"This is a priceless treasure in the development of intracranial human neuroscience."
Written by | Lost little bees
Source | "Medical Community" public account
Kate Folladori was hospitalized for more than a month. She had never been more eager to anticipate her seizures than she had at the moment.
Fladori has suffered from epilepsy for 20 years and has tried a variety of medications, but his condition is still stubborn. In 2019, the team at Baylor St. Luke's Medical Center in the United States opened her brain shell and placed electrodes inside the brain parenchyma. She is then awakened to record neural activity in an attempt to find the starting location of the abnormal episode.
After a series of tests, the medical team wrapped her head in layers of sterilized material. But the brain shell is not fully closed, and the electrodes are still inside.
The medical team wanted to monitor her seizure patterns. Doctors say the results of the monitoring may be able to assess whether Vladori can undergo brain tissue resection surgery or implant a brain pacemaker to suppress seizures.
Photo caption: Doctor implants electrodes in Kate Folladori's brain. /Science
After weeks of monitoring, Vladori was restless. The long wait bored her, and even produced some surreal feelings: it was raining outside the window, but she thought she was watching the rainy show.
Until the team of Sameer Sheth, a neurosurgeon at Baylor College of Medicine in the United States, visited. They asked Fradori to respond to the prompts on the computer screen and record her brain activity through an instrument.
"Life suddenly lit up." Fladori said, "Give you something to do, give you a goal — that's everything to me." ”
Vladori provided the Sameer Sheth team with a rare and important set of information. "This is a priceless treasure in the development of intracranial human neuroscience." Khara Ramos, former director of the Neuroethics Program at the National Institute of Neurological Diseases and Stroke, paid tribute to the subjects.
"Without invasive surgery, scientists wouldn't be able to gather information and visualize brain activity." But that's also the biggest problem, Science reports: Everything scientists do, not for treatment, just to complete their research, and most studies can't be repeated because of individual patient differences.
Image from Science
Invades the brain while awake
Capture both temporal and spatial information
Samir Shea's team hopes to obtain a "real-time topographic map" of brain activity from monitoring.
They argue that while non-invasive techniques such as magnetic resonance and EEG can also study brain function, they can only monitor a single dimension in time or space, not both.
The exception is invasive neuromodulation techniques. It requires brain surgery on the patient, placing electrodes under the dura mater and/or inside the brain parenchyma to directly detect neuronal activity. In this state, spatial and temporal data can be accurate to both millimeters and milliseconds.
This kind of "real-time topographic map of the brain" has a long history, and some techniques have been applied to clinical treatment.
Beginning in the 1930s and 1940s, Canadian neurosurgeon Wilder Penfield et al. treated epilepsy by removing parts of the brain. During the procedure, Penfield uses probes (low-level currents) to sequentially stimulate exposed brain tissue in different areas. Since the brain does not have pain receptors, patients do not feel pain during stimulation.
When electrodes are stimulated to a specific area, some parts of the patient's body move involuntarily. If the part responsible for "somatic sensation" is stimulated, the patient seems to actually feel that some part of the body is being touched. In this way, Penfield et al. discovered the "Cortical topography."
Image courtesy of ResearchGate
At the therapeutic level, invasive neuromodulation techniques are translated into deep brain stimulation (DBS), epidural stimulation, etc. Among them, DBS can be used to treat severe, drug-insensitive neuropsychiatric disorders. Indications for the current positive efficacy include Parkinson's disease, idiopathic tremor, dystonia, and refractory obsessive-compulsive disorder. In particular, Parkinson's disease and idiopathic tremor, the clinical effect is confirmed by data.
Invasive techniques are also used in clinical research on a variety of diseases, such as depression, tics, eating disorders, chronic phantom limb pain, addiction, and vegetative arousal.
Therapeutic devices that remain in the brain for a long time are also useful "research tools". Nanthia Suthana, a professor of neuroscience at UCLA, said some devices can both perform electrical stimulation and read neural activity. "People who are paralyzed or lose limbs are rare subjects. Some agreed to implant neural recording devices and participate in research. This may help to develop new brain-computer interfaces to help them regain their motor capacity. ”
Itzhak Fried, a professor of neurosurgery at UCLA's David Geffen School of Medicine, said: "We have almost touched the most basic neural mechanisms in humans. ”
Yitzhak Fried estimates that about 30 research teams in North America are conducting intracranial neuroscience research on epilepsy patients. "When I started researching in this area about 20 years ago, there were less than 10 teams and projects."
Image caption: The subdural network is a thin plastic pad, slightly smaller than a credit card; the stereoEEG probe is a thin wire about 1 mm in diameter that can be inserted into the skull to record areas deep in the brain. /Science
The Ethical Dilemma of Invasive Brain Stimulation Techniques
However, invasive surgery for the sole purpose of research is unethical.
"Subjects are a uniquely vulnerable group." Winston Chiong, a neuroscientist and ethicist at the University of California, San Francisco, believes there must be abuse.
Due to ethical implications, how to recruit patients has always been the biggest difficulty in the development of such technologies.
Bioethicists have long discouraged this "dual-role consent," in which the primary members of the research team are precisely the patient's attending physicians.
Bioethicists believe that patients may perceive themselves as "responsible" for their doctors and their research, or develop a sense of obedience, misinterpreting the study as having a therapeutic effect. But basic scientific research attached to medical procedures usually does not provide clinical benefit to subjects.
A patient who was invited by an attending physician to join the trial confessed to Science that trusting the physician was an important reason for his participation in the study. If you ask another person, you will not agree.
In light of the above, some teams are using a hybrid consent process. The attending physician is responsible for introducing the study and answering patient questions. Another member of the research team who was not involved in the patient's treatment was responsible for communicating the informed consent component, signing documents, etc.
The question arises again: how to measure and articulate risk when communicating with invitees is extremely challenging.
Most research teams agree that the only risk of having subjects play computer games with electrodes plugged in or answering questions while monitoring for abnormal discharges is fatigue.
But the surgical risk is difficult to assess. In the case of an open skull, the study took at least 20-30 minutes to extend the procedure. This may increase the rate of infection. At the same time, additional electrodes are temporarily placed during brain surgery for study, or the chance of complications such as cerebral hemorrhage is increased.
The participants' understanding and memory of the risk were also uncertain factors. In a study that explored brain activity during eye movements, only about 23 percent of the 22 Parkinson's patients who agreed to participate recalled any of the informed risks they were told about 1 week after the informed consent procedure ended.
In order to solve this problem, some scholars have suggested adopting the "repetition method". That is, after the researcher explained the risk to the subject, he asked the latter to repeat the explanation.
Between the many gray areas of invasive technology in medical ethics, on January 19, local time, the journal Neuron published "Ethical Commitment, Principles and Practices to Guide human intracranial neuroscience research".
One of the important principles is that scientific research should not influence clinical decision-making.
In the case of dbs to monitor epilepsy, for example, patients can be anesthetized throughout the process or they can wake up halfway. After 2019, Samir Sheas' dbs surgery was performed under general anesthesia. There is research support, which can improve patient comfort, significantly reduce complications, and shorten the duration of surgery. "But some DBS studies require intraoperative wake-up of patients. This is not my usual practice. Therefore, I stopped such studies. ”
From September 6 to 7, 2018, the International Symposium on Neuroscience Innovation was held in Shanghai. Gary Marchant, director of the Center for Law, Technology and Innovation at Arizona State University, pointed out at the meeting that the biggest problem in the development of neurotechnology lies in regulation. "This technology is increasingly being used outside of clinical practice, and there is currently no appropriate regulatory body to deal with these situations. Moreover, technology is evolving much faster than regulation. ”
Invasive brain stimulation focuses more on clinical applications in China
Vladori was one of the lucky ones, and the research did bring her clinical benefits.
During the epilepsy monitoring, doctors found the "problem." They install DBS in a specific location. In the two years after the operation, she did not have any more epilepsy.
This also gave Fradori a new perspective on medical research. She said she would be "more willing" to participate in research in the future.
The mainland has also done a lot of invasive neuromodulation technology implementation.
In 2017, Xiao Li (pseudonym) underwent craniotomy for a brain tumor. Xiao Li was awakened during the operation, and the doctor used a weak electric current to stimulate the boundary between the tumor and normal brain tissue while observing Xiao Li's response to ensure the accuracy of the resection range.
In 2018, 19-year-old Xiaohua (pseudonym) discovered a brain tumor. The surgery is difficult, and a little carelessness can cause paralysis of the left arm. Doctors also opted for intraoperative arousal, which pinpointed the location of the tumor through a neuroimaging navigation system to ensure that damage to the motor function area was minimized while removing the tumor.
Earlier, in 2014, a study treated refractory neuralgia through invasive nerve stimulation. The researchers compared and analyzed in detail the mechanisms and effects of peripheral nerve stimulation, nerve root stimulation, spinal cord stimulation, deep brain stimulation and motor cortex stimulation. It was eventually confirmed that motor cortical stimulation was more effective in the treatment of peripheral neuralgia and central neuralgia. Due to the limited sample size of the study, the researchers believe that a large sample study is also needed.
As can be seen in the above cases, the application of invasive neuromodulation techniques in mainland China is more clinically focused. There are also some scholars who try to expand the scope of its application, but also for ethical reasons, this type of research is difficult to do large sample sizes.
bibliography:
1.Kelly Servick. Science, 2022, 375(6578).doi: 10.1126/science.ada0251
2. The truth of the sudden awakening of craniotomy "intraoperative awakening" was broadcast live. China Youth Network
3. The patient wakes up during craniotomy The doctor removes the tumor while chatting What is this operation?. Tencent Health
4. Gong Jin. Invasive neurostimulation for the treatment of refractory neuralgia. Chinese Journal of Therapeutic Medicine, 2014, 23(11): 980-982
5.Ethical commitments, principles, and practices guiding intracranial neuroscientific research in humans. NEUROVIEW.doi.org/10.1016/j.neuron.2021.11.011
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