Transcranial Recording of Electrophysiological Neural Activity in the Rodent Brain in vivo Using Functional Photoacoustic Imaging of Near-Infrared Voltage-Sensitive Dye.

Jeeun Kang,Maged M Harraz,Albert Gjedde,Dean F Wong,Shilpa D Kadam,Heather Valentine,Julie Fedorko,Adarsha P Malla,Ping Yan,Arman Rahmim,Leslie M Loew,Haichong K Zhang,Jin U Kang,Emad M Boctor

doi:10.3389/fnins.2019.00579

Abstract

Minimally-invasive monitoring of electrophysiological neural activities in real-time—that enables quantification of neural functions without a need for invasive craniotomy and the longer time constants of fMRI and PET—presents a very challenging yet significant task for neuroimaging. In this paper, we present in vivo functional PA (fPA) imaging of chemoconvulsant rat seizure model with intact scalp using a fluorescence quenching-based cyanine voltage-sensitive dye (VSD) characterized by a lipid vesicle model mimicking different levels of membrane potential variation. The framework also involves use of a near-infrared VSD delivered through the blood-brain barrier (BBB), opened by pharmacological modulation of adenosine receptor signaling. Our normalized time-frequency analysis presented in vivo VSD response in the seizure group significantly distinguishable from those of the control groups at sub-mm spatial resolution. Electroencephalogram (EEG) recording confirmed the changes of severity and frequency of brain activities, induced by chemoconvulsant seizures of the rat brain. The findings demonstrate that the near-infrared fPA VSD imaging is a promising tool for in vivo recording of brain activities through intact scalp, which would pave a way to its future translation in real time human brain imaging.

Highlights

The quantification and monitoring of brain function is a major goal of neuroscience and clinical researches into the underlying mechanisms of the working brain (Raichle and Mintun, 2006; Friston, 2009)
Note that the non-specific quantum yield at 25-fold K+ gradient is due to a limited sensitivity to differentiate the subtle membrane potential variation—The specificity of the estimation becomes proportionally improved as more K+ gradient is given
The proof-of-concept in vivo validation study demonstrated that the non-invasive functional PA (fPA) voltage-sensitive dye (VSD) imaging without any invasive craniotomy or skull thinning procedures is capable of differentiating the generalized depolarization events in the seizure group from those in control groups (Figure 4), which well agreed with EEG validation (Figure 6)

Summary

Introduction

The quantification and monitoring of brain function is a major goal of neuroscience and clinical researches into the underlying mechanisms of the working brain (Raichle and Mintun, 2006; Friston, 2009). Optical imaging approaches have been used to monitor the brain function of small animals but have limited dynamic ranges and cover only superficial tissue depths because of light scattering and absorbance during penetration of biological tissue (Hillman, 2007; Devor et al, 2012). These optical approaches require invasive craniotomy for imaging of deeper brain region, with problematic long-term consequences such as dural regrowth, greater likelihood of inflammatory cascade initiation, and lack of translational practicality to nonhuman primate and to human studies, including those for neuropsychiatric disorders (Heo et al, 2016). Minimally-invasive monitoring of electrophysiological brain activities in real-time remains a task at hand in neuroimaging, with the aim to quantify brain functions in the depths of brain tissue at sub-mm spatial resolution, without need for invasive craniotomy or skull thinning techniques

Methods

Results

Conclusion