David L. Woods - US grants

During the 60 msec which follow the delivery of auditory signals, neural messages travel from the brainstem to auditory cortex and association areas. Coterminously, a series of electical deflections -- the middle-latency auditory evoked potentials (MAEPs) -- appear over the fronto-central scalp. Due to their great sensitivity to auditory processing of tones across the audiometric spectrum, MAEPs could play an important role in audiological diagnosis. They could also help to clarify the contribution of forebrain systems in normal hearing, and aid in diagnosing structural damage to these systems. However, the utilization of MAEPs remains hampered by a lack of understanding of their fundamental properties. Herein, we propose a series of experiments to clarify their functional properties and neuroanatomical generators, and to elucidate the stimulation and recording procedures necessary for further clinical and research applications. These experiments are designed to answer the following questions: 1) What stimulus features elicit MAEPs? Which MAEP components are produced by stimulus offset, changes in sutmulus frequency, or changes in the apparent spatial position of tones? Which components show binaural interaction? 2) What are the scalp distributions of MAEP components? Do the distributions change with changes in tone frequency and/or ear of stimulus delivery? 3) What are the characteristics of adaptation which occur when stimuli are repeated at very high rates? Do scalp distributions changes during adaptation? 4) What are the auditory processes indexed by different MAEP components? What specificity of adaptation is observed when certain attributes of the stimulus are repeated and others are varied? 5) What are the neuroanatomical generators of the MAEP? How are MAEPs affected by lesions of the neocortex or diencephalon?

Middle latency auditory evoked potential (MAEPs, latencies 10-70 msec) provide a direct measure of the electrical activity associated with the short-latency thalamic and cortical analysis of sounds in humans. However, despite increasing clinical use little is known about their most fundamental properties. For example, the cortical and subcortical structures involved in MAEP generation remain in dispute, and it is uncertain how they are organized: do they have tonotopic and/or spatiotopic organizations like auditory structures in many species? We will address these basic issues in five experiments. Two new techniques will be incorporated in all studies. First, we will record detailed scalp topographies from 32 electrodes and extract Laplacean MAEPs (LAP-MAEPs) over temporal sites. LAP-MAEPs enhance the resolution of MAEPs to focal generators in auditory cortex. Second, we will correlate MAEP distributions with the relative orientations of candidate MAEP generators measured directly from high-resolution MRI scans. We will use these improved techniques to study the organization of MAEP generators for processing the intensity (Experiment I), frequency (Experiment II), and spatial position (Experiment III) of auditory signals. Hypotheses about MAEP generators will be further tested in two experiments that take advantage of our well-delineated clinical populations. In Experiment IV, we will record MAEPs in patient groups with focal lesions of candidate MAEP generators, including the superior temporal plane and auditory cortex, dorsolateral frontal cortex, inferior parietal lobe, the posterior thalamus and basal ganglia. In Experiment V, we will compare MAEPs from the scalp and cortical surface in patient undergoing craniotomies. The experiments in normal subjects and patients form a comprehensive sequence that will provide a better understanding of the shortlatency analysis of sounds in the human brain, and enhance the clinical utility of MAEPs in neurological and neurosurgical applications.

Recordings from primate cortex have shown that different features of visual stimuli are analyzed in distinct cortical fields. How does the perceptual system recombine these features to form a coherent percept? Clues are available from studies of visual search . Subjects rapidly detect targets distinguished from distracting stimuli by single features (e.g., color) but are slow and error-prone when targets are distinguished by conjointed features (e.g., color and orientation). According to Treisman's feature integration theory, single features of stimuli are processed automatically and in parallel in different feature maps. However, visual feature integration (VFI) requires a serial process in which objects must first be localized before their features can be bound together by an attentional scan. Unfortunately, it is difficult to study the physiology of VFI in search tasks since the experimenter can never be certain which stimulus the subject is processing. A new paradigm, rapid serial visual presentation (RSVP), permits VFI to be studied for stimuli presented one-by-one. Four experiments are proposed using RSVP tasks. For comparison, a fifth experiment utilizing visual search is also included. In all experiments, behavioral analysis will be combined with multi-channel recording of event- related brain potentials (ERPs). ERP difference waves associated with the processing of individual stimulus features and with feature integration will be isolated to provide insight into the localization and timing of VHI. Preliminary results show ERP difference waves related to feature conjunction over frontal and parietal regions at latencies of 200-250 ms. Event-related difference spectra (ERDs) will also be used to localize cortical activity associated with VFI. Preliminary data show ERD changes related to visual feature processing over the right parietal and occipital scalp. In all experiments, behavioral and electrophysiological results from normal subjects will be compared with data from patients with focal cortical lesions of the lateral parietal lobe, dorsolateral prefrontal cortex, or posterior superior temporal plane. Lesions in the regions have been shown to impair VFI in visual search tasks. Behavioral and electrophysiological results from normal subjects and patients will be used to test a model in which different VFI operations are localized to distinct cortical regions; the "master map" of locations in lateral parietal cortex, the scan of the master map controlled by dorsolateral prefrontal cortex with a variable aperture of attentional scan controlled by the temporal/parietal junction.

The long-term goal of this project is to understand the brain preparatory states and processes which bias whether a given environmental event will be perceived or responded to. Spatial attention was selected as a model system for exploring preparatory set because it fosters a convergence of psychology and neurophysiology in both humans and animals. The proposed work will contribute to an understanding of the role of inhibitory mechanisms in integrating voluntary and reflexive visual orienting to provide a coherent continuity of visual experience and of visually guided behavior in humans. The experiments will examine the effects of saccade preparation on two inhibitory phenomena operative in regulating visual orienting, inhibition of return (IOR) and the fixation offset effect (FOE), and they will define the role of fronto-collicular circuits in mediating the effects of saccade preparation. They will measure the effect of preparatory precues on detecting and responding to visual signals in normal individuals and neurological patients with chronic, unilateral brain lesions involving the dorsolateral prefrontal cortex, the posterior association cortex and hemianopic patients with striate cortex lesions. The experiments will: 1) identify the cortical substrates for location-based and object-based IOR activated by exogenous visual signals; 2) determine whether endogenously generated IOR affects location-based, or object-based representations; 3) define the role of the frontal eye fields in the endogenous generation of IOR by saccade preparation; 4) investigate the effect of saccade preparation on the FOE for saccades toward and away from visual target signals and; 5) define the role of fronto-collicular circuits in mediating saccade preparation effects on the FOE.

The project will test the hypothesis that there are two separate attention processes mediated by posterior association cortex: One which conjoins visual features in the process of object recognition, an a second which selects objects for action. In addition the studies will investigate whether these two processes are independent and, if so, identify the neural substrate underlying each. Most of the research will involve experiments that test the attentional abilities of patients with lesions of posterior association cortex. One series of experiments will investigate patients with clinical extinction to determine the degree to which simple visual features are processed in the unattended field in comparison to the ipsilesional field. It is predicted that processing of simple features in the contralesional field will be comparable to that for features in the ipsilesional field, and that the deficit in extinction will reflect primarily a failure to transfer the percept to the action system. A second series of studies will test patients without clinical extinction in a task to examine illusory conjunctions, a phenomenon in which information from different objects is erroneously combined. It is predicted that these patients will show a deficit in feature integration in the contralesional field.

[unreadable] DESCRIPTION (provided by applicant): Although human auditory cortex has traditionally been subdivided into auditory cortical fields based largely on anatomical analysis and the extrapolation of functional data from other primate species, much remains to be discovered about human auditory cortical organization. Extrapolating functional data from other species is problematic because the human specialization for speech processing may have significantly altered auditory cortical organization. We propose two groups of experiments using high-resolution functional magnetic resonance imaging (fMRI) and improved landmark-based mapping procedures to provide detailed functional maps of human auditory cortical fields. Since our preliminary results indicate that attention-related activations equal or exceed those produced by the stimuli themselves, attention will be controlled and manipulated in all experiments. Activations to nonattended stimuli will elucidate automatic sensory responses, whereas attention-related differences in activations will clarify the optional, higher-cognitive operations involved in audition. Experiments 1-3 will use simple stimuli to derive auditory field maps in humans similar to those obtained in macaques. Experiments 4-7 will use speech and speech-control stimuli to characterize speech-related activations. Repeated single-subject testing and improved imaging procedures will permit auditory cortical fields to be mapped with unprecedented detail during the processing of simple sounds, syllables and coherent speech.

sound perception; speech recognition; computer system design /evaluation; hearing; computer program /software; clinical research; human subject;

Patients who develop Alzheimer?s disease (AD) show performance declines in tests of episodic memory, executive functioning, and attention more than a decade before symptoms become apparent to their physician or family. The rate of this performance decline is the primary outcome measure in ongoing clinical trials evaluating interventions aimed at delaying AD onset. However, current clinical trials rely on measures from ?paper and pencil? tests of cognition that are manually-administered and scored, costly, inefficient, subject to examiner bias, and fail to comprehensively record and quantify test performance. Moreover, because of the limited number of licensed examiners, manual tests will be increasingly unable to meet the demand for cognitive assessments as the population ages. Although computerized tests help meet this demand by increasing the sensitivity, efficiency, comprehensiveness, and objectivity of cognitive testing, existing commercial test batteries lack the sensitivity, validity, and reliability of ?gold standard? manual assessments now used in clinical trials. In this ?fast-track? application, we propose to enhance the computerized tests of the California Cognitive Assessment Battery (CCAB), a set of empirically-validated, computerized versions of ?gold standard? manual tests. CCAB tests are more efficient, reliable, objective, and precise than their manual-test counterparts, while providing more detailed, comprehensive, and easily accessible archival records of longitudinal test performance. We will then test the enhanced CCAB?s sensitivity to longitudinal cognitive decline in older individuals, including those at increased risk of cognitive decline based on their APOE genotype. During Phase I, we will restructure the individual CCAB tests for self-administration on tablets and add automatic speech recognition to objectively score verbal responses and measure verbal-response latencies. We will also incorporate telemedical capabilities to enable examiners to interact with patients and administer tests at remote sites. During Phase II, we will develop a secure, encrypted database for hosting and analyzing anonymized data. We will compare performance on CCAB tests and equivalent manual tests, and develop regression functions for translating CCAB scores to equivalent manual test scores, and vice versa. Finally, we will evaluate the sensitivity of the CCAB tests to cognitive decline in 420 older paid volunteers, tested at six-month intervals over a two-year period. We will identify baseline performance measures, including practice effects (incidental improvements that occur when tests are repeated), that predict subsequent cognitive decline in individuals with and without genotype risk factors for AD. In addition, we will create CCAB licensing and data-management tools to provide researchers with free access to CCAB tests and anonymized data during the 4-year SBIR. Summary: Enhanced versions of the California Cognitive Assessment Battery (CCAB) will reduce the cost, expand the reach, and improve the sensitivity of tests of age- related cognitive decline in patients at risk for AD.

Patients who develop Alzheimer?s disease (AD) show performance declines in tests of episodic memory, executive functioning, and attention more than a decade before symptoms become apparent to their physician or family. The rate of this performance decline is the primary outcome measure in ongoing clinical trials evaluating interventions aimed at delaying AD onset. However, current clinical trials rely on measures from ?paper and pencil? tests of cognition that are manually-administered and scored, costly, inefficient, subject to examiner bias, and fail to comprehensively record and quantify test performance. Moreover, because of the limited number of licensed examiners, manual tests will be increasingly unable to meet the demand for cognitive assessments as the population ages. Although computerized tests help meet this demand by increasing the sensitivity, efficiency, comprehensiveness, and objectivity of cognitive testing, existing commercial test batteries lack the sensitivity, validity, and reliability of ?gold standard? manual assessments now used in clinical trials. In this ?fast-track? application, we propose to enhance the computerized tests of the California Cognitive Assessment Battery (CCAB), a set of empirically-validated, computerized versions of ?gold standard? manual tests. CCAB tests are more efficient, reliable, objective, and precise than their manual-test counterparts, while providing more detailed, comprehensive, and easily accessible archival records of longitudinal test performance. We will then test the enhanced CCAB?s sensitivity to longitudinal cognitive decline in older individuals, including those at increased risk of cognitive decline based on their APOE genotype. During Phase I, we will restructure the individual CCAB tests for self-administration on tablets and add automatic speech recognition to objectively score verbal responses and measure verbal-response latencies. We will also incorporate telemedical capabilities to enable examiners to interact with patients and administer tests at remote sites. During Phase II, we will develop a secure, encrypted database for hosting and analyzing anonymized data. We will compare performance on CCAB tests and equivalent manual tests, and develop regression functions for translating CCAB scores to equivalent manual test scores, and vice versa. Finally, we will evaluate the sensitivity of the CCAB tests to cognitive decline in 420 older paid volunteers, tested at six-month intervals over a two-year period. We will identify baseline performance measures, including practice effects (incidental improvements that occur when tests are repeated), that predict subsequent cognitive decline in individuals with and without genotype risk factors for AD. In addition, we will create CCAB licensing and data-management tools to provide researchers with free access to CCAB tests and anonymized data during the 4-year SBIR. Summary: Enhanced versions of the California Cognitive Assessment Battery (CCAB) will reduce the cost, expand the reach, and improve the sensitivity of tests of age- related cognitive decline in patients at risk for AD.

Patients who develop Alzheimer's disease (AD) show performance declines in tests of episodic memory, executive functioning, and attention more than a decade before symptoms become apparent to their physician or family. The rate of this performance decline is the primary outcome measure in ongoing clinical trials evaluating interventions aimed at delaying AD onset. However, current clinical trials rely on measures from ?paper and pencil? tests of cognition that are manually-administered and scored, costly, inefficient, subject to examiner bias, and fail to comprehensively record and quantify test performance. Moreover, because of the limited number of licensed examiners, manual tests will be increasingly unable to meet the demand for cognitive assessments as the population ages. Although computerized tests help meet this demand by increasing the sensitivity, efficiency, comprehensiveness, and objectivity of cognitive testing, existing commercial test batteries lack the sensitivity, validity, and reliability of ?gold standard? manual assessments now used in clinical trials. In this ?fast-track? application, we propose to enhance the computerized tests of the California Cognitive Assessment Battery (CCAB), a set of empirically-validated, computerized versions of ?gold standard? manual tests. CCAB tests are more efficient, reliable, objective, and precise than their manual-test counterparts, while providing more detailed, comprehensive, and easily accessible archival records of longitudinal test performance. We will then test the enhanced CCAB?s sensitivity to longitudinal cognitive decline in older individuals, including those at increased risk of cognitive decline based on their APOE genotype. During Phase I, we will restructure the individual CCAB tests for self-administration on tablets and add automatic speech recognition to objectively score verbal responses and measure verbal-response latencies. We will also incorporate telemedical capabilities to enable examiners to interact with patients and administer tests at remote sites. During Phase II, we will develop a secure, encrypted database for hosting and analyzing anonymized data. We will compare performance on CCAB tests and equivalent manual tests, and develop regression functions for translating CCAB scores to equivalent manual test scores, and vice versa. Finally, we will evaluate the sensitivity of the CCAB tests to cognitive decline in 420 older paid volunteers, tested at six-month intervals over a two-year period. We will identify baseline performance measures, including practice effects (incidental improvements that occur when tests are repeated), that predict subsequent cognitive decline in individuals with and without genotype risk factors for AD. In addition, we will create CCAB licensing and data-management tools to provide researchers with free access to CCAB tests and anonymized data during the 4-year SBIR. Summary: Enhanced versions of the California Cognitive Assessment Battery (CCAB) will reduce the cost, expand the reach, and improve the sensitivity of tests of age- related cognitive decline in patients at risk for AD.