Targeting the Medial Prefrontal Cortex with Transcranial Focused Ultrasound Alleviates Adolescent Sleep-Deprivation-Induced Persistent Postsurgical Pain in Adulthood
Jing Yang, Han Bo, Pin Lv, Tiantian Sun, Qingling Duan, Huijie Zhu, Wei Zhang, Xiaoping Gu, Hairong Zheng, Bing Zhang, Zhengliang Ma
Research 2026 · 10.34133/research.1437
Abstract
Adolescent sleep deprivation (SD) increases latent vulnerability to pain, a major risk factor for persistent postsurgical pain (PPSP) in adulthood, yet the underlying mechanisms remain unclear. Given the limitations of current pharmacological treatments, noninvasive transcranial focused ultrasound (TFUS) offers a promising neuromodulatory alternative; however, its therapeutic efficacy for PPSP remains unknown. Here, we utilized a mouse model of adolescent SD followed by an adult plantar incision to elucidate how early sleep loss drives long-term PPSP and to systematically investigate the therapeutic potential and underlying mechanisms of TFUS. By integrating resting-state functional magnetic resonance imaging, chemogenetics, and behavioral assays, we demonstrated that medial prefrontal cortex glutamatergic (mPFC Glu ) hypoactivity mediates this SD-driven PPSP development. To evaluate TFUS intervention, we first screened various stimulation paradigms and identified that 200-Hz pulse repetition frequency TFUS optimally activated mPFC Glu neurons and effectively alleviated PPSP. Mechanistically, guided by single-nucleus RNA sequencing, we found that TFUS activates the mechanosensitive transient receptor potential channel 5 (TRPC5) to promote Homer1-dependent glutamatergic synaptic plasticity. This molecular cascade subsequently ameliorates mPFC Glu hypoactivity and normalizes aberrant network-level gamma oscillations and spike-gamma phase locking. Collectively, our findings suggest that adolescent SD precipitates adult PPSP via mPFC Glu dysfunction and that TFUS alleviates this condition through an integrated pathway linking molecular mechanosensation to network rhythm recovery. These results offer a novel therapeutic paradigm and provide a mechanistic foundation for developing noninvasive TFUS strategies to manage PPSP in vulnerable patients.
Abstract via europepmc.
Exposures
Exposure 1: TFUS over right mPFC (PRF 40, 200, 1000 Hz)
Target: ventromedial prefrontal cortex — “right mPFC”
Device: not reported
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 2,000 | ✓✓✓ |
| Pulse duration (ms) | 2.5, 0.5, 0.1swept | ✓✓✓ |
| Pulse repetition frequency (Hz) | 40, 200, 1,000swept | ✓✓✓ |
| Duty cycle (%) | 10 | ✓✓✓ |
| Sonication duration (s) | 1 | ✓✓✓ |
| 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 | |
| Isppa, domain unspecified (W/cm²) | 6.75 | ✓✓✓⚑ |
| Ispta, domain unspecified (W/cm²) | 0.0844 | ✓✓✓⚑ |
Tone-burst sinusoidal waves at 2 MHz, DC 10%, PRF 40, 200 or 1000 Hz, 1 s pulse train followed by 8 s intersonication interval. Therapeutic sessions: 20 min per session, single session or 7 d (20 min/d).
Flags from extraction
exposures[0].unspecified_domain.ispta_w_cm2— Paper gives 84.38 mW/cm (superscript lost in extraction); recorded as 0.08438 W/cm2. Isppa and Ispta look inconsistent with 10% DC; domain not stated.exposures[0].unspecified_domain.isppa_w_cm2— Intensities stated for the therapeutic 200/1000 Hz sessions; domain not stated.n_subjects— Only per-experiment group sizes given; no total.exposures[0].device.family— Driver system named (GreenValley) but transducer maker not named.exposures[0].target.terms— mPFC at AP +1.9, DV -1.9 in mouse; mapped to ventromedial_prefrontal_cortex (mPFC synonym).