Thesis (Ph.D.)--University of Western Australia, 2007.

Thesis (Ph. D.)--Case Western Reserve University, 2010. / [School of Medicine] Department of Biomedical Engineering. Includes bibliographical references.

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Alzheimer's disease (AD) is the neurodegenerative disease responsible for the majority of dementia cases across the United States. Its pathology involves the accumulation of protein plaques in areas of the brain directly involved with learning and memory formation, causing cognitive impairments and loss of independence in everyday life. Deep brain stimulation (DBS) is a relatively young field in medicine that has gained a great deal of traction with its efficacious clinical outcomes in neurological diseases including Parkinson's disease, epilepsy, depression and obsessive-compulsive disorder. More recently, researchers have sought to discover the proper application of DBS to improve the formation of episodic memory to provide a comparable or superior therapy for AD. Many experiments have been performed using different electrical parameters, hardware, or locations stimulated in the brain, which produced mixed results for benefits in memory reinforcement. Of the various brain structures available to target, the Entorhinal Cortex (EC) has been shown to lead to numerous positive outcomes. Additionally, one study used a novel approach, applying DBS in response to the neural activity of the individual brain during memory encoding tasks, which produced improvements in memory performance. This proposal aims to use these modalities in concert - a closed-loop stimulation approach that monitors neural activity and targeting the EC - in AD dementia patients to act as an adjuvant therapy to current acetylcholinesterase inhibitor medications that provide weak efficacy when used alone. This will be conducted in a 2 year, multicenter, double-blind, randomized controlled clinical trial comparing treatment with dual therapy consisting of DBS and an acetylcholinesterase inhibitor, to those with acetylcholinesterase inhibitor monotherapy. Participants will have mild or moderate AD at baseline, evaluated using the Mini-Mental State Examination and their progress in both experimental arms will be recorded using the 13 item Alzheimer's Disease Assessment Subscale-Cognitive over a 2-year period. Investigators will study the primary outcome of delaying cognitive decline, with secondary effects involving the differences between age groups, stages of AD and how frequently stimulation was received in those within the DBS and standard therapy group. The results from this study have the potential to further improve future approaches involving DBS in the treatment of AD dementia, as the projected number of those affected by the disease continues to grow with advances in modern medicine.

The present series of experiments was designed to assess the utility of a discrimination procedure for measuring the affective properties of rewarding brain-stimulation. If the rewarding and discriminative stimulus properties of electrical brain stimulation were related, they may share a common substrate and be affected similarly by the same pharmacological manipulations. In Experiment 1, a discrimination procedure was developed to measure the cue properties of EBS delivered to the ventral tegmental area (VTA). Rats with VTA electrodes were trained to obtain food pellets by making a discriminated operant response on one of two levers following pulses of high intensity stimulation, or on the alternate lever after low intensity pulses. Following training, the rats were given tests in which generalized responding to intermediate intensities was measured. These tests were repeated either with conditions kept constant, or with the absolute intensities of the cues delivered within a sesion increased or decreased relative to baseline. The tests with higher or lower intensity ranges were intended to mimic the conditions that might prevail if the perceived intensities of the EBS were modified by drugs. The results of this experiment indicated that generalization gradients remained stable across three tests with conditions kept constant. When higher or lower current ranges were delivered, the discriminated responses were appropriately biased towards one lever or the other, resulting in lateral shifts in the generalization gradients. These results verified that the discrimination procedure provided a stable measure of the EBS stimulus properties, and that this measure was sensitive to changes in the intensities of the cues. In Experiment 2, tests for EBS generalization and self-stimulation (ICSS) were given after injections of vehicle, d-amphetamine (1.0 mg/kg and 2.0 mg/kg) and haloperidol (.075 mg/kg and .10 mg/kg). The results indicated that these doses of amphetamine and haloperidol did not affect the EBS generalization. However, during ICSS sessions, 2.0 mg/kg amphetamine decreased threshold and increased rates for ICSS whereas .10 mg/kg haloperidol resulted in an increase in threshold. These results suggest a dissociation of the stimulus properties of EBS from the DA reward substrate. In Experiment 3, the rats were tested for generalization after injections of physostigmine (.25 mg/kg and .50 mg/kg), scopolamine (.10 mg/kg and .25 mg/kg) and vehicle. Only the high dose of physostigmine (.50 mg/kg) produced significant differences in responding in this experiment. After injection of this drug, lower intensity stimuli elicited responding on the lever appropriate for the high current intensity, indicating a possible augmentation of the stimulus property of a fixed intensity of brain stimulation. The results of this study indicate that the cue properties of VTA brain-stimulation are dissociable from EBS reward related to the activation of DA neurons. However, evidence is provided which suggests that cholinergic neurons may be involved in the mediation of the EBS cues. In as much as cholinergic neurons are also involved in the rewarding effects of VTA brain-stimulation, these results may indicate a relationship between the cue properties of VTA EBS and an acetylcholine reward system. / Arts, Faculty of / Psychology, Department of / Graduate

Parkinson's disease is a progressively debilitating disease that affects about 1% of the world's population, and does not differentiate between genders or races. The disease is caused by the death of the dopaminergic neurons in the basal ganglia nuclei, especially those in the substantia nigra pars compacta. Subsequent loss of dopamine production engenders the cardinal symptoms of bradykinesia, rigidity, akinesia, and postural instability found in all patients with Parkinson's disease. While there are several types of Parkinson's disease, the majority of the cases are made up of the idiopathic and Levodopa responsive type. The current consensus on treatment is to use medications until the patient becomes refractory to all medicines. It is only at this point will the surgical option deep brain stimulation be considered. while this procedure comes with a higher risk of post surgery complications, the benefits it offers patients with advanced Parkinson's disease are far superior to those offered patients by medications. It reasons then that patients would benefit more if they received this treatment earlier in the course of the disease. The mechanisms, side effects, costs, cost-effectiveness, and long term effects on quality of life of deep brain stimulation will be compared with those of medications to assess whether it is worthwhile to use this treatment for patients with mild Parkinson's disease.

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