Ralph D. Freeman - US grants

Binocular interaction will be studied by extracellular single unit recording in the visual cortex of normal cats and in those that have been reared with strabismus or monocular deprivation. Binocular interaction will also be investigated psychophysically in normal human subjects and those with a history of strabismus or amblyopia or both. There are four principal objectives: (1) To compare stimulus specificity of right and left receptive fields of binocular cortical cells. Qualitative observations susggest that the two eyes are well matched. Experiments are proposed to determine this quantitatively for normal and for strabismic cats to see if there are differences between deviated and non-deviated eyes and between convergent and divergent conditions. (2) To study types and extent of binocular interaction for stimuli which are optimal and matched for the two eyes. For normal cats sinusoidal gratings will be presented dichoptically with one phase-shifted with respect to the other, while responses are recorded from cells in the visual cortex. Response patterns involving phase-specific and non-specific facilitation and suppression will be studied to determine the organization of binocular receptive fields. In addition, these patterns will be compared with those from bar stimuli to test the hypothesis that disparity and spatial frequency tuning are correlated. Dichoptically presented matched stimuli (gratings) will also be used to study strabismic and monocularly deprived kittens to test the hypothesis that binocular connections remain after monocular excitation is ineffective. Finally, stereoacuity will be studied as a function of spatial frequency in humans with normal and abnormal binocular vision. (3) To investigate binocular interaction for unmatched stimuli. Experiments similar to those described above will be conducted using, for one eye, gratings with non-optimal contrast, orientation, or direction to assiss limits of binocular interaction in cats and humans with abnormal binocular vision. (4) To determine the extent of interocular transfer of visual adaptation effects in cats and humans with normal and abnormal binocular vision. By relating neurophysiological and psychophysical observations these investigations should clarify aspects of normal and abnormal binocular function.

DESCRIPTION: (Applicant?s Abstract) Continued CORE grant support is sought for a highly productive group of NEI supported investigators from departments of Chemistry, Molecular and Cell Biology, Optometry, Vision Science, Psychology, and the Lawrence Berkeley Laboratory. Among these investigators, there are 23 NEI grants, including 16 R01 grants, 2 MERIT awards, 2 training grants, and 2 subcontracts. The areas of research of these investigators include questions about basic visual functions at different levels of the visual pathway. There are clinical interests in areas ranging from the cornea to the retina to the visual cortex. Methodology includes molecular, biophysical and cellular approaches, psychophysical studies of sensory and motor functions, neurophysiological and neuroanatomical investigations, and modeling. The following CORE modules support the work of this group: (1) Machine Shop (2) Electronics Shop (3) Biostatistics and Computer Module. The shops design, fabricate, maintain, modify, and repair essential items of equipment used by CORE investigators. This activity is limited to items that are not commercially available. Cutting edge experiments often require custom made devices that are made by the skillful, knowledgeable, and experienced staff of these modules. When necessary, repairs or adjustments may be made during experiments. This real-time service may be extremely important in determining the success of a given experiment. The third module, Biostatistics and Computer services, offers a wide range of support. From the optimal design of protocols, to the elements of a clinical trial, to the choice of appropriate statistical analysis tools, the biostatistics component is extremely valuable. The computer services portion of this module is a recent addition. It offers a complete range of software and hardware services that should be of major benefit to all CORE investigators. CORE support for these modules is of crucial importance to Berkeley?s vision research programs. These programs are highly relevant to, and consistent with the ultimate goal of preserving and restoring human vision.

The long-term objective of this research is to determine how visual information is encoded and transformed in the brain. To achieve this goal, it is necessary to understand neural wiring patterns within the visual pathway. The traditional approach has involved the study of single neurons and their synaptic connections, but relatively little is known about how a given cell's function is correlated with that of others. Yet, simultaneous firing patterns of groups of cortical neurons must underlie visual perception. The proposed project will utilize an electrophysiological approach to determine response properties of small groups of cortical neurons, as well as single cells. Previous studies have focused primarily on spatial aspects of receptive field structure. The work planned in this proposal examines both temporal and spatial response parameters to obtain a more complete description of visual cortical function. The analysis provides receptive field profiles in two dimensions of space and one dimension of time. In addition, a new technique will be employed to obtain complete spatiotemporal maps of temporally correlated discharge from pairs of cells whose firing patterns are measured simultaneously. This analysis provides a powerful tool because it can show how the activity of one cell contributes to the spatiotemporal receptive field of another cell. These methods will be used to address the following specific projects. (1) Spatiotemporal information processing in binocular pathways will be examined with respect to the mechanism of binocular disparity encoding and the joint analysis of disparity and motion processing in complex cells. (2) The genesis of spatiotemporal receptive fields in the visual cortex will be explored by multiple cell analysis and by development of quantitative, physiologically plausible models that may be tested experimentally. (3) Spatiotemporal information processing in monocular pathways will be investigated with respect to four questions. (a) How are transient responses of cortical cells related to those of a steady-state nature? (b)What is the spatiotemporal organization of surround inhibition? (c) What mechanisms underlie plasticity of receptive field structure? (d) Are the receptive fields of nearby simple cells organized for phase encoding of visual images? These studies will reveal important aspects of spatiotemporal function in the retinogeniculocortical pathway. Eventually, this should lead to improvements in the diagnosis and treatment of visual disorders.

vision; biomedical equipment resource; biomedical facility;

The long-term objective of this research is to determine how central visual pathways in the brain encode and transmit spatial and temporal information. The proposed project utilizes neurophysiological methods to record from single neurons or from small groups of cells in striate and parastriate visual cortex. (1) Intercellular connections: (a) A hypothesis will be tested that simple-to-simple cell communication underlies direction selectivity. (b) Predictions of a disparity energy model will be explored by recording simultaneously from binocular simple and complex cells. (c) Different processing levels will be investigated for members of complex-to-complex cell pairs. (d) A conjecture will be addressed that phase disparity tuning of neighboring complex cells involves quadrature encoding. (2) Functional properties of area 18: (a) Contrast sensitivities and dynamic ranges will be compared in areas 17 and 18. (b) A hypothesis will be examined that near and far cell function in area 18 may be accounted for by a disparity energy model. (c) the joint processing of motion and depth will be investigated. (d) Temporal tuning, timing, and filtering characteristics will be determined. (e) An analysis of nonlinear function will be made by using white noise stimuli. (3) Center-surround receptive field organization: (a) Surround characteristics will be examined to determine spatial distributions and properties. (b) Timing characteristics between center and surround will be explored to examine the hypothesis that surround inhibition arises from local intracortical connections. (c) A hypothesis will be tested that surround suppression participates in contrast normalization. (d) A possibility will be explored that surround suppression is part of the near and far disparity encoding process. These investigations will provide fundamental insights into receptive field organization and neural circuitry in the visual system. This basic information about normal visual function will help form a framework for the diagnosis and treatment of visual disorders.

DESCRIPTION (provided by applicant): The research in this laboratory is concerned with central visual pathways in the brain. The long-term objective is to determine how specific visual functions are encoded and transmitted within these pathways. This objective will be greatly facilitated by the development and use of non-invasive functional neuroimaging techniques such as functional magnetic resonance imaging (fMRI). The proposed research concerns the coupling between neural activity, brain metabolism and hemodynamics, which is fundamental to functional neuroimaging. The project will utilize this laboratory's extensive experience with studies of the visual system, and innovative combinations of microelectrode sensors to determine the relationships between neuronal responses, activity-dependent changes in tissue oxygenation (i.e. oxygen responses) and blood flow. The following investigations will be conducted. (1) Relationships between neural activity, tissue oxygenation and blood flow. Laser Doppler flow and combined microelectrode sensors will be used to determine key relationships between neural activity, tissue oxygenation and blood flow within central visual pathways of an animal preparation. The spatial-temporal relationship between neural activity and activity-dependent oxygen responses will be characterized. The consistency of this coupling for different brain lamina, brain regions, and stages of the aging process will be investigated. (2) Enhancement of activity-dependent oxygen responses. Stimulus, respiratory, and pharmacological factors will be explored to enhance the specificity and signal-to-noise ratios of activity-dependent oxygen responses in an animal preparation. (3) Neural, metabolic, and vascular coupling: applications to BOLD fMRI. Parallel fMRI measurements will be made in human subjects and the results compared with those obtained from the animal preparation. The goal is to improve the spatial resolution and specificity of blood-oxygen-level-dependent (BOLD) fMRI. These investigations are based on the considerable background this laboratory has in functional organization of central visual pathways. By use of innovative experimental techniques, it will be possible to establish rigorous links between neural, metabolic, and vascular factors that underlie the interpretation of fMRI. The use of non-invasive imaging has revolutionized brain science and has become a critical tool in the clinical diagnosis of disease. The planned studies will utilize the visual system to provide insights that will apply broadly to other brain functions.

DESCRIPTION (provided by applicant): Noninvasive neuroimaging has become a powerful investigative and diagnostic tool for the study of the brain. It enables simultaneous observation of neural activity in all brain areas. It can be applied to awake behaving human subjects who are engaged in specific tasks. It provides an examination of the brain in a natural condition, and it enables analysis of large-scale patterns. Examination can be made in two primary states, a resting one in which only spontaneous activity occurs and an active one in which neural activity patterns are based on specific behavior or sensory stimulation. Currently, a major limitation in this process is that neural function is not measured directly. It is inferred from hemodynamic measurements. A major improvement in neuroimaging is possible by the establishment of direct connections between hemodynamic measurements and neural function. To do this, it is necessary to establish the neural basis of hemodynamic functional connectivity. Investigations are proposed in the visual system that will contribute toward this goal. We will examine functional connectivity between the lateral geniculate nucleus (LGN) of the thalamus and the visual cortex. We will also measure neurovascular coupling in lamina of the LGN and among cortical layers. Finally, we will study effects of electrical interference on normal neurovascular coupling by the application of electrical stimulation in the form of transcranial magnetic stimulation (TMS). Our first goal is to study neural and hemodynamic functional connectivity in the LGN and visual cortex. To do this, we will utilize sensors positioned simultaneously in LGN and visual cortex or between two areas in visual cortex to study relationships between hemodynamic and neuronal connectivity. Measurements will be made in both a passive resting state and an active condition in which neural activity is stimulated. The second goal is to examine neurovascular coupling across layers within both the thalamus and the visual cortex. The third goal is to apply TMS and measure changes in neurovascular connectivity in the cortico-geniculate pathway. We will also monitor these changes in real time by use of simultaneous TMS and functional magnetic resonance imaging (fMRI) in human subjects. And finally we will examine how altered connectivity from TMS application can constitute a condition of neural plasticity. Together, these studies will have direct application to the use of noninvasive neuroimaging and electrical stimulation techniques for the treatment of clinical disorders. PUBLIC HEALTH RELEVANCE: Studies are planned to examine the primary relationships of neural and hemodynamic systems in the central visual pathway. These investigations will elucidate significant connections between the neural processing of visual information and the associated hemodynamic functions. Results will have direct application to noninvasive neuroimaging and will be relevant to both basic and clinical applications.