背外侧前额叶皮质损伤 z-bo 2020-11-23 342

　　Introduction: In the past few decades, the dorsolateral prefrontal cortex (dlPFC) has been extensively studied, revealing its role in the integration of multiple cognitive attributes in the context of working memory, and its significance in risk-related decision-making . Several studies on non-human primates have also emphasized the role of dlPFC in the psychological representation of spatiotemporal motion sequences, that is, subjects must replicate a series of motions after a period of time. Although related to motor control, in humans, there is evidence that the role of dlPFC and the basal ganglia (global neural circuit) in controlling and predicting grip strength contributes to manual dexterity, supplementing the sensorimotor cortex (M1/S1), motor The main grip-related activities expected in the anterior cortex, auxiliary motor area, cingulate motor area, posterior and inferior parietal cortex, and cerebellum. As pointed out by Ehrsson et al. The dlPFC activity associated with precise grip strength may also reflect parallel behavioral factors, such as spatial attention, short-term memory of tactile information, choice of exercise response, and focused automatic monitoring of exercise performance. However, although the role of dlPFC in motor learning has been established, when the motor task becomes more and more "automatic", the activation of dlPFC seems to gradually disappear, which may reflect the delegation of responsibility to the "lower" brain structure. Recently, Kaeser and his colleagues reported raw data on the role of dlPFC in the characterization of exercise habits. In this study, the authors performed dlPFC cortical biopsies on two macaques and evaluated their effects on sequential motor behavior (habituation). Compared with control monkeys, animals with dlPFC (zone 46) impaired had a significant impact on the spatiotemporal sequence, while the exercise performance itself (score) was not affected. In addition, the first indication is that there is a relationship between the size of the dlPFC biopsy and the degree of change in exercise habits, because the small biopsy has less influence on the exercise sequence than the large biopsy. However, due to the limited number of cases (n=2), it is clear that more data is needed to support this hypothesis, including both the number of cases and the variability of the precise location of the dlPFC lesion. In addition, functional magnetic resonance imaging (fmri) studies on human subjects have also emphasized the role of dlPFC in performing motor tasks that require some control (prediction) of grip strength. The study aims to test a new treatment strategy based on the non-human primate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Parkinson’s disease model Transplantation of the Autologous Adult Nerve Cell Ecosystem (ANCE). In this case, 4 adult female macaques (a few months before MPTP treatment) were subjected to unilateral biopsy of dlPFC to provide the cell material needed to obtain ANCE. The monkeys have previously been trained to perform quantitative exercise (manual dexterity) tasks, including the "modified Brinkman board" task and the "reach out to grab drawer" task. Therefore, the purpose of the current research on non-human primates is to expand preliminary data on the role of the prefrontal cortex (PFC) in exercise habits, and mainly test that dlPFC does help predict the precise force to be generated when it is known in advance. The hypothesis of the grip strength required at level is as recently reported in humans.

　　The data was collected from four adult female macaques (Mk-MY, Mk-LY, Mk-MI, Mk-LL), weighing 3.0.-5.0 kg, and the age at the beginning of behavior training was 4 to 8 years, which is longer than the current data collection time 3 years early. In other words, the macaques are highly trained to complete two motor tasks. The rooms are equipped with abundant facilities, including an outdoor space and free drinking water. Each monkey completes one or two different behavioral tasks with an experimenter every day. Before being transferred to the behavioral laboratory, each animal was first voluntarily placed on a monkey chair and weighed. In addition, during the entire experiment, appetite, social behavior, and fur status were treated daily. After the behavioral test, the monkeys will get cereal cakes, vegetables and fruits every day.

　　Behavioral task: The manual dexterity assessment is first based on the "Modified Brinkman Board" task, which includes particles recovered from 25 horizontal holes and 25 vertical holes, randomly distributed in a plexiglass plate, and each hole contains a banana flavor Food particles. The size and shape of the hole forced the monkey to use precise grip strength (the relative position of the thumb and index finger) to successfully retrieve the food particles. Each hand performs the task separately, 3 days a week. The number of food particles correctly recovered in the first 30 seconds corresponds to the score, which reflects the athletic performance. Evaluate the sports performance of MK-LL in different ways. In fact, mk-LL takes a mixture of two behaviors, either grabbing the particles one after another as expected, or sometimes bringing all the particles into the mouth Previously, several pellets were taken out in succession and stored in the palm of the hand, as described by Kaeser et al. Due to this random change, the MK-LL motion performance is calculated by calculating the total number of single particles correctly taken out and the total number of multiple particles taken out correctly in the entire task, which corresponds to the "total score". In addition, the exercise strategy (habit) is evaluated according to the time selection sequence (visiting 50 holes in sequence). The exercise strategy derived from the sequential interviews is still a qualitative assessment of exercise habits. In order to quantify the exercise habit data, the same statistical method as before was used. Each hole is assigned a spatial position number according to its position on the horizontal left and right axis of the "modified Brinkman board". Summarize the absolute value of 50 differences and give the index of the system movement sequence. For example, when a monkey gradually moves from the leftmost hole to the rightmost of the board along the horizontal axis, since the difference between the spatial position (left=small number) and the time series is small, the exercise habits index is a small number . In contrast, a systematic scan of the board from right to left produces a large exercise habit index, and for each hole, the difference between the number of spatial positions and the number of sequences is large. This index can be used to evaluate whether the monkey repeats the same sequence during daily training. For example, the change in this index reflects the change in the selection order from one daily activity to the next, while a small variability reflects the stable selection order in consecutive sessions. Note that since mk-LL does not perform the "modified Brinkman board" task in accordance with the standard single particle grabbing procedure, it is not possible to evaluate exercise strategies. The second movement task is the task of "reaching out and grabbing the drawer", which is used to quantitatively control the generation and time course of grip strength and load (tension) force. The design of this task forces the monkey to open a drawer with one hand to resist different resistances. The task of "reaching out and grabbing the drawer" requires a firm grip on the drawer handle between the thumb and index finger (grip strength) and a strong pull on the drawer (load force), both of which are monitored. A standard task consists of performing ten correct consecutive tests on each different resistor, with each hand. The correct test is defined as successfully opening the drawer and then using the grip to fully extract the pellets. Each task starts with the least resistance (R0). After ten correct trials on R0, the monkey gets an extra reward (a slice of almond), and then the resistance increases to R3. After R3 has performed ten correct trials, he gets an extra reward again, and the resistance increases to R5. Once one hand completes the three resistances, the other hand follows the same pattern. This report analyzes two different parameters. The first is the maximum grip strength produced in each test. The second is the maximum load force, which is also measured in each test. Remove the first trial of each resistance from the main analysis because it represents an outlier (unknown resistance at the beginning of a new series of trials). In a separate analysis, the force generated at each resistance in the first test is compared with the force generated in subsequent tests at the same resistance. The four monkeys complete this task two to three times a week. One of the monkeys (MK-MI) completed the drawer task correctly with only his left hand (due to injury to his right hand). In fact, MK-MI does not use precise grip movements to hold the handle of the drawer with the right hand, but uses another strategy (single finger to push the upper part of the handle) to prevent any grip force measurement.

　　Surgery: Before surgery, each animal was first lightly sedated under ketamine (10 mg/kg), midazolam (0.1 mg/kg) and methadone (0.2 mg/kg), and prepared for surgery. Each animal received intramuscular injection of methadone (0.2 mg/kg) and was treated with the painkiller carprofen (4 mg/kg; subcutaneous), atropine (0.05 mg/kg; intramuscular injection) to reduce bronchial secretions and antibiotics (8.75 mg/kg; subcutaneous injection zh), dexamethasone (0.3 ml/kg; normal saline dilution 1:1; intramuscular injection). After the animals entered the operating room, they were perfused intravenously (femoral vein) with 1% propofol, diluted with lactated Ringer's solution, 125mg ketamine (20ml propofol, 40ml lactated Ringer's solution, 1.25ml ketamine) to ensure deep anesthesia. Adjust the infusion rate to maintain the optimal level of anesthesia. During the entire operation, the level of anesthesia and physiological status are controlled according to arterial oxygen saturation, heart rate (ECG), ventilation, and body temperature. Then the animal was placed in a stereotactic frame, and the head was fixed with ear rods for surgery. In order to reduce the pain caused by the fixed point, a layer of local pain relief cream is applied to the ear rod. Local injection of lidocaine anesthetize the incision site. After the incision, the muscle tissue is pushed to the side to expose the skull, allowing the craniotomy (dlPFC) above the head of the frontal lobe. However, in order to reduce the impact of craniotomy, the size of the bone opening was minimized; therefore, various grooves (such as the arcuate groove and the main groove) could not be clearly identified and could not guide the precise location of the biopsy. It turned out that from a monkey to The next monkey, this is variable. The opening of the three monkey skulls is on the left side (MK-LY, MK-MI and ML-LL), while in MK-MY it is on the right. The size of the bone flap is about 1 square centimeter. After the bone is taken out, the dura mater is cut open, and a piece of dlPFC cortical tissue is taken out and placed directly into the storage medium. Cauterize the injured blood vessel, put the bone flap back in place, and fix it with histological glue. Muscle tissue and skin are sutured. After the operation, each animal was monitored until it fully recovered. When monkeys eat normally, their signs are considered stable.

　　Magnetic Resonance Imaging: Use MRI to determine the precise location of the biopsy, and then proceed to the MPTP follow-up program. Each animal was first lightly sedated with ketamine (10 mg/kg) and midazolam. After each monkey was transported to the MRI facility, 1% propofol was intravenously infused, diluted with Ringer's lactic acid solution and 125 mg ketamine hydrochloride, and anesthetized. Adjust the infusion rate to ensure the best anesthesia level (continuous monitoring of ECG and oxygen saturation). In addition, place a warm water bag filled with hot water around the monkey's body to maintain body temperature. Use the three-dimensional transverse T1 weighted acquisition protocol to collect data on the GE 3T magnet. The parameters are as follows: Field of view: 256×256, TR: 7.248, TE: 3.032, FS: 3. Due to the animal's prone position, the image is rotated. After proper rotation, the brain is extracted from the skull and represented in a three-dimensional view before being shown. Estimate the location of each biopsy and its volume (corresponding to gray matter) based on the MRI image. Note that biopsy cannot be histologically verified, because when MPTP treatment is performed, the second dlPFC biopsy is performed near the first biopsy. Therefore, before MPTP treatment, the two biopsies cannot be distinguished, and only the first biopsy is relevant to the current behavioral study.

　　Result: The location and size of the biopsy: Based on MRI, the scope and location of the cortical biopsy were identified and reconstructed. The biopsy was transferred to the surface of the corresponding brain. The dlPFC biopsy volume was 7, 14, 16, and 7 cubic millimeters, respectively. In Mk-MY, the biopsy is located at the forefront of dlPFC, about 5 mm from the midline, and most likely to overlap the transition zone between Brodmann cortex 9 and 10. In addition, relative to the midline, about 5 mm outside, but closer to the caudal end, the biopsy of Mk-LY appears to be located in the rostral region of zone 9. The lesion of MK-MI is located in the dlPFC area. The fourth monkey (MK-LL), considering that its biopsy does not involve dlPFC, MK ll should be treated as an outlier here.

　　Improved Brinkman board task: Behavioral scoring data based on the number of particles recovered within 30 s showed that the monkeys showed basically stable manual dexterity before the dlPFC biopsy. The data obtained from time-selective sequence analysis showed that monkeys followed a largely repeatable strategy (exercise habit) to empty the plate before the biopsy, in other words, the time series visited 50 wells along the left-right axis. Interestingly, as shown by MK-MY in Figures 2a and b, dlPFC or PMd-r biopsy neither affects the scoring nor the time series of well visits. In fact, statistical analysis comparing scores and time series before and after biopsy did not show any statistically significant differences. These conclusions are applicable to both the ipsilateral arm and the contralateral arm of the four monkeys, except for the contralateral hand of MK-MY and the contralateral hand of MK-Ly. The statistically significant difference does show that the post-biopsy score is not inadequate, because the post-biopsy score is actually higher, thus supporting that the lesion has no harmful effects; we can conclude that in the "modified Brinkman plate" task, dlPFC biopsy has the advantages of this study Compared with the larger and different location biopsy (area 46) performed previously, there is no systematic impact on performance and exercise habits.

　　Drawer grab task: The results obtained from the task of reaching and grabbing the drawer are divided into three relative drawer opening resistances, namely R0, R3 and R5. For each resistance, the data is divided into two stages: pre-biopsy and post-biopsy. For each hand, the pre-biopsy and post-biopsy times are adjacent to each other for direct comparison. Quantitative data shows that whether it is before or after biopsy, resistance has an impact on maximum grip strength and maximum load force. As expected, the maximum force increases parallel to the resistance. The greater the resistance, the greater the force required to grasp the knob or pull the drawer.