Title

Multimodal MRI, Behavioral Testing, and Histology in a Rat Model of Transient Focal Cerebral Ischemia : A Dissertation

Date

May 2006

UMMS Affiliation

Graduate School of Biomedical Sciences

Document Type

Dissertation, Doctoral

Subjects

Brain Ischemia; Magnetic Resonance Imaging; Ischemic Attack, Transient; Rats; Disease Models, Animal; Academic Dissertations

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

Cerebral ischemia is defined as a decrease in blood flow to the brain. It is most often caused by obstruction of a cerebral blood vessel, and is recognized by the World Health Organization as the leading cause of serious adult disability and one of the top three causes of adult death worldwide. Most survivors demonstrate partial restitution of function over time, but the underlying recovery mechanism(s) remain unclear especially in a subset of patients with persistent neurological morbidities despite normal-appearing brain on neuroimaging. The optimal way to understand any human disease state is via clinical studies. Unfortunately, well-controlled experiments in humans are difficult due to small patient populations, the presence of numerous confounding variables, and ethical issues associated with invasive or discomforting experimental procedures. Anesthetized animal models of cerebral ischemia afford a means of avoiding the above difficulties. However, anesthesia and physiological perturbations that occasionally follow brain ischemia may affect the reliability of certain tools used to study this disease, such as functional magnetic resonance imaging (fMRI). Therefore, the central goals of this thesis were: 1) to evaluate the feasibility of performing fMRI in anesthetized and awake animals, 2) to assess fMRI responses under various perturbations of cerebral perfusion and tissue oxygenation in order to identify key factors that may modulate functional signal changes following ischemia, and 3) to utilize fMRI, behavioral tests and histology in an anesthetized animal model of transient focal cerebral ischemia to explore postischemic changes in brain pathology/function and how they relate to changes in behavior.

In the first study of this dissertation, I report the evaluation of fMRI responses in anesthetized and awake animals. Anesthesia is frequently used in animal models of cerebral ischemia, but is known to alter brain perfusion and metabolism which may, in turn, affect fMRI responsivity. Perfusion-based fMRI was used to evaluate cerebral blood flow (CBF) and blood oxygenation level-dependent (BOLD) responses to hypercapnia in awake and isoflurane-anesthetized rats. Hypercapnia produced significant CBF and BOLD fMRI signal changes throughout the cerebrum in awake and isoflurane-anesthetized groups. These results show that perfusion-based fMRI can successfully detect stimulus-evoked hemodynamic changes in the brains of both conscious and isoflurane-anesthetized animals.

The second study of this dissertation: 1) investigates the effects of alterations in cerebral perfusion and oxygenation on fMRI signal changes, and 2) examines the self-consistency of an imaging-based formalism for the calculation of the cerebral metabolic rate of oxygen (CMRO2). Functional MRI responses to a stimulus can be described in terms of relative or absolute signal change. A relative fMRI response is defined as a percent-change relative to its own respective baseline value. An absolute fMRI response is defined as a quantitative change relative to a single fixed baseline value that serves as a control. Thus, an absolute fMRI signal change is largely independent of the baseline state and may more accurately index brain activity when baseline fMRI signals change significantly over time due to, for example, hemodynamic-metabolic disturbances that occur during and/or after brain ischemia. To address these issues, the effects of inspired hypoxic, normoxic, hyperoxic, and hypercapnic gases on baseline and forepaw stimulation-evoked changes in BOLD and CBF fMRI signals were examined in isoflurane-anesthetized rats. Relative fMRI responses to forepaw stimulation varied-whereas. absolute responses were similar--across gas conditions. These results demonstrate that absolute measurements of fMRI signal change may lend a more accurate measure of brain activity during states of altered basal physiology as well as support the self-consistency of the imaging-based CMRO2 formalism under these conditions.

The third and last study of this dissertation utilized multimodal MRI, behavioral tests, and histology at acute to chronic periods following transient middle cerebral artery occlusion (tMCAO) in the rat to examine the evolution of pathological, functional, and behavioral parameters following transient focal cerebral ischemia. MRI was used to track the evolution of brain pathology and function following cerebral ischemia, and it was found that the cerebral sensorimotor network, critical for sensory and motor behavioral functions, showed profoundly abnormal signal changes that required up to one day to normalize. Adhesive removal, forepaw placement and beam-walk behavioral tests demonstrated sensorimotor dysfunctions that gradually improved but remained long after the recovery of MRI parameters. Postmortem histology confirmed the presence of selective neural cell death within the sensorimotor network at time points when behavior was abnormal. These results suggest that subtle postischemic pathological changes in the brain undetectable by MRI may be responsible for persistent behavioral deficits-a finding which may be relevant to a clinical subset of patients with persistent neurological morbidities despite negative MRI results following cerebral ischemia.

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