Gregory McCarthy - US grants

The long term objectives of this program of research are to increase the usefulness of event-related potentials (ERPs) in cognitive neuroscience and clinical neurophysiology and to investigate issues related to functional localization of sensory, motor, and cognitive processing. The proposed studies emphasize intracranial ERP recording in humans supplemented by scalp recordings taken before and after neurosurgical excisions, and by intracranial recordings in monkeys. Specific aims during the next five years are: 1. To identify ERPs sensitive to visual and somatosensory selective attention, to determine in what brain regions these ERPs are generated, and to characterize their temporal course. ERP evidence for the sequential movement of attention in visual space will be sought. These studies will be carried out in patients with intracranial electrodes placed in relevant sensory cortex, and in normal subjects. 2. To identify ERPs sensitive to semantic and repetition priming, to determine in what brain regions these ERPs are generated, and to examine the effects of attention upon these linguistic processes to determine their degree of automaticity. These studies will also investigate attentional shifts between different channels of linguistic information on the basis of inter-channel priming. 3. To continue our studies of hippocampal ERPs, particularly those which have been associated with scalp-recorded P300 and N400, and to examine the effects of unilateral amygdalo-hippocampectomy. 4. To provide improved ERP techniques for localization of face, trunk, and leg areas of sensorimotor cortex, the second somatosensory area, and supplementary motor and sensory areas during neurosurgery. 5. To provide better understanding of the function of the supplementary motor area, particularly in the initiation and control of voluntary movements including speech-related movement. Movement-related potentials will be recorded from this and from other regions of frontal cortex of chronically implanted patients. 6. To continue application of improved methods for identifying the brain structures and specific cell populations that generate ERPs. Empirical scalp and intracranial potential distributions win be compared with calculated distributions using a realistic model of the shape and conductivity of the human head. The proposed research takes advantage of established clinical collaborations with the Epilepsy Surgery Program of the West Haven VA Medical Center and Yale University School of Medicine in which ERP recordings from the cortical surface and chronically implanted depth electrodes in human patients are obtained. These studies will be augmented by comparable studies in normal human subjects and in non-human primates.

DESCRIPTION:(provided by applicant) In this competing renewal, we propose to continue two research themes concerned with the study of the visual processing of complex forms that were established during the current period of funding. The first concerns visual processing within the ventral occipitotemporal region of the human brain. We propose a series of experiments to investigate the degree to which processing in this region is category specific, and the degree to which processing is influenced by expertise. These studies will further attempt to determine whether processing within putative category specific regions are influenced by cognitive and attentional factors and, if so, when in time these factors influence processing. These latter studies will help determine the validity of our assertion that strong modularity may be temporally limited. The second line of inquiry concerns processing along the lateral temporal-parietal region - particularly within and near the superior temporal sulcus (STS). Our prior studies and those of other groups have indicated that this region is sensitive to the perception of biological motion such as shifts in eye gaze and mouth movements. We propose to systematically map this region to determine if indeed it is selectively influenced by biological as compared to complex non-biological motion and, if so, whether there is an organizational principle along the STS for the type of motion perceived, such as a somatotopic organization. Finally we will investigate whether activity in this region is sensitive to the social relevance of the perceived motion - whether the action is intentional, and whether the action is goal directed within the established context. As in our prior period of funding, we will conduct parallel studies using functional magnetic resonance imaging (functional MRI, or fMRI) and intracranial event-related potential (ERP) recording. This proposal will benefit from technological developments in high-field (4 Tesla or 4 T) neuroimaging that improve functional resolution, and from recent developments in pulse-sequence design that recover susceptibility-related signal loss in ventral temporal regions.

The thesis of this proposal is that prefrontal cortex is a critical anatomical substrate for working memory and, furthermore, that different regions of prefrontal cortex are critical for working memory in different information domains (spatial, object and verbal memory). Frontal lobe dysfunction in schizophrenia results in deficits in working memory which, in turn, underlie much of the symptomatology of the disease. Using magnetic resonance imaging (MRI), we propose to examine the neuroanatomical regions involved in different domains of working memory in humans. Our research plan encompasses three specific aims: (1) Use MR activation imaging to examine the differential activation of dorsolateral and lateral inferior regions of the prefrontal cortex during performance of spatial and object working memory tasks. Our prediction is that spatial memory tasks will increase blood flow in dorsolateral areas and object memory will activate lateral inferior regions. We will also compare the distribution of activated prefrontal regions in spatial and object memory tasks to verbal memory tasks constructed to share the same stimulus and response requirements. (2) Use MR activation imaging to examine the distributed network properties of working memory systems; for example, the posterior parietal cortex should be differentially activated in spatial memory functions; the inferotemporal regions in object memory functions; and the left posterior superior temporal gyrus in linguistic tasks. (3). Use MR activation imaging to examine hippocampal activation. Additional tasks in which novel visual and auditory stimulus pairs must be associated will be used to examine relative activation of hippocampus and prefrontal regions in associative memory tasks. The proposed research will also include the further development of MR activation imaging. This new technique shows great promise as an alternative modality for activation imaging with the potential for widespread application.

The NDSU Collaborative for Mathematics and Science Teacher Preparation (NDSU-CoMSTeP) is a three-year, single-institution, CETP Track I project designed to increase the number of middle and senior high school science and mathematics teachers prepared in North Dakota. The undergraduate students at North Dakota State University (NDSU) and Turtle Mountain Community College (TMCC) are the target recruitment populations. The project goals are to: (1) at least double the number of science and mathematics teachers prepared by the two institutions, (2) significantly increase the number of Native American science and mathematics teachers, and (3) develop a model for increasing the number and cultural diversity of secondary science and mathematics teachers prepared in rural regions. The project involves three interventions: (1) proactive recruitment of students from first and second year university /college science and mathematics courses and high school seniors into teaching career tracks, (2) undergraduate student involvement in science/mathematics teaching interest groups designed to support and enrich the students' desires to enter teaching, and (3) the reform of teaching in undergraduate science and mathematics courses in order to improve the quality of learning for all, but particularly for those students in the science and mathematics teacher preparation programs.

The NDSU Graduate Student-University-School (GraSUS) Collaborative for Science, Mathematics, Engineering and Technology is a project in which graduate and advanced undergraduate students (fellows)will work with science and mathematics teachers in grade 6-12 classrooms. The project uses problem-or inquiry-based learning, in which solutions of interesting real -life problems promote students' learning, problem-solving skills, creative thinking, and teamwork. Challenging problems will be selected to reflect existing school curriculum in the context of the research and applications from core SMET disciplines at the university. The school courses involved include mathematics, general science, environmental science, chemistry, physics and biology. Real-life applications in these areas will come from the same disciplines and from several engineering, agricultural, and technology disciplines. The graduate and undergraduate
fellows will receive pedagogical training. Summer workshops will involve school teachers and university faculty in planning and development activities with the fellows. The project's expected outcomes include enhanced communication and teaching skills for the fellows, enriched learning by K- 12 students,
professional development opportunities for K- 12 teachers, and stronger partnerships between NDSU and local school districts. This project will build upon several other similar and successful programs at NDSU.

DESCRIPTION (provided by applicant) This Program Project will investigate the functional neuroanatomy of the human brain using high-field functional magnetic resonance imaging (functional MRI), electrophysiology, and behavior. The four scientific projects are strongly linked by their focus on the relationship between brain and behavior. The projects are organized into a logical progression from sensory processing through response selection. Project 1 considers the relationship between performance in elemental visual psychophysical tasks and the quantitative structural anatomy of primary visual cortex (Vl). This project is technically challenging and depends upon high-resolution fMRI-based retinotopic mapping to discriminate V1 from other visual areas. Project 2 also focuses upon early visual processing, however its emphasis is upon changes in processing as a function of directed attention. Project 3 builds directly upon Project 2 by investigating the domain specificity (space or feature) of attended visual attributes that must be maintained in a transient memory store for later processing. Project 3 also investigates the role of response processing and sequential expectancies in prefrontal cortex. Project 4 will investigate the manner in attention is attracted automatically or reflexively by novel and/or distracting stimuli. The scientific projects are supported by three Cores. Core A is administrative. Core B will develop methods in high-field functional MRI designed to improve the functional resolution of brain imaging. This core will develop and implement methods to improve the specificity of the MR signal to brain parenchyma, to recover signal lost to large scale susceptibility artifacts in ventral frontal and medial temporal regions, and to improve the spatial and temporal resolution of BOLD contrast. Core C will develop and implement methods for experimental control, physiological monitoring, and analysis of structural and functional image data.

[unreadable] DESCRIPTION (provided by applicant): Neuroimaging research using magnetic resonance imaging, magnetic resonance spectroscopy, magnetic resonance microscopy, and dense array electrical recording involves the acquisition of very large data structures that then must be transformed through a series of compute-intensive post-processing tasks into meaningful information. This project is jointly submitted by NIH-supported investigators at Duke University and the University of North Carolina who primarily use neuroimaging methods. The investigators are representative of four interdisciplinary centers that support neuroimaging research at these institutions: (1) The Duke-UNC Brain Imaging and Analysis Center (jointly funded by both universities), (2) the Center for In- Vivo Microscopy (a NIH National Research Resource Center), (3) the Center for Advanced Magnetic Resonance Development, and (4) the Center for Cognitive Neuroscience. The directors of these centers and their collaborating scientists have found that the sheer volume of data resulting from improved acquisition methods and improved hardware has made it increasingly difficult to fully analyze data in a timely manner. Some important computational processes are unfeasible, such as the creation of 3D chemical shift images. Other routine processes such as 3D spatial normalization of a time series of image volumes require many hours of processing on our single processor workstations. We are requesting funds to purchase a high performance multiprocessor computer to facilitate these and other processing requirements. [unreadable] [unreadable] Our proposal trades heavily upon the recent installation at Duke University of an IBM Storage Area Network (SAN) with capacious multi-terabyte storage capacity for the use of its high technology centers. The proposed multiprocessor system would be connected directly to this SAN via a fiber channel adapter. Thus, the benefits of the SAN to our group of investigators would be fully realized by the proposed computational resource. Our proposal also benefits from the close collaboration that already exists among the included centers in scientific endeavors, in the development of analytical software, and in the management of large research instruments.

Core A is the administrative core of this Program Project Grant. Core A will support the overall administration of this Program Project Grant by preparing and/or assisting in the preparation of all progress reports, by supervising finances, by keeping records of all imaging studies and study participants, by processing subject payments, by processing all MRI scan charges, by maintaining all consent forms and IRB protocols, and by tracking all archived media. Core A will also organize and support the annual visit of the External Advisory Committee.

prefrontal lobe /cortex; short term memory

The Data Acquisition and Analysis Core is both a service and development core that will support the data[unreadable] acquisition and analysis needs of all investigators. By consolidating support resources into this Core, we will[unreadable] achieve efficiencies in data acquisition and analysis and economies of scale that will enable us to increase[unreadable] our PPG from five to nine faculty investigators and to greatly expand our scientific scope. The Data[unreadable] Acquisition and Analysis Core has five major Aims. The first Aim is to provide direct services to all[unreadable] investigators within this Program Project Grant (PPG). These services include (1) a service for recruiting,[unreadable] screening, and scheduling all experimental subjects forfMRI experiments, (2) the provision of a PPGdedicated[unreadable] experimenter to supervise and run all experimental sessions (in addition to the certified MR[unreadable] technologist provided by the Brain Imaging and Analysis Center to acquire images for all studies), (3) the[unreadable] provision of a PPG-dedicated data analyst who will assess the quality of all MRI data using purpose-built[unreadable] software tools, and who will guide all fMRI data through all preprocessing steps of the image analysis[unreadable] pipeline. The second Aim is to support the acquisition of all intracranial event-related potential (ERP) studies[unreadable] performed at Yale University for all PPG investigators. The third Aim is to maintain all visual and auditory[unreadable] stimulus delivery systems, response manipulanda, eye trackers, experimental control computers, and[unreadable] experimental control software. The fourth Aim is to leverage the BIAC's participation in the NIH/NCRR's[unreadable] Bioinformatics Research Network (BIRN) consortium so that all software tools developed by BIRN scientists[unreadable] and software engineers are integrated into the PPG's data analysis pipeline. The fifth Aim is to develop a[unreadable] semi-automated system based for data documentation and data provenance that incorporates principles[unreadable] from the FDA's "Good Clinical Practices" guidelines.

The goal is to investigate brain systems that mediate cognitive, affective, and reward[unreadable] processing in humans and to determine how these systems are influenced by late life depression, by[unreadable] genetic risk factors associated with depression, and by experimental manipulations of serotonin[unreadable] levels. Behavioral challenge tasks will be use during functional magnetic resonance imaging (fMRI) to[unreadable] investigate four specific aims: (1) We will complete studies initiated in the current funding period that[unreadable] investigate the influence of vascular lesions upon the interaction of ventral systems for emotional[unreadable] regulation and dorsal systems for executive control in patients with late life depression. These[unreadable] on-going studies also include an assessment of current clinical status, and whether treatment has[unreadable] led to a remission from depression. (2) We will characterize genetic influences upon the neural[unreadable] processing of emotional and rewarding stimuli using a task developed in current period that[unreadable] measures activity in amygdala, ventromedial and orbital frontal cortex, and ventral frontal cortex, and a[unreadable] second task that measures activity in striatal, midbrain, and dorsal systems associated with[unreadable] decisions about rewards. (3) We will evaluate the effects of neurotransmitter levels upon the neural[unreadable] processing of emotional and rewarding stimuli. Neuroimaging and neurophysiological studies[unreadable] reveal correlations between measures of neuronal activity and measures of behavioral states (e.g.,[unreadable] mood, decision preference, response time). Such correlations suggest functional relationships, but[unreadable] typically remain untested. To functionally probe the effects of emotional/reward systems upon[unreadable] executive processing systems, we will pharmacologically manipulate levels of the neurotransmitter[unreadable] serotonin using ATD. Observation of systematic shifts in mood, behavioral preferences, or sensitivity[unreadable] to reward outcomes would have profound implications for understanding phenotypic variation in[unreadable] behavior associated with conditions such as depression, addiction, and anxiety syndromes. (4) We[unreadable] will evaluate the effects of mood changes upon the neural processing of emotional and rewarding[unreadable] stimuli. A common consequence of depression is anhedonia, or the inability to derive pleasure (or[unreadable] other emotional reaction) from normally rewarding stimuli. We will use procedures developed in the[unreadable] current period to manipulate mood state over short time intervals, and we will investigate how[unreadable] transient negative mood influences activation in brain systems that process emotional and rewarding[unreadable] stimuli.

DESCRIPTION (provided by applicant): In this competing renewal, we propose a coordinated series of multimodal experiments to study the properties of a putative model brain network that rapidly detects animate agents on the basis of their body form and/or motion, and infers the agent's goals and intentions from an analysis of its motion and its identity. These competencies are essential for successful social processing. As dysfunction of social processing is a core deficit in neurodevelopmental and psychiatric disorders as diverse as autism spectrum disorders, William's syndrome, social anxiety disorder, and schizophrenia, we believe that elucidating the properties of this network may lead to a deeper understanding of these disorders and advance strategies for treatment. We will use a multi-modal approach consisting of functional MRI, EEG/ERP, and direct cortical stimulation to best characterize the location, timing, and covariation of neural activity in widespread brain regions presumed to comprise this network. Advanced directed connectivity and decoding analyses will be used to analyze the flow of information among the network nodes. These studies will benefit from our opportunity to stimulate and record directly from subdural electrodes the human brain in patients in the Yale Epilepsy Surgery Program. This proposal comprises four specific aims. In the first aim, we will investigate the timing and directed connectivity upon VOTC processing of faces and body forms. In the second aim, we will investigate the timing and directed connectivity upon LOTC processing of animacy detection and intention attribution. In the third aim, we will investigate changes in directed connectivity between the pSTS and FG as a consequence of the form and motion presented by an animate agent. In the fourth aim, we will investigate the access of semantic information regarding animate agents in the VATL. PUBLIC HEALTH RELEVANCE: Debilitating deficits in social processing is a core symptom of many psychiatric and neurodevelopmental disorders as diverse as schizophrenia, Williams syndrome, social anxiety disorders, and autistic spectrum disorders. Rapid progress has been made in identifying brain regions sensitive to socially relevant cue such as emotional face expressions, gaze shifts, biological motion, and to important social competences such as the inference of another's goals and intentions. Thus, our focus in this competing renewal is on investigating the connections between components of a brain network that associates people's identities and intentions in the service of predicting future behavior - the essence of social processing. Understanding the nature of information transactions among the nodes of this putative network should deepen our insights into the aforementioned clinical disorders and eventually lead to better treatments.