Evidence of Long-range nerve pathways connecting and coordinating activity in secondary lymph organs
Victoria Cotero, Tzu-Jen Kao, John Graf, Jeffrey Ashe, Christine Morton, Sangeeta S. Chavan, Stavros Zanos, Kevin J. Tracey, Christopher M. Puleo
Bioelectronic Medicine 2020 · 10.1186/s42234-020-00056-2
Abstract
Background Peripheral nerve reflexes enable organ systems to maintain long-term physiological homeostasis while responding to rapidly changing environmental conditions. Electrical nerve stimulation is commonly used to activate these reflexes and modulate organ function, giving rise to an emerging class of therapeutics called bioelectronic medicines. Dogma maintains that immune cell migration to and from organs is mediated by inflammatory signals (i.e. cytokines or pathogen associated signaling molecules). However, nerve reflexes that regulate immune function have only recently been elucidated, and stimulation of these reflexes for therapeutic effect has not been fully investigated. Methods We utilized both electrical and ultrasound-based nerve stimulation to activate nerve pathways projecting to specific lymph nodes. Tissue and cell analysis of the stimulated lymph node, distal lymph nodes and immune organs is then utilized to measure the stimulation-induced changes in neurotransmitter/neuropeptide concentrations and immune cellularity in each of these sites. Results and conclusions In this report, we demonstrate that activation of nerves and stimulated release of neurotransmitters within a local lymph node results in transient retention of immune cells (e.g. lymphocytes and neutrophils) at that location. Furthermore, such stimulation results in transient changes in neurotransmitter concentrations at distal organs of the immune system, spleen and liver, and mobilization of immune cells into the circulation. This report will enable future studies in which stimulation of these long-range nerve connections between lymphatic and immune organs can be applied for clinical purpose, including therapeutic modulation of cellularity during vaccination, active allergic response, or active auto-immune disease.
Abstract via europepmc.
Exposures
Exposure 1: Ultrasound neurostimulation directly above the popliteal lymph node
Target: other — “popliteal lymph node (surrounding neural tissue)”
Device: Sonic Concepts · Sonic Concepts · H106 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 1,100 | ✓✓✓ |
| Pulse duration (ms) | 0.136 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 2,000 | ✓✓✓ |
| Duty cycle (%) | 27pulse duration × PRF gives 27.272% | ✓✓✓ |
| Sonication duration (s) | 60 | ✓✓✓⚑ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not reported | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported | |
| Pressure, domain unspecified (kPa) | 830 | ✓✓✓ |
An ultrasound stimulus was applied directly above the popliteal lymph node using the peripheral pFUS device, with total duration of a single stimulus not surpassing a single 1-min pulse; WBC/neutrophil/lymphocyte counts were compared with and without (sham CTRL) this stimulation.
Flags from extraction
exposures[0].target.terms— the target is neural tissue in and around the popliteal lymph node, not a listed nervous-system structure; classified as 'other' with target.label describing the site.exposures[0].timing.sonication_duration_s— methods state total duration of a single stimulus 'not surpassing a single 1 min pulse', an upper bound rather than a precisely stated exposure duration; recorded as 60 s (the stated maximum) and flagged.sham_type— figure legend describes a 'sham CTRL' condition (no ultrasound) but the mechanism (inactive transducer vs. simple omission) is not described; classified as 'other'.unspecified_domain.pressure_kpa— domain (free field vs in situ) for the 0.83 MPa peak positive pressure is not stated by the paper; recorded as unspecified_domain.