Bertram R. Payne - US grants

The goal of the proposed experiments is to investigate the structural and functional organization of interhemispheric connections of visual areas 17, 18 and 19 in cat cerebral cortex. To achieve this goal, the morphology and synaptology of cells which project axons through the corpus callosum will be determined to ascertain if any of the neurons are non-pyramidal cells which are inhibitory in function. In addition, we will examine the types of synapses which local and long-distance axon collaterals of callosally projecting pyramidal cells form and the nature of their postsynaptic targets. This part of the study will reveal the morphological bases by which callosally projecting neurons in one hemisphere can influence the functions of nearby neurons in the same hemisphere and distant neurons in the contralateral hemisphere. The region of visual space represented in the callosal cell zone and callosal terminal zone of each area will be determined by compiling topographic maps and comparing these maps to the location of the callosal zones defined in the same animal. This part of the study will provide us with insights into the relative contributions played by different cortical areas in one hemisphere in the processing of visual information in the opposite hemisphere. Such insights are important if we are to understand the mechanisms which allow the two hemispheres to operate as an integrated whole.

DESCRIPTION (Adapted from applicant's abstract): Lesions of the cerebral cortex sustained early in life provoke system-wide repercussions that include substantial rewiring of remaining subcortical and cortical pathways. These repercussions contribute significantly to functional compensations by cortical neurons and to the sparing of cognitive and perceptual processes that are profoundly impaired following equivalent damage incurred by the mature brain. The long-term goal of the proposed work is to identify the classes of functions that are spared by the early cortical damage, and to identify the neural basis of the sparing. The specific aim of the proposed work is to investigate the contributions which the expanded visual pathway through LGN to cortical area PMLS makes to operations spared by early lesions of areas 17 and 18. Studies will be carried out on cats which incurred damage of areas 17 and 18 on the day of birth or at one month of age, and comparison data will be collected from intact cats and cats which incurred equivalent damage in adulthood. Two projects are proposed: 1) to reveal the components and obtain a measure of the strength-of-coupling in the expanded retino-LGN- PMLS pathway. From these data we will infer the types of visual signals that are transmitted through LGN to cortex; and, 2) to uncouple the expanded retino-LGN-PMLS pathway in mature cats to ascertain the contribution the pathway makes to the spared behaviors. A battery of behavioral tests will be employed for functions normally associated with area PMLS, with damaged areas 17 and 18, and with the X and Y signal streams. The behavioral tasks will reveal the importance of the retino- LGN-pathway expansions to the spared behaviors. The proposed work will provide detailed information on the capacities of the immature brain to compensate for perceptual and cognitive functions lost or impaired following equivalent damage of the mature cerebrum. The identification of these capacities is important for steering future anatomical, physiological and behavioral efforts directed at comprehending the consequences of early cerebral cortical damage, and for developing therapeutic strategies that attempt to enhance the sparing of cortical functions.

DESCRIPTION (adapted from applicant's abstract): The long term goal is to identify cortical circuits underlying cognitive functions. This endeavor requires the elucidation of the essential contributions that cerebral loci make to cognitive processes. The projects will concentrate on occipito-parietal (OP) & occipito-temporal (OT) contributions to visual perception and cognition of space, action and forms, and to memory. The specific aim of the proposed work is to test two interlinked hypotheses: 1) Each area within OP and OT cortices makes multiple, yet unique, combinations of essential contributions to perception, cognition and memory; 2) Permanent lesion-induced deactivations can be accompanied by neural compensations that attenuate and mask the magnitude of these contributions. Work will focus on cat middle and posterior suprasylvian cortices (areas 7, aMS, pMS, dPS, PSs and vPS), and the hypotheses will be tested by applying multi-site cooling deactivation (#1), or permanent lesion-induced deactivation (#2), to disrupt distinct combinations of a battery of specific visually guided behaviors. The data will be used to generate the first comprehensive compendium of the multiple and characteristic combinations of neural contributions each of the constituent areas in OP and OT cortices make to different aspects of perception, cognition and the memory. The compendium will highlight similarities, overlap, differences, lateralization, uniqueness and nested hierarchy of contributions areas make to cognitive and higher brain functions. The compendium is a requisite for accurately identifying and interpreting neural compensations that may emerge following cerebral lesions. Together, the acquired knowledge is essential for the future development of biologically-realistic, functionally-based models of cerebral operations. Moreover, the knowledge will: 1) form the foundation of future studies of emergent and higher-order integrative processes; and 2) guide future investigative studies on defective cerebral systems that underlie diminished cognitive function, agnosia, and visual neglect and other sequelae of damage of visuoparietal and visuotemporal regions.

DESCRIPTION (Provided by applicant): Brain lesions incurred early in life produce a different brain from that reached after normal development. The lesion-induced modifications are specific & ordered and they contribute to sparing of cognitive processes that are severely handicapped by equivalent lesions incurred by the mature brain. The long-term goal is to identify classes of spared functions and the structures contributing to them. The specific aim of the proposed work is to test the two component hypothesis that: 1) cognitive functions are spared by early lesions of areas 17 & 18, & 2) the contributions to cognition made by middle suprasylvian (MS) cortex, in the parietal region, and by ventral posterior suprasylvian (vPS) cortex, in the temporal region, differ from contributions the same regions make to cognition & behavior in the intact brain. Normally these two regions make clearly discriminable, and non-overlapping, contributions to cognition of space & action, and to learning, memory & recognition of forms. Studies will be carried out on mature cats that incurred damage of areas 17 & 18 on P1, P28, and in adulthood (P180), and normative data will be collected from intact cats. After extensive training on a battery of behavioral tasks designed to define the magnitude of the cognitive sparing, cooling loops will be implanted to temporarily deactivate MS or vPS cortices and assess the contributions the two regions make to the spectrum of spared functions. The behavioral tasks will reveal: 1) classes of spared cognitive functions; 2) age dependent differences in sparing; 3) whether remaining MS & vPS regions adopt functions normally associated with areas 17 & 18; & 4) whether functions normally localized to either MS or vPS cortices become dispersed, as substantial rewirings suggest. The work will provide detailed information on the capacities of the immature cerebral cortex to compensate for cognitive functions severely handicapped following equivalent damage of the mature cerebrum. The identification of these capacities is important for comprehending the spectrum of consequences of early cerebral cortical damage, and for developing therapeutic strategies that attempt to enhance the sparing of cognitive functions.

DESCRIPTION (adapted from applicant's abstract): The long term goal is to identify cortical circuits underlying cognitive functions. This endeavor requires the elucidation of the essential contributions that cerebral loci make to cognitive processes. The projects will concentrate on occipito-parietal (OP) & occipito-temporal (OT) contributions to visual perception and cognition of space, action and forms, and to memory. The specific aim of the proposed work is to test two interlinked hypotheses: 1) Each area within OP and OT cortices makes multiple, yet unique, combinations of essential contributions to perception, cognition and memory; 2) Permanent lesion-induced deactivations can be accompanied by neural compensations that attenuate and mask the magnitude of these contributions. Work will focus on cat middle and posterior suprasylvian cortices (areas 7, aMS, pMS, dPS, PSs and vPS), and the hypotheses will be tested by applying multi-site cooling deactivation (#1), or permanent lesion-induced deactivation (#2), to disrupt distinct combinations of a battery of specific visually guided behaviors. The data will be used to generate the first comprehensive compendium of the multiple and characteristic combinations of neural contributions each of the constituent areas in OP and OT cortices make to different aspects of perception, cognition and the memory. The compendium will highlight similarities, overlap, differences, lateralization, uniqueness and nested hierarchy of contributions areas make to cognitive and higher brain functions. The compendium is a requisite for accurately identifying and interpreting neural compensations that may emerge following cerebral lesions. Together, the acquired knowledge is essential for the future development of biologically-realistic, functionally-based models of cerebral operations. Moreover, the knowledge will: 1) form the foundation of future studies of emergent and higher-order integrative processes; and 2) guide future investigative studies on defective cerebral systems that underlie diminished cognitive function, agnosia, and visual neglect and other sequelae of damage of visuoparietal and visuotemporal regions.

DESCRIPTION (provided by applicant): Our long-term aim is to rehabilitate neural spatial neglect. Unilateral neglect is a complex neurological disorder induced by unilateral brain damage that is characterized by lack of conscious perception, awareness, attention, and cognition of objects in the space contralateral to the brain damage. In a cat model of spatial neglect, unilateral deactivation of posterior and inferior parietal cortex induces a profound neglect of objects in the contralateral hemifield. Paradoxically, the neglect is reversed by additional deactivation of the homotopic region in the contralateral hemisphere. This model system offers the opportunity to investigate the neural mechanisms which, when damaged, produce neglect, and to develop an effective therapeutic strategy to reverse neglect in humans. The Specific Aims of the proposed work are to test three hypotheses on: 1) the use of repetitive transcranial magnetic stimulation (rTMS) to reverse neglect in a cat model, 2) to learn more about the primary & secondary functional impacts of lesions and stimulations on the attention network, & 3) interactions of lesions & rTMS on distant structures as the impact of the lesion emerges & when it is stable. The knowledge gained will aid the development of therapeutic and interventional strategies for application to human patients suffering from neglect. Animal studies provide the best possibility of studying the neglect syndrome, and its paradoxical reversal, in a highly systematic way and with considerable anatomical rigor. Our model of spatial neglect will allow systematic identification and dissection of pathways affected by the lesion, provide insights into the brain mechanisms underlying the reversal of neglect, lead to the development of therapeutic strategies to rehabilitate and ultimately reverse neurological neglect in human patients. Our over riding goal is to minimize rTMS parameters yet provide maximum therapeutic duration. It is a realistic goal that can be achieved with the proposed whole-animal behavioral assays and supplemented by the brain-wide network analyses on the functional impacts and interactions of parietal lesions and applied TMS on neurons. The data are of obvious translational importance for neurorehabilitation of neglect and may have wider-ranging impact on other neurologic and psychiatric diseases.