Transcranial focused ultrasound selectively increases perfusion and modulates functional connectivity of deep brain regions in humans

Abstract

BackgroundLow intensity, transcranial focused ultrasound (tFUS) is a re-emerging brain stimulation technique with the unique capability of reaching deep brain structures non-invasively.Objective/HypothesisWe sought to demonstrate that tFUS can selectively and accurately target and modulate deep brain structures in humans important for emotional functioning as well as learning and memory. We hypothesized that tFUS would result in significant longitudinal changes in perfusion in the targeted brain region as well as selective modulation of BOLD activity and BOLD-based functional connectivity of the target region.MethodsIn this study, we collected MRI before, simultaneously during, and after tFUS of two deep brain structures on different days in sixteen healthy adults each serving as their own control. Using longitudinal arterial spin labeling (ASL) MRI and simultaneous blood oxygen level dependent (BOLD) functional MRI, we found changes in cerebral perfusion, regional brain activity and functional connectivity specific to the targeted regions of the amygdala and entorhinal cortex (ErC).ResultstFUS selectively increased perfusion in the targeted brain region and not in the contralateral homolog or either bilateral control region. Additionally, tFUS directly affected BOLD activity in a target specific fashion without engaging auditory cortex in any analysis. Finally, tFUS resulted in selective modulation of the targeted functional network connectivity.ConclusionWe demonstrate that tFUS can selectively modulate perfusion, neural activity and connectivity in deep brain structures and connected networks. Lack of auditory cortex findings suggests that the mechanism of tFUS action is not due to auditory or acoustic startle response but rather a direct neuromodulatory process. Our findings suggest that tFUS has the potential for future application as a novel therapy in a wide range of neurological and psychiatric disorders associated with subcortical pathology.

A review of functional neuromodulation in humans using low-intensity transcranial focused ultrasound

“…The seemingly inconsistent tFUS effects between Cain et al (2021b) [54] and Kuhn et al (2023) [55] were discussed as likely due to the differences in the vasculature and connectivity of the thalamus. In a single-participant study by Schafer et al (2021) [56], tFUS applied to the unilateral entorhinal cortex increased the cerebral blood perfusion in the targeted area, consistent with the findings of Kuhn et al (2023) [55]. In a study by Nakajima et al (2022) [22], suppressive tFUS to the subthalamic nucleus (STN) and the anterior putamen of the right basal ganglia were also investigated, respectively, both of which resulted in impairments in stopping performance during a stop-signal task.…”

“…It also decreased perfusion throughout the cerebrum for at least several minutes following tFUS, as observed by using arterial spin labeling (ASL). In another study employing ASL and BOLD-fMRI, Kuhn et al (2023) [55] found that tFUS directed at the right amygdala and left entorhinal cortex selectively increased perfusion and BOLD responses in the targeted brain region and its functional connectivity to other regions. The seemingly inconsistent tFUS effects between Cain et al (2021b) [54] and Kuhn et al (2023) [55] were discussed as likely due to the differences in the vasculature and connectivity of the thalamus.…”

“…In another study employing ASL and BOLD-fMRI, Kuhn et al (2023) [55] found that tFUS directed at the right amygdala and left entorhinal cortex selectively increased perfusion and BOLD responses in the targeted brain region and its functional connectivity to other regions. The seemingly inconsistent tFUS effects between Cain et al (2021b) [54] and Kuhn et al (2023) [55] were discussed as likely due to the differences in the vasculature and connectivity of the thalamus. In a single-participant study by Schafer et al (2021) [56], tFUS applied to the unilateral entorhinal cortex increased the cerebral blood perfusion in the targeted area, consistent with the findings of Kuhn et al (2023) [55].…”

Dynamic Changes in Human Brain Connectivity Following Ultrasound Neuromodulation

“…Therefore, the number of human-based studies is rapidly growing. While many of them enlighten the processes which underpin FUS (increased cortical excitability [11][12][13][14][15] through GABA inhibition [16]; brain activity in the target region could be either increased [12,[17][18][19][20][21] or decreased [22]; altered functional connectivity [13,16,17,23,24]; increased NMDA-dependent synaptic plasticity [25]), others already moved into more complex research on behavioural changes (sensory discrimination [18,[26][27][28]; motor inhibition [11,[29][30][31]; reaction time [32]; approach and withdrawal behaviours [33]; mood [24]; pain [34]; fear [35]), and the more audacious focused on pathological conditions (epilepsy[36-38]; Alzheimer's disease [39] and other dementia [40]; consciousness disorders [41]; tremor [42]; Parkinson's disease [43]; depression [44]; chronic pain [45]). However, FUS outcomes remain complex to interpret due to an incomplete understanding of the mechanisms involved.…”

Transcranial focused ultrasound activates feedforward and feedback cortico-thalamo-cortical pathways by selectively activating excitatory neurons

“…Low-intensity transcranial focused ultrasound (tFUS) is increasingly deemed as a promising noninvasive neuromodulation technology for modulating brain activity. Studies have shown that tFUS unequally modulates activities of neuronal subpopulations [1][2][3], and affects neural pathways [4][5][6][7] by delivering pulsed mechanical energy to target brain areas with high spatial specificity and deep penetration.…”