Safety of focused ultrasound neuromodulation in humans with temporal lobe epilepsy

John M. Stern, Norman M. Spivak, Sergio A. Becerra, Taylor P. Kuhn, Alexander S. Korb, David Kronemyer, Négar Khanlou, Samuel D. Reyes, Martin M. Monti, Caroline Schnakers, Patricia Walshaw, Inna Keselman, Mark S. Cohen, William Yong, Itzhak Fried, Sheldon E. Jordan, Mark E. Schafer, Jerome Engel, Alexander Bystritsky

Brain Stimulation 2021, 14, 1022-1031 · 10.1016/j.brs.2021.06.003

human patientepilepsyhistology molecularbehaviour

Abstract

Objective Transcranial Focused Ultrasound (tFUS) is a promising new potential neuromodulation tool. However, the safety of tFUS neuromodulation has not yet been assessed adequately. Patients with refractory temporal lobe epilepsy electing to undergo an anterior temporal lobe resection present a unique opportunity to evaluate the safety and efficacy of tFUS neuromodulation. Histological changes in tissue after tFUS can be examined after surgical resection, while further potential safety concerns can be assessed using neuropsychological testing. Methods Neuropsychological functions were assessed in eight patients before and after focused ultrasound sonication of the temporal lobe at intensities up to 5760 mW/cm 2 . Using the BrainSonix Pulsar 1002, tFUS was delivered under MR guidance, using the Siemens Magnetom 3T Prisma scanner. Neuropsychological changes were assessed using various batteries. Histological changes were assessed using hematoxylin and eosin staining, among others. Results With respect to safety, the histological analysis did not reveal any detectable damage to the tissue, except for one subject for whom the histology findings were inconclusive. In addition, neuropsychological testing did not show any statistically significant changes in any test, except for a slight decrease in performance on one of the tests after tFUS. Significance This study supports the hypothesis that low-intensity Transcranial Focused Ultrasound (tFUS) used for neuromodulation of brain circuits at intensities up to 5760 mW/cm 2 may be safe for use in human research. However, due to methodological limitations in this study and inconclusive findings, more work is warranted to establish the safety. Future directions include greater number of sonications as well as longer exposure at higher intensity levels to further assess the safety of tFUS for modulation of neuronal circuits.

Abstract via europepmc.

Specieshuman

Subjects8 participants

Sessions per subject1

Randomisednot reported

Blindingnot reported

Sham / controlnone

Auditory controlnot reported

Readout timingoffline

Anaesthesianot applicable

Readoutshistology molecular, behaviour — Rey Auditory Verbal Learning Test (RAVLT); Rey-Osterrieth Complex Figure Test (ROCFT); Brief Visuospatial Memory Test-Revised (BVMT-R); Taylor Complex Figure Test (TCFT); TUNEL, H&E and vanadium acid fuchsin (VAF)/toluidine blue histology of resected tissue

Direction of effectmixed or unclearNeuropsychological testing showed no significant change on most measures, but a small, statistically significant decline in RAVLT (verbal memory) scores pretest-to-posttest was seen for Group B; histology in 7/8 participants showed no damage, while one participant had inconclusive acidophilic-neuron/extravasation findings of unclear cause (possibly surgical artifact).

Adverse eventsobservedNo significant histopathologic damage was detected by TUNEL, H&E or VAF/toluidine blue staining in 7 of 8 participants; one participant (BX08) had acidophilic neurons and extravasation in both sonicated and non-sonicated tissue, of unclear/inconclusive relation to tFUS since the non-sonicated tissue was also damaged during resection. Neuropsychological testing showed a significant but slight decline in RAVLT scores pretest-to-posttest for Group B.

Exposures

Exposure 1: tFUS to anterior temporal lobe prior to resection; 'activation' (50% duty) and 'suppression' (5% duty) pulsing paradigms

Target: temporal lobe — “anterior temporal lobe”
Device: BrainSonix · BrainSonix Inc. · BX Pulsar ✓

Pulse timing
Waveform	pulsed
Fundamental frequency (kHz)	650	✓✓✓
Pulse duration (ms)	2, 0.5swept	✓✓✓
Pulse repetition frequency (Hz)	250, 100swept	✓✓✓
Duty cycle (%)	50, 5swept	✓✓✓
Sonication duration (s)	0.5, 30swept	✓✓✓

Pressure and intensity, by domain
Free-field pressure (kPa)	140, 1,985swept	✓✓✓
Free-field Isppa (W/cm²)	0.66, 152.1swept	✓✓✓
Free-field Ispta (W/cm²)	0.33, 7.61swept	✓✓✓
In-situ estimate	deratingmean or range across subjects
In-situ pressure (kPa)	110, 1,727swept	✓✓✓
In-situ Isppa (W/cm²)	0.5, 115.2swept	✓✓✓
In-situ Ispta (W/cm²)	0.25, 5.76swept	✓✓✓⚑

Protocol, in the paper’s words

Two pulsing paradigms, classified as 'activation' (50% duty cycle, 8 sonications of 0.5 s, 2 ms pulse width, 250 Hz PRF) and 'suppression' (5% duty cycle, 2 sonications of 30 s, 0.5 ms pulse width, 100 Hz PRF), were delivered to the anterior temporal lobe under MRI guidance concurrently with T2*-weighted BOLD imaging, at least one day before scheduled resective surgery. Initial delivery was limited to a derated ISPTA of 720 mW/cm2 (Group A, BX01/BX02), with later participants (Group B, BX03/04/05/08; Group C, BX07) receiving up to a derated ISPTA of 5760 mW/cm2. One participant (BX07) did not receive the suppression paradigm.

Flags from extraction

exposures[0].in_situ.ispta_w_cm2 — 0.72 and 5.76 W/cm2 are the two derated ISPTA safety-limit tiers used across participant groups (Group A vs Groups B/C), not a stated continuous range; represented as a two-element list to capture the dose escalation across the study.
exposures[0].free_field.*, exposures[0].in_situ.pressure_kpa, exposures[0].in_situ.isppa_w_cm2 — Table 2 ('Ultrasound exposure values') gives detailed per-participant-group, per-dose-level ISPTA, Pr, ISPPA, MI and TIC values for the 5% and 50% duty-factor conditions, but the extracted table markup is garbled/misaligned (merged cells, ambiguous row-to-value correspondence); these more granular acoustic values were not extracted to avoid mis-assigning numbers to the wrong column.
direction_of_effect — Study was designed primarily as a safety/feasibility study; the only functional readout (neuropsychological testing) showed an inconsistent pattern (mostly null, one significant decline) so direction is coded as mixed_or_unclear rather than inhibitory/excitatory.
adverse_events — Histology in one of eight participants (BX08) showed acidophilic neurons/extravasation, but the paper states this finding is inconclusive because the non-sonicated control tissue from the same participant was also damaged (likely by the resection procedure itself).