Mechanism and Application of DBS in the Treatment of PD

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 research group previously tested the behavioral changes of rats in the low frequency electric stimulation group of substantia nigra and the sham stimulation group using behavioral experiments such as nesting experiment and water maze experiment, and found that rats in the low frequency electric stimulation group performed better in the nesting experiment and water maze experiment, suggesting that low frequency electric stimulation of substantia nigra can improve the memory behavioral performance of rats with Parkinson's disease.

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 0/10/130Hz, 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.The washout period was 1 hour.

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 (including 10 consecutive event clips and 10 jump event clips) are presented in pseudo-random order. Before each video was played, a cross mark 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 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 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 epi