ABSTRACT
Non-human primate (NHP) models have been recommended as ideal animal models for preclinical,
translational stroke research by the Stroke Therapy Academic Industry Roundtable (STAIR) committee due to
translational failures in rodents and significant cerebrovascular, neuroanatomical and biomolecular similarities
between NHPs and humans. In response to this recommendation, Dr. Nudo (one of PIs on the current proposal),
has pioneered and further developed NHP stroke models in the past few decades. Although clinically-relevant
NHP stroke models are now available, limitations in imaging modalities that can map neural activates in deep
brains of awake monkeys are hindering the current research. Functional magnetic resonance imaging (fMRI)
has been widely used to detect functional changes in the brain. However, this technique is limited by poor
temporal and spatial resolution when collecting functional information. Particularly, for brain research involving
awake, behaviorally active monkeys, the limited temporal resolution of fMRI can be a significant barrier because
of motion artifacts. Alternatively, many studies have used chronic, invasive microelectrode implants for recording
action potential and local field potentials in awake monkeys; however, microelectrode electrical recording is quite
invasive, has poor spatial resolution, and does not provide depth-resolved information.
We propose to develop a wearable, whole brain imaging system based on the emerging photoacoustic (PA)
imaging (PAI) for ischemic stroke research with NHP models. Ischemic stroke is characterized by changes in
hemodynamics in the brain. Triggered by the occlusion of a major cerebral artery or its branches, ischemic stroke
leads to cerebrovascular adaptations both acutely and chronically. PAI, based on optical absorption contrast, is
intrinsically sensitive to the changes in brain hemodynamics including both blood volume (perfusion) and blood
oxygenation (oxygen consumption). Therefore, PAI offers excellent ability to understand the acute and chronic
cerebrovascular adaption after stroke, as well as hemodynamic changes resulting from functional activation in
the brain. Built on our strong expertise in PA brain imaging, especially in PAI of an awake behaviorally active
rhesus monkey, we propose to develop a real-time wearable PA brain imaging system that can be used for deep
brain mapping through a cranial window. By utilizing state-of-the-art capacitive micromachined ultrasonic
transducer (CMUT) technology, the proposed PAI technology can provide depth-resolved functional information
in deep brain regions in real-time with high spatial resolution. Two aims are proposed: 1) Evaluate and optimize
a wearable, multi-wavelength CMUT-based PAI system for real-time visualization of functional activation in the
NHP brain; and 2) Image changes in brain functional activations and cerebrovascular adaptations in an NHP
stroke model in a longitudinal study. The success of this study will provide answers to important scientific
questions about stroke with NHP models, and pave the way for new stroke therapy development.