditions completely thus allowing an independent regulation of NC according to the metabolic needs of cortical stimulation.

Neurovascular coupling in Alzheimer patients: Effect of acetylcholine-esterase inhibitors

Dualistic effects of acetylcholine-esterase inhibitors on neuronal as well as vasoregulative function have been debated. This study investigated for the first time effects of medication on both components. Visually evoked potentials and resultant hemodynamic responses were assessed in Alzheimer patients (n=31) without vascular lesions in a MRI scan and compared to controls (n=20). After baseline recordings (AD0) tests were repeated under 2x1.5 to 2x3mg (AD1) and 2x4.5 to 2x6mg (AD2) rivastigmine/d. Long-term effects were investigated under 6 months of medication (AD2L). The ADAS, MMSE and DEMTECT were used to assess cognitive function at AD0, AD2 and AD2L. Improvement in vasoregulative function was independent from changes in evoked potentials. Acetylcholine-esterase inhibitors demonstrate substantial vascular effects in humans, which are independent from changes in neuronal function.

Effects of inducible nitric oxide synthase inhibition or norepinephrine on the neurovascular coupling in an endotoxic rat shock model

IntroductionThe inducible nitric oxide synthase (iNOS) plays a crucial role in early sepsis-related microcirculatory dysfunction. Compared to a catecholamine therapy we tested effects of a specific iNOS-inhibitor (1400W) on the microcirculatory function in the brain.MethodsSeventy SD-rats (280-310 g) were divided into 1 control and 6 sepsis groups. Sepsis groups received 1 or 5 mg/kg lipopolysaccharide (LPS) intravenously to induce a moderate or severe sepsis syndrome. Thirty minutes later rats were further randomized into subgroups receiving moderate volume therapy alone or additionally continuous norepinephrine (NE) or 1400W infusion. Separately, effects of 1400W on neurofunctional parameters were investigated in 3 rats without sepsis induction. Performing electric forepaw-stimulation evoked potentials (N2-P1 amplitude, P1-latency) and local hemodynamic responses were recorded with surface electrodes and laser Doppler over the somatosensory cortex at baseline and repeatedly after LPS administration. Cytokine levels (tumor necrosis factor-alpha (TNFα), interleukin-6 (IL6), interferon-gamma (IFNγ)) and cell destruction markers (neuron-specific enolase (NSE), S-100 calcium binding protein B (S100B)) were obtained at the end of experiments.ResultsDuring sepsis progression resting cerebral blood flow increased and functionally activated hemodynamic responses decreased in a dose-dependent manner. Whereas 1400W and NE improved blood pressure, only 1400W stabilized resting flow levels. However, both regimens were ineffective on the functionally coupled flow responses and destruction markers were similar between groups.ConclusionsNE and 1400W appeared to be ineffective in mitigating the effects of sepsis on the neurovascular coupling. Other regimens are needed to protect the cerebral microcirculation under septic conditions.

Autonomic dysfunction affects cerebral neurovascular coupling

ObjectiveAutonomic failure (AF) affects the peripheral vascular system, but little is known about its influence on cerebrovascular regulation. Patients with familial amyloidotic polyneuropathy (FAP) were studied as a model for AF.MethodsTen mild (FAPm), 10 severe (FAPs) autonomic dysfunction FAP patients, and 15 healthy controls were monitored in supine and sitting positions for arterial blood pressure (ABP) and heart rate (HR) with arterial volume clamping, and for blood flow velocity (BFV) in posterior (PCA) and contralateral middle cerebral arteries (MCA) with transcranial Doppler. Analysis included resting BFV, cerebrovascular resistance parameters (cerebrovascular resistance index, CVRi; resistance area product, RAP; and critical closing pressure, CrCP), and neurovascular coupling through visually evoked BFV responses in PCA (gain, rate time, attenuation, and natural frequency).ResultsIn non-stimulation conditions, in each position, there were no significant differences between the groups, regarding HR, BP, resting BFV, and vascular resistance parameters. Sitting ABP was higher than in supine in the three groups, although only significantly in controls. Mean BFV was lower in sitting in all the groups, lacking statistical significance only in FAPs PCA. CVRi and CrCP increased with sitting in all the groups, while RAP increased in controls but decreased in FAPm and FAPs. In visual stimulation conditions, FAPs comparing to controls had a significant decrease of natural frequency, in supine and sitting, and of rate time and gain in sitting position.InterpretationThese results demonstrate that cerebrovascular regulation is affected in FAP subjects with AF, and that it worsens with orthostasis.