Ultrasonic Neuromodulation for Alzheimer's Disease
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: University of Utah
Disqualifiers: Stroke, Suicidal ideation, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This study will evaluate a new form of non-invasive deep brain therapy for individuals with Alzheimer's disease. Low-intensity transcranial focused ultrasound stimulation will first be delivered using a range of stimulation parameters during psychophysical and physiological monitoring. A well-tolerated stimulation protocol will be selected for subsequent testing in a blinded randomized sham-controlled cross-over trial. The trial will evaluate brain target engagement using magnetic resonance imaging, PET imaging, and numerical scales of cognitive performance.
Will I have to stop taking my current medications?
The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.
What data supports the effectiveness of the treatment Diadem prototype for Alzheimer's Disease?
Research shows that transcranial pulse stimulation (TPS), a type of ultrasound brain treatment, can improve memory and cognitive function in Alzheimer's patients for up to three months. It also helps reduce depressive symptoms and is well-tolerated with no major side effects.
12345Is ultrasonic neuromodulation safe for humans?
Ultrasonic neuromodulation, including techniques like transcranial pulse stimulation (TPS) and low intensity focused ultrasound (LIFU), has been studied for safety in humans. Studies show that these methods are generally well-tolerated with no major side effects, although some participants reported mild symptoms like neck pain and headaches, which were temporary. Overall, the safety profile is similar to other non-invasive brain stimulation methods.
13467How does the treatment Diadem prototype differ from other treatments for Alzheimer's disease?
The Diadem prototype uses ultrasonic neuromodulation, a novel non-invasive technique that uses ultrasound waves to target and modulate brain activity, which is different from traditional drug-based treatments. This method can focus on specific brain areas with high precision, potentially improving memory networks and cognitive function without major side effects.
138910Eligibility Criteria
This trial is for individuals aged 65-80 with mild cognitive impairment or early-stage dementia due to Alzheimer's, confirmed by specific biomarkers. Participants must have a certain level of cognitive function (MOCA > 18) and be able to complete an MRI. Those with recent strokes, other brain diseases, or suicidal thoughts cannot join.Inclusion Criteria
I have mild memory problems or mild dementia due to Alzheimer's, confirmed by tests.
I am between 65 and 80 years old.
MOCA > 18
Exclusion Criteria
Suicidal ideation
I cannot undergo an MRI scan.
I have had a stroke or been diagnosed with cerebral amyloid angiopathy in the last year.
+1 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Initial Stimulation and Monitoring
Low-intensity transcranial focused ultrasound stimulation delivered with various parameters during psychophysical and physiological monitoring
4 weeks
Multiple visits for parameter testing and monitoring
Blinded Randomized Sham-Controlled Cross-Over Trial
Testing of selected stimulation protocol in a blinded randomized sham-controlled cross-over trial
8 weeks
Regular visits for treatment and assessments
Follow-up
Participants are monitored for safety and effectiveness after treatment using cognitive assessments and imaging
4 weeks
2 visits (in-person)
Participant Groups
The study tests the Diadem prototype, which uses low-intensity ultrasound waves aimed at the brain to improve cognition in Alzheimer's patients. It includes initial testing to find a safe protocol followed by a blinded comparison where some get real treatment and others don't.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: Active stimulationExperimental Treatment1 Intervention
Low-intensity transcranial focused ultrasound stimulation of deep brain targets affected by Alzheimer's disease.
Group II: Sham stimulationPlacebo Group1 Intervention
Sham stimulation that applies the device in the same way as verum but only delivers auditory sounds correspoding to the ultrasonic pulses.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of UtahSalt Lake City, UT
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Who Is Running the Clinical Trial?
University of UtahLead Sponsor
References
Transcranial Pulse Stimulation with Ultrasound in Alzheimer's Disease-A New Navigated Focal Brain Therapy. [2023]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.
Transcranial pulse stimulation (TPS) improves depression in AD patients on state-of-the-art treatment. [2022]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.
General-Purpose Ultrasound Neuromodulation System for Chronic, Closed-Loop Preclinical Studies in Freely Behaving Rodents. [2022]Transcranial focused ultrasound stimulation (tFUS) is an effective noninvasive treatment modality for brain disorders with high clinical potential. However, the therapeutic effects of ultrasound neuromodulation are not widely explored due to limitations in preclinical systems. The current preclinical studies are head-fixed, anesthesia-dependent, and acute, limiting clinical translatability. Here, this work reports a general-purpose ultrasound neuromodulation system for chronic, closed-loop preclinical studies in freely behaving rodents. This work uses microelectromechanical systems (MEMS) technology to design and fabricate a small and lightweight transducer capable of artifact-free stimulation and simultaneous neural recording. Using the general-purpose system, it can be observed that state-dependent ultrasound neuromodulation of the prefrontal cortex increases rapid eye movement (REM) sleep and protects spatial working memory to REM sleep deprivation. The system will allow explorative studies in brain disease therapeutics and neuromodulation using ultrasound stimulation for widespread clinical adoption.
First evidence of long-term effects of transcranial pulse stimulation (TPS) on the human brain. [2022]With the high spatial resolution and the potential to reach deep brain structures, ultrasound-based brain stimulation techniques offer new opportunities to non-invasively treat neurological and psychiatric disorders. However, little is known about long-term effects of ultrasound-based brain stimulation. Applying a longitudinal design, we comprehensively investigated neuromodulation induced by ultrasound brain stimulation to provide first sham-controlled evidence of long-term effects on the human brain and behavior.
Transcranial ultrasound pulse stimulation reduces cortical atrophy in Alzheimer's patients: A follow-up study. [2023]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.
A retrospective qualitative report of symptoms and safety from transcranial focused ultrasound for neuromodulation in humans. [2021]Low intensity transcranial focused ultrasound (LIFU) is a promising method of non-invasive neuromodulation that uses mechanical energy to affect neuronal excitability. LIFU confers high spatial resolution and adjustable focal lengths for precise neuromodulation of discrete regions in the human brain. Before the full potential of low intensity ultrasound for research and clinical application can be investigated, data on the safety of this technique is indicated. Here, we provide an evaluation of the safety of LIFU for human neuromodulation through participant report and neurological assessment with a comparison of symptomology to other forms of non-invasive brain stimulation. Participants (N = 120) that were enrolled in one of seven human ultrasound neuromodulation studies in one laboratory at the University of Minnesota (2015-2017) were queried to complete a follow-up Participant Report of Symptoms questionnaire assessing their self-reported experience and tolerance to participation in LIFU research (Isppa 11.56-17.12 W/cm2) and the perceived relation of symptoms to LIFU. A total of 64/120 participant (53%) responded to follow-up requests to complete the Participant Report of Symptoms questionnaire. None of the participants experienced serious adverse effects. From the post-hoc assessment of safety using the questionnaire, 7/64 reported mild to moderate symptoms, that were perceived as 'possibly' or 'probably' related to participation in LIFU experiments. These reports included neck pain, problems with attention, muscle twitches and anxiety. The most common unrelated symptoms included sleepiness and neck pain. There were initial transient reports of mild neck pain, scalp tingling and headache that were extinguished upon follow-up. No new symptoms were reported upon follow up out to 1 month. The profile and incidence of symptoms looks to be similar to other forms of non-invasive brain stimulation.
Non-invasive transcranial ultrasound stimulation for neuromodulation. [2022]Transcranial ultrasound stimulation (TUS) holds great potential as a tool to alter neural circuits non-invasively in both animals and humans. In contrast to established non-invasive brain stimulation methods, ultrasonic waves can be focused on both cortical and deep brain targets with the unprecedented spatial resolution as small as a few cubic millimeters. This focusing allows exclusive targeting of small subcortical structures, previously accessible only by invasive deep brain stimulation devices. The neuromodulatory effects of TUS are likely derived from the kinetic interaction of the ultrasound waves with neuronal membranes and their constitutive mechanosensitive ion channels, to produce short term and long-lasting changes in neuronal excitability and spontaneous firing rate. After decades of mechanistic and safety investigation, the technique has finally come of age, and an increasing number of human TUS studies are expected. Given its excellent compatibility with non-invasive brain mapping techniques, such as electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), as well as neuromodulatory techniques, such as transcranial magnetic stimulation (TMS), systemic TUS effects can readily be assessed in both basic and clinical research. In this review, we present the fundamentals of TUS for a broader audience. We provide up-to-date information on the physical and neurophysiological mechanisms of TUS, available readouts for its neural and behavioral effects, insights gained from animal models and human studies, potential clinical applications, and safety considerations. Moreover, we discuss the indirect effects of TUS on the nervous system through peripheral co-stimulation and how these confounding factors can be mitigated by proper control conditions.
Ultrasonic neuromodulation. [2022]Ultrasonic waves can be non-invasively steered and focused into mm-scale regions across the human body and brain, and their application in generating controlled artificial modulation of neuronal activity could therefore potentially have profound implications for neural science and engineering. Ultrasonic neuro-modulation phenomena were experimentally observed and studied for nearly a century, with recent discoveries on direct neural excitation and suppression sparking a new wave of investigations in models ranging from rodents to humans. In this paper we review the physics, engineering and scientific aspects of ultrasonic fields, their control in both space and time, and their effect on neuronal activity, including a survey of both the field's foundational history and of recent findings. We describe key constraints encountered in this field, as well as key engineering systems developed to surmount them. In closing, the state of the art is discussed, with an emphasis on emerging research and clinical directions.
GHz Ultrasonic Chip-Scale Device Induces Ion Channel Stimulation in Human Neural Cells. [2021]Emergent trends in the device development for neural prosthetics have focused on establishing stimulus localization, improving longevity through immune compatibility, reducing energy re-quirements, and embedding active control in the devices. Ultrasound stimulation can single-handedly address several of these challenges. Ultrasonic stimulus of neurons has been studied extensively from 100 kHz to 10 MHz, with high penetration but less localization. In this paper, a chip-scale device consisting of piezoelectric Aluminum Nitride ultrasonic transducers was engineered to deliver gigahertz (GHz) ultrasonic stimulus to the human neural cells. These devices provide a path towards complementary metal oxide semiconductor (CMOS) integration towards fully controllable neural devices. At GHz frequencies, ultrasonic wavelengths in water are a few microns and have an absorption depth of 10-20 µm. This confinement of energy can be used to control stimulation volume within a single neuron. This paper is the first proof-of-concept study to demonstrate that GHz ultrasound can stimulate neurons in vitro. By utilizing optical calcium imaging, which records calcium ion flux indicating occurrence of an action potential, this paper demonstrates that an application of a nontoxic dosage of GHz ultrasonic waves [Formula: see text] caused an average normalized fluorescence intensity recordings >1.40 for the calcium transients. Electrical effects due to chip-scale ultrasound delivery was discounted as the sole mechanism in stimulation, with effects tested at α = 0.01 statistical significance amongst all intensities and con-trol groups. Ionic transients recorded optically were confirmed to be mediated by ion channels and experimental data suggests an insignificant thermal contributions to stimulation, with a predicted increase of 0.03 oC for [Formula: see text] This paper paves the experimental framework to further explore chip-scale axon and neuron specific neural stimulation, with future applications in neural prosthetics, chip scale neural engineering, and extensions to different tissue and cell types.
Ultrasonic modulation of neural circuit activity. [2019]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.