Cortical Structure and Function in Blindness and following Restored Vision

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，通过对人类参与者的非侵入性磁共振成像（MRI）证实。虽然我们的初步研究重复了盲人参与者在他们的“视觉”皮层中产生跨模态反应（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纤维沿光学辐射的相干性破坏）的发现，但我们也发现这些测量中盲人之间存在巨大的差异。这种可变性是系统性的，在功能测量（即枕叶静息血流量与跨模态反应共变）和结构测量（视光辐射干扰与视觉皮层萎缩相关）中，盲人受试者之间存在很强的相关性，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，包括失明的发病年龄、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，类似于耳蜗植入治疗耳聋的经验（HJ Lee等，2007）。最近的治疗进展旨在逆转先天性失明（即针对Leber氏先天性黑内障的靶向基因治疗2，LCA； Cideciyan等人，2008；Maguire等人，2008）和获得性失明（即针对年龄相关性黄斑变性植入视网膜芯片；Thanos等人，2007）。最近，我们已经证明，在犬LCA模型中，基因治疗导致治疗后皮质对视觉刺激的反应增加（Aguirre等人，2007）。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层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几项MRI测量。这些测量将是结构性的（皮质灰质厚度和白质体积；扩散张量成像的白质一致性）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）。我们将检验这样一个假设，即某些改变在受试者中聚集在一起，这些改变反过来又与每个患者视力丧失的临床病史的个体特征相关。在RPE65-LCA致盲患者群体中，我们将进一步确定哪些措施通过成功的视网膜基因治疗来改变以恢复视力，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和区域连接与皮质功能的相互作用的决定因素，系统地阐明视力丧失的大脑可塑性。我们的结果将对失明的治疗具有直接的转化价值，无论是在盲人代偿策略的发展，还是对眼科治疗的临床试验的指导。

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.