Clinical Support Department of Shenzhen Yingchi Technology Co.,Ltd.

Has this happened to you? Your usually kind grandfather seems to have a strange temper and starts to forget what he just heard. He loses his sense of three-dimensionality and may fall down the stairs. As time goes by, his memory becomes confused, as if he has returned to the past, back to his childhood. Later, he may even forget how to speak, eat and sleep... The culprit behind all this is Alzheimer 's disease (AD) .

The Alzheimer's Disease Branch of the China Association of Geriatric Care (ADC), in collaboration with Peking University Sixth Hospital, the Chronic Disease Center of the Chinese Center for Disease Control and Prevention, the Aging Communication Branch of the Chinese Society of Gerontology and Geriatrics, and media professionals, has determined the theme of my country's World Alzheimer's Disease Month (Day) in 2024 as "Act Now: Light up the Light of Memory."

TMS improves the cognitive functions of AD patients, including memory , visual space, executive function, comprehension and language function, through several mechanisms - cerebral cortical excitability and neural plasticity, reducing the generation of Aβ, and regulating brain network disconnection. We will launch new content around the theme of this Alzheimer's Day: TMS treatment mechanism, common parameters, the latest treatment paradigm and auxiliary examination and evaluation technology. Let's start with the first part: TMS treatment mechanism and common parameters.

1. Stimulation frequency

20Hz is the best!

• Efficacy: high frequency > low frequency. Related studies have shown that high frequency rTMS is more effective in treating AD than low frequency rTMS.

• Reason: High-frequency rTMS is more likely to induce long - term potentiation (LTP) of synapses and improve cognitive function. High-frequency rTMS can also improve cerebral blood perfusion, while the blood flow in cognitive function-related areas of AD patients (such as the hippocampus, parietal lobe, temporal lobe, and prefrontal lobe) is significantly reduced.

• High frequency range selection: 20 Hz rTMS can more effectively improve the cognitive function of AD patients than 1 and 10 Hz, but whether higher frequency stimulation schemes (such as 40 Hz) can achieve better therapeutic effects still needs further clinical research, and the safety also needs to be determined.

2. Stimulation Target

There are large differences in the brain areas activated by different stimulation sites

• Stimulating the bilateral DLPFC area can improve the patient's image naming accuracy or improve the patient's overall cognitive function.

• Stimulate the right inferior frontal gyrus area to improve the patient's attention and psychomotor speed.

• Stimulate the precuneus area to enhance the patient's episodic memory function.

• For patients with mild to moderate AD, the hippocampus area was stimulated, and the results showed that the functional connectivity of the patients' default network was enhanced, and their language and learning abilities were improved.

Theoretically, the cognitive impairment of AD involves multiple brain regions, and the possibility of multi-target rTMS having a better therapeutic effect cannot be ruled out. However, considering the difficulty in accurate positioning and the interaction between different brain regions, there is still a lack of relevant clinical research. In the future, it can be combined with neuronavigation technology. Here we recommend the first NMPA-certified TMS navigation system in China - transcranial magnetic stimulation 3D navigation system (① camera, system precision, ② time efficiency, ③ compatible with a variety of stimulators, MEP modules, ④ support for custom brain function areas). Combined with the patient's clinical symptoms, in-depth exploration of the effect of multi-target rTMS in treating AD.

3. Stimulation intensity and duration

• The intensity range is generally 80% to 120% RMT. The latest consensus recommends that the first treatment intensity be ≤ 100% RMT, and then the treatment intensity should be adjusted individually according to the patient's condition.

• Evaluation criteria: The optimal rTMS stimulation intensity may be related to the degree of cognitive impairment of the patient.

• Reason: rTMS treatment with 90% RMT can improve cognitive impairment in patients with mild to moderate AD. However, some studies have shown that rTMS treatment of this intensity has no significant effect on patients with mild AD, but has a more significant effect on patients with moderate to severe AD.

• Treatment duration: It is recommended that AD patients receive rTMS intensive treatment in the acute phase, followed by long-term rTMS consolidation treatment.

• Reason: The long-term therapeutic effect of rTMS also depends on the cumulative effect of multiple stimulations, which may be related to LTP.

• Example: Related studies have shown that long-term rTMS (> 20 times) can better improve the cognitive function of AD patients compared with short-term rTMS (≤ 3 times).

4. Mechanism of action 1

Reduce Aβ deposition and Tau protein hyperphosphorylation

• AD pathological feature 1: The massive production of Aβ leads to its deposition. rTMS treatment can reduce the deposition of β-amyloid protein in the brain of familial AD mice.

• AD pathological feature 2: Aβ clearance disorder leads to deposition. rTMS treatment can improve its clearance efficiency in the brain excretion pathway.

• In addition, rTMS treatment activates lysosomal degradation and clearance of Aβ plaques by reducing the expression of apolipoprotein E and protein phosphatase 2A, and enhances hippocampal autophagy in APP/PS1 mice, resulting in a corresponding decrease in the related pathogenic marker proteins Aβ, Tau protein and its downstream molecules in the progression of AD. This not only restores the spatial learning ability of mice and repairs memory defects, but also alleviates cognitive impairment of learning and memory, providing new ideas and experimental basis for the early prevention and treatment of AD.

5. Mechanism of action 2

Promotes synaptic plasticity and hippocampal neurogenesis

• The most widely accepted mechanism of rTMS is the regulation of synaptic plasticity of hippocampal neurons. The regulation effect of rTMS varies with the frequency of stimulation. Low-frequency stimulation leads to a decrease in the amplitude of excitatory synaptic potentials, resulting in an LTD effect. Conversely, high-frequency stimulation can increase the amplitude of excitatory synaptic potentials, resulting in an LTP effect.

• Hippocampal nerve damage in AD patients exacerbates neuronal loss and accelerates the progression of the disease. rTMS with appropriate parameters can promote hippocampal neurogenesis, which may be one of the mechanisms by which rTMS improves cognitive function in AD patients.

6. Mechanism of action 3

Regulates neurotransmitters and neurotrophins

• rTMS can increase the content of 5 - HT and 5 - HT receptors, and promote the release of dopamine in the mesolimbic and striatal regions, thereby slowing down the cognitive decline in AD patients.

• rTMS improves cognitive dysfunction by maintaining the balance between glutamatergic and GABAergic systems.

• High-frequency rTMS improved patients' spatial cognition and hippocampal synaptic plasticity impairment, which may be related to the activation of BDNF/TrkB signaling.

7. Mechanism of Action 4

Reduce neuroinflammation and regulate glial cells

• Early intervention with rTMS can reduce the levels of proinflammatory cytokines such as IL - 6, IL - 1β and TNF - α, regulate the PI3K/AKT/GLT - 1 signaling pathway, create a favorable brain environment, and thus alleviate neuroinflammatory responses, restore synaptic plasticity, and thus reduce neuronal loss and cell apoptosis.

• High-frequency rTMS attenuated cognitive impairment and reactive gliosis, suggesting its potential role in regulating the inflammatory response in AD.

8. Mechanism of Action 5

Inhibit oxidative stress and protect mitochondrial function

• After two weeks of high-frequency rTMS treatment over the left parietal lobe, AD patients showed an increase in visual recognition memory function, which benefited from an increase in antioxidant capacity and a decrease in oxidase activity.

• rTMS can noninvasively regulate and balance BDNF and oxidative stress levels, thereby exerting a beneficial antioxidant effect on AD patients.

• rTMS evaluated the disruption of mitochondrial membrane potential in ischemic stroke and found that rTMS has a potential role in regulating mitochondrial function.

Statement 

1.This content is organized by the Clinical Support Department of Shenzhen Yingchi Technology Co.,Ltd. Criticisms and corrections are welcome. For reprint, please indicate the source.

2.References:

張梁英,王永軍.重復經顱磁刺激治療阿爾茨海默病的刺激參數及作用機制研究進展[J].神經疾病與精神衛生,2023,23(12):874-878.