Non-invasive peripheral nerve stimulation via focused ultrasound in vivo

Matthew E Downs, Stephen A Lee, Georgiana Yang, Seaok Kim, Qi Wang, Elisa E Konofagou

Physics in Medicine & Biology 2018, 63, 035011 · 10.1088/1361-6560/aa9fc2

rodenthealthyemg mepbehaviourhistology molecularother

Abstract

Focused ultrasound (FUS) has been employed on a wide range of clinical applications to safely and non-invasively achieve desired effects that have previously required invasive and lengthy procedures with conventional methods. Conventional electrical neuromodulation therapies that are applied to the peripheral nervous system (PNS) are invasive and/or non-specific. Recently, focused ultrasound has demonstrated the ability to modulate the central nervous system and ex vivo peripheral neurons. Here, for the first time, noninvasive stimulation of the sciatic nerve eliciting a physiological response in vivo is demonstrated with FUS. FUS was applied on the sciatic nerve in mice with simultaneous electromyography (EMG) on the tibialis anterior muscle. EMG signals were detected during or directly after ultrasound stimulation along with observable muscle contraction of the hind limb. Transecting the sciatic nerve downstream of FUS stimulation eliminated EMG activity during FUS stimulation. Peak-to-peak EMG response amplitudes and latency were found to be comparable to conventional electrical stimulation methods. Histology along with behavioral and thermal testing did not indicate damage to the nerve or surrounding regions. The findings presented herein demonstrate that FUS can serve as a targeted, safe and non-invasive alternative to conventional peripheral nervous system stimulation to treat peripheral neuropathic diseases in the clinic.

Abstract via europepmc.

Speciesmouse

Subjects42 animals

Sessions per subjectnot reported

Randomisednot reported

Blindingsingle

Sham / controlnone

Auditory controlnot reported

Readout timingboth

Anaesthesiaanaesthetised

Readoutsemg mep, behaviour, histology molecular, other — EMG of the tibialis anterior muscle during/after FUS sciatic nerve stimulation; open field behavioral test; H&E histology; thermocouple temperature measurement; acoustic radiation force/tissue-displacement measurement

Direction of effectexcitatoryFUS stimulation of the sciatic nerve elicited EMG responses and visible muscle contraction (excitation), abolished by downstream nerve transection; effects attributed to a mechanical, not thermal, mechanism.

Adverse eventsnone observedBlinded histology and open-field behavioral testing showed no damage for FUS parameters found effective for stimulation; damage was only observed for supra-threshold 'positive control' parameters (5.4 MPa, 90% DC, 1 kHz PRF, 0.5 s) or pressures/durations beyond the effective range (>100 ms at 5.7 MPa, 90% DC).

Exposures

Exposure 1: FUS stimulation of the sciatic nerve (parameter sweep)

Target: sciatic nerve — “sciatic nerve”
Device: Sonic Concepts · Sonic Concepts · SU-107 ✓

Pulse timing
Waveform	pulsed, continuous
Fundamental frequency (kHz)	3,570	✓✓✓
Pulse duration (ms)	not reported	⚑
Pulse repetition frequency (Hz)	1,000	✓✓✓
Duty cycle (%)	15, 35, 50, 90, 100swept	✓✓✓
Sonication duration (s)	0.004, 1swept	✓✓✓

Pressure and intensity, by domain
Free-field pressure (kPa)	1,100, 8,300swept	✓✓✓
Free-field Isppa (W/cm²)	not reported
Free-field Ispta (W/cm²)	not reported
In-situ estimate	derating
In-situ pressure (kPa)	700, 5,400swept	✓✓✓⚑
In-situ Isppa (W/cm²)	not reported
In-situ Ispta (W/cm²)	not reported

Protocol, in the paper’s words

FUS parameters were swept across peak negative pressure, stimulation duration, and duty cycle at a fixed 1 kHz PRF; each parameter combination was tried n=5 times for a total of 2000 trials. A 100% duty cycle condition is described as continuous wave. Successful stimulation (eliciting reproducible EMG/muscle activation) required pressures and duty cycles above 3.2 MPa and 35%, respectively; sub-experiments for histology, open-field testing and thermocouple measurements used fixed parameters within this swept range (e.g., 4.5 MPa/90% DC/4.5-9 ms for histology and open field; 0.7-5.4 MPa/100% DC/5 ms for thermocouple).

Flags from extraction

n_subjects — n=42 is given as the overall number of mice 'used in all experiments'; a separate electrical-stimulation cohort (n=9) is mentioned later and it is unclear whether these 9 are included in the 42.
exposures[0].unspecified_domain.pressure_kpa — Text does not explicitly state whether the 1.1-8.3 MPa 'employed' pressure range is a free-field (water/transducer output) value or already accounts for tissue attenuation; placed here rather than free_field because domain is not stated.
exposures[0].in_situ.pressure_kpa — Reported_as vocabulary (single_value / mean_or_range_across_subjects) does not cleanly describe a parameter-sweep range; recorded as not_reported for reported_as.
exposures[0].timing.pulse_duration_ms — Paper gives duty cycle and PRF plus an overall 'stimulation duration' (the sonication/train length), but does not separately state an individual pulse width; not computed here per the no-arithmetic rule.
exposures[0].timing.waveform — 100% duty cycle condition is explicitly called continuous wave elsewhere in Results ('100% DC (continuous wave)'), while other duty cycles are pulsed; both are recorded as a list.