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

基本信息

批准号：
8792218
负责人：
Geoffrey Karl Aguirre
金额：
$ 39.2万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8792218
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 Health Human Hypertrophy Image Individual Knowledge Language Leber&apos 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 prognostic value response restoration retina implantation skills therapeutic development visual deprivation visual stimulus visual threshold white matter young adult

项目摘要

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.

描述（由申请人提供）：早期失明会导致大脑的结构和功能改变，如人参与者中无创，磁共振成像（MRI）所证明的那样。虽然我们的初步研究复制了盲人参与者在其“视觉”皮层中产生交叉模式反应的发现（即激活听觉刺激），并改变了皮质结构（即视觉皮层白质的萎缩，白质纤维的萎缩，并且沿光辐射的白质纤维相干性破坏），我们还会发现彼此的衡量标准范围内的可变性。这种可变性是系统的，在功能措施（即，具有跨模式反应的静止血流）和结构测量中（视觉辐射干扰与视觉皮层萎缩相关）之间的静止受试者之间的相关性很强。因此，视觉途径的不同变化可能取决于单个临床特征，包括失明的年龄，失明的严重程度，视觉丧失的速度以及补偿能力的发展（例如盲文阅读）。了解这些形式的神经可塑性可以指导选择在眼科治疗后最有可能恢复有用视力的患者的选择，类似于耳蜗植入的聋哑治疗经验（HJ Lee等，2007）。最近的治疗发展旨在逆转过先天性（即，对Leber先天性amaurosis的靶向基因治疗2，LCA； Cideciyan等，2008; Maguire等，2008），并获得（即，年龄相关的巨质质量变性的视网膜碎片）。最近，我们证明了LCA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，2007）。一个重要的翻译问题是，在眼科处理后，大脑结构和功能的特定变化是否可以预测皮质反应的恢复和有用的视力。我们将从完全和不完全盲人的不同人群中获得几项MRI措施。这些措施将既是结构性的（皮质灰质厚度和白质体积；通过扩散张量成像的白质连贯性）和功能（静息脑灌注；跨模式激活听觉刺激；静息状态；静止状态；激活标准化的亮度调节）。我们将测试以下假设：某些改变跨受试者聚集在一起，并且这些改变反过来又与每个患者视力丧失的个体特征有关。在RPE65-LCA失明的患者中，我们将进一步确定成功的视网膜基因治疗以恢复视力的修改，哪些措施可以预测功能结果。这些研究将通过确定临床病史的决定因素以及从皮质中的区域连通性和功能的相互作用来系统地阐明视力丧失的大脑可塑性。我们的结果将在盲目的补偿策略发展以及针对眼科治疗的临床试验的指导下，具有直接的翻译价值来治疗失明。