Don L. Jewett - US grants

The goal of this research is to establish the surface potential patterns of elements of the Auditory Brainstem Response (ABR) in terms of the different axonal shapes and positions of neurons in the brainstem auditory system. The 3-Dimensional Lissajous Trajectory (3-CLT) is the resulting waveform when recordings from three orthogonally-placed electrodes are simulatneously plotted in three-dimensional voltage space. The 3-CLT of the ABR is known to produce planar curves whose shape and position are determined (at least in part) by the zonal portions of activated brainstem neurons. This research will examine the 3-CLT consequences of different axonal shapes and positions by placing a frog's nerve within a cat's skull filled with Ringer's solution, at the location of known brainstem axons. The success of this biological modelling will be measured by comparison with 3-CLT recordings from anesthetized cats, especially those in which only the VIIIth nerve is active. If successful, the research can be extended to study the likely contributions to human ABR recordings of specific neurons in the auditory brainstem system. Such an ability will provide more information as to how to interpret pathological changes in the ABR, a common clinical tool. Non-standard electrode placements to maximize the detection of abnormalities in specific neurons could be planned on the basis of this research. In addition, the effects of pre-amplifier filters, signal-to-noise ratio, and stimulus rate and intensity will be studied. Simpler methods for analyzing the 3-CLT will be evaluated using vector-time plots, and etection of straight line segments by analysis of the first derivative of the recorded waveforms.

The overall goal of this project is to advance basic science knowledge of the ABR (Auditory Brainstem Response), recorded in humans, based upon recent developments in multi-channel recordings. Several lines of research will be pursued. First, it will be determined whether the ABR in humans, in whole or in part, can be modelled as an equivalent dipole. Humans will be studied recording from electrodes placed on the scalp according to the standard 10-20 system. Two lines of evidence will be used to determine if the potentials are consistent with an eccentric dipole generator: a) comparison of the dipole generator estimated from two different electrode arrays. b) comparison of the surface potential distribution of the ABR at each point in time, with potentials recorded from dipoles placed in a volume-conductor molded from the head of the subject. The testing of surface potential distribution related to a dipole in the internal auditory meatus will also contribute to the question as to whether wave II of the ABR is due to the VIIIth nerve action potential entering the cranium. Second, the effects of signal filters on the ABR waveforms will be studied as they affect the orientation, magnitude, or detection of the equivalent dipole. Third, the effects of muscle artifacts on the potentials recorded at different scalp locations will be determined, as well as whether nearfield muscle recordings provide a better means of excluding artifact-containing sweeps. Finally, the signal-to-noise ratio of different electrode locations for recording the ABR in humans will be studied in order to determine the optimal locations for electrodes. This research is directly related to the medical uses of the ABR, which includes diagnosis of hearing deficits in newborns, infants, and adults, as well as diagnosis of neurological abnormalities in children and adults.

While auditory evoked responses are often used for objective assessment of hearing, especially in infants, such responses do not provide an adequate measure of low-frequency hearing. This, in turn, makes more difficult the selection of a hearing aid appropriate for the patient's hearing deficit. Evaluation of the auditory evoked response is especially difficult because of the brain's response to transient changes in the sound stimulus, and because of temporal overlap of the responses. Both of these problems are eliminated by a new method, to be tested in this research, which retrieves auditory evoked responses to continuous low-frequency tones. If successful, this research will overcome a major problem in the evaluation of low-frequency hearing in infants.

This contract represents Small Business Innovation Reserach (SBIR) Phase I contract award, and supports performance of a research study to assess the feasibility of developing improved research methodologies for analyzing alterness/attention in humans by means of evoked responses. The contractor will outline the hardward and software for design and development, during Phase 2, of a PC-based computer system which can record attention- related evoked-responses at high repetition rates.

Oscillatory rhythms in the brain are of interest to both physiologists and biopsychologists because they may be part of a mechanism of "sensory- binding' which is hypothesized to synchronize neuronal activity related to a perceptual object. One of the brain waves studied occurs when auditory stimuli are presented at regular intervals at a repetition-rate near 40- Hz. We can now show that these "steady-state" potentials are generated by summation of a series of transient evoked-responses synchronized to the stimuli. The transient waveforms are different at different repetition- rates. They also show differences depending upon whether or not the stimulus is perceived as having "temporal continuity", which in Gestalt psychology is referred to as "sequential integration". These new evoked-responses provide a possible tool for bridging between physiological experiments in animals and biopsychological experiments in humans, concerning brain mechanisms related to sensory or cognitive processes. PROPOSED COMMERCIAL APPLICATION: This research provides the foundation for commercialization of a PC-based system which can record transient evoked-responses to "steady-state" stimuli. The demand for the system will come from research laboratories and clinical facilities which record cortical evoked-responses, in either humans or animals.

DESCRIPTION: (Adapted from the applicant's abstract) This is a Phase I proposal to develop stimuli and recording techniques for auditory brainstem hearing tests (ABR) that will be sensitive to low-frequency auditory thresholds. Currently, ABR tests using clicks or low-frequency tone pips have difficulty in reflecting low-frequency thresholds. The investigator will use a specially designed low-frequency stimulus to evoke the ABR, in combination with a high-frequency masker to eliminate the confounding contributions of the high-frequency fibers. The investigator proposes to test this technique in both normal-hearing adults and adults with high-frequency hearing loss in this phase of the project.

The goal of this research is to further develop the apparatus necessary to carry out an innovative new method of recording evoked responses at higher-than-usual stimulation rates, the responses being called G-waves. Theoretical considerations and experimental evidence suggest that a "binding" process may underlie perception, and the possibility exists that G-waves are an indication of such binding, and hence might be related to "higher" mental processes described by Gestalt psychology. If so, the apparatus to be developed will provide a new tool for neuroscientists. In the longer term, the apparatus may be important for clinicians who are diagnosing and treating patients with possible cortical dysfunction. The project will concentrate on providing hardware and software that will allow others to study and use G-waves and on establishing the best methods for reliably recording G-waves. PROPOSED COMMERCIAL APPLICATION: The hardware and software developed in the project will be of interest to laboratories that study or use evoked responses. The methods may be licensed to manufacturers of evoked response equipment.

(Adapted from Applicant's Abstract). Specific language impairment is characterized by deficits in processing rapid, short auditory stimuli. This deficit may account for the difficulties that some persons have in language comprehension and expression (i.e., dyslexia). AMS (acoustically modified speech) training which first decreases and the systematically increases stimulus presentation rate has been shown to be an effective treatment. However, there is no electro-diagnostic method available to detect and diagnose the SLI condition. The applicants have identified a transient "oscillatory" evoked response not previously recorded in humans or animals. These responses, called G waves, have potential for the detection of differences in SLI subjects because G-waves are markedly affected by the stimulus repetition rate. The equipment necessary for optimal stimuli to detect SLI dysfunction needs to be determined. The equipment designed on this project will have relevance to the functioning of the brain when it functions less-than optimally in SLI and thus is related to human health. With continued success of AMS training it can be predicted that a market for diagnostic equipment will develop. The specific aims of this Phase I project are to develop the techniques for a computer to generate the complex tone pip stimuli needed for the project and to test whether the resulting evoked responses can distinguish SLI subjects and controls. PROPOSED COMMERCIAL APPLICATION: If successful, the computer system will provide a basis for electro-diagnosis of this medical condition.

The long-term goal is to improve research methodologies for study of alertness/attention. in humans by means of evoked responses obtained when stimuli are provides-at high repetition-rates. This will be accomplished further development of new techniques, both computerized. and behavioral, needed to demonstrate effects of attention/alertness under these special stimulus conditions. High stimulus rates invoke b, rain functions not present at lower rates, such as G-waves, and may provide indications of "temporal binding" mechanisms within the cortex. The experiments will show that the improved techniques work appropriately and are better than presently-available methods. The improvements may well lead to new advances because these responses cannot be obtained now. The project will also determine the hardware/software requirements necessary to meet the needs of laboratory researchers who will first use these techniques. This research is health-related because it is likely to provide data, unavailable by any other means, about brain functions that can be affected by both normal aging, as well as by disease (such as Alzheimer's).

The goal of this research is to develop an innovative new method of using auditory evoked responses as a measure of state of arousal, of depth of sleep, and of factors of importance in sleep disorders. The new method, utilizing higher-than-usual stimulation rates to record G-waves from the scalps of humans; will be compared with standard measures of depth of sleep recorded from EEG, EOG, and EMG electrodes. Since our Phase I studies suggest that G-waves are affected by sleep, and since G-waves provide new measures of brain activity, the research proposed here will determine the correlations of changes in these new measures with changes in standard measures of sleep. Other studies will look for optimum stimulus and stimulation parameters. G-waves may provide a new tool for clinicians who are diagnosing and treating patients with sleep disorders.

We have recently developed a new analysis technique for evoked- response research that has shown that the "steady-state" response called the "auditory-evoked 40-Hz response" is actually made up of a series of overlapping transient evoked-responses, not previously recorded in humans or animals. These evoked responses, which we call "G-waves", have potential significance because of the possibility that they are related to mechanisms of perceptual "binding" in cortical function, as well as to some aspects of perception. This application describes a project to study the method that reveals these waves, so as to ensure that the obtained waveforms are valid. We will also study the effects of noise reduction using "whitening". This basic research has relevance to human health because it involves a new means to monitor the functioning of the brain, which in turn could help in understanding brain dysfunctions, especially as regards to cortical physiology and sensory activity. The recording techniques use non-invasive, scalp recordings. This makes the findings applicable to psychophysiological experiments, as well as to clinical tests.

DESCRIPTION(Adapted from applicant's abstract): Multiple-channel brain evoked-response data is often recorded from the scalp, either electrically, or magnetically. The analysis of this multi-channel data commonly utilizes mathematical models, which assume that the neural generators of the evoked-response are dipoles. Such DSL can be accurate or inaccurate, depending upon many factors, most of which are not accessible to the researchers or clinicians who use the DSL. The problem is compounded by the fact that a given model may be accurate for dipoles in some locations, but not accurate for dipoles in other locations. Furthermore, the use of the least-square error by the DSL has been shown to increase dipole parameter errors. A method of evaluating whether insidious errors may be present in DSL analysis has been developed, based upon the fact that poor models show a sensitivity to neural-generator wave shape. The applicants have developed a proprietary, technically innovative method to utilize this sensitivity as an error-signal to allow adaptive-adjustment of model constants to reduce errors. The Phase I research will test this method using computer simulations. This research is health-related because DSL methods are widely used to analyze human brain activity, whether normal or abnormal. PROPOSED COMMERCIAL APPLICATION: The methodology will be incorporated into existing or future DSL software under license, since it would remove the present uncertainty of DSL results.

DESCRIPTION (provided by applicant): DSL (Dipole-Source Localization) is a commonly used analysis technique in which an iterative computer search algorithm in a mathematical model is used to find dipoles that can explain a given evoked-response. DSL results lack any direct proof of accuracy. There are good reasons to expect inaccurate results, due to inaccurate parameters in the model. One of the inaccuracies concerns skull and scalp resistivities. The problem is worse with infants because the skull resistivity must change as the calvarium calcifies. The applicant has simulated a method of estimating critical DSL model parameters, knowing that an inaccurate model can be made accurate. The proposed project will test this method in infants and children, using recorded evoked responses. The "gold standard" for accuracy will be based on MRI recordings from the same subjects.

DESCRIPTION (provided by applicant): The evoked response called the ABR (Auditory Brainstem Response) is affected by nerve compression by acoustic neuromas, but is not presently sensitive enough to detect small tumors. If the ABR could be used to detect tumors, it would reduce overall medical costs and also provide a means to judge rate of tumor progression. This project proposes to improve the sensitivity of the ABR to nerve compression by acoustic neuromas by two means: 1) using a new chirp-stimulus recently published, which provides stimulation of all VIIIth nerve fibers, including those subserving low-frequencies. 2) stimulating at very high stimulus repetition-rates. A new method has been developed by Abratech Corporation which permits recording the ABR at the high stimulus repetition-rates likely to be needed for detection of small tumors. The research proposed will test the sensitivity of the new method combined with the new chirp-stimulus, in patients who have small acoustic neuromas. This proposal is health-related because it is directed towards a known health-problem: the diagnosis and monitoring of acoustic neuromas.

[unreadable] DESCRIPTION (provided by applicant): A new method for recovering superposed waveforms when the evoked-response is longer than the interval between stimuli has been recently invented. The new method is called QSD (q-Sequence Deconvolution). QSD can recover brain responses not previously observed because standard evoked-response technique is limited to responses shorter than the period of the stimulus repetition-rate. This project will build a visual stimulator for recording superposed VEPs (Visual Evoked Potentials). The project will then test whether the VEP responds at stimulus repetition-rates, which overlap the VEP. If it does, then the potentials may differ from those seen at slower [unreadable] stimulation rates. [unreadable] [unreadable] The project will also test whether stimuli more complex than checkerboards provide any [unreadable] additional measure of brain function. [unreadable] [unreadable] This project is health related because evoked-responses are widely used for screening and [unreadable] diagnostic testing. If the stimulator provides previously-unrecorded VEPs, then it is possible [unreadable] that such potentials could be of scientific and clinical use. Because the potentials are obtained [unreadable] from scalp electrodes it is easy to utilize such evoked-responses for clinical testing. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): We are developing means to reduce errors in Dipole Source Localization (DSL). DSL is commonly used to analyze brain waves for clinical and research purposes. It is known from our work and the work of others that the models used to compute the DSL are not perfect, but it is not known how much the imperfect models affect the solutions obtained. Based upon our prior work, and some new concepts, we have developed the DSME (Dipole-Source Model- Error). We have tested its efficacy in spheres, and will do so in headshape models in this project. We will compare errors both by simulations, and also by determining whether the DSL has errors when analyzing evoked-responses from known neural generators. The health-related aspects include the clinical uses of evoked-responses and DSL, and the fact that improvements in the accuracy of the technique will improve these uses.

DESCRIPTION (provided by applicant): This project will study electrical brain-activity measures that may be able to indicate whether or not long-term memory is occurring, under light sedation. The goal is to develop a brain-monitor to be used in the operating room to ascertain if a patient's level of anesthesia has become too light, such that the patient can experience pain, and understand what is occurring in the operating room, and remember the experience. Such an event is rare, but traumatic. No present brain-analysis system accurately distinguishes the boundary in light anesthesia, between that level in which there will be explicit-memory and that level in which explicit-memory is missing. The fundamental scientific goal is to provide a tool for further investigations of the mechanisms of explicit memory, in animals as well as humans. If the goal were achieved, it would offer the chance to develop a clinical tool for analysis, diagnosis, or prognosis of medical conditions involving changes in memory (for which present tools are often inadequate). The project is health-related in that it addresses a problem in clinical medicine, and will provide a solution to that problem, if successful. PUBLIC HEALTH RELEVANCE: This project is relevant to public health because it studies humans and their reactions to sedation under anesthetic agents, to find a way to detect whether, in an operation, the patient is alert enough to remember experiences. This is a rare event in surgery, but should be prevented, if possible, with the techniques that will be developed in this research.

DESCRIPTION (provided by applicant): This project will develop software for Web-based "Compendia", which is defined as "a concise, yet comprehensive, organization of a body of knowledge, together with its evaluation." Such Compendia will for a basis for Outlined-Knowledge on the Web. The software will use a new standard, the Web-Citation-Protocol. The Protocol offers a new method of creating references in the scientific/medical literature. The project will direct the development of the Protocol, and then program the software necessary to implement it. An important feature of the Web-Citation-Protocol is the ability to create Citations (called on the Web as "Links") with additional information added by Citing Authors. The additional information will aid the Reader in deciding which Citations to follow, and will be presented in a spreadsheet format that will allow the Reader to sort on variables-of-interest to the Reader at that time. The software will allow mapping of both Cited Articles and Citing Articles. The project incorporates means by which the information in Compendia and that collected about the citations can be different for different scientific/medical fields, and change when such fields change. Both Web-based Compendia and the WebCitation-Protocol are in this way adaptable, rather than fixed. This project is directly related to the mission of NLM and NIH Institutes to make medical and scientific knowledge readily accessible to the public, to the medical profession, and to scientists. This mission will be enhanced by improving scientific and medical article citations to enhance recovery of information from web-based repositories. PUBLIC HEALTH RELEVANCE: This project is directly related to Public Health because it will provide an easy method to disseminate scientific knowledge over the Web, to both specialists and the public, by means not presently available.