Abstract
AbstractBackgroundTreatments 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.MethodsAs 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.ResultsThis 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.DiscussionCollectively, 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:NCT02522429August 13, 2015March 10, 2016https://clinicaltrials.gov/ct2/show/NCT02522429
Publisher
Cold Spring Harbor Laboratory