Therapeutic devices for probing electrical and chemical activity in deep brain disorders

点击翻译按钮获取中文摘要

 DESCRIPTION (provided by applicant): Devices capable of probing the elaborate interactions between electrical and chemical (ie. dopamine) neural signals that embody the basal ganglia brain circuits will improve treatment approach of subcortically based disorders and ability to elucidate their pathophysiological mechanisms. The neuroactive chemical, dopamine, along with its major role in controlling basal ganglia operations, are implicated in many debilitating disorders- movement disorders including Parkinson's disease, psychiatric and mood disorders such as depression and anxiety, etc. Current treatment have limited efficacy while the ability to develop better restorative strategies is aggravated by our limited understanding of these complex brain circuits including the role of dopamine signaling known to innervate all basal ganglia structures along with their projection targets across the brain. Furthermore, the targeted basal ganglia areas are situated deep in the brain volume, which limits the methods that can be employed to monitor its activity in situ. The first aim is to employ microfabrication techniques to manufacture high aspect ratio electrodes with multiple (4) different functions to probe the multifaceted nature of the basal ganglia-local and multi-site recording and modulation of electrical and chemical activity. These "injectrodes" will be able to record both electrical neural activity and dopamine fluctuations from a dense micro- array of electrode sites at the site of drug infusion or electrical stimulation. This multimodal probe will allow unparalleled analysis (with superior temporal and spatial resolution) of cell-type specific neural activity in the form o their electrical and chemical signaling domains-essential to understand etiological mechanisms and identify drug targets for brain disorders. Fast scan cyclic voltammetry performed at multi-electrode carbon arrays integrated at the injectrode tip allows for chemical recording of dopamine fluctuations at millisecond timescales at several sites proximal to the site of stimulation or infusion. The injectrode may also afford improved remediation of pathological brain states by adaptively disturbing the aberrant activity based on detected electrical and chemical discharge patterns for closed-loop treatment. The second aim is to validate the injectrode device. Local field potentials and spike activity along with dopamine fluctuations will be monitored in response to locally delivered stimuli in nonhuman primates. These studies will be combined with behavioral studies related to trained saccadic eye movement tasks. Therapeutic efficacy will be determined by measuring both behavioral and physiological neural activity along with physiological response during the long term use of the closed-loop injectrode systems as chronically implanted in rodent models of Parkinson's disease. The proposed studies will generate advanced tools to probe the brain from multiple functional domains and ameliorate aberrant brain circuits in a localized and efficacious manner and may reveal important neurochemical mechanisms critical to basal ganglia functionality. Furthermore, the generated devices may be applied towards in situ high throughput screening of neuropharmacological agents for drug discovery.