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Safe and Effective Stimulation of Neural Tissue


Principal InvestigatorAffiliationContract NumberLink
Bill Agnew, Ph.D.HMRIN01-NS8-2388

Project Title: Safe and Effective Stimulation of Neural Tissue, June,1997



a. Introduction:

The Neural Prosthesis Program (NPP) of the National Institute of Neurological Disorders and Stroke supports research and development on aids for the neurologically disabled. These neural prostheses involve the use of electrical stimulation for selective activation and/or inhibition of neurons in the central and peripheral nervous systems. Several new neural prostheses are being investigated that will require intracortical stimulation of cerebral cortex with multiple microelectrodes. Studies of intracortical stimulation with single penetrating microelectrodes have established safe levels of stimulation under certain stimulating conditions, but more information is needed about the safe limits for multiple, closely spaced, penetrating microelectrodes such as would be used in advanced visual prostheses.

Progress has been made on understanding the causes of tissue damage that can occur at high levels of stimulation. In order to minimize tissue damage, more information is needed on methods of preventing damage, the safety of new biomaterials, as well as better methods of physically stabilizing microelectrodes in neural tissue. The possibility of using multicontact, silicon microelectrodes with long shanks to access buried cortical tissue also needs to be investigated. Silicon microelectrodes are presently being fabricated by another contractor in the NPP.

Histopathological, neurochemical and neurophysiological techniques must be applied to determine the effects of both acute and chronic activation of cortical tissue. When physiological or histopathological evidence of detrimental alteration of neural function or structure is noted, research should be undertaken to determine the mechanism(s). Electrodes to be used will include discrete wire intracortical microelectrodes as well as silicon microcircuit microelectrodes furnished by the Project Officer.

The results of this work will be of value not only to neural prosthesis investigators, but also to neurophysiologists who utilize electrical stimulation as a tool in fundamental studies of the nervous system. This request for proposals represents a competitive renewal of similar on-going research which is being supported by the NPP (Contract # N01-NS-5-2324). A related study in the NPP is developing safe and effective techniques of chronically stimulating the lumbosacral spinal cord (Contract # N01-NS-5-2333). A bibliography of publications resulting from research supported by the NPP and quarterly progress reports from current contracts can be obtained, on the internet at:

b. Technical Specifications:

Independently, and not as an agent of the government, the contractor shall exert its best efforts to develop cortical stimulating microelectrodes and to evaluate the effects of electrical stimulation on neural and surrounding tissue in non-human animals. Chimpanzees should not be proposed unless there are no other acceptable animal models.

I. Specifically, the contractor shall:

A. Design and fabricate cortical penetrating microelectrodes with exposed geometric surface areas of less than or equal to 6.00 x 10-6 sq cm suitable for chronic stimulation of cerebral neurons at various cortical depths including buried cortical neurons separated from the cortical surface by both the superficial cortical layers and the intervening white matter. These shall include:

1. Discrete wire microelectrodes with activated iridium surfaces.

2. Arrays of 4 to 128 parallel microelectrode shanks in 2 x 2, 4 x 4, 8 x 8, and 8 x 16 configurations with nearest neighbors separated by 500 microns or less. The arrays up to the 4 x 4 configuration may be fabricated by the offeror using discrete wires. All array configurations may be produced by combining linear arrays of silicon microcircuit stimulating probes which will be furnished by the Project Officer during the first year of the contract. It is possible that some of 8 x 8 and 8 x 16 configurations will be furnished by the Project Officer completely assembled but without lead wires. Provision of an activated iridium coating on the microelectrode contact surface and attachment of connecting leads to these probes will be the responsibility of the offeror, but in no case should you assume that more than 16 leads need be connected. Lead connections must be made directly at the non-implanted ends of the silicon probes unless using probes supplied with integral silicon ribbon cables, in which case connections must be made at the end of the ribbon cables.

3. Design and incorporate features in the above microelectrodes to minimize their movement within the cortical tissue after insertion. Consideration should be given to the effects of fibrous tissue encapsulation on both the microelectrodes and their lead wires.

B. Study the effects of cerebral cortical stimulation through the microelectrodes in I.A.1. and I.A.2. on surrounding neural, vascular, glial and other nearby tissues and on extracellular fluid. The stimulation should be at levels demonstrated neurophysiologically to activate target cortical neurons (ref. Schmidt, E.M., Bak, M.J., Hambrecht, F.T., Kufta, C.V., O'Rourke, D.K., and Vallabhanath, P., 1996, Feasibility of a visual prosthesis for the blind based on intracortical microstimulation of the visual cortex. Brain, 119, pp.507-522). The stimulation with arrays of microelectrodes should include both true simultaneous stimulation through each of the contacts as well as rapid sequential stimulation (interleaved stimuli) through each of the contacts at levels just below those known to produce damage with single intracortical microelectrodes.

1. Examine the tissue with both light and electron microscopy.

2. Determine the relationships between tissue damage at various microelectrode depths and in various cerebral cortical regions, and the stimulus variables of pulse frequency, charge density, charge per phase, and current density (based on geometric, and if possible, on real exposed microelectrode area) using current regulated, chronic stimulation. (Chronic stimulation is defined in this study as a total stimulation period in excess of seven hours.)

3. Examine possible mechanisms of tissue damage including mechanical trauma, mass activation of cortical neurons and changes in the composition of key constituents of the extracellular fluid surrounding the neurons including glucose using stimulation levels at or below those known to cause histopathological damage using the above described microelectrodes.

4. Attempt to determine the cause of reactive cell aggregation around the tips of pulsed microelectrodes and methods of reducing this effect.

5. Determine whether tissue "conditioning" techniques can be developed to reduce or prevent tissue damage. These techniques might include:

a. Exploration of the use of a gradual increase in the stimulus level (e.g., charge per phase, stimulus frequency, stimulus train length, etc.) starting at a safe level that is known not to produce damage.

b. Exploration of the use of pharmaceutical manipulation such as receptor or channel blocking agents during stimulation.

6. As state-of-the-art silicon intracortical microelectrodes become available from other investigators in the Neural Prosthesis Program, evaluate representative samples with respect to I.B.1 through I.B.3. The maximum number of microelectrode arrays which will be supplied by the Project Officer will not exceed 45 over the duration of this project or 22 per year.

C. Evaluate the biocompatibility of in-vitro characterized test materials supplied by the Project Officer.

1. Samples of the materials are to be implanted between the dura and the arachnoid or intracortically in mammals for periods greater than 12 weeks.

2. Study histopathologically the effects of these materials on the surrounding neural, vascular, glial, and other nearby tissue.

3. The maximum number of samples of these test materials which will be supplied by the Project Officer will not exceed twenty (20) over the duration of this project or ten (10) samples per year.

II. In the performance of this contract, the Contractor shall coordinate its experimental program through the Project Officer with results of experimental findings developed by other collaborators in the Neural Prosthesis Program. Adjustments and changes so indicated shall be approved in advance by the Project Officer.

Last Modified November 24, 2008