Peter E. Turkeltaub, M.D., Ph.D. - US grants

DESCRIPTION (provided by applicant): Although cognitive systems are critical to the educational and social development of children, few studies have explored the development of neuronal systems subserving cognition. While functional neuroimaging has been a valuable tool for the study of the neural basis of cognition in adults, imaging studies of normal children have historically been limited due to the radiation exposure associated with the techniques. Only recently has functional magnetic resonance imaging (fMRI) emerged as a non-invasive functional imaging tool posing little to no risk to the subject, making it suitable for the study of normal children. In this study, fMRI, in conjunction with a battery of neuropsychological assessments, will be used to investigate the functional neuroanatomical bases of cognitive skill acquisition. Seven-, ten-, and twenty-year-old subjects will be scanned while performing implicit word identification, letter identification, object identification, and visually triggered finger movement tasks. Areas of significant developmental change will be evaluated. Correlations between task-related activity and performance on neuropsychological measures will further delineate the neural correlates of behavior. Conjunction analysis between the age-related changes in the four tasks will be used to assess the relationship between the development of word identification, letter identification, object identification, and basic sensory and motor systems. This work will provide novel insight into the neurophysiological correlates of normal cognitive development, information which is essential to the future investigation of developmental disorders of language and cognition. Previous research suggests that several distributed brain areas represent the mature substrates for these tasks. Developmental changes will likely include shifts from immature areas to these mature systems, increased laterality of activation, and changes in extent of activation. Some developmental changes will be specific to single cognitive tasks while others will represent more general cognitive or sensorimotor maturation.

? DESCRIPTION (provided by applicant): Aphasia, an acquired impairment of language and communication, affects about one million Americans, and causes significant long-term disability. People with aphasia often feel that they can say certain words in their heads, even though they can't say them aloud. Because this sense of successful inner speech is hard to verify, clinicians cannot be sure whether these reports are meaningful, and if so, what they can tell us about the internal mental processes of word-finding. Remarkably, although the sense of successful inner speech is an everyday experience for many people with aphasia, only one prior study, published in 1976, directly asked people with aphasia about their inner speech and tested whether these self-reports are meaningful. Building on this prior work using modern techniques, this project examines how subjective reports of inner speech relate to objective measures of the psychological and neural processes of word-finding. The main hypothesis is that the sense of successful inner speech emerges from access to a phonological word form. A corollary of the hypothesis is that brain activity related to phonological access corresponds with the subjective report of whether inner speech is correct or not. We will test these hypotheses using an inner/aloud naming task, phonological judgments, and functional MRI of inner naming. These tests examine whether reports of inner speech predict (1) subsequent aloud speech, (2) access to phonological information about the same words, and (3) brain activity when calling these words to mind. The study is designed to test hypotheses at the single-subject level because individual differences in language and cognitive deficits are expected to influence insight into inner speech. Pilot data collected to date demonstrate that self-reports of inner speech in aphasia are meaningful and likely reflect phonological access as hypothesized. We have also found that self-reports of inner speech predict word-by-word success in subsequent anomia treatment, demonstrating the clinical importance of this work. This research will provide a new source of information to study language and aphasia, and potentially a new way to guide individualized aphasia therapy. Further, this research will improve our understanding of the personal experience of having aphasia, an important goal for clinicians, people with aphasia, and their families.

? DESCRIPTION (provided by applicant): Each year, 250,000 people in the US suffer strokes that impact their ability to communicate through language (aphasia), and in two-thirds of these cases, recovery is incomplete. Currently, standard treatment for aphasia is limited to speech therapy, but neuromodulation using transcranial direct current stimulation (tDCS) offers a safe, inexpensive adjunct treatment with the potential to boost neural function and recovery. To date, all neuromodulation studies of aphasia have stimulated the lesioned region or the opposite hemisphere, with varying results. Therefore, the optimal site of neuromodulation for post-stroke aphasia has yet to be established. Clinical and neuroimaging evidence suggest that the cerebellum is involved in a variety of language functions, including naming and verbal fluency, which are often impaired in people with aphasia. In particular, the right posterior cerebellum connects to and shows correlated activity with left-hemisphere language cortices. The cerebellum is crucial for optimizing skill acquisition, and this role in skill learning could improe the effectiveness of rehabilitation following cerebral cortical stroke. To date, no study has performed cerebellar tDCS in people with aphasia. This project will test the hypothesis that enhancing right cerebellar modulation of left frontal cortex will improve aphasia recovery when applied during five days of traditional speech therapy. The effectiveness of right cerebellar tDCS on language functions will be measured in participants with aphasia from left frontal strokes. Participants will receive both real and sham tDCS in a crossover design. To determine the neurobiological mechanism by which cerebellar tDCS affects recovery, structural and functional neuroimaging will measure pre- and post-treatment alterations in cortical and cerebellar activity and cerebro-cerebellar connectivity. TDCS is an inexpensive treatment with potentially powerful therapeutic possibilities. Given the role of the cerebellum in both language and skill acquisition, the right cerebellum offers an innovative site for neuromodulation using tDCS in people with aphasia. This project may produce findings that will impact not only the millions of people living with aphasia, but also those with strokes affecting motor, prefrontal and parietal cortices to which the cerebellum projects. Through the use of neuroimaging, this project will provide information about how the brain changes during this therapeutic intervention, broadening our understanding of the impact of neuromodulation following brain injury. This has far-reaching impact on all neural injury, well beyond the population studied in this proposal.

Language impairment, or aphasia, is a common problem after left hemisphere stroke, and causes significant long-term disability. After the initial period of healing, recovery from stroke relies on plasticity in brain networks spared from direct stroke damage. Thus, to improve behavioral and biological treatments for aphasia, we must understand how spared brain structures and connections contribute to recovery. Over a century of research has demonstrated that left hemisphere areas surrounding the stroke and right hemisphere areas symmetric to the normal left hemisphere language network participate in aphasia recovery. However, the mechanisms by which these areas are recruited and their roles in language recovery remain unclear, particularly for the ?right hemisphere language network.? We propose to examine the role of spared brain structures and connections in recovery of core language functions in a large group of left hemisphere stroke survivors and matched controls. The innovative methods address major limitations of prior studies by accounting for individual differences in stroke severity, using task-independent brain structure and connectivity measures, and examining several core language functions as defined by statistical analysis of an extensive behavioral assessment battery. Preliminary studies using this new approach suggest that parts of the right hemisphere language network grow after stroke, and that these changes improve language outcomes. Based on these findings, we hypothesize that recruitment of the right hemisphere language network after left hemisphere stroke compensates for language deficits. We will test this hypothesis against multiple alternative hypotheses, using advanced brain imaging methods to test for effects throughout spared parts of the brain. Analyses will examine how spared brain structures and connections contribute to language recovery, accounting for individual differences in stroke severity. We will additionally test for signs of brain plasticity after stroke and test relationships between stroke location and patterns of brain plasticity to better understand the mechanisms of recovery. New multi- modal analysis methods will integrate the brain structure and connectivity data, providing a more complete picture of recovery of language functions than has been possible before. This research will significantly advance our understanding of the biological basis of aphasia recovery, which will be vital in order to design maximally effective treatments.