Rebound Excitation of Epileptiform Activities by Transcranial Focused Ultrasound Stimulation
Taewon Choi, Minseok Koo, Jaesoon Joo, Taekyung Kim, Young-Min Shon, Jinhyoung Park
2022 · 10.1101/2022.04.30.490021
Abstract
Background Conventional neurostimulations to treat epilepsy have adverse effects caused by post-inhibitory rebound excitations. Although ultrasound brain stimulation is feasible in inducing anticonvulsant effects, its association with paradoxical rebound excitations is unknown. Objective This study aimed at demonstrating rebound excitations with transcranial focused ultrasound. The modulations of epileptiform activities toward both suppressive and excitatory responses were investigated by changing ultrasonic transmit sequences. Methods In a pentylenetetrazol-injected acute epilepsy rat model, transcranial focused ultrasound stimulation was applied on the thalamus to modulate epileptiform activities. The parameters differentiated for pulse sequences were the pulse length, pulse pressure, and interval between the pulses. Sonication effects were assessed by electroencephalography (n=38), immuno-histochemical analysis (n=24), and optical measurement of cerebral blood volume changes (n=18). Results While ultrasonic patterns of stimuli at long intervals showed antiepileptic effects on electroencephalography, those at short intervals showed rebound excitatory responses followed by inhibitory activities. Further, suppressive states induced by inhibitory stimulations were transformed into excitatory states by applying a consecutive series of short bursts at higher acoustic pressure. Cerebral blood volume changes demonstrated consistent results with electroencephalography. Immunohistochemistry revealed that both inhibitory and excitatory neuronal cells were activated to generate rebound excitatory conditions, while inhibitory cells were activated for suppressive conditions. Conclusions In our study, variations in ultrasound stimulation patterns could modulate epileptiform activities in both upregulated and downregulated directions.
Abstract via europepmc.
Exposures
Exposure 1: Right anterior thalamic nuclei, 690 kHz, sequences TX1 to TX6
Target: anterior thalamic nucleus — “right anterior thalamic nuclei (ATN)”
Device: custom-built · DeL Piezo Specialties LLC. (PZT element) · 690 kHz single-element ring transducer (DL-47 PZT), fabricated in-house ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 690 | ✓✓✓ |
| Pulse duration (ms) | 5 | ✓✓✓⚑ |
| Pulse repetition frequency (Hz) | 100 | ✓✓✓ |
| Duty cycle (%) | 50pulse duration × PRF gives 50% | ✓✓✓ |
| Sonication duration (s) | 0.25, 10, 20, 40swept | ✓✓✓⚑ |
| 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 | |
| Pressure, domain unspecified (kPa) | 250, 1,000swept | ✓✓✓⚑ |
Pulses of a 5 ms, 3,450-cycle, 690 kHz burst at 100 Hz (50% duty). TX1 to TX4: low pressure (0.25 MPa), six bursts of 10 s (TX1), 20 s (TX2) or 40 s (TX3, TX4) with burst intervals of 50, 40, 40 and 20 s. TX5: 1.0 MPa, 250 ms bursts every 30 s for 5 min. TX6: TX3 followed by TX5 after a 3 min rest.
Flags from extraction
n_subjects— 59 rats were used in total including PTZ-only and normal controls and separate cohorts for EEG, histology and optical imaging; the number exposed to ultrasound is not stated as one total.exposures[0].unspecified_domain.pressure_kpa— 0.25 MPa for TX1 to TX4 and 1.0 MPa for TX5; the paper does not say whether these are free-field or in-brain values.exposures[0].timing.pulse_duration_ms— Burst rule resolved by arithmetic: the 5 ms burst at 100 Hz gives the stated 50% duty cycle, so 5 ms is the pulse and the 10 to 40 s bursts are trains.exposures[0].timing.sonication_duration_s— 10, 20 and 40 s trains for TX1 to TX4; TX5 uses 250 ms bursts, described in the protocol text only.exposures[0].target.terms— Target stated as right ATN from stereotactic coordinates; the beam focus is 4.7 mm long axially.sham_type— PTZ-injected rats without tFUS (PTZ-control) and normal controls; no sham device condition.