• Niranjan Khadka and Marom Bikson.
• Department of Psychiatry, Laboratory for Neuropsychiatry and Neuromodulation, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: nironzan@gmail.com.
• Neuromodulation. 2022 Dec 1; 25 (8): 129913111299-1311.

ObjectivesWe 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.Materials And MethodsWe 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.ResultsElectrical current crosses between the brain parenchyma (interstitial space) and capillaries, producing BBB electric fields (EBBB) that are >400x of the average parenchyma electric field (ĒBRAIN), which in turn modulates transport across the BBB. Specifically, for a BBB space constant (λBBB) and wall thickness (dth-BBB), the analytical solution for maximal BBB electric field (EABBB) is given as: (ĒBRAIN × λBBB)/dth-BBB. Electrical current in the brain parenchyma is distorted around brain capillaries, amplifying neuronal polarization. Specifically, capillary ultrastructure produces ∼50% modulation of the ĒBRAIN over the ∼40 μm inter-capillary distance. The divergence of EBRAIN (Activating function) is thus ∼100 kV/m2 per unit ĒBRAIN.ConclusionsBBB stimulation by principle 1 suggests novel therapeutic strategies such as boosting metabolic capacity or interstitial fluid clearance. Whereas the spatial profile of EBRAIN 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).Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.

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