Department of Biomedical Engineering, National Yang Ming Chiao Tung University, No.155, Sec.2, Linong St., Taipei 11221, Taiwan, Republic of China.
Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University, 12F., Education & Research Building, Shuang-Ho Campus, No. 301, Yuantong Rd., New Taipei City 23564, Taiwan, Republic of China.
J Neural Eng. 2024 Sep 4;21(5). doi: 10.1088/1741-2552/ad7322.
With prolonged life expectancy, the incidence of memory deficits, especially in Alzheimer's disease (AD), has increased. Although multiple treatments have been evaluated, no promising treatment has been found to date. Deep brain stimulation (DBS) of the fornix area was explored as a possible treatment because the fornix is intimately connected to memory-related areas that are vulnerable in AD; however, a proper imaging biomarker for assessing the therapeutic efficiency of forniceal DBS in AD has not been established.This study assessed the efficacy and safety of DBS by estimating the optimal intersection volume between the volume of tissue activated and the fornix. Utilizing a gold-electroplating process, the microelectrode's surface area on the neural probe was increased, enhancing charge transfer performance within potential water window limits. Bilateral fornix implantation was conducted in triple-transgenic AD mice (3 × Tg-AD) and wild-type mice (strain: B6129SF1/J), with forniceal DBS administered exclusively to 3 × Tg-AD mice in the DBS-on group. Behavioral tasks, diffusion tensor imaging (DTI), and immunohistochemistry (IHC) were performed in all mice to assess the therapeutic efficacy of forniceal DBS.The results illustrated that memory deficits and increased anxiety-like behavior in 3 × Tg-AD mice were rescued by forniceal DBS. Furthermore, forniceal DBS positively altered DTI indices, such as increasing fractional anisotropy (FA) and decreasing mean diffusivity (MD), together with reducing microglial cell and astrocyte counts, suggesting a potential causal relationship between revised FA/MD and reduced cell counts in the anterior cingulate cortex, hippocampus, fornix, amygdala, and entorhinal cortex of 3 × Tg-AD mice following forniceal DBS.The efficacy of forniceal DBS in AD can be indicated by alterations in DTI-based biomarkers reflecting the decreased activation of glial cells, suggesting reduced neural inflammation as evidenced by improvements in memory and anxiety-like behavior.
随着预期寿命的延长，记忆缺陷的发病率，特别是在阿尔茨海默病（AD）中，有所增加。尽管已经评估了多种治疗方法，但迄今为止尚未发现有前途的治疗方法。由于穹窿与 AD 中易受影响的与记忆相关的区域密切相关，因此探索了穹窿的深部脑刺激（DBS）作为一种可能的治疗方法；然而，尚未建立用于评估 AD 中穹窿 DBS 治疗效果的适当成像生物标志物。这项研究通过估计组织激活体积与穹窿之间的最佳交点体积来评估 DBS 的疗效和安全性。利用镀金工艺，增加了神经探针上微电极的表面积，从而在潜在的水窗限制内提高了电荷转移性能。在三转基因 AD 小鼠（3×Tg-AD）和野生型小鼠（品系：B6129SF1/J）中进行了双侧穹窿植入，仅在 DBS-on 组的 3×Tg-AD 小鼠中进行了穹窿 DBS。对所有小鼠进行行为任务、扩散张量成像（DTI）和免疫组织化学（IHC），以评估穹窿 DBS 的治疗效果。结果表明，穹窿 DBS 可挽救 3×Tg-AD 小鼠的记忆缺陷和焦虑样行为增加。此外，穹窿 DBS 积极改变了 DTI 指数，例如增加各向异性分数（FA）和降低平均弥散度（MD），同时减少小胶质细胞和星形胶质细胞计数，提示在前扣带回皮质、海马体、穹窿、杏仁核和 3×Tg-AD 小鼠的穹窿 DBS 后，修正的 FA/MD 与内侧前额叶皮质、海马体、穹窿、杏仁核和内嗅皮质中的细胞计数减少之间存在潜在的因果关系。DTI 基于生物标志物的变化可以指示 AD 中穹窿 DBS 的疗效，这些生物标志物反映了神经胶质细胞激活的减少，表明神经炎症减少，这可以通过改善记忆和焦虑样行为来证明。
