Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT06400017 |
| Other study ID # |
JQ23038-2 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
May 30, 2024 |
| Est. completion date |
December 31, 2026 |
Study information
| Verified date |
May 2024 |
| Source |
Beijing Tiantan Hospital |
| Contact |
lin shi, M.D. |
| Phone |
008615210466780 |
| Email |
shilin2015[@]foxmail.com |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Project name: The mechanism and application of deep brain stimulation in the treatment of
Parkinson's disease
Objective:
To test the hypothesis that electrical stimulation of substantia nigra regulates cognitive
dysfunction in Parkinson's disease and to reveal its electrophysiological mechanism.
Study design:
This study is a self-controlled prospective cohort study. By comparing the behavioral
characteristics of the memory paradigm under microelectrode stimulation during DBS operation
and the characteristics of the underlying electrophysiological signals, and the behavioral
characteristics of the memory paradigm and the characteristics of brain network activity
under electrical stimulation when DBS is turned on 1 month after surgery. The regulatory
effect of substantia nigra DBS on memory network was analyzed.
Cases: 60
Case selection:
Inclusion criteria:
1)Voluntarily participate in the clinical study and sign the informed consent; 2) Age 50-70
years old, gender unlimited; 3) The clinical diagnosis is consistent with typical PD, and the
medical history is less than 20 years; 4) Patients who intend to use 3.0T magnetic resonance
compatible dual-channel DBS device (G106R or G106RS, Beijing Pinchi Company) for bilateral
subthalamic nucleus DBS surgery to control PD symptoms; 5) MRI excluded patients with obvious
structural changes; 6) The visual acuity and hearing of the subjects were basically normal,
and the compliance was good, and they could complete the tasks listed in the experimental
scheme in accordance with the standards.
Exclusion criteria:
1)Serious mental, cognitive and psychological disorders, unable to sign informed consent or
cooperate with the operation and various tasks; 2) There are contraindications for
neurosurgery, such as hydrocephalus, cerebral atrophy, cerebrovascular sequelae, heart
disease and other cardiovascular and cerebrovascular diseases; 3) There are concomitant
diseases that seriously affect health, such as tumors, serious abnormalities of liver and
kidney function (indexes more than 3 times normal); 4) There is intracranial space
occupation, cerebrovascular disease, mental illness, other neurological diseases,
claustrophobia, or there is an implant in the body, which affects the nuclear magnetic scan;
5) The results of the Mini-Mental State Scale (MMSE) <24 or the Montreal Cognitive Assessment
Scale (MoCA) <18 in the preoperative assessment, or the results of other scales indicate the
presence of severe dementia.
therapeutic schedule： This study did not change the patient's overall treatment regimen, and
only electrical stimulation was tested during and 1 month after DBS surgery
Efficacy evaluation:
Effectiveness evaluation index (primary efficacy index and secondary efficacy index) :
accuracy of memory paradigm, response speed Safety evaluation indicators: blood pressure,
heart rate, dual frequency index, patient complaints and symptoms
Statistical methods:
The group t test was used to compare the normal distribution between the measurement data
groups. For measurement data with non-normal distribution, Wilcoxon rank sum test was used
for comparison between groups.
The study period is January 1, 2024 - December 31, 2026.
Description:
Research background The core symptoms of Parkinson's disease (PD) include motor symptoms and
non-motor symptoms, among which cognitive dysfunction is the most common and one of the most
overlooked non-motor symptoms in patients with advanced PD. Cross-sectional studies have
shown that up to 40% of PD patients are combined with cognitive dysfunction at the time of
diagnosis, which is manifested by functional decline in memory, executive, attention,
language, visuospatial ability and other cognitive subfields. Among them, the memory
impairment subtype with episodic memory function decline as the main manifestation is the
most common and the fastest progressing. About 10% to 15% of patients with these
manifestations will progress to dementia each year, which is four to six times higher than
the age-matched non-PD population, and more than 80% of patients with PD will develop
dementia within 10 years of diagnosis of PD. This increasing cognitive and memory dysfunction
seriously affects the quality of life of patients and the overall treatment effect, often
leading to accelerated deterioration of the disease, bringing a heavy burden to the family
and society. It can be seen that in-depth exploration of the formation mechanism of PD
cognitive and memory dysfunction and the establishment of effective intervention means have
become an important proposition to be solved urgently in the field of PD research.
The applicant's previous study found that deep brain stimulation (DBS) is an effective means
to treat Parkinson's disease, and low frequency electrical stimulation of the substantia
nigra can improve episodic memory function in patients with Parkinson's disease. Therefore,
the applicant team intends to further study the regulatory effect and mechanism of substantia
nigra electrical stimulation on episodic memory, reveal the mechanism of its improvement of
cognitive function from the theoretical level, clarify its regulatory effect on cognitive
impairment from the technical level, and verify the potential of its treatment of cognitive
impairment from the application level, so as to solve the major clinical needs in the
diagnosis and treatment of PD cognitive impairment. Bring the Gospel to 5 million PD
patients, and help the construction of Beijing International Science and Technology
Innovation Center.
Research purpose
1. Main Objective: To verify the hypothesis that electrical stimulation of substantia nigra
can regulate cognitive dysfunction in Parkinson's disease, and to reveal its
electrophysiological mechanism.
2. Secondary objective: To explore the safety and side effects of electrical stimulation of
substantia nigra in regulating cognitive dysfunction.
Research design types, principles and test steps
1. Research design This was a self-controlled prospective cohort study.
2. Sample size and research plan In this study, 60 patients with Parkinson's disease who
met the inclusion and exclusion criteria were selected to undergo MRI compatible DBS
device implantation. By comparing the behavioral characteristics of the memory paradigm
under microelectrode stimulation during DBS operation and the characteristics of the
electrophysiological signals behind it, The behavioral characteristics of memory
paradigm and brain network activity during electrical stimulation of DBS at 1 month
after operation were analyzed, and the regulatory effect of substantia nigra DBS on
memory network was analyzed.
3. Study duration January 1, 2024 - December 31, 2026
4. Use DBS equipment and program control 1) DBS equipment manufacturers DBS equipment:
dual-channel rechargeable Deep brain stimulation pulse generation System (G106R)
compatible with 3.0T magnetic resonance scanning, produced by Beijing Pinchi Medical
Equipment Co., LTD.
2) Parameter setting Contact selection: According to the electrode position in the image
(target reconstruction through CT scan), the electrode located in the substantia nigra is
selected as the negative electrode, the contact near the upper part of the substantia nigra
is selected as the positive electrode, and the bipolar stimulation mode is selected.
Stimulation parameters: The frequency was selected as 5/10/20/60/130/150Hz, the pulse width
remained unchanged at 90μs, the side effects of patients were observed, and the voltage was
slowly increased to 2.0V; The patient voltage was 0 during the spurious stimulation.
Side effects: paresthesia, local pain, palpitation, chest tightness, etc. 5. Memory paradigm
The episodic memory task paradigm used in this study was designed with the Psychtoolbox (v3.0
version) based on MATLAB2018b(MathWorks, USA). During the operation, the episodic memory
paradigm test was conducted 2-3 times for each subject according to the situation, and the
total duration of the test was no more than 30 minutes for each subject, or it was stopped at
any time according to the subject's will. The paradigm is divided into two phases, in the
memory coding phase, 20 silent episodic memory clips (each about 6 seconds long, including 10
consecutive event clips and 10 jump event clips) are presented in pseudo-random order. Before
each video was played, a cross mark (0.5s - 1.5s) would appear in the center of the screen to
remind subjects to look at the center of the screen and reduce eye movement. After each video
was played, in order to ensure participants' participation in the passive viewing process,
participants were asked to answer questions related to the video (such as determining whether
most scenes of the video took place "indoors" or "outdoors"). After the participants
memorized and encoded 20 short films, they entered the scene recognition stage. At the
beginning of the task, a cross mark (0.25s-0.75s) appeared in the center of the screen to
remind subjects to pay attention to the task, and then scene pictures were displayed
(pictures were from 20 films played or not played in the memory coding stage). Subjects were
asked to judge whether the scene shown was a selection of short films played in the free
memory coding stage. The whole experiment process, the subjects used reactor (RB - 840)
answer keys, and the stimulus (video and pictures), and subjects button at the end of your
answer by task related electrical synchronizer C - Pod (Cedrus, Us) sends pulses from the
experimental computer to Neuro Omega to form time stamps (TTL pulses). Time permitting, the
memory encoding and scene recognition phase will be repeated 3-4 times (keeping the same
experimental format but replacing it with different experimental clips and test pictures).
Research methods
1. Clinical trials were conducted to verify the regulatory effect of electrical stimulation
of substantia nigra under different stimulation modes on episodic memory impairment in PD,
and to establish the interdependence between the changes in the firing mode of substantia
nigra neurons and the changes in episodic memory function.
1. To evaluate the impact of substantia nigra DBS on episodic memory function of PD
subjects: For PD patients to be treated with bilateral subthalaminal nucleus DBS, the
cognitive memory function, mental behavior symptoms and daily living ability of the
patients were assessed by neuropsychological scale, and those meeting the criteria were
selected to be included in the group. The MRI compatible dual-channel DBS device was
implanted into the subthalamic nucleus as the target. During the operation, the lowest
contact of the DBS electrode was implanted into the substantia nigra according to the
electrophysiological signal, and the remaining contact was implanted into the
subthalamic nucleus. The position of DBS electrode implantation was reconstructed, and
the electrode contacts in or close to the substantia nigra were selected to perform
24-hour substantia nigra DBS under different parameter combinations such as high
frequency and low frequency. Neuropsychological scale was used to evaluate the cognitive
memory function of patients, and the influence of substantia nigra DBS under different
parameters on the episodic memory function of PD subjects was analyzed. Then to evaluate
the effect of substantia nigra DBS on episodic memory function of PD subjects.
2. To study the electrophysiological mechanism of the substantia nigra's participation in
episodic memory activities: the experiment of episodic memory task was completed during
DBS surgery, and the multi-mode neural electrophysiological signals of brain regions
such as substantia nigra, subthalamic nucleus, and dorsolateral prefrontal cortex were
recorded synchronously during the process of episodic memory activities, and the
behavioral results (accuracy rate, reaction time, etc.) of the completion of the
episodic memory tasks were calculated; The dynamic activation/inhibition relationship
among the substantia nigra, subthalamic nucleus, dorsolateral prefrontal cortex and
other brain regions was analyzed, and the response sequence and dynamic changes of the
peak potential, local field potential, and cortical potential under the time-locking
relationship were observed, so as to clarify the mutual driving relationship between the
brain regions related to episodic memory activities. The activity characteristics of
neurons in substantia nigra that respond to episodic memory event boundaries were
analyzed, and the relationship between the change of discharge frequency and the
formation process of episodic memory events was studied, and the significance of the
change of activity on episodic memory events was discussed, so as to analyze the
electrophysiological mechanism of various brain regions involved in episodic memory
activities.
3. To determine the key time nodes and dose-effect correspondence of the regulation of
episodic memory formation by electrical stimulation of substantia nigra:
microstimulation or macro stimulation delivered by microelectrode during DBS surgery can
be used to predict the effect or side effects of electrical stimulation, and then
prepare for the implantation of macro electrode, which is a routine operation in
surgery. In this study, the operation of episodic memory paradigm was controlled by
programming, and micro-stimulus or macro-stimulus was given before, during and after the
presentation of stimuli, respectively, to observe the effects of electrical stimulation
with different frequencies, different modes and different stimulation regions on
behavioral performance of episodic memory (accuracy rate, reaction time, etc.). To
establish the dose-effect correspondence between the relative time node of electrical
stimulation, micro-stimulation sites, micro-stimulation parameters and the result of
memory formation, and identify the key time node of the regulation of episodic memory
formation by electrical stimulation of substantia nigra.
2. Through the study of brain structure and functional connectomics, the optimal stimulus
mode and stimulus parameters of substantia nigra DBS regulating episodic memory dysfunction
were revealed.
1. The influence of substantia nigra DBS on the functional brain network related to
episodic memory was explored by means of functional magnetic resonance imaging (fMRI)
technology: the DBS device implanted in this study was an MRI-compatible dual-channel
DBS device, and the activity of the brain network could be evaluated by fMRI scanning
technology when the device was turned on. In this study, the enrolled patients completed
the fMRI scanning of the resting state and the episodic memory task state in the
substantia nigra DBS state, calculated the behavioral results (accuracy rate, reaction
time, etc.) of the subjects in different groups to complete the episodic memory task,
and analyzed the change characteristics and dynamic evolution of the dependent signal of
blood oxygen level in the fMRI task state. The brain regions with activation/inhibition
of episodic memory task states and their activation/inhibition relationship in time
series were analyzed, and the correlation between behavioral results and the
characteristics of fMRI signal changes in task states in each group was studied, so as
to explore the functional changes of episodic memory brain network before and after
substania nigra DBS in PD patients.
2. Verify the results of animal experiments through brain structural connectomics studies,
and clarify the correlation between the activated tissue of substantia nigra DBS and the
changes in cognitive function: Lead DBS toolkit was used to calculate substantia nigra
DBS stimulation-activated tissue volume (VTA) under different parameters, and cognitive
behavioral evaluation results under different stimulus parameters were collected,
experimental data and patient data of each group were sorted out. The machine learning
toolkit was used to analyze the correlation and weight between the changes in behavioral
results of the subjects' episodic memory and the subgroups (diagnosis, age, disease
course, preoperative evaluation results, imaging indicators, electrophysiological
indicators, VTA, fMRI indicators and other information, etc.), so as to clarify the
correlation between DBS activated tissue of substantia nigra and the changes in episodic
memory function. To search for biomarkers that can predict the changes of episodic
memory after DBS, and reveal the optimal stimulation mode and stimulation parameters of
substantia nigra DBS in regulating cognitive dysfunction
Concomitant medication Patients will continue to take Parkinson's disease drugs at
preoperative dose (or according to the doctor's advice) during perioperative and
postoperative periods, and this experiment will not affect the drug usage and dosage of
patients.
Observation indicators and inspection time
1. Clinical evaluation: Two evaluations were conducted before surgery and one month after
surgery, including the following contents: 1) general information (age, gender, age of
onset and course of disease); 2) Drug treatment (drug type, dose, time and side
effects); 3) Behavioral assessment: PD patients were evaluated using the Unified
Parkinson's Disease Rating Scale(UPDRS) version 3.0; 4) Neuropsychology: In this study,
multiple neuropsychological scales will be used for comprehensive assessment of
patients, including Mini-mental State Examination (MMSE), the Montreal Cognitive
Assessment Scale (MoCA), the Frontal Lobe Function Rating Scale (FAB), the Hamilton
Depression Rating Scale for Depression(HRSD), and the Hamilton Anxiety Scale (HRSA).
2. MRI data: 3D T1, T2 axis, T2 crown, BOLD (on and off), DTI sequence. Two times were
collected before surgery and one month after surgery.
3. Memory paradigm test data: This project will start the memory paradigm test after the
microelectrode enters the substania nigra during the DBS operation, and give electrical
stimulation test when some memory stimuli are presented, so as to observe the baseline
memory accuracy rate of subjects and the changes in the recognition accuracy rate of
new/old objects under the state of electrical stimulation. In addition, when the
subjects returned to the hospital one month after the operation, the memory function of
the subjects was evaluated with the memory paradigm in the magnetic resonance and fMRI
environment, and the changes in the fMRI signal and connectivity of the brain functional
areas were observed. Then, the behavioral characteristics of the memory paradigm and the
activity characteristics of the brain network under the state of electrical stimulation
when DBS was turned on were studied by post-processing analysis technology. The
regulatory effect of substantia nigra DBS on memory network was analyzed. We will
monitor blood pressure, heart rate, dual-frequency index and other indicators when
patients complete the normal form experiment during DBS surgery, and judge whether
patients can continue to complete the experiment according to the patient's chief
complaint and symptom changes. If all indicators change in a negative direction, the
experiment will be terminated timely according to the situation. The safety of using
electrical stimulation of substantia nigra to regulate cognitive function was evaluated
according to the changes of blood pressure, heart rate, dual frequency index, complaints
and symptoms of patients after completing the normal form experiment.
Follow-up time Follow-up will be completed at DBS startup 1 month after surgery.
Clinical evaluation
1. Efficacy evaluation: Changes in the corresponding clinical scales of patients at each
follow-up point are shown in observation indicators and examination time.
2. Safety evaluation: Adverse events were described by the number of adverse events and the
incidence rate, and the incidence rate was tested for significance between groups. At
the same time, the specific manifestation, degree and relationship between all adverse
events and devices were described in detail. Including surgery-related adverse
reactions, stimulus-related adverse reactions and device-related adverse reactions.
Known and potential risks and benefits of the project, as well as risk disposal plans In this
study, participants will be required to complete a cognitive function test during the
operation, which only requires a simple operation of the keyplate and lasts for about 20-30
minutes, during which the operation will be stopped and the surgical incision will be covered
with a sterile towel. Previous results of similar studies conducted in our center and other
centers show that this testing process does not significantly increase the degree of
infection of the incision. Nor does it significantly increase the overall risk of surgery; In
part of the testing process, we will use a micro-current below 50uA for electrical
stimulation, which is not substantially different from the electrical stimulation used to
test the efficacy in surgery, and the intensity is significantly weaker than the efficacy
test current. Previous studies have not found that such intensity of the current will induce
epilepsy, bleeding, necrosis and other complications, and the subjects have not reported
obvious subjective discomfort. In addition, this study requires access to your medical
information and other privacy, and while we are fully prepared to deal with the issue of data
disclosure, it does not rule out such a risk. About 1 month after the operation, when the
subjects participated in the follow-up, the changes of cognitive function under electrical
stimulation of the substania nigra were tested by a professional program control physician.
The parameters of electrical stimulation used in the process were all within the safe range,
and there was usually no obvious discomfort, and the effects of electrical stimulation
disappeared immediately after the stimulator was turned off. This project will use an
MRI-compatible DBS device that has passed safety testing before it is marketed and generally
poses no additional risk, but because it is still relatively new to the market, it is still
prudent to watch for discomfort or other changes during MRI scans. Overall, there was no
significant increase in preoperative, intraoperative, or postoperative risk.
This study will actively reconstruct the electrode position for patients after DBS, and
provide patients with more accurate and effective program control, which will help improve
the therapeutic effect of DBS surgery. At the same time, this study will provide follow-up
treatment and follow-up help and suggestions for patients, which will help patients improve
their experience of medical treatment and treatment. In addition, considering that
participating in this study will require the cooperation of the subjects during and after the
operation, which may lead to a slight extension of the operation time, and the need for
debugging and corresponding inspection after the operation, the project team will cooperate
with Beijing Pinchi Medical Equipment Co., Ltd. to apply for the reduction of part of the
equipment cost (about 55,000 yuan in total) for you. Including 1 DBS electrode (the market
price is about 25,000 yuan), 2 electrode locks (the market price is 15,000 yuan/piece, a
total of about 30,000 yuan); In addition, we will facilitate your follow-up visit and arrange
for your doctor to advise you on follow-up treatment. Note: The specific content of remission
needs to be determined according to the degree of cooperation of the subjects and the
completion of the experiment. All remission will be completed before and after the completion
of the 1-month postoperative scan.
Data preservation The researchers established an independent study number for each subject,
named the corresponding data with the study number, and deleted the patient name and hospital
number information from all the data. The study data included behavioral data in.mat format,
CT and MRI data in.dcm format, EEG data in.mpx format and image data in.mp4 format. Keep the
original data for 10 years after the completion or termination of the study.
Data security inspection Data and safety monitors were set up in this study, all adverse
events were recorded in detail, properly handled and tracked until properly resolved or the
disease was stable, and serious adverse events and unexpected events were reported to the
ethics Committee, competent authorities, sponsors and drug regulatory authorities in a timely
manner in accordance with relevant systems; The principal investigator conducts a cumulative
review of all adverse events on a regular basis, and investigator meetings are convened when
necessary to assess the risks and benefits of the study.
Statistical processing SPSS 22.0 software or SAS9.4 were used for analysis. In bilateral
tests, P < 0.05 was considered to have significant differences. Measurement data were
described by mean, standard deviation, maximum, minimum, median, 25th and 75th quantile.
Group t test was used to compare the normal distribution measurement data among groups. For
measurement data with non-normal distribution, Wilcoxon Rank Sum test was used for
inter-group comparison.
Ethical considerations The clinical study is conducted only after the protocol is approved by
the Ethics Committee before the study begins. Before each subject is enrolled in this study,
the investigator has the responsibility to fully introduce to the subject or his legal agent
the purpose, procedure and possible risks of this study, as well as relevant information
about alternative treatment, and sign a written informed consent, which should let the
subject know that they have the right to withdraw from this study at any time, and the
informed consent will be retained as a clinical study document for future reference.
Participants' personal information will be protected from disclosure during the study.
Confidentiality of information The subjects' medical information will be combined and used to
study treatments. All information will be coded and will not contain the subject's name or
any other information that directly identifies the subject. Information that is not relevant
to the study (such as information about previous illnesses, infectious disease history) will
not be provided to other parties.
