Neurovascular-modulation

Abstract Neurovascular-modulation is based on two principles that derive directly from brain vascular ultra-structure, namely an exceptionally dense capillary bed (BBB length density: 972 mm/mm 3 ) and a blood-brain-barrier (BBB) resistivity ( ρ ~ 1×10 5 Ω.m) much higher than brain parenchyma/interstitial space ( ρ ~ 4 Ω.m) or blood ( ρ ~ 1 Ω.m). Principle 1: Electrical current crosses between the brain parenchyma (interstitial space) and vasculature, producing BBB electric fields (E BBB ) that are > 400x of the average parenchyma electric field (Ē BRAIN ), which in turn modulates transport across the BBB. Specifically, for a BBB space constant (λ BBB ) and wall thickness (d th-BBB ): analytical solution for maximum BBB electric field (E A BBB ) is given as: (Ē BRAIN × λ BBB ) / d th-BBB . Direct vascular stimulation suggests novel therapeutic strategies such as boosting metabolic capacity or interstitial fluid clearance. Boosting metabolic capacity impacts all forms of neuromodulation, including those applying intensive stimulation or driving neuroplasticity. Boosting interstitial fluid clearance has broad implications as a treatment for neurodegenerative disease including Alzheimer’s disease. Principle 2: Electrical current in the brain parenchyma is distorted around brain vasculature, amplifying neuronal polarization. Specifically, vascular ultra-structure produces ~50% modulation of the average parenchyma electric field (Ē BRAIN ) over the ~40 μm inter-capillary distance. The divergence of E BRAIN (activating function) is thus ~100 kV/m 2 per unit average parenchyma electric field (Ē BRAIN ). This impacts all forms of neuromodulation, including Deep Brain Stimulation (DBS), Spinal Cord Stimulation (SCS), Transcranial Magnetic Stimulation (TMS), Electroconvulsive Therapy (ECT), and transcranial electrical stimulation (tES) techniques such a transcranial Direct Current Stimulation (tDCS). Specifically, whereas spatial profile of E BRAIN along neurons is traditionally assumed to depend on macroscopic anatomy, it instead depends on local vascular ultra-structure.