Cerebrovascular Resistance Research Articles

Depression and Cognitive Impairment-Extrahepatic Manifestations of NAFLD and NASH.

Non-alcoholic fatty liver disease (NAFLD) and its complication non-alcoholic steatohepatitis (NASH) are important causes of liver disease worldwide. Recently, a significant association between these hepatic diseases and different central nervous system (CNS) disorders has been observed in an increasing number of patients. NAFLD-related CNS dysfunctions include cognitive impairment, hippocampal-dependent memory impairment, and mood imbalances (in particular, depression and anxiety). This review aims at summarizing the main correlations observed between NAFLD development and these CNS dysfunctions, focusing on the studies investigating the mechanism(s) involved in this association. Growing evidences point at cerebrovascular alteration, neuroinflammation, and brain insulin resistance as NAFLD/NASH-related CNS manifestations. Since the pharmacological options available for the management of these conditions are still limited, further studies are needed to unravel the mechanism(s) of NAFLD/NASH and their central manifestations and identify effective pharmacological targets.

1-5COMPARISON OF CEREBRAL BLOOD FLOW IN POSTERIOR CIRCULATION BETWEEN HYPERTENSIVE AND NORMOTENSIVE INDIVIDUALS

Background and Purpose: Hypertension is known to be associated with cerebrovascular remodelling, raised cerebrovascular resistance and reduced resting cerebral blood flow (CBF) relative to the healthy normotensive individual. This study aimed to compare the CBF in posterior circulation between hypertensive and normotensive individuals. Methods: We collected data of transcranial doppler (TCD) examination from Neurosonology Division in Adam Malik General Hospital from January 2014 until December 2019. We included data of the right vertebral artery (RVA), left vertebral artery (LVA) and basilar artery (BA). The parameters included were mean flow velocity (MFV) and peak systolic velocity (PSV) to measure CBF and pulsatility index to assess the vascular resistance. We excluded patients with a history of stroke and patients with signs of stenosis from TCD examination. Results: There were 330 subjects included in this study, consisted of 160 hypertensive patients and 170 normotensive subjects. The mean age was 62.4 ± 8.1 years old. Compared to normotensive subjects, hypertensive patients had significantly lower MFV in RVA [29.71 ± 7.97 vs32.74 ± 9.07, p = 0.001] and in LVA [29.71 ± 9.68 vs 32.61 ± 9.06, p = 0.005]; lower PSV in RVA [50.57 ± 13.9 vs 54.11 ± 14.5, p = 0.024] and in LVA [48.3 ± 15.30 vs 52.6 ± 15.01, p = 0.011. There was no significant difference of MFV and PSV in BA between hypertensive and normotensive subjects [33.2 ± 1.06 vs 34.6 ± 1.06, p = 0.23 and 56.11 ± 17.5 vs 56.3 ± 17.5, p = 0.91, respectively]. The pulsatility index was higher in hypertensive patients compared to normotensive subjects in RVA [1.08 ± 0.24 vs 1.01 ± 30, p = 0.014] and in LVA [1.06 ± 0.28 vs 0.99 ± 0.33, p = 0.052] and in BA [1.14 ± 0.24 vs 1.03 ± 0.27, p = 0.001] although these were still within normal range. Conclusion: Hypertensive patients exhibited lower blood flow in posterior cerebral circulation compared to healthy normotensive subjects.

The short-term effects of sedentary behaviour on cerebral hemodynamics and cognitive performance in older adults: a cross-over design on the potential impact of mental and/or physical activity

BackgroundSedentary behaviour might be a potential risk factor for cognitive decline. However, the short-term effects of sedentary behaviour on (cerebro) vascular and cognitive performance in older people are unknown.MethodsWe used a cross-over design with 22 older adults (78 years, 9 females) to assess the short-term hemodynamic and cognitive effects of three hours uninterrupted sitting and explored if these effects can be counteracted with regular (every 30 min) two-minute walking breaks. In addition, we investigated if low versus high mental activity during the three hours of sitting modified these effects. Before and after each condition, alertness, executive functioning, and working memory were assessed with the Test of Attentional Performance battery. Additionally, cerebral blood flow velocity (Transcranial Doppler) and blood pressure (Finapres) were measured in rest, and during sit-to-stand and CO2 challenges to assess baroreflex sensitivity, cerebral autoregulation, and cerebral vasomotor reactivity.ResultsNo short-term differences were observed in cognitive performance, cerebral blood flow velocity, baroreflex sensitivity, cerebral autoregulation, or cerebral vasomotor reactivity across time, or between conditions. Blood pressure and cerebrovascular resistance increased over time (8.6 mmHg (5.0;12.1), p < 0.001), and 0.23 in resistance (0.01;0.45), p = 0.04). However, these effects were not mitigated by mental activity or by short walking breaks to interrupt sitting.ConclusionsIn older individuals, three hours of sitting did not influence cognitive performance or cerebral perfusion. However, the sitting period increased blood pressure and cerebrovascular resistance, which are known to negatively impact brain health in the long-term. Importantly, we found that these effects in older individuals cannot be mitigated by higher mental activity and/or regular walking breaks.Trial registrationClinical trial registration URL: https://www.toetsingonline.nl/. Unique identifier: NL64309.091.17. Date of registration: 06–02–2018.

Pulling back on the push-pull effect: use of lower body negative pressure to protect against drops in cerebral perfusion during airflight manoeuvres.

Pulling back on the push-pull effect: use of lower body negative pressure to protect against drops in cerebral perfusion during airflight manoeuvres.

Cerebral macro- and microcirculatory blood flow dynamics in successfully treated chronic hypertensive patients with and without white mater lesions

The mechanisms of high blood pressure (HBP) -related brain pathology progression remain relatively unclear. We investigated whether lowering BP in chronic HBP patients normalizes cerebral perfusion dynamics at resistance vessel and capillary levels. Sixty-seven patients with HBP and 49 age- and sex-matched healthy controls underwent simultaneous recordings of middle cerebral artery blood flow velocity (CBFV), BP, and end-tidal CO2 concentration. Thirty-four controls and 28 patients underwent additional near-infrared spectroscopy recordings (oxygenated [O2Hb] and deoxygenated [HHb] hemoglobin). Degree of microcirculatory white matter lesions was graded by Fazekas scale. Dynamic cerebral autoregulation (dCA) was assessed by transfer function analysis. BP was successfully lowered (patients = 89 ± 15 mm Hg, controls = 87 ± 17), but cerebrovascular resistance was higher in BP patients (p < 0.05). BP-CBFV phase was lower in very low frequency (VLF) (left/right: 48 ± 20°/44 ± 17; controls: 61 ± 20/60 ± 21; p < 0.001) and low frequency (LF) (34 ± 14/35 ± 14; controls: 48 ± 20/44 ± 17; p < 0.05) ranges. Gain was higher in VLF range (in %/ mm Hg 0.56 ± 0.44/0.59 ± 0.49; controls: 0.32 ± 0.29/0.34 ± 0.32; p ≤ 0.005). BP-CBFV phase and gain did not differ across Fazekas groups. Across all patients, the capillary phases and gains (CBFV-[O2Hb], CBFV-[HHb]) were comparable to controls. Successfully treated chronic HBP results in normal brain capillary hemodynamics while the resistance vessel state is disturbed (phase decrease, gain increase).

Rapid changes in vascular compliance contribute to cerebrovascular adjustments during transient reductions in blood pressure in young, healthy adults.

Characterization of dynamic cerebral autoregulation has focused primarily on adjustments in cerebrovascular resistance in response to blood pressure (BP) alterations. However, the role of vascular compliance in dynamic autoregulatory processes remains elusive. The present study examined changes in cerebrovascular compliance and resistance during standing-induced transient BP reductions in nine young, healthy adults (3 women). Brachial artery BP (Finometer) and middle cerebral artery blood velocity (BV; Multigon) waveforms were collected. Beginning 20 beats before standing and continuing 40 beats after standing, individual BP and BV waveforms of every second heartbeat were extracted and input into a four-element modified Windkessel model to calculate indexes of cerebrovascular resistance (Ri) and compliance (Ci). Standing elicited a transient reduction in mean BP of 20 ± 9 mmHg. In all participants, a large increase in Ci (165 ± 84%; P < 0.001 vs. seated baseline) occurred 2 ± 2 beats following standing. Reductions in Ri occurred 11 ± 3 beats after standing (Ci vs. Ri delay: P < 0.001). The increase in Ci contributed to maintained systolic BV before the decrease in Ri. The present results demonstrate rapid, large but transient increases in Ci that precede reductions in Ri, in response to standing-induced reductions in BP. Therefore, Ci represents a discreet component of cerebrovascular responses during acute decreases in BP and, consequently, dynamic autoregulation.NEW & NOTEWORTHY Historically, dynamic cerebral autoregulation has been characterized by adjustments in cerebrovascular resistance following systematic changes in blood pressure. However, with the use of Windkessel modeling approaches, this study revealed rapid and large increases in cerebrovascular compliance that preceded reductions in cerebrovascular resistance following standing-induced blood pressure reductions. Importantly, the rapid cerebrovascular compliance response contributed to preservation of systolic blood velocity during the transient hypotensive phase. These results broaden our understanding of dynamic cerebral autoregulation.

Mineralocorticoid receptor antagonism prevents associated parenchymal arteriole remodeling

Obesity, a major risk factor for cerebrovascular injury, is associated with an increase in mineralocorticoid receptor (MR) activation. Obesity induced middle cerebral artery remodeling can be prevented by MR antagonism. However, the role of obesity‐induced MR activation in cerebral parenchymal arteriole (PA) remodeling has not been defined. PAs are responsible for regulating microcirculatory blood flow and play a significant role in cerebrovascular resistance. We tested the hypothesis that obesity induced PA remodeling is remediated by MR antagonism. Three‐week‐old Sprague Dawley rats were randomized to a control or high fat (HF) diet. At 12 weeks of age, 50% of rats in each group began treatment with the MR antagonist, Canrenoic acid (20mg/kg/day; CAN). PA structure in 24 week‐old rats was assessed by pressure myography under calcium‐free and zero flow conditions at 60 mmHg. Data are presented as means ± SEM, n = 3–10 per group. MR antagonism increased systolic blood pressure in HF‐diet only (HF+Vehicle: 125 ± 6 vs HF+CAN: 153 ± 6 mmHg, p&lt;0.01). At the time of euthanasia, HF‐fed rats, both vehicle and CAN treated, had more abdominal fat per body weight than controls (Control+Vehicle: 1.44 ± 0.37 vs HF+Vehicle: 4.31 ± 0.44 % of body weight, p&lt;0.01; Control+CAN: 2.26 ± 0.33 vs HF+CAN: 4.70 ± 0.44 % of body weight, p&lt;0.01). HF‐diet decreased PA outer diameter (Control+Vehicle: 85.00 ± 5.51 vs HF+Vehicle: 49.09 ± 3.55 μm, p&lt;0.01) that was reversed by MR antagonism (HF+Vehicle: 49.09 ± 3.55 vs HF+CAN: 96.00 ± 3.49 μm, p&lt;0.01). HF‐diet decreased PA lumen diameter (Control+Vehicle: 68.67 ± 6.74 vs HF+Vehicle: 34.59 ± 2.72 μm, p=0.028) that was reversed by MR antagonism (HF+Vehicle: 34.59 ± 2.72 vs HF+CAN: 73.17 ± 7.38 μm, p&lt;0.01). HF‐diet tended to decrease PA vessel wall area (Control+Vehicle: 1948 ± 55 vs HF+Vehicle: 973 ± 148 μm2, p=0.103); MR antagonism increased wall area in HF‐fed rats (HF+Vehicle: 973 ± 148 vs HF+CAN: 2027 ± 234 μm2, p=0.016). Vascular remodeling is associated with cerebrovascular injury and cognitive impairment. Our results suggest that inward hypotrophic PA remodeling is MR dependent providing a potential therapeutic target to combat obesity‐induced cerebrovascular disease.Support or Funding InformationThis work was supported by National Institutes of Health (NIH) Grants R01‐HL‐137694‐01 to W. F. Jackson and A. M. Dorrance.

Sex Differences in Baseline and Reactive Cerebrovascular Compliance

Adjustments in cerebrovascular resistance represent the primary characterization of cerebral autoregulation to date. However, recent studies have demonstrated that cerebrovascular compliance contributes to the relationship between BP and cerebral blood velocity (BV) during dynamic changes in BP. Therefore, the present study tested the hypotheses that i) hypotension‐induced autoregulatory processes involve increases in cerebrovascular compliance and ii) sex differences exist in cerebrovascular compliance. Twenty young healthy adults (24 ± 3 years, 10 females) completed a sit‐to‐stand protocol involving three minutes of sitting and three minutes of standing while brachial artery BP (Finapres Finometer) and middle cerebral artery BV (Multigon Neurovision) were collected. Individual BP (with temporal shift) and corresponding BV waveforms were input into a four‐element lumped parameter Windkessel model to calculate indices of cerebrovascular compliance (Ci) and resistance (Ri). Beginning 20 beats prior to standing and continuing 40 beats following the stand, every other heartbeat was extracted so that a total of 30 beats were analyzed (i.e., 10 beats during sitting, 20 beats during standing). Seated baseline Ci was calculated as the average of the 10 beats of sitting. Peak Ci minus seated baseline Ci determined the change in (Δ) Ci. Females demonstrated higher Ci than males during seated baseline (1.1e−3 ± 4.4e−4 vs. 7.1e−4 ± 2.1e−4 cm·s−1·mmHg−1; P = 0.04, d = 1.3). Upon standing, large and rapid increases in Ci were observed in both groups but females exhibited a lesser increase when compared with males (114 ± 48 vs. 202 ± 50 %; P &lt; 0.01, d = 1.8). No differences were observed in peak Ci with standing (females: 2.1e−3 ± 6.7e−4, males: 2.1e−3 ± 5.5e−4 cm·s−1·mmHg−1; P = 0.89). While the drop in mean BP with standing was attenuated in females compared with males (−14 ± 5 vs. −25 ± 9 mmHg; P &lt; 0.01, d = 1.5), no relationship existed between Δ Ci and Δ mean BP (b = −7.0e−7 cm·s−1·mmHg−2; r2 = 3.0e−4; b P = 0.94). Importantly, the increase in Ci preceded reductions in Ri (2 ± 2 vs. 11 ± 4 beats following standing; P &lt; 0.01, d = 2.8). Therefore, large and rapid increases in Ci occur with standing‐induced hypotension that contribute to dynamic cerebral autoregulation. Further, females demonstrate attenuated Ci responses to standing despite exhibiting higher seated baseline Ci compared with males.Support or Funding InformationSupported by the Natural Sciences and Engineering Research Council of Canada.

Transient cerebral blood flow responses during microgravity

PurposeA number of studies has well described central cardiovascular changes caused by changing gravity levels as they occur e.g. during parabolic flight. limited data exists describing the effect of microgravity on the cerebrovascular system and brain perfusion. MethodsIn this study middle cerebral artery velocity (MCAv) of 16 participants was continuously monitored on a second-by-second basis during 15 consecutive parabolas (1G, 1,8G, 0G, 1,8G) using doppler ultrasound. Simultaneously central cardiovascular parameters (heart rate, mean arterial blood pressure, cardiac output) were assessed. ResultsResults revealed an immediate reaction of central cardiovascular parameters to changed gravity levels. In contrast, changes in MCAv only initially were in accordance with a normal cerebral autoregulation. Whereas all of the measured central cardiovascular parameters seemed to have reached a steady state after approximately 8 s of microgravity, MCAv, after an initial decrease with the onset of microgravity, increased again during the second half of the microgravity phase. ConclusionIt is concluded that this increase in MCAv during the second half of the microgravity period reflects a decrease of cerebrovascular resistance caused by a pressure driven increased venous outflow and/or a contraction of precapillary sphincters in order to avoid hyperperfusion of the brain.

Transient Orthostatic Hypertension During Head-Up Tilt Test in Young Adults: A Phenotype of Blood Pressure Variability.

The mechanisms underlying orthostatic hypertension (OHT) remain poorly understood. The authors evaluated the cardiovascular, cerebrovascular dynamics, and autonomic response to head-up tilt test (HUTT) in young adults with symptoms of orthostatic intolerance and transient OHT. Forty-four female subjects were included (34 ± 13 years old) and categorized in three groups after a 30-minute 70° passive HUTT: symptomatic patients with OHT (surge of systolic blood pressure ≥20 mm Hg for at least 5 minutes at any given time during HUTT), orthostatic intolerance (symptomatic patients without orthostatic blood pressure changes), and healthy asymptomatic control subjects. At baseline, OHT patients had lower systolic blood pressure than orthostatic intolerance patients (103 ± 8 vs. 116 ± 10 mm Hg, p < 0.01) and lower baroreflex sensitivity than control subjects (15.8 ± 8.3 vs. 27.1 ± 11.7 ms/mm Hg, p = 0.01). On tilt, cardiac output decreased in OHT patients from 6.1 ± 1.4 L/minute during baseline to 5.2 ± 0.8 L/minute after 10 minutes of HUTT (p = 0.01). In OHT patients at 30 minutes of HUTT, sympathetic efferent heart activity was higher (77.4 ± 14.9 normalized units or nu) than orthostatic intolerant patients (63.5 ± 11.8 nu, p = 0.02) and control subjects (65.8 ± 11.2 nu, p = 0.05). Cerebrovascular resistance in OHT was higher than control subjects after 30 minutes (2.2 ± 0.8 vs. 1.6 ± 0.3 cm/second, respectively, p = 0.02). This study demonstrates that transient OHT can occur at any given time during HUTT. These patients exhibit a decrease in cardiac output and a hyperadrenergic response to tilt.

Precapillary sphincters maintain perfusion in the cerebral cortex

Active nerve cells release vasodilators that increase their energy supply by dilating local blood vessels, a mechanism termed neurovascular coupling and the basis of BOLD functional neuroimaging signals. Here, we reveal a mechanism for cerebral blood flow control, a precapillary sphincter at the transition between the penetrating arteriole and first order capillary, linking blood flow in capillaries to the arteriolar inflow. The sphincters are encircled by contractile mural cells, which are capable of bidirectional control of the length and width of the enclosed vessel segment. The hemodynamic consequence is that precapillary sphincters can generate the largest changes in the cerebrovascular flow resistance of all brain vessel segments, thereby controlling capillary flow while protecting the downstream capillary bed and brain tissue from adverse pressure fluctuations. Cortical spreading depolarization constricts sphincters and causes vascular trapping of blood cells. Thus, precapillary sphincters are bottlenecks for brain capillary blood flow.

Neurovascular effects of umbilical cord blood-derived stem cells in growth-restricted newborn lambs

BackgroundNeonatal ventilation exacerbates brain injury in lambs with fetal growth restriction (FGR), characterized by neuroinflammation and reduced blood-brain barrier integrity, which is normally maintained by the neurovascular unit. We examined whether umbilical cord blood stem cell (UCBC) treatment stabilized the neurovascular unit and reduced brain injury in preterm ventilated FGR lambs.MethodsSurgery was performed in twin-bearing pregnant ewes at 88 days’ gestation to induce FGR in one fetus. At 127 days, FGR and appropriate for gestational age (AGA) lambs were delivered, carotid artery flow probes and umbilical lines inserted, lambs intubated and commenced on gentle ventilation. Allogeneic ovine UCBCs (25 × 106 cells/kg) were administered intravenously to lambs at 1 h of life. Lambs were ventilated for 24 h and then euthanized.ResultsFGR (n = 6) and FGR+UCBC (n = 6) lambs were growth restricted compared to AGA (n = 6) and AGA+UCBC (n = 6) lambs (combined weight, FGR 2.3 ± 0.4 vs. AGA 3.0 ± 0.3 kg; p = 0.0002). UCBC therapy did not alter mean arterial blood pressure or carotid blood flow but decreased cerebrovascular resistance in FGR+UCBC lambs. Circulating TNF-α cytokine levels were lower in FGR+UCBC vs. FGR lambs (p < 0.05). Brain histopathology showed decreased neuroinflammation and oxidative stress, increased endothelial cell proliferation, pericyte stability, and greater integrity of the neurovascular unit in FGR+UCBC vs. FGR lambs.ConclusionsUmbilical cord blood stem cell therapy mitigates perinatal brain injury due to FGR and ventilation, and the neuroprotective benefits may be mediated by stabilization of the neurovascular unit.

Dissociation of Cerebral Blood Flow and Femoral Artery Blood Pressure Pulsatility After Cardiac Arrest and Resuscitation in a Rodent Model: Implications for Neurological Recovery.

BackgroundImpaired neurological function affects 85% to 90% of cardiac arrest (CA) survivors. Pulsatile blood flow may play an important role in neurological recovery after CA. Cerebral blood flow (CBF) pulsatility immediately, during, and after CA and resuscitation has not been investigated. We characterized the effects of asphyxial CA on short‐term (<2 hours after CA) CBF and femoral arterial blood pressure (ABP) pulsatility and studied their relationship to cerebrovascular resistance (CVR) and short‐term neuroelectrical recovery.Methods and ResultsMale rats underwent asphyxial CA followed by cardiopulmonary resuscitation. A multimodal platform combining laser speckle imaging, ABP, and electroencephalography to monitor CBF, peripheral blood pressure, and brain electrophysiology, respectively, was used. CBF and ABP pulsatility and CVR were assessed during baseline, CA, and multiple time points after resuscitation. Neuroelectrical recovery, a surrogate for neurological outcome, was assessed using quantitative electroencephalography 90 minutes after resuscitation. We found that CBF pulsatility differs significantly from baseline at all experimental time points with sustained deficits during the 2 hours of postresuscitation monitoring, whereas ABP pulsatility was relatively unaffected. Alterations in CBF pulsatility were inversely correlated with changes in CVR, but ABP pulsatility had no association to CVR. Interestingly, despite small changes in ABP pulsatility, higher ABP pulsatility was associated with worse neuroelectrical recovery, whereas CBF pulsatility had no association.ConclusionsOur results reveal, for the first time, that CBF pulsatility and CVR are significantly altered in the short‐term postresuscitation period after CA. Nevertheless, higher ABP pulsatility appears to be inversely associated with neuroelectrical recovery, possibly caused by impaired cerebral autoregulation and/or more severe global cerebral ischemia.

Transcranial Doppler waveform changes due to increased cerebrovascular resistance and raised intracranial pressure in a patient with cirrhosis: A difference in shapes, not in numbers

We report and discuss a case that illustrate the clinical utility of transcranial Doppler (TCD) ultrasound in a patient with cirrhosis. A 43-year-old female presented with acute decompensation of cirrhosis with hepatic encephalopathy, requiring mechanical ventilation. TCD showed low diastolic flow velocities and high pulsatility index (PI) consistent with increased cerebrovascular resistance (CVR). The flow velocities and PI normalized over a period of few days and correlated well with neurological improvement after treatment. Subsequently, the patient developed a large intracerebral hemorrhage with mass effect. The TCD measurements in intracranial hypertension were similar to those with cirrhosis and hepatic encephalopathy. However, the windkessel notch in the systolic phase of TCD waveform, related to the distensibility of arterial wall, was absent during raised intracranial pressure (ICP). The absence of a windkessel notch may help to differentiate a high downstream resistance due to raised ICP from increased CVR.

Cerebrovascular Dynamics During Continuous Motor Task.

We investigated the cerebral autoregulation (CA) dynamics parameter phase and gain change when exposed to a longlasting motor task. 25 healthy subjects (mean age ± SE, 38±2.6 years, 13 females) underwent simultaneous recordings of spontaneous fluctuations in blood pressure (BP), cerebral blood flow velocity (CBFV), and end-tidal CO(2) (ETCO(2)) over 5 min of rest followed by 5 min of left elbow flexion at a frequency of 1 Hz. Tansfer function gain and phase between BP and CBFV were assessed in the frequency ranges of very low frequencies (VLF, 0.02-0.07 Hz), low frequencies (LF, 0.07-0.15), and high frequencies (HF, >0.15). CBFV increased on both sides rapidly to maintain an elevated steady state until movement stopped. Cerebrovascular resistance fell on the right side (rest 1.35±0.06, movement 1.28±0.06, p<0.01), LF gain decreased from baseline (right side 0.97±0.07 %/mm Hg, left 1.01±0.09) to movement epoch (right 0.73±0.08, left 0.76±0.06, p</=0.01). VLF phase decreased from baseline (right 1.03±0.05 radians, left 1.10±0.06) to the movement epoch (right 0.81±0.07, left 0.82±0.10, p?0.05). CA regulates continuous motor efforts by changes in resistance, gain and phase.

Estimation of pulsatile cerebral arterial blood volume based on transcranial doppler signals

ObjectiveMathematical modeling of cerebral hemodynamics by descriptive equations can estimate the underlying pulsatile component of cerebral arterial blood volume (CaBV). This way, clinical monitoring of changes in cerebral compartmental compliances becomes possible. Our aim is to validate the most adequate method of CaBV estimation in neurocritical care. ApproachWe retrospectively reviewed patients with severe traumatic brain injury (TBI) [admitted from 1992–2012] and continuous transcranial Doppler (TCD) monitoring of cerebral blood flow velocity (FV) displaying either plateau waves of intracranial pressure (ICP), episodes of controlled, mild hypocapnia, or vasopressor-induced increases in arterial blood pressure (ABP). Each cohort was analyzed with continuous flow forward (CFF, pulsatile blood inflow and steady blood outflow) or pulsatile flow forward (PFF, both blood inflow and outflow are pulsatile) modeling approaches for estimating the pulse component of CaBV. Spectral pulsatility index (sPI, the first harmonic of the FV pulse/mean FV) can be estimated using the compliance of the vascular bed (Ca) and the cerebrovascular resistance (CVR – here, Ra). We compared three possible methods of assessing Ca (C1: the CFF model, C2 and C3: the PFF models based on ABP or cerebral perfusion pressure (CPP) pulsations, respectively) and combined them with three possible methods of assessing Ra (Ra1= ABP/FV, Ra2= the resistance area product, and Ra3= CPP/FV). Linear regression techniques were applied to describe the strength of each CaBV estimator (a combination of Ca and Ra) against sPI. Main ResultsThe combination of C1 and Ra3 (PI_C1Ra3) was the superior descriptor of CaBV as approximated by sPI for both the plateau waves and the hypocapnia cohorts (r = 0.915 and r = 0.955, respectively). The combination of C1 and Ra1 (PI_C1Ra1) was nearly as robust in the vasopressors cohort (r = 0.938 and r = 0.931, respectively). SignificanceTCD-based estimation of CaBV pulsations seems to be feasible when employing the CFF modeling approach.

Ex Utero Extracorporeal Support as a Model for Fetal Hypoxia and Brain Dysmaturity

Congenital heart disease (CHD) is associated with abnormal fetal brain development, a phenomenon that may be related to decreased cerebral oxygen delivery in utero. We used an artificial womb model to test the hypothesis that decreasing fetal oxygen delivery would reproduce physiologic changes identified in fetuses with CHD. Experimental (hypoxemic) fetal lambs (mean gestational age, 111 ± 3 days; n= 4) and control animals (112 days; n= 5) were maintained in the artificial womb for a mean of 22 ± 6 days. Oxygen delivery was reduced to 15.6 ± 1.0 mL/kg/min in the hypoxemia animals versus 21.6 ± 2.0 mL/kg/min in the control animals. Blood chemistry analysis and sonographic evaluation were performed daily. An additional control group (n= 7) was maintained in utero and harvested for analysis at gestational age 134 ± 4 days. Physiologic variables were monitored continuously, and no statistical differences between the groups were identified. Fetal oxygen delivery and arterial partial pressure of oxygen were remarkably lower in the experimental group longitudinally. Increased umbilical artery and decreased middle cerebral artery resistance resulted in a lower cerebral to umbilical resistance ratio, similar to the brain sparing effect observed in human fetuses with CHD. Experimental brains were smaller than control brains in relation to the calvarium on magnetic resonance. Sustained hypoxemia in fetal sheep leads to altered cerebrovascular resistances and loss of brain mass, similar to human fetuses with CHD. This unique model provides opportunities to investigate the pathologic process underlying CHD-associated brain dysmaturity and to evaluate potential fetal neuroprotective therapies.

Influence of neurovascular mechanisms on response to tDCS: an exploratory study.

The beneficial effects of transcranial direct current stimulation (tDCS) for stroke rehabilitation are limited by the variability in changes in corticomotor excitability (CME) after tDCS. Neuronal activity is closely related to cerebral blood flow; however, the cerebral hemodynamics of neuromodulation in relation to neural effects have been less explored. In this study, we examined the effects of tDCS on cerebral blood velocity (CBv) in chronic stroke survivors using transcranial Doppler (TCD) ultrasound in relation to changes in CME and described the neurovascular characteristics of tDCS responders. Middle cerebral artery (MCA) CBv, cerebrovascular resistance (CVRi) and other cerebral hemodynamics-related variables were continuously measured before and after 15min of 1mA anodal tDCS to the lesioned lower limb M1. tDCS did not modulate CBv in thewhole group and upon TMS-based stratification of responders and non-responders. However, at baseline, responders demonstrated lower CME levels, lower CBv and higher CVRi as compared to non-responders. These results indicate a possible difference in baseline CME and CBv intDCS responders that may influence their response to neuromodulation. Future trials with a large sample size and repeated baseline measurements may help validate these findings and establish a relationship between neuromodulation and neurovascular mechanisms in stroke.

Increased Blood Flow Velocity in Middle Cerebral Artery and Headache Upon Ingestion of Ice Water.

Introduction: “Headache attributed to ingestion or inhalation of a cold stimulus” (HICS) is one of the most common primary headache disorders. Little is known about the pathophysiology of HICS and other headache disorders. The aim of this study was to analyze mean flow velocity (MFV) and cerebrovascular resistance (RI) in both middle cerebral arteries (MCA) upon ingestion of ice water.Methods: The MFV and RI in both MCAs was continuously measured by transcranial sonography. HICS was induced by drinking 200 ml of ice water.Results: In all volunteers, the ingestion of ice water led to a decrease in RI, which was accompanied by an increase in MFV. In volunteers with induced HICS, MFV were significantly higher compared to volunteers that did not experience HICS. In volunteers with HICS, MFV increased even more significantly when lacrimation occurred compared to volunteers in which it did not. In volunteers without induced HICS, MFV was higher in those volunteers with a positive history of HICS than in those with a negative HICS history.Conclusion: This study revealed a raised MFV upon ingestion of ice water. Volunteers with a provoked case of HICS had a higher MFV than volunteers without HICS. The increase in MFV was even higher when the headache was accompanied by lacrimation. This may indicate an involvement of the trigeminal-parasympathetic vasodilator reflex.

Determining differences between critical closing pressure and resistance-area product: responses of the healthy young and old to hypocapnia.

Healthy ageing has been associated with lower cerebral blood flow velocities (CBFVs); however, the behaviour of hemodynamic parameters associated with cerebrovascular tone (critical closing pressure, CrCP) and cerebrovascular resistance (resistance-area product, RAP) remains unclear. Specifically, evidence supports ageing being associated with greater cerebrovascular tone and resistance during exercise with elevated CrCP and RAP in older individuals at rest and during exercise. Comprehensive hemodynamic assessment of CrCP and RAP during hyperventilation-induced hypocapnia in two distinct age groups (young ≤ 49 and old > 50) has not been described. CBFV in the middle cerebral artery (CBFV, transcranial Doppler), blood pressure (BP, Finometer) and end-tidal CO2 (EtCO2, capnography) were recorded in 104 healthy individuals (43 young [age 33.8 (9.3) years], 61 old [age 64.1 (8.5) years]) during a minimum of 60s of metronome-driven hyperventilation-induced hypocapnia. Autoregulation index was calculated as a function of time, using a moving window autoregressive-moving average model. CBFV was reduced in response to age (p < 0.0001) and hypocapnia (p = 0.023) (young 57.3 (14.4) vs. 44.9cms-1 (11.1), old 51.7 (12.9) vs. 37.8cms-1 (9.6)). Critical closing pressure (CrCP) increased significantly in response to hypocapnia (young 37.6 (18.5) vs. 39.7mmHg (16.0), old 33.9 (13.5) vs. 39.3mmHg (11.4); p < 0.0001). Resistance-area product was increased in response to age (p = 0.001) and hypocapnia (p = 0.004) (young 1.02 (0.40) vs. 1.09mmHgcms-1 (11.07), old 1.16 (0.34) vs. 1.34mmHgcms-1 (0.39)). RAP and not CrCP mediates differences in cerebrovascular resistance responses to hypocapnia between the healthy young and old individuals.