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）：正如人类参与者的非侵入性磁共振成像（MRI）所证明的那样，早期失明会导致大脑的结构和功能改变。虽然我们的初步研究重复了这一发现，即盲人参与者在其“视觉”皮层内产生跨模式反应（即对听觉刺激的激活），并改变了皮层结构（即视觉皮层白质萎缩和白质破坏）。沿光辐射的物质纤维相干性），我们还发现这些测量值在盲区中存在巨大的变异性。这种变异性是系统性的，在功能测量（即枕叶协变中的静息血流与跨模式反应）和结构测量（视辐射干扰与视觉皮层萎缩相关）内，盲人受试者之间具有很强的相关性，但低结构和功能测量之间的相关性。因此，视觉通路的不同改变可能取决于个体的临床特征，包括失明的发病年龄、失明的严重程度、视力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最有可能在眼科治疗后恢复有用视力的患者，类似于治疗耳聋的人工耳蜗植入经验（HJ Lee 等，2007）。最近的治疗发展旨在逆转先天性失明（即针对 Leber 先天性黑蒙 2，LCA 的靶向基因治疗；Cideciyan 等人，2008 年；Maguire 等人，2008 年）和后天性失明（即植入视网膜芯片以治疗与年龄相关的失明）黄斑变性；Thanos 等，2007）。最近，我们已经证明，在 LCA 犬模型中进行基因治疗会导致治疗后皮质对视觉刺激的反应增加（Aguirre 等，2007）。一个重要的转化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。我们将从完全失明和不完全失明的不同人群中获得一些 MRI 测量结果。这些测量将是结构性的（皮质灰质厚度和白质体积；通过扩散张量成像的白质相干性）和功能性的（静息脑灌注；听觉刺激的跨模式激活；静息态连接；标准化亮度调制的激活））。我们将检验这样一个假设：某些改变在受试者之间聚集在一起，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。在因 RPE65-LCA 失明的患者群体中，我们将进一步确定哪些措施可以通过成功的视网膜基因治疗进行修改以恢复视力，以及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以及皮质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中的大脑可塑性。我们的结果将对失明的治疗具有直接的转化价值，无论是在制定失明补偿策略还是指导眼科治疗的临床试验方面。