First-in-human low-intensity focused ultrasound targeting striatal circuits in schizophrenia: feasibility, safety, and effects on hallucinations and striatal-temporal functional connectivity

Karuna Subramaniam, Grace Attalla, Miriam Mathew, John L. Alvarez, Ehsan Dadgar-Kiani, Rajiv Mahadevan, Srikantan Nagarajan, Keith R Murphy

2026 · 10.64898/2026.01.10.26343837

human patientschizophreniafmriclinical scale

Abstract

Background Auditory hallucinations are among the most disabling symptoms in individuals with schizophrenia (SZ) and are linked to aberrant signaling within deep-striatal circuits, such as the nucleus accumbens (NAc) and caudate head (CH). However, causal tests of striatal involvement have been limited by the inaccessibility of these structures using noninvasive neuromodulatory techniques. Low-intensity focused ultrasound (LIFU) provides millimeter-scale precision capable of modulating deep-brain circuits, but its feasibility and impact on hallucinations in SZ remain unknown. Methods SZ participated in a within-subject cross-over feasibility trial including two active LIFU sessions (NAc, CH) and one sham control (unfocused sonication), spaced one-week apart. Resting-state fMRI and hallucination symptoms were acquired at baseline and immediately post-sonication. Results LIFU was delivered safely and well-tolerated in all patients. Acoustic simulations show consistent engagement of both striatal targets across subjects. Clinically, SZ demonstrated significant reductions in hallucination severity following active LIFU to NAc and CH, relative to baseline. Mechanistically, SZ exhibited abnormally high striatal–superior temporal cortex (STC) connectivity at baseline. Immediately after sonication, active LIFU to NAc and CH produced robust reductions in striatal–STC coupling in SZ. Conclusions This first-in-human study demonstrates that deep striatal LIFU is safe, feasible, and produces functional-connectivity changes accompanied by hallucination severity reductions in SZ. The convergence of symptom improvement with reduced striatal–STC coupling provides mechanistic proof-of-concept evidence that this circuit provides a promising biomarker and therapeutic LIFU target in psychosis and motivates larger sham-controlled trials to test the causal role of striatal circuitry in hallucination generation in SZ.

Abstract via europepmc.

Specieshuman

Subjects3 participants

Sessions per subject3

Randomisedyes

Blindingsingle

Sham / controlunfocused or detuned

Auditory controlmatched device sound

Readout timingboth

Anaesthesianot applicable

Readoutsfmri, clinical scale — Visual Analog Scale and AVHRS for hallucinations; resting-state fMRI striatal-superior temporal connectivity

Direction of effectmixed or unclearHallucination severity and frequency fell after active LIFU to NAc and CH, and striatal-STC connectivity fell relative to baseline; no formal sham comparison was possible.

Adverse eventsnone observedNo adverse events associated with stimulation; mild transient auditory sensations reported; simulated temperature rise at most 0.6 C and MI under 1.9.

Exposures

Exposure 1: LIFU to nucleus accumbens (NAc)

Target: nucleus accumbens — “nucleus accumbens (NAc)”
Device: Attune · Attune Neurosciences · ATTN201 ✓

Pulse timing
Waveform	pulsed
Fundamental frequency (kHz)	500	✓✓✓
Pulse duration (ms)	3	✓✓✓
Pulse repetition frequency (Hz)	20	✓✓✓
Duty cycle (%)	6pulse duration × PRF gives 6%	✓✓✓
Sonication duration (s)	40	✓✓✓⚑

Pressure and intensity, by domain
Free-field pressure (kPa)	not reported
Free-field Isppa (W/cm²)	not reported
Free-field Ispta (W/cm²)	not reported
In-situ estimate	simulationmean or range across subjects
In-situ pressure (kPa)	430, 650, 730, 830swept	✓✓✓⚑
In-situ Isppa (W/cm²)	7.72, 22.86swept	✓✓✓
In-situ Ispta (W/cm²)	not reported

Protocol, in the paper’s words

20 Hz pulse repetition frequency, 6% duty cycle (3 ms pulses, 50 ms interval), applied in 40 s on / 20 s off cycles for 30 minutes per hemisphere (60 minutes total). Bilateral 64-element arrays; one active session per target plus an unfocused sham session, a week apart.

Exposure 2: LIFU to caudate head (CH)

Target: caudate nucleus — “caudate head (CH)”
Device: Attune · Attune Neurosciences · ATTN201 ✓

Pulse timing
Waveform	pulsed
Fundamental frequency (kHz)	500	✓✓✓
Pulse duration (ms)	3	✓✓✓
Pulse repetition frequency (Hz)	20	✓✓✓
Duty cycle (%)	6pulse duration × PRF gives 6%	✓✓✓
Sonication duration (s)	40	✓✓✓

Pressure and intensity, by domain
Free-field pressure (kPa)	not reported
Free-field Isppa (W/cm²)	not reported
Free-field Ispta (W/cm²)	not reported
In-situ estimate	simulationmean or range across subjects
In-situ pressure (kPa)	560, 600, 610, 620, 690swept	✓✓✓
In-situ Isppa (W/cm²)	12.47, 15.77swept	✓✓✓
In-situ Ispta (W/cm²)	not reported

Protocol, in the paper’s words

Flags from extraction

exposures[0].in_situ.pressure_kpa — Table 2 lists per-subject simulated target pressures in MPa but the table text is garbled; no pressure value recorded
exposures[0].timing.sonication_duration_s — 40 s on / 20 s off cycles for 30 min per hemisphere; 40 s taken as the length of one uninterrupted train
blinding — Participants blinded and none identified sham; assessor blinding not stated
n_subjects — Only 3 participants; one lacked post-LIFU imaging and one reported no hallucinations before sham
direction_of_effect — Hallucination severity and striatal-STC connectivity fell after active LIFU; neuronal direction not assessed