Early blindness leads to structural and functional alteration of the brain, as demonstrated with non-invasive, magnetic resonance imaging (MRI) in human participants. While our preliminary studies replicate the finding that blind participants develop cross-modal responses within their """"""""visual"""""""" cortex (i.e., activation to an auditory stimulus), and have altered cortical structure (i.e., atrophy of the visual cortex white matter and disruption of white matter fiber coherence along the optic radiations), we also find enormous variability across the blind in these measures. This variability is systematic, with a strong correlation across blind subjects within functional measures (i.e., resting blood flow in the occipital lobe covaries with cross-modal responses) and within structural measures (optic radiation disruption correlates with visual cortex atrophy), but a low correlation between structural and functional measures. Different alterations in the visual pathway may therefore depend upon individual clinical features, including age at onset of blindness, severity of blindness, rapidity of visual loss, and development of compensatory abilities (e.g., Braille reading). Understanding these forms of neural plasticity could guide selection of patients most likely to regain useful vision following ophthalmologic treatment, similar to cochlear implant experience for treatment of deafness (HJ Lee et al., 2007). Recent therapeutic developments aim to reverse blindness that is congenital (i.e., targeted gene therapy for Leber's congenital amaurosis 2, LCA;Cideciyan et al., 2008;Maguire et al., 2008) and acquired (i.e., implanted retinal chip for age-related macular degeneration;Thanos et al., 2007). Recently, we have demonstrated that gene therapy in a canine model of LCA leads to increased cortical responses to visual stimuli after treatment (Aguirre et al., 2007). An important translational question is whether specific alterations of brain structure and function can predict restoration of cortical responses and useful vision following ophthalmologic treatment. We will obtain several MRI measures from a diverse population of both completely and incompletely blind individuals. These measures will be both structural (cortical gray matter thickness and white matter volume;white matter coherence by diffusion tensor imaging) and functional (resting cerebral perfusion;cross-modal activation to auditory stimulation;resting-state connectivity;activation to a standardized luminance modulation). We will test the hypothesis that certain alterations cluster together across subjects, and that these alterations are in turn related to individual features of the clinical history of vision loss in each patient. In a population of patients with blindness from RPE65-LCA, we will further determine which of these measures are modified by successful retinal gene therapy to restore vision, and which measures are predictive of functional outcome. The studies will systemically elucidate brain plasticity in vision loss by identifying the determinant factors both of clinical history and from the interplay of regional connectivity and function in the cortex. Our results will have direct translational value for the treatment of blindness, both in the development of compensatory strategies for the blind and for the guidance of clinical trials for ophthalmologic therapy.

Public Health Relevance

In response to early visual loss, both structural and functional changes occur in the brain's visual pathways, which may be the basis for compensatory nonvisual skills. We will examine how these changes are related to each other and to the nature and history of vision loss across a group of blind, human participants. One group of participants will be studied before and after retinal gene-therapy, and the ability of pre-treatment brain measures to predict recovered visual function will be determined.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY020516-02
Application #
8213506
Study Section
Central Visual Processing Study Section (CVP)
Program Officer
Wiggs, Cheri
Project Start
2011-02-01
Project End
2016-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
2
Fiscal Year
2012
Total Cost
$400,000
Indirect Cost
$150,000
Name
University of Pennsylvania
Department
Neurology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Aguirre, Geoffrey K; Butt, Omar H; Datta, Ritobrato et al. (2017) Postretinal Structure and Function in Severe Congenital Photoreceptor Blindness Caused by Mutations in the GUCY2D Gene. Invest Ophthalmol Vis Sci 58:959-973
Spitschan, Manuel; Lucas, Robert J; Brown, Timothy M (2017) Chromatic clocks: Color opponency in non-image-forming visual function. Neurosci Biobehav Rev 78:24-33
Aguirre, Geoffrey K; Datta, Ritobrato; Benson, Noah C et al. (2016) Patterns of Individual Variation in Visual Pathway Structure and Function in the Sighted and Blind. PLoS One 11:e0164677
Emerit, Michel Boris; Baranowski, Camille; Diaz, Jorge et al. (2016) A New Mechanism of Receptor Targeting by Interaction between Two Classes of Ligand-Gated Ion Channels. J Neurosci 36:1456-70
Spitschan, Manuel; Datta, Ritobrato; Stern, Andrew M et al. (2016) Human Visual Cortex Responses to Rapid Cone and Melanopsin-Directed Flicker. J Neurosci 36:1471-82
Downs, Louise M; Scott, Erin M; Cideciyan, Artur V et al. (2016) Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused by NPHP5 mutation. Hum Mol Genet 25:4211-4226
Butt, Omar H; Benson, Noah C; Datta, Ritobrato et al. (2015) Hierarchical and homotopic correlations of spontaneous neural activity within the visual cortex of the sighted and blind. Front Hum Neurosci 9:25
Spitschan, Manuel; Aguirre, Geoffrey K; Brainard, David H (2015) Selective stimulation of penumbral cones reveals perception in the shadow of retinal blood vessels. PLoS One 10:e0124328
Spitschan, Manuel; Jain, Sandeep; Brainard, David H et al. (2014) Opponent melanopsin and S-cone signals in the human pupillary light response. Proc Natl Acad Sci U S A 111:15568-72
Benson, Noah C; Butt, Omar H; Brainard, David H et al. (2014) Correction of distortion in flattened representations of the cortical surface allows prediction of V1-V3 functional organization from anatomy. PLoS Comput Biol 10:e1003538

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