TABLE 2.

Features of different modes of pharmacologic neurointerventions.

Modality	Features
Systemic delivery (IV or oral)	• Noninvasive; Most convenient and conventional mode of delivery • Limited to therapeutics that can cross the BBB (Alavijeh et al., 2005) • High potential for adverse effects due to drug and metabolite action in the body and off-target brain regions (Alavijeh et al., 2005)
Direct Brain Injection and Convection-enhanced delivery	• Highly invasive; potentially injures brain along the cannula path • Directly bypasses the BBB; no limitation on therapeutic agents that could be delivered (Chen et al., 1999) • High spatial resolution, though potentially limited extent of delivery beyond immediate injection zone (Sampson et al., 2010)
Intrathecal administration	• Minimally invasive; requires lumbar or cervical cisternal puncture • Directly bypasses the BBB; no limitation on therapeutic agents that could be delivered (Kim et al., 2016) • Poor penetration into the brain parenchyma (Burch et al., 1988) • Treats the whole cerebrospinal fluid compartment (Burch et al., 1988)
Osmotic BBBO	• Minimally invasive; requires intra-arterial delivery of an osmotic agent and the agent of interest; carries the technical requirements and risks of catheter angiography (Burkhardt et al., 2012) • Temporarily opens the BBB; no definite limitation on therapeutic agents that could be delivered (Burkhardt et al., 2012) • Treats the whole brain region subtended by the artery being infused (Joshi et al., 2011) • Unclear long-term risk profile of increasing BBB permeability, particularly if repeated • Potential for significant acute adverse effects if not well controlled (Marchi et al., 2007)
FUS-mediated BBBO	• Noninvasive; uses ultrasound-induced stable cavitation of intravenously delivered microbubbles (McDannold N. et al., 2006) • Temporarily opens the BBB; no definite limitation on therapeutic agents that could be delivered • High spatial resolution defined by the ultrasound field (Ghanouni et al., 2015) • Unclear long-term risk profile of increasing BBB permeability, particularly if repeated (Kovacs et al., 2018) • Potential for significant acute adverse effects if not well controlled (Baseri et al., 2010)
Ultrasonic drug uncaging	• Noninvasive; uses ultrasound-induced release of drugs from intravenously-administered circulating nanocarriers (Airan, 2017) • Does not disrupt BBB; limited to small hydrophobic therapeutics that can cross the BBB (Wang et al., 2018) • High spatial and temporal resolution defined by the ultrasound field and the action of the drug (Wang et al., 2018) • Potential hypersensitivity-like reaction to the nanoparticles (Moghimi, 2018)

BBB, blood–brain barrier; BBBO, blood–brain barrier opening; FUS, focused ultrasound.