Non‐invasive peripheral focused ultrasound neuromodulation of the celiac plexus ameliorates symptoms in a rat model of inflammatory bowel disease
Kainat Akhtar, Zall Hirschstein, Allison Stefanelli, Emilia Iannilli, Aditya Srinivasan, Linda Barenboim, Mustafa Balkaya, Alexandra Cunha, Aliyah Audil, Eliyahu M. Kochman, Fuyee Chua, Maya Ravi, Saisree Mikkilineni, Hanel Watkins, William O'Connor, Ying Fan, Victoria Cotero, Jeffrey Ashe, Christopher Puleo, Tzu‐Jen Kao, Damian S. Shin
Experimental Physiology 2021 · 10.1113/ep088848
Abstract
New findings What is the central question of this study? Does peripheral non-invasive focused ultrasound targeted to the celiac plexus improve inflammatory bowel disease? What is the main finding and its importance? Peripheral non-invasive focused ultrasound targeted to the celiac plexus in a rat model of ulcerative colitis improved stool consistency and reduced stool bloodiness, which coincided with a longer and healthier colon than in animals without focused ultrasound treatment. The findings suggest that this novel neuromodulatory technology could serve as a plausible therapeutic approach for improving symptoms of inflammatory bowel disease. Abstract Individuals suffering from inflammatory bowel disease (IBD) experience significantly diminished quality of life. Here, we aim to stimulate the celiac plexus with non-invasive peripheral focused ultrasound (FUS) to modulate the enteric cholinergic anti-inflammatory pathway. This approach may have clinical utility as an efficacious IBD treatment given the non-invasive and targeted nature of this therapy. We employed the dextran sodium sulfate (DSS) model of colitis, administering lower (5%) and higher (7%) doses to rats in drinking water. FUS on the celiac plexus administered twice a day for 12 consecutive days to rats with severe IBD improved stool consistency scores from 2.2 ± 1 to 1.0 ± 0.0 with peak efficacy on day 5 and maximum reduction in gross bleeding scores from 1.8 ± 0.8 to 0.8 ± 0.8 on day 6. Similar improvements were seen in animals in the low dose DSS group, who received FUS only once daily for 12 days. Moreover, animals in the high dose DSS group receiving FUS twice daily maintained colon length (17.7 ± 2.5 cm), while rats drinking DSS without FUS exhibited marked damage and shortening of the colon (13.8 ± 0.6 cm) as expected. Inflammatory cytokines such as interleukin (IL)-1β, IL-6, IL-17, tumour necrosis factor-α and interferon-γ were reduced with DSS but coincided with control levels after FUS, which is plausibly due to a loss of colon crypts in the former and healthier crypts in the latter. Lastly, overall, these results suggest non-invasive FUS of peripheral ganglion can deliver precision therapy to improve IBD symptomology.
Abstract via europepmc.
Exposures
Exposure 1: FUS to celiac plexus, once or twice daily
Target: nerve plexus, ganglion — “celiac plexus”
Device: custom-built · custom made 2.5 MHz, FUS transducer ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 2,500 | ✓✓✓ |
| Pulse duration (ms) | 0.12 | ✓✓✓⚑ |
| Pulse repetition frequency (Hz) | 5 | ✓✓✓ |
| Duty cycle (%) | not reportedpulse duration × PRF gives 0.06% | |
| Sonication duration (s) | 180 | ✓✓✓ |
| 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 |
3 min of FUS once or twice daily (twice daily sessions about 6 h apart) for 12 days, bursts of 300 carrier cycles (first 120 us ON, 199.88 ms OFF) repeated at 5 Hz, drive amplitude 300 mV peak-to-peak from the function generator. Mock FUS used the same procedure with the equipment turned off.
Flags from extraction
n_subjects— 60 rats in the main groups plus an additional 20 rats in recovery experiments; sample sizes per analysis vary with exclusions; not all received FUSblinding— DAI and stool scoring by unblinded personnel; histology scored by three blinded personnel; recorded as singleexposures[0].timing.pulse_duration_ms— 120 us converted to 0.12 ms; burst of 300 cycles equals the ON period so burst is the pulseexposures[0].free_field— No pressure or intensity reported, only a 300 mV drive amplitudeexposures[0].target.terms— Celiac plexus (celiac ganglion and superior mesenteric plexus) mapped to nerve_plexus and ganglionn_sessions_per_subject— Once or twice daily for 12 days depending on group; not a single number