Quantitative Electrophysiology to Link Neuroplasticity, Brain State, and Behavioral Change in Human Visual Cortex - PROJECT SUMMARY / ABSTRACT Rehabilitation of central visual disorders like amblyopia and cortical visual impairment depends on synaptic plasticity, the changes in synaptic connections between neurons in the brain. A major regulator of synaptic plas- ticity is brain state - the moment-to-moment fluctuations in attention, arousal, emotions and other factors sep- arate from the actual content of experience - but brain states are generally left uncontrolled in treatment. Con- trolling brain state may be particularly important for brain stimulation therapies like repetitive transcranial mag- netic stimulation (rTMS), which mediate their effect through induction of neuroplasticity. The goal of this re- search proposal is to explore how attentional state - an experimentally tractable, well-understood, and disease- relevant brain state mechanism - regulates rTMS-induced neuroplasticity to the human visual cortex (Aim 1) and frontal eye fields (FEF, Aim 2). Changes in the steady-state visual evoked potential (ssVEP) contrast-response function following rTMS provide a high signal-to-noise neural readout of visual cortical neuroplasticity, while changes in psychophysical contrast discrimination sensitivity provides a perceptual readout of plasticity. During rTMS, subjects will orient attention to either the same or opposite retinotopic visual field to which rTMS is tar- geted, to determine how attentional state affects the propensity of rTMS to induce neuroplasticity. Powerful quantitative linking models will then be used to link rTMS-induced neural changes to perceptual changes, and to determine which neural changes most contribute to behavioral change (Aim 3). These experiments will pro- vide novel evidence that attentional state controls the neuroplasticity effects of brain stimulation. Moreover, they will help identify the cortical circuit mechanisms that are affected by rTMS and which of these mechanisms are most determinative of behavioral change following rTMS. Together this provides fundamental knowledge in hu- man visual cortical plasticity addressing NEI’s Area of Emphasis Biology and Neuroscience of Vision, and will inform the development of brain state control paradigms to augment the efficacy of rehabilitative neuromodula- tion therapies for visual disorders including hemineglect, cerebral scotoma, and amblyopia, in line with NEI’s core programs on Strabismus/Amblyopia/Visual Processing and Low Vision/Blindness Rehabilitation. In the process, the candidate will expand upon his background in in vivo synaptic plasticity and optical physiology in autism animal models to gain expertise in core methods of human neuroscience including rTMS, MRI, EEG, visual spatial attention paradigms, and computational modeling, learning from Stanford mentors who are au- thorities in these techniques (Dr. Nolan Williams, Dr. Tony Norcia, and Dr. Justin Gardner). He will take full advantage of Stanford’s vibrant intellectual environment, interacting with clinicians and researchers to bridge the gap between basic neuroscience bench and the clinic bedside. This training will allow the candidate to estab- lish a unique research niche at the interface of neuromodulation, neuroplasticity, and brain states and eventually lead a translational program to implement neuromodulation-assisted behavioral and rehabilitation therapies.
