Thesis (M. Phil.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 144-153).

Thesis (Ph. D.)--University of Hong Kong, 1992. / Photocopy of typescrpt.

Thesis (M.Phil.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 144-153) Also available in print.

Thesis (Ph. D.)--Florida State University, 2005. / Advisor: Dr. Chalres C. Ouimet, Florida State University, College of Arts and Sciences, Dept. of Psychology. Title and description from dissertation home page (viewed Sept. 19, 2005). Document formatted into pages; contains x, 83 pages. Includes bibliographical references.

Thesis (M.S.)--Florida State University, 2003. / Advisor: Dr. Frank Johnson, Florida State University, College of Arts and Sciences, Dept. of Psychology. Title and description from dissertation home page (viewed Sept. 24, 2003). Includes bibliographical references.

INTRODUCTION: Major depressive disorder (MDD) is characterized by ongoing feelings of guilt, sadness, and memory and cognition impairment. It is a multidimensional illness that affects many functionally integrated pathways of the brain. Understanding the underlying brain dysfunction that gives rise to this complex illness has been challenging, and by extension the search for appropriate treatments. MDD patients who are considered treatment resistant make up the primary population that receives electroconvulsive therapy (ECT). Remarkably, ECT shows a 75% remission rate in this patient population and is considered the “gold standard” treatment for major depression. Although the exact mechanism of its function is unknown, it is well accepted that the induced grand-mal seizure confers its therapeutic effect. The seizure likely has broad effect that somehow corrects the underlying dysfunction in brain circuitry. Here, we specifically examined studies of functional connectivity and metabolite changes. METHODS: Through literature search, we examined six studies in functional connectivity and four studies in magnetic resonance spectroscopy (MRS). RESULTS: Functional Connectivity: Studies have found that after bilateral ECT treatments, patients with major depression showed reduction of functional connectivity (FC) from the left dorsolateral prefrontal cortex (DLPFC) to other cortical and limbic structures. Correlated activity between the superior frontal gyri, middle frontal gyri and angular gyri were significantly increased after ECT. Hyperdeactivation of the orbitofrontal cortex to negative emotional stimuli in patients was decreased, and it was associated with improvement in depressive symptoms. Regional activity in the subgenual anterior cingulate cortex (sgACC) and functional connectivity between the sgACC and left hippocampus in treatment naïve patients after ECT were increased and correlated to reduction of depressive symptoms. Reduced connectivity between the amygdale and sgACC and increased connectivity between the amygdale and DLPFC was found by sequential assessments over a course of ECT treatments. Lastly, ECT increased the functional connectivity between DLPFC and the default mode network. MRS: Studies found decreased levels of glutamate or glx (glutamate/glutamine/ GABA) in patients in the anterior cingulate cortex and dorsolateral prefrontal cortex (DLPFC) compared to healthy controls. Additionally, it was found that glx levels increased after ECT treatments and that this increase was only in those who responded to treatment. Lastly, GABA level increased after ECT treatment in the occipital cortex. Discussion: Results from functional connectivity and brain metabolite studies in patients with major depression point to induced neuroplasticity as part of ECT’s therapeutic mechanism. Remodeling connectivity and mediating metabolite changes both will require modifications at the synaptic level. The wide spread changes seen in several different brain regions that have been implicated in depression further suggests that ECT’s effects are both highly specific and broad. CONCLUSION: Electroconvulsive therapy has consistently demonstrated impressive efficacy among the most severely depressed patients and is known to produce widely distributed effects in the brain. However, this also makes assessing its therapeutic mechanism challenging. Magnetic resonance imaging studies assessing functional connectivity and brain metabolite levels have demonstrated that ECT likely produces neuroplastic changes to remodel aberrant connectivity and dysfunctional excitatory and inhibitory neurotransmission in cortical and limbic areas. Although these findings should be interpreted with caution, this field of research has provided an unprecedented opportunity to examine the living brain in great detail. Further studies with larger sample sizes and improved technical specifications will likely yield greater results.

Cortical injuries, such as those caused by stroke and other insults, are the leading cause of death and disability worldwide. While thrombolytics can be used to restore blood flow immediately following the onset of symptoms of an ischemic stroke, there are currently no neurorestorative therapeutics that can enhance long-term recovery of function following injury. Neuregulins are a family of growth factors involved with the survival and function of neurons and glia. Glial Growth Factor 2 (GGF2) is an isoform of neuregulin-1 that has demonstrated significant effects in the recovery of function in rodent models of stroke. Histological analyses suggest GGF2 promotes recovery by enhancing endogenous mechanisms to reduce inflammation and promote plasticity. To further explore the efficacy of GGF2, we used our rhesus monkey model of cortical injury and fine motor impairment to compare the rate and pattern of recovery in monkeys treated with GGF2. Twenty-four young adult male monkeys (ages 4-10 years old) were pre-trained on our task of fine motor function of the hand before undergoing surgery to produce a cortical lesion limited to the hand representation of the primary motor cortex on one side. Intravenous (IV) administration of GGF2 (0.5 mg/kg) began 24 hours after surgery and continued daily for 7 days. This was followed by 21 days of sub-cutaneous administration of GGF2 at two different dose levels (0.1 mg/kg or 0.3 mg/kg). Post-operative testing began two weeks after the lesion and continued for 12 weeks. All trials were video recorded and latency to retrieve a reward was quantitatively measured to assess the trajectory of post-operative response latency and grasp pattern compared to pre-operative levels. The results showed no significant differences between the groups in the recovery of fine motor function. Moreover, all vehicle control monkeys returned to their pre-operative levels of latency and grasp pattern despite no significant differences in lesion volume from the experimental groups. In addition to measures of behavioral recovery, we processed the brain tissue with immunohistochemistry to investigate the role of GGF2 treatment in reducing the pro-inflammatory response of microglia and enhancing axonal sprouting and synaptogenesis following injury. All groups had a greater density of Iba1+ microglia in the perilesional grey matter and sublesional white matter, but there were no significant differences in the numerical density or phenotypes of microglia between the groups. We also found no significant differences in axonal sprouting between the groups. However, GGF2 treatment did enhance expression of synaptophysin in the contralesional hemisphere of monkeys that received subcutaneous doses of GGF2 following the initial 7 days of intravenous GGF2 treatment. This suggests that high dose GGF2 treatment may enhance plasticity of compensatory circuits involving the intact hemisphere and that this effect is dose dependent. In addition, we followed up these analyses using a subset of monkeys from the larger GGF2 study to optimize and validate a method that labels newly synthesized myelin. This is accomplished by in vivo administration of a choline analog, propargylcholine (P-Cho) that labels newly synthesized myelin and can be visualized post-mortem. Our results demonstrate effective and stable incorporation of P-Cho with post injection survival of 1 to 6 weeks. Using this method to quantify new myelin after cortical injury to the primary motor cortex, showed significantly greater P-Cho labeling and co-localization with myelin basic protein (MBP) in the white matter underlying the ipsilesional hemisphere when compared with the contralesional hemisphere. This validates P-Cho for assessing myelin plasticity in a nonhuman primate brain and how it might be used to assess therapeutics aimed at inducing remyelination and enhancing myelin synthesis. Finally, this dissertation also includes the comparison of sex differences in recovery of motor function after cortical injury. In a cohort of aged male and female monkeys, postmortem analysis showed no differences in lesion volume between the males and females. However, behaviorally, the females returned to their pre-operative latency and grasp patterns significantly faster and more completely than the males. These findings demonstrate the need for additional studies to further investigate the role of estrogens and other sex hormones that may differentially affect recovery outcomes in the primate brain. Collectively, the results presented in this dissertation highlight the complexity of evaluating treatments and mechanisms underlying recovery of function by enhancing neuroplasticity. Specifically, we were unable to effectively evaluate GGF2 as a treatment due to the behavioral recovery of all control monkeys. Follow up studies should investigate treatment with GGF2 in aging monkeys and compare the results with our findings. Additionally, it is necessary to further explore the recovery of fine motor function in young monkeys. Finally, our study showing sex differences in recovery of function provides evidence that sex hormones may play a significant role in providing neuroprotection in the aging brain following cortical injury. Future studies should measure post-operative estrogen levels and evaluate supplementation as a potential treatment option.

There is growing knowledge that neuronal circuitry undergoes alteration throughout development. Experience plays a key role in the reorganization of neuronal circuitry through the various mechanisms of learning. For example, when an animal is deprived of sensory input such as light in one or both sides of the eye, it can result in blindness on that side. In a study of rats placed in either isolated or enriched environments, those placed in enriched environments performed better on learning tests (maze test) than those placed in isolated environment. There was increased neurogenesis, synaptogenesis, myelination and angiogenesis in rats placed in enriched environments. These were all as a result of learning, which induces neuroplasticity in the nervous system. The goals of this study were to determine how evoked movement is altered by changes in key parameters of light stimulation: intensity and period and to determine if one hour of light (optogenetic) stimulation could give rise to plastic changes in the nervous system as indicated by alterations in spontaneous motility. To ascertain how evoked motor activity influences neuronal activity through learning and experience, optogenetics was employed to evoke movement in an embryonic chick at embryonic day nine (E9) after electroporation of a channelrhodopsin variant, ChIEF, into the neural tube. I first attempted to determine the optimal intensity needed to cause neuroplasticity in an embryonic chick by varying current to a LED light to produce three different light intensities. A protocol of 5 pulses of light with a period of 2 seconds was used to illuminate the right leg of 5 embryonic chicks with each intensity. To determine the optimal period of stimulation, I varied the period to 3 s and 4 s with one animal. Stimulation for an hour with a training protocol of 1800 pulses/hour (with a period of 2 s) of blue light (470 nm) was then used to illuminate the right thigh of the embryonic chick. There were varied responses to light of all intensities used for stimulation, but high light intensity (maximum - 100%) seemed to have produced the best responses in terms of producing the largest joint angle changes and shortest latencies of movement in all joints of the leg of embryonic chick. Movements of the hip and ankle joints were the most robust. This was closely followed by those of the mid (83.33%) intensity. Therefore, it can be inferred that the greater the intensity of light, the better the response. The training protocol did not produce significant changes in embryonic activity. There were some decreases in joint angles and variable spontaneous movement duration in all animals used but there could be some changes going on at the neuronal or muscular level which were beyond the scope of this study to investigate. It is my hope that this study will provide some knowledge pertinent to the treatment or management of neurodevelopmental disorders that may result in paraplegia or Erb's palsy.

The physiological significance of noradrenergic sympathohabenular ingrowth following medial septal lesions was investigated. Following septal lesions, sympathetic fibers originating in the superior cervical ganglia are known to sprout into the medial habenular nuclei, and into the hippocampal formation. Previous work involving sympathohippocampal ingrowth showed that firing rates in septal animals with no ingrowth showed that firing rates in septal animals with no ingrowth were higher than rates of septal animals with ingrowth and controls. Those results suggested that sympathetic ingrowth in the hippocampus had some functional capability in a modulatory manner. The primary aim of the present study was to determine if the peripheral sympathetic ingrowth into the medial habenular nuclei following a septal lesion is functionally significant. The results showed that firing rates of neurons of the medial habenulae in animals receiving septal lesions were significantly higher than rates of control animals and septal lesioned + ganglionectomized animals.

Stroke outcome is highly variable. Experiments in this thesis test the hypothesis that experience prior to a stroke is an important variable in the manifestation of stroke. Optokinetic tracking was used to evaluate the effects of visual cortex stroke and MCA occlusion in rats. Normal laboratory rats showed a small, but significant decrease in tracking thresholds following visual cortex stroke. Animals with developmental visuomotor experience or reach training experience in adulthood, however, had tracking thresholds which were substantially increased, and the effects of visual cortex strokes were greater. MCA occlusions did not affect tracking behaviour. These data indicate that specific experiences engage neural plasticity that can alter brain function. These changes can, in turn, affect the behavioural manifestation of a stroke. Understanding the effect that environmental experience has on stroke outcome promises to enable better characterization of strokes, and set appropriate behavioural baselines for the measurement of recovery of function. / vi, 135 p. : ill. ; 29 cm