Alvaro Pascual-Leone - US grants

Major depressive disorder (MDD) is a greatly debilitating illness affecting a large number of individuals. Cortical and subcortical brain dysfunctions play a role in the pathophysiology of MDD, but the neurophysiology of the regulation of mood in health and disease remains largely unclear. A deeper understanding about the neuroregulation of mood and its dysfunction in depression would help improve treatment of MDD. Currently, treatment of MDD is not always successful and is frequently associated with unpleasant side-effects. The development of a safer therapy for depression, specially for medication-resistant forms, with fewer side-effects would be greatly desirable. In the last few years, several studies suggest that non-invasive, non-convulsive repetitive transcranial magnetic stimulation (rTMS) is a useful tool in the study of the neural organization of mood and emotion in health and disease and furthermore, that rTMS of the left prefrontal cortex has a therapeutic potential in MDD. However, the mechanisms of action of rTMS remain largely unclear and the potential side-effects of this technique have not been systematically explored. We propose the systematic study of the effects on mood and the safety of different rTMS settings. Effects of rTMS in depressed patients and in normal volunteers will be compared in order to enhance our understanding about the neuroregulation of emotion. In depressed patients, the antidepressant effects of rTMS might primarily be due to an increase in left prefrontal cortical activity, thus normalizing the interhemispheric prefrontal activity balance by rather different mechanisms than ECT. This hypothesis will be tested by correlating the mood effects of the different rTMS parameters with their effects onto cortical excitability and regional cortical cerebral blood flow evaluated with single photon emission tomography (SPECT). Studies of the effects of different rTMS parameters on a battery of neuropsychological and neurochemical tests will further illustrate the mechanisms of action of rTMS and address potential side effects. These studies will lead to the development of a safe method of non-convulsive rTMS for MDD, grounded on a deeper understanding of the mechanisms of action of rTMS and the neuroregulation of emotion. In case that the antidepressant effects of rTMS suggested by previous studies are ratified in the present project, this method will then be testable in future studies comparing rTMS with other treatment modalities of depression.

DESCRIPTION (provided by applicant): In our initial funding cycle we compared sighted subjects who were visually deprived for five days with non-visually deprived sighted subjects as they learned tactile Braille character recognition. Serial psychophysics and functional magnetic resonance imaging (fMRI) studies revealed that (1) visually deprived subjects learn tactile Braille reading significantly faster than non-visually deprived sighted subjects; and that (2) learning Braille in visually deprived subjects is associated with activation of occipital visual cortex. Furthermore, we found that auditory information processing can also be associated with activation of the occipital cortex in visually deprived subjects. These results are reminiscent of the findings in early blind subjects in whom the occipital cortex is recruited for tactile Braille reading and auditory processing. However, the rapid time course of our findings in the blindfolded sighted subjects is remarkable and raises questions about its functional significance and underlying mechanisms. The present proposal is designed to address these issues. Visually deprived normal subjects with or without intensity tactile stimulation and Braille teaching will be compared with sighed controls. Comparisons will be made with-in subjects across time and across subjects comparing the different study groups. All subjects will undergo three experiments repeated at various times during the study. First, we will use fMRI of a spatial and a non-spatial visual, tactile and auditory task to reveal information about which specific brain areas are activated in association with a given perceptual operation and sensory modality. We hypothesize that (1) the same occipital areas recruited during visual spatial tasks in sighted subjects will also be recruited, in the visually-deprived state, during auditory and tactile spatial tasks; and (2) the same relation will be true for the non-spatial tasks, but less involvement of the occipital cortex will be noted. Second, transcranial magnetic stimulation (TMS) will be used to provide information about whether and when the contribution of a given cortical region is critical for task performance. We hypothesize that (1) in blindfolded subjects performance in spatial tasks (both tactile or auditory versions) will be disrupted by TMS of the occipital cortex easier than performance in non-spatial tasks; and that (2) the timing of TMS of the occipital cortex for disruption of spatial tactile and auditory tasks will be different. Finally, transcranial stimulation during fMRI will be used to study changes in functional connectivity of the visual cortex that may arise during the visual-deprivation and account for the activation of the visual cortex during tactile and auditory processing. The results will further characterize cross modal plasticity during visual deprivation, and illustrate fundamental aspects of the mechanisms involved in determining cortical functional specificity and those engaged in perceptual representation of the world.

DESCRIPTION (provided by applicant): This K24 Midcareer Investigator Award application outlines a program of patient-oriented research involving the use of transcranial magnetic stimulation (TMS) in the study and modulation of brain plasticity during the acquisition of new skills and the recovery of function after a stroke. The principal investigator, Alvaro PascuaI-Leone, M.D., Ph.D., completed his neurology training in 1990 and a fellowship in human cortical physiology and motor control under the mentorship of Prof. Mark Hallett at the NINDS in 1994. He is an accomplished clinical investigator in the areas of motor learning and brain plasticity and has a proven track record as a mentor for graduate students, fellows, and junior faculty pursuing careers in behavioral neurology related clinical investigation. He has devoted much of his career to the development of TMS as a novel tool for the investigation of brain-behavior relations and a non-invasive method for modulation of cortical brain activity. Since 1999 he is an associate director of the Harvard-Thorndike General Clinical Research Center (GCRC). This application encompassess 6 broad specific aims that address: (1) the role of efferent demand and afferent input on human cortical plasticity in the normal adult; (2) the impact of focal brain injury on motor learning-related adult human cortical plasticity; (3) the modification of brain plasticity and motor learning in the setting of cortico-subcortical pathology; (4) the modulation of brain plasticity by mental imagery; (5) the modulation of brain plasticity by repetitive TMS; and (6) the mechanisms of action of TMS on the brain. Translational efforts combining insights from basic experiment on animal models, computer modelling, neurogenetics, neurohysiology, neuroimaging, cognitive neuroscience, and neurological studies are a cornerstone of these aims that provide different clearly defined paths for fellows and junior faculty to pursue patient-oriented clinical research under the guidance of clinical research and laboratory mentors. Regular meetings with Dr. PascuaI-Leone, multidisciplinary conferences, focused clinical rotations, participation in a clinical investigation course, continuing medical education courses on TMS, and a newly established mentorship program, co-directed by Dr. PascuaI-Leone, will round out the trainees experience. Taken together this work should provide novel insights into strategies to enhance recovery of function after brain injury and, at the same time, provide superb training for the next cadre of clinical investigators who will be counted on to extend this effort.

DESCRIPTION (provided by applicant): This K24 Midcareer Investigator Award application outlines a program of patient-oriented research involving the use of transcranial magnetic stimulation (TMS) in the study and modulation of brain plasticity during the acquisition of new skills and the recovery of function after a stroke. The principal investigator, Alvaro PascuaI-Leone, M.D., Ph.D., completed his neurology training in 1990 and a fellowship in human cortical physiology and motor control under the mentorship of Prof. Mark Hallett at the NINDS in 1994. He is an accomplished clinical investigator in the areas of motor learning and brain plasticity and has a proven track record as a mentor for graduate students, fellows, and junior faculty pursuing careers in behavioral neurology related clinical investigation. He has devoted much of his career to the development of TMS as a novel tool for the investigation of brain-behavior relations and a non-invasive method for modulation of cortical brain activity. Since 1999 he is an associate director of the Harvard-Thorndike General Clinical Research Center (GCRC). This application encompassess 6 broad specific aims that address: (1) the role of efferent demand and afferent input on human cortical plasticity in the normal adult; (2) the impact of focal brain injury on motor learning-related adult human cortical plasticity; (3) the modification of brain plasticity and motor learning in the setting of cortico-subcortical pathology; (4) the modulation of brain plasticity by mental imagery; (5) the modulation of brain plasticity by repetitive TMS; and (6) the mechanisms of action of TMS on the brain. Translational efforts combining insights from basic experiment on animal models, computer modelling, neurogenetics, neurohysiology, neuroimaging, cognitive neuroscience, and neurological studies are a cornerstone of these aims that provide different clearly defined paths for fellows and junior faculty to pursue patient-oriented clinical research under the guidance of clinical research and laboratory mentors. Regular meetings with Dr. PascuaI-Leone, multidisciplinary conferences, focused clinical rotations, participation in a clinical investigation course, continuing medical education courses on TMS, and a newly established mentorship program, co-directed by Dr. PascuaI-Leone, will round out the trainees experience. Taken together this work should provide novel insights into strategies to enhance recovery of function after brain injury and, at the same time, provide superb training for the next cadre of clinical investigators who will be counted on to extend this effort.

DESCRIPTION: State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project. Describe concisely the research design and methods for achieving these goals. Avoid summariesof past accomplishments and the use of the first person. This abstract is meant to serve as a succinct and accurate description of the proposed work when separated from the application. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE PROVIDED. This is a revised submission of a proposal to use psychophysics and brain imaging to investigate the brain activity associated with the processing of environmental visual information presented to the auditory system in blind and sighted individuals. Peter Meijer developed the first camera-based auditory display to preserve a significant amount of environmental visual information in sound, while taking into account the major constraints imposed by both the human auditory system and the frequency-time uncertainty relation (The vOICe, U.S. Patent 5,097,326). The vOICe results in a vision substitution tool for the blind providing a means of presenting live image-to-sound converted scenery and permits the study of cross-modal plasticity. Three groups of subjects will be studied: sighted controls, blind, and sighted-blindfolded subjects,. We will compare results across and within groups before and after training in the use of the image-to-sound conversion system. Training will be conducted daily for four weeks and will combine formal instruction using controlled exercises and more naturalistic, immersive use of the vOICe by the subject while navigating the environment in the laboratory. Three main tasks of decoding and processing visual information by the auditory system will be studied to address: (1) Topographic organization, (2) Mechanisms of object identification, and (3) Object constancy. Behavioral measures, functional magnetic resonance imaging (fMRI), and transcranial magnetic stimulation (TMS) will be used. We expect to find significant differences between the groups of subjects in the behavioral measures and brain activity associated with the processing of image-to-sound converted information. This study will provide critical insights into the mechanisms underlying cross-modal plasticity and processing of environmental spatial visual information presented via the auditory system in blind, as well as about metamodal object and space representation. Image-to-sound conversion may eventually become a suitable prosthesis for the blind. PERFORMANCE SITE(S) (organization, city, state) Beth Israel Deaconess Medical Center KEY PERSONNEL. See instructions. Use continuation pages as neededto provide the required information in the format shown below. Start with Principal Investigator. List all other key personnel in alphabetical order, last namefirst. Name Organization Role on Project Alvaro Pascual-Leone, MD, PhD Beth Israel Deaconess Med Ctr PI Gottfried Schlaug, MD, PhD Beth Israel Deaconess Med Ctr Co-investigator Peter Meijer, PhD Philips Research Consultant Amir Amedi, PhD Beth Israel Deaconess Med Ctr Co-investigator, Post-doc Disclosure Permission Statement. Applicable to SBIR/STTR Only. Seeinstructions. O Yes I I No PHS 398 (Rev. 05/01) Page 2 Number pages consecutively at the bottom throughout Form Page 2 the application. Do not use suffixes such as 2a, 2b. Principal Investigator/Program Director (Last, First, Middle): PASCUAL-LEONE, Alvaro The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT

DESCRIPTION (provided by applicant): Recognizing faces, a critical social skill, is among the most challenging perceptual and memory tasks the human visual system performs. Some patients with cerebral lesions suffer from prosopagnosia, a relatively selective failure to recognize faces. The overall aim of our work is to advance our understanding of the basis of this unusual failure in different patients, both in its functional and anatomic aspects, information that is important also for cognitive theories of normal face processing. We focus on several key issues. First, in some patients the recognition problem is due to a failure to perceive the structure of a face. By using facial stimuli with carefully manipulated changes, we will characterize the type of structural encoding that is lacking. These focus upon theorized distinctions between features, external contour, internal facial geometry, and normative rules of facial structure. We compare these data to parallel studies of normal subjects viewing inverted faces, a maneuver said to disable the normal adult human expertise with faces. Our protocols will address not only what is seen in faces but also how these data are processed in both normal subjects and patients. We will also use non-facial stimuli to determine if the encoding defect is selective for faces or involves other objects, a point of theoretical importance debated in both the patient and functional imaging literature. To clarify the specificity of the perceptual encoding defects in prosopagnosia that we uncover, we perform parallel studies in similar patients with medial occipitotemporal damage but not prosopagnosia. We use both behavioral studies to characterize their function, and functional imaging to characterize the structure-function correlations in both prosopagnosic and non-prosopagnosic controls. Second, we focus on another stage in cognitive models of face processing, facial memories. We use imagery to examine not only the status of facial memories, but the type of facial memories present (feature- or configuration-based). We hypothesize that anterior temporal structures may be critical to this function, and propose a study of patients with temporal lobectomy to address the question of the anatomic correlate of facial memories. Last, we integrate the perceptual and imagery data in prosopagnosia in a study of covert recognition. From our prior work, we hypothesize that covert or unconscious recognition is the residual product of a partially damaged face network in the brain. We propose a functional imaging experiment to test this hypothesis.

Age; Alogia; Alogias; Anepia; Anepias; Aphasia; Aphasia, Broca; Aphasia, Frontocortical; Aphasia, Motor; Aphasia, Nonfluent; Area; Blood flow; Broca Aphasia; CRISP; Computer Retrieval of Information on Scientific Projects Database; Dysphasia, Broca; Enrollment; Functional Magnetic Resonance Imaging; Funding; Grant; Individual; Institution; Investigators; Light; Logagnosia; Logamnesia; Logamnesias; Logasthenia; Logasthenias; MRI, Functional; Magnetic Resonance Imaging, Functional; Motor Cortex; NIH; Names; National Institutes of Health; National Institutes of Health (U.S.); Numbers; Patients; Photoradiation; Population; Purpose; Research; Research Personnel; Research Resources; Researchers; Resources; Source; Speech; Today; United States National Institutes of Health; Verbal Aphasia Syndrome; Week; Work; chronic stroke; enroll; fMRI; improved; interest; new therapeutics; next generation therapeutics; novel therapeutics; repetitive transcranial magnetic stimulation

Address; Area; Brain; Brain region; CRISP; Comprehension; Computer Retrieval of Information on Scientific Projects Database; Disease; Disorder; Encephalon; Encephalons; FLR; Failure (biologic function); Functional Magnetic Resonance Imaging; Funding; Goals; Grant; Institution; Investigators; MRI, Functional; Magnetic Resonance Imaging, Functional; Methods and Techniques; Methods, Other; Modality; Motor; Motor Cortex; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nervous; Nervous System, Brain; Participant; Research; Research Personnel; Research Resources; Researchers; Resources; Sensory; Social isolation; Source; Techniques; Temporal Lobe; Transcranial magnetic stimulation; United States National Institutes of Health; base; developmental disease/disorder; developmental disorder; disability; disease/disorder; fMRI; failure; neural; relating to nervous system; temporal cortex; temporal lobe/cortex

Apoplexy; Brain; CRISP; Cerebral Stroke; Cerebrovascular Apoplexy; Cerebrovascular Stroke; Cerebrovascular accident; Chronic; Clinical Trials; Clinical Trials, Unspecified; Computer Retrieval of Information on Scientific Projects Database; Dose; Encephalon; Encephalons; Frequencies (time pattern); Frequency; Funding; Grant; Hemipareses; Image; Institution; Investigators; Methods; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nervous System, Brain; Patients; Phase; Reporting; Research; Research Personnel; Research Resources; Researchers; Resources; Safety; Site; Source; Stroke; Target Populations; United States National Institutes of Health; Vascular Accident, Brain; brain attack; cerebral vascular accident; chronic stroke; clinical efficacy; clinical investigation; hemiparetic; imaging; motor deficit; repetitive transcranial magnetic stimulation; stroke

Area, Broca; Broca's area; CRISP; Clinical Trials; Clinical Trials, Unspecified; Computer Retrieval of Information on Scientific Projects Database; Controlled Clinical Trials; Cross-Over Studies; Cross-Over Trials; Crossover Studies; Crossover Trials; Funding; Goals; Grant; Institution; Investigators; Language; Middle Inferior Frontal Convolution; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; Neurons; Pars Triangularis; Patients; Phase; Research; Research Personnel; Research Resources; Researchers; Resources; Site; Source; Structure of Broca's area; System; System, LOINC Axis 4; United States National Institutes of Health; Work; aphasic; autism spectrum disorder; base; clinical investigation; improved; neuronal; skills

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).

Long after playing a game of squash or reading this abstract, the memory of playing and reading continues to be processed by the brain. These "off-line" processes improve game performance and understanding of this abstract, and more generally, enhance adaptive behavior. These off-line processes have, for at least the last 100 years, been recognized to play a critical role in determining subsequent recall of facts, events and skills. Yet, the mechanisms engaged to support off-line processing are very poorly understood, and there remains considerable debate over multiple competing models. With support from the National Science Foundation, Dr. Edwin Robertson and colleagues at Harvard Medical School will distinguish amongst these models by determining which brain areas are vital to off-line memory processing over sleep and wakefulness. According to one model, largely supported by functional imaging work, the same brain areas support off-line processing over wakefulness and sleep (Uniform Model). In contrast, recent behavioral studies have shown that different types of processing occur over wakefulness and sleep (Differential Model). Finally, there may be a mixture of these two models with some brain areas being engaged regardless of brain state; whereas others areas may be engaged only over sleep or wakefulness (Hybrid Model). In a set of experiments, Dr. Robertson and colleagues will use Transcranial Magnetic Stimulation (TMS), a non-invasive technique for stimulating small regions of the brain, to establish those brain areas that are critical to off-line processing over wakefulness and sleep. These experiments will reconcile the contrasting perspectives offered by contemporary models and so provide novel insights into off-line processing, which is critical for the retention, and sometimes the enhancement of recently acquired memories.

Work from this project will provide a unified conceptual foundation that bridges the gulf between viewing off-line memory processing as requiring time, independent of brain state (i.e. sleep vs. wakefulness), and the alternative in which brain state alters the mechanisms engaged to support off-line processing. A greater understanding of off-line processing may translate into novel therapeutic strategies to improve the recovery of motor skills lost following brain damage such as a stroke (for example by modulating brain areas or brain states). Funding from this award will strengthen ties across several collaborating laboratories, providing a rich substrate for undergraduate and graduate students' training over a wide selection of disciplines from cognitive psychology to chronobiology.

DESCRIPTION (provided by applicant): Transcranial magnetic stimulation (TMS) to the left dorsal-lateral prefrontal cortex (DLPFC) can be useful in the treatment of depression, and the Neuronetics(R)' Neurostar TMS protocol was approved in October of 2008 by the Food and Drug Administration for therapy of certain forms of medication-resistant depression. However, clinical responses are heterogeneous and effect size can be limited. One factor known to contribute to this response variability is differences in the specific site of stimulation in and around the DLPFC. Recent evidence from our lab suggests that the efficacy of different DLPFC targets is related to the connectivity of each target site with deeper limbic regions, specifically the subgenual cingulate. Based on these findings, we have proposed a novel connectivity-based targeting approach to identify the optimal stimulation site in individual patients to maximize antidepressant response. The goal of this project is to empirically validate this approach in actual patients undergoing TMS for depression. Patients referred for treatment by their psychiatrist and found eligible for the FDA-approved Neurostar TMS protocol will be eligible for the study. Participants will undergo an MRI scan including sequences specific to resting state functional connectivity MRI (rs-fcMRI) prior to a four week TMS treatment course (daily sessions Monday to Friday on four consecutive weeks) using FDA approved parameters. The site of TMS administration in each patient will be defined according to the FDA approved Neurostar protocol, but recorded with a noninvasive stereotactic registration system. Clinical antidepressant response to the TMS treatment paradigm will be assessed using the Hamilton Depression Rating Scale (HDRS). Upon completion of the TMS treatment course, clinical response (change in HDRS) will be evaluated as a function of the functional connectivity of the stimulation site as characterized by rs-fcMRI. Our hypothesis is that patients with better clinical response (greater change in HDRS) will show stronger functional connectivity between the stimulation site and deep limbic regions, especially the subgenual. Further, we hypothesize that patients with better clinical response will show a closer approximation between their actual stimulation site and their optimal stimulation site identified with our connectivity-based targeting technique. Should these hypotheses prove correct, the results would lend important insight into the antidepressant mechanism of TMS in depression and provide the foundation for a larger randomized clinical trial to better individually tailor TMS and thus improve its antidepressant efficacy across patients.

DESCRIPTION (provided by applicant): Neuromodulation using non-invasive stimulation techniques in humans is one of the most promising advances in treatment of neurological damage. While extensive work has been done in developing these techniques for therapy targeting the brain, there has been little emphasis on targeting spinal cord directly. We recently a developed a human repetitive stimulation paradigm to target spinal cord that is safe, effective, well tolerated, and results in lasting spinal excitability enhancement. In a small pilot study we showed that this spinal excitability modulation could be replicated in affected lower limb muscles of chronic spinal cord injury patients. Objective: In the present study we aim to: (1) determine if spinal excitability is raised following spinal associative stimulation (SAS) in a larger sample of SCI patients with lower limb paralysis, (2) examine the time-course of after effects, and (3) establish the functional consequences by measuring the change in voluntary motor activation associated with raised spinal excitability, assessed by the presence of background EMG during attempted muscle contraction. Methods: Since our prior work showed that the excitability modulation is contingent upon the paired technique, and not placebo or peripheral stimulation alone, we will provide the real stimulation paradigm in 30 chronic incomplete SCI patients, using a within subjects, pre-post intervention design. The principal outcome measure will be H-reflex threshold as per our previous work in healthy subjects. We will secondarily examine how the effect changes over time by repeating the baseline measures at 0, 15 and 30 minutes post intervention. We additionally be recording surface EMG during attempted maximal voluntary contractions at each of the time points. We expect that spinal excitability will be raised for at least 15 minutes post intervention, and that voluntary activation may be enhanced in association with heightened excitability. Results/Conclusions: If, as predicted, we establish conclusively that our method termed spinal associative stimulation is effective in SCI patients, this could profoundly influence the field of non-invasive stimulation, and open up the potential for a range of techniques for spinal cord targeting, including down-regulating excitability in the presence of spasticity. Significance: Spinal associative stimulation is the first paired non-invasive technique based on known timing-dependent interactions in spinal networks, to modulate spinal excitability. Further, it is one few techniques in humans, ever developed targeting spinal cord, including invasive stimulation.

DESCRIPTION (provided by applicant): Type 2 Diabetes Mellitus (DM2) is a major cause of disability and death, affecting nearly 26 million people in the US. Nearly three quarters of those affected have DM-related damage to their nervous system that can include behavioral and cognitive deficits, and increase the risk of dementia. We seek to advance our understanding of the neurobiological substrate for these cortical brain consequences of DM2 and develop a reliable assay for their early detection and longitudinal assessment. We hypothesize that cognitive dysfunction in DM2 is associated with alterations in cortical brain plasticity that can b demonstrated by trans-cranial magnetic stimulation (TMS). We propose to apply single- and paired-pulse TMS to evaluate cortical reactivity in individuals with DM2 as compared with matched, healthy controls. Mechanisms of cortical plasticity will be further explored by assessing the modulation of cortical reactivity induced by a specific repetitive TMS protocol known as theta burst stimulation (TBS). The comparison of the motor responses induced by single-pulse TMS before and following TBS provides a noninvasive measure of brain plasticity in humans. Cognitive testing and a motor learning task will be used to demonstrate the behavioral correlates of this measure of plasticity. Magnetic resonance imaging and magnetic resonance spectroscopy will provide further insights into the neurobiological substrates of the neurophysiologic findings. Our pilot studies support the feasibility of our approach and provide supportive evidence for our hypothesis. We thus anticipate that data from the proposed study will address an important need for a rapid, noninvasive, reliable and safe method to diagnose, evaluate and follow cortical brain dysfunction in DM2. If successful, TMS-based measures of cortical reactivity and plasticity will provide a reliable and objective assessment of DM2-associated brain dysfunction, and eventually serve as useful biomarkers to evaluate cognitive dysfunction in DM2, inform the development of effective therapies and assess treatment response in future clinical trials.

DESCRIPTION (provided by applicant): Spinocerebellar ataxia (SCA) refers to a family of genetic diseases that cause progressive problems with gait and balance, as well as other debilitating symptoms. Even though the genes responsible for many of the SCA subtypes are known, and even though we know that they all are associated with damage of the cerebellum and other specific parts of the brain, there is no cure for SCA and we still lack an effective symptomatic treatment. We propose a novel approach using noninvasive transcranial magnetic stimulation (TMS) to improve balance, gait, and posture in patients with SCA. We will recruit 20 patients with genetically-confirmed SCA. Half will be randomly assigned to a real intervention, and half to a sham (i.e., control) intervention. The TMS intervention will consist of 20 stimulatio sessions over a four week period. At baseline and at follow-up, all patients will undergo comprehensive assessments including several SCA rating scales, along with sophisticated tests of balance (i.e., walking, standing and muscle coordination). Patients will also complete a series of neurophysiologic tests to evaluate the function of the cerebellum and its connections before and after the intervention. This will help us test the clinical utility of the intervention and als gain new knowledge about the basis for the disability in SCA. In pilot studies we have shown already that TMS is safe when applied to the cerebellum and that it can improve balance in patients. We now will conduct a more systematic, larger, carefully controlled proof- of-principle clinical trial We anticipate that patients receiving real rTMS will show better balance, fewer falls, and improved mobility while those undergoing sham stimulation will show no benefits. If our prediction is correct, this study will provide evidence-based support for a new treatment to improve the lives of patients with SCA, and the proposed quantitative evaluations will examine possible objective end-points for a future, larger multi-site clinical trial.

DESCRIPTION (provided by applicant): The clinical, social and financial burden of Autism Spectrum Disorders (ASD) is staggering. They are the most prevalent of the developmental disorders and their incidence is rising. However, the ASD phenotype variability is large, and ASD symptoms can manifest over a range of ages and to different degrees. In part for these reasons, the ASD clinical diagnosis is challenging and often is not made until 3-5 years of age. Thus, there remains an unmet need for a valid and reliable endophenotype which would facilitate ASD diagnosis early in life, enable efficient study of ASD risk factors, and eventually serve as a useful biomarker to inform the development of effective therapies and assess treatment response in future clinical trials. The overarching goal of this proposal is to explore te utility of transcranial magnetic stimulation (TMS) measures of brain plasticity as a novel neurophysiologic endophenotype in high- and low-functioning adults and children with ASD. Our work to date demonstrates the potential utility of these measures in higher-functioning adults with ASD, and pilot data support the feasibility and safety of applying the same measures to children and lower functioning individuals in whom the value of such an endophenotype would be particularly high. We thus propose to apply single-pulse TMS to evaluate the modulation in corticospinal reactivity induced by a specific repetitive TMS protocol known as theta burst stimulation (TBS). The comparison of the motor responses induced by single-pulse TMS before and following TBS is a unique noninvasive measure of brain plasticity in humans, and we have found that it shows a reliable abnormality in high-functioning adult individuals with ASD. Our hypothesis is that the alteration of TBS-induced modulation of TMS responses is a common neuropathophysiologic trait that is reliably linked to the ASD phenotype, and that will not be limited to high functioning adults but be also valid in children and low-functioning individuals. W thus anticipate that data from the proposed studies will address an important need for a rapid, noninvasive, reliable and safe endophenotype available to patients with ASD across ages and level of function.

? DESCRIPTION (provided by applicant): The goal of this proposal is to advance our understanding of the neurobiological substrates of mild cognitive impairment (MCI) that may lead to progressive age-related dementias such as Alzheimer's disease (AD), and develop a reliable assay for their early detection and longitudinal assessment. MCI patients who go on to develop AD show evidence of increasing accumulation of amyloid beta (A?) in the brain cortex. We hypothesize that A? toxicity directly impairs mechanisms of plasticity that will be demonstrable by a non-invasive neurophysiologic method and account for cognitive dysfunction. We will evaluate mechanisms of cortical plasticity in individuals with MCI and compare them to an existing cohort of intact healthy controls. Positron emission tomography (PET) imaging will be used to classify MCI individuals as A?+ and A?-. Mechanisms of cortical plasticity will be explored by assessing the modulation of cortical reactivity induced by a specific repetitive transcranial magnetic stimulation (TMS) protocol known as theta burst stimulation (TBS). The comparison of the motor responses induced by single-pulse TMS before and following TBS provides a noninvasive measure of brain plasticity in humans. Cognitive testing and tasks of learning and memory will be used to demonstrate the behavioral correlates of this measure of plasticity. Our pilot studies demonstrate the feasibility of our approach and provide supportive evidence for our hypothesis. We anticipate that data from this study will address an important need for a rapid, noninvasive, reliable, repeatable, and safe method to directly assess the efficacy of neuroplastic mechanisms in MCI. If successful, TMS-based measures of cortical reactivity and plasticity will provide an objective assessment of pathophysiological changes in MCI and may serve as a translatable biomarker to assess cognitive dysfunction in MCI, inform the development of effective therapies and evaluate treatment response in future clinical trials.

Across the world's languages, certain sound combinations occur more frequently than others. However, the basis of these regularities is unknown. Some researchers have suggested that combinations such as "lbog" are rare because they require more complex articulatory gestures than combinations like "blog." Another possibility is that combinations such as "lbog" tend to be avoided because they violate much more abstract linguistic constraints on allowable syllable structures. The investigators will evaluate these possibilities by examining the role of the articulatory motor system in speech perception using both noninvasive brain stimulation and behavioral methods. Clarifying the relative contributions of speech motor processes and linguistic knowledge is critical to the diagnosis and treatment of speech language disorders, to first- and second-language acquisition, and to reading.

This research explores the role of embodiment and abstraction in speech perception. It proposes that speech is represented at multiple levels (embodied phonetics and abstract phonological rules) with different susceptibility to motor simulation, depending on (a) the level of analysis and (b) a speaker's linguistic experience. The proposed experiments test this hypothesis by combining brain stimulation and behavioral experiments. Using MRI-guided Transcranial Magnetic Stimulation (TMS), the research team will disrupt activity in brain regions linked to motor action (the cortical representation of the left orbicularis oris muscle in BA4) and brain regions linked to combinatorial phonological operations (left pars triangularis, PTr, BA 45), and assess the impact on two tasks that rely differentially on phonetic processing or the putatively abstract phonological computation of syllable structure. While it is unlikely that either task or brain region is selective to a single level of analysis, these experiments gauge whether they differ in their degree of participation. If phonetic categorization requires motor simulation, then disruption of BA4 should affect phonetic categorization more than it affects the computation of syllable structure. Alternatively, if the computation of syllable structure relies on disembodied processes effected by the PTr, then the disruption of BA45 should produce a stronger effect on syllable structure than on phonetic categorization. Projects 1 and 2 examine these predictions with speakers of English and Russian (languages that contrast in their syllabic inventory). The group comparison evaluates experience-dependent plasticity or uniformity in the engagement of the motor system across tasks. Projects 3 and 4 suppress articulation mechanically. If the greater contribution of BA4 to phonetic categorization reflects its role in motor simulation, then results from disruption of the orbicularis oris muscle by TMS and mechanical suppression should converge.

ABSTRACT Repetitive Transcranial Magnetic Stimulation (rTMS) is a noninvasive brain stimulation technique capable of modulating activity in the targeted brain region and its connected brain circuits beyond the duration of the stimulation itself. rTMS is utilized in neuroscience research to investigate brain function during human cognition and behavior, and to understand brain pathophysiology in neuropsychiatric diseases. Clinically, rTMS protocols have diagnostic and therapeutic utility across a wide spectrum of disease states, and four rTMS devices are cleared by the Food and Drug Administration (FDA) for treatment of medication-resistant depression. However, the variability of the neuromodulatory effects of rTMS and its sources are ill-defined. This knowledge gap represents a fundamental limitation for both, the interpretation of rTMS results and the design of studies. For example, it is challenging to calculate or assess the sample size for a study, and one cannot optimize rTMS parameters for an individual without knowing whether individual differences in rTMS response are reproducible. In addition, one cannot assume that rTMS protocols tested in motor cortex will produce similar neuromodulatory effects when administered to other brain regions. In this proposal we will use MRI-guided rTMS in combination with EMG, EEG and behavioral measures to characterize the variability of rTMS effects in primary motor cortex (M1) and in dorsolateral prefrontal cortex (DLPFC). In a cohort of 60 subjects, we will evaluate the inter-subject and intra-subject test-retest reliability of the modulatory effects of the most widely used rTMS protocols applied to M1. We will compare the impact of different rTMS protocols on corticospinal excitability (measured via motor-evoked potentials), cortical excitability (measured via simultaneous TMS-EEG), and motor performance (using a sequential finger tapping task). Each subject will undergo a total of 10 TMS-EMG-EEG-behavior sessions, evaluating repeated sessions of excitatory and inhibitory protocols. In a separate cohort of 60 subjects, we will evaluate the transfer of rTMS effects across brain regions by applying 10 Hz rTMS and iTBS to both M1 and DLPFC. Each subject will undergo a total of 10 TMS-EEG-behavior sessions contrasting stimulation protocols across regions (M1 versus DLPFC). All subjects will undergo extensive baseline assessment, including detailed exam, neuropsychological measures, structural and resting-state functional-connectivity MRI, computational modeling, laboratory and genetic testing, and EEG to identify predictors of inter-subject variability in response to rTMS. All data will be placed in a secure repository and made publicly accessible to other investigators. This study will define the reproducibility of the neuromodulatory effects of rTMS, quantifying the intrinsic variability of the method within and across individuals, across levels of analysis (neurophysiologic and behavioral) and brain regions (M1 versus DLPFC). These results will serve as a foundation to guide the planning, development and interpretation of all future studies utilizing rTMS to modulate brain function.

ABSTRACT Repetitive Transcranial Magnetic Stimulation (rTMS) is a noninvasive brain stimulation technique capable of modulating activity in the targeted brain region and its connected brain circuits beyond the duration of the stimulation itself. rTMS is utilized in neuroscience research to investigate brain function during human cognition and behavior, and to understand brain pathophysiology in neuropsychiatric diseases. In patients with Alzheimer's disease (AD) rTMS-driven approaches are being explored as early diagnostic biomarkers, markers of disease progression, and potential therapeutic intervention. However, while there is great promise in these techniques, the variability of the neuromodulatory effects of rTMS and its sources are ill-defined, especially for AD and related dementias. This knowledge gap represents a fundamental limitation for both the interpretation of rTMS results and the design of future studies. For example, it is challenging to calculate or assess the sample size for a study, and one cannot optimize rTMS parameters for an individual without knowing whether individual differences in rTMS response are reproducible. In addition, one cannot assume that rTMS protocols tested in motor cortex will produce similar neuromodulatory effects when administered to other brain regions. We propose to assess the test-retest reliability of the neuromodulatory effects of rTMS in well- cahracterized patients with AD dementia. Mechanisms of cortical plasticity will be explored by assessing the modulation of cortical reactivity induced by a specific rTMS protocol known as intermittent theta burst stimulation (iTBS). The comparison of the motor responses induced by single-pulse TMS before and following iTBS provides a noninvasive measure of the mechanisms of cortical plasticity in humans. We will investigate the efficacy and reliability of this technique first in the motor cortex, where it is best understood, and then apply it to the parietal cortex, which is more directly affected by AD-associated pathology. Our pilot studies demonstrate the feasibility of our approach and provide supportive evidence for our hypothesis that the mechanisms of plasticity are abnormal in AD and rTMS measures offer reliable and valuable biomarkers. All subjects will undergo extensive baseline assessment, including detailed exam, neuropsychological measures, structural and resting-state functional-connectivity MRI, computational modeling, laboratory and genetic testing, and EEG to identify predictors of inter-subject variability in response to rTMS. All data will be placed in a secure repository and made publicly accessible to other investigators This study will define the reproducibility of the neuromodulatory effects of rTMS, quantifying the intrinsic variability of the method within and across individuals, across modes of assessment (electromyography versus electroencephalography) and brain regions (motor versus parietal). These results will serve as a foundation to guide the planning, development and interpretation of all future studies utilizing rTMS to modulate brain function in both healthy aging and dementia.

PROJECT SUMMARY Deep brain stimulation (DBS) has had great impact, helping patients with disorders such as Parkinson's disease and obsessive?compulsive disorder (OCD), and with great potential for other disorders such as depression and Alzheimer's disease. DBS, being a surgical procedure, bears the potential for complications that limit its deployment and adoption. Transient non-invasive brain stimulation methods, such as transcranial magnetic stimulation (TMS) and transcranial current stimulation (tCS), also show therapeutic potential and have been used in many human clinical and neuroscientific investigations, but they fail to achieve focality at depth. In a paper we recently published in Cell, we reported the initial stages of development of a non-invasive, steerable, 3D focal brain stimulation method that has the potential in the future to transform the risk-benefit ratio for DBS by providing an alternative without the need for surgery, as well as to improve the precision of other non-invasive methods such as TMS or tCS. We showed that by delivering two electric fields at slightly different carrier frequencies, which are themselves too high to recruit effective neural firing but for which the offset frequency is low enough to drive neural activity, we can create an electric field envelope at the offset frequency. We found that this low-frequency modulated electric field can cause neurons to be electrically activated at a deep focus, without driving neighboring, or overlying, brain regions. We now propose to refine this technology for multiple clinically relevant targets and collaboratively deploy them into several relevant settings, including the demonstration of early human translation assessing feasibility, safety, steerability, and depth selectivity. Specifically, we will (Aim 1) optimize TI stimulation for three targets of clinical interest, basal forebrain, central thalamus, and visual cortex, for investigation in humans and mice; (Aim 2) translate TI stimulation to human and demonstrate safety, steerable precision, and depth selectivity; (Aim 3) develop TI implementations of anesthesia, in rodent models. In this way we will deliver to the clinical community a technology ready for clinical trials in a diversity of clinical contexts.

ABSTRACT Delirium is a common and costly problem, affecting up to half of hospitalized older adults, and resulting in substantial morbidity, cognitive decline, loss of functional independence, and increased mortality. Delirium is particularly problematic in patients with Alzheimer's dementia who have an increased risk for delirium, and in whom delirium accelerates the rate of cognitive decline. However, our understanding of the neurological basis of the risk for and effects of delirium in a given individual remains very limited. This project seeks to address this important knowledge gap by utilizing magnetic resonance imaging (MRI)-guided (neuronavigated) transcranial magnetic stimulation (TMS) with simultaneous electroencephalography (EEG) and electromyography (EMG) to evaluate cortical function in patients undergoing elective surgery. In a prospective cohort of 180 patients we will examine whether decreased brain network connectivity and altered mechanisms of cortical plasticity as characterized by TMS-EEG-EMG are associated with the risk of developing post-operative delirium. We will record TMS-evoked potentials (TEP) from dorsolateral prefrontal cortex, inferior parietal lobule, and primary motor cortex, before and after intermittent theta-burst stimulation (iTBS). We hypothesize that baseline EEG spectral power and connectivity, TMS-based measures of cortical reactivity and connectivity, and iTBS measures of cortical plasticity will be decreased in patients who subsequently develop delirium, and that patients with greater abnormalities in EEG features and TMS measures at baseline will have greater delirium severity and greater short-term cognitive decline after an episode of delirium. We will correlate neurophysiologic measures with changes in cognitive performance and subsequent cognitive decline in patients with versus without delirium. We hypothesize that EEG alpha power and connectivity, TMS reactivity, TEP cortical connectivity, and efficacy of the mechanisms of cortical plasticity will show greater decreases in patients with delirium than in those without, and will correlate with the magnitude of cognitive decline. Finally, in patients with a previously observed episode of delirium (in SAGES I) we will compare those with and without a history of delirium, and hypothesize that cortical physiology abnormalities will correlate with long-term cognitive decline after delirium (complicated delirium). Ultimately, our results will define neurophysiologic characteristics that can identify individuals with a vulnerable brain susceptible to delirium and subsequent cognitive decline, will provide novel tools to efficiently assess the effectiveness of interventions to help increase individual cerebral resilience and reduce the risk of delirium, and will guide development of therapeutic interventions to help normalize cerebral dysfunction and minimize long-term cognitive decline after delirium.