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


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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.
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Received: 1 October 2021 Revised: 29 November 2021 Accepted: 15 December 2021 Published online: 28 January 2022
DOI: 10.1002/trc2.12245
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
Roland Beisteiner,Department of Neurology,
Medical University of Vienna, Spitalgasse 23,
A-1090 Vienna, Austria.
Funding information
Medical University of Vienna and University of
Vienna, Grant/AwardNumber: SO10300020;
STORZMedical; Austrian Science Fund,
Grant/AwardNumber: KLIF455
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
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.
Alzheimer’s disease, brain stimulation, depression, functional connectivity, functional magnetic
resonance imaging, transcranial pulse stimulation, ultrasound
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. 1of5
2of5 MATT ET AL.
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.
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
3. Single ultrasound pressure pulses were applied using a
NEUROLITH TPS generator (Storz Medical AG): duration about 3 µs,
0.2 mJ mm2energy 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),
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).
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
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.
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:
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
4of5 MATT ET AL.
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
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
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.).
This work was supported by research grants from STORZ Medical
(including equipment, to R.B). R.B. is President of the Organization for
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.
Eva Matt
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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.
... Instead, another non-invasive brain stimulation technique, Transcranial Pulse Stimulation (TPS), is now being used in a phase III study (NCT05983575). This novel ultrasoundbased stimulation allows targeting precise regions of interest, and it is reported to improve depression in AD patients [199]. The study is a multicenter, randomized, double-blinded, placebo-controlled phase 3 study comparing a LIPUS-Brain transcranial low-intensity pulsed-wave ultrasound device to a placebo in patients with early AD, and now it is in the enrollment phase. ...
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In an ever-increasing aged world, Alzheimer’s disease (AD) represents the first cause of dementia and one of the first chronic diseases in elderly people. With 55 million people affected, the WHO considers AD to be a disease with public priority. Unfortunately, there are no final cures for this pathology. Treatment strategies are aimed to mitigate symptoms, i.e., acetylcholinesterase inhibitors (AChEI) and the N-Methyl-D-aspartate (NMDA) antagonist Memantine. At present, the best approaches for managing the disease seem to combine pharmacological and non-pharmacological therapies to stimulate cognitive reserve. Over the last twenty years, a number of drugs have been discovered acting on the well-established biological hallmarks of AD, deposition of β-amyloid aggregates and accumulation of hyperphosphorylated tau protein in cells. Although previous efforts disappointed expectations, a new era in treating AD has been working its way recently. The Food and Drug Administration (FDA) gave conditional approval of the first disease-modifying therapy (DMT) for the treatment of AD, aducanumab, a monoclonal antibody (mAb) designed against Aβ plaques and oligomers in 2021, and in January 2023, the FDA granted accelerated approval for a second monoclonal antibody, Lecanemab. This review describes ongoing clinical trials with DMTs and non-pharmacological therapies. We will also present a future scenario based on new biomarkers that can detect AD in preclinical or prodromal stages, identify people at risk of developing AD, and allow an early and curative treatment.
... Observou-se também melhora do humor. 16 O sistema original do TPS deriva da aplicação das ondas de choque extracorpóreas, utilizadas há 3 décadas para afecções musculoesqueléticas, e foi aperfeiçoado com um sistema de neuronavegação através de reconstrução da arquitetura encefálica por imagem de RMN. Este novo recurso recebeu a conformidade europeia (CE). ...
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Não há dúvidas sobre os prejuízos na vida humana, extensivos à família e sociedade como um todo, abrangendo todos os aspectos funcionais das pessoas envolvidas, além do indivíduo, originados dos traumatismos cranioencefálico, agudos e crônicos, externos ou internos: acidentes, atropelamentos, quedas, crimes, acidente vascular cerebral, doenças com neurodegeneração progressiva, resultando em estados demenciais. No que se refere aos quadros crônicos, enfrentamos dificuldades diagnósticas, pela persistente impossibilidade, quase que total, de dispormos de exames subsidiários que tiveram notável progresso tecnológico nos últimos vinte e cinco anos, a exemplo dos exames através de imagens funcionais.
... Activation of regions linked to depression, such as the extended dorsolateral prefrontal cortex, seems to mitigate depressive symptoms in AD patients. Therefore, TPS could potentially serve as an innovative supplementary treatment for depression in AD and other neuropsychiatric disorders [21]. Furthermore, blood-brain barrier disruption for drug delivery effect is known [18]. ...
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The article discusses the use of transcranial pulse stimulation (TPS), a treatment method that uses ultrasound to penetrate the brain up to 8 cm. The article aims to review published studies on the effects of TPS on Alzheimer's disease and to link the mechanism of the treatment with the pathophysiology of the disease. The discussion highlights the pathological triad of senile plaques, neurofibrillary tangles, and granular degeneration that causes Alzheimer's disease. Patients with diabetes mellitus are predisposed to degenerative diseases, and the overlap between Alzheimer's disease and obesity may be explained by the use of streptozotocin, which generates reactive oxygen species leading to DNA damage and cell death. The accumulation of beta-amyloid in the brain, mitochondrial malfunction, decreased production of ATP, and energy insufficiency is also discussed. The article concludes that TPS is a potential treatment for Alzheimer's disease and that it can boost the expression of growth factors, enhance the flow of blood to the brain, trigger the creation of novel blood vessels, and promote the regeneration of nerves.
... Ultrasound neuromodulation is mainly achieved through ultrasonic mechanical effects [3], cavitation effects [4], and thermal effects [5]. Recent studies have manifested that transcranial low-intensity focused ultrasound can treat Parkinson's disease [6][7][8], epilepsy [9][10][11], Alzheimer's disease (AD) [12][13][14], and depression [15][16][17]. Moreover, transcranial focused ultrasound (tFUS) combined with microbubbles (MBs) can reversibly and precisely open the blood-brain barrier (BBB) repeatedly in specific areas of the brain, thus allowing drugs to cross the BBB into specific brain areas for achieving specific therapy [18]. ...
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Objective: Ultrasound neuromodulation has become an emerging method for the therapy of neurodegenerative and psychiatric diseases. The phased array ultrasonic transducer enables multi-target ultrasound neuromodulation in small animals, but the relatively large size and mass and the thick cables of the array limit the free movement of small animals. Furthermore, spatial interference may occur during multi-target ultrasound brain stimulation with multiple micro transducers. Approach: In this study, we developed a miniature power ultrasound transducer and used the virtual source time inversion method and 3-D printing technology to design, optimize, and manufacture the acoustic holographic lens to construct a multi-target ultrasound neuromodulation system for free-moving mice. The feasibility of the system was verified by in vitro transcranial ultrasound field measurements, in vivo dual-target blood-brain barrier opening experiments, and in vivo dual-target ultrasound neuromodulation experiments. Main results: The developed miniature transducer has a diameter of 4.0 mm, a center frequency of 1.1 MHz, and a weight of 1.25 g. The developed miniature acoustic holographic lens had a weight of 0.019 g to generate dual-focus transcranial ultrasound. The ultrasonic field measurements' results showed that the bifocal's horizontal distance was 3.0 mm, the -6 dB focal spot width in the x-direction was 2.5 and 2.25 mm, and 2.12 and 2.24 mm in the y-direction. Finally, the in vivo experimental results showed that the system could achieve dual-target blood-brain barrier opening and ultrasound neuromodulation in freely-moving mice. Significance: The ultrasonic neuromodulation system based on a miniature single-element transducer and the miniature acoustic holographic lens could achieve dual-target neuromodulation in awake small animals, which is expected to be applied to the research of non-invasive dual-target ultrasonic treatment of brain diseases in awake small animals.
Background: Transcranial pulse stimulation (TPS) is a novel noninvasive ultrasonic brain stimulation that can increase cortical and corticospinal excitability, induce neuroplasticity, and increase functional connectivity within the brain. Several trials have confirmed its potential in treating Alzheimer's disease (AD). Objective: To investigate the effect and safety of TPS on AD. Design: A systematic review. Methods: PubMed, Embase via Ovid, Web of Science, Cochrane Library, CNKI (China National Knowledge Infrastructure), VIP (China Science and Technology Journal Database), and WanFang were searched from inception to April 1, 2023. Study selection, data extraction, and quality evaluation of the studies were conducted by two reviewers independently, with any controversy resolved by consensus. The Methodological Index for Nonrandomized Studies was used to assess the risk of bias. Results: Five studies were included in this review, with a total of 99 patients with AD. For cognitive performance, TPS significantly improved the scores of the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) test battery, Alzheimer's Disease Assessment Scale (cognitive), Montreal Cognitive Assessment, and Mini-Mental Status Examination. For depressive symptoms, TPS significantly reduced the scores of the Alzheimer's Disease Assessment Scale (affective), Geriatric Depression Score, and Beck Depression Inventory. By functional magnetic resonance imaging, studies have shown that TPS improved cognitive performance in AD patients by increasing functional connectivity in the hippocampus, parahippocampal cortex, precuneus, and parietal cortex, and activating cortical activity in the bilateral hippocampus. TPS alleviated depressive symptoms in AD patients by decreasing functional connectivity between the ventromedial network (left frontal orbital cortex) and the salience network (right anterior insula). Adverse events in this review, including headache, worsening mood, jaw pain, nausea, and drowsiness, were reversible and lasted no longer than 1 day. No serious adverse events or complications were observed. Conclusions: TPS is promising in improving cognitive performance and reducing depressive symptoms in patients with AD. TPS may be a safe adjunct therapy in the treatment of AD. However, these findings lacked a sham control and were limited by the small sample size of the included studies. Further research may be needed to better explore the potential of TPS. Patient and public involvement: Patients and the public were not involved in this study.
A noninvasive brain–computer interface is a central task in the comprehensive analysis and understanding of the brain and is an important challenge in international brain-science research. Current implanted brain–computer interfaces are cranial and invasive, which considerably limits their applications. The development of new noninvasive reading and writing technologies will advance substantial innovations and breakthroughs in the field of brain–computer interfaces. Here, we review the theory and development of the ultrasound brain functional imaging and its applications. Furthermore, we introduce latest advancements in ultrasound brain modulation and its applications in rodents, primates, and human; its mechanism and closed-loop ultrasound neuromodulation based on electroencephalograph are also presented. Finally, high-frequency acoustic noninvasive brain–computer interface is prospected based on ultrasound super-resolution imaging and acoustic tweezers.
Background: MR-guided focused ultrasound is a promising intervention for treatment-resistant mental illness, and merits contextualized ethical exploration in relation to more extensive ethical literature regarding other psychosurgical and neuromodulation treatment options for this patient population. To our knowledge, this topic has not yet been explored in the published literature. Objective: The purpose of this paper is to review and discuss in detail the neuroethical implications of MR-guided focused ultrasound for neuropsychiatric illness as an emerging treatment modality. Methods: Due to the lack of published literature on the topic, the approach involved a detailed survey and review of technical and medical literature relevant to focused ultrasound and established ethical issues related to alternative treatment options for patients with treatment-resistant, severe and persistent mental illness. The manuscript is structured according to thematic and topical findings. Results: This technology has potential benefits for patients suffering with severe mental illness, compared with established alternatives. The balance of technical, neuroscientific and clinical considerations should inform ethical deliberations. The nascent literature base, nuances in legal classification and permissibility depending upon jurisdiction, influences of past ethical issues associated with alternative treatments, tone and framing in media articles, and complexity of clinical trials all influence ethical assessment and evaluations of multiple stakeholders. Recommendations for future research are provided based on these factors. Conclusion: Salient ethical inquiry should be further explored by researchers, clinicians, and ethicists in a nuanced manner methodologically, one which is informed by past and present ethical issues related to alternative treatment options, broader psychiatric treatment frameworks, pragmatic implementation challenges, intercultural considerations, and patients' ethical concerns.
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Stroke as the leading cause of adult long-term disability and has a significant impact on patients, society and socio-economics. Non-invasive brain stimulation (NIBS) approaches such as transcranial magnetic stimulation (TMS) or transcranial electrical stimulation (tES) are considered as potential therapeutic options to enhance functional reorganization and augment the effects of neurorehabilitation. However, non-invasive electrical and magnetic stimulation paradigms are limited by their depth focality trade-off function that does not allow to target deep key brain structures critically important for recovery processes. Transcranial ultrasound stimulation (TUS) is an emerging approach for non-invasive deep brain neuromodulation. Using non-ionizing, ultrasonic waves with millimeter-accuracy spatial resolution, excellent steering capacity and long penetration depth, TUS has the potential to serve as a novel non-invasive deep brain stimulation method to establish unprecedented neuromodulation and novel neurorehabilitation protocols. The purpose of the present review is to provide an overview on the current knowledge about the neuromodulatory effects of TUS while discussing the potential of TUS in the field of stroke recovery, with respect to existing NIBS methods. We will address and discuss critically crucial open questions and remaining challenges that need to be addressed before establishing TUS as a new clinical neurorehabilitation approach for motor stroke recovery.
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Autistic spectrum disorder (ASD) is a common developmental disorder in children. The latest non-intrusive brain stimulation (NIBS) technology—transcranial pulse stimulation (TPS)—has been proven effective in older adults with mild neurocognitive disorders and adults with major depressive disorder. Nonetheless, there is so far no robust randomized controlled trial (RCT) conducted on adolescents with ASD nationwide. This study proposes a two-armed (verum TPS group vs. sham TPS group), double-blinded, randomized, sham-controlled trial. Both groups will be measured at four timepoints, namely, baseline (T1), 2 weeks immediately after post-TPS intervention (T2), and at the 1-month (T3) and 3-month (T4) follow-ups. Thirty-four subjects, aged between 12 and 17, diagnosed with ASD will be recruited in this study. All subjects will be computerized randomised into the verum TPS group or the sham TPS group on a 1:1 ratio. All subjects will undertake functional MRI (fMRI) before and after the 2-weeks TPS interventions, which will be completed in 2 weeks’ time. This will be the first RCT evaluating the efficacy of TPS adolescents with ASD in Hong Kong. Clinical Trial Registration:, identifier: NCT05408793.
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Introduction: Ultrasound for the brain is a revolutionary therapeutic concept. The first clinical data indicate that 2-4 weeks of therapy with transcranial pulse stimulation (TPS) improve functional networks and cognitive performance of Alzheimer's disease (AD) patients for up to 3 months. No data currently exist on possible benefits concerning brain morphology, namely the cortical atrophy characteristic of AD. Methods: We performed a pre-/post-therapy analysis of cortical thickness in a group of N = 17 AD patients. Results: We found a significant correlation between neuropsychological improvement and cortical thickness increase in AD-critical brain areas. Discussion: AD patients who benefit from TPS appear to manifest reduced cortical atrophy within the default mode network in particular, whose memory-related subsystems are believed to be disrupted in AD. TPS may therefore hold promise as a new add-on therapy for AD.
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Purpose: Increasing attention has been paid to low-intensity transcranial focused ultrasound (tFUS) for its potential therapeutic effects in Alzheimer's disease (AD). While preclinical studies have shown promising therapeutic effects of low-intensity tFUS in AD models, its efficacy and safety remain unclear in humans. In this pilot study, we investigated the effects of low-intensity tFUS on blood-brain barrier opening, the regional cerebral metabolic rate of glucose (rCMRglu), and cognition in patients with AD. Methods: After receiving institutional review board approval, four patients with AD received tFUS to the hippocampus immediately after an intravenous injection of a microbubble ultrasound contrast agent. Sonication was delivered at low-intensity, at a pressure level below the threshold for blood-brain barrier opening. Patients underwent brain magnetic resonance imaging, 18F-fluoro-2-deoxyglucose positron emission tomography, and neuropsychological assessments before and after the tFUS procedure. A whole-brain voxel-wise paired t test was conducted to compare rCMRglu before and after tFUS. Results: The sonication, as anticipated, did not show evidence of active blood-brain barrier opening on T1 dynamic contrast-enhanced magnetic resonance imaging. rCMRglu in the superior frontal gyrus (P<0.001), middle cingulate gyrus (P<0.001), and fusiform gyrus increased after tFUS (P=0.001). Patients demonstrated mild improvement in measures of memory, executive, and global cognitive function following tFUS. No adverse events were reported. Conclusion: These results suggest that hippocampal sonication with low-intensity tFUS may have beneficial effects on cerebral glucose metabolism and cognitive function in patients with AD. Further larger studies are needed to confirm the therapeutic efficacy of tFUS in AD.
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Brain diseases are one of the most important problems in our rapidly ageing society. Currently, there are not many effective medications and surgical options are limited due to invasiveness and non‐invasive brain stimulation techniques cannot be well targeted and cannot access deep brain areas. A novel therapy is transcranial ultrasound which allows a variety of treatments without opening of the skull. Recent technological developments generated three revolutionary options including 1) targeted non‐invasive surgery, 2) highly targeted drug, antibody, or gene therapy via local opening of the blood–brain barrier, and 3) highly targeted brain stimulation to improve pathological brain functions. This progress report summarizes the current state of the art for clinical application and the results of recent patient investigations.
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Transcranial focused ultrasound (tFUS) is an emerging method for non-invasive neuromodulation akin to transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). tFUS offers several advantages over electromagnetic methods including high spatial resolution and the ability to reach deep brain targets. Here we describe two experiments assessing whether tFUS could modulate mood in healthy human volunteers by targeting the right inferior frontal gyrus (rIFG), an area implicated in mood and emotional regulation. In a randomized, placebo-controlled, double-blind study, participants received 30 s of 500 kHz tFUS or a placebo control. Visual Analog Mood Scales (VAMS) assessed mood four times within an hour (baseline and three times after tFUS). Participants who received tFUS reported an overall increase in Global Affect (GA), an aggregate score from the VAMS scale, indicating a positive shift in mood. Experiment 2 examined resting-state functional (FC) connectivity using functional magnetic resonance imaging (fMRI) following 2 min of 500 kHz tFUS at the rIFG. As in Experiment 1, tFUS enhanced self-reported mood states and also decreased FC in resting state networks related to emotion and mood regulation. These results suggest that tFUS can be used to modulate mood and emotional regulation networks in the prefrontal cortex.
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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. A new clinical brain stimulation technique is introduced, based on single ultrashort ultrasound pulses (transcranial pulse stimulation, TPS). Comprehensive feasibility, safety, and efficacy data for this new therapy are provided. Two weeks TPS treatment of 35 Alzheimer's patients reveals high treatment tolerability, no major side effects, and improved memory performance lasting up to three months.
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Ultrasound (US) is recognized for its use in medical imaging as a diagnostic tool. As an acoustic energy source, US has become increasingly appreciated over the past decade for its ability to non-invasively modulate cellular activity including neuronal activity. Data obtained from a host of experimental models has shown that low-intensity US can reversibly modulate the physiological activity of neurons in peripheral nerves, spinal cord, and intact brain circuits. Experimental evidence indicates that acoustic pressures exerted by US act, in part, on mechanosensitive ion channels to modulate activity. While the precise mechanisms of action enabling US to both stimulate and suppress neuronal activity remain to be clarified, there are several advantages conferred by the physics of US that make it an appealing option for neuromodulation. For example, it can be focused with millimeter spatial resolutions through skull bone to deep-brain regions. By increasing our engineering capability to leverage such physical advantages while growing our understanding of how US affects neuronal function, the development of a new generation of non-invasive neurotechnology can be developed using ultrasonic methods.
Focused ultrasound (FUS) is a disruptive medical technology, and its implementation in the clinic represents the culmination of decades of research. Lying at the convergence of physics, engineering, imaging, biology and neuroscience, FUS offers the ability to non-invasively and precisely intervene in key circuits that drive common and challenging brain conditions. The actions of FUS in the brain take many forms, ranging from transient blood-brain barrier opening and neuromodulation to permanent thermoablation. Over the past 5 years, we have seen a dramatic expansion of indications for and experience with FUS in humans, with a resultant exponential increase in academic and public interest in the technology. Applications now span the clinical spectrum in neurological and psychiatric diseases, with insights still emerging from preclinical models and human trials. In this Review, we provide a comprehensive overview of therapeutic ultrasound and its current and emerging indications in the brain. We examine the potential impact of FUS on the landscape of brain therapies as well as the challenges facing further advancement and broader adoption of this promising minimally invasive therapeutic alternative.
Transcranial ultrasound (TUS) provides a noninvasive neuromodulation method that has greater spatial precision than existing methods. The present study examined TUS, for the first time, as a potential depression intervention. Twenty-four college students with mild to moderate depression were randomly assigned to an Active TUS Condition or Placebo TUS (no power administered). Participants completed five TUS sessions within seven days. Although depression scores did not change differentially for TUS/Placebo, trait worry decreased in the Active TUS Condition and increased in the Placebo condition. Additionally, those in TUS Active Condition had an increase in global affect over the course of the study, whereas those in the Placebo Condition did not. These results have significant implications for the potential utility of TUS as an intervention for anxiety disorders or worry-related psychopathology, warranting future investigation of the impact of TUS in a larger sample.
Background: Repetitive transcranial magnetic stimulation (rTMS) is thought to be effective in alleviating cognitive symptoms in patients with amnestic mild cognitive impairment (aMCI), but the mechanisms related to network modification are poorly understood. Objective: Here we tested rTMS efficacy and explored the effect of rTMS-induced changes in the default mode network (DMN) and their predictive value for treatment response. Methods: Twenty-one subjects clinically diagnosed with aMCI were recruited to complete a 10-session randomized and sham-controlled rTMS treatment targeting the right dorsolateral prefrontal cortex. Resting-state functional magnetic resonance imaging in tandem with neuropsychological assessments were administered before and after the intervention. Changes in functional connectivity of the DMN and relevant brain regions, as well as the correlations between baseline functional connectivity and clinical rating scales were calculated in order to elucidate the mechanism of treatment response to rTMS therapy. Results: Compared to the sham group, the rTMS group achieved improvement of neuropsychological performance and significant functional connectivity changes within the DMN. Group×Time interactions were found between posterior cingulate gyrus and right fusiform gyrus (F (1,19) = 17.154, p = 0.001), and also left anterior cingulate gyrus (F (1,19) = 3.908, p = 0.063), showing an rTMS-induced deactivation of functional connectivity within the DMN. Baseline functional connectivity analysis of seeds within the DMN in the rTMS group revealed negative correlation with AVLT-Recognition score changes. Conclusion: rTMS-induced hypoconnectivity within DMN is associated with clinical cognitive improvements in patients with aMCI. Further, pre-rTMS baseline activity of the DMN at rest may be a predictor for favorable rTMS treatment response.