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

Abstract 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.


INTRODUCTION
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. in Alzheimer's disease (AD) patients already receiving state-of-theart treatment. 3,4 In patients with chronic disorders of consciousness, improved clinical responsiveness has been reported. 5,6 In addition, reduction of cortical atrophy in AD core areas has been described after TPS treatment. 7 While the exact cellular mechanisms of ultrasoundinduced neuromodulation are still under research, stimulation likely has an effect on cell membranes and mechanosensitive ion channels that further influence transmitter and neurotrophic factor concentrations and induce neuroplastic changes. 8 In AD patients, depression is a major and particularly problematic comorbidity. Therapeutic effects of anti-depressive medication are often limited and novel therapeutic approaches that may work as addon therapy are urgently needed. Here, we provide the very first data on such a possible new add-on therapy. We investigate anti-depressive effects of the novel clinically approved TPS therapy. In our previous multicenter AD study, improvements in depression scores were reported for up to 3 months after receiving stimulation. 3 A specific subanalysis of neuropsychological and functional imaging data from this first clinical study with navigated ultrasound is presented.

Patients
We included 20 patients from our previous study 3  the protocol, relevant intracerebral pathology unrelated to AD (e.g., brain tumor), hemophilia or blood clotting disorders or thrombosis, corticosteroid treatment within the last 6 weeks before first treatment.
After dropout, 18 patients with fMRI completed the study (informed consent was obtained).

Study design
Patients received TPS treatment for 4 weeks, with three sessions per week (except for three patients for only 2 weeks, one patient for 3 weeks). MRI data acquisition and neuropsychological tests were performed the week before and after TPS therapy. bilateral lateral parietal cortex (extending to Wernicke's area, 2 × 400 pulses per hemisphere), and extended precuneus cortex (2 × 600 pulses). As previously described, 3 individual real time tracking allowed standardized focal brain stimulation across the study participants.

Depression scores
Out of 18 patients included in this study, 14 were able to complete the BDI-II questionnaires in both sessions. On average, BDI-II score

Functional connectivity
ROI-to-ROI FC analysis using all default CONN ROIs revealed a single significant result: TPS treatment reduced FC between the left frontal orbital cortex (FOrb L; part of the ventromedial network) and the right anterior insula (AInsula R; part of the salience network defined by the CONN toolbox, Figure 2A). Intriguingly, all patients displayed a positive FC between these ROIs at baseline ( Figure 2B). To elucidate FC characteristics between the FOrb L and the AInsula R in a healthy sample, the meta-analysis tool Neurosynth (based on resting state FC data of 1000 healthy subjects) was used. 12 In contrast to our patients, the resulting Neurosynth FC map of the FOrb L (Montreal Neurological Institute coordinates X = -44, Y = 34, Z = -12) showed a negative FC to the AInsula R as normal situation (peak FC: r = -0.24).

Correlation analysis
FC values between the left FOrb L and the right AInsula R were positively correlated with the BDI-II score (rho = .434, P = .021, N = 28, Figure 1B). Higher FC values between these ROIs ( = higher disruption of normal connectivity) corresponded to more pronounced depressive symptoms. have been shown to form anti-networks, that is, negatively correlated networks. 11 This typical negative correlation in healthy persons has also been confirmed for FOrb L and AInsula R by using the FC meta-analysis tool Neurosynth. 12 A likely hypothesis therefore is that due to AD depression, the negative correlation between these areas was disrupted in our AD patients but improved after TPS. This was evident in the comprehensive ROI-to-ROI analysis as This is the first demonstration of ameliorating depressive symptoms in AD patients using ultrasound stimulation; however, there are limitations to be considered. There was no sham stimulation as a control condition. Nevertheless, the long-term course of BDI improvements as well as the specificity of network changes render a pure placebo effect unlikely. 16 Additionally, our previous neuropsychological and functional data showed that treatment response was confined to stimulated areas. 3 Concerning treatment duration, our study stimulated over a course of 2 to 4 weeks. Future studies may want to investigate longer treatment periods as well as long-term functional outcomes.
Further, the small sample size (though comparable to other recent work in this field 14,17 ) limits any premature conclusions on the generalizability of the findings.
In conclusion, we present evidence that ultrasound stimulation may be a relevant add-on treatment option for depressive symptoms in

CONFLICTS OF INTEREST
This work was supported by research grants from STORZ Medical (including equipment, to R.B). R.B. is President of the Organization for