Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT06314139 |
| Other study ID # |
YanmingXu001 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
September 1, 2022 |
| Est. completion date |
June 1, 2023 |
Study information
| Verified date |
March 2024 |
| Source |
West China Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Essential tremor (ET) is one of the most common movement disorders in adults. The prevalence
rate among the elderly over 65 years old is about 4.6%. Tremor usually worsens with age,
leading to disability and loss of independence, which has an adverse impact on the quality of
life of patients. However, the traditional first-line treatment drugs are neither effective
enough nor completely safe for ET patients. Although surgical procedures such as deep brain
stimulation (DBS) and thalamotomy can be used to better control unilateral limb tremor, many
patients are reluctant to choose surgical treatment because it's invasive. Therefore, there
is an urgent need to develop new drugs or non-invasive therapies as a better treatment option
for ET.
The pathology of the disease is not yet clear, it is generally believed that genetic, aging
and environmental factors are related to ET. Hyperactivity of cerebellar function and changes
of cerebello-thalamo- cortical (CTC) pathways are currently considered to be the most
important pathophysiological mechanisms of ET. Therefore, the cerebellum and cortex may be
the best targets for the treatment of tremor.
Continuous theta burst stimulation (cTBS) is one of the non-invasive electrophysiological
techniques characterized by plexus stimulation, which is similar to low-frequency repetitive
transcranial magnetic stimulation (rTMS) but closer to the physiological state of neural
activity, and may inhibit the excitability of the stimulated cortex. The stimulation duration
is greatly shortened, which is simpler and easier than the low-frequency rTMS of 20-30
minutes. In addition, functional near infrared spectroscopy (fNIRS) is a new non-invasive
functional neuroimaging technique. It mainly uses the difference characteristics of
oxyhemoglobin and deoxyhemoglobin in brain tissue for near-infrared light absorption at
different wavelengths of 600-900nm. The efficacy, safety, and mechanisms involved in
non-invasive stimulation therapy for ET patients are still unclear. There are few studies on
the treatment of ET with cTBS, and the sample size is small (the largest sample includes only
23 ET patients). Additionally, there was a lack of exploration on the therapeutic mechanism
of cTBS for ET patients. Therefore, the investigators conducted a double-blind, randomized,
sham-controlled clinical trial to evaluate the safety and efficacy of cTBS in the treatment
of ET patients over both cerebellar and cortical area.
Description:
Essential tremor (ET), also known as idiopathic tremor, is one of the most common movement
disorders in adults. The prevalence rate among the elderly over 65 years old is about 4.6%.
It is characterized by simple kinetic and/or postural tremor of the arms, with or without
various combinations of midline tremors (MT)-such as the neck, voice, and facial tremors.
About 30%~70% of ET patients have family history, and most of them are autosomal dominant.
Tremor usually worsens with age, leading to disability and loss of independence, which has an
adverse impact on the quality of life of patients. However, the traditional first-line
treatment drugs are neither effective enough nor completely safe for ET patients. Although
surgical procedures such as deep brain stimulation (DBS) and thalamotomy can be used to
better control unilateral limb tremor, many patients are reluctant to choose surgical
treatment because it's invasive. Therefore, there is an urgent need to develop new drugs or
non-invasive therapies as a better treatment option for ET.
The pathology of the disease is not yet clear, it is generally believed that genetic, aging
and environmental factors are related to ET. Hyperactivity of cerebellar function and changes
of cerebello-thalamo- cortical (CTC) pathways are currently considered to be the most
important pathophysiological mechanisms of ET. The degenerative changes of cerebellum in ET
patients are prominent, such as the loss of Purkinje cells and focal axonal swelling. In
addition, imaging, electrophysiological studies and clinical observations show that the
cerebral cortex may also be involved. Studies have shown that the activity of cortical area
is related to the frequency of tremor, and there have been reports on the disappearance of ET
after cortical infarction. Therefore, the cerebellum and cortex may be the best targets for
the treatment of tremor.
Transcranial magnetic stimulation (TMS) is a non-invasive electrophysiological technique for
nerve stimulation and nerve regulation invented by Anthony Barker in 1985. Its principle is
to use electromagnetic fields to generate induced electric fields in the brain, change
abnormal brain waves of patients, and regulate the secretion of neurotransmitters and
hormones closely related to emotion, cognition, sleep and other functions in the brain, so as
to achieve the therapeutic effect. Continuous theta burst stimulation (cTBS) is characterized
by plexus stimulation, which is similar to low-frequency rTMS but closer to the physiological
state of neural activity, and may inhibit the excitability of the stimulated cortex.
Moreover, the intervention time of CTBS is only 40 seconds, the stimulation intensity is
lower, and the stimulation duration is greatly shortened, which is simpler and easier than
the low-frequency rTMS of 20-30 minutes. The investigators hypothesized that CTBS would
reduce the excitability of cerebellar cortex, thereby reducing the amplitude of tremor, and
play a therapeutic role in ET patients.
Functional near infrared spectroscopy (fNIRS) is a new non-invasive functional neuroimaging
technique in recent years. fNIRS mainly uses the difference characteristics of oxyhemoglobin
and deoxyhemoglobin in brain tissue for near-infrared light absorption at different
wavelengths of 600-900nm to directly detect the hemodynamic activities of cerebral cortex in
real time, and then through observing such hemodynamic changes, discover the neurovascular
coupling law, so as to deduce the neural activities of the brain. In the past 20 years, the
hardware manufacturing and improvement of functional near-infrared spectroscopy technology
and data processing methods have become more and more perfect, making the fNIRS technology,
which uses near-infrared light to observe brain neural activities, to study various cognitive
activities emerge in endlessly and develop rapidly. fNIRS is based on light intensity.
Optical imaging equipment has high cost performance and is not vulnerable to electromagnetic
interference from TMS pulses. It can conduct more detailed research on cortical connectivity,
excitability and dynamic changes induced by cTBS.
Studies by Chuang et al. showed that after the treatment of cTBS over motor cortex or
premotor cortex, the tremor amplitude of ET patients decreased significantly, but the tremor
frequency remained unchanged. Hellriegel et al. included 10 ET patients and 10 healthy
controls. They performed a single cTBS treatment on the primary motor cortex of the patients.
They found that compared with the control group, the cTBS group reduced the total power of
tremor assessed by the accelerometer, but this beneficial effect was subclinical, that is,
the tremor assessment of the patients had no significant change before and after treatment.
Bologna et al. included 16 ET patients and 11 healthy controls. They were treated with cTBS
and sham stimulation in the right cerebellar hemisphere with crossing over after a one-week
washout period. The results showed that the tremor was not significantly improved before and
after CTBS treatment. They also pointed out that multiple stimuli may be effective. However,
there is a lack of research on the therapeutic mechanism of cTBS in the treatment of ET. The
combination of transcranial magnetic stimulation (TMS) and neuroimaging provides a new way to
explore the mechanisms involved. High frequency rTMS could improve mild cognitive impairment
after stroke and increase the concentration of oxyhemoglobin in prefrontal lobe. Study have
observed the changes of activation mode of cerebral cortex during upper limb movement in
stroke patients before and after repeated transcranial magnetic stimulation (rTMS) treatment
through near infrared brain functional imaging (fNIRS). Struckmann et al. used fNIRS
technology to compare the changes of prefrontal blood oxygen response in patients with
depression before and after intermittent TBS treatment. They also confirmed that the oxygen
and hemoglobin of patients did change before and after treatment, and further discussed the
mechanism.
To sum up, there are few domestic and international clinical studies on the treatment of ET
with CTBS, and the sample size is small (the largest sample includes only 23 ET patients).
The results showed that the placebo effect was strong, and all of them were stimulated by
single site, and the effect was not significant. Additionally, there was a lack of
exploration on the therapeutic mechanism of cTBS for ET patients. Therefore, The
investigators will conduct a double-blind, randomized, sham-controlled clinical trial to
evaluate the safety and efficacy of cTBS in the treatment of ET patients over both cerebellar
and cortical area. fNIRS technology will be applied to provide new ideas for the
pathophysiological mechanism and treatment of ET.
