Transcranial Focused Ultrasound to the Right Prefrontal Cortex Improves Mood and Alters Functional Connectivity in Humans

Joseph L. Sanguinetti, Stuart Hameroff, Ezra E. Smith, Tomokazu Sato, Chris M. W. Daft, William J. Tyler, John J. B. Allen

Frontiers in Human Neuroscience 2020, 14 · 10.3389/fnhum.2020.00052

human healthyhealthybehaviourfmri

Abstract

Transcranial focused ultrasound (tFUS) is an emerging method for non-invasive neuromodulation akin to transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). tFUS offers several advantages over electromagnetic methods including high spatial resolution and the ability to reach deep brain targets. Here we describe two experiments assessing whether tFUS could modulate mood in healthy human volunteers by targeting the right inferior frontal gyrus (rIFG), an area implicated in mood and emotional regulation. In a randomized, placebo-controlled, double-blind study, participants received 30 s of 500 kHz tFUS or a placebo control. Visual Analog Mood Scales (VAMS) assessed mood four times within an hour (baseline and three times after tFUS). Participants who received tFUS reported an overall increase in Global Affect (GA), an aggregate score from the VAMS scale, indicating a positive shift in mood. Experiment 2 examined resting-state functional (FC) connectivity using functional magnetic resonance imaging (fMRI) following 2 min of 500 kHz tFUS at the rIFG. As in Experiment 1, tFUS enhanced self-reported mood states and also decreased FC in resting state networks related to emotion and mood regulation. These results suggest that tFUS can be used to modulate mood and emotional regulation networks in the prefrontal cortex.

Abstract via europepmc.

Specieshuman

Subjects25, 9swept participants

Sessions per subject1

Randomisedyes

Blindingdouble

Sham / controlinactive transducer, none

Auditory controlpost hoc check

Readout timingoffline

Anaesthesianot applicable

Readoutsbehaviour, fmri — Visual Analog Mood Scale (VAMS) - Global Affect and Global Vigor; resting-state fMRI seed-to-voxel functional connectivity

Direction of effectmixed or uncleartFUS to the right IFG increased self-reported positive mood (Global Affect, and Global Vigor in Experiment 2) relative to baseline/placebo, while resting-state functional connectivity between the rIFG and left prefrontal/limbic areas (subgenual cortex, orbitofrontal cortex, dorsal ACC, entorhinal cortex) decreased and connectivity with premotor cortex increased; DMN connectivity generally decreased.

Adverse eventsnot reportedAll intensity levels were well below FDA guidelines (global maximum Ispta below 720 mW/cm2, Isppa below 190 mW/cm2); estimated Isppa delivered to brain tissue after skull attenuation would be unlikely to exceed 16.2 W/cm2.

Exposures

Exposure 1: tFUS to right inferior frontal gyrus (rIFG)

Target: inferior frontal gyrus — “right inferior frontal gyrus (rIFG; BA45), targeted via F8 EEG electrode location”
Device: Blatek · Neurotrek, Inc., Boston, MA (transducer element: Blatek, Inc., Pittsburgh, PA) ✓

Pulse timing
Waveform	pulsed
Fundamental frequency (kHz)	500	✓✓✓
Pulse duration (ms)	0.065	✓✓✓
Pulse repetition frequency (Hz)	40	✓✓✓
Duty cycle (%)	0.26, 0.5sweptpulse duration × PRF gives 0.26%	✓✓✓
Sonication duration (s)	30, 120swept	✓✓✓

Pressure and intensity, by domain
Free-field pressure (kPa)	1,270, 1,260swept	✓✓✓
Free-field Isppa (W/cm²)	54	✓✓✓
Free-field Ispta (W/cm²)	0.13, 0.272swept	✓✓✓
In-situ estimate	deratingsingle value
In-situ pressure (kPa)	not reported
In-situ Isppa (W/cm²)	16.2	✓✓✓⚑
In-situ Ispta (W/cm²)	not reported

Protocol, in the paper’s words

Experiment 1 (n=24 tFUS-Active, double-blind, placebo-controlled): 30 s of tFUS with 0.26% duty cycle, pulse repetition period 23 ms; mood assessed by VAMS at baseline and 10, 20, 30 min post-tFUS. Experiment 2 (n=9, single-arm, no control condition): 2 min of tFUS with duty cycle increased to 0.5%; resting-state fMRI acquired before tFUS and 20 min after, with VAMS at baseline, 10 and 30 min post-tFUS.

Flags from extraction

n_subjects — Experiment 1 (n=24 tFUS-Active, of 48 total incl. placebo) and Experiment 2 (n=9, single-arm) are independent samples of participants; listed as separate group sizes rather than summed since the paper never states a combined total.
exposures[0].in_situ.isppa_w_cm2 — The 16.2 W/cm2 estimate is derated using a generic literature-cited 70-80% skull absorption figure (Legon et al., 2018), not a measurement specific to this study's participants; a separate, patient-specific k-Wave simulation is also reported giving a 53% reduction in intracranial peak pressure, but no corresponding kPa/W-cm2 value is stated for that simulation.
sham_type — Experiment 1 used a double-blind placebo (inactive transducer, no ultrasound output) condition; Experiment 2 was single-arm with no control condition at all ('There was no control condition').
auditory_control — No active auditory masking was implemented; participants who reported hearing a buzzing/clicking sound from the device were compared post hoc to those who did not, finding no significant difference in mood effects, but this is a post hoc analysis rather than an active control method.