Neural Correlates of Behavioral Recovery Following Ultrasonic Thalamic Stimulation in Chronic Disorders of Consciousness
Josh A. Cain, Norman M. Spivak, John P. Coetzee, Julia S. Crone, Micah A. Johnson, Evan S. Lutkenhoff, Courtney Real, Manuel Buitrago-Blanco, Paul M. Vespa, Caroline Schnakers, Martin M. Monti
2023 · 10.1101/2023.07.13.23292523
Abstract
Background Treatments aimed at hastening recovery from disorders of consciousness (DOC; e.g., coma, the vegetative state) have lagged behind a rapidly advancing science of these conditions. In part, this is due to the difficulty in selectively targeting the many deep regions of the brain known to be key for recovery from DOC. The (re)emergence of low intensity focused ultrasound (LIFU) neuromodulation addresses this gap by providing a non-invasive, safe, and relatively low-cost means to exert neuromodulatory effects, anywhere in the brain, with relatively high spatial precision. Methods As part of this first-in-man clinical trial, a cohort of 10 patients with chronic DOC underwent two sessions of MR-guided thalamic LIFU, with concomitant functional neuroimaging, one week apart. Behavioral responsiveness, measured with the Coma Recovery Scale Revised (CRS-R), was assessed at multiple time-points both before and after each LIFU session. Changes in clinical score before and after each session were compared within subjects. Results This convenience sample of sample of chronic DOC patients included, at entry, 4 Minimally Conscious State plus (MCS+), 4 Minimally Conscious State minus (MCS-) and 2 Vegetative State (VS) patients (6 male; mean age = 39.1, mean time since injury = 56.75 months; 4 anoxic and 6 traumatic injuries). We find a significant linear increase over time in CRS-R total score with thalamic LIFU exposure. Functional imaging reveals changes in brain-wide activity and thalamo-cortical connectivity of the targeted thalamus (but not the contralateral, non-targeted, thalamus), during LIFU administration. Strikingly, these effects are associated with the degree of behavioral recovery observed following exposure. Discussion Collectively, these results are the first to suggest the efficacy of thalamic LIFU for the treatment of chronic DOC and extend our previous investigations in acute DOC populations. Indeed, results from both cohorts support the safety, feasibility, and preliminary efficacy of LIFU, as evaluated by gold-standard clinical assessments. Moreover, imaging results in both datasets provide a convergent biological link uniting neuromodulatory thalamic LIFU and the observed behavioral recovery. These first-in-man findings provide a key foundation to motivate further exploration of this technique (e.g., LIFU parameterization, optimal number and timing of exposures) and invite a sham-control clinical trial, in a larger cohort, to assess, in a blinded fashion, the technique’s efficacy. Clinical Trial number, date of submission, date of first enrollment, registration link: NCT02522429 August 13, 2015 March 10, 2016 https://clinicaltrials.gov/ct2/show/NCT02522429
Abstract via europepmc.
Exposures
Exposure 1: Thalamic LIFU in chronic DOC
Target: centromedian nucleus, thalamus — “central thalamus (caudal CL nucleus and CM-PF complex), preferentially left”
Device: BrainSonix · Brainsonix · single-element transducer, 71.5mm curvature ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 650 | ✓✓✓ |
| Pulse duration (ms) | 0.5 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 100 | ✓✓✓ |
| Duty cycle (%) | 5pulse duration × PRF gives 5% | ✓✓✓ |
| Sonication duration (s) | 30 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | deratingsingle value | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | 14.39 | ✓✓✓⚑ |
| In-situ Ispta (W/cm²) | 0.72 | ✓✓✓⚑ |
Ten 30-second on blocks separated by 30 s off periods, delivered inside the MRI. Two sessions one week apart (one patient received one), each with CRS-R assessments before and after.
Flags from extraction
exposures[0].in_situ.ispta_w_cm2— Paper gives 719.73 mW/cm2; recorded as 0.71973 W/cm2 (unit conversion).exposures[0].in_situ.isppa_w_cm2— Intensities are tissue-derated at 0.3 dB/cm-MHz (no skull term stated); quote carries LaTeX.n_sessions_per_subject— Nine patients received two sessions, C5 received one.randomised— Single-arm open-label study; recorded as not randomised and unblinded from the design, not from an explicit statement.