Hybrid Optical System for Studying the Dynamic Regulation of Blood Flow/Metabolism in the Adult Brain

Cerebral blood flow (CBF) and oxygen delivery are tightly controlled to meet neuronal energy demands; however, studying dynamic neurovascular coupling in the human brain is challenging due to the lack of methods that can measure rapid changes in CBF and tissue oxygenation. This report presents an in-house-developed hybrid time-resolved near-infrared spectroscopy/diffuse correlation spectroscopy (TR-NIRS/DCS) device and its use to track dynamic CBF and tissue oxygen saturation (StO2) responses simultaneously with sub-second resolution following a vasodilatory stimulus (i.e., a hypercapnic challenge). Cerebrovascular reactivity (CVR) experiments were performed on 10 healthy participants (mean age: 27 years) using a computer-controlled gas delivery system to manipulate breath-to-breath inspired CO2 levels. TR-NIRS and DCS data were acquired continuously at a sampling frequency of 3 Hz to capture dynamic CBF and oxygenation responses. CVR measurements derived from oxyhemoglobin and deoxyhemoglobin concentrations were 3.4 ± 2.6 and 3.0 ± 1.9 %/mmHg, respectively. Their dynamic component, a fitted exponential coefficient that defines the speed of the response as per the hemodynamic response function, was estimated to be 32 ± 16 and 33 ± 28 seconds. The corresponding CVR value and dynamic component derived from CBF was 3.5 ± 3.6 %/mmHg and 33 ± 18 seconds. These experiments demonstrated that the optical system had sufficient temporal resolution to capture the dynamics of the oxygenation and CBF responses to a vasodilatory stimulus

Digging Deeper with Diffuse Correlation Spectroscopy

Patients with neurological diseases are vulnerable to cerebral ischemia, which can lead to brain injury. In the intensive care unit (ICU), neuromonitoring techniques that can detect flow reductions would enable timely administration of therapies aimed at restoring adequate cerebral perfusion, thereby avoiding damage to the brain. However, suitable bedside neuromonitoring methods sensitive to changes of blood flow and/or oxygen metabolism have yet to be established. Near-infrared spectroscopy (NIRS) is a promising technique capable of non-invasively monitoring flow and oxygenation. Specifically, diffuse correlation spectroscopy (DCS) and time-resolved (TR) NIRS can be used to monitor blood flow and tissue oxygenation, respectively, and combined to measuring oxidative metabolism. The work presented in this thesis focused on advancing a DCS/TR-NIRS hybrid system for acquiring these physiological measurements at the bedside. The application of NIRS for neuromonitoring is favourable in the neonatal ICU since the relatively thin scalp and skull of infants has minimal effect on the detected optical signal. Considering this application, the validation of a combined DCS/NIRS method for measuring the cerebral metabolic rate of oxygen (CMRO2) was investigated in Chapter 2. Although perfusion changes measured by DCS have been confirmed by various flow modalities, characterization of photon scattering in the brain is not clearly understood. Chapter 3 presents the first DCS study conducted directly on exposed cortex to confirm that the Brownian motion model is the best flow model for characterizing the DCS signal. Furthermore, a primary limitation of DCS is signal contamination from extracerebral tissues in the adult head, causing CBF to be underestimated. In Chapter 4, a multi-layered model was implemented to separate signal contributions from scalp and brain; derived CBF changes were compared to computed tomography perfusion. Overall, this thesis advances DCS techniques by (i) quantifying cerebral oxygen metabolism, (ii) confirming the more appropriate flow model for analyzing DCS data and (iii) demonstrating the ability of DCS to measure CBF accurately despite the presence of a thick (1-cm) extracerebral layer. Ultimately, the work completed in this thesis should help with the development of a hybrid DCS/NIRS system suitable for monitoring cerebral hemodynamics and energy metabolism in critical-ill patients

Clinical Brain Monitoring with Time Domain NIRS: A Review and Future Perspectives

Near-infrared spectroscopy (NIRS) is an optical technique that can measure brain tissue oxygenation and haemodynamics in real-time and at the patient bedside allowing medical doctors to access important physiological information. However, despite this, the use of NIRS in a clinical environment is hindered due to limitations, such as poor reproducibility, lack of depth sensitivity and poor brain-specificity. Time domain NIRS (or TD-NIRS) can resolve these issues and offer detailed information of the optical properties of the tissue, allowing better physiological information to be retrieved. This is achieved at the cost of increased instrument complexity, operation complexity and price. In this review, we focus on brain monitoring clinical applications of TD-NIRS. A total of 52 publications were identified, spanning the fields of neonatal imaging, stroke assessment, traumatic brain injury (TBI) assessment, brain death assessment, psychiatry, peroperative care, neuronal disorders assessment and communication with patient with locked-in syndrome. In all the publications, the advantages of the TD-NIRS measurement to (1) extract absolute values of haemoglobin concentration and tissue oxygen saturation, (2) assess the reduced scattering coefficient, and (3) separate between extra-cerebral and cerebral tissues, are highlighted; and emphasize the utility of TD-NIRS in a clinical context. In the last sections of this review, we explore the recent developments of TD-NIRS, in terms of instrumentation and methodologies that might impact and broaden its use in the hospital

Orally Available Near Infrared Imaging Agents for the Early Detection of Diseases

Early detection and treatment of diseases has the potential to dramatically improve patient outcomes. Diseases like cancer have shown remarkably higher survival rates when the cancer is detected early, before it has had a chance to metastasize and migrate to different regions. One way to increase rates of early detection is to implement annual screenings. Current screening methods often focus on blood tests, which gather molecular information from the circulation, or imaging, which provides anatomical details. Molecular imaging has the ability to provide both types of information, but the high cost and radiation risk often preclude its use in population screening. In this thesis, we hypothesized that near-infrared fluorescent imaging agents could be administered orally and yield sufficient contrast for disease diagnosis. The use of NIR fluorescent targeting ligands provides both spatial and molecular information while making the entire process fast, inexpensive, completely non-invasive, and safe with the use of non-ionizing radiation. For proof-of-concept studies to develop this novel technique, we selected integrin of the form αvβ3 as the target, and a high affinity peptidomimetic as the ligand. The major challenge of developing an orally available imaging agent is that orally available drugs are typically small in size and lipophilic in nature, while imaging agents tend to be larger in size and hydrophilic. In spite of these challenges, an IRDye800CW-labeled agent had an oral absorption of 2.3% and was selected for studies in the detection of two diseases: breast cancer and rheumatoid arthritis. Mammography uses x-rays to detect suspicious lesions when screening for breast cancer but only provides anatomical data, which has lead to high false positive rates and an estimated $4 billion in expenditure due to overdiagnosis. The IRDye800CW agent was dosed at 5 mg/kg in an orthotopic tumor xenograft mouse model. Live animal imaging at 6, 24 and 48 hours post administration showed the highest target to background ratio of ~4 at 48 hours and histology showed high uptake of the agent by macrophages and breast cancer cells. Rheumatoid arthritis (RA) is an autoimmune disease that leads to largely irreversible joint damage over time, but effective treatments are available. Therefore, there is intense interest in early detection of RA to prevent further damage, and some studies have even indicated that the disease could be cured if detected early. However, current methods lack the sensitivity to detect RA at an early stage. Oral delivery of the IRDye800CW agent in a collagen antibody induced arthritis mouse model showed significantly higher uptake in the inflamed joints compared to healthy joints. To scale the expected signal to clinically relevant depths, we developed a 3D COMSOL model for optical simulations of RA detection in the human hand. The simulations showed that for target to background concentration ratios of the imaging agent of 5.5 and 6.5, there was 95% and 98% probability of detection of the inflamed joint. The in vivo mouse model had an estimated target to background concentration ratio of ~20, which makes the detection of RA in humans very promising. This dissertation demonstrates the oral delivery of molecular imaging agents for the detection of breast cancer and RA in relevant mouse models. These studies provide the foundation to develop a range of oral molecular imaging agents for other biomarkers and diseases with the potential for earlier diagnosis to improve patient outcomes.PHDChemical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/147662/1/sumitbh_1.pd

SYNTHESIS OF DYE LIBRARIES FOR NEURODEGENERATIVE DISEASE AND UNIQUE FRET STUDY

Ph.DDOCTOR OF PHILOSOPH