Deep brain stimulation (DBS) is an established therapy for various movement disorders and is now being investigated to treat a widening range of neurological and neuropsychiatric conditions. However, to fully realize the promise of DBS as a therapy, we need to better understand how it modulates neuronal activity within both the local DBS target and in the brain as a whole. The focus of this proposal is to advance a novel method of field-shaping central thalamic-DBS (fsCT-DBS) to modulate arousal and cognition. Arousal regulation is profoundly impacted in patients with structural brain injuries and is a common and untreated sequelae of many patients suffering from neurodegenerative and neuropsychiatric illnesses. In prior work we discovered a novel method of CT-DBS, where anodes and cathodes are separated across multiple implanted DBS leads within a specific region of the central thalamus, here termed `field-shaping CT-DBS' (fsCT-DBS). Here we will prospectively test and characterize behavioral performance of animals during fsCT-DBS. The central hypothesis to be tested here is that robust regulation of arousal with fsCT-DBS arises through selective delivery of electric stimulation to a specific fiber tract within the central thalamus, the medial aspect of the dorsal thalamic tegmental tract (DTTm). This fiber tract consists of axons originating from central thalamic nuclear groups and brainstem arousal centers that project to the anterior forebrain and are believed to play a crucial role in supporting cognition through the regulation of activity levels and brain-wide communication.
The aims of this proposal seek to establish an anatomically accurate predictive biophysical model of the DTTm and to systematically test new modes of fsCT-DBS to enhance the use and capacity of cognitive resources in healthy behaving macaque monkeys. First, state-of-the-art biomedical imaging will be combined with ultrahigh- resolution optical imaging to construct predictive biophysical models of the DTTm. Second, the effects of fsCT- DBS on DTTm recruitment will be measured by comparing performance on a sustained attention/vigilance task and in two paradigms requiring additional cognitive resources, a set-shifting categorization task and a working memory task. The latter two tasks require cognitive flexibility, a faculty that is degraded in the majority of patients with neuropsychiatric disorders and structural brain injuries. Third, the use of adaptive fsCT-DBS will be explored using a new clinical-grade closed-loop DBS device. The identification and predictive biophysical modeling of the local fsCT-DBS target, the DTTm, the use of multipolar field shaping to validate the model predictions through behavior and large-scale physiology, and exploration of close-loop DBS are all highly innovative aspects of this proposal as they will improve our understanding of how to precisely target fsCT-DBS to robustly and reliability regulate anterior forebrain activity and support cognition. The use of healthy non- human primates as a model to validate the proposed approach is essential to guiding and facilitating design specifications for a new clinical-grade fsCT-DBS system for use in humans.
The proposed research is relevant to public health because deep brain stimulation (DBS) holds great promise as a therapy for millions of individuals who live with chronic neurological and neuropsychiatric disabilities and for whom no effective therapies exist. The goal of this research is to develop new methods for DBS that utilize anatomical and biophysical modeling to effectively target electrical stimulation within the key node of the arousal regulation network in order to recruit neurocognitive resources that support cognition. The project is relevant to the mission of the National Institutes of Neurological Disorders and Stroke as we are seeking fundamental knowledge about how brain activity within the brain is organized, and how best to reestablish order ultimately to reduce the burden of brain disease and injury on individuals, their families and society.
