Department of Psychiatry, Laboratory for Neuropsychiatry and Neuromodulation, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Department of Biomedical Engineering, The City College of New York, CUNY, New York, NY, USA.
Neuromodulation. 2022 Dec;25(8):1299-1311. doi: 10.1111/ner.13338. Epub 2022 Feb 15.
We consider two consequences of brain capillary ultrastructure in neuromodulation. First, blood-brain barrier (BBB) polarization as a consequence of current crossing between interstitial space and the blood. Second, interstitial current flow distortion around capillaries impacting neuronal stimulation.
We developed computational models of BBB ultrastructure morphologies to first assess electric field amplification at the BBB (principle 1) and neuron polarization amplification by the presence of capillaries (principle 2). We adapt neuron cable theory to develop an analytical solution for maximum BBB polarization sensitivity.
Electrical current crosses between the brain parenchyma (interstitial space) and capillaries, producing BBB electric fields (E) that are >400x of the average parenchyma electric field (Ē), which in turn modulates transport across the BBB. Specifically, for a BBB space constant (λ) and wall thickness (d), the analytical solution for maximal BBB electric field (E) is given as: (Ē × λ)/d. Electrical current in the brain parenchyma is distorted around brain capillaries, amplifying neuronal polarization. Specifically, capillary ultrastructure produces ∼50% modulation of the Ē over the ∼40 μm inter-capillary distance. The divergence of E (Activating function) is thus ∼100 kV/m per unit Ē.
BBB stimulation by principle 1 suggests novel therapeutic strategies such as boosting metabolic capacity or interstitial fluid clearance. Whereas the spatial profile of E is traditionally assumed to depend only on macroscopic anatomy, principle 2 suggests a central role for local capillary ultrastructure-which impact forms of neuromodulation including deep brain stimulation (DBS), spinal cord stimulation (SCS), transcranial magnetic stimulation (TMS), electroconvulsive therapy (ECT), and transcranial electrical stimulation (tES)/transcranial direct current stimulation (tDCS).
我们考虑了脑毛细血管超微结构在神经调节中的两个后果。首先，电流穿过细胞间隙和血液之间会导致血脑屏障（BBB）极化。其次，毛细血管周围的细胞间电流流变形会影响神经元刺激。
我们开发了 BBB 超微结构形态的计算模型，首先评估 BBB 处的电场放大（原则 1）和毛细血管存在时神经元极化的放大（原则 2）。我们采用神经元电缆理论来开发最大 BBB 极化敏感性的解析解。
电流穿过脑实质（细胞间隙）和毛细血管，产生的 BBB 电场（E）是平均实质电场（Ē）的>400 倍，这反过来又调节了 BBB 的转运。具体来说，对于 BBB 空间常数（λ）和壁厚度（d），最大 BBB 电场（E）的解析解为：（Ē×λ）/d。脑实质中的电流在脑毛细血管周围发生畸变，放大了神经元极化。具体来说，毛细血管超微结构在 40 μm 的毛细血管间距离内使 Ē 产生约 50%的调制。因此，E 的发散（激活函数）约为每单位 Ē 100 kV/m。
原则 1 提示 BBB 刺激的新治疗策略，例如增强代谢能力或细胞间液清除。而 E 的空间分布传统上被认为仅取决于宏观解剖结构，原则 2 则提示了局部毛细血管超微结构的核心作用，这会影响包括深部脑刺激（DBS）、脊髓刺激（SCS）、经颅磁刺激（TMS）、电惊厥疗法（ECT）和经颅电刺激（tES）/经颅直流电刺激（tDCS）在内的多种神经调节形式。
