Name: a pilot study on the repetitive transcranial magnetic stimulation of a&#946; and tau levels in rhesus monkey cerebrospinal fluid
Uploaded: 2021-09-03T15:00:00
Description: Watch this Scientific Journal Video about A Pilot Study on the Repetitive Transcranial Magnetic Stimulation of AÎ² and Tau Levels in Rhesus Monkey Cerebrospinal Fluid at JoVE.com

The authors would like to thank Sichuan Green-House Biotech Co., Ltd for providing the monkey chair and other relative devices. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

All the experiments were performed under the Guidance for the Care and Use of Laboratory Animals, formulated by the Ministry of Science and Technology of the People&#39;s Republic of China, as well as the principles of the Basel Declaration. Approval was given by the Animal Care Committee of the Sichuan University West China Hospital (Chengdu, China). Figure 1 shows the single-blind, self-controlled study design used here.
1. rTMS devices
<ol>
	<li>Use an 8-shap...

<ol>
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A&#946;1-42, a well-established biomarker of AD, is a CSF core biomarker related to A&#946; metabolism and amyloid plaque formation in the brain and has been widely used in clinical trials and the clinic26. Recent studies have shown that the CSF A&#946;42/A&#946;40 ratio is a better diagnostic biomarker of AD than A&#946;42 alone because it is a better indicator of the AD-type pathology27,28. Tau...

Amyloid-&#946; (A&#946;) and tau are important CSF biomarkers. A&#946; consists of 42 amino acids (A&#946;1-42), which is the product of transmembrane amyloid precursor protein (APP) hydrolyzed by &#946;- and &#947;-secretases1. A&#946;1-42 may aggregate into extracellular amyloid plaques in the brain because of its solubility characteristics1,2. Tau is a microtubule-associated protein that is mainly present in axons and is involved in anterograde axonal transport3. Abnormal tau hyperphosphorylation is mainly induced by the imbalance between kinases and phosphatases, resulting in the detachment of tau from microtubules and the formation of neurofibrillary tangles (NFT)1. The concentration of tau increases in the CSF because tau and phosphorylated tau proteins (pTau) are released into the extracellular space during the neurodegenerative process. Previous studies have shown that CSF biomarkers are relevant to the three main pathological changes of the Alzheimer&#39;s disease (AD) brain: extracellular amyloid plaques, intracellular NFT formation, and neuron loss4. Abnormal concentrations of A&#946; and tau present in the early stage of AD, thus allowing early AD diagnosis5,6.
In 2016, Tsai et al. found that non-invasive light-flickering (40 Hz) reduced the levels of A&#946;1-40 and A&#946;1-42 in the visual cortex of pre-depositing mice7. Recently, they further reported that auditory tone stimulation (40 Hz) improved recognition and spatial memory, reduced amyloid protein levels in the hippocampus and auditory cortex (AC) of 5XFAD mice, and decreased pTau concentrations in the P301S tauopathy model8. These results indicate that non-invasive techniques could impact A&#946; and tau metabolism.
As a non-invasive tool, transcranial magnetic stimulation (TMS) could electrically stimulate neural tissue, including the spinal cord, peripheral nerves, and cerebral cortex9. Moreover, it can modify the excitability of the cerebral cortex at the stimulated site and in the functional connections. Therefore, TMS has been used in the treatment of neurodegenerative disorders and prognostic and diagnostic tests. The most common form of clinical intervention in TMS, rTMS, can induce cortex activation, modify the excitability of the cortex, and regulate cognitive/motor function.
It was reported that 20 Hz rTMS had an in vitro neuroprotective effect against oxidative stressors, including glutamate and A&#946; and improved the overall viability of monoclonal hippocampal HT22 cells in mice10. After 1 Hz rTMS stimulation, the &#946;-site APP-cleaving enzyme 1, APP, and its C-terminal fragments in the hippocampus were considerably reduced. Notably, the impairment of long-term potentiation, spatial learning, and memory in hippocampal CA1 was reversed11,12. Bai et al. investigated the effect of rTMS on the A&#946;-induced gamma oscillation dysfunction during a working memory test. They concluded that rTMS could reverse A&#946;-induced dysfunction, resulting in potential benefits for working memory13. However, there are few reports on the effects of rTMS on tau metabolism and the dynamic changes in A&#946; and tau in CSF before and after rTMS. This protocol describes the procedure for investigating the effects of rTMS at different frequencies (low frequency, 1 Hz; high frequencies,20 Hz, and 40 Hz) on A&#946; and tau levels in rhesus monkey CSF.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Anesthesia Puncture Kit for Single Use</td>
			<td>Weigao, Shandong, China</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>CCY-I magnetic field stimulator</td>
			<td>YIRUIDE MEDICAL, Wuhan, China</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>GraphPad Prism version 7.0</td>
			<td>GraphPad Software, Inc., San Diego, CA, USA</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Human Amyloid Beta and Tau Magnetic Bead Panel</td>
			<td>EMD Millipore Corporation, Billerica, MA 01821 USA</td>
			<td></td>
			<td>liquid chip detection</td>
		</tr>
		<tr>
			<td>MILLIPLEX Analyst 5.1</td>
			<td>EMD Millipore Corporation, Billerica, MA 01821 USA</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Monkey Chair HH-E-1</td>
			<td>Brainsight, Cambridge, MA 02140 USA</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Zoletil 50</td>
			<td>Virbac, France</td>
			<td></td>
			<td>zolazepam&#8211;tiletamine</td>
		</tr>
	</tbody>
</table>

a pilot study on the repetitive transcranial magnetic stimulation of a&#946; and tau levels in rhesus monkey cerebrospinal fluid

Previous studies have demonstrated that a non-invasive light-flickering regime and auditory tone stimulation could affect A&#946; and tau metabolism in the brain. As a non-invasive technique, repetitive transcranial magnetic stimulation (rTMS) has been applied for the treatment of neurodegenerative disorders. This study explored the effects of rTMS on A&#946; and tau levels in rhesus monkey cerebrospinal fluid (CSF). This is a single-blind, self-controlled study. Three different frequencies (low frequency, 1 Hz; high frequencies, 20 Hz and 40 Hz) of rTMS were used to stimulate the bilateral-dorsolateral prefrontal cortex (DLPFC) of the rhesus monkey. A catheterization method was used to collect CSF. All samples were subjected to liquid chip detection to analyze CSF biomarkers (A&#946;42, A&#946;42/A&#946;40, tTau, pTau). CSF biomarker levels changed with time after stimulation by rTMS. After stimulation, the A&#946;42 level in CSF showed an upward trend at all frequencies (1 Hz, 20 Hz, and 40 Hz), with more significant differences for the high-frequencies (p &lt; 0.05) than for the low frequency. 
After high-frequency rTMS, the total Tau (tTau) level of CSF immediately increased at the post-rTMS timepoint (p &lt; 0.05) and gradually decreased by 24 h. Moreover, the results showed that the level of phosphorylated Tau (pTau) increased immediately after 40 Hz rTMS (p &lt; 0.05). The ratio of A&#946;42/A&#946;40 showed an upward trend at 1 Hz and 20 Hz (p &lt; 0.05). There was no significant difference in the tau levels with low-frequency (1 Hz) stimulation. Thus, high-frequencies (20 Hz and 40 Hz) of rTMS may have positive effects on A&#946; and tau levels in rhesus monkey CSF, while low-frequency (1 Hz) rTMS can only affect A&#946; levels.

The results showed that rTMS could affect the A&#946; and tau levels in rhesus monkey CSF. CSF biomarker levels changed with time after rTMS stimulation at different frequencies (1 Hz, 20 Hz, and 40 Hz).
A&#946;42 and A&#946;42/A&#946;40 
As shown in Figure 4A, after 1 Hz rTMS stimulation, the A&#946;42 levels gradu...

Watch this Scientific Journal Video about A Pilot Study on the Repetitive Transcranial Magnetic Stimulation of AÎ² and Tau Levels in Rhesus Monkey Cerebrospinal Fluid at JoVE.com

A Pilot Study on the Repetitive Transcranial Magnetic Stimulation of A&#946; and Tau Levels in Rhesus Monkey Cerebrospinal Fluid

Here, we describe the procedure for a pilot study to explore the effect of repetitive transcranial magnetic stimulation with different frequencies (1 Hz/20 Hz/40 Hz) on A&#946; and tau metabolism in rhesus monkey cerebrospinal fluid.

Previous studies have demonstrated that a non-invasive light-flickering regime and auditory tone stimulation could affect A&#946; and tau metabolism in ...

This protocol uses serial cisterna magna CSF sampling method to explore the effects of rTMS on alpha-beta and tau levels in rhesus monkey. This technique uses a novel CSF sampling method allowing for repeated CSF sampling under fully awake conditions with low risks of adverse events. Demonstrating the procedure will be Ying-Qian Zhang, a research assistant from the Department of Physiology at Southwest Medical University, and Hui-Xin Tan, a graduate student from Sichuan University.After administering analgesia and confirming successful anesthetization, place the five-year-old male rhesus monkey on the operating table in the lateral decubitus position and disinfect the area around the lower back. Hunch its back and bring its knees toward the chest. Insert a spinal needle between the lumbar vertebrae L4 to L5 and push it in until there is a pop indicating entry into the lumbar cistern where the ligamentum flavum is housed.Continue to push the needle further until there is a second pop indicating entry into the dura mater, then withdraw the stylet from the spinal needle and collect drops of CSF. Next, perform catheter insertion under fluoroscopic guidance by inserting the epidural catheter through the puncture needle into the subarachnoid space until it is buoyant in the cisterna magna. Then for port implantation, make a five centimeter incision from the puncture site toward the head and isolate the skin from the subcutaneous tissue to place the sampling port.Connect the port to the end of the epidural catheter, implant the port under the skin and suture the incision. For CSF collection, use the cage bars to restrain the monkey and keep its back bent. Then wipe with an alcohol swab and insert the syringe into the center of the sampling port to extract CSF from the cisterna magna through the catheter.Discard the first 200 microliters of CSF, then collect one milliliter of CSF for analysis. Fix the monkey on the monkey chair before the experiment to avoid interruption during the rTMS intervention, then collect CSF for biomarker analysis when the monkey is awake to avoid the influence of anesthetic drugs. On the third day after the subarachnoid catheterization and two weeks before the start of the experiment, subject the monkey to adaptive training with the monkey chair twice a day for 30 minutes each time.Conduct the rTMS adaptive training or sham stimulation one week after the adaptive training with the monkey chair and one week before the start of the formal experiment to avoid hindering the progress of the experiment by vibrations and sounds during the stimulation process. For sham stimulation, use a sham coil that produces vibration and sound but does not generate a magnetic field. After stimulation, offer food to the monkey to help it adapt to the process.Localize the bilateral dorsolateral prefrontal cortex according to the international 10 to 20 system and conduct three different sessions of rTMS using three different frequencies without a washout period exceeding 24 hours. Perform the first, second, and third sessions twice a day for three consecutive days. To analyze the four CSF biomarkers, use a minimally invasive catheterization method to collect the CSF.Collect CSF at five time points with four samples at each time point at three-minute intervals. After collecting a total of 60 samples for three frequencies, number and store them in a minus 80 degree Celsius refrigerator for up to one month. After the experiment, subject all samples to liquid chip detection according to the manufacturer's instructions.After one hertz rTMS stimulation, Abeta42 levels gradually increased over 24 hours. Similarly with rTMS at 20 hertz, the Abeta42 levels increased with time and reached a peak at six hours after stimulation. In contrast, after 40 hertz stimulation, Abeta42 levels significantly increased immediately at the post-rTMS time point, then decreased slowly.The ratio of Abeta42 to Abeta40 showed an upward trend after stimulation with one and 20 hertz rTMS and significantly increased two hours after stimulation. However, there was no significant difference in the ratio at 40 hertz. The tTau levels in CSF immediately increased after 20 and 40 hertz rTMS stimulation and decreased gradually.However, there was no significant difference after one hertz stimulation. The pTau level immediately increased after 40 hertz stimulation and decreased to below baseline level after 24 hours. In contrast, for the one and 20 hertz stimulation, the pTau level showed a downward trend.Researchers requiring multiple samples of monkey CSF can consider this serial cisterna magna CSF sampling method.

Research

JoVE Journal

Neuroscience

A Novel Approach for Documenting Phosphenes Induced by Transcranial Magnetic Stimulation

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Combined Transcranial Magnetic Stimulation and Electroencephalography of the Dorsolateral Prefrontal Cortex

Transcranial magnetic stimulation (TMS) is a non-invasive method that produces neural excitation in the cortex by means of brief, time-varying magnetic ...

Bilateral Assessment of the Corticospinal Pathways of the Ankle Muscles Using Navigated Transcranial Magnetic Stimulation

Distal leg muscles receive neural input from motor cortical areas via the corticospinal tract, which is one of the main motor descending pathway in humans ...

In Vivo Imaging of Cerebrospinal Fluid Transport through the Intact Mouse Skull using Fluorescence Macroscopy

Cerebrospinal fluid (CSF) flow in rodents has largely been studied using ex vivo quantification of tracers. Techniques such as two-photon microscopy and ...