Intraoperative Auditory Gating in Parkinson’s Disease
(NARSAD; Novel Clinical and Translational Methods Pilot Grant pending). Auditory gating is estimated by measuring the amplitude of the auditory evoked response to paired clicks, and is defined as a decrease in the brain’s response to the second of two (paired) auditory clicks. Measured by EEG, evidence supports the theory that the auditory gating deficit found in both schizophrenia and Parkinson’s disease is both a surrogate marker of cognitive deficits, and a biomarker for successful therapeutic intervention. Cognitive deficits contribute significantly to disease morbidity, but are currently untreated. This project will initially focus on identification of the brain regions in which auditory gating can be measured with microelectrode recording during standard-of-care DBS surgery. The deep brain regions implicated in the auditory gating pathway will subsequently be investigated to determine if transient DBS improves auditory gating and ultimately cognitive function. If successful, these investigations will lead to both a more complete understanding of the auditory gating pathway in the brain, and to the identification of candidate nodes for therapeutic DBS intervention for the treatment of the cognitive deficits found in brain disorders such as Parkinson’s disease and schizophrenia.
Pediatric Secondary Dystonia
(AEF and Children’s Hospital Colorado Directorship). Secondary dystonia is one of the most common movement disorders resulting from brain injury, and is typically refractory to medical treatment. Patients with medically refractory dystonia are increasingly considered for GPi-DBS. DBS provides significant therapeutic benefit in primary dystonia, but therapeutic response to GPi-DBS in secondary dystonia is highly variable. Enhancing our understanding of etiology, mechanism, pathophysiology, and response to DBS, will help to identify appropriate candidates for this treatment in the future, and to develop novel therapies for those patients who prove not to be candidates for GPi-DBS. Systematic collection of videotaped disease ratings scales, resting-state functional brain MRI and DTI, and intraoperative neurophysiological recordings (MER and LFP), will be collected pre-operatively and for a one-year follow up, with categorization of parameters according to DBS response. Information obtained from this study will guide future evaluation of secondary dystonia patients.
Michael Graner's research focuses on the immunology and biology of brain tumors. From a clinical perspective, he is interested in vaccine design and implementation, which includes the search for appropriate combinations of therapies to enhance immune responses or to downplay the role of tumor-induced immune suppression. He is a patent-holder on a vaccine process that generates a material from tumors that is enriched for a class of proteins called chaperones (sometimes called stress proteins or heat shock proteins). These proteins are potent immune stimulators that also carry antigenic components from the tumor that lead to activated immune responder cells specifically targeting the tumor. This vaccine is a personalized therapy that is made from the patient’s own tumor. We are moving this vaccine towards a clinical trial in both human and canine patients, the latter in conjunction with collaborators at the Animal Cancer Center at the Colorado State University College of Veterinary Medicine and Biomedical Sciences. At a more basic/translational science level, we are also interested in the biologic and immunologic activities of exosomes and microvesicles. These are “tiny fat balls” that are released from most all cell types, but tumor cells are quite prodigious at it. Dr Graner’s group was the first to identify these vesicles from brain tumor cells, and they have also demonstrated their presence in the sera of patients with high grade gliomas. Because exosomes and microvesicles contain a sampling of the lipids, proteins, and RNAs of the tumor cells, the vesicles may be useful as tumor biomarkers found in an accessible compartment, blood. Also, the fat balls have profound influences on immune responses and tumor growth, particularly in terms of modulation of the microenvironment to the benefit of the tumor. We have gathered together an eclectic group of researchers on this campus, and from Colorado State and Colorado School of Mines, to study the biology, biochemistry, and immunology of these vesicles from the atomic level to the level of individual patients.