Deep brain nuclei are integral components of large-scale circuits mediating important cognitive and sensorimotor functions. However, because they fall outside the domain of conventional non-invasive neuromodulatory techniques, their study has been primarily based on neuropsychological models, limiting the ability to fully characterize their role and to develop interventions in cases where they are damaged. To address this gap, we used the emerging technology of non-invasive low-intensity focused ultrasound (LIFU) to directly modulate left lateralized basal ganglia structures in healthy volunteers. During sonication, we observed local and distal decreases in blood oxygenation level dependent (BOLD) signal in the targeted left globus pallidus (GP) and in large-scale cortical networks. We also observed a generalized decrease in relative perfusion throughout the cerebrum following sonication. These results show, for the first time using functional MRI data, the ability to modulate deep-brain nuclei using LIFU while measuring its local and global consequences, opening the door for future applications of subcortical LIFU.

The promotion of recovery in patients who have entered a disorder of consciousness (DOC; e.g., coma or vegetative states) following severe brain injury remains an enduring medical challenge despite an ever-growing scientific understanding of these conditions. Indeed, recent work has consistently implicated altered cortical modulation by deep brain structures (e.g., the thalamus and the basal ganglia) following brain damage in the arising of, and recovery from, DOCs. The (re)emergence of low-intensity focused ultrasound (LIFU) neuromodulation may provide a means to selectively modulate the activity of deep brain structures noninvasively for the study and treatment of DOCs. This technique is unique in its combination of relatively high spatial precision and noninvasive implementation. Given the consistent implication of the thalamus in DOCs and prior results inducing behavioral recovery through invasive thalamic stimulation, here we applied ultrasound to the central thalamus in 11 acute DOC patients, measured behavioral responsiveness before and after sonication, and applied functional MRI during sonication. With respect to behavioral responsiveness, we observed significant recovery in the week following thalamic LIFU compared with baseline. With respect to functional imaging, we found decreased BOLD signals in the frontal cortex and basal ganglia during LIFU compared with baseline. In addition, we also found a relationship between altered connectivity of the sonicated thalamus and the degree of recovery observed post-LIFU.

Low-intensity focused ultrasound (LIFU) is an increasingly applied method for achieving non-invasive brain stimulation. However, transmission of ultrasound through the human skull can substantially affect focal point characteristics of LIFU, including dramatic attenuation in intensity and refraction of focal point location. These effects depend on a high-dimensional parameter space, making these effects difficult to estimate from previous work. Instead, focal point properties of LIFU experiments are often estimated using numerical simulation of LIFU sonication through skull. However, this procedure presents many entry barriers to even computationally savvy investigators and often requires expensive computational hardware, impeding LIFU research. We present a novel MATLAB toolbox (data: doi:10.5068/D1QD60; Matlab Scripts: https://doi.org/10.5281/zenodo.5811122) for rapidly estimating beam properties of LIFU transmitted through bone. Users provide specific values for frequency of LIFU, bone thickness, angle at which LIFU is applied, depth of the LIFU focal point, and diameter of the transducer used and receive an estimation of the degree of refraction/attenuation expected for the given parameters.

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

We present the first causal evidence in the healthy human brain linking the central thalamus to vigilance and the pulvinar to visuospatial attention using low-intensity transcranial focused ultrasound stimulation (tFUS). In a within-subjects, counterbalanced design, 27 healthy volunteers completed the Psychomotor Vigilance Task (PVT), a vigilance task, and the Egly-Driver Task (EDT), which assesses visuospatial attention, before and after central thalamus, pulvinar, and sham sonication with tFUS. Central thalamic sonication significantly impaired performance on both tasks in a manner consistent with decreases in arousal. Targeting the pulvinar with tFUS resulted in more subtle changes in visuospatial attention. Participants were less reactive to visual stimuli presented in the visual field contralateral to the affected pulvinar. These results demonstrate that tFUS can elicit measurable behavioral changes in healthy volunteers and underscores its potential as a high-resolution tool for non-invasive brain mapping, capable of differentiating functional contributions of thalamic regions only millimeters apart.