Michael M. Merzenich - US grants

Recent studies have revealed that the details of somatosensory cortical maps are dynamically maintained and are alterable by experience in adult primates. Substantial changes in map topography in receptive sizes are seen consequent from peripheral nerve transection, amputation, or differential tactile stimulation of restricted skin surfaces. Cortical maps also reorganize after induction of restricted cortical lesions. With that reorganization, skin surfaces formerly represented within lesions come to be represented in the cortex surrounding them. In this renewal period, studies will be directed toward a further definition of the "rules" of cortical map alteration with experience. Behavioral and chronic physiological studies are designed to determine what features of input are actually correlated in the control of the input "selection" underlying map dynamism and territorial competition. They shall also reveal distance limits for reorganization for different cortical fields suspected on anatomical grounds to have greatly different capacities for use-dependent modifications. They shall further test the hypothesis that map changes are a consequence of changes in synaptic effectiveness and not a consequence of sprouting or movements of terminal arbors; shall determine whether inputs from different receptors can dominate the driving of the same neuronal population at different times; shall determine whether input "selection" by middle-layer cortical neurons is by groups of neurons or occurs cell by cell. Correlative studies shall be conducted in Al in the cat and in area 4 in the owl monkey, to determine whether they have the same dynamic properties. In parallel more practical experiments will be directed toward evaluating the time course of observed physiological "recover" from stroke; toward defining cortical distance limits for recovery in fields in what is expected to be differences on anatomical grounds; and toward evaluating the consequences for the rate and the quality of recovery of heavy passive and active differential use of the skin surfaces formerly represented in the cortical zone of the infarct. We shall also determine whether the time courses of cortical map alterations by experience can be modulated by factors effecting "state-dependent" learning, and shall attempt to determine whether maps can be pharmaceutically stabilized, or restabilized or hyperstabilized. It is believed that these studies might provide insight into possible origins or some forms of mental illness.

This project focuses on the design aspects of multicontract cochlear implants concentrating on the factors that affect their ability to be removed and replaced, possibly with dimensionally different implants. The new designs must cause minimal mechanical trauma and foreign body reaction in middle and inner ear structures. It is anticipated that this will include improvements in surface materials, electrode geometries and implant fixation techniques as compared with presently existing electrode arrays. Evaluation will be in non-deaf animal models of the developing child. The decision to use a non-deaf model is based on the fact that hair cells are sensitive indicators of disturbances of cochlear structure and function. Also, in deaf models with implanted electrode arrays, cochlear damage produced by inducing deafness complicates the interpretation of damage caused by the implant itself.

This award provides funds to aid in the purchase of optical microscopy equipment. The equipment will be located in a central facility where it will be available to a group of neuroscientists in the Keck Center for Integrative Neuroscience. The scientists are all interested in various aspects of local circuit analysis of the mammalian central nervous system (CNS). The goal of their studies is an improved understanding of how small groups of neurons generate behavior. The instruments requested will be used for combined anatomical and physiological studies of brain function that include the use of double or triple labeling techniques. The development of new instrumentation for optical microscopy and of new methods that permit specific labeling of certain cells or certain cell constituents has been key to progress in our understanding of many aspects of cellular and developmental biology. Neuroscience has benefited greatly from these developments, since they permit the rapid and reliable identification of particular neurons or groups of neurons in the brain or at other sites that typically contain many nerve cells or similar morphology.

The overall objective of this ongoing grant research is to further document how learned and remembered stimuli are represented by the distributed responses of cortical neurons; to further define the specific, distributed cortical unit response changes and the neuronal cell assembly changes that underly cortical contributions to learning and non-declarative memory; to further determine how these dynamic self- organizing cortical processes might contribute to the origins of and the expressions of functional human disabilities; and to further specify a realistic cortical network model, on the path to developing a general theory of cortical operations and function. At this stage of these studies, the research focus is directed toward resolving how learned, spatiotemporally complex stimuli are represented by distributed neuronal responses within somatosensory and auditory cortical fields; how cortical dynamics account for the representations of temporal input feature repertoires and temporal sequence learning; specifically how inputs delivered into the cortex are integrated or segregated, and are bound as singular perceptual events by cortical plasticity/representational processes; how strong, behaviorally documented plasticity-induced changes in cortical integration and segmentation times can be accounted for by cortical change mechanisms; how the processing of temporally sequenced inputs and their plasticity relates to, and possibly accounts for the genesis of the main behavioral expressions of speech reception/language- based learning disabilities (LDs); and how powerful effects of expectation shape our perceptions and learning in the dynamic cerebral cortical machinery. This continuation proposal research is organized to continue the development of a crucial foundation science for understanding the contributions of learning and brain self-organization to the many expressions of human neurological dysfunction and disability. Its findings contribute to the further specification of a general model of cortical dynamics and function, directed toward ultimately defining the basic principles of perception and cognition in terms of brain mechanisms and process rules.

surgery; biomedical facility; animal colony; surgery material /equipment; learning; neural information processing; animal communication behavior;

An overall objective of our research is to create a foundation science for understanding the contributions of cortical plasticity and learning to the origins of, and the expressions of human neurological disability, and to use that new understanding to guide remediation therapies. In this project, we shall study cortical plastic changes induced by repetitive, stereotyped, cognitively important movement exercises generating coincident afferent inputs that degrade the cortical representations of muscle and skin afferent information in the cortex. We shall further document the neurology of emergent repetitive strain injuries (RSI) including focal dystonias of the hand (Fdh) generated by this behavioral training, and relate training-generated de-differentiation of brain representations of movements and feedback sensory information controlling movements to the progression of sensorimotor dysfunction. We shall define the relationship of experience- induced changes in SI and MI to the onset and progression of pain and inflammation in the arm, and determine whether or not pain onset a) enables or amplifies, or b) could be triggered by dynamic, parralel cortical representational degradation. We shall determine whether induced plastic changes in motor and sensory cortical fields are posturally specific, which is signature feature of emergent focal dystonias. We shall determine whether or not and how postural strain might contribute to RSI/FDh genesis. Finally, we shall evaluate remediation training strategies in this primate model, to access behavioral strategies for redifferentiating cortical representations of sensory afferents and movements that have been degraded by RSI/FDh-inducing behaviors. This study should lead to a fundamental change in how we view cortical plasticity and learning contributions to chronic neurological disease, and could have a major impact on the development of more effective remediation therapies for this very large and growing patient group.

DESCRIPTION: (Adapted from applicant's abstract): In these proposed Javits grant continuation studies, we focus directly on nine important, understudied aspects of cortical plasticity, in experiments that shall be conducted in primate and rodent models. First we shall define how the cortex creates-and expresses by the distributed responses of cortical neurons and by learning-based specialization of its processing machinery-sequence-dependent and context-dependent representation of complex acoustic and tactile inputs. Second, we shall further define how cortical plasticity is modulate separately and synergistically by cholinergic, dopaminergic, adrenegic and serotonergic control system that enable, and differentially amplify learning-induced cortical change. Third, we school further document, and compare and interrelate, behaviorally-driven vs. modulatroy -control-system/ acoustic-stimulation pairing-driven plasticity across the three dimension of cortical columns and minicolumns. Fourth, we shall define the spefic ways in which leaning-induced plasticity is modulated as a function of the predictability of inputs. Fifth, we shall further elaborate studies of "catastrophic' plasticity, specificity, specifically studying forms that appear to arise in human populations as one probable cause of severe behavioral impairments. Sixth, we shall reconstruct the ontogeny if development of the cortical processing of complex acoustic inputs. Seventh, we shall develop animal models designed to test the hypothesis that signal-to-noise conditions that apply for the young cortex underlie the quality and the extent of the progressive refinement of its complex-signal processing machinery, and thereby largely account for variations in complex signal processing abilities (speech and language development, reading ability, "intelligence") in human populations. Eighth, we shall define in detail, the ways in which plastic changes generated within "secondary" cortical fields are derived from, or are independent of, the evolution of processing refinements in "primary" sensory cortical areas. Ninth, these studies shall result in the development and elaboration of two new classes experimental models, designed to facilitate the study of molecular aspects of cortical plasticity mechanisms in mice, and the study of cellular and synaptic dynamics and plasticity in vitro experiments in rats. They experiments bare important implication for the further development of brain plasticity-based strategies for the remediation of neurological impairments, and for the amelioration of the symptoms of progressive neurological and psychiatric illness.

SUBPROJECT ABSTRACT NOT AVAILABLE

The overall objective of this project is to determine specific ways in which learning-induced changes in cortical representations contribute to the origins of and the expressions of acquired and developmental movement disorders and severe disorders of language, and to use that understanding as a source of insight for defining the forms of new neuroscience-based therapies designed to remediate them. We shall further develop and elaborate models of origin of a) focal dystonias of the hand (fDh); b) the usually-severe language disorder component of pervasive developmental disorders (PDDs); and c) some forms of generalized developmental dystonia and cerebral generate representations of learned stimuli and behaviors. It has already contributed to a growing appreciation of what postnatal functional self-organizing mechanisms contribute to human performance ability and disability and to the specific mechanisms that underlie these cortical cellular, synaptic and circuit changes process. Our principal focus is directed toward creating special models of "catastrophic plasticity" that have human neuropathology parallels. It is hypothesized that catastrophic cortical plasticity underlies the emergence of acquired movement disorders and repetitive strain injury symptoms in adults, and accounts for some of the major deficits of pervasive developmental disorders, developmental generalized dystonias and some forms of cerebral palsy. A more complete understanding of the neurological origins of the deficits contributed by the progressive learning in a defectively functionally self- organizing brains will provide crucial insights into possible forms of a new class of remediative training strategies and our understanding the physiological impacts of brain trauma, oxygen deprivation, or inherited weaknesses that contribute-along with learning to the origins of these severely disabling conditions. The continuation experiments are designed to deepen our understanding of the complex neurological origins of these common human maladies, and to provide us with information that will guide the development of remedial training strategies that could allow us to more effectively help many of these severely impaired individuals.

DESCRIPTION (PROVIDED BY APPLICANT): The overall objective of this Fast-Track proposal is to develop and evaluate a novel, neuroscience-based multimedia training program for the treatment of cognitive deficits in schizophrenia. Neurocognitive deficits are a core feature of schizophrenia, and inhibit schizophrenics' ability to participate in rehabilitation programs, maintain social relationships, gain and maintain employment, and function independently in the community. An intervention that substantively improved schizophrenics' cognitive functioning could reduce the negative sequelae of this illness. A rapidly growing body of evidence from the neuroscience of developmental and adult brain plasticity has led to increased understanding of the neurological bases of learning and memory, and supported a specific disease-origin model of schizophrenia. We propose to develop an intensive, neuroscience-based multimedia intervention, rooted in this new disease-origin model, to ameliorate cognitive functioning and symptom expression in schizophrenia. A preliminary, incomplete form of the proposed multimedia training program has been evaluated in a pilot study with 13 schizophrenics. This training significantly ameliorated important neurocognitive deficits in most subjects, improved cognitive functioning in areas that were not targeted in training, and reduced positive psychotic symptoms. Based on these findings, we propose to create a revised and expanded training program to more directly, completely, and powerfully address a broader range of neurocognitive impairments predictive of functional outcomes in schizophrenia. We have already developed 2 of the 3 modules that will comprise the training program. Phase I of this Fast- Track proposal aims to support the development of a critical third training module targeting associative and executive cognitive processes, and to obtain feasibility and acceptability data to inform program revisions. In Phase II, we will conduct a randomized, controlled trial to evaluate the neurological and broader clinical impact of this innovative therapeutic product. This self-administered, computer-based therapy could be marketed worldwide to health care professionals who treat schizophrenics, and to families who care for them.

[unreadable] DESCRIPTION (provided by applicant): Virtually everyone experiences significant decline in cognitive abilities as they age. In vision, these deficits manifest as problems with visual recognition, visual working memory, and visual processing efficiency and speed. Despite the prevalence of these problems in the aged and the severe impact they eventually have on quality of life (e.g., recognition of friends, driving), there is currently no effective treatment for these deficits - they are accepted as a natural part of the aging process. However, an increasing body of research indicates that these cognitive declines are substantially contributed to by the degradation of function in the central visual system. Over the past thirty years, the related fields of experimental psychology, perceptual learning, and "brain plasticity" (the study of the brain's ability to reorganize itself in response to behavioral demands) have defined systematic ways to use behavioral training procedures to improve the function of central sensory systems in the brain. We have previously applied brain plasticity research to create models of a variety of developmental disabilities (autism, language and reading impairments) and adult disabilities (acquired focal dystonias, Parkinsonism, schizophrenia, depression, progressive functional losses in aging). A variety of animal and human studies demonstrate that a brain plasticity based training strategy can be effectively employed to drive large-scale therapeutic benefits for functionally deteriorating, aged individuals. We now propose to use this knowledge and practical experience to create and test a set of intensive computer-based visual training exercises that target visual processing impairments in older adults suffering from age-related cognitive decline. The long term goals of the training exercises are 1) to significantly improve the representational fidelity of the visual system and substantially improve visual sensory performance, visual cognition, and overall quality of life in older adults and 2) to significantly advance the state of the art in the area of visual system plasticity-based approaches for the functional rehabilitation of visually guided behavior. This proposal represents a direct contribution to human health in that it should result in the creation of a training program designed to enhance the cognitive performance of virtually all people as they age. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This phase 1 SBIR proposal supports the development of a practical rehabilitative strategy to efficiently and inexpensively remediate focal dystonia of the hand (FHd), a professionally-devastating movement disorder with no currently effective treatments. An early prototype of a brain plasticity-based training strategy has been successfully implemented at the UCSF Department of Physical Therapy and Rehabilitative Science where it has been shown to be effective in restoring sensory and motor hand function. However, this clinic-based treatment strategy is cumbersome, expensive, and inherently repetitious and boring. Because re-normalization of hand control in FHd demands intensive daily exercise over a period of several weeks, there are significant problems with patient non-compliance. These problems are effectively addressed by the product model that will be created with the support of this SBIR. It will support the development of three simple training devices that shall be used in a multidimensional training program designed to rapidly, efficiently and completely restore normal sensory and hand motor control abilities. Exercises are controlled in an adaptive 'computer game' format, and are designed to optimize learning rates, closely control attentional focus, and strongly reward the trainee. By its nature, these training programs are designed to be engaging and delightful. They provide extensive feedback to the patient to assure their compliance. The software fully documents the patients compliance and progress, and (optionally) automatically sends relevant data to a supervising professional therapist. Our specific aims are as follows: Specific Aims 1 and 2: Construct prototypes of 1) three sensory stimulation devices and 2) the software programs to control these devices in progressive, adaptive, and enjoyable training tasks. Specific Aim 3: In a pilot effect size study, evaluate the extent to which this training approach will renormalize patients' sensorimotor function and restore their ability to work and function independently. This novel therapeutic strategy is directly relevant to human health because it offers the opportunity to radically change the therapeutic landscape for FHd by providing a practical and affordable treatment for this common and costly human malady.

stimulus /response