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.

Full text

Received: 1 October 2021 Revised: 29 November 2021 Accepted: 15 December 2021 Published online: 28 January 2022
DOI: 10.1002/trc2.12245
SHORT REPORT
Transcranial pulse stimulation (TPS) improves depression in AD
patients on state-of-the-art treatment
Eva Matt Gregor Dörl Roland Beisteiner
Department of Neurology, Medical University
of Vienna, Vienna, Austria
Correspondence
Roland Beisteiner,Department of Neurology,
Medical University of Vienna, Spitalgasse 23,
A-1090 Vienna, Austria.
Email: roland.beisteiner@meduniwien.ac.at
Funding information
Medical University of Vienna and University of
Vienna, Grant/AwardNumber: SO10300020;
STORZMedical; Austrian Science Fund,
Grant/AwardNumber: KLIF455
Abstract
Introduction: Ultrasound-based brain stimulation is a novel, non-invasive therapeu-
tic 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 stimula-
tion (TPS) have shown memory and cognitive improvementsfor 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 func-
tional 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 dorso-
lateral 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.
KEYWORDS
Alzheimer’s disease, brain stimulation, depression, functional connectivity, functional magnetic
resonance imaging, transcranial pulse stimulation, ultrasound
1INTRODUCTION
Recently, the novel therapeutic concept of ultrasound-based brain
stimulation has been introduced as a promising clinical add-on
therapy.1With 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.2The small ultrasound foci are inde-
pendent from pathological conductivity changes and therefore brain
areas can be targeted with unprecedented precision. First clinical stud-
ies with navigated ultrasound have shown cognitive improvements
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
© 2022 The Authors. Alzheimer’s & Dementia: TranslationalResearch & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
in Alzheimer’s disease (AD) patients already receiving state-of-the-
art 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.7While the exact cellular mechanisms of ultrasound-
induced neuromodulation are still under research, stimulation likely
has an effect on cell membranes and mechanosensitive ion channels
that further influence transmitter and neurotrophic factor concentra-
tions and induce neuroplastic changes.8
In AD patients, depression is a major and particularly problem-
atic comorbidity. Therapeuticeffects of anti-depressive medication are
Alzheimer’s Dement. 2022;8:e12245. wileyonlinelibrary.com/journal/trc2 1of5
https://doi.org/10.1002/trc2.12245

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often limited and novel therapeutic approaches that may work as add-
on 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 previ-
ous multicenter AD study, improvements in depression scores were
reported for up to 3 months after receiving stimulation.3A specific sub-
analysis of neuropsychological and functional imaging data from this
first clinical study with navigated ultrasound is presented.
2METHODS
2.1 Patients
We included 20 patients from our previous study3for whom func-
tional magnetic resonance imaging (fMRI) data were available. Clinical
AD was diagnosed according to International Classification of Diseases
10th revision (F00) and National Institute on Aging criteria. While most
patients suffered from mild to moderate AD with a Mini-Mental State
Examination (MMSE) score of ≥18, an MMSE cutoff was not imple-
mented to minimize inclusion criteria and heighten patient variability
(mean MMSE =20.94, standard deviation =5.8, range =6–30). Specif-
ically, inclusion criteria were clinically stable patients with probable
AD, at least 3 months of stable antidementia therapy (if any), age ≥18,
signed informed consent. Exclusion criteria were noncompliance with
the protocol, relevant intracerebral pathology unrelated to AD (e.g.,
brain tumor), hemophilia or blood clotting disorders or thrombosis, cor-
ticosteroid treatment within the last 6 weeks before first treatment.
After dropout, 18 patients with fMRI completed the study (informed
consent was obtained).
2.2 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 per-
formed the week before and after TPS therapy.
2.3 TPS treatment and regions of interest
TPS generates single ultrashort pulses with a broad frequency spec-
trum that can be administered with a repetition frequency range of
1to8Hz
3. Single ultrasound pressure pulses were applied using a
NEUROLITH TPS generator (Storz Medical AG): duration about 3 µs,
0.2 mJ mm−2energy flux density,pulse repetition frequency 5 Hz, 6000
pulses per session. Individual regions of interest (ROIs) were defined
by a neurologist (R.B.) to target brain areas relevant to AD. These
included the classical AD and depression stimulation target dorsolat-
eral prefrontal cortex, areas of the memory (including default mode
network) and language networks. Specifically, ROIs comprised: bilat-
eral frontal cortex (dorsolateral prefrontal cortex and inferior frontal
cortex extending to Broca’s area, 2 ×800 pulses per hemisphere),
RESEARCH IN CONTEXT
1. Systematic review: Depression is a widespread comor-
bidity of Alzheimer’s disease (AD). Our previous and very
first AD study indicated that ultrasound-based brain stim-
ulation further improves memory, cognitive functions,
and network connectivity in patients already on state-
of-the-art treatment. Intriguingly, also depression scores
improved up to 3 months. The present study performs a
detailed subanalysis of possible antidepressive transcra-
nial pulse stimulation (TPS) effects based on neuropsy-
chological and functional imaging data. No similar study
on antidepressive effects of ultrasound in AD is available
(PubMed search).
2. Interpretation: Results indicate a specific antidepressive
effect of TPS brain stimulation, which is based on a nor-
malization of functional connectivity between key net-
works for depression.
3. Future directions: We provide first evidence that TPS
brain stimulation is an effective tool as add-on therapy for
AD patients on state-of-the-art treatment. Future studies
with precisely targeted TPS may open novel avenues for
add-on effects on neuropsychiatric symptoms.
bilateral lateral parietal cortex (extending to Wernicke’s area, 2 ×400
pulses per hemisphere), and extended precuneus cortex (2 ×600
pulses). As previously described,3individual real time tracking allowed
standardized focal brain stimulation across the study participants.
2.4 MRI parameter
MRI sequences were acquired using a 3 T SIEMENS PRISMA MR
with a 64-channel head coil. For anatomical navigation scans, a T1-
weighted structural image was recorded using a MPRAGE sequence
(TE/TR =2.7/1800 ms, inversion time =900 ms, flip angle =9◦,res-
olution 1 mm isotropic). For functional images, a T2*-weighted EPI
sequence was used, with 38 slices aligned to AC-PC and covering the
whole brain (TE/TR =30/2500 ms, flip angle =90◦, in-plane accelera-
tion =GRAPPA 2, FOV =230 ×230 mm, voxel size =1.8 ×1.8 ×3 mm,
25% gap). Two hundred fifty volumes (10 minutes 25 seconds) for rest-
ing state fMRI were recorded.
2.5 Behavioral assessments
For detailed analysis of depressive symptoms and correlation
with fMRI results, the Beck Depression Inventory (BDI-II) was
used. BDI-II values were not normally distributed according to
Kolmogorov-Smirnov test and were thus analyzed using the nonpara-
metric Wilcoxon test for two paired variables (SPSS v24).

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FIGURE 1 Depression reduction and functional connectivity correlation. A, Beck Depression Inventory (BDI) score before and after
transcranial pulse stimulation (TPS). Depressive symptoms improved significantly (* P<.05) after the stimulation. B, Correlation between BDI-II
depression score and region of interest (ROI)-to-ROI functional connectivity (FC) between left frontal orbital cortex (FOrb L) and right anterior
insula (AInsula R). Data for the baseline are depicted in blue and for the post-stimulation sessions after the TPS interventions in red. The significant
positive correlation (rho =.434, P=.021, N =28) indicates that increased FC between these ROIs corresponds to more severe depressive
symptoms
2.6 Functional connectivity analysis
For the resting state data analysis, all preprocessing procedures and
analyses were performed using the CONN toolbox v19c.9The CONN
default preprocessing comprised realignment, unwarping, slice-time
correction, band segmentation, normalization, outlier detection, and
smoothing (8 mm full width half-maximum kernel). Subsequently, data
were denoised using a band pass filter (0.008 to 0.09 Hz), removing
motion confounds (six motion parameters and their first derivatives),
applying aCompCor10 and scrubbing. Bivariate correlations of the cor-
rected time series of all voxels were calculated for first-level analysis.
On group level, an ROI-to-ROIanalysis was performed including all 164
default ROIs in the CONN toolbox (Harvard-Oxford cortical and sub-
cortical ROIs and network ROIs derived from the HCP dataset). Based
on fMRI depression literature affected key networks are the default
mode network, the ventromedial network, and the salience network.11
The post-stimulation session was compared to the baseline using the
connection threshold 0.05 p-FDR corrected, combined with a multi-
voxelpattern analysis omnibus test on ROI level (cluster threshold 0.05
p-uncorrected). Individual functional connectivity (FC) values of signif-
icant ROI-to-ROI connections (post-stimulation vs. baseline) were cor-
related with BDI-II scores using non-parametric Spearman rank corre-
lation analysis.
3RESULTS
3.1 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
was 7.36 (standard deviation [SD] =5.09, N =14) at baseline and 5.00
(SD =4.11, N =14) in the post-stimulation session (Figure 1A). Com-
parison between both sessions using the non-parametric Wilcoxontest
revealed a significant improvement of depressive symptoms after TPS
interventions (P=.037, two-tailed).
3.2 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 eluci-
date 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 (Mon-
treal 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).
3.3 Correlation analysis
FC values between the left FOrb L and the right AInsula R were pos-
itively 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.

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FIGURE 2 Functional connectivity changes after transcranial pulse stimulation (TPS) treatment in Alzheimer’s disease patients. A, Region of
interest (ROI) functional connectivity (FC). ROI-to-ROI analysis resulted in a significantly lower FC between the left frontal orbital cortex (FOrbL)
and the right anterior insula (AInsula R) in the post stimulation session compared to the baseline. B, Individual FC between FOrb L and AInsula R in
the baseline and in the post-stimulation session with the mean values marked in gray. At baseline, the FC values of all patients were positive, but
after the stimulation the FC values decreased in 15 out of 18 patients
4DISCUSSION
We introduce a possible novel add-on therapy for depression in AD
patients based on navigated ultrasound pulses (TPS). Stimulation of
multiple brain areas, including extended dorsolateral prefrontal cor-
tex, led to a significant improvement in BDI-II evaluations. Considering
mood improvements in healthy subjects13 and depressed students,14
there now are several lines of evidence that precisely 3D-navigated
ultrasound may become a valuable add-on therapy for depression. This
will offer an additional chance for AD patients, already on state-of-the-
art treatment (i.e., anti-dementia medication, cognitive training, occu-
pational and physical therapy, dietary measures, etc.).
Corresponding to improvement of AD depression, FC data showed
a significant connectivity normalization between the ventromedial
network (VMN) and the salience network (SN). The VMN and SN
have been proposed as relevant networks regarding depression and
have been shown to form anti-networks, that is, negatively corre-
lated networks.11 This typical negative correlation in healthy per-
sons has also been confirmed for FOrb L and AInsula R by using
the FC meta-analysis tool Neurosynth.12 A likely hypothesis there-
fore 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
well as in our single patient data; in 15 out of 18 patients the cor-
relation coefficient decreased, indicating a trend toward the typical
negative FC. The remaining three patients, showing an increase in
FC, can potentially be viewed as atypical responders. Future stud-
ies may clarify individual response patterns. Current understand-
ing of functional networks in depression is still incomplete15 and is
even less clear for depression as a comorbidity in AD. Our observa-
tion provides a possible functional basis for depression improvement
in AD.
This is the first demonstration of ameliorating depressive symptoms
in AD patients using ultrasound stimulation; however, there are limi-
tations 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 stim-
ulated areas.3Concerning 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 field14,17) limits any premature conclusions on the generalizabil-
ity of the findings.
In conclusion, we present evidence that ultrasound stimulation may
be a relevant add-on treatment option for depressive symptoms in
AD and possibly also in depression. For patients already on optimized
pharmacological therapy, this holds the possibility to improve, besides
memory functions, also depressive symptoms and increase quality
of life. While promising, further investigations are needed to better
understand stimulation effects on the functional basis of depressive
symptoms.
ACKNOWLEDGMENTS
This work was supported by a research-cluster grant from the Medi-
cal University of Vienna and University of Vienna (SO10300020) and
by research grants from STORZ Medical (to R.B.). MRI methodology
was partially developed via support of the Austrian Science Fund (FWF
KLIF455, to R.B.).
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

MATT ET AL.5of5
Human Brain Mapping Alpine Chapter and the Austrian Society for
fMRI (unpaid). E.M. received travel grants from the Austrian Research
Association (ÖFG). G.D. has nothing to declare.
ORCID
Eva Matt https://orcid.org/0000-0003-2343-2191
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How to cite this article: Matt E, Dörl G, Beisteiner R.
Transcranial pulse stimulation (TPS) improves depression in
AD patients on state-of-the-art treatment. Alzheimer’s Dement.
2022;8:e12245. https://doi.org/10.1002/trc2.12245