Jeffrey R. Binder - US grants

The immediate goal of this project is to develop FMRI as a technique for investigating the cerebral organization of language. Achievement of this goal requires that a variety of standardized activation procedures be developed and that precise descriptions be obtained of the salient variables influencing FMRI responses. A systematic series of activation experiments is proposed, based on techniques drawn from psychophysics, cognitive psychology, and neuropsychology. It is hypothesized that elementary acoustic stimulus variables including rate, intensity, and duration affect the magnitude and spatial distribution of FMRI responses in auditory sensory regions of the cortex. The first Specific Aim of this project is to measure the relationships between FMRI responses and these stimulus variables. An understanding of these stimulus effects will enable the design and interpretation of subsequent groups of experiments using more complex tasks. It is hypothesized that the auditory cortical regions concerned with speech perception possess an internal functional organization for processing linguistic and non-linguistic features of speech. Consequently, a second Specific Aim of the project is to map these regions in an effort to clarify the anatomic basis of early speech processing. These studies will exploit the phenomenon of selective attentional modulation to identify functionally specialized areas for low- level acoustic processing, phonetic perception, intonation, and voice discrimination. Finally, it is hypothesized that activation in higher association areas depends on cognitive processing demands distinct from the physical stimulus. The final Specific Aim of this project is to characterize the FMRI responses associated with cognitive language behaviors which require phonologic and semantic processing functions. Component systems mediating phonetic discrimination, phonological manipulation, and verbal working memory will be mapped using a set of contrasting subtraction paradigms. The structure of semantic representation in posterior association areas will be investigated by manipulating category and modal attributes of retrieved information during a semantic decision task. The role of the left frontal lobe in semantic and phonological functions will be investigated using a hierarchical set of task subtraction experiments. In achieving these aims, this project will lay the foundation for a broader, long-term goal to use FMRI in improving the diagnosis and treatment of brain diseases affecting language function, including dementia, stroke, dyslexia, and epilepsy. This long- term goal is one component of the stated long-range objective of this program project: to develop FMRI for clinical applications in neuropsychiatric illness.

This investigation will evaluate the efficacy and safety of intravenous aptiganel in two different doses compared to placebo in patients with acute cerebral ischemic. Treatment must begin within six hours of onset.

Task-induced decreases in cerebral blood flow are a frequent finding in functional brain imaging research but have not been adequately explained. Many of the brain areas that typically show such decreases have also been implicated in semantic processing. One hypothesis accounting for both observations is that attention-dependent, unsolicited semantic processing occurs during conscious resting state and is interrupted by shifting of attention to non-semantic tasks. Non-semantic tasks thus produce decreases in neural activity in regions normally engaged in semantic processing during rest or "thinking"). The specific aims of this proposal are to test the main predications of this model using functional magnetic resonance imaging (fMRI) and behavioral measures of semantic processing capacity. First, the model predicts that changing the attentional demands, or difficulty, or a non-semantic task should produce correlated changes in task-induced signal decreases measured with fMRI. More importantly, these changes should be correlated with reductions in semantic processing capacity measured during the same task conditions. Specific Aim 1 is to test these predictions by correlating changes in semantic processing capacity and fMRI signal decreases during controlled manipulations of attentional load in non-semantic task. Second, the model predicts that semantic tasks should not cause fMRI signal decreases, as these tasks engage the same brain areas that are engaged in semantic processing during rest. Specific Aim 2 is to test this prediction by measuring fMRI signal decreases during controlled manipulations of semantic processing load while attentional load is held constant. If correct, the main hypotheses will provide a unifying account of disparate findings from functional imaging studies of semantic processing, an explanation for at least some task induced "deactivations," and much needed information about resting state brain activity that would be broadly applicable to the design and interpretation of functional imaging experiments. These data could also provide novel research approaches to neuropsychiatric conditions characterized by abnormal thought content, including schizophrenia, obsessive compulsive disorder, affective disorder, and autism.

functional magnetic resonance imaging; preoperative state; neurosurgery; epilepsy; patient care management; memory; language; brain mapping; bioimaging /biomedical imaging; neuropsychological tests; human subject; clinical research;

DESCRIPTION (provided by applicant): Brain surgery is an effective treatment for people who suffer from intractable epilepsy, and the most common type of epilepsy surgery is removal of the anterior temporal lobe (ATL). Removal of the left ATL, however, causes cognitive side effects, particularly partial loss of language and memory ability, in about half of these patients. The goal of this project is to identify factors that determine which patients will experience these side effects so that they can be avoided or minimized. Many epilepsy centers have begun to use functional magnetic resonance imaging (fMRI) to map language and memory zones prior to surgery, but the meaning of these maps is unclear. Most of the fMRI methods in current use are not reliable at detecting functional areas in the ATL. More fundamentally, it is unknown whether areas judged to be active by fMRI are critically necessary for normal function. Little progress has been made on this fundamental issue because of the difficulty involved in obtaining systematic preoperative and outcome data in a sufficient number of patients. This project will create a consortium of eight epilepsy surgery centers with state of the art fMRI facilities, dubbed the FMRI in Anterior Temporal Epilepsy Surgery (FATES) group, to study the role of fMRI in epilepsy surgery. Roughly 220 patients who undergo left ATL removal will be studied before and after surgery, using neuropsychological tests, standard MRI, a well-validated fMRI measure of language dominance, and a novel fMRI method that is very sensitive at detecting activation responses in the ATL. The chief function of the ATL is to rapidly retrieve and integrate conceptual (semantic) knowledge, such as during sentence comprehension and discourse. The study will test the hypothesis that cognitive outcome after left ATL surgery depends on both the degree to which ATL semantic networks are damaged during surgery and on the degree to which language functions are lateralized to the left hemisphere, as the latter indicates how tightly the left ATL semantic system is coupled to other language systems. This large, systematic, prospective data set will also clarify the relative importance of many other factors in determining cognitive and seizure outcome, including the cognitive status of the patient and amount of seizure- related damage to the hippocampus prior to surgery, the amount of ATL tissue removed during surgery, and the amount of hippocampal tissue removed. The achievement of these aims will have a profound impact on clinical practice and optimal care for patients with intractable epilepsy. Current presurgical fMRI methods lack standardization and provide data of unclear significance. This research will provide the first definitive information about the validity of using fMRI for surgical planning, will provide a new model for the conduct of such validation studies, and will help bring about standardization of fMRI protocols for this application.

Concepts are the building blocks of human cognition, providing the basic content for language, episodic memory, social interaction, planning, and many other essential capabilities. Modern evidence suggests that human conceptual knowledge is represented in a widely distributed and hierarchically organized system involving much of the brain. Despite the central importance of this cognitive domain, there are large gaps in our understanding of very fundamental issues concerning how concepts are represented and organized at a systems level. This project addresses several of these gaps using a novel, high-dimensional, biologically based model of word meaning that captures the extent to which a concept is derived from various types of sensory, action, emotional, spatial, temporal, and cognitive experiences. We use this model in a series of information-based analyses of fMRI data and multivariate analyses of lesion-deficit correlations in patients with stroke. Our main hypothesis is that much of conceptual knowledge is represented in abstract form within content-specific experiential networks and multi-level convergences between these networks. Aim 1 is to clarify the detailed architecture of these hierarchical convergences, including intermediate crossmodal networks that we hypothesize arise in the brain due to proximity of neural processing streams and systematic covariation between experiential dimensions. Aim 2 is to test the hypothesis that event concepts (e.g., PARTY, ACCIDENT, SNEEZE) are primarily represented in inferior parietal convergence networks due to strong contributions from motion, action, spatial, and temporal experiences in the formation of these concepts, whereas object concepts have stronger representation in temporal lobe convergence networks that capture static multisensory experiences. Aim 3 is to clarify how concept categories are differentially represented and how this organization gives rise to category-related impairments in patients with focal brain damage. We hypothesize that neural representations of both concrete and abstract categories emerge from differently weighted mixtures of experiential information at high levels in the representational hierarchy. The high-dimensional, experiential representation of word meaning on which these hypotheses are based, combined with advanced fMRI techniques for mapping information content, makes it possible to address these basic knowledge gaps systematically for the first time. Combining state-of-the-art lesion-deficit correlation analyses with these healthy brain fMRI studies provides a powerful means of establishing causal links between fMRI activity patterns and successful concept retrieval. Understanding this large, complex, and particularly human brain system has far- reaching implications for understanding a range of neurological conditions that impair knowledge representation and retrieval, is likely to be transformative in the realm of functional mapping for brain surgery, and will be a prerequisite for developing rational and effective rehabilitation strategies for such patients, including future therapies involving modulatory stimulation, brain-machine interfaces, and biological repair.