Non-ablative disease-modifying effects of magnetic resonance-guided focused ultrasound in neuromelanin-producing parkinsonian rodents
Joan Compte, Marion Tible, Thais Cuadros, Jordi Romero-Gimenez, Ariadna Laguna, Jean-François Aubry, Erik Dumont, Charlotte Constans, Thomas Tiennot, Mathieu D. Santin, Stephane Lehericy, Miquel Vila
2023 · 10.1101/2023.08.08.552410
Abstract
Age-dependent accumulation of the brain pigment neuromelanin has been implicated in the pathogenesis of Parkinson’s disease (PD). In humans, intracellular and extracellular neuromelanin levels are increased in PD postmortem brains and boosting neuromelanin production in rodents compromises neuronal function and viability and triggers a PD-like phenotype. Focused ultrasound has been shown to reduce ultraviolet light-induced skin hyperpigmentation in guinea pig and to remove brain extracellular β-amyloid plaques in Alzheimer’s mouse models. Here we show that repeated application of transcranial focused ultrasound (tFUS) is able to decrease intracellular and extracellular neuromelanin levels in neuromelanin-producing parkinsonian rats, compared to sham-treated animals, without the need for any additional therapeutic agent or intervention. Reduced neuromelanin levels in tFUS-treated animals were associated with decreased Lewy-like pathology, preserved dopaminergic phenotype, attenuated nigrostriatal degeneration, reduced glial activation, and long-term recovery of motor function. Our findings indicate that tFUS treatment applied at prodromal/early disease stages provides by itself extended structural and functional preservation of the nigrostriatal pathway in neuromelanin-producing parkinsonian rats without causing overt neuronal damage. This FDA-approved technology should thus be explored further as a noninvasive method with neuroprotective potential in PD and to maintain neuromelanin to levels below its pathogenic threshold within the aging population. One Sentence Summary Transcranial focused ultrasound reduces age-dependent neuromelanin accumulation and provides therapeutic benefit in parkinsonian rats
Abstract via europepmc.
Exposures
Exposure 1: tFUS to the substantia nigra (SN) in neuromelanin-producing parkinsonian rats
Target: substantia nigra — “SN (substantia nigra), ipsilateral to AAV-TYR injection”
Device: IGT / Imasonic · Imasonic (transducer); Image Guided Therapy (IGT), Pessac, France (Thermoguide guidance system) ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 1,500 | ✓✓✓ |
| Pulse duration (ms) | 3 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 10.31 | ✓✓✓⚑ |
| Duty cycle (%) | not reportedpulse duration × PRF gives 3.093% | |
| Sonication duration (s) | 600 | ✓✓✓ |
| Free-field pressure (kPa) | 1,050 | ✓✓✓ |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | 1.1 | ✓✓✓ |
| 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 |
MRI-guided tFUS/sham treatments were performed once a week for 3 consecutive weeks, targeting the SN ipsilateral to AAV injections. The power of the tFUS ultrasound beam was initially set at 5% corresponding to a Peak Negative Pressure of 1.05 MPa in water according to the calibration, with a duration of 3 ms every 97 ms for 600 repetitions (10 minutes), corresponding to Ispta=1.1 W/cm2. Behavioural/histological effects were assessed at 4 months post-AAV injection, ~2.5 months after the last tFUS application.
Flags from extraction
exposures[0].timing.pulse_repetition_frequency_hz— PRF was not stated directly; converted from the stated inter-pulse period ('a duration of 3 ms every 97 ms') to ~10.3 Hz, a unit conversion rather than an inference.sham_type— The paper contrasts 'tFUS' vs 'sham' treatment groups but never describes what the sham procedure physically involved (transducer powered off, blocked, aimed away, etc.).n_subjects— Only the two constituent tFUS-treated group sizes (EV:tFUS n=6, TYR:tFUS n=6) are stated; the paper never states a combined total, so both group sizes are listed rather than summed.blinding— Blinding is stated only for outcome assessors ('investigator blinded to the experimental groups') during behavioural/histological quantification; no statement is made about blinding of the individuals administering tFUS/sham treatment.