Stem cell-derived brain organoids for controlled studies of transcranial neuromodulation
Jan Kubanek, Matthew Wilson, Richard D. Rabbitt, Celeste J. Armstrong, Alexander J. Farley, H. M. Arif Ullah, Alex Shcheglovitov
Heliyon 2023 · 10.1016/j.heliyon.2023.e18482
Abstract
Transcranial neuromodulation methods have the potential to diagnose and treat brain disorders at their neural source in a personalized manner. However, it has been difficult to investigate the direct effects of transcranial neuromodulation on neurons in human brain tissue. Here, we show that human brain organoids provide a detailed and artifact-free window into neuromodulation-evoked electrophysiological effects. We derived human cortical organoids from induced pluripotent stem cells and implanted 32-channel electrode arrays. Each organoid was positioned in the center of the human skull and subjected to low-intensity transcranial focused ultrasound. We found that ultrasonic stimuli modulated network activity in the gamma and delta ranges of the frequency spectrum. The effects on the neural networks were a function of the ultrasound stimulation frequency. High gamma activity remained elevated for at least 20 minutes following stimulation offset. This approach is expected to provide controlled studies of the effects of ultrasound and other transcranial neuromodulation modalities on human brain tissue.
Abstract via europepmc.
Exposures
Exposure 1: 270 kHz focused US through human skull to organoid
Target: brain organoid — “human cortical organoids (single-rosette cortical organoids)”
Device: Sonic Concepts · Sonic Concepts · H-115 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 270 | ✓✓✓⚑ |
| Pulse duration (ms) | not reportedimplied by duty cycle ÷ PRF: 0.8333 ms (not stated by the paper) | ⚑ |
| Pulse repetition frequency (Hz) | 60 | ✓✓✓ |
| Duty cycle (%) | 5 | ✓✓✓ |
| Sonication duration (s) | 900 | ✓✓✓ |
| 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) | 650 | ✓✓✓⚑ |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | 0.682 | ✓✓✓ |
5 min baseline, 15 min ultrasound, then 20 min without ultrasound; pulsed at 60 Hz PRF and 5% duty cycle. Sham delivered the 885 kHz stimulus 20 mm off-target.
Exposure 2: 885 kHz focused US through human skull to organoid
Target: brain organoid — “human cortical organoids (single-rosette cortical organoids)”
Device: Sonic Concepts · Sonic Concepts · H-115 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 885 | ✓✓✓ |
| Pulse duration (ms) | not reportedimplied by duty cycle ÷ PRF: 0.8333 ms (not stated by the paper) | |
| Pulse repetition frequency (Hz) | 60 | ✓✓✓ |
| Duty cycle (%) | 5 | ✓✓✓ |
| Sonication duration (s) | 900 | ✓✓✓ |
| 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) | 650 | ✓✓✓ |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | 0.682 | ✓✓✓ |
5 min baseline, 15 min ultrasound, then 20 min without ultrasound; pulsed at 60 Hz PRF and 5% duty cycle. Sham delivered the 885 kHz stimulus 20 mm off-target.
Flags from extraction
exposures[0].in_situ.pressure_kpa— 0.65 MPa 'at target' at the organoid location, set with a hydrophone through the human skull; recorded as in situ measurement.exposures[0].fundamental_frequency_khz— 270 kHz is the transducer fundamental and 885 kHz a harmonic of the same transducer.n_subjects— 6 organoids stated via channel count; only 3 of 6 organoids responded for the 885 kHz high gamma effect.auditory_control— Organoids lack sensory organs so no auditory pathway exists; no separate control experiment.exposures[0].timing.pulse_duration_ms— Pulse duration not stated; only PRF and duty cycle given.exposures[0].unspecified_domain.ispta_w_cm2— ISPTA 682 mW/cm2 converted to W/cm2; domain not stated.