Feasibility of Doppler Ultrasound for Cortical Cerebral Blood Flow Velocity Monitoring During Major Non-cardiac Surgery of Newborns

Background and Aim: Newborns needing major surgical intervention are at risk of brain injury and impaired neurodevelopment later in life. Disturbance of cerebral perfusion might be an underlying factor. This study investigates the feasibility of serial transfontanellar ultrasound measurements of the pial arteries during neonatal surgery, and whether perioperative changes in cerebral perfusion can be observed and related to changes in the perioperative management.Methods: In this prospective, observational feasibility study, neonates with congenital diaphragmatic hernia and esophageal atresia scheduled for surgical treatment within the first 28 days of life were eligible for inclusion. We performed transfontanellar directional power Doppler and pulsed wave Doppler ultrasound during major high-risk non-cardiac neonatal surgery. Pial arteries were of interest for the measurements. Extracted Doppler ultrasound parameters were: peak systolic velocity, end diastolic velocity, the resistivity index and pulsatility index.Results: In 10 out of 14 patients it was possible to perform perioperative measurements; the others failed for logistic and technical reasons. In 6 out of 10 patients, it was feasible to perform serial intraoperative transfontanellar ultrasound measurements with directional power Doppler and pulsed wave Doppler of the same pial artery during neonatal surgery. Median peak systolic velocity was ranging between 5.7 and 7.0 cm s−1 and end diastolic velocity between 1.9 and 3.2 cm s−1. In patients with a vasoactive-inotropic score below 12 the trend of peak systolic velocity and end diastolic velocity corresponded with the mean arterial blood pressure trend.Conclusion: Perioperative transfontanellar ultrasound Doppler measurements of the pial arteries are feasible and provide new longitudinal data about perioperative cortical cerebral blood flow velocity.Trial Registration:https://www.trialregister.nl/trial/6972, identifier: NL6972.

Regional and depth-dependence of cortical blood-flow assessed with high-resolution Arterial Spin Labeling (ASL)

Methods for imaging of cerebral blood flow do not typically resolve the cortex and thus underestimate flow. However, recent work with high-resolution MRI has emphasized the regional and depth-dependent structural, functional and relaxation times variations within the cortex. Using high-resolution Arterial Spin Labeling (ASL) and T1 mapping acquisitions, we sought to probe the effects of spatial resolution and tissue heterogeneity on cortical cerebral blood flow (CBF) measurements with ASL. We acquired high-resolution (1.6mm) 3 whole brain ASL data in a cohort of 10 volunteers at 3T, along with T1 and transit-time (ATT) mapping, followed by group cortical surface-based analysis using FreeSurfer of the different measured parameters. Fully resolved regional analysis showed higher than average mid-thickness CBF in primary motor areas (+15%,p<0.002), frontal regions (+17%,p<0.01) and auditory cortex, while occipital regions had lower average CBF (-20%,p<10−5). ASL signal was higher towards the pial surface but correction for the shorter T1 near the white matter surface reverses this gradient, at least when using the low-resolution ATT map. Similar to structural measures, fully-resolved ASL CBF measures show significant differences across cortical regions. Depth-dependent variation of T1 in the cortex complicates interpretation of depth-dependent ASL signal and may have implications for the accurate CBF quantification at lower resolutions.

Altered Cerebral Blood Flow and Potential Neuroprotective Effect of Human Relaxin-2 (Serelaxin) During Hypoxia or Severe Hypovolemia in a Sheep Model

Specific neuroprotective strategies to minimize cerebral damage caused by severe hypoxia or hypovolemia are lacking. Based on previous studies showing that relaxin-2/serelaxin increases cortical cerebral blood flow, we postulated that serelaxin might provide a neuroprotective effect. Therefore, we tested serelaxin in two emergency models: hypoxia was induced via inhalation of 5% oxygen and 95% nitrogen for 12 min; thereafter, the animals were reoxygenated. Hypovolemia was induced and maintained for 20 min by removal of 50% of the total blood volume; thereafter, the animals were retransfused. In each damage model, the serelaxin group received an intravenous injection of 30 µg/kg of serelaxin in saline, while control animals received saline only. Blood gases, shock index values, heart frequency, blood pressure, and renal blood flow showed almost no significant differences between control and treatment groups in both settings. However, serelaxin significantly blunted the increase of lactate during hypovolemia. Serelaxin treatment resulted in significantly elevated cortical cerebral blood flow (CBF) in both damage models, compared with the respective control groups. Measurements of the neuroproteins S100B and neuron-specific enolase in cerebrospinal fluid revealed a neuroprotective effect of serelaxin treatment in both hypoxic and hypovolemic animals, whereas in control animals, neuroproteins increased during the experiment. Western blotting showed the expression of relaxin receptors and indicated region-specific differences in relaxin receptor-mediated signaling in cortical and subcortical brain arterioles, respectively. Our findings support the hypothesis that serelaxin is a potential neuroprotectant during hypoxia and hypovolemia. Due to its preferential improvement of cortical CBF, serelaxin might reduce cognitive impairments associated with these emergencies.

Reduced cerebral blood flow in an α-synuclein transgenic mouse model of Parkinson’s disease

There is increasing evidence that widespread cortical cerebral blood flow deficits occur early in the course of Parkinson’s disease. Although cerebral blood flow measurement has been suggested as a potential biomarker for early diagnosis of Parkinson’s disease, as well as a means for tracking response to treatment, the relationship of cerebral blood flow to α-synucleinopathy, a major pathological hallmark of Parkinson’s disease, remains unclear. Therefore, we performed arterial spin-labeling magnetic resonance imaging and diffusion tensor imaging on transgenic mice overexpressing human wild-type α-synuclein and age-matched controls to measure cerebral blood flow and degenerative changes. As reported for early-stage Parkinson’s disease, α-synuclein mice exhibited a significant reduction in cortical cerebral blood flow, which was accompanied by motor coordination deficits and olfactory dysfunction. Although no overt degenerative changes were apparent in diffusion tensor imaging images, magnetic resonance imaging volumetric analysis revealed a significant reduction in olfactory bulb volume, similar to that seen in Parkinson’s disease patients. Our data, representing the first report of cerebral blood flow deficit in an animal model of Parkinson’s disease, suggest a causative role for α-synucleinopathy in cerebral blood flow deficits in Parkinson’s disease. Thus, α-synuclein transgenic mice comprise a promising model to study Parkinson’s disease-related mechanisms of cerebral blood flow deficits and to investigate further its utility as a potential biomarker for Parkinson’s disease.

Abstract WP295: Remote Limb Ischemic Conditioning in Murine Focal Cerebral Ischemia

Background & Aims: Remote ischemic conditioning (RIC) could induce brain protection in cerebral ischemia. The conditioning can be divided into pre-, per- and post-conditioning. The aim of this study is to clarify which RIC is the most effective in murine focal ischemia. Methods: Adult male C57BL/6 mice were used in this study. Transient focal cerebral ischemia was produced with nylon-suture model by occluding middle cerebral artery (MCAO) for 45 minutes. Cortical cerebral blood flow (rCBF) was continuously measured during ischemia with laser Doppler flowmeter. Twenty-four hours after MCAO, the animals were sacrificed and their brains were removed. After cutting coronal 1-mm brain sections, infarct volume was measured after TTC staining. Fifty mice were divided into five groups (each n=10); sham RIC group, delayed preRIC group (RIC 24 hours before MCAO), early preRIC group (RIC 5 minutes before MCAO), perRIC group (RIC during MCAO), and postRIC group (RIC 5 minutes after MCAO). Hind limb ischemia was induced by making the snare as tight as possible using a hemostatic forceps for 5 minutes followed by loosening it for 5 minutes. Four cycles were performed as RIC. Results: Infarct volume were 58.8±10.1 mm 3 in sham RIC, 54.8±19.4 mm 3 in delayed preRIC, 69.3±10.8 mm 3 in early preRIC, 38.0±22.1 mm 3 in perRIC, and 64.5±13.5 mm 3 in postRIC groups. Infarct volume in perRIC was significantly smaller than that in sham RIC and other groups (P<0.01). However, infarct volume of other RIC groups was not different with sham RIC group. After MCAO, rCBF reduced to 15.6% of baseline level in sham RIC, 11.2% in delayed preRIC, 11.9% in early preRIC, 13.4% in perRIC, and 10.8% in postRIC group. No difference was found in residual rCBF among all groups. At the end of MCAO, rCBF compared to rCBF immediate after occlusion was 102±21% in sham RIC, 112±25% in delayed preRIC, 98±22% in early preRIC, 131±33% in perRIC and 105±19% postRIC groups. Relative rCBF change at the end of MCAO in perRIC was significantly more than that in sham RIC group (P<0.05). Conclusions: Among four RIC procedures, only perRIC showed clear brain protection against transient MCAO. Change during rCBF may suggest that enhancement of collateral circulation play a role in part on brain protective effect of perRIC.