Carl R. Olson - US grants

The long-term goal of this research is to reveal the nature of functions served by the cingulate gyrus, a major division of the cerebral hemisphere found in all mammals including humans. The functions of the cingulate gyrus are poorly understood. Cingulate cortex was once thought to serve visceral or emotional functions because it was believed to be strongly connected to the limbic system. Recent studies have demonstrated that the limbic connections of the cingulate gyrus are weak and, by contrast, that connections to cortical sensory and motor areas are strong. Thus cingulate cortex may serve high-order functions related to sensory analysis and motor control. This proposal describes a program of electrophysiological research on the cingulate gyrus of behaving cats. The research will focus on the cat because the anatomical organization of the feline cingulate gyrus is well understood. It will focus on eye movements because, in the context of standard oculomotor tasks, it is possible to establish clearly the relation of neuronal activity to sensory, motor and complex behavioral variables. The results will permit conclusions regarding the general functions of cingulate cortex. Knowledge concerning the functions of the cingulate gyrus will throw light on the biological mechanisms of human cognition and will form a basis for recognizing and treating impairments that arise from damage to midline cortex.

biomedical equipment purchase;

space perception; neurons; eye movements; cerebral cortex; visual fields; neural information processing; saccades; visual perception; neural transmission; biological signal transduction; behavioral /social science research tag; neurophysiology; Macaca;

The purpose of this project is characterize the cognitive and behavioral circumstances under which neurons in the dorsolateral prefrontal cortex (DLPFC) of the rhesus macaque monkey are active. The general hypothesis to be tested is that neurons of the DLPFC are active under circumstances which behavior must be controlled through the deliberate maintenance of internal states rather than by external stimuli or automatic processes. In four experiments, the activity of single neurons in the DLPFC will be monitored while monkeys perform tasks in which the level of demand placed on endogenous control is systematically manipulated. Manipulated task parameters will include: the number and nature of items held in work memory (experiment 1); the degree to which the stimulus-response associations have become automatized (experiment 2); the degree to which correct responses are opposed by innately prepotent response tendencies (experiment 3); and the degree to which correct responses are opposed by prepotent response tendencies learned in other task contexts (experiment 4). At a general level, the results of these experiments will help to characterize the cognitive functions of DLPFC and will thereby provide a framework for assessing and understanding prefrontal-dependent cognitive functions in normal and schizophrenic human subjects. At a specific level, they will provide insight into the nature of neural events underlying the mass signals detected by functional imaging in human subject will provide insight into the nature of neural events underlying the mass signals detected by functional imaging in human prefrontal cortex (Project-Cohen); and they will open up the possibility of testing in primates the impact of DLPFC of pharmacological and lesion interventions now being developed in rat studies (Projects-Zigmond and -Grace).

The long-term goal of this project is to apply Functional Magnetic Resonance imaging (fMRI) techniques to the awake behaving monkey so that powerful single unit recording techniques can be combined with more global views of brain function from MRI. The ability to correlate changes with direct electrical recordings will help to further clarify and extend the usefulness of fMRI. fMRI will have the potential to compensate for the two major limits of single-neuron recording in behaving monkeys - inability to survey the whole brain and inability to resolve detail at the level of cortical columns and patches. We have equipped a rhesus monkey with a cranial implant identical to those used for rigid head restraint during single-neuron recording. Activities during the preceding grant year have involved building basic apparatus and piloting fundamental methodology for the study of monkeys in the 4.7-T Bruker AVANCE-DRX. We constructed a cradle by which to support an anesthetized monkey in the 4.7-T scanner, with the head rigidly fixed inside the RF coil. In order to allow the monkey to hold the arms in a forward position during functional, we have designed and built a hemicylindrical RF coil with excellent RF homogeneity and sensitivity, which leaves free the space beneath the head. As a first step towards obtaining functional MR images of the monkey, using BOLD, we have detected a hemodynamic change in rhesus monkey cortex induced by a direct intervention (hypercapnia). We chose to manipulate blood flow with hypercapnia, rather than with brain activity, so as to circumvent the possible disruption, by anesthesia, of the functional linkage between brain activity and blood flow. This project will achieve a formal status of a TRD project begining next grant year, and experiments will continue towards carrying out fMRI in the awake monkey.

With National Science Foundation support Dr. James McClelland and the Center for the Neural Basis of Cognition (CNBC) , a consortium of Carnegie Mellon University and the University of Pittsburgh will purchase a 24 processor compute server and a 500 Gb disk array, together with necessary ancillary facilities for backup, archival storage and data presentation. These will be augmented by desktop display stations necessary for individual researchers to access these resources. The center provides a nexus for scientists who wish to understand how cognitive processes arise from underlying neural mechanisms, how anomalous forms of cognition arise from biological disturbances, and how experience and brain development interact to give rise to the emergence of cognitive functions. The center brings together the methods of behavioral analysis, neurophysiology, functional imaging and computational modeling, in an effort to understand how functions such as perception, attention, memory and language emerge from interactions among neurons in the brain. The research in the Center has a range of foci, which can be grouped into the areas of memory and learning, language, attention and control of processing and perception and spatial cognition. In addition, several laboratories address general principles of neural function relevant to many aspects of cognition and several have contributed to the development of tools for computational modeling or functional imaging research. The effort to understand the neural basis of cognition requires the exploitation of computational technologies. This applies both in the area of analysis of experimental data obtained from functional imaging and neuronal recording studies, and in the area of computational modeling of cognitive and neural functions. Functional imaging studies in particular generate masses of raw data that must be processed and carefully treated to extract small signals from noisy inputs. To model cognition, likewise, places greater and greater demands on computing technologies as they are applied to understanding how detailed aspects of the physiology of the brain may influence the time-course and the outcome of cognition.

This award provides the CNBC with a powerful cost-effective centralized computing facility which will significantly enhance the research of 17 faculty members and assist in the research and training of 21 post-doctoral fellows and 44 graduate students. The instrumentation will also be utilized by undergraduates and therefore serve valuable research and training functions.

Project: BCS 9983241 PI: Behrmann, M.

The project is to hold a symposium at Carnegie-Mellon University in June, 2000 on the topic of Perceptual Organization in Vision. The aim of the symposium is to bring together researchers from a variety of disciplines to consider mechanisms of perceptual organization. Both behavioral and neural approaches will be considered. Behavioral approaches will include those arising from research in cognitive psychology, developmental psychology, and animal behavior studies. Neural approaches will include results from single neuron recording studies, from neuropsychological studies of patients with discrete lesions and from functional neuroimaging studies. Qualitative and computational approaches will also be incorporated. The following types of questions will be examined in the course of the symposium: What are the heuristics involved in perceptual organization? Are these predetermined and/or are they experience-dependent? Do they operate only feedforward or is the system interactive, combining bottom-up and topdown knowledge in deriving organizational structure? Do they operate "early" or "late" or is it perhaps more parallel than sequential? What is an object? What is the role of attention in perceptual organization? What specific neural mechanisms mediate perceptual organization? The general goal of the meeting will be to review the current state of the field from a multidisciplinary perspective by bringing together researchers who might not ordinarily exchange ideas, to provide the opportunity for junior scientists to interact with leaders in the field, to identify future research directions, and to disseminate the results broadly. The results of the symposium will be published as the 31st in the series of the Carnegie Cognition Symposium volumes.

DESCRIPTION (provided by applicant): Object-centered spatial awareness - awareness of the location, relative to an object, of its parts - plays an important role in many aspects of perception, cognition and action. One possible basis for this form of spatial awareness is the existence in the brain of neurons with response fields defined relative to an object-centered reference frame. Evidence for such a mechanism has been provided by the finding that neurons in the supplementary eye field (SEF) fire differentially as a function of object-centered direction when monkeys make eye movements to the right or left end of a horizontal bar. Research carried out during the preceding and first support period of the current grant established object-centered direction selectivity in the SEF as a robust and replicable phenomenon and demonstrated, among other findings, that it was independent of visual stimulus selectivity and could not be accounted for in terms of body-centered motor signals. In addition, it extended into inferotemporal cortex (IT) the study of neural representations underlying the representation of object structure. Findings from this period have provided support for the general conclusion that there are neurons in the cerebral cortex which encode spatial information relative to an abstract non-motoric reference frame. Projects to be carried out during the next support period have as their twofold general aim: (1) to test the idea that object-centered representations in the SEF subserve cognitive processes more general than the selection of targets for eye movements; and (2) to compare directly object-centered activity in the SEF and in other, related cortical areas of the frontal and parietal lobes. Five main series of experiments will be carried out. Series 1 will assess the validity of the gain-field model according to which SEF neurons exhibit object-centered direction selectivity only during planning of eye movements into the classic motor field. Series 2 will assess whether SEF neurons carry object-centered signals when monkeys perform a task requiring them to remember object-centered locations without making movements to them. Series 3 will test the hypothesis that the object-centered neuronal activity in the SEF is correlated with object-centered visual attention as measured at the level of inferotemporal cortex. Series 4 will investigate whether neurons in the frontal eve field (FEF) carry object-centered signals.

DESCRIPTION OF OVERALL PROJECT (provided by applicant): This Integrative Behavioral Science Center seeks to develop a framework for understanding human cognition, grounded in principles specifying the character of human cognitive processes, and constrained by properties of the underlying neural mechanisms. The Center will exploit this framework to guide formulation of explicit, testable models of normal and disordered cognition, including models of the development of cognitive functions and of their disintegration as a result of brain damage or disease. A fundamental tenet is that cognition is an emergent phenomenon, arising from the interactions of cooperating processing elements organized into specialized populations. One aim of the center will be to investigate the utility of explicit models that are formulated in terms of this approach, addressing many aspects of cognition including semantic knowledge, language processing, cognitive control, perception, learning and memory. A second aim will also investigate the principles that are embodied in the models, including principles of learning, processing, and representation. Learning will be a central focus, since it plays a crucial role in cognitive development, acquisition of skills, formation of memories, and remediation of cognitive functions. A third aim of the Center will be to incorporate constraints from neuroscience. Findings from neuroscience will guide the specification of the principles and the formulation of domain-specific details of particular models, and will provide target experimental observations against which to assess the adequacy of the models. In addition, the Center will make use of neurophysiological methods in animals and functional brain imaging in humans to test predictions and generate additional data needed to constrain and inform model development. The Center will provide training funds for interdisciplinary research fellowships, to train junior scientists in the convergent use of behavioral, computational, and neuroscience methodologies. The outcome of the Center's efforts will be a fuller characterization of the nature of human cognitive processes, a clearer formulation of the underlying principles, and a more complete understanding of normal and disordered functions across many domains of cognition.

All research in this Center is directed at testing a general hypothesis concerning the origin of the information processing deficits of schizophrenia. The hypothesis states that molecular alterations among GABA neurons give rise to abnormalities of cerebral cortical oscillatory activity and that abnormal oscillatory activity gives rise to impaired information processing. Testing this hypothesis will lead to an improved understanding of the pathophysiological mechanisms that underlie impaired information processing in schizophrenia and will thereby pave the way to the development of novel, mechanistically-based treatments. Project 3 will contribute to the attainment of the goals of the Center by characterizing cognition-related oscillatory activity in the cerebral cortex of behaving monkeys. Experiments conducted under Aim 1 will focus on gamma-band (30-80 Hz) oscillations in frontal cortex that accompany the preparation to overcome a prepotent response. Experiments conducted under Aim 2 will focus on gamma-band oscillations in occipitotemporal cortex that accompany selective visual attention. Experiments conducted under Aim 3 will focus on theta-band (4-8 Hz) oscillations in occipitotemporal cortex evoked by displays consisting of a central and a peripheral visual stimulus. In each experiment, oscillatory activity will be examined at multiple levels of spatial resolution (dural surface potential, local field potential and action potential). In each experiment, the dependence of oscillatory activity on GABA neurotransmission will be assessed by measuring the impact of locally administered agents that exert a potentiating (benzodiazepine) or blocking (GABA antagonist) effect at GABA-A receptors. In each experiment, three fundamental hypotheses will be tested: (1) that the amplitude of oscillatory activity depends on the task conditions;(2) that oscillatory activity recorded at an intracranial site is correlated with oscillatory activity recorded at the overlying cortical surface;(3) that oscillatory activity depends on GABA neurotransmission. By improving our understanding (a) of how cortical oscillatory activity recorded at the brain surface is related to intracranial oscillatory activity and (b) of how intracranial oscillatory activity depends on GABA, the results will increase our understanding of the neural mechanisms that underlie scalprecorded oscillatory activity in healthy subjects. This will form a basis for drawing inferences about the pathophysiological mechanisms that underlie abnormal cognition-related oscillatory activity in schizophrenia. An understanding of the pathophysiology will form a foundation for the development of novel mechanistically based treatments aimed at ameliorating the cognitive impairments of schizophrenia.

DESCRIPTION (provided by applicant): Inferotemporal cortex (IT) plays a crucial role in object vision as indicated by the fact that injury to it results in profound recognition deficits. The role played by IT in object recognition has been elucidated by research carried out over several decades in macaque monkeys. This has indicated that neurons in IT are pattern selective. Each neuron responds to certain complex images and not others. To gain an understanding of the nature of neuronal pattern selectivity in IT - and hence to cast light on the nature of the neural machinery that underlies visual pattern recognition - is the aim of experiments described in this proposal. Three series of experiments will be carried out. The approach in each case will be to measure the responses of neurons to displays consisting of discrete parts that can be manipulated independently so as to determine how the response to the whole is built up from the responses to the parts. Series 1 will ask whether IT neurons as a population represent, in a dimensionally reduced code, a family of shapes consisting of joined linear segments and having roughly the complexity of alphanumeric characters. Series 2 will ask whether neurons in IT are selective for the arrangement of elements in an image and, if so, whether selectivity is invariant across changes in size and location. Series 3 will ask how neuronal activity in IT represents displays consisting of items in an array, including words and hierarchical stimuli.

In tasks requiring attention and working memory, prefrontal and parietal cortex exhibit functional connectivity in the form of oscillatory phase-locking. Project 4 will test the general hypothesis that phase-locking depends on direct connections between the two areas originating from neurons in layer 3. By monitoring electrical activity simultaneously at fine intervals from the cortical surface to the white matter, while monkeys engage in working memory (Aim 1) and attenfion (Aim 2), the experiments will test the speciflc predicfion that signs of funcfional connectivity are maximal in layer 3. By monitoring the electrical activity of identified projection neurons and by examining the impact of blocking projections between the two areas, the experiments will test the specific prediction that direct projections are critical for functional connectivity (Aim 3). Results obtained in Project 4 will have direct relevance to the Central Hypothesis regarding the origin of cognitive deflcits in schizophrenia. This hypothesis states that cognifive deficits arise because pathological changes in layer 3 pyramidal cells interfere with functional connectivity between prefrontal and parietal cortex. Projects 1-3 will focus on the properties of layer 3 pyramidal cells in the healthy brain and in schizophrenia. Project 5 will focus on funcfional connectivity in the healthy brain and in schizophrenia as measured with coherence and causality analyses. The unique contribufion of Project 4 will be to link these domains of inquiry by establishing the role of layer 3 neurons in functional connectivity as assessed with coherence and causality analyses. RELEVANCE (See instructions): This project will establish the role of layer 3 neurons in the cognitive deflcits in schizophrenia.

DESCRIPTION (provided by applicant): One of the most basic and general functions of the brain is to detect the occurrence of unexpected and therefore potentially informative events. This function rests on two foundations. First, the brain must extract from ongoing experience information about the transitional statistics of the environment: information about what events tend to follow what other events. Second, it must monitor ongoing experience so as to signal when predictions based on previously experienced transitional statistics are violated. We know that the brain accomplishes these feats but we know little about the underlying neuronal mechanisms. We propose to investigate this problem by studying a phenomenon recently discovered in the primate visual system: prediction suppression. Prediction suppression is induced by allowing a monkey to view repeatedly a display in which images follow each other in fixed sequence. During subsequent viewing, neurons in area TE, a visual area in the temporal lobe, respond weakly to images in the trained sequence but respond strongly to images that appear out of sequence. This phenomenon possesses potential as a test bed for the study of neural mechanisms mediating predictive processes in the brain. The general goal of the proposed project is to answer fundamental outstanding questions about prediction suppression so as to solidify the status of the phenomenon as a model for studying the neural mechanisms of predictive processes. We propose three sets of experiments. In all of them, we will expose monkeys, during a training period, to dynamic displays governed by fixed transitional statistics and then, during a testing period, will monitor neuronal responses to predicted and unpredicted sequences. Experiments in the first series will characterize the conditions required for inducing prediction suppression. Experiments in the second series will characterize the neural processes initiated by presenting a predictive stimulus. Experiments in the third series will determine whether prediction suppression is manifest at visual processing stages before and after the level of area TE.

We rely for object recognition on hierarchical processing of visual input by the ventral stream of cortical visual areas. The chain begins in low-order cortex (including area V2) where neuronal activity represents local features and terminates in inferotemporal cortex (including area TE) where neuronal activity represents global images. Neuronal function in the ventral stream is subject to alteration by visual experience. One particularly robust form of visual plasticity is familiarity suppression. Familiarity suppression can be induced in TE by allowing subjects to view the same set of images repeatedly over the course of days and weeks. At the end of the familiarization period, the mean strength of neuronal responses in TE is less for the familiar images than for novel controls. On the assumption that familiarity suppression is specific to TE, it has been thought to serve some function related to late-stage processing of the global image. Recently, however, familiarity suppression has been shown to occur even in V2, where neurons represent local features and not entire objects. On the basis of this observation, we propose that familiarity suppression, far from being specific to late-stage processing of the global image, arises from principles of unsupervised statistical learning operative at each stage of the ventral stream and expressed at each stage relative to the nature and scale of represented visual information. We will test this general idea by using semi-chronic multielectrode arrays to monitor neuronal population activity simultaneously in V2 and TE during image familiarization. Experiments under Aim 1 will test the hypothesis that familiarity suppression develops independently in V2 and is not just fed back from TE. Experiments under Aim 2 will test the hypothesis that familiarization enhances the cooperative representation of an image by neuronal populations in V2 and TE. Experiments under Aim 3 will test the idea that the synaptic alterations underlying the impact of familiarization obey a Hebbian learning rule.