Martha J. Farah - US grants

This research focuses on the ability to generate mental images, or "see with the mind's eye." The first goal of the research is to learn about the organization and neural localization of image generation by studying the image generation abilities of brain-damaged patients. The specific questions addressed are: What are the separable components of image generation ability? What parts of the brain are critical for these components? The second goal of the research proposed here is to clarify the nature of the underlying cognitive deficit in certain types of visual/spatial disorders that follow brain-damage. This aspect of the research involves testing the hypothesis that a loss of imagery ability underlies the following clinically relevant visual/spatial disorders: Visual retention deficits, visuo-constructive deficits, and topographic disorientation. The methodology consists of administering a set of tasks designed to selectively tap different components and type of image generation (detailed visual, "sheletal" visual, and auditory) to a variety of patients selected either for lesion location (right, left, anterior, posterior) or visual/spatial deficit (topographic disorientation, constructional apraxia, visual retention deficit). Degree of association or dissociation between different types of image generation will reveal the organization of image generation. Relations between image generation deficit and lesion location will reveal critical brain areas for image generation (including testing a specific hypothesis about the localization of visual image generation). Correlations between clinical visual/spatial deficits and image generation deficits will test hypotheses about the role of imagery deficits in clinically relevant disorders.

The purpose of this RCDA is to enable me to learn computational modelling of cognitive processes, with the goal of applying this method of understanding human spatial cognition in its normal state and after brain damage. This, in turn, will allow me to develop explicit, mechanistic accounts of spatial information processing in the brain, and of the underlying cognitive deficit in the different visual/spatial disorders that follow brain damage. Through a combination of courses, lab visits, and supervised modelling projects in the early years of the RCDA, I will gain the knowledge and skills necessary to begin modelling the neural bases of spatial cognition in earnest. During this time I will also be conducting neuropsychological research of spatial cognition, which will provide constraints for these computational models, addressing such issues as: the spatial reference frames used in coding location, allocating attention, and recognizing objects; the interface between the spatial structure of objects and their surrounding environment; and the format of supramodal representations of space. In the later years of the RCDA, I envision an ongoing interaction between the ideas and constraints uncovered through modelling (which will guide the neuropsychological research by providing hypotheses and predictions) and those emerging from the neuropsychological research (which will influence modelling strategy by providing empirical constraints for neurally plausible models). My long-term career goals are to understand the neural bases of human spatial cognition at a mechanistic level. Whereas the traditional 'box and arrow' models of cognitive psychology provide some insights into this matter, it is computational models that provide both a language for expressing models of mechanism and a methodology for testing their sufficiency. Learning to build and evaluate computational models is a time-consuming proposition; the RCDA would allow me to devote the time needed for this. At CMU I have many colleagues who are leaders in the field of computational modelling, from whom I can learn, and excellent computational facilities. My home department is planning to build in the area of cognitive neuroscience, further enriching the environment relative to this proposal.

DESCRIPTION (Adapted from Applicant's Abstract): This research has two related goals: To understand the ways in which the brain represents space, and to explain clinical visual/spatial disorders in terms of the underlying spatial representations that have been impaired by brain damage. The first goal involves characterizing both the functional architecture of spatial representation in terms of the spatial frames of reference (i.e. coordinate systems) used to code spatial position, the relation between the internal spatial structure of objects and their location in space, and the modality-specificity of spatial representations. The investigator also will attempt to localize the representations so delineated by examination of lesion site in patients who are and are not impaired in a particular form of spatial representation. The second goal is to determine which clinically observable visual-spatial disorders (including hemispatial neglect, constructional apraxia, visual disorientation, closure deficits, visual agnosia, topographic disorientation, and disorders of personal space) are attributable to impaired spatial representation (as opposed to impairments in memory or executive processes, for example), and to begin to characterize the nature of the impairment of spatial representation where such an impairment is implicated.

After 10 years as a PI in research on cognitive impairments following stroke, and some recent preliminary work on cognition in AIzheimer's disease (AD), l have decided to turn my attention more fully towards the dementias. Although cognitive neuroscience has generally concentrated on focal brain damage, I believe that AD and other dementias, including Parkinson's disease, Huntington's disease and semantic dementia, have much to teach us about the functioning of the normal mind and its neural substrates, particularly with respect to semantic memory and visual cognition, my two areas of specialization. In addition, the dementias represent a major public health problem, and the cognitive neuroscience approach may be able to contribute towards solutions to this problem. I am therefore requesting support to undertake five years of study, research, and career development in the cognitive neuroscience of dementia. During this period I will carry out the proposed research on semantic memory and visual cognition in AD while learning more about AD and other dementias. My goal is to become as competent in research on dementia as I am now in research on focal brain damage, and thereby to contribute to our basic-science understanding of the dementias and to advances in the diagnosis and management of these diseases.

Semantic memory, or general knowledge about objects and events in the world, appears to be severely affected in most patients with Alzheimer's Disease (AD). The goal of the proposed research is a deeper understanding of semantic processing in AD. In overview, the following issues concerning semantic memory will be addressed. First of all, is semantic memory impaired, or does the appearance of impairment come from an attentional impairment? Second, are certain types of semantics knowledge more vulnerable to AD, and if so, why? Third, can an impairment of semantic memory account for other problems that seem, on the face things, not semantic but perceptual or lexical? Fourth, what is the relation between semantic impairments and visual impairments in the confrontation naming difficulties of AD patients? Finally, what is the status of the visual-semantic process of mental imagery in AD? The methods to be used include empirical studies of patients with AD and normal subjects, and computer simulation. We have drawn on the theoretical framework of cognitive psychology in designing studies of semantic memory, vision, and mental imagery in AD. In addition, concepts from parallel distributed processing (PDP) have guided the formulation of hypotheses concerning semantic memory in AD, and PDP computer simulations will provide tests of the computational adequacy of these hypotheses. In addition, new predictions of the computational hypotheses have been derived and will form the basis of further empirical tests with human subjects.

Early Experience and Neurocognitive Development: Socioeconomic Variables

Abstract

With National Science Foundation support, Dr. Farah will conduct a one-year study attempting to begin to characterize the cognitive outcomes of childhood poverty in terms of the framework of Cognitive Neuroscience. Dr. Farah aims to partition the known cognitive disparities, previously assessed with the relatively blunt instruments of IQ tests and school achievement measures, into 7 key neurocognitive systems using selective behaviorally-based neurocognitive tasks. These tasks are as follows: Dorsolateral prefrontal/working memory, Ventromedial prefrontal /reward processing, Anterior cingulate/conflict monitoring, Parietal/spatial, Occipito-temporal/pattern vision, Temporal/memory, and Fronto-temporal/language. This partitioning may isolate the neurocognitive system or systems that are most sensitive to the effects of experiential factors related to socio-economic-status (SES). If such systems can be delineated, then researchers may be in a position to discover the potentially causal factors in the family and home environment, from a wide array of factors previously measured with the low SES participants, from somatic factors such as lead levels to psychological factors such as parental depression and stress.

The primary goal of this proposal is to address the question: Given that SES has been shown to affect cognitive development, what underlying systems of the developing mind and brain are impacted by the complex bundle of experiential factors that constitute SES? Brain development involves a complex interplay between innate and experiential factors. Our understanding of the role of experience comes from animal and human evidence. Experimental manipulation of the environment of young animals has demonstrated profound effects of environmental stimulation and the presence of stressors on brain health. Studies of children raised under conditions of extreme deprivation, such as Romanian orphanages, have found measurable differences in brain development. What has not been established is the effect of differences in early experience within the normal range for our society. One dimension on which normal children's experience may differ is related to their family's socioeconomic status (SES). Furthermore, SES is known to impact a wide range of measures of cognitive development, from IQ tests to school achievement. The present project begins with the assumption that these SES disparities in cognitive development are not to be explained in terms of innate differences between families, but are instead due to some of the many experiential differences that correlate with SES.

DESCRIPTION (provided by applicant): This exploratory R21 grant application is intended to establish research paradigms for, and make preliminary progress toward, understanding the neural bases of individual differences in the personality trait of impulsivity. Given the demonstrated relation between impulsive personality and negative health behavior, including drug use, a better understanding of this personality trait would be of considerable public health value. Relatively little is known about how normal personality is reflected in the brain. Most of what we do know relates to neurochemistry, as opposed to the more "molar" systems level typical of cognitive neuroscience. As such, the overall goal of this application is to relate normal variation in impulsivity to variation in brain function at this "molar" level of description, that is, in terms of large-scale networks of functionally delineated brain regions. Preliminary work by the principal investigator suggests that systematic relationships can be found between personality impulsivity and brain function at this level of analysis. Normal subjects' performance on a battery of behavioral tasks showed a strong association between a common measure of impulsivity and the functions of prefrontal cortex (PFC). The specific aims of this research are: (1) to go beyond global descriptions of PFC function, to discover which subsystem(s) of PFC are related to personality differences in impulsivity; (2) to go beyond a single conception of impulsivity, to consider the neural bases of several other well-known (and uncorrelated) measures of impulsivity; (3) to gather both hypothesis-driven and exploratory functional MRI data, for purposes of testing hypotheses generated from Aims 1 and 2, concerning the differences in brain function that underlie the normal personality trait of impulsivity, and for exploring the various ways in which differences in brain activation could relate to impulsivity.

The current capability of neuroscience to monitor and alter brain function has profound ethical implications, which scientists and the public have only begun to examine. Two recent major conferences were devoted to surveying the ethical implications of progress in neuroscience, one at the University of Pennsylvania entitled "Ethics and the Cognitive Neuroscience Revolution" and one at Stanford University entitled "Neuroethics: Mapping the Field." These conferences promoted the dissemination of ideas among individuals and the wider public. The current series of workshops will take the next step, in the form of intensive dialogue among relevant experts that will give form and direction to the field of neuroethics. Specifically, the meetings are designed to accomplish the following objectives: (1) Define issues of highest priority for neuroethics; (2) Elucidate scientific progress and obstacles; (3) Engage ethicists and policy specialists in the areas most relevant to each particular issue, to help understand the most directly relevant moral principles and social traditions, relevant regulations or policies now in place, and analogous precedents in other fields; (4) With the relevant scientists and ethicists, collaboratively develop policy positions on each issue; and (5) For each issue, write and submit an article summarizing the major conclusions for publication in a widely read or generalist journal.

DESCRIPTION (provided by applicant): Beginning as early as preschool, and persisting throughout childhood and beyond, individuals of low SES perform below their middle class counterparts on a variety of psychometric tests. The cognitive disparities between poor and middle class children are robust, persistent over time, and have consequences for future life success. The research proposed here seeks to characterize the nature of the disparity in terms of the underlying systems of the mind and brain affected by poverty. Additional goals are to understand the relation of these underlying effects to both antecedent early life experiences and resultant future life trajectories. Specifically, the theoretical framework and methods of Cognitive Neuroscience will be used to address several basic questions about the relation between poverty and cognitive development. First and foremost: What underlying systems of the developing mind and brain are impacted by poverty? This project will partition the known cognitive disparities, previously assessed with the relatively complex tasks of standardized psychological assessment, into seven key neurocognitive systems: Parietal/spatial, Occipito-temporal/pattern vision, Temporal/memory, and Fronto-temporal/language, Lateral prefrontal/working memory, Ventromedial prefrontal/reward processing, and Anterior cingulated/conflict monitoring. This will be accomplished with behavioral testing and functional neuroimaging of a cohort of carefully screened middle school-aged low SES children and a middle SES comparison group. Subsequently, the results of the neurocognitive analysis will be used in the search for causal mechanisms, drawing upon a rich database of information about the life experiences of the low SES children. Neurocognitive systems mediating resilience and successful adolescence will also be sought.

DESCRIPTION (provided by applicant): This research seeks to understand the relations among socioeconomic status (SES), early life experience, and learning in adolescents. Previous research has shown that learning ability is positively correlated with SES, and preliminary studies suggest that the effects of childhood experience on hippocampal development may in part account for this. The present research will test hypotheses concerning the nature and causes of the SES disparity in learning ability by examining its scope and limits across different types of learning and different neural systems, and assessing its relation to early experience, including stress, stress-buffering parental nurturing and related constructs. The relation of these laboratory-based measures to student learning in school will also be investigated. The methods to be used include (a) behavioral tasks, developed within the multiple memory systems framework of cognitive psychology and cognitive neuroscience, to assess different forms of memory, (b) structural and functional neuroimaging studies of memory systems and (c) prospectively collected data on childhood experience and SES from a longitudinal study of adolescent participants. The relevance of this research to the mission of NIH lies in the crucial role played by learning in the academic, occupational and personal lives of all Americans, and the prospect of preserving and fostering the learning ability in at-risk youth though the application of insights from the cognitive neuroscience of memory, stress, and early experience.

This action funds a project in Ethics Education in Science and Engineering entitled the Neuroethics Learning Collaborative at the University of Pennsylvania under the direction of M.J. Farah.

Neuroscience is increasingly used for purposes outside of its traditional medical applications, from brain imaging for lie detection to neuropsychopharmaceuticals for enhancing mental function in normal individuals. The current generation of neuroscience graduate students is among the scientists and citizens who grapple with the ethical issues surrounding the role of neuroscience in society. This project educates the neuroscientists of the future in the field of "neuroethics," the ethical, legal and social implications of their field. To maximize the educational impact of the program, it is offered online, in real time and for free, to faculty and graduate students "attending" from several remote sites. The course is delivered through an online social learning platform designed to encourage neuroscience graduate students from multiple universities to share profiles and to engage in discussion across institutional boundaries. This platform additionally allows for the course to develop into a robust open educational resource. As the instruction and learning activity proceeds, the course content is "recorded" day-by-day, and posted for "play back" as an archive by anyone interested in participating in the course on their own, and in their own time, including students, faculty, industry scientists and journalists. The program includes a number of different instructional formats, some based on traditional classroom education and some using the networking capabilities of the world-wide web. There are also student debates and faculty panel discussions. The subject matter includes the uses of psychopharmaceuticals and other methods for brain enhancement, new applications of brain imaging outside of clinical research and practice, and the implications of neuroscience for legal and moral conceptions of responsibility.

DESCRIPTION (provided by applicant): Neuroscience in Your World: A Partnership for Neuroscience Education Across the K-12 Spectrum. The Franklin Institute Neuroscience in Your World is an innovative collaboration between The Franklin Institute and the Center for Neuroscience &Society at the University of Pennsylvania to engage K-12 students and teachers in learning about the importance of neuroscience in their world. The proposed work will create a tiered set of learning experiences that frame core concepts of neuroscience in the relevant context of students'worldview at different developmental stages. Aligning cognitive goals and social development across the K-12 spectrum, the project will build the framework for a learning progression that, at younger grades, reaches a very broad audience at an introductory level of scientific content and, at higher grades, targets increasingly focused audiences with deeper levels of experience. Program content will focus on topics in brain function, learning, social behavior, and societal impacts of neuroscience, emphasizing personal aspects of health and behavior that influence how we perceive and interact with the world around us. The project will include a combination of field trips to and programs delivered at The Franklin Institute, courses implemented at nearby high schools and a digital toolkit of educational materials and teacher professional development resources that will be distributed online. Summative evaluation will determine the effects of the project components on participating students and teachers from the Philadelphia region. Evaluation methods will include pre-post student surveys, teacher surveys, and on-site observations, using for comparison either a waiting group for field trip evaluation or a simulcast group for on-site course evaluation. The suite of programs developed through this project will create the foundation for a successful and sustainable infrastructure for neuroscience education in Philadelphia and beyond. PUBLIC HEALTH RELEVANCE: Neuroscience in Your World: A Partnership for Neuroscience Education Across the K-12 Spectrum The Franklin Institute. From sensing to moving to thinking to feeling, neuroscience explains how we perceive and interact with the world around us. Through the proposed Neuroscience in Your World educational programs, students and teachers across the K-12 spectrum will explore how the brain works in their own bodies and mediates their interactions with their environment. This understanding will enable them to comprehend and make better choices about their own health, behavior and ultimately, their future.

DESCRIPTION (provided by applicant): The primary goal of these meetings is the development and exchange of ideas concerning the ethical, legal and societal implications of new developments in clinical neuroscience. These include issues arising from functional neuroimaging, behavioral genetics, molecular neurobiology and their applications to understanding normal and abnormal brain function. More specifically, each conference will: (1) bring leading clinical neuroscientists together with experts on bioethics, law and society to identify issues at the intersection of neuroscience and society;(2) organize the knowledge base for each issue, noting what is relevant, what is known and what is not known;(3) foster bidirectional exchange of ideas between researchers and clinicians;(4) disseminate the results of these presentations and exchanges beyond the conference by creating videos of the sessions to post online and by contributing a collaboratively written article on a key issue in clinical neuroethics to the peer-reviewed archival literature. State-of-the-art translational and clinical neuroscience will be paired with analyses of their broader societal impact, for an audience including laboratory and clinical scientists. We anticipate at least half of the audience will be graduate students, fellows and early- career scientists, and will offer these individuals the opportunity for mentoring and poster presentations in addition to other conference activities. PUBLIC HEALTH RELEVANCE: This conference series will focus on the ethical, legal and social implications of recent advances in clinical neuroscience, with the objective of integrating state-of-the-art translational and clinical neuroscience with analyses of their broader societal impact. Awareness of these broader issues is essential for guiding basic and translational research toward the most responsible and beneficial outcomes.