Manipulation of Subcortical and Deep Cortical Activity in the Primate Brain Using Transcranial Focused Ultrasound Stimulation
Davide Folloni, Lennart Verhagen, Rogier B. Mars, Elsa Fouragnan, Charlotte Constans, Jean-François Aubry, Matthew F.S. Rushworth, Jérôme Sallet
Neuron 2019, 101, 1109-1116.e5 · 10.1016/j.neuron.2019.01.019
Abstract
The causal role of an area within a neural network can be determined by interfering with its activity and measuring the impact. Many current reversible manipulation techniques have limitations preventing their application, particularly in deep areas of the primate brain. Here, we demonstrate that a focused transcranial ultrasound stimulation (TUS) protocol impacts activity even in deep brain areas: a subcortical brain structure, the amygdala (experiment 1), and a deep cortical region, the anterior cingulate cortex (ACC, experiment 2), in macaques. TUS neuromodulatory effects were measured by examining relationships between activity in each area and the rest of the brain using functional magnetic resonance imaging (fMRI). In control conditions without sonication, activity in a given area is related to activity in interconnected regions, but such relationships are reduced after sonication, specifically for the targeted areas. Dissociable and focal effects on neural activity could not be explained by auditory confounds.
Abstract via europepmc.
Exposures
Exposure 1: Experiment 1: amygdala TUS
Target: amygdala — “amygdala”
Device: Sonic Concepts · Sonic Concepts, Bothell, WA, USA · H115-MR (64 mm diameter, 51.74 mm focal depth, 250 kHz) ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 250 | ✓✓✓ |
| Pulse duration (ms) | 30 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 10 | ✓✓✓ |
| Duty cycle (%) | 30pulse duration × PRF gives 30% | ✓✓✓ |
| Sonication duration (s) | 40 | ✓✓✓ |
| Free-field pressure (kPa) | 1,150, 1,270swept | ✓✓✓⚑ |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | simulationsingle value | |
| In-situ pressure (kPa) | 1,440 | ✓✓✓ |
| In-situ Isppa (W/cm²) | 64.9 | ✓✓✓ |
| In-situ Ispta (W/cm²) | 19.5 | ✓✓✓ |
A single 40-s train of pulsed ultrasound (250 kHz) comprising 30-ms bursts every 100 ms (duty cycle 30%) was directed to the target region using a single-element transducer with a region-specific water-filled coupling cone; recordings of neural (fMRI) activity began ~30 min after the end of the 40-s TUS train ('offline' protocol).
Exposure 2: Experiment 2: ACC TUS
Target: anterior cingulate cortex — “anterior cingulate cortex (ACC)”
Device: Sonic Concepts · Sonic Concepts, Bothell, WA, USA · H115-MR (64 mm diameter, 51.74 mm focal depth, 250 kHz) ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 250 | ✓✓✓ |
| Pulse duration (ms) | 30 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 10 | ✓✓✓ |
| Duty cycle (%) | 30pulse duration × PRF gives 30% | ✓✓✓ |
| Sonication duration (s) | 40 | ✓✓✓ |
| Free-field pressure (kPa) | 1,150, 1,270swept | ✓✓✓ |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | simulationsingle value | |
| In-situ pressure (kPa) | 780 | ✓✓✓ |
| In-situ Isppa (W/cm²) | 18.8 | ✓✓✓ |
| In-situ Ispta (W/cm²) | 5.63 | ✓✓✓ |
A single 40-s train of pulsed ultrasound (250 kHz) comprising 30-ms bursts every 100 ms (duty cycle 30%) was directed to the target region using a single-element transducer with a region-specific water-filled coupling cone; recordings of neural (fMRI) activity began ~30 min after the end of the 40-s TUS train ('offline' protocol).
Flags from extraction
exposures[0].free_field.pressure_kpa— Free-field pressure (1.15-1.27 MPa measured in water) is reported as a general calibration range across the study, not broken out separately per target; midpoint (1.21 MPa) recorded per exposure and applied identically to both experiments.auditory_control— No masking/deafening procedure was used; instead the carrier (250 kHz) and pulse-envelope/PRF (10 Hz) were deliberately chosen to fall outside the macaque audible range, and neural recording began ~30 min after TUS ended. Classified as 'other' since no listed category matches this design-based control.randomised— Paper states all available animals took part with no pre-selection or restriction on group allocation, implying non-random, opportunistic assignment; not explicitly labelled 'randomised' or 'non-randomised' by the authors.
Notes: Two exposures correspond to Experiment 1 (amygdala, n=4) and Experiment 2 (ACC, n=3); an additional n=9 animals served as no-stimulation controls (some overlap with the 11 total animals). In-situ (simulated, finite-element head model) pressure/intensity values are target-specific and taken directly from the text; free-field (water-measured) pressure is a general per-study calibration range.