Analgesic effect of simultaneously targeting multiple pain processing brain circuits in an aged humanized mouse model of chronic pain by transcranial focused ultrasound
Min Gon Kim, Chih-Yu Yeh, Kai Yu, Zherui Li, Kalpna Gupta, Bin He
APL Bioengineering 2025 · 10.1063/5.0236108
Abstract
Low-intensity transcranial focused ultrasound (tFUS) has recently been shown to noninvasively and non-pharmacologically modulate pain hypersensitivity with high spatial specificity and deep brain penetration. However, the lack of knowledge about its effectiveness for pain management in older subjects vulnerable to severe pain who are also at increased risk of cognitive impairment, presents significant challenges. Additionally, current opioid pain treatments require hospital visits, limiting unwanted serious side effects with multiple liabilities, and device-based pain treatments are typically administered at medical facilities with bulky and expensive equipment, limiting accessibility and thus highlighting the need for at-home non-pharmacological treatment options. Here, we present a more accessible, noninvasive tFUS pain treatment strategy for senior subjects. This approach involves simultaneously targeting multiple pain-processing circuits using a battery-powered, compact, and low-cost ultrasound analog front end (UAFE). We developed and evaluated the performance of the UAFE capable of generating sufficiently high-amplitude output with significantly lower noise levels compared to a commercial transmitter. Using a humanized sickle mouse model of chronic hyperalgesia, we found that tFUS stimulation targeting multiple pain-processing circuits effectively reduces heat hyperalgesia in aged female mice. In addition to its efficacy, our behavioral-based safety assessment revealed no adverse effects on motor functions. These results suggest that using a battery-powered, compact UAFE to simultaneously target multiple pain-processing circuits can effectively suppress heat pain-related behaviors in aged female sickle mice without negatively impacting motor coordination and balance. This highlights the potential for further development of fully home-based tFUS pain treatment for seniors.
Abstract via europepmc.
Exposures
Exposure 1: Single-element transducer, simultaneous S1HL and AI
Target: primary somatosensory cortex, insular cortex — “hindlimb of the primary somatosensory cortex (S1HL) and agranular insular (AI)”
Device: Blatek · Blatek Industries, Inc. · AT31529 single-element, driven by custom battery-powered ultrasound analog front end (UAFE) ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 500 | ✓✓✓⚑ |
| Pulse duration (ms) | 0.2 | ✓✓✓⚑ |
| Pulse repetition frequency (Hz) | 40 | ✓✓✓ |
| Duty cycle (%) | not reportedpulse duration × PRF gives 0.8% | ⚑ |
| Sonication duration (s) | 0.4 | ✓✓✓⚑ |
| Free-field pressure (kPa) | 148 | ✓✓✓⚑ |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | measurementsingle value | |
| In-situ pressure (kPa) | 101, 104swept | ✓✓✓⚑ |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported |
Tone burst duration 200 us, PRF 40 Hz, ultrasound duration 400 ms, inter-sonication interval 4 s, total sonication time 20 min, single session; hind paw withdrawal latency tested 10 and 15 min after.
Exposure 2: 128-element random array, single circuit at a time
Target: primary somatosensory cortex, insular cortex, primary motor cortex — “S1HL, AI or M1 individually”
Device: Sonic Concepts · Sonic Concepts, Inc. · H276 128-channel random array ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 1,500 | ✓✓✓ |
| Pulse duration (ms) | 0.2 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 40 | ✓✓✓ |
| Duty cycle (%) | not reportedpulse duration × PRF gives 0.8% | |
| Sonication duration (s) | 0.4 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | measurementsingle value | |
| In-situ pressure (kPa) | 82, 90swept | ✓✓✓⚑ |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported |
Tone burst duration 200 us, PRF 40 Hz, ultrasound duration 400 ms, inter-sonication interval 4 s, total sonication time 20 min, single session; hind paw withdrawal latency tested 10 and 15 min after.
Flags from extraction
exposures[0].timing.pulse_duration_ms— Source text reads '200 ls' (OCR of 200 microseconds); recorded as 0.2 ms.exposures[0].timing.duty_cycle_pct— Duty cycle is not stated; not computed from TBD and PRF.exposures[0].free_field.pressure_kpa— Stated as a peak-to-peak pressure in free water; recorded as given.exposures[0].in_situ.pressure_kpa— Hydrophone pressure at S1HL and AI in the presence of a mouse skull (101-104 kPa); peak versus peak-to-peak not stated.exposures[1].in_situ.pressure_kpa— Array pressures around 90 (S1HL) and 82 kPa (AI) in the presence of a mouse skull, stated with a citation to prior work; recorded as the range.n_subjects— No total stated. Group sizes: multi-target tFUS N = 10; array S1HL and AI 'N = 7.8' (garbled in text, read as 7 and 8); M1 N = 7. Negative control N = 9 not listed. Group sizes given as a list, not summed.exposures[1].target.terms— M1 stimulation with the array is described in the Discussion (supplementary Fig. S4).blinding— Hot-plate tests were video-recorded for a blind assessment; no statement about blinding of the operator or randomisation.exposures[0].fundamental_frequency_khz— Fig. 4 legend says single session at 500 kHz or 1.5 MHz; per-setup frequencies taken from the text.exposures[0].timing.sonication_duration_s— Ultrasound duration (UD) of 400 ms taken as one train; trains repeated every 4 s for a total sonication time of 20 min.