放射調節手術對慢性酒精攝取的效果：迷你豬模式中的行為、大腦結構與功能性連結變化

Abstract

酒精使用疾患（Alcohol Use Disorder, AUD）長期以來對公共健康與社會經濟造成重大挑戰。然而以人類受試者進行慢性飲酒對大腦影響的研究，在實驗倫理上具有高度的困難性。現有認知行為與藥物治療的酒癮療效亦相對有限。本研究使用李宋迷你豬（Lee-Sung Miniature Pigs, LSPs; n = 14）為模型，以非侵入性放射神經調節手術作為介入手段，針對大腦酬賞系統的一個主要結構--依核（Nucleus Accumbens, NAc）進行調節，探討慢性飲酒所引發之大腦結構與功能性改變。迷你豬在進行長達2-3年的行為訓練後，針對飲酒量可超越人類大量飲酒(Binge Drinking)標準的個體，在其雙側依核施予一次性低劑量(Dmax = 30 Gy，5 mm collimeter)的放射調節手術。透過磁振造影（Magnetic Resonance Imaging, MRI）與擴散張量影像（Diffusion Tensor Imaging, DTI）與冷凍切片檢測結構變化，並以靜息態功能性連結（Resting-State Functional Connectivity）及飲酒渴求行為進行縱向追蹤，且於術後評估動物的運動活動（Locomotor Activity），探討慢性飲酒所引發之大腦網絡改變，並評估放射手術對大腦神經網絡的影響。結果顯示，慢性飲酒會導致依核與海馬迴(Hippocampus)灰質結構減損、穹窿(Fornix)白質束的非等向性指標（Fractional Anisotropy, FA）上升，以及依核與背側前扣帶迴（dorsal Anterior Cingulate Cortex, dACC）間功能性連結降低。接受放射手術後，飲酒行為顯著減少，且未影響日常進食動機。在術後第12個月，依核與背側前扣帶迴間功能性連結出現延遲性增強，但未造成對依核結構或細胞層級的損傷。此結果顯示，慢性飲酒可能導致酬賞與記憶迴路的結構性改變，而穹窿非等向性指標的增加可能反映功能性補償機制。值得注意的是，放射手術能在不造成結構損傷的情況下有效降低飲酒渴求，並可能促進功能性連結重組。然而，樣本數較小且功能性連結變化軌跡仍具個體差異為本研究之限制，未來研究應審慎詮釋並以更大樣本驗證放射性調節、飲酒行為改變與功能性連結變化之間的關係。本研究指出，以低劑量放射手術作為慢性飲酒的聚焦型神經調節策略具有潛力，僅需一次治療即可在迷你豬模型中誘發持續一年的行為改善。

Alcohol use disorder (AUD) poses persistent public health and socioeconomic challenges. However, controlled experimental studies on the effects of objectively measured chronic alcohol consumption on brain structure remain difficult to conduct in human participants. Moreover, the effectiveness of current cognitive, behavioural, and pharmacological interventions is still limited. Non-invasive radiosurgical neuromodulation targeting the reward system has emerged as a potential interventional tool. In this study, we used Lee-Sung miniature pigs (LSPs; n = 14) to investigate the structural and functional brain changes associated with chronic alcohol consumption and to evaluate the effects of low-dose, non-invasive radiosurgery (Dmax = 30 Gy, 5 mm collimeter) targeting the bilateral nucleus accumbens (NAc). Structural alterations were examined using magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and cryo-sectioning, while resting-state functional connectivity and alcohol-craving behaviors were assessed longitudinally, and locomotor activity was assessed at one post-surgical time point. Chronic alcohol consumption was associated with reduced gray matter integrity in the NAc and hippocampus, increased fractional anisotropy (FA) in the fornix, and decreased NAc–dorsal anterior cingulate cortex (dACC) functional connectivity. The bilateral NAc may exhibit differential alterations in functional connectivity in response to chronic alcohol use. Radiosurgery significantly reduced alcohol consumption without altering their appetitive motivation. A delayed increase in NAc-dACC functional connectivity emerged 12 months after surgery. No structural or cellular damage to the NAc was observed after radiosurgery. These results suggest that chronic alcohol consumption may lead to structure alterations in reward and memory circuits, while increased FA in the fornix may reflect functional compensatory mechanism. Importantly, radiosurgical neuromodulation reduced alcohol-craving behavior without affecting daily appetitive function or NAc integrity, and may promote potential functional reorganization. Nonetheless, given the small sample size and individual variability in functional connectivity trajectories, interpretations of the link between radiosurgical modulation, behavioral improvement and functional connectivity changes should be made with caution. This study highlights low-dose radiosurgery as a promising focal neuromodulation strategy for chronic alcohol consumption, with a single intervention producing one-year-sustained behavioral reductions in a large animal model, and lays preliminary groundwork for future translational research.