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.

Keywords: Alzheimer's disease; brain stimulation; ultrasound.

Figure 1

Transcranial Pulse Stimulation technique TPS. A) Goggles (affixed to the head) and TPS handpiece are equipped with infrared reflectors for visualization and tracking of the TPS focus to regions of interest in individual anatomical MR images. For TPS treatment plenty of bubble‐free ultrasound gel has to be applied on skin and hair at the treatment area to avoid acoustic impedance borders. B) TPS applies ultrashort ultrasound pulses lasting about 3 µs (left) which reduce the risk for brain heating or secondary maxima. Previous brain sonication techniques typically use ultrasound trains in the range of several hundred ms (right). C) Reliable focal targeting of TPS either to a single stimulation focus (left) or for targeting region of interest borders (blue circles, right). Each pulse leaves a colored mark inside the ROI with colors indicating local pulse counts (yellow to pink = low to high numbers). Consent for publishing this figure exists.

Figure 2

TPS neuromodulation in ten healthy subjects. A) Transcranial pulse stimulation (TPS): Highly focal stimulation of the primary somatosensory representation of the right hand, definied on individual MR images. B) Study design: sham and verum stimulation were compared within the same subjects. 1 baseline measurement of median nerve somatosensory evoked potentials (SEPs) was followed by three runs of TPS stimulation (10/100/1000 pulses in fixed order), each followed by an additional recording of SEPs. C) SEP results: Increase of TPS neuromodulation effects with an increase of pulses: with ten pulses N140 decreased (verum stimulation in red), with 100 pulses additionally N70 increased and with 1000 pulses also P27 decreased.

Figure 3

Neuropsychological improvements in Alzheimer's disease after TPS therapy. CERAD score changes (mean +/− 1 standard error) over time. Significant score changes relative to the baseline Prestim are marked by an asterisk. A) The global outcome parameter for the patients cognitive state CERAD CTS (corrected total score) improves significantly after TPS treatment. B) The CERAD logistic regression score (LR) also improved. LR focuses on tests important for AD type dementia. Results for CERAD Factors are shown in (C)–(E). Whereas C) Memory and D) Verbal functions improved over time, E) Figural functions declined. This can be explained by the fact that occipito‐parietal areas involved in figural processing, were not included in the treatment scheme.