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Preventive and Therapeutic Effects of Low-Intensity Ultrasound Stimulation on Migraine in Rats

Leiqiang Yao, Rong Chen, Hui Ji, Xingran Wang, Xiangjian Zhang, Yi Yuan

IEEE Transactions on Neural Systems and Rehabilitation Engineering 2022 · 10.1109/tnsre.2022.3199813

rodentotherbehaviourcerebral haemodynamics

Abstract

This study sought to systematically evaluate the prophylactic and therapeutic effects of low-intensity transcranial ultrasound stimulation on migraine in rats. We used video recordings to assess the head scratching behavior and laser speckle contrast imaging to record the changes in cerebral blood flow velocity of freely moving rats in a healthy group, migraine group, migraine group with ultrasound prevention, and migraine group with ultrasound therapy. Results demonstrated that (1) head scratching during migraine attacks in rats was accompanied by an decrease in cerebral blood flow; (2) both ultrasound prevention and therapy significantly reduced the number of head scratches but did not reduce the cerebral blood flow velocity; and (3) the number of head scratches in the ultrasound stimulation groups was not affected by the auditory effect. These results reveal that low-intensity ultrasound has the potential to be used clinically in the prevention and therapeutic treatment of migraine.

Abstract via europepmc.

Speciesrat (Sprague-Dawley)
Subjects7, 7, 5, 5swept animals
Sessions per subject1
Randomisednot reported
Blindingnot reported
Sham / controlactive control site, no treatment control
Auditory controldeafened subjects
Readout timingoffline
Anaesthesiaboth
Readoutsbehaviour, cerebral haemodynamics — head-scratching count over 2 h by video; laser speckle contrast imaging of CBF in freely moving rats
Direction of effectnot assessedNeural activity was not recorded; ultrasound given before (prevention) or after (therapy) nitroglycerin reduced head scratches versus untreated migraine rats and did not change the nitroglycerin-induced fall in CBF velocity.
Adverse eventsnot reportedTemperature rise from ultrasound was estimated by equation at about 8.2e-3 C; no in-vivo safety assessment described.

Exposures

Exposure 1: whole-brain TUS, prevention and therapy groups

Target: whole brain or unfocused — “the whole rat brain was stimulated by ultrasound and there were no specific brain targets”
Device: Olympus / Panametrics · Olympus, USA · V323-SU ✓

Pulse timing
Waveformpulsed
Fundamental frequency (kHz)500✓✓✓
Pulse duration (ms)not reportedimplied by duty cycle ÷ PRF: 0.5 ms (not stated by the paper)⚑
Pulse repetition frequency (Hz)1,000✓✓✓⚑
Duty cycle (%)50✓✓✓⚑
Sonication duration (s)0.4✓✓✓⚑
Pressure and intensity, by domain
Free-field pressure (kPa)not reported
Free-field Isppa (W/cm²)not reported
Free-field Ispta (W/cm²)not reported
In-situ estimatenot 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)500✓✓✓⚑
Isppa, domain unspecified (W/cm²)8.3✓✓✓
Protocol, in the paper’s words

Methods state 500 kHz, stimulation duration 400 ms, PRF 1 kHz and duty cycle 50%; the Fig. 1 legend and Discussion state SD 15 min, PRF 1 Hz and duty cycle 5%. TUS for 15 min given either before (Pre) or after (The) subcutaneous nitroglycerin; burst/pulse duration cannot be resolved.

Flags from extraction

  • exposures[0].timing.duty_cycle_pct — Methods text gives 400 ms / 1 kHz / 50% while the Fig. 1 legend and Discussion give 15 min / 1 Hz / 5%; the Methods values are recorded for PRF and duty cycle.
  • exposures[0].timing.pulse_repetition_frequency_hz — Conflicts with the 1 Hz PRF in the Fig. 1 legend and Discussion; Methods value 1 kHz recorded.
  • exposures[0].timing.sonication_duration_s — 15 min (900 s) from the group description; Methods parameter sentence instead gives 'stimulation duration' 400 ms.
  • exposures[0].timing.pulse_duration_ms — Burst rule unresolved because the two parameter sets disagree; left not_reported.
  • exposures[0].unspecified_domain.pressure_kpa — Reported as peak-to-peak pressure of 0.5 MPa (converted to 500 kPa); domain not stated although a hydrophone was used under the skull for field mapping.
  • n_subjects — 56 is the total rats used, including 14 untreated control and migraine-only animals that received no ultrasound; ultrasound groups had 7, 7, 7, 7, 5 and 5 rats, with groups 5-6 receiving ultrasound near the ear.
  • sham_type — Sham-1 groups: ultrasound applied close to the ear but not through brain tissue; Sham-2 groups: same mode as real TUS in deafened rats; migraine group received no ultrasound.
  • exposures[0].target — Paper states the whole brain was stimulated with no specific target.