Cortical Structure and Function in Blindness and following Restored Vision

失明和视力恢复后的皮质结构和功能

• 批准号: 8041648
• 负责人: Geoffrey Karl Aguirre
• 金额: $ 40万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8041648
• 关键词: Acoustic Stimulation; Adult; Aftercare; Age; Age of Onset; Age related macular degeneration; Animal Model; Anisotropy; Area; Atrophic; Auditory; Automobile Driving; Behavioral Genetics; Blindness; Blood flow; Brain; Brain imaging; Brain-Derived Neurotrophic Factor; Canis familiaris; Cerebrum; Childhood; Classification; Clinical; Clinical Trials; Cochlear Implants; Comprehension; Data; Data Collection; Development; Diagnostic; Diffusion Magnetic Resonance Imaging; Factor Analysis; Fiber; Financial compensation; Functional Magnetic Resonance Imaging; Gene Transfer; Genetic; Genetic Polymorphism; Human; Hypertrophy; Image; Implant; Individual; Knowledge; Language; Leber' s amaurosis; Light; Magnetic Resonance Imaging; Measures; Modeling; Nature; Neuronal Plasticity; Occipital lobe; Optics; Outcome Measure; Participant; Patient Selection; Patients; Perfusion; Photic Stimulation; Population; Population Heterogeneity; Predictive Value of Tests; Protocols documentation; RPE65 protein; Radiation; Reading; Recording of previous events; Recovery; Recovery of Function; Rest; Retinal; Retinal Degeneration; Sensory; Severities; Somatic Cell; Structure; Testing; Thick; Variant; Vision; Visual; Visual Cortex; Visual Pathways; Visual impairment; Visually Impaired Persons; Work; area V1; auditory stimulus; base; blind; braille; deafness; experience; functional outcomes; gene therapy; gray matter; luminance; member; patient population; prognostic; response; restoration; skills; therapeutic development; visual deprivation; visual stimulus; visual threshold; white matter; young adult

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：早期失明导致大脑的结构和功能改变，如人类参与者的非侵入性磁共振成像（MRI）所示。虽然我们的初步研究重复了盲人参与者在他们的“视觉”皮层（即，对听觉刺激的激活），并且具有改变的皮层结构（即，视觉皮层白色物质的萎缩和沿着视辐射的白色物质纤维相干性的破坏），我们还发现在这些测量中盲人之间存在巨大的差异。这种变异性是系统性的，在功能测量中，盲受试者之间具有很强的相关性（即，枕叶中的静息血流与交叉模态响应相关）和结构测量（视辐射破坏与视皮层萎缩相关）内，但结构和功能测量之间的相关性较低。因此，视觉通路的不同改变可能取决于个体的临床特征，包括失明开始时的年龄、失明的严重程度、视力丧失的速度和代偿能力的发展（例如，盲文阅读）。了解这些形式的神经可塑性可以指导选择最有可能在眼科治疗后恢复有用视力的患者，类似于用于治疗耳聋的耳蜗植入经验（HJ Lee等人，2007年）。 最近的治疗发展旨在逆转先天性失明（即，Leber先天性黑蒙的靶向基因治疗2，LCA; Cideciyan等，2008; Maguire等人，2008）和收购（即，用于年龄相关性黄斑变性的植入视网膜芯片; Thanos等，2007年）。最近，我们已经证明，在LCA的犬模型中的基因治疗导致治疗后对视觉刺激的皮质反应增加（Aguirre等人，2007年）。一个重要的翻译问题是，大脑结构和功能的特定改变是否可以预测眼科治疗后皮质反应和有用视力的恢复。 我们将从完全和不完全失明的不同人群中获得几项MRI测量结果。这些测量将是结构性的（皮质灰质厚度和白色物质体积;通过扩散张量成像的白色物质相干性）和功能性的（静息脑灌注;听觉刺激的跨模态激活;静息状态连接;标准化亮度调制的激活）。我们将检验这样的假设，即某些改变在受试者中聚集在一起，并且这些改变反过来与每个患者视力丧失临床史的个体特征相关。在RPE 65-LCA失明患者人群中，我们将进一步确定这些措施中的哪些被成功的视网膜基因治疗修改以恢复视力，以及哪些措施可预测功能结果。这些研究将通过确定临床病史和皮层区域连接和功能相互作用的决定因素，系统地阐明视力丧失的大脑可塑性。我们的研究结果将对失明的治疗具有直接的转化价值，无论是在盲人补偿策略的制定还是在眼科治疗临床试验的指导方面。 公共卫生相关性：作为对早期视力丧失的反应，大脑的视觉通路发生了结构和功能的变化，这可能是补偿性非视觉技能的基础。我们将研究这些变化是如何相互关联的，以及它们与一组盲人参与者视力丧失的性质和历史的关系。一组参与者将在视网膜基因治疗前后进行研究，并确定治疗前大脑测量预测恢复视觉功能的能力。