遺傳性視網膜疾病（inherited retinal diseases， IRDs）在臨床表現與基因型上皆具高度異質性，而病灶的空間分布往往決定了全視野視網膜電圖（full-field electroretinogram， ffERG）能否偵測到病變。廣泛性退化會反映在整體的全視野訊號中，局部性的黃斑部失養症（macular dystrophy， MD）卻常被掩蓋，因為病變的黃斑部僅佔整體反應的一小部分，而此反應主要由健康的周邊視網膜所主導。本研究旨在探討：ffERG 傳統上以能量為基礎的判讀所遺漏的訊息，是否能藉由非線性、非定態的調變分析加以還原，並特別著重於黃斑部失養症。 本研究使用取自國立臺灣大學醫學院附設醫院門診病患、經去識別化的 ffERG 臨床紀錄，共 174 位病患、188 筆檢查，涵蓋七個臨床分組：健康對照組、黃斑部失養症、熄滅型（flat）ERG、錐桿細胞失養症、Bietti 結晶樣視網膜失養症，以及典型與中心周圍型色素性視網膜炎。每筆反應皆在五種 ISCEV 標準刺激條件下記錄，並以改良式完整集成經驗模態分解（ICEEMDAN）進行分解，再以希爾伯特—黃轉換（HHT）、振幅與頻率調變之全希爾伯特頻譜分析（HHSA-AM、HHSA-FM）及內在事件相關電位（iERP）加以分析。組間差異以群集式置換檢定評估，並以兩項經振幅正規化的個體層級指標整合上述結果圖。此外，透過僅保留每位病患單一紀錄的敏感度分析，以及納入年齡為共變量的共變數分析（ANCOVA），檢驗結果的穩健性。 結果顯示，各廣泛性退化組在所有條件下皆與對照組明顯區隔，證實了分析流程的有效性；相對地，黃斑部失養症在以能量為基礎的 HHT 中幾乎無法與對照組區分，僅在中間層、內層視網膜相關的條件下達到顯著。調變域則還原出一組雖小卻一致、且侷限於錐細胞路徑的黃斑部失養症特徵，其中最具辨識度者，為錐細胞單獨刺激下的振幅調變過度增強——此方向在所有組別中獨一無二，其餘各組皆呈下降。一項跨條件的錐細胞區功率比值，使黃斑部失養症成為唯一高於健康基準的分組，並經單因子變異數分析證實。該效應對於世代中重複回診的資料結構及受試者年齡皆具穩健性；由於黃斑部失養症為最年輕的;Inherited retinal diseases (IRDs) are clinically and genetically heterogeneous disorders in which the spatial distribution of pathology determines whether the full-field electroretinogram (ffERG) can detect them. Generalized degenerations are expressed in the combined full-field signal， whereas focal macular dystrophy (MD) is characteristically concealed， because the affected macula contributes only a small fraction of a response dominated by the healthy peripheral retina. The purpose of this study was to test whether information overlooked by the conventional energy-based reading of the ffERG can be recovered through nonlinear， non-stationary modulation analysis， with particular attention to macular dystrophy. The data comprised de-identified clinical ffERG recordings obtained from outpatients at National Taiwan University Hospital， totaling 188 examinations from 174 patients across seven clinically defined groups: healthy control， macular dystrophy， extinguished or flat ERG， cone-rod dystrophy， Bietti crystalline dystrophy， and typical and pericentral retinitis pigmentosa. Each response was recorded under five ISCEV-style stimulus conditions and decomposed using improved complete ensemble empirical mode decomposition with adaptive noise. The signals were then analyzed with the Hilbert-Huang transform (HHT)， Holo-Hilbert spectral analysis of amplitude and frequency modulation (HHSA-AM and HHSA-FM)， and the intrinsic event-related potential (iERP). Group differences were assessed by cluster-based permutation testing， and two amplitude-normalized， subject-level indices condensed the resulting maps. Robustness was examined through a sensitivity analysis restricting the data to one recording per patient and through an analysis of covariance controlling for participant age. The generalized groups separated strongly from controls across all conditions， validating the analytic pipeline， whereas macular dystrophy was largely indistinguishable from controls in the energy-based HHT， reaching significance only in an intermediate-layer， inner-retinal condition. The modulation domain recovered a small but convergent macular-dystrophy signature confined to the cone pathway. Its most distinctive feature was an amplitude-modulation excess under cone-isolated stimulation， unique in sign among all groups， which were otherwise uniformly suppressed. A cross-condition cone-region power ratio placed macular dystrophy alone above the healthy baseline， and the group effect was confirmed by one-way analysis of variance. The effect was robust to the repeat-visit structure of the cohort and to participant age; because macular dystrophy was the youngest group， the age association was conservative with respect to the finding. The effect further localized to a single cone-dominant intrinsic mode. These findings indicate that the full-field electroretinogram carries recoverable， macular-relevant information in its modulation structure that a conventional energy reading discards. Holo-Hilbert analysis can therefore convert a routine ffERG into a more sensitive probe of retinal response organization， supporting a candidate modulation-domain signature for macular dystrophy that the present cross-sectional design identifies but cannot yet validate for individual diagnosis.
