Optical techniques to study drug-induced neurovascular and cellular changes in vivo

Substance abuse results in profound and wide-ranging changes in brain chemistry, morphology, physiology, and function. Although researchers have made enormous strides in identifying the receptors for each major drug of abuse and in clarifying the neural circuitry involved in addictive processes, the physiological and functional changes in the brain during drug use or after chronic exposure to substances of abuse are not fully understood. For example, one of the most serious medical risks of cocaine abuse is stroke due to the drug’s disruption of blood fow in the brain. About 25%-60% of cocaine-induced strokes can be attributed to cerebral vasospasm and ischemia (Johnson et al. 2001; Buttner et al. 2003; Bartzokis et al. 2004; Bolouri and Small 2004). The resultant neurologic defcits can range from mild and transient (e.g., facial paralysis) to severe with permanent disability (e.g., tetraplegia (Spivey and Euerle 1990)). Brain imaging studies have documented marked decreases in cerebral blood fow (CBF) and blood volume (CBV) in cocaine abusers (Volkow et al. 1988; Pearlson et al. 1993; Wallace et al. 1996; Gollub et al. 1998). However, the mechanisms underlying cocaine-induced CBF reduction, cerebral vasospasm, and ischemia are poorly understood. The possibilities include (1) direct vasoconstrictive effects elicited via cocaine-induced intracellular calcium ([Ca²⁺]i) increase in vascular smooth muscle cells (Zhang et al. 1996), (2) indirect vasoconstriction secondary to the release of sympathomimetic amines, (3) a local anesthetic action secondary to blockade of ion channels, or (4) an indirect effect of reduced neural activity and metabolic demand (Volkow et al. 1988). Therefore, separation of the cellular effects from the vascular effects of cocaine is crucial to understanding the mechanisms that lead to neurovascular toxicity in cocaine abusers. The ability to distinguish the cellular effects from the vascular effects of cocaine remains a technical challenge for neurophotonics and brain mapping communities because the technological requirements necessary for this endeavor include Multiparameter detection or imaging to enable simultaneous quantifcation of the changes in hemodynamics, tissue oxygenation, and cellular activity induced by cocaine 1. High temporal resolution to enable capturing real-time dynamic changes and brain responses during drug intoxication 2. High spatial resolution to permit separation of vascular compartments (e.g., artery, vein, and capillary) and image their vascular hemodynamic changes without fuorescence labeling 3. A relatively large feld of view (FOV) to provide 2D or 3D quantitative images of the CBF velocity (CBFv) networks and cerebrovascular angiography In the neuroimaging feld, a noninvasive and high spatiotemporal-resolution imaging of cerebral hemodynamic and cellular (e.g., neuronal) response to drug challenge remains a major challenge. Although conventional neuroimaging tools such as positron emission tomography (PET) and functional MRI (fMRI) have greatly advanced our understanding of the pharmacological and physiological effects of cocaine (Volkow et al. 1988; Gollub et al. 1998), the spatial resolution of these imaging techniques (e.g., >1 mm) is insuffcient to resolve individual vascular compartments or cells (London et al. 1990; Lee et al. 2003). While optical microscopy (e.g., multiphoton microscopy) has shown some promise for visualizing capillary vasculature and cellular details of the cerebral cortex of rodents in vivo, its FOV is too small and the image depth is limited (e.g., ~300 um) (Helmchen and Waters 2002). Other imaging approaches using intrinsic hemoglobin contrast such as intrinsic signal imaging (IOS) (Frostig et al. 2005), laminar optical tomography (LOT) (Hillman et al. 2004), and laser speckle imaging (LSI) (Dunn et al. 2001) have been reported to map the brain’s hemodynamic activity with improved spatial resolution; while IOS excels in the spatial domain with ~50 um resolution (Frostig et al. 2005), LOT is unable to resolve individual vessels and LSI only measures “relative” changes in CBFv. To tackle this challenge, we have developed optical-fber-based diffusion and fuorescence (ODF) spectroscopy (Figure 7.1) and multimodality optical/fuorescence imaging (OFI) platforms to permit simultaneous assessment of cerebral hemodynamics and cellular activities in cortical brain in vivo. In this chapter, we will present the state-of-the-art optical techniques developed in our labs, focusing on their technical capabilities that enable simultaneous recordings and dynamic measurements to capture the physiological changes from the cortex of a living brain. We will summarize their application to drug abuse and drug addiction—one of the common but serious brain diseases to study the complex neurovascular and cellular activity changes in the brain induced by stimulants such as cocaine.