Variability of Brain Reorganization in Blindness - PROJECT SUMMARY Severe vision loss affects ~40 million people worldwide1 and more as the population ages3. The success of sight restoration and use of sensory aids for blind individuals depends on poorly-understood factors: some people do not gain functional sight despite invasive procedures37-40. Mitigating this problem requires mapping the impacts of reduced vision on the brain, which may preclude rehabilitation efforts. Following early-onset blindness, the visual cortex (VC) undergoes plastic reorganization4-6,14,17 that may crucially affect its capacity to process restored vision and employ compensatory strategies24. However, little effort has been made to understand the variability of brain reorganization across blind individuals and its implications for sight restoration and compensatory abilities. Contributing to improved individually-tailored visual rehabilitation, we propose to study multi-scale variability in the brains of blind individuals using temporal, neurochemical, and spatial analyses of neuroimaging and behavioral data. First, we will study if the blind VC retains a higher-than-typical plasticity potential with neurochemical and temporal dynamics fMRI measures. Since visual experience in early development facilitates VC stabilization42,79, and short-term dark exposure elicits plasticity41,80,81, we predict sustained plasticity in blind individuals. This would clarify mechanisms of brain maturation and the potential to harness and revive adult plasticity for rehabilitation. Second, we will investigate how visual experience affects individual differences in brain development, testing if blindness results in more variable brain organization. Assessing brain-wide connections of the blind VC and its atypical responses to non-visual tasks, we will test if VC plasticity affords more variable outcomes which can explain contradictory group-level findings about VC role in blindness. We will examine the pattern of VC compensatory engagement in blindness, testing whether plasticity in blindness can change typical VC sensory functions for higher- level cognitive roles or if it is restricted by neuroanatomical limitations, clarifying the capacity for plasticity in the human brain. Finally, we will determine if VC has a single consistent role in all blind individuals or if distinct individual patterns emerge, patterns that could be employed for individualized rehabilitation. We will examine whether unique and longitudinally-stable whole-brain patterns of plasticity relate to compensatory behavioral abilities in blind individuals for touch82-84, hearing63,85-87, memory88-92 and language93,94 and to VC non-visual recruitment. We will further use such individual plasticity patterns to predict which blind individuals may benefit from a sensory aid (sensory substitution), revealing if different subtypes of plasticity can indicate behavioral capacities across individuals and be employed as rehabilitation biomarkers. Overall, this project will improve our understanding of brain plasticity principles in blindness, and open a path to defining biomarkers for personalized treatments for visual impairment.