Clinical trial NCT05331560: Transcranial Pulse Stimulation Open-label Self-controlled Trial For Mild Neurocognitive Disorder
Official title: Efficacy and Safety of Transcranial Pulse Stimulation (TPS) in Older Adults With Mild Neurocognitive Disorder - an Open-label Self-controlled Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Mild Neurocognitive Disorder
Keywords: Transcranial pulse stimulation
mild neurocognitive disorder
open-label
self-controlled trial
Lead sponsor: The University of Hong Kong
Sponsor class: OTHER
Collaborators: name: Storz Medical AG
First posted: 2022-04-15
Enrollment: 20
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Background:

A significant proportion of older adults suffered from age-related diseases particularly dementia, also known as major neurocognitive disorder (NCD), which is becoming a worldwide health burden. In principle, Interventions for dementia should have optimal benefits at the earliest preclinical stage yet no evidence has been found to support a particular pharmacological approach in preventing cognitive decline during the stage of mild NCD. Non-invasive brain stimulation (NIBS), on the other hand, is increasingly recognized as a potential alternative to tackle this problem. Typical NIBS include transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS). A new kind of NIBS named Transcranial Pulse stimulation (TPS) is also recently used for treating patients with Alzheimer's disease (AD).TPS is a kind of NIBS that uses repetitive sin ultrashort pulses in the ultrasound frequency range to stimulate the brain, and it can provide better spatial precision and reach deeper brain regions comparing to tDCS and TMS. The mechanism of TPS is to convert the mechanical TPS stimulus into biochemical responses, thus influence some fundamental cell functions. A recent study showed that there is a significant improvement in using TPS in treating AD. However, there has been no study investigating the effect of TPS on older adults with mild NCD.

Objective:

This study is an open-label self-controlled study to assess the effectiveness and tolerability of TPS on cognition in older adults with mild NCD. We hypothesized that a 2-week TPS intervention could significantly improve patient's global cognition which will be maintained for 12 weeks.

Design:

The current study is an open-label self-controlled interventional trial of TPS guided by neuro-navigation using structural MRI. All participants will undergo the treatment as usual (TAU) period as self-controlled for 12 weeks. They will then receive a six-session TPS intervention for 2 weeks with three sessions per week. A 12 weeks post-intervention assessment will then be conducted.

Data Analysis:

Primary outcome and secondary outcomes assessment would be carried out at baseline, after TAU period, immediately after the intervention and 12 weeks after the intervention. The primary outcome will be the change of the Hong Kong Chinese version of the Montreal Cognitive Assessment (HK-MoCA). The secondary outcome includes specific cognitive domains, daily functioning, mood, and apathy. The intention-to-treat analysis would be carried out.

Significance:

The result of the current study would provide further data on the effectiveness and tolerability of TPS as a new treatment in patients with mild NCD.

Detailed description: Background Age-related diseases, particularly dementia, now known as major neurocognitive disorder (NCD), are a great health burden in Hong Kong and worldwide. Interventions that aim to ameliorate cognitive decline or prevent dementia offer a compelling alternative paradigm for reducing the impact of the disease, not only on individuals but also on their families and on society. In principle, to achieve its optimal benefits, intervention for dementia should begin at the earliest preclinical stage. However, no evidence has been found to support a pharmacological approach to the prevention, reduction, or postponement of cognitive decline during the stage of mild NCD. Besides pharmacological approaches, non-invasive brain stimulation (NIBS) is increasingly recognised as a potential alternative to tackle this problem. The typical examples of NIBS are transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS). Besides these, there is a new NIBS named transcranial pulse stimulation (TPS), also known as low-intensity extracorporeal shock wave therapy (Li-ESWT), which recently obtained CE marking in 2018 for the treatment of the central nervous system (CNS) in patients with mild to moderate Alzheimer's disease (AD).

The introduction of TPS TPS is using repetitive single ultrashort pulses in the ultrasound frequency range to stimulate the brain. With a neuro-navigation device, TPS can achieve this in a highly focal and precisely targeted manner. TPS differs from tDCS and TMS using direct or induced electric current. Using electric current to stimulate the brain may be limited by the problem of conductivity and failure to reach deep brain regions. Instead, low-intensity focused ultrasound provides good spatial precision and resolution to noninvasively modulate subcortical areas, despite the problem of skull attenuation. Using lower ultrasound frequencies TPS can successfully improve skull penetration in humans.

Biological mechanism of TPS The basic mechanism of TPS is mechanotransduction. It is a biological pathway through which the cells convert the mechanical TPS stimulus into biochemical responses, thus influencing some fundamental cell functions such as migration, proliferation, differentiation, and apoptosis. The ultrashort ultrasound pulse could enhance the cell proliferation and differentiation in cultured neural stem cell, which plays an important role in the repair of brain function in CNS diseases. The TPS may affect neurons and induce neuroplastic effects through several pathways including increasing cell permeability, stimulation of mechanosensitive ion channels, the release of nitric oxide resulting in vasodilation, increased metabolic activity and angiogenesis, stimulation of vascular growth factors (VEGF) and stimulation of brain derived neurotrophic factor (BDNF).

Clinical effects of TPS Focused ultrasound demonstrated the neuromodulation effect in the human brain. Focused ultrasound can modulate the amplitude of somatosensory evoked potentials (SEPs) when targeted at the cortical regions that generate these potentials and even the deep structure such as the thalamus. TPS, previously named as Li-ESWT was applied to five patients with unresponsive wakefulness syndrome. They received 4-week (3 times per week) treatment, 4000 pulses each, every 6 months for an average of two to four years. There was significant improvement in the vigilance and in three patients the percutaneous endoscopic gastrostomy (PEG) tube could be removed due to improved oropharyngeal motor function. In the most recent study, TPS was applied to 35 elderly with AD. They were treated in 3 TPS sessions (6000 pulses each) per week for 2-4 weeks, either over classical AD affected sites such as the dorsolateral prefrontal cortex, areas of the memory and language network, or over all accessible brain areas (global brain stimulation). Significant improvement in the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) score was demonstrated (immediately as well as 1 and 3 months after stimulation. fMRI also showed significant increased connectivity within the memory network.

Safety issue of TPS TPS uses very low energy for the brain stimulation. In vivo animal TPS study did not cause any tissue damage despite using 6-7-fold higher energy levels compared with those in human studies. Furthermore, the intervention did not cause any serious adverse effects such as intracranial bleeding, oedema or other intracranial pathology, as confirmed with MRI in a previous AD study. Few subjects reported headache (4%), pain or pressure (1%) and mood deterioration (3%). The CE marked TPS system has proven to be safe in \>1500 treatments.

Eligibility criteria: Inclusion Criteria:

* 1. 60 years of age or above
* 2. Chinese ethnicity
* 3. Mild neurocognitive disorder (NCD) meeting the 5th Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria
* 4. At least 3 months of stable anti-dementia therapy prior to enrolment (unchanged medication, if receiving)
* 5. Written informed consent

Exclusion Criteria:

* 1. A HK-MoCA score below the second percentile according to the subject's age and education level
* 2. Alcohol or substance dependence
* 3. Concomitant unstable major medical conditions or major neurological conditions such as brain tumour, brain aneurysm
* 4. Haemophilia or other blood clotting disorders or thrombosis
* 5. Significant communicative impairments
* 6. Participants with any metal implant in brain or treated area of the head

Primary outcomes:
measure: Change in Global Cognition
timeFrame: Baseline, 12-week Treatment-As-Usual, Immediate after 2-week TPS Treatment, 12-week Follow-up
Secondary outcomes:
measure: Changes in Verbal Fluency
timeFrame: Baseline, 12-week Treatment-As-Usual, Immediate after 2-week TPS Treatment, 12-week Follow-up
measure: Change in Working Memory
timeFrame: Baseline, 12-week Treatment-As-Usual, Immediate after 2-week TPS Treatment, 12-week Follow-up
measure: Change in Executive Functioning
timeFrame: Baseline, 12-week Treatment-As-Usual, Immediate after 2-week TPS Treatment, 12-week Follow-up
measure: Change in Attention
timeFrame: Baseline, 12-week Treatment-As-Usual, Immediate after 2-week TPS Treatment, 12-week Follow-up
measure: Change in Depressive Symptoms
timeFrame: Baseline, 12-week Treatment-As-Usual, Immediate after 2-week TPS Treatment, 12-week Follow-up
measure: Change in Daily Functioning
timeFrame: Baseline, 12-week Treatment-As-Usual, Immediate after 2-week TPS Treatment, 12-week Follow-up
measure: Change in Apathy
timeFrame: Baseline, 12-week Treatment-As-Usual, Immediate after 2-week TPS Treatment, 12-week Follow-up
measure: Change in Adverse Effects and Risk Indicators
timeFrame: Across 6 TPS Treatment sessions
measure: Changes in Brain Regional Volume Differences and White Matter Hyperintensities (WMH)
timeFrame: Baseline, 12-week Follow-up
measure: Change in Brain Functional Connectivity
timeFrame: Baseline, 12-week Follow-up
measure: Change in Brain-Derived Neurotrophic Factor (BDNF)
timeFrame: Baseline, Immediate after 2-week TPS Treatment
Other outcomes:
Locations:
city: Hong Kong
country: Hong Kong
facility: The Hong Kong Jockey Club Building for Interdisciplinary Research
Study officials:
affiliation: The University of Hong Kong
name: Calvin Pak Wing Cheng, MBBS (HKU)
role: PRINCIPAL_INVESTIGATOR
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