A causal role of anterior prefrontal-putamen circuit for response inhibition revealed by transcranial ultrasound stimulation in humans
Koji Nakajima, Takahiro Osada, Akitoshi Ogawa, Masaki Tanaka, Satoshi Oka, Koji Kamagata, Shigeki Aoki, Yasushi Oshima, Sakae Tanaka, Seiki Konishi
Cell Reports 2022, 40, 111197 · 10.1016/j.celrep.2022.111197
Abstract
Stopping an inappropriate response requires the involvement of the prefrontal-subthalamic hyperdirect pathway. However, how the prefrontal-striatal indirect pathway contributes to stopping is poorly understood. In this study, transcranial ultrasound stimulation is used to perform interventions in a task-related region in the striatum. Functional magnetic resonance imaging (MRI) reveals activation in the right anterior part of the putamen during response inhibition, and ultrasound stimulation to the anterior putamen, as well as the subthalamic nucleus, results in significant impairments in stopping performance. Diffusion imaging further reveals prominent structural connections between the anterior putamen and the right anterior part of the inferior frontal cortex (IFC), and ultrasound stimulation to the anterior IFC also shows significant impaired stopping performance. These results demonstrate that the right anterior putamen and right anterior IFC causally contribute to stopping and suggest that the anterior IFC-anterior putamen circuit in the indirect pathway serves as an essential route for stopping.
Abstract via europepmc.
Exposures
Exposure 1: TUS to M1 (Stage 1)
Target: primary motor cortex — “primary motor cortex (right FDI-M1 hand area)”
Device: NeuroFUS · Sonic Concepts (sold by Brainbox) · NeuroFUS CTX-500 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 500 | ✓✓✓ |
| Pulse duration (ms) | 30 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 10 | ✓✓✓ |
| Duty cycle (%) | not reportedpulse duration × PRF gives 30% | ⚑ |
| Sonication duration (s) | 40 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | 30 | ✓✓✓ |
| Free-field Ispta (W/cm²) | 9 | ✓✓✓ |
| 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 |
An offline paradigm (based on Verhagen et al. 2019) was used: 30-ms ultrasound bursts repeated every 100 ms for a total of 40 s per stimulation. At Stage 1, TUS targeted the FDI hand region of left M1 and MEPs to single-pulse TMS were recorded before and every 5 min for 60 min after TUS. At Stages 3 and 5, subjects performed the stop-signal task for 3 runs before and 5 runs after TUS (pre- and post-TUS); stimulated regions were pseudorandomly counterbalanced across subjects.
Exposure 2: TUS to STN (Stage 3)
Target: subthalamic nucleus — “subthalamic nucleus (STN)”
Device: NeuroFUS · Sonic Concepts (sold by Brainbox) · NeuroFUS CTX-500 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 500 | ✓✓✓ |
| Pulse duration (ms) | 30 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 10 | ✓✓✓ |
| Duty cycle (%) | not reportedpulse duration × PRF gives 30% | |
| Sonication duration (s) | 40 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | 35.8 | ✓✓✓ |
| Free-field Ispta (W/cm²) | 10.7 | ✓✓✓ |
| 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 |
An offline paradigm (based on Verhagen et al. 2019) was used: 30-ms ultrasound bursts repeated every 100 ms for a total of 40 s per stimulation. At Stage 1, TUS targeted the FDI hand region of left M1 and MEPs to single-pulse TMS were recorded before and every 5 min for 60 min after TUS. At Stages 3 and 5, subjects performed the stop-signal task for 3 runs before and 5 runs after TUS (pre- and post-TUS); stimulated regions were pseudorandomly counterbalanced across subjects.
Exposure 3: TUS to anterior putamen (Stage 3)
Target: putamen — “anterior putamen”
Device: NeuroFUS · Sonic Concepts (sold by Brainbox) · NeuroFUS CTX-500 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 500 | ✓✓✓ |
| Pulse duration (ms) | 30 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 10 | ✓✓✓ |
| Duty cycle (%) | not reportedpulse duration × PRF gives 30% | |
| Sonication duration (s) | 40 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | 35.8 | ✓✓✓ |
| Free-field Ispta (W/cm²) | 10.7 | ✓✓✓ |
| 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 |
An offline paradigm (based on Verhagen et al. 2019) was used: 30-ms ultrasound bursts repeated every 100 ms for a total of 40 s per stimulation. At Stage 1, TUS targeted the FDI hand region of left M1 and MEPs to single-pulse TMS were recorded before and every 5 min for 60 min after TUS. At Stages 3 and 5, subjects performed the stop-signal task for 3 runs before and 5 runs after TUS (pre- and post-TUS); stimulated regions were pseudorandomly counterbalanced across subjects.
Exposure 4: TUS to posterior putamen (Stage 3, control)
Target: putamen — “posterior putamen (anatomical control)”
Device: NeuroFUS · Sonic Concepts (sold by Brainbox) · NeuroFUS CTX-500 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 500 | ✓✓✓ |
| Pulse duration (ms) | 30 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 10 | ✓✓✓ |
| Duty cycle (%) | not reportedpulse duration × PRF gives 30% | |
| Sonication duration (s) | 40 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | 35.8 | ✓✓✓ |
| Free-field Ispta (W/cm²) | 10.7 | ✓✓✓ |
| 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 |
An offline paradigm (based on Verhagen et al. 2019) was used: 30-ms ultrasound bursts repeated every 100 ms for a total of 40 s per stimulation. At Stage 1, TUS targeted the FDI hand region of left M1 and MEPs to single-pulse TMS were recorded before and every 5 min for 60 min after TUS. At Stages 3 and 5, subjects performed the stop-signal task for 3 runs before and 5 runs after TUS (pre- and post-TUS); stimulated regions were pseudorandomly counterbalanced across subjects.
Exposure 5: TUS to aIFC (Stage 5)
Target: inferior frontal gyrus — “anterior inferior frontal cortex (aIFC)”
Device: NeuroFUS · Sonic Concepts (sold by Brainbox) · NeuroFUS CTX-500 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 500 | ✓✓✓ |
| Pulse duration (ms) | 30 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 10 | ✓✓✓ |
| Duty cycle (%) | not reportedpulse duration × PRF gives 30% | |
| Sonication duration (s) | 40 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | 35.8 | ✓✓✓ |
| Free-field Ispta (W/cm²) | 10.7 | ✓✓✓ |
| 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 |
An offline paradigm (based on Verhagen et al. 2019) was used: 30-ms ultrasound bursts repeated every 100 ms for a total of 40 s per stimulation. At Stage 1, TUS targeted the FDI hand region of left M1 and MEPs to single-pulse TMS were recorded before and every 5 min for 60 min after TUS. At Stages 3 and 5, subjects performed the stop-signal task for 3 runs before and 5 runs after TUS (pre- and post-TUS); stimulated regions were pseudorandomly counterbalanced across subjects.
Exposure 6: TUS to MFC (Stage 5, control)
Target: dorsolateral prefrontal cortex — “middle frontal cortex (MFC, anatomical control)”
Device: NeuroFUS · Sonic Concepts (sold by Brainbox) · NeuroFUS CTX-500 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 500 | ✓✓✓ |
| Pulse duration (ms) | 30 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 10 | ✓✓✓ |
| Duty cycle (%) | not reportedpulse duration × PRF gives 30% | |
| Sonication duration (s) | 40 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | 35.8 | ✓✓✓ |
| Free-field Ispta (W/cm²) | 10.7 | ✓✓✓ |
| 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 |
An offline paradigm (based on Verhagen et al. 2019) was used: 30-ms ultrasound bursts repeated every 100 ms for a total of 40 s per stimulation. At Stage 1, TUS targeted the FDI hand region of left M1 and MEPs to single-pulse TMS were recorded before and every 5 min for 60 min after TUS. At Stages 3 and 5, subjects performed the stop-signal task for 3 runs before and 5 runs after TUS (pre- and post-TUS); stimulated regions were pseudorandomly counterbalanced across subjects.
Flags from extraction
n_subjects— Reported as group sizes, not a combined total: 20 subjects participated in Stages 1 and 3, and 20 (nominally distinct, same demographic breakdown) participated in Stage 5; the paper does not state whether these are the same or different individuals.exposures[5].target.terms— The paper calls this region 'middle frontal cortex (MFC)' without further anatomical detail; mapped here to dorsolateral_prefrontal_cortex based on its stated location adjacent to the aIFC (MNI 44, 36, 22), but this mapping is uncertain.exposures[0].timing.duty_cycle_pct— Not stated numerically by the paper; 30 ms bursts every 100 ms would arithmetically imply 30%, but this was not computed per instructions.randomised— The paper states that stimulated-region order was 'pseudorandomly counterbalanced across subjects', but there is no sham arm in this study (anterior/posterior putamen and aIFC/MFC serve as within-study anatomical controls), so this reflects order randomisation rather than real-vs-sham allocation.