SBIR-STTR Award

This is an application to test the feasibility of reducing tinnitus by pairing left vagus nerve stimulation (VNS) with tone presentations to reorganize the auditory cortical frequency map. Approximately ten percent of adults experience some degree of tinnitus, the perception of sound in the absence of an environmental acoustic stimulus. For one percent of the adult population, the experience is so severe that it makes it difficult to hear, work, or sleep. There is no general treatment for tinnitus, although several treatments can alleviate or reduce tinnitus in some patients. Recent studies suggest that pathological reorganization of frequency mapping in the auditory cortex is a major contributor to the symptoms of tinnitus in many patients. In normal individuals, there is an evenly distributed tonotopic organization of the cortical auditory map and spontaneous synchronous activity is not observed. When tinnitus is present, the tonotopic organization is unevenly distributed and spontaneous synchronous activity is observed, which is believed to account for the tinnitus. This spontaneous activity is believed to result from the uneven tonotopic organization of the auditory cortex. We propose to develop a neuroprosthetic approach for the treatment of tinnitus by pairing tone presentations with stimulation of the VNS to induce therapeutic reorganization of the uneven tonotopic quality of the auditory cortical frequency map. Electrophysiological studies will be used to evaluate the effect of tone pairing with VNS to direct frequency specific changes on both tonotopic mapping and spontaneous synchronous activity. Behavioral studies conducted in an animal model of tinnitus will evaluate the potential clinical efficacy of this proposed therapy. Based on preliminary observations, pairing tones with VNS is expected to 1) realign the auditory cortex frequency map, 2) decrease spontaneous synchronous activity in the auditory cortex, and 3) eliminate the tinnitus perception. Combining this technique with current pharmacological, behavioral, and auditory therapies could greatly improve outcomes for a currently unmet medical need.

Public Health Relevance:
MicroTransponder, Inc. is developing a novel treatment for tinnitus. This is an application to test the feasibility of reducing tinnitus by pairing left vagus nerve stimulation (VNS) with tone presentations to reorganize the auditory cortical frequency map. Current pharmacological, auditory, and training therapies are likely to be more effective if coupled with a mechanism to stimulate therapeutic cortical plasticity.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:
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In Phase I, we demonstrated the feasibility of using VNS stimulation paired with tone presentations to completely reverse the effects of tinnitus in a rat model of the disease. The Specific Aim of Phase II is to accumulate data for the submission of an IDE application for testing the safety and efficacy of our therapeutic VNS device in humans. Approximately 12 million individuals in the United States have been diagnosed with tinnitus of which ~1 million have severe tinnitus interfering with their daily activities. Although many advances have been made in symptomatic treatments, these treatments are unable to eliminate the tinnitus sensation in most patients. Our therapeutic device will use a PC based software package to allow for computer controlled VNS to be paired with the presentation of tones. This system will be easily deployable as a laptop PC driven rehabilitation therapy device. We have partnered with Texcel (East Longmeadow, MA) to use their StimX VNS stimulation device and software to deliver our therapy in the clinic. The Texcel system is currently in clinical trials for an unrelated indication. While we have proven the feasibility of pairing tone and VNS to reverse tinnitus in rats in Phase I, we must now investigate stimulus parameters more thoroughly in order to develop a rational protocol for humans. VNS parameters have translated well from rats to humans for epilepsy, depression, and learning. It therefore seems reasonable to use a rat model of tinnitus to set the first order parameters for treating tinnitus in humans. Along these same lines, it seems reasonable to use a rat model to evaluate several possible clinical confounds that might occur. In addition, while obtaining FDA approval for testing therapies in humans does not require a mechanistic explanation; experience has shown this to be very useful; we will investigate such a mechanism at a very high level. In parallel to these animal studies, we will be developing the software needed to drive the StimX device at the appropriate parameters for tinnitus therapy. The software is not currently designed to stimulate at our desired parameters. Finally, we will test the software modification and our proposed initial clinical stimulation protocol for efficacy in a rat model of tinnitus. If this final test is successful, we will then assemble and file an IDE for clinical testing. Filing this IDE will conclude a successful Phase II study. We expect to start a clinical trail within 90 days of concluding this Phase II study. If VNS-induced plasticity is effective in treating tinnitus in patients, the technology may also be useful to treat other neurological conditions, including stroke, chronic pain, and epilepsy by pairing each of these conditions with appropriate external cues to retrain pathologically altered neural circuits.

Public Health Relevance:
This is a Phase II SBIR application to develop a therapy for tinnitus. Our Phase I studies demonstrated that our overall therapeutic approach can induce lasting and complete reverse of tinnitus using a safe and inexpensive method of vagal nerve stimulation paired with presentation of sounds. Tinnitus is a devastating disease for millions of Americans. Severe forms of tinnitus are debilitating and untreated. This project will move our therapy toward clinical trials to test efficacy in humans.

Public Health Relevance Statement:
Project Narrative This is a Phase II SBIR proposal to develop a therapy for tinnitus. Our Phase I studies demonstrated that our overall therapeutic approach can induce lasting and complete reverse of tinnitus using a safe and inexpensive method of vagal nerve stimulation paired with presentation of sounds. Tinnitus is a devastating disease for millions of Americans. Severe forms of tinnitus are debilitating and untreated. This project will move our therapy toward clinical trials to test efficacy in humans.

Project Terms:
American; Animals; Apoplexy; CNS plasticity; Cerebral Stroke; Cerebrovascular Apoplexy; Cerebrovascular Stroke; Cerebrovascular accident; Chest; Clinic; Clinical; Clinical Evaluation; Clinical Research; Clinical Study; Clinical Testing; Clinical Trials; Clinical Trials, Unspecified; Common Rat Strains; Computer Programs; Computer software; Computers; Cues; Data; Depression; Devices; Diagnosis; Disease; Disease model; Disorder; Epilepsy; Epileptic Seizures; Epileptics; Esthesia; Evaluation; Funding; Goals; Government; Grant; Hand; Human; Human, General; Implant; Individual; Intention; Investigation; Lead; Learning; Left; Letters; Mammals, Rats; Man (Taxonomy); Man, Modern; Manufacturer; Manufacturer Name; Medical Device; Mental Depression; Methods; Modeling; Modification; Nerve; Nervous; Neurologic; Neurological; Neuronal Plasticity; Patients; Pb element; Persons; Phase; Physical Health Services / Rehabilitation; Physiologic pulse; Preparation; Programs (PT); Programs [Publication Type]; Protocol; Protocols documentation; Pulse; Rat; Rattus; Rehabilitation; Rehabilitation therapy; Rehabilitation, Medical; Review Literature; Ringing-Buzzing-Tinnitus; SBIR; SBIRS (R43/44); Seizure Disorder; Sensation; Small Business Innovation Research; Small Business Innovation Research Grant; Software; Sound; Sound - physical agent; Sterilization; Stimulus; Stroke; System; System, LOINC Axis 4; TXT; Technology; Testing; Text; Therapeutic; Thorace; Thoracic; Thorax; Time; Tinnitus; Translating; Translatings; United States; Vascular Accident, Brain; Writing; base; brain attack; cerebral vascular accident; chronic pain; chronic painful condition; clinical investigation; clinical test; computer program/software; design; designing; develop software; developing computer software; disease/disorder; disorder model; efficacy testing; epilepsia; epileptiform; epileptogenic; experience; heavy metal Pb; heavy metal lead; language translation; laptop; neural circuit; neural circuitry; neural plasticity; neuroplasticity; phase 1 study; phase 2 study; pre-clinical; preclinical; programs; public health relevance; rehabilitative; research clinical testing; safety testing; software development; sound; stroke