2nd Place Co- Winner: Soren Cobb – C. Frank Webber Prize Competition

ABSTRACT

Applying a non-invasive pulsed Doppler technique for the characterization of cerebral blood flow in mouse models

SOREN COBB       McGovern Medical School at UTHealth

      Class of 2025

 

Sponsored by: Iraida Sharina, PhD, Department of Internal Medicine/Cardiology
Supported by: Iraida Sharina, PhD, Department of Internal Medicine/Cardiology
Key Words: Pulsed Doppler, cerebral blood flow, middle cerebral artery, SNP

Background and Purpose: Current methods place significant limitations on the efficiency of in-vivo studies of the cerebral hemodynamics of rodents with respect to both time and resources. Invasive methods such as intrinsic optical signal imaging (IOSI) and optical coherence tomography angiography (OCTA) require chronic cranial window preparation, a procedure that requires significant time investment and is often limited to specific age ranges [1]. While clinical Doppler systems developed for use in humans have been adapted for use in mice, they are unable to evaluate peripheral vessels in mice with precision due to poor spatial and temporal resolution. Other non-invasive methods include laser Doppler flowmetry (LDF) and laser speckle contrast imaging (LSCI), which have a depth of penetration of < 1mm, limiting use in rodents with thicker skulls, as well as near-infrared diffuse correlation spectroscopy (DCS), which uses expensive photodiodes and lasers [2]. The purpose of this study is to validate the use of a high-frequency and high-resolution pulsed Doppler system, specifically developed for use on peripheral vessels of mice, as a new method to evaluate the cerebral blood flow (CBF) of mice at the middle cerebral artery (MCA) in real-time and with high sensitivity and efficiency.

Materials and Methods: The high-frequency and high-resolution Doppler spectrum analyzer (DSWP) and Doppler Flow Velocity System (DFVS) used in this study were developed at Baylor College of Medicine to characterize blood flow of peripheral vessels in mice [3]. Mice were anesthetized by isoflurane 2% and the DFVS probe was positioned to measure blood flow velocity in the MCA before and after intraperitoneal injection of either SNP 1mg/kg or a vehicle PBS solution as a control. Baseline peak flow velocity (PFV) and subsequent changes to peak flow velocity were characterized by analyzing 6 cardiac cycles within captures of 1 second windows of the corresponding Doppler wave form at established time points before and after injection. Maximal vasodilatory response at the MCA was measured as the maximum percentage decrease in peak flow velocity compared to baseline.

Results: The maximal vasodilatory response at the MCA of mice receiving intraperitoneal injection of SNP 1mg/kg was observed at 3 minutes post-injection, corresponding with an average decrease in PFV from baseline of 24.94% for males (n = 5) and 38.55% for females (n = 5). When compared to the control group (n = 6) at 3 minutes post-injection, this represented a significant difference in the maximal vasodilatory response for both males (p = 7.00E-06) and females (p = 5.86E-06).

Conclusions: Our results demonstrate the ability of the high-frequency and high-resolution Doppler system to characterize changes in MCA flow with high sensitivity under the pharmacological intervention of a well characterized nitric oxide donor, SNP. This study will be continued by applying these methods to characterize changes in MCA flow during a surgical carotid artery occlusion to confirm these findings and validate the method. The proposed method is unique, can be performed in real-time, and confers high efficiency with respect to time and resources; therefore, it may be beneficial to the study of disturbed blood flow velocities in mouse models of a wide variety of human cerebral pathologies, including vascular dementia, Alzheimer’s disease, and sGC-related pathologies.

References:

  1. Li Y, Rakymzhan A, Tang P, Wang RK. Procedure and protocols for optical imaging of cerebral blood flow and hemodynamics in awake mice. Biomed Opt Express. 2020 May 26;11(6):3288-3300. doi: 10.1364/BOE.394649.
  2. Huang C, Gu Y, Chen J, Bahrani AA, Abu Jawdeh EG, Bada HS, Saatman K, Yu G, Chen L. A Wearable Fiberless Optical Sensor for Continuous Monitoring of Cerebral Blood Flow in Mice. IEEE J Sel Top Quantum Electron. 2019 Jan-Feb;25(1):6900108. doi: 10.1109/JSTQE.2018.2854597.
  3. Reddy AK, Jones AD, Martono C, Caro WA, Madala S, Hartley CJ. Pulsed Doppler signal processing for use in mice: design and evaluation. IEEE Trans Biomed Eng. 2005 Oct;52(10):1764-70. doi: 10.1109/tbme.2005.855710.