Transcranial Ultrasound Innovations Ready for Broad Clinical Application

Beisteiner, Roland; Lozano, Andrés M.

doi:10.1002/advs.202002026

Cited by 38 publications

(41 citation statements)

References 64 publications

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“…Thus, a large body of preclinical and clinical evidence suggests that the blood–brain barrier (BBB) opening by FUS can be done safely [ 54 , 55 ]. However, potential risks should be noted, including microbleeds, cellular vacuolation, ischemia due to vasoconstriction, cerebral edema, and direct cellular injury from physical forces, even at the typical low sound pressure [ 56 ]. Since most neuromodulation studies have been done without BBB opening and generated clear neurophysiologial effects, non-BBB opening ultrasound ("focused" and "unfocused") might be a safer therapeutic option.…”

Section: Discussionmentioning

confidence: 99%

Effects of transcranial ultrasound stimulation pulsed at 40 Hz on Aβ plaques and brain rhythms in 5×FAD mice

Park

Hoang

Nguyen

et al. 2021

Transl Neurodegener

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Background Alzheimer’s disease (AD) is the most common cause of dementia, and is characterized by amyloid-β (Aβ) plaques and tauopathy. Reducing Aβ has been considered a major AD treatment strategy in pharmacological and non-pharmacological approaches. Impairment of gamma oscillations, which play an important role in perception and cognitive function, has been shown in mouse AD models and human patients. Recently, the therapeutic effect of gamma entrainment in AD mouse models has been reported. Given that ultrasound is an emerging neuromodulation modality, we investigated the effect of ultrasound stimulation pulsed at gamma frequency (40 Hz) in an AD mouse model. Methods We implanted electroencephalogram (EEG) electrodes and a piezo-ceramic disc ultrasound transducer on the skull surface of 6-month-old 5×FAD and wild-type control mice (n = 12 and 6, respectively). Six 5×FAD mice were treated with two-hour ultrasound stimulation at 40 Hz daily for two weeks, and the other six mice received sham treatment. Soluble and insoluble Aβ levels in the brain were measured by enzyme-linked immunosorbent assay. Spontaneous EEG gamma power was computed by wavelet analysis, and the brain connectivity was examined with phase-locking value and cross-frequency phase-amplitude coupling. Results We found that the total Aβ42 levels, especially insoluble Aβ42, in the treatment group decreased in pre- and infra-limbic cortex (PIL) compared to that of the sham treatment group. A reduction in the number of Aβ plaques was also observed in the hippocampus. There was no increase in microbleeding in the transcranial ultrasound stimulation (tUS) group. In addition, the length and number of microglial processes decreased in PIL and hippocampus. Encelphalographic spontaneous gamma power was increased, and cross-frequency coupling was normalized, implying functional improvement after tUS stimulation. Conclusion These results suggest that the transcranial ultrasound-based gamma-band entrainment technique can be an effective therapy for AD by reducing the Aβ load and improving brain connectivity.

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Section: Discussionmentioning

confidence: 99%

Effects of transcranial ultrasound stimulation pulsed at 40 Hz on Aβ plaques and brain rhythms in 5×FAD mice

Park

Hoang

Nguyen

et al. 2021

Transl Neurodegener

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“…Recently, the novel therapeutic concept of ultrasound‐based brain stimulation has been introduced as a promising clinical add‐on therapy. 1 With navigated ultrasound techniques (focused ultrasound [FUS], transcranial pulse stimulation [TPS]) neuromodulation is no longer limited to superficial brain areas but allows 3D targeting of deep areas of the human brain. 2 The small ultrasound foci are independent from pathological conductivity changes and therefore brain areas can be targeted with unprecedented precision.…”

Section: Introductionmentioning

confidence: 99%

Transcranial pulse stimulation (TPS) improves depression in AD patients on state‐of‐the‐art treatment

Matt

Dörl

Beisteiner

2022

A&D Transl Res & Clin Interv

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Introduction Ultrasound‐based brain stimulation is a novel, non‐invasive therapeutic approach to precisely target regions of interest. Data from a first clinical trial of patients with Alzheimer's disease (AD) receiving 2‐4 weeks transcranial pulse stimulation (TPS) have shown memory and cognitive improvements for up to 3 months, despite ongoing state‐of‐the‐art treatment. Importantly, depressive symptoms also improved. Methods We analyzed changes in Beck Depression Inventory (BDI‐II) and functional connectivity (FC) changes with functional magnetic resonance imaging in 18 AD patients. Results We found significant improvement in BDI‐II after TPS therapy. FC analysis showed a normalization of the FC between the salience network (right anterior insula) and the ventromedial network (left frontal orbital cortex). Discussion Stimulation of areas related to depression (including extended dorsolateral prefrontal cortex) appears to alleviate depressive symptoms and induces FC changes in AD patients. TPS may be a novel add‐on therapy for depression in AD and as a neuropsychiatric diagnosis.

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“…While the I SPPA for TPS lies within the FDA limits for cephalic use (I SPPA = 190 W/ cm 2 ), the I SPTA is marginally higher (I SPTA = 94 mW/cm 2 ) and the MI exceeds respective FDA limits (MI = 1.90) [26]. However, comprehensive animal studies exist for therapeutic ultrasound applications and have been used for the successful clinical certification process of TPS [13]. Indeed, TPS is clinically certified as therapy for Alzheimer's disease (CE mark).…”

Section: Transcranial Pulse Stimulation (Tps)mentioning

confidence: 99%

“…Recently, we introduced transcranial pulse stimulation (TPS) [11][12][13], a new NIBS technique that is based on single ultrashort ultrasound pulses (3 µs, repeated every 200-300 ms). With a lateral resolution comparable to tFUS, TPS allows a spatially distinct brain stimulation as well.…”

Section: Introductionmentioning

confidence: 99%

First evidence of long-term effects of transcranial pulse stimulation (TPS) on the human brain

et al. 2022

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Background With the high spatial resolution and the potential to reach deep brain structures, ultrasound-based brain stimulation techniques offer new opportunities to non-invasively treat neurological and psychiatric disorders. However, little is known about long-term effects of ultrasound-based brain stimulation. Applying a longitudinal design, we comprehensively investigated neuromodulation induced by ultrasound brain stimulation to provide first sham-controlled evidence of long-term effects on the human brain and behavior. Methods Twelve healthy participants received three sham and three verum sessions with transcranial pulse stimulation (TPS) focused on the cortical somatosensory representation of the right hand. One week before and after the sham and verum TPS applications, comprehensive structural and functional resting state MRI investigations and behavioral tests targeting tactile spatial discrimination and sensorimotor dexterity were performed. Results Compared to sham, global efficiency significantly increased within the cortical sensorimotor network after verum TPS, indicating an upregulation of the stimulated functional brain network. Axial diffusivity in left sensorimotor areas decreased after verum TPS, demonstrating an improved axonal status in the stimulated area. Conclusions TPS increased the functional and structural coupling within the stimulated left primary somatosensory cortex and adjacent sensorimotor areas up to one week after the last stimulation. These findings suggest that TPS induces neuroplastic changes that go beyond the spatial and temporal stimulation settings encouraging further clinical applications.

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Transcranial Ultrasound Innovations Ready for Broad Clinical Application

Cited by 38 publications

References 64 publications

Effects of transcranial ultrasound stimulation pulsed at 40 Hz on Aβ plaques and brain rhythms in 5×FAD mice

Effects of transcranial ultrasound stimulation pulsed at 40 Hz on Aβ plaques and brain rhythms in 5×FAD mice

Transcranial pulse stimulation (TPS) improves depression in AD patients on state‐of‐the‐art treatment

First evidence of long-term effects of transcranial pulse stimulation (TPS) on the human brain

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