This is a resubmitted application for Mentored Patient-Oriented Research Career Development Award (K23). The overall goal of this research is to understand how we perceive body orientation relative to our external environment, and how these perceptions become distorted and disorienting to patients with vestibular disease. The vestibular system provides a strong independent source of information about head orientation relative to gravity and plays a key role in spatial orientation. In humans, the function(s) of the many areas of the cerebral cortex that have access to and process information from the vestibular system are largely unknown. This project is based on a compelling preliminary finding that shows a small region of parietal cortex (SMGp) plays a central role in the accurate perception of one's sense of upright. This result suggests a more general function for this area;taking disparate information from visual, vestibular and proprioceptive sensors, which are inherently received and processed in different coordinate frames, and then integrating them into a coherent spatial orientation. Such a mechanism is an absolute requirement for successful motor responses to the changing demands of one's environment.
The specific aims of this research project are to 1) study further the functional role of the SMGp in spatial orientation by systematic approach to different sensory modalities that contribute to upright perception ( i.e., using a functional model of spatial orientation) 2) probe the function of the corresponding area within the left hemisphere in upright perception 3) address whether the focal effect of TMS can modify perceptual adaptation of the sense of uprightness, as a potential treatment modality. Candidate: Amir Kheradmand is shortly to be an Assistant Professor in the Departments of Neurology and Otolaryngology at the Johns Hopkins Hospital. He earned an M.D. at the Tehran University of Medical Sciences in 2003 and completed residency training in Neurology at the University of Massachusetts in 2010. As a two-year postdoctoral fellow he has been studying the mechanisms involved in perception of upright with the emphasis on the functional role of the cerebral cortex in processing of inputs from the vestibular system. This work has been primarily under the mentorship of Dr. Zee and it was supported by an NIH training grant through the Johns Hopkins Center for Hearing and Balance and the Department of Biomedical Engineering. Dr. Kheradmand's short term goals in research are to 1) learn techniques for experiment design and data analysis in the psychophysics of perception, 2) learn Bayesian statistics, analysis and modeling to apply to the functional model of spatial orientation, and 3) gain more practical knowledge in using transcranial magnetic stimulation, and in the clinic, to gain experience in the neurophysiological techniques of clinical neurotology. His long term goal is to become an independent investigator in the field of vestibular perception and accomplished academic neurotologist. Environment: The investigations described in this proposal will be performed in the Vestibular/Eye Movement Laboratory, directed by Dr. Zee, in the Neurology Department at Johns Hopkins Hospital. A team of mentors and advisers (Dr. David Zee, Dr. Mark Shelhamer, Dr. John Carey, Dr. Pablo Celnik, and Dr. Dora Angelaki) from across departments and institutions will provide mentorship and oversee timely achievement of the stated goals in this proposal. All mentors are leaders in their respective fields and have a strong track record of mentoring young investigators to independence. Necessary equipment, software and engineering support are readily available to Dr. Kheradmand through the Vestibular/Eye Movement Laboratory. Research: The series of hypotheses and experiments proposed in this project provide a unique opportunity not only to explore how the brain creates the fundamental perception of upright, but also to suggest treatments for the disabling symptoms in patients with dizziness, imbalance and spatial disorientation. Through the research experience acquired by this work, intensive mentoring, and didactic activities, this K23 career development award will allow the primary investigator, Dr. Amir Kheradmand, to become an independent investigator conducting translational research in the field of vestibular physiology.

Public Health Relevance

Dizziness and imbalance are among the most common medical symptoms reported in general practice, accounting for 3-6% of visits across frontline healthcare settings. Many patients, who have had a vestibular disturbance, are left with persistent dizziness, unusual sensitivity to head motion or visual stimuli or sudden feelings of motion or unsteadiness, and falls. The aim of this study is to address the role of the vestibular system in spatial orientation and its function at the perceptual level to devise new treatment strategies for the incapacitating symptoms of patients with chronic dizziness and imbalance.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Mentored Patient-Oriented Research Career Development Award (K23)
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Communication Disorders Review Committee (CDRC)
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Sklare, Dan
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Johns Hopkins University
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Winnick, Ariel; Sadeghpour, Shirin; Otero-Millan, Jorge et al. (2018) Errors of Upright Perception in Patients With Vestibular Migraine. Front Neurol 9:892
Otero-Millan, Jorge; Winnick, Ariel; Kheradmand, Amir (2018) Exploring the Role of Temporoparietal Cortex in Upright Perception and the Link With Torsional Eye Position. Front Neurol 9:192
Kheradmand, Amir; Winnick, Ariel (2017) Perception of Upright: Multisensory Convergence and the Role of Temporo-Parietal Cortex. Front Neurol 8:552
Otero-Millan, Jorge; TreviƱo, Carolina; Winnick, Ariel et al. (2017) The video ocular counter-roll (vOCR): a clinical test to detect loss of otolith-ocular function. Acta Otolaryngol 137:593-597
Otero-Millan, Jorge; Kheradmand, Amir (2016) Upright Perception and Ocular Torsion Change Independently during Head Tilt. Front Hum Neurosci 10:573
Kheradmand, Amir; Gonzalez, Grisel; Otero-Millan, Jorge et al. (2016) Visual perception of upright: Head tilt, visual errors and viewing eye. J Vestib Res 25:201-9
Otero-Millan, Jorge; Roberts, Dale C; Lasker, Adrian et al. (2015) Knowing what the brain is seeing in three dimensions: A novel, noninvasive, sensitive, accurate, and low-noise technique for measuring ocular torsion. J Vis 15:11
Kheradmand, Amir; Lasker, Adrian; Zee, David S (2015) Transcranial magnetic stimulation (TMS) of the supramarginal gyrus: a window to perception of upright. Cereb Cortex 25:765-71