Low intensity focused ultrasound (LIFU) is poised to become a paradigm-shifting technology with the potential to deliver non-invasive, reversible, and focal deep brain stimulation. Best understood as a type of transcranial ultrasound, LIFU uses acoustic energy to modulate regional brain activity, reaching deep and subcortical brain regions implicated in psychiatric disorders at high spatial precision [1]. In contrast to high intensity focused ultrasound, which is thermally ablative, LIFU appears to reversibly modulate neural activity, presumably without injury.
There is an emerging literature describing potential mechanisms of LIFU. One possibility is thermal (i.e., the mechanism underlying ablative high intensity focused ultrasound), yet LIFU delivers insufficient energy to meaningfully raise tissue temperature. Other mechanisms have been proposed, including opening of mechanosensitive ion channels, and even microtubule resonance (for the interested reader, see [2]). There are also growing indications of the promise of this technology. Nonhuman primate work demonstrates that LIFU can reversibly suppress amygdala and anterior cingulate activity, with effects lasting up to several hours after sonication [3]. In humans, LIFU has been shown to attenuate amplitudes of somatosensory-evoked potentials when targeting the somatosensory cortex [4], and modulate pain perception when applied to the subcortical thalamus [5] in healthy participants. Few studies have evaluated LIFU in patients, though an initial report indicated that thalamic-targeted LIFU may improve symptoms in patients with disorders of consciousness [6].
Like any neuromodulation, there are important technical elements to understand. LIFU uses a piezoelectric transducer that converts electrical signal into an acoustic beam, typically focused to a small ellipsis a few millimeters wide and centimeters long. A duty cycle describes the time in a cycle the machine is on and the total energy delivered is expressed in units of intensity, typically constrained by the US Food and Drug Administration’s upper limit of safety for diagnostic ultrasound. Furthermore, because LIFU is delivered through the skull, individual variability (e.g., skull density and composition) may impact accurate administration.
As with any new field, there is no shortage of important questions. First and foremost, is LIFU safe? As mentioned above, safety standards were developed before the current technology existed, underscoring the need to carefully establish safe use. Since LIFU uses acoustic (i.e., mechanical) energy, and many deep brain regions are adjacent to important components of the cerebral vasculature (e.g., circle of Willis), very cautious implementation is warranted. To date, LIFU appears to disrupt neural targets, though the directionality of effects (i.e., inhibitory or excitatory) is yet unknown. Whether this technology reliably modulates deep brain regions is an active area of inquiry; if successful, LIFU will open an entirely novel way to evaluate neurophysiological and clinical effects from direct target engagement.
In pursuit of answers, we launched a first-in-patient study to apply a controlled use of LIFU to modulate the amygdala in depressed patients (NCT05147142), and the first patient received LIFU in October 2021. Caveats aside, LIFU is poised to be a transformative technology in neuropsychiatric research and treatment. For the first time, non-invasive, reversible deep brain stimulation may be within our reach.
References
Arulpragasam AR, et al. Low intensity focused ultrasound for non-invasive and reversible deep brain neuromodulation-A paradigm shift in psychiatric research. Front Psychiatry. 2022;13:825802.
Dell’Italia J, et al. Current state of potential mechanisms supporting low intensity focused ultrasound for neuromodulation. Front Hum Neurosci. 2022;16:872639.
Folloni D, et al. Manipulation of subcortical and deep cortical activity in the primate brain using transcranial focused ultrasound stimulation. Neuron. 2019;101:1109–1116.e5
Legon W, et al. Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans. Nat Neurosci. 2014;17:322–9.
Badran BW, et al. Sonication of the anterior thalamus with MRI-Guided transcranial focused ultrasound (tFUS) alters pain thresholds in healthy adults: A double-blind, sham-controlled study. Brain Stimul. 2020;13:1805–12.
Monti MM, et al. Non-invasive ultrasonic thalamic stimulation in disorders of consciousness after severe brain injury: a first-in-man report. Brain Stimul. 2016;9:940–1.
Funding
Effort on this article was supported by NIMH (U01 MH123427). NSP is additionally supported by NIH grants (R01 MH120126, P20 GM130452) and US Department of Veterans Affairs (I50 RX002864, I01 RX002450, I01 HX002572, and I01 CX002088). ARA is supported by U01 MH123427. The views expressed here are the authors’ and do not reflect the position or policies of the NIMH or VA.
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Philip, N.S., Arulpragasam, A.R. Reaching for the unreachable: low intensity focused ultrasound for non-invasive deep brain stimulation. Neuropsychopharmacol. 48, 251–252 (2023). https://doi.org/10.1038/s41386-022-01386-2
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DOI: https://doi.org/10.1038/s41386-022-01386-2
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