Daniel Tranel - US grants

The principal objective of this project is the continuation of our research on the neural basis of face processing. We plan to explore further the ability of patients with defective recognition of face identity to recognize facial expressions. we aim at uncovering the factors that account for this, and which, in turn, might shed light on the normal mechanisms for the recognition of faces. We will also investigate whether face agnostics can generate facial expressions normally. In a second line of studies, we attempt to validate the idea that the unusually high degree of visual "ambiguity" in faces (as defined by similarities in local and global shapes and overall configuration) largely explains the "special" status of faces as a class of stimuli. Another set of studies will explore the ability of face agnostics to recognize entities other than faces that also require identification at a unique level, e.g., unique landscapes and buildings. We will continue to explore the phenomenon of nonconscious face recognition in face agnostic patients. The significance of the studies outlined under this project ties directly into the objectives specified for Memory and Language. In particular, the studies will contribute to our understanding of the neural mechanisms that subserve learning and recognition in humans, at systems level. In this project, the emphasis will be on learning and recognition processes that are responsible for disambiguating entities at the most subordinate level of taxonomy, i.e., the individual exemplar level. Faces are the quintessential instance of such stimuli and as such they warrant special investigation. These studies are also important in the potential consolidation and expansion of knowledge regarding the ability of the brain to learn and to recognize at a nonconscious, covert level. In addition to the value of such knowledge to further understanding of the neural underpinnings of learning and memory, such information will provide a basis for developing behavioral management programs tailored to the needs of patients with visual recognition disorders.

Studies in neurological patients with lesions suggest that the normal process of retrieving words which denote actions depends on regions in left premotor/prefrontal cortex. The aim of this project is to further the understanding of the neural basis of the lexicon, as it pertains to actions and spatial relationships. We will test four principal hypotheses in a series of [150]H2O PET experiments conducted in 45 normal native English speaking adults: (1) The retrieval of words for actions depends on neural structures partially segregated from those underlying retrieval of words for concrete entities. (2) The retrieval of words for actions performed with manipulable artifacts depends on neural structures partially segregated from those underlying the retrieval of words for actions performed without such artifacts. (3) The neural substrate for the retrieval of words for actions is independent of the sensory modality in which the action stimulus is presented (e.g., visual [pictures] versus auditory [associated sounds]). (4) The retrieval of words which denote spatial relationships depends on neural structures partially segregated from those underlying retrieval of words for concrete entities or actions. In the experiments planned to address these hypotheses, we expect to uncover the neural structures underlying various aspects of spoken language, so as to shed eight on the normal physiology of language processing which may be used in the evaluation of subjects with language deficits such as aphasias, and in conjunction with Project 2, also to help understand language processes in deaf and hearing impaired individuals. Such knowledge may ultimately be of help in the search for ways to improve the understanding of language processing by deaf signers, and inform the development of rehabilitation strategies for individuals with acquired language disorders such as aphasias.

DESCRIPTION (provided by applicant): This renewal application requests support for integrated, broad-based, fundamental, multidisciplinary predoctoral training of first- and second-year (pre-thesis) students in neuroscience at the University of Iowa. The application builds on more than two decades of success in training Ph.D. students, on recent successes in matriculating and training increasingly top-caliber students, and on stable, mature leadership, including a highly experienced Program Director. The Program, which is small but stellar, draws on a long tradition of close interactions among scientists with primary appointments in basic and clinical departments, and their availability to mentor students, formally and by example, in the interplay between basic and clinical research. The training faculty members are 38 extramurally-funded neuroscientists with research interests that span the gamut of neuroscience, from biophysical and pharmacological properties of ion channels, to synaptic proteins and signaling molecules, to neural mechanisms of higher functions such as language, memory, and decision-making. The preceptors have extensive experience and success training students. Students participate in a well-developed, mature curriculum that offers broad and fundamental training in neuroscience, spanning the breadth of the field in terms of levels of analysis (from genes to molecules to cells to integrated functional systems) and diversity of approaches (from ion channels and patch clamp microelectrodes to transgenic and gene-knockout mouse models to human lesion-deficit and functional neuroimaging to translational research), with a special focus on the neuroscience of disease and disorders (including an NIH-supported Neurobiology of Disease course), along with training in statistics and experimental design. The program incorporates three laboratory rotations, regular programmatic activities (laboratory meetings, seminars, journal clubs, retreats), and comprehensive training in responsible conduct of research. The "value-added" feature of this Program is especially compelling - NIH training grant dollars enhance every aspect of the Program, and have contributed directly to unprecedented success during the current funding period, including increases in the quantity and quality of applicants, matriculation and retention of students from diverse backgrounds (including racial/ethnic, disabled, disadvantaged), decreased time-to-degree, publication records of students, and placement of graduates in prominent neuroscience-related academic positions. To extend these accomplishments, this renewal request asks for six slots per year to support first- and second-year students. RELEVANCE: The Iowa Neuroscience Training Program emphasizes a highly interdisciplinary orientation, and is tightly tied to the jointly sponsored NIH predoctoral neuroscience mission to foster work toward the diagnosis, treatment, and prevention of nervous system disorders, and the basic sciences fundamental to this purpose. The Program remains committed to training a diverse and highly expert workforce of neuroscientists, who will then assume leadership roles related to the Nation's biomedical and behavioral research agenda.

[unreadable] DESCRIPTION (provided by applicant): [unreadable] [unreadable] The neuroscience graduate program at the University of Iowa currently lacks a course that links neurobiological disease mechanisms to clinical features while also emphasizing areas of current and future investigation. The RFA for "Course Development in the Neurobiology of Disease" provides us at Iowa with an opportunity to address this much-needed component of neuroscience training. The timing is ideal for the development of such a course at Iowa; the neuroscience faculty, and departmental and college administrators all support this endeavor, and neuroscience is a key growth area at Iowa. The two neuroscientists directing the development and implementation of this course, Drs. Paulson and Tranel, bring to the project an ideal, complementary blend of clinical and scientific expertise. The primary objective is to create a Neurobiology of Disease course that provides training neuroscientists with a broad, thematic understanding of disease mechanisms in nervous system disorders. With the aid of an Advisory Committee, the faculty team will develop a one-semester course that educates students in fundamental features of neurological and neuropsychiatric diseases and prepares them for future research directions. The course will be arranged thematically into five major neuroscience disease groups and will be integrated into the required core curriculum for neuroscience graduate students. More than 35 neuroscience faculty at Iowa, experts in a wide range of diseases, have expressed a strong interest in participating in this course. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): This research application is in response to #RFA-DA-06-004. At the heart of drug and alcohol abuse is bad decision-making, especially in response to social influences. This decision-making defect is highly reminiscent of the social decision-making impairments that characterize neurological patients with damage to ventromedial prefrontal cortex (VMPC). The VMPC patients provide a neurological model of social decision- making gone awry. There is evidence at both preclinical and clinical levels that the VMPC is a key brain region in drug abuse, and we propose that VMPC dysfunction and defective social decision-making may characterize individuals who abuse and become addicted to drugs and alcohol. In this research application, we plan to conduct studies in neurological patients in order to flesh out the neurobiological underpinnings of social decision-making, taking advantage of the unique Iowa Patient Registry that contains neuropsychological and neuroanatomical data for thousands of patients. A particular focus is on gender differences. We have intriguing preliminary findings suggesting that there might be an important sex-related difference in the relationship between the VMPC and social decision-making: in men, the right VMPC might be critical, whereas in women, the left VMPC might be critical. The experiments will test three specific aims: (1) To determine whether there is sex-related functional asymmetry of the VMPC in regard to social decision- making, using tasks such as the Ultimatum Game, Trust Game, Iowa Gambling Task, and Ellsberg Tasks; (2) To extend the investigation of sex-related functional asymmetry to other brain structures known to be critical for social and affective processes related to decision-making, namely, the amygdala and the insular cortex; (3) To investigate developmental influences on the relationship between the VMPC and social- decision making and emotional processing, by studying patients who incurred VMPC damage early in life. The experiments will furnish important new information about the neurobiological underpinnings of social decision-making and emotional processing. The link with substance abuse is direct: the decision-making deficits in VMPC patients have striking similarities with those evident in drug and alcohol abusers and addicts ("myopia for the future"). Thus, our research could help pinpoint sources of neural dysfunction that contribute to bad decision-making of the type that characterizes drug and alcohol abuse. Public health relevance: This research will help us understand how various parts of the brain are important for social decision-making and emotional processing, whether there are gender differences in these brain- behavior relationships, and how these relationships develop. The research could help inform treatment and prevention of drug and alcohol abuse disorders, as well as social conduct disorders, personality disorders, and anxiety and mood disorders, all of which have high comorbidity with drug and alcohol abuse. [unreadable] [unreadable] [unreadable]

Project Summary: Aneurysmal subarachnoid hemorrhage (aSAH) has a high mortality rate (~60%), with a large proportion of the survivors becoming functionally dependent. aSAH survivors have long term cognitive deficits and memory impairment in their productive years with major responsibilities with respect to work and family. In a 30-year nationwide population-based cohort study using data from Danish medical databases, the authors computed the absolute risks and hazard ratios (HR) of dementia up to 30 years after stroke. Compared with the general population, the HR (95% confidence interval) for dementia among ischemic stroke survivors was 1.72 (1.66?1.77), 2.70 (2.53?2.89) after intracerebral hemorrhage, and 2.74 (2.45?3.06) after aSAH. Why is that?? In aSAH subjects, accumulation of hemoglobulin (Hb) and non-heme iron (Fe) which are the natural byproduct lysis of red blood cells leads to significant neuronal cells death. Several preclinical studies in animals showed that both products lead to neuronal death and atrophy of any brain structures exposed to it and specifically the hippocampus and amygdala. These data were replicated in human, where authors found, the level of ferritin (Ft) in CSF, a reporter of the amount of Fe in brain, was found to strongly correlate with progression to Alzheimer's disease (AD). What is the mechanistic pathway of this process?? Our group showed that Hb is toxic to neuronal cells in vitro and adding deferiprone (De) attenuated and reversed this effect significantly. We then confirmed these results in a mouse model of intraventricular hemorrhage. Additionally, in a proof-of-concept study we showed that De significantly decreased Ft in CSF (p<0.0001) suggesting a potential therapeutic effect. Furthermore, others also showed in preclinical studies using different animal models, Fe chelating agents decrease Fe content both in the subarachnoid space and intraventricular improving the functional and cognitive outcome in these animals. Therefore, we propose this grant to test the hypothesis that deferiprone, a lipid soluble Fe chelating agent and therefore diffuse easily across the blood-brain barrier, will significantly decrease Ft (a reporter of total non-heme Fe content in CSF) in subjects with aSAH and hence improve cognitive function. To test this hypothesis, we propose a phase 1/2a single-center randomized double-blinded placebo vs. De trial that recruits and enrolls 66 subjects with aSAH who require placement of EVD as a standard of care. Subjects will be randomized equally into 2 groups: A) placebo & B) 15 mg/kg bid for 21 days. Ft will be collected daily from CSF. We will also test the cognitive changes using the Montreal Cognitive Assessment test along with a battery of well-standardized and widely used cognitive tests that measure various aspects of cognitive and behavioral functioning. We will also assess the volume of hippocampus and amygdala in this cohort and compare them to a matched, historic control cohort using specific MRI protocol. These tests will be correlated with the Ft content in CSF and the volume of hippocampus and amygdala on imaging studies obtained.