Transcranial Pulse Stimulation with Ultrasound in Alzheimer's Disease—A New Navigated Focal Brain Therapy

Abstract

Ultrasound‐based brain stimulation techniques may become a powerful new technique to modulate the human brain in a focal and targeted manner. However, for clinical brain stimulation no certified systems exist and the current techniques have to be further developed. Here, a clinical sonication technique is introduced, based on single ultrashort ultrasound pulses (transcranial pulse stimulation, TPS) which markedly differs from existing focused ultrasound techniques. In addition, a first clinical study using ultrasound brain stimulation and first observations of long term effects are presented. Comprehensive feasibility, safety, and efficacy data are provided. They consist of simulation data, laboratory measurements with rat and human skulls and brains, in vivo modulations of somatosensory evoked potentials (SEP) in healthy subjects (sham controlled) and clinical pilot data in 35 patients with Alzheimer's disease acquired in a multicenter setting (including neuropsychological scores and functional magnetic resonance imaging (fMRI)). Preclinical results show large safety margins and dose dependent neuromodulation. Patient investigations reveal high treatment tolerability and no major side effects. Neuropsychological scores improve significantly after TPS treatment and improvement lasts up to three months and correlates with an upregulation of the memory network (fMRI data). The results encourage broad neuroscientific application and translation of the method to clinical therapy and randomized sham‐controlled clinical studies.

Transcranial Ultrasound Innovations Ready for Broad Clinical Application

“…[51] However, recent technologies have been considerably improved and a novel pulsed stimulation approach has been introduced, which can avoid these dangers (TPS). [41] Extending the previous animal data, the TPS study is also the first to report on minor transient events associated with ultrasound brain stimulation in humans. The authors found rare events of headache (4% of participants), mood deterioration (3%), pain (8%), and painless pressure sensations (17%) in their patient population.…”

“…This system applies a different ultrasound technology that is based on single ultrashort ultrasound pulses (transcranial pulse stimulation [TPS]). [41] The pulse durations are not in the millisecond range but the microsecond range (about 3 µs duration), and single pulses are repeated with a frequency between 4 and 8 Hz. Again, every target area is sonicated for several minutes.…”

“…Progress has also been made to avoid brain heating and secondary stimulation maxima. [41] For a typical brain stimulation study with healthy human subjects a single target area-which is important for the investigated brain function-is individually predefined and then targeted with or without neuronavigation. Changes in brain function are monitored behaviorally and via electroencephalography or fMRI.…”

“…Setting with the transcranial pulse stimulation system (TPS) for individualized brain stimulation therapy. [41] With TPS transcranial ultrasound can be targeted with millimeter precision to every superficial and deep area of the patient's brain.…”

“…However, very recently a first clinical study was performed and also investigated long-term effects in 35 Alzheimer's patients. [41] Using the clinically approved TPS technique, data from precise stimulation of a single small focus (primary somatosensory cortex) and from stimulating multiple areas of a cognitive network have been recorded. With TPS, the typical procedure requires recording of individual anatomical MRI data for individual definition of target areas.…”