Photoacoustic Tomography For Functional Brain Imaging And Acupuncture-induced Cerebral Cortex Mapping

Modern brain imaging techniques have provided a foundation for the development of neuroscience.At present,the tools based on brain function and structure mapping have been mainly divided into two types: the macroscopic imaging modality and the microscopic imaging modality.It is necessary to effectively integrate brain information based on the macroscopic and microscopic findings.Photoacoustic tomography(PAT),a hybrid imaging modality,can readily encompass both the microscopic and macroscopic information with the same contrast mechanism.This technique has evolved into one of the latest research methods in the field of neuroscience.In this paper,we have developed a non-invasive PAT-based brain function visualization strategy.PAT with rich optical contrast and high ultrasound resolution(up to tens of ?m spatial resolution and up to tens of ms temporal resolution),shows powerful abilities to provide functional and structural images of the whole cerebral cortex and deep brain at the vascular scale.This technique can be used to study functional activities in both brain oxygenation and metabolism.Using real-time PAT,functional brain areas with specific neural activities can be localized accurately,and the long-term brain signals can be also tracked.The basic theory of PAI was introduced at first.One of the main challenges in photoacoustic brain imaging is the light penetration depth.Another challenge is the detection of ultrasound signals through the skull.Several schemes to overcome this two technical difficulties of photoacoustic brain imaging were proposed.After that,in this dissertation,two sets of photoacoustic tomography systems were designed and built,and a technical platform for brain function imaging was constructed,which opened up a new field of application of functional photoacoustic brain imaging.Intensive and innovative research has been carried out on the development of new contrast agents,the delivery of contrast agents,drug response,monitoring of hemorrhagic stroke,monitoring and treatment of ischemic stroke,monitoring of acupuncture-induced neuromodulation.These applications are related to the mechanism of neuroscience and the difficulties of diagnosis and treatment,which have filled the gap of photoacoustic brain imaging in this field.PAT can be widely used in the research on the physiological and pathological functions of small animal brains.This technology is expected to open a new era of functional optical brain imaging and further promote the improvement of brain science.The main research contents of this dissertation are summarized as follows:1.Two sets of photoacoustic tomography systems were designed and built,and the technical platform for functional brain imaging was constructed.The second set of PAT system based on array-detector and multi-channel acquisition was an overall upgrade of the first set.2.We present a detailed review about various exogenous contrast agents for photoacoustic and thermoacoustic molecular imaging.In addition,challenges and future directions of photoacoustic and thermoacoustic molecular imaging in the field of translational medicine are also discussed.3.Acupuncture was used as a contrast agent for PAT for the first time.A new composite photoacoustic contrast agent based on combined acupuncture at Yanglingquan and Gold nanospheres injection was reported for the first time.The experimental results showed that the composite contrast agent can improve the imaging contrast between cerebral cortex vessels and surrounding background tissues.4.For the first time,a strategy of contrast enhanced PAT for living mouse was developed based on the combination of PEG-GNRs and acupuncture(ST36).At the same time,it also provides new clues for the mechanism of acupuncture-induced enhancement of drug delivery and improvement of drug efficacy.5.For the first time,we utilized photoacoustic tomography(PAT)to study hemodynamic effects of berberine in mice.Our results provide compelling evidence that both berberine can increase the HbT concentration to varied extent in certain brain regions.This study also suggests that PAT provides a powerful tool for visualizing brain hemodynamic changes induced by drugs and selection of drug dosage.6.We have shown that PAT is capable of noninvasively monitoring the pathophysiological processes of collagenase induced ICH in vivo for the first time.Specifically,it can provide morphological changes of hematoma lesions including the hematoma location,shape and size over a long period of time noninvasively.It also allows one to obtain the hemodynamic change of perihemmatoma regions,hematoma occupying effect,and reduction of cerebral blood flow in the surrounding hemorrhagic area induced by hematoma compression.Our results suggest that PAT provides a unique tool for visualizing hemodynamics involved in brain diseases such as ICH.7.We have shown that a novel dual-modality strategy that combines PAT and LSI(Laser speckle imaging)is capable of monitoring the acupuncture-treatment processes of cerebral ischemia in vivo for the first time.We obtained that acupuncture at Yanglingquan acupoint caused certain changes of hemoglobin concentration and blood flow.We also observed the increase of vessel size and reperfusion.Our results suggest that PAT provides a unique tool for monitoring the progress of treatments and evaluating the mechanism of acupuncture on stroke.Importantly,based on the experimental study of two types of stroke,it is the first time to provide strong evidence for PAT technology to differentiate ischemic stroke from hemorrhagic stroke.8.In vivo and in vitro studies were carried out to verify the pre-clinical feasibility of PAT brain imaging.Pre-clinical capability of photoacoustic imaging was evaluated by in vivo brain imaging in rats with trauma and in vitro brain imaging in rhesus monkeys,which demonstrated the potential of PAT in neonatal brain imaging.9.For the first time,a visualization technical platform based on PAT for acupuncture brain science has been proposed.For the first time,a comprehensive mapping of cerebral hemodynamic changes induced by acupuncture at 17 acupoints on mice was drawn based on more than 200 cases of PAT experimental results.Our results provide compelling evidence that acupuncture at different acupoints can cause different changes of the HbT concentration to varied extent in 10 brain regions.This technology were expected to become an important "modern inspection" technique to explain the "secret" of acupuncture and to write the "dictionary" of acupuncture.In addition,a home-made mouse holder was designed for acupuncture in PAT imaging.