Focused ultrasound neuromodulation of the spleen activates an anti-inflammatory response in humans

• Published in: Brain stimulation Vol. 16; no. 3; pp. 703 - 711
• Main Authors: Zanos, Stavros, Ntiloudi, Despoina, Pellerito, John, Ramdeo, Richard, Graf, John, Wallace, Kirk, Cotero, Victoria, Ashe, Jeff, Moon, Jessica, Addorisio, Meghan, Shoudy, David, Coleman, Thomas R., Brines, Michael, Puleo, Chris, Tracey, Kevin J., Chavan, Sangeeta S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2023; Elsevier
• Subjects: Bioelectronic medicine; Cholinergic anti-inflammatory pathway; Cytokines; Humans; Inflammation; Neural Pathways; Spleen; Spleen - diagnostic imaging; Ultrasonic Therapy - methods; Ultrasonic Waves; Ultrasonography; Ultrasound; Spleen; Cytokines; tumor necrosis factor; Cholinergic anti-inflammatory pathway; splenic focused ultrasound stimulation; Inflammation; lipopolysaccharide; Ultrasound; Bioelectronic medicine
• ISSN: 1935-861X; 1876-4754; 1876-4754
• DOI: 10.1016/j.brs.2023.04.003

Focused ultrasound stimulation (FUS) activates mechanosensitive ion channels and is emerging as a method of noninvasive neuromodulation. In preclinical studies, FUS of the spleen (sFUS) activates an anti-inflammatory neural pathway which suppresses acute and chronic inflammation. However, the relevance of sFUS for regulating inflammatory responses in humans is unknown. Here, we used a modified diagnostic ultrasound imaging system to target the spleen of healthy human subjects with 3 min of continuously swept or stationary focused pulsed ultrasound, delivered at three different energy levels within allowable safety exposure limits. Potential anti-inflammatory effects of sFUS were assessed by measuring sFUS-elicited changes in endotoxin-induced tumor necrosis factor (TNF) production in whole blood samples from insonified subjects. We found that stimulation with either continuously swept or focused pulsed ultrasound has an anti-inflammatory effect: sFUS lowers TNF production for >2 h, with TNF returning to baseline by 24 h following sFUS. This response is independent of anatomical target (i.e., spleen hilum or parenchyma) or ultrasound energy level. No clinical, biochemical, or hematological parameters are adversely impacted. This is the first demonstration that sFUS suppresses the normal inflammatory response in humans, with potential implications for noninvasive bioelectronic therapy of inflammatory disorders. •The anti-inflammatory effect of focused ultrasound neuromodulation of the spleen (sFUS) in humans is unknown.•We conducted a preregistered, randomized, sham controlled study in healthy volunteers.•sFUS suppresses TNF production in whole blood samples exposed to an endotoxin.•Effect is independent of insonification mode, continuously swept vs. focused pulsed.•No clinical or laboratory parameters are adversely affected.