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 i s 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 i s 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.

Public Health Relevance

Improved treatment for a number of debilitating disorders (Parkinson's disease, mood disorders, movement disorders, etc.) rooted in the dysfunctional activity of deeper brain areas (basal ganglia) are needed and require advances in the methods used to study these complex brain networks. A new device is proposed that is capable of probing the elaborate electrical and chemical (dopamine) interactions essential to the functioning of these brain areas and may potentially elucidate the causative mechanisms of their associated disease states as well as more effective ameliorative strategies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Langhals, Nick B
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Massachusetts Institute of Technology
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Schwerdt, Helen N; Zhang, Elizabeth; Kim, Min Jung et al. (2018) Cellular-scale probes enable stable chronic subsecond monitoring of dopamine neurochemicals in a rodent model. Commun Biol 1:144
Schwerdt, Helen N; Kim, Min Jung; Amemori, Satoko et al. (2017) Subcellular probes for neurochemical recording from multiple brain sites. Lab Chip 17:1104-1115
Schwerdt, Helen N; Shimazu, Hideki; Amemori, Ken-Ichi et al. (2017) Long-term dopamine neurochemical monitoring in primates. Proc Natl Acad Sci U S A 114:13260-13265