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.

In article number 1902583, Roland Beisteiner and co‐workers describe a brain activation technique for treatment of Alzheimer's disease. Transcranial pulse stimulation (TPS) applies ultrashort ultrasound pulses to activate neuronal resources. A therapeutic breakthrough is secure clinical targeting and access to deep brain areas. After 2 weeks of treatment, memory performance improves for up to 3 months.

Establishing a reliable correspondence between lesioned brains and a template is challenging using current normalization techniques. The optimum procedure has not been conclusively established, and a critical dichotomy is whether to use input data sets which contain skull signal, or whether skull signal should be removed. Here we provide a first investigation into whether clinical fMRI benefits from skull stripping, based on data from a presurgical language localization task. Brain activation changes related to deskulled/not-deskulled input data are determined in the context of very recently developed (New Segment, Unified Segmentation) and standard normalization approaches. Analysis of structural and functional data demonstrates that skull stripping improves language localization in MNI space — particularly when used in combination with the New Segment normalization technique.

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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.