Name: conventional and threshold-tracking transcranial magnetic stimulation tests for single-handed operation
Uploaded: 2021-08-16T13:30:00.000+00:00
Duration: 8 min 24 s
Description: Watch this Scientific Journal Video about Conventional and Threshold-Tracking Transcranial Magnetic Stimulation Tests for Single-handed Operation at JoVE.com

This study was financially supported mainly by the two grants from Lundbeck Foundation (Grant number R290-2018-751) and Independent Research Fund Denmark (Grant number: 9039-00272B).

NOTE: All subjects must give their written consent prior to the examination, and the protocol must be approved by the appropriate local ethical review board(s). All methods described here were approved by the Regional Scientific Ethical Committee and the Danish Data Protection Agency.
The TMS method involves three stages: 1) preparation of the subject, 2) recording the TMS, and 3) analyzing the results.
1. Preparation of the subject
<ol>
	<li>Assess the subjects&#39; medical history and ask whether the subject has epilepsy, a pacemaker, or any kind of metallic devices/implants in the body, and for the female subjects, whether she is pregnant.</li>
	<li>Instruct the subject in detail about the examinations and invite them to give written consent.
	<ol>
		<li>Inform the subject about the application of magnetic stimulation to the scalp and that each examination takes approximately 10 min.</li>
		<li>Explain that the stimulation will be heard as a click sound and is meant to evoke a muscle twitch and that some stimuli may feel slightly unpleasant.</li>
		<li>Explain that the stimulation can be turned off at any time if signaled by the subject.</li>
	</ol>
	</li>
	<li>Ask the subject to wear a swimming cap.</li>
	<li>Clean the subject&#39;s hand contralateral to the studied hemisphere.</li>
	<li>Place the active recording electrode over the first dorsal interosseous (FDI) muscle and the reference electrode on the 2nd metacarpophalangeal joint.</li>
	<li>Place a ground electrode on the dorsum of the hand.</li>
	<li>Connect the recording and ground electrodes to the amplifier.</li>
	<li>Instruct the subject to remain alert but relaxed during the examination.</li>
</ol>
2. TMS recording
NOTE: The description below applies to the specific software and instruments used (see the Table of Materials); these will need to be adapted for other hardware.
<ol>
	<li>Turn on the TMS device.</li>
	<li>Start the semi-automated recording software using the protocol for TMS recordings.</li>
	<li>Select the gain and gating options from the menu (Table 1). Click on OK to continue.</li>
	<li>Select the protocol CSP from the main options.</li>
	<li>Place the coil at approximately 4 cm left in the binauricular line from the vertex, with the handle pointing 45&#176; to the parasagittal plane for posterior-anterior current induction.</li>
	<li>Increase the stimulus intensity manually by clicking on the Insert key until an MEP is obtained.</li>
	<li>Move the position of the coil slightly while monitoring MEPs to find the hotspot.</li>
	<li>Draw the outline of the coil on a swimming cap once the hotspot is located to enable constant coil positioning.</li>
	<li>Click on OK to initiate the automated stimulation protocol. 
	NOTE: The recording continues automatically, starting with the determination of the RMT at 200 &#181;V.</li>
	<li>Instruct the subject to maintain comfortable activation of the FDI muscle to measure the active motor threshold (AMT) for a 200 &#181;V response.</li>
	<li>Click on OK to measure the silent periods with or without a pause between the 3 groups of 10 up and down cycles of stimuli. 
	NOTE: For each group of 10, the stimulus is increased from 0.8 to 1.6 &#215; RMT200, at intervals of 0.2, and then repeated in the reverse order.</li>
	<li>Tell the subject to relax after the last stimulus and click on OK to return to the main menu.</li>
	<li>Select the protocol SICI from the main options.</li>
	<li>Select the planned ISIs to be studied from the menu SICI ISI options and the number of stimuli at each ISI from the menu Number of stimuli per ISI if the defaults are not used.</li>
	<li>Select the ASICI from the menu. 
	NOTE: The recording continues automatically, starting with the determination of the RMT at 200 &#181;V and then at 1000 &#181;V. SICI recording starts automatically after the determination of the RMT and continues for approximately 10 min. Test stimulus is fixed at RMT1000 and conditioning stimuli at 70% of RMT200. The following ISIs are selected in a pseudorandom order: 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, and 7 ms. Test-alone stimuli are given after each three paired stimuli. Thus, each paired stimulus is delivered 10 times, making a total of 120 stimuli.</li>
	<li>Ensure that the coil position is stable by observing the outline on the swimming cap, MEP on the screen, and contractions in the muscle during the recording.</li>
	<li>When the screen returns automatically to the main menu options when the protocol is completed, select the TSICIp from the menu. 
	NOTE: The recording continues automatically, starting with the determination of the RMT at 200 &#181;V and then SICI recording for approximately 10 min. RMT200 is tracked continuously by decreasing stimulus by 1% maximal stimulator output (MSO) if the response is more than 250 &#181;V and increasing it by 1% if the response is less than 160 &#181;V. The test-alone stimuli alternate with paired stimuli, and the paired stimuli are delivered with pseudorandomized ISIs: 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, and 7 ms. Thus, a total of 120 stimuli are delivered, 10 times for each of the 9 paired stimuli and test-alone stimuli after each three paired stimuli.</li>
	<li>After the screen returns automatically to the main menu options when the protocol is completed, click on Finish unless another protocol will be run.</li>
	<li>Finish the recording by clicking on the Close file and save data button.</li>
</ol>
3. TMS analyses
<ol>
	<li>Start the analyzing software program to do the analyses offline.</li>
	<li>Select the recording which will be analyzed and click on the OK button.</li>
	<li>Select Create TMS MEM file option from the TMS menu for the analysis.</li>
	<li>Click on OK to save the MEM file.</li>
	<li>Click on Plot TMS MEM/MEF option from the TMS menu for the comparison of the individual subject&#180;s recording with a group of healthy controls.</li>
	<li>Click on the 1st option on the MEF file name menu. Then, click on the MEF file with which the comparison will be made from the list of MEF files.</li>
	<li>Click on the 1st option on the MEM file name menu. Then, click on the MEM file with which the comparison will be made from the list of MEM files.</li>
	<li>Superimpose the MEM and MEF files using different options of 95% confidence intervals, standard deviations, or standard errors.</li>
</ol>

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C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Novel+threshold+tracking+techniques+suggest+that+cortical+hyperexcitability+is+an+early+feature+of+motor+neuron+disease.">Novel threshold tracking techniques suggest that cortical hyperexcitability is an early feature of motor neuron disease.</a> Brain. 129, 2436-2446 (2006).</li><li>Vucic, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Utility+of+threshold+tracking+transcranial+magnetic+stimulation+in+ALS.">Utility of threshold tracking transcranial magnetic stimulation in ALS.</a> Clinical Neurophysiolology Practice. 3, 164-172 (2018).</li><li>Vucic, S., Kiernan, M. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Axonal+excitability+properties+in+amyotrophic+lateral+sclerosis.">Axonal excitability properties in amyotrophic lateral sclerosis.</a> Clinical Neurophysiolology. 117 (7), 1458-1466 (2006).</li><li>Vucic, S., Howells, J., Trevillion, L., Kiernan, M. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Assessment+of+cortical+excitability+using+threshold+tracking+techniques.">Assessment of cortical excitability using threshold tracking techniques.</a> Muscle Nerve. 33 (4), 477-486 (2006).</li><li>Tankisi, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Short-interval+intracortical+inhibition+as+a+function+of+inter-stimulus+interval:+Three+methods+compared.">Short-interval intracortical inhibition as a function of inter-stimulus interval: Three methods compared.</a> Brain Stimululation. 14 (1), 22-32 (2021).</li><li>Samusyte, G., Bostock, H., Rothwell, J., Koltzenburg, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Short-interval+intracortical+inhibition:+Comparison+between+conventional+and+threshold-tracking+techniques.">Short-interval intracortical inhibition: Comparison between conventional and threshold-tracking techniques.</a> Brain Stimululation. 11 (4), 806-817 (2018).</li><li>Noreika, V., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Alertness+fluctuations+when+performing+a+task+modulate+cortical+evoked+responses+to+transcranial+magnetic+stimulation.">Alertness fluctuations when performing a task modulate cortical evoked responses to transcranial magnetic stimulation.</a> Neuroimage. 223, 117305 (2020).</li><li>Boroojerdi, B., Kopylev, L., Battaglia, F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Reproducibility+of+intracortical+inhibition+and+facilitation+using+the+paired-pulse+paradigm.">Reproducibility of intracortical inhibition and facilitation using the paired-pulse paradigm.</a> Nerve. 23 (10), 1594-1597 (2000).</li><li>Rossi, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Safety+and+recommendations+for+TMS+use+in+healthy+subjects+and+patient+populations,+with+updates+on+training,+ethical+and+regulatory+issues:+Expert+Guidelines.">Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: Expert Guidelines.</a> Clinical Neurophysiolology. 132 (1), 269-306 (2021).</li><li>&#216;rskov, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Comparison+of+figure-of-8+and+circular+coils+for+threshold+tracking+transcranial+magnetic+stimulation+measurements.">Comparison of figure-of-8 and circular coils for threshold tracking transcranial magnetic stimulation measurements.</a> Neurophysiologie Clinique. 51 (2), 153-160 (2021).</li></ol>

HB and JH receive royalties from UCL for sales of the Qtrac software used in this study. The other authors have no potential conflicts of interest.

TMS measurement, as programmed in the recording software, is a highly automated procedure. However, particular attention is required to obtain reliable results. In the recording stage, it is important to ensure a consistent MEP response over the hotspot and then keep the coil in the same position relative to the skull of the subject throughout the whole recording. As vigilance has a prominent influence on cortical excitability20, special care is needed to keep the subject relaxed but alert.
To keep the subject alert, short questions should be posed regularly. Additionally, the examiner should keep an eye on muscle contractions to ascertain whether the target muscle is being stimulated. Moreover, the examiner should monitor the screen to observe whether the MEP amplitude or the threshold changes are indicating any coil displacement, in addition to checking the outline on the swimming cap. If the coil has been displaced, the user should try to replace it in position using the drawing. If this fails, the recording should be restarted. The influence of coil displacement is minimized in these protocols by the pseudorandom order of the ISIs and by giving a test-alone stimulus after each set of three paired stimuli. Another way to enable the position of a TMS coil to be tracked in real time is by a neuronavigation system. Such systems are commercially available and effective; however, the high cost limits their use. Please note that no data is provided here on patients with ALS or other neurodegenerative disorders. Additional challenges may arise in these patients such as low amplitudes due to peripheral motor neuron loss, spontaneous activity, and inexcitability.
All protocols in this study (single- and paired-pulse) were carried out with a figure-of-eight coil (Magstim, D70 Remote coil) connected to a Bistim2 Module. This was done to maintain a comparable strength of magnetic field between the protocols as the stimulus is attenuated when passing through the Bistim module. The system was set to the Independent Bistim Triggering mode allowing individual external triggering of the two Magstim 2002 units. For single-pulse protocols, the intensity of one of the units was set to 0% MSO. The recordings are made using a recording protocol, which is a part of a software program. For the other types of magnetic stimulators, only one unit is required.
A limitation of the TMS method is the variability. Previous studies showed that the inter-individual variability is higher than intra-day or inter-day variability on the same subject19,21. Attention should be paid to the standardization of the method and to eliminate possible technical mistakes that can affect reliability. TMS cannot be used in certain conditions such as patients with a pacemaker or epilepsy. International rules for safety should be followed22. Additionally, slight discomfort may be expected, particularly if a circular coil23 is used. However, the discomfort is often minimal and need not cause discontinuation of the examination.
The methods described in this manuscript are automated both for recordings and analyses compared to the existing methods. This allows the recordings to be performed by a single operator, and the operator does not need to interfere with anything other than keeping the coil in the same place. Each protocol has been designed to take ~10 min, which makes it possible to run several protocols in an hour, the time that will probably take for one protocol with the existing manual methods. The magnetic stimuli are delivered every 4 s in this study; however, other magnetic devices allow faster stimulation, allowing the recording duration for each protocol to be reduced to less than 5 min. The software described here also allows the selection of different ISIs, numbers of stimuli for each ISI, and conditioning stimulus level. A major advance of the method described here is a gating function, which automatically removes traces when the subject is not relaxed.
In conclusion, the methods described here can provide invaluable information to understand the underlying mechanisms of several brain disorders, particularly neurodegenerative disorders, such as ALS, and may have diagnostic value. Further studies are necessary for different patient populations and larger groups to determine the diagnostic value of conventional and threshold-tracking TMS measures, and whether these measures may indeed be used as biomarkers for neurodegenerative disorders. Studies recording TMS in different muscles and both upper and lower extremities are also warranted.

Transcranial magnetic stimulation (TMS) of the motor cortex is a non-invasive method for examining cortical physiology and the pathophysiology of many neurological conditions, including neurodegenerative diseases1. The primary motor cortex is stimulated using suprathreshold TMS pulses to produce a motor response in the target muscle. This response is called the motor-evoked potential (MEP). TMS serves as a useful tool that interrogates cortical and potentially subcortical motor networks2. Single-pulse TMS can assess cortical reactivity, resting motor threshold (RMT), MEP amplitude, and cortical silent period (CSP)2. Cortical inhibition can be probed using paired-pulse TMS at interstimulus intervals (ISIs) of 2-3 ms (SICI) or ~100&#8239;ms (LICI)3,4,5.
SICI is mediated by gamma-aminobutyric acid (GABA)A and LICI by GABAB receptors as indicated by their pharmacology4,5. The circuitry underlying SICF is mediated in part by glutamatergic N-methyl-D-aspartic acid (NMDA) receptors6,7. MEP amplitude is reduced if TMS is preceded by electrical stimulation of a peripheral sensory nerve. This effect is called afferent inhibition and is known as SAI when the ISI is ~20-25 ms and LAI at longer ISIs of 200-1000 ms between the electrical stimulation of the peripheral nerve and the single pulse of TMS8,9,10. SAI is modulated by cholinergic activity11; however, LAI is significantly understudied, and the neural circuits underlying this phenomenon are unclear 10.
MEP amplitudes are variable, and endpoint estimates in conventional TMS (cTMS) methods usually use arithmetic averages of 10 to 20 responses evoked with a fixed stimulus intensity. An alternative approach is threshold-tracking TMS, first described over 20 years ago12,13. In this case, the intensity of successive stimuli is varied to achieve a fixed target amplitude response. Both conventional and threshold-tracking techniques can be used with different ISIs. In the first version of this approach applied to SICI, namely &#39;serial&#39; threshold-tracking (T-SICIs), a similar tracking method was used to the one employed in nerve excitability testing: the &#39;threshold&#39; was first estimated at one interstimulus interval (ISI) and then tracked serially at successive ISIs. This method has been widely used by one group and advocated as a potential biomarker for ALS because of its high diagnostic utility14,15,16,17. However, their findings have yet to be confirmed by any other research group14,15,16,17.
The serial approach is efficient when reference thresholds are stable, as in peripheral nerves. However, when thresholds fluctuate widely, as is the case for corticospinal excitability, serial tracking has been found to have the disadvantage of seriously distorting the ISI-dependence of SICI18. Therefore, an alternative &#39;parallel&#39; threshold-tracking paradigm may be more appropriate for SICI (T-SICIp)18,19 and other paired-pulse protocols, in which thresholds are estimated independently, in parallel, for different ISIs.
Despite their promise, existing TMS methods have not yet been accepted in clinics as reliable diagnostic tests or biomarkers in clinical trials. This may be due to several limitations of the existing TMS methods, such as time consumption, demand for manual operation, and poor reproducibility. To help overcome these limitations, this paper describes a suite of recently developed automated, fast, single- and paired-pulse TMS protocols, designed for single-handed operation and to enable comparison between conventional and serial and parallel threshold-tracking approaches.
The equipment used here includes a TMS machine, an isolated linear bipolar constant-current stimulator, a noise eliminator to remove 50-60 Hz electrical interference, an electromyography amplifier, and a data acquisition system. The software is versatile enough to operate with other amplifiers, stimulators, and recording conditions.

<table><tbody><tr><td>50 Hz Noise Eliminator</td><td>Digitimer Ltd</td><td></td><td>Humbug</td></tr><tr><td>Analogue-to-Digital Converter</td><td>National Instruments</td><td></td><td>NI-6221</td></tr><tr><td>Recording program</td><td>Digitimer Ltd (copyright University College London)</td><td></td><td>QtracS.EXE</td></tr><tr><td>TMS recording protocol</td><td>Digitimer Ltd (copyright QTMS Science)</td><td></td><td>QTMSG-12 recording protocol</td></tr><tr><td>Disposable surface recording electrodes</td><td>AMBU</td><td></td><td>Ambu&amp;reg; BlueSensor NF</td></tr><tr><td>Figure-of-8 coil</td><td>Magstim Co. Ltd, Whiteland, Wales, UK</td><td></td><td>Magstim&amp;reg; D70 Remote Coil</td></tr><tr><td>Isolated EMG amplifier</td><td>Digitimer Ltd</td><td></td><td>D440</td></tr><tr><td>Isolated linear bipolar constant-current stimulator</td><td>Digitimer Ltd</td><td></td><td>DS5</td></tr><tr><td>TMS device</td><td>Magstim Co. Ltd, Whiteland, Wales, UK</td><td></td><td>Magstim&amp;reg; 2002 stimulators (2 MagStim units are required )</td></tr><tr><td>Analysis and plotting program</td><td>Digitimer Ltd (copyright University College London)</td><td></td><td>QtracP.EXE</td></tr></tbody></table>

conventional and threshold-tracking transcranial magnetic stimulation tests for single-handed operation

Most single-pulse transcranial magnetic stimulation (TMS) parameters (e.g., motor threshold, stimulus-response function, cortical silent period) are used to examine corticospinal excitability. Paired-pulse TMS paradigms (e.g., short- and long-interval intracortical inhibition (SICI/LICI), short-interval intracortical facilitation (SICF), and short- and long-latency afferent inhibition (SAI/LAI)) provide information about intracortical inhibitory and facilitatory networks. This has long been done by the conventional TMS method of measuring changes in the size of the motor-evoked potentials (MEPs) in response to stimuli of constant intensity. An alternative threshold-tracking approach has recently been introduced whereby the stimulus intensity for a target amplitude is tracked. The diagnostic utility of threshold-tracking SICI in amyotrophic lateral sclerosis (ALS) has been shown in previous studies. However, threshold-tracking TMS has only been used in a few centers, in part due to the lack of readily available software but also perhaps due to uncertainty over its relationship to conventional single- and paired-pulse TMS measurements.
A menu-driven suite of semi-automatic programs has been developed to facilitate the broader use of threshold-tracking TMS techniques and to enable direct comparisons with conventional amplitude measurements. These have been designed to control three types of magnetic stimulators and allow recording by a single operator of the common single- and paired-pulse TMS protocols.
This paper shows how to record a number of single- and paired-pulse TMS protocols on healthy subjects and analyze the recordings. These TMS protocols are fast and easy to perform and can provide useful biomarkers in different neurological disorders, particularly neurodegenerative diseases such as ALS.

The following results were obtained in one healthy subject. RMT for a 200 &#181;V (RMT200) or a 1000 &#181;V (RMT1000) peak-to-peak response were detected by a &#39;4&#8594;2&#8594;1&#39; tracking rule and logarithmic regression as previously described18. The RMT200 was 52.1% MSO, and the RMT1000 was 59.8% MSO.
All paired-pulse TMS options may be determined in amplitude, parallel threshold-tracking, and serial threshold-tracking modes. Here, only the amplitude and parallel threshold-tracking modes will be summarized. Accordingly, the ISIs, the number of stimuli at each ISI, and the level of stimulus intensity for the conditioning stimuli may be selected from the Menu. Here, we only describe the default options for these.
Figure 1&#160;shows the setup, including stimulation with a figure-of-eight coil, recording with surface electrodes, the computer with installed software, the TMS machine, the noise eliminator to remove 50-60 Hz electrical interference, the isolated linear bipolar constant-current stimulator, the electromyography amplifier, and a data acquisition system.
Figure 2&#160;shows SICI as A-SICI (Figure 2A) and T-SICI parallel (Figure 2B) as described in the protocol section. Figure 3 shows LICI as A-LICI (Figure 3A) and T-LICI parallel (Figure 3B). For A-LICI, after finding the hotspot, the program determines RMT1000 and sets both test and conditioning stimuli to this amplitude. Test-alone stimuli are delivered as every 4th stimulus, and conditioning+test stimuli at intervals of 50, 100, 150, 200, 250, and 300 ms are delivered pseudorandomly. Ten stimuli are delivered at each ISI. Similarly, for T-LICI, 10 paired pulses at the same 6 ISIs as for A-LICI from 50 to 300 ms are delivered, and the thresholds for RMT200 are tracked while conditioning stimulus is set to 120% of the tracked RMT200.
Figure 4&#160;shows SICF as A-SICF (Figure 4A) and T-SICF parallel&#160;(Figure 4B). For A-SICF, after finding the hotspot, the program determines RMT50 and RMT1000. Test stimuli are then set to RMT1000 and conditioning stimuli to 90% of RMT50. The range of ISIs is from 1 to 4.9 by 0.3 ms. Test-alone stimuli are delivered as every 4th or 5th stimulus, and the 14 conditioning+test stimuli are delivered in pseudorandom order. As for A-SICF, T-SICF is measured at 14 ISIs from 1 to 4.9 ms, and the threshold is tracked with 10 paired pulses at each ISI.
Figure 5&#160;shows SAI as A-SAI (Figure 5A) and T-SAI parallel (Figure 5B). SAI protocols involve stimulating the somatosensory afferents in the nerve and recording the effects on the MEP excited ~20 ms later. This MEP latency (&#39;N20&#39;) is important for the timing of the stimuli. The program asks the user to select the latency from a range (16-23 ms) or to specify it if outside this range. To determine the N20 latency, a conventional somatosensory evoked potential may be performed, or age- and height-corrected laboratory controls may be used.
For the A-SAI, the electrical stimulus intensity for a 1-mV compound muscle action potential is first determined (EMT1000). Then, the hotspot is found for magnetic stimulation, and RMT1000 is determined. The program then combines magnetic and electrical stimuli with ISIs from N20-2 to N20+12 ms. Test-alone stimuli are given as every 4th stimulus, while the conditioning+test stimuli are given in pseudorandom order. For T-SAI similar to A-SAI, EMT1000 is first determined. Then, stimulation switches to the magnetic stimulus, and the hotspot is determined in the usual way. The program then determines RMT200 in a manner similar to the other tracking protocols. Further, the program then runs straight into tracking SAI, with the ISI between electrical stimulus and magnetic test stimulus increased in 1 ms steps from N20-2 to N20+12 ms.
Figure 6&#160;shows LAI as A-LAI (Figure 6A) and T-LAI parallel (Figure 6B). The LAI protocols for recording long-interval afferent inhibition are the same as for SAI, except that because the intervals are much longer (200 to 1000 ms, in 100 ms steps), the N20 interval is disregarded and does not have to be entered.
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/62787/62787fig01.jpg" /> 
Figure 1: The setup. Setup includes stimulation with a figure-of-eight coil, recording with surface electrodes, the computer with installed software, the TMS machine, the noise eliminator to remove 50-60 Hz electrical interference, the isolated linear bipolar constant-current stimulator, the electromyography amplifier, and a data acquisition system. Abbreviation: TMS = transcranial magnetic stimulation. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/62787/62787fig01large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/62787/62787fig02.jpg" /> 
Figure 2: A-SICI and T-SICI plotted as a function of interstimulus intervals from 1 ms to 7 ms. (A) A-SICI plotted as the amplitude of conditioned response as a percentage of control. (B) T-SICI plotted as threshold changes (inhibition as percentage of control). Abbreviations: A-SICI = amplitude of short-interval intracortical inhibition; T-SICI = threshold changes in short-interval intracortical inhibition; MEP = motor-evoked potential; RMT = resting motor threshold. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/62787/62787fig02large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/62787/62787fig03.jpg" /> 
Figure 3: A-LICI and T-LICI plotted as a function of interstimulus intervals from 1 ms to 300 ms. (A) A-LICI plotted as the amplitude of conditioned response as a percentage of control. (B) T-LICI plotted as threshold changes (inhibition as a percentage of control). Abbreviations: A-SICI = amplitude of short-interval intracortical inhibition; T-SICI = threshold changes in short-interval intracortical inhibition; MEP = motor-evoked potential; RMT = resting motor threshold. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/62787/62787fig03large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 4" class="xfigimg" src="/files/ftp_upload/62787/62787fig4v2.jpg" /> 
Figure 4: A-SICF and T-SICF plotted as a function of interstimulus intervals from 1 ms to 4.9 ms. (A) A-SICF plotted as the amplitude of conditioned response as a percentage of control. (B) T-SICF plotted as threshold changes (inhibition as a percentage of control). Abbreviations: A-SICF = amplitude of short-interval intracortical facilitation; T-SICF = threshold changes in short-interval intracortical facilitation; MEP = motor-evoked potential; RMT = resting motor threshold. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/62787/62787fig4v2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 5" class="xfigimg" src="/files/ftp_upload/62787/62787fig05.jpg" /> 
Figure 5: A-SAI and T-SAI plotted as a function of interstimulus intervals from 20 ms to 35 ms. (A) A-SAI plotted as the amplitude of conditioned response as a percentage of control. (B) T-SAI plotted as threshold changes (inhibition as a percentage of control). Abbreviations: A-SAI = amplitude of short-latency afferent inhibition; T-SAI = threshold changes in short-latency afferent inhibition; MEP = motor-evoked potential; RMT = resting motor threshold. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/62787/62787fig05large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 6" class="xfigimg" src="/files/ftp_upload/62787/62787fig06.jpg" /> 
Figure 6: A-LAI and T-LAI plotted as a function of interstimulus intervals from 200 ms to 1000 ms. (A) A-LAI plotted as the amplitude of conditioned response as a percentage of control. (B) T-LAI plotted as threshold changes (inhibition as a percentage of control). Abbreviations: A-LAI = amplitude of long-latency afferent inhibition; T-LAI = threshold changes in long-latency afferent inhibition; MEP = motor-evoked potential; RMT = resting motor threshold. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/62787/62787fig06large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
Table 1: The available TMS protocols in the software. Abbreviations: TMS = transcranial magnetic stimulation; SICI = Short interval intracortical inhibition; SICF = Short interval intracortical facilitation; LICI = Long interval intracortical inhibition; SAI = Short latency afferent inhibition; LAI = Long latency afferent inhibition; &#181;V = microvolt. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/62787/Table 1 (13).xlsx" target="_blank">Please click here to download this Table.</a>

Watch this Scientific Journal Video about Conventional and Threshold-Tracking Transcranial Magnetic Stimulation Tests for Single-handed Operation at JoVE.com

Conventional and Threshold-Tracking Transcranial Magnetic Stimulation Tests for Single-handed Operation

We present a suite of standardized single- and paired-pulse transcranial magnetic stimulation (TMS) recording protocols, with options for conventional amplitude measurements and threshold-tracking. This program can control three different types of magnetic stimulators and is designed to enable all tests to be performed conveniently by a single operator.

Most single-pulse transcranial magnetic stimulation (TMS) parameters (e.g., motor threshold, stimulus-response function, cortical silent period) are used ...

conventional-threshold-tracking-transcranial-magnetic-stimulation

Nanyang Technological University

Research

JoVE Journal

Neuroscience

5.7K Views.  Aarhus University Hospital. Onze protocollen zullen het bredere gebruik van TMS-technieken voor het volgen van drempels vergemakkelijken en directe vergelijkingen met conventionele amplitudemetingen mogelijk maken. Deze protocollen zijn ontworpen om drie soorten magnetische stimulatoren te besturen en om opname, door een enkele operator, van de gemeenschappelijke TMS-protocollen met één en gepaarde puls mogelijk te maken. Deze tms-protocollen met één en gepaarde puls zijn snel en gemakkelijk te leren.Ze maken...

Video: Conventional and Threshold-Tracking Transcranial Magnetic Stimulation Tests for Single-handed Operation

Transcranial Magnetic Stimulation for Investigating Causal Brain-behavioral Relationships and their Time Course

Transcranial magnetic stimulation (TMS) is a safe, non-invasive brain stimulation technique that uses a strong electromagnet in order to temporarily disrupt information processing in a brain region, generating a short-lived &#8220;virtual lesion.&#8221; Stimulation that interferes with task performance indicates that the affected brain region is necessary to perform the task normally. In other words, unlike neuroimaging methods such as functional magnetic resonance imaging (fMRI) that indicate correlations between brain and behavior, TMS can be used to demonstrate causal brain-behavior relations. Furthermore, by varying the duration and onset of the virtual lesion, TMS can also reveal the time course of normal processing. As a result, TMS has become an important tool in cognitive neuroscience. Advantages of the technique over lesion-deficit studies include better spatial-temporal precision of the disruption effect, the ability to use participants as their own control subjects, and the accessibility of participants. Limitations include concurrent auditory and somatosensory stimulation that may influence task performance, limited access to structures more than a few centimeters from the surface of the scalp, and the relatively large space of free parameters that need to be optimized in order for the experiment to work. Experimental designs that give careful consideration to appropriate control conditions help to address these concerns. This article illustrates these issues with TMS results that investigate the spatial and temporal contributions of the left supramarginal gyrus (SMG) to reading.

Transcranial magnetic stimulation (TMS) is a technique for non-invasively disrupting neural information processing and measuring its effect on behavior. When TMS interferes with a task, it indicates that the stimulated brain region is necessary for normal task performance, allowing one to systematically relate brain regions to cognitive functions.

Transcranial magnetic stimulation (TMS) is a safe, non-invasive brain stimulation technique that uses a strong electromagnet in order to temporarily ...

Behavior

Treating Clinical Depression with Repetitive Deep Transcranial Magnetic Stimulation Using the Brainsway H1-coil

Repetitive transcranial magnetic stimulation (rTMS) is an emerging non-pharmacological approach to treating many brain-based disorders. rTMS uses electromagnetic coils to stimulate areas of the brain non-invasively. Deep transcranial magnetic stimulation (dTMS) with the Brainsway H1-coil system specifically is a type of rTMS indicated for treating patients with major depressive disorder (MDD) who are resistant to medication. The unique H1-coil design of this device is able to stimulate neuronal pathways that lie deeper in the targeted brain areas than those reached by conventional rTMS coils. dTMS is considered to be low-risk and well tolerated, making it a viable treatment option for people who have not responded to medication or psychotherapy trials for their depression.
Randomized, sham-control studies have demonstrated that dTMS produces significantly greater improvement in depressive symptoms than sham dTMS treatment in patients with major depression that has not responded to antidepressant medication. In this paper, we will review the methodology for treating major depression with dTMS using an H1-coil.

Here we present a protocol outlining the methodology for treatment of Major Depressive Disorder using the deep Transcranial Magnetic Stimulation (dTMS) system.

Repetitive transcranial magnetic stimulation (rTMS) is an emerging non-pharmacological approach to treating many brain-based disorders. rTMS uses ...

Intracortical Inhibition Within the Primary Motor Cortex Can Be Modulated by Changing the Focus of Attention

It is well recognized that an external focus (EF) compared with an internal focus (IF) of attention improves motor learning and performance. Studies have indicated benefits in accuracy, balance, force production, jumping performance, movement speed, oxygen consumption, and fatiguing task. Although behavioral outcomes of using an EF strategy are well explored, the underlying neural mechanisms remain unknown. A recent TMS study compared the activity of the primary motor cortex (M1) between an EF and an IF. More precisely, this study showed that, when adopting an EF, the activity of intracortical inhibitory circuits is enhanced.
On the behavioral level, the present protocol tests the influence of attentional foci on the time to task failure (TTF) when performing submaximal contractions of the first dorsal interosseous (FDI). Additionally, the current paper describes two TMS protocols to assess the influence of attentional conditions on the activity of cortical inhibitory circuits within the M1. Thus, the present article describes how to use single-pulse TMS at intensities below the motor threshold (subTMS) and paired-pulse TMS, inducing short-interval intracortical inhibition (SICI) when applied to the M1. As these methods are assumed to reflect the responsiveness of GABAergic inhibitory neurons, without being affected by spinal reflex circuitries, they are well suited to measuring the activity of intracortical inhibitory circuits within the M1.
The results show that directing attention externally improves motor performance, as participants were able to prolong the time to task failure. Moreover, the results were accompanied by a larger subTMS-induced electromyography suppression and SICI when adopting an EF compared to an IF. As the level of cortical inhibition within the M1 was previously demonstrated to influence motor performance, the enhanced inhibition with an EF might contribute to the better movement efficiency observed in the behavioral task, indicated by a prolonged TTF with an EF.

Using two different transcranial magnetic stimulation (TMS) protocols, this manuscript describes how to measure and compare cortical inhibition within the primary motor cortex when adopting different attentional foci.

It is well recognized that an external focus (EF) compared with an internal focus (IF) of attention improves motor learning and performance. Studies have ...

Brain State-dependent Brain Stimulation with Real-time Electroencephalography-Triggered Transcranial Magnetic Stimulation

The effect of a stimulus to the brain depends not only on the parameters of the stimulus but also on the dynamics of brain activity at the time of the stimulation. The combination of electroencephalography (EEG) and transcranial magnetic stimulation (TMS) in a real-time brain state-dependent stimulation system allows the study of relations of dynamics of brain activity, cortical excitability, and plasticity induction. Here, we demonstrate a newly developed method to synchronize the timing of brain stimulation with the phase of ongoing EEG oscillations using a real-time data analysis system. This real-time EEG-triggered TMS of the human motor cortex, when TMS is synchronized with the surface EEG negative peak of the sensorimotor &#181;-alpha (8-14 Hz) rhythm, has shown differential corticospinal excitability and plasticity effects. The utilization of this method suggests that real-time information about the instantaneous brain state can be used for efficacious plasticity induction. Additionally, this approach enables personalized EEG-synchronized brain stimulation which may lead to the development of more effective therapeutic brain stimulation protocols.

This paper describes real-time electroencephalography-triggered transcranial magnetic stimulation to study and modulate human brain networks.

The effect of a stimulus to the brain depends not only on the parameters of the stimulus but also on the dynamics of brain activity at the time of the ...

Effects of Transcranial Alternating Current Stimulation on the Primary Motor Cortex by Online Combined Approach with Transcranial Magnetic Stimulation

Transcranial Alternating Current Stimulation (tACS) is a neuromodulatory technique able to act through sinusoidal electrical waveforms in a specific frequency and in turn modulate ongoing cortical oscillatory activity. This neurotool allows the establishment of a causal link between endogenous oscillatory activity and behavior. Most of the tACS studies have shown online effects of tACS. However, little is known about the underlying action mechanisms of this technique because of the AC-induced artifacts on Electroencephalography (EEG) signals. Here we show a unique approach to investigate online physiological frequency-specific effects of tACS of the primary motor cortex (M1) by using single pulse Transcranial Magnetic Stimulation (TMS) to probe cortical excitability changes. In our setup, the TMS coil is placed over the tACS electrode while Motor Evoked Potentials (MEPs) are collected to test the effects of the ongoing M1-tACS. So far, this approach has mainly been used to study the visual and motor systems. However, the current tACS-TMS setup can pave the way for future investigations of cognitive functions. Therefore, we provide a step-by-step manual and video guidelines for the procedure.

Transcranial Alternating Current Stimulation (tACS) allows the modulation of cortical excitability in a frequency-specific fashion. Here we show a unique approach which combines online tACS with single pulse Transcranial Magnetic Stimulation (TMS) in order to "probe" cortical excitability by means of Motor Evoked Potentials.

Transcranial Alternating Current Stimulation (tACS) is a neuromodulatory technique able to act through sinusoidal electrical waveforms in a specific ...

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 field pulses. The initiation of cortical activation or its modulation depends on the background activation of the neurons of the cortical region activated, the characteristics of the coil, its position and its orientation with respect to the head. TMS combined with simultaneous electrocephalography (EEG) and neuronavigation (nTMS-EEG) allows for the assessment of cortico-cortical excitability and connectivity in almost all cortical areas in a reproducible manner. This advance makes nTMS-EEG a powerful tool that can accurately assess brain dynamics and neurophysiology in test-retest paradigms that are required for clinical trials. Limitations of this method include artifacts that cover the initial brain reactivity to stimulation. Thus, the process of removing artifacts may also extract valuable information. Moreover, the optimal parameters for dorsolateral prefrontal (DLPFC) stimulation are not fully known and current protocols utilize variations from the motor cortex (M1) stimulation paradigms. However, evolving nTMS-EEG designs hope to address these issues. The protocol presented here introduces some standard practices for assessing neurophysiological functioning from stimulation to the DLPFC that can be applied in patients with treatment resistant psychiatric disorders that receive treatment such as transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), magnetic seizure therapy (MST) or electroconvulsive therapy (ECT).

The protocol presented here is for TMS-EEG studies utilizing intracortical excitability test-retest design paradigms. The intent of the protocol is to produce reliable and reproducible cortical excitability measures for assessing neurophysiological functioning related to therapeutic interventions in the treatment of neuropsychiatric diseases such as major depression.

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 and can be assessed using transcranial magnetic stimulation (TMS). Given the role of distal leg muscles in upright postural and dynamic tasks, such as walking, a growing research interest in the assessment and modulation of the corticospinal tracts relative to the function of these muscles has emerged in the last decade. However, methodological parameters used in previous work have varied across studies making the interpretation of results from cross-sectional and longitudinal studies less robust. Therefore, use of a standardized TMS protocol specific to the assessment of leg muscles&#39; corticomotor response (CMR) will allow for direct comparison of results across studies and cohorts. The objective of this paper is to present a protocol that provides the flexibility to simultaneously assess the bilateral CMR of two main ankle antagonistic muscles, the tibialis anterior and soleus, using single pulse TMS with a neuronavigation system. The present protocol is applicable while the examined muscle is either fully relaxed or isometrically contracted at a defined percentage of maximum isometric voluntary contraction. Using each subject&#39;s structural MRI with the neuronavigation system ensures accurate and precise positioning of the coil over the leg cortical representations during assessment. Given the inconsistency in CMR derived measures, this protocol also describes a standardized calculation of these measures using automated algorithms. Though this protocol is not conducted during upright postural or dynamic tasks, it&#160;can be used to assess bilaterally any pair of leg muscles, either antagonistic or synergistic, in both neurologically intact and impaired subjects.

The present protocol describes the simultaneous, bilateral assessment of the corticomotor response of the tibialis anterior and soleus during rest and tonic voluntary activation using a single pulse transcranial magnetic stimulation and neuronavigation system.

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 ...

Measuring and Manipulating Functionally Specific Neural Pathways in the Human Motor System with Transcranial Magnetic Stimulation

Understanding interactions between brain areas is important for the study of goal-directed behavior. Functional neuroimaging of brain connectivity has provided important insights into fundamental processes of the brain like cognition, learning, and motor control. However, this approach cannot provide causal evidence for the involvement of brain areas of interest. Transcranial magnetic stimulation (TMS) is a powerful, noninvasive tool for studying the human brain that can overcome this limitation by transiently modifying brain activity. Here, we highlight recent advances using a paired-pulse, dual-site TMS method with two coils that causally probes cortico-cortical interactions in the human motor system during different task contexts. Additionally, we describe a dual-site TMS protocol based on cortical paired associative stimulation (cPAS) that transiently enhances synaptic efficiency in two interconnected brain areas by applying repeated pairs of cortical stimuli with two coils. These methods can provide a better understanding of the mechanisms underlying cognitive-motor function as well as a new perspective on manipulating specific neural pathways in a targeted fashion to modulate brain circuits and improve behavior. This approach may prove to be an effective tool to develop more sophisticated models of brain-behavior relations and improve diagnosis and treatment of many neurological and psychiatric disorders.

This article describes new approaches to measure and strengthen functionally specific neural pathways with transcranial magnetic stimulation. These advanced noninvasive brain stimulation methodologies can provide new opportunities for the understanding of brain-behavior relations and development of new therapies to treat brain disorders.

Understanding interactions between brain areas is important for the study of goal-directed behavior. Functional neuroimaging of brain connectivity has ...

Combined Peripheral Nerve Stimulation and Controllable Pulse Parameter TMS

Combined Peripheral Nerve Stimulation and Controllable Pulse Parameter Transcranial Magnetic Stimulation to Probe Sensorimotor Control and Learning

Skilled motor ability depends on efficiently integrating sensory afference into the appropriate motor commands. Afferent inhibition provides a valuable tool to probe the procedural and declarative influence over sensorimotor integration during skilled motor actions. This manuscript describes the methodology and contributions of short-latency afferent inhibition (SAI) for understanding sensorimotor integration. SAI quantifies the effect of a convergent afferent volley on the corticospinal motor output evoked by transcranial magnetic stimulation (TMS). The afferent volley is triggered by the electrical stimulation of a peripheral nerve. The TMS stimulus is delivered to a location over the primary motor cortex that elicits a reliable motor-evoked response in a muscle served by that afferent nerve. The extent of inhibition in the motor-evoked response reflects the magnitude of the afferent volley converging on the motor cortex and involves central GABAergic and cholinergic contributions. The cholinergic involvement in SAI makes SAI a possible marker of declarative-procedural interactions in sensorimotor performance and learning. More recently, studies have begun manipulating the TMS current direction in SAI to tease apart the functional significance of distinct sensorimotor circuits in the primary motor cortex for skilled motor actions. The ability to control additional pulse parameters (e.g., the pulse width) with state-of-the-art controllable pulse parameter TMS (cTMS) has enhanced the selectivity of the sensorimotor circuits probed by the TMS stimulus and provided an opportunity to create more refined models of sensorimotor control and learning. Therefore, the current manuscript focuses on SAI assessment using cTMS. However, the principles outlined here also apply to SAI assessed using conventional fixed pulse width TMS stimulators and other forms of afferent inhibition, such as long-latency afferent inhibition (LAI).

Author Spotlight: Combined Peripheral Nerve Stimulation and Controllable Pulse Parameter Transcranial Magnetic Stimulation to Probe Sensorimotor Control and Learning  

Short-latency afferent inhibition (SAI) is a transcranial magnetic stimulation protocol to probe sensorimotor integration. This article describes how SAI can be used to study the convergent sensorimotor loops in the motor cortex during sensorimotor behavior.

Skilled motor ability depends on efficiently integrating sensory afference into the appropriate motor commands. Afferent inhibition provides a valuable ...

Study Design for Navigated Repetitive Transcranial Magnetic Stimulation for Speech Cortical Mapping

The cortical areas involved in human speech should be characterized reliably prior to surgery for brain tumors or drug-resistant epilepsy. The functional mapping of language areas for surgical decision-making is usually done invasively by electrical direct cortical stimulation (DCS), which is used to identify the organization of the crucial cortical and subcortical structures within each patient. Accurate preoperative non-invasive mapping aids surgical planning, reduces time, costs, and risks in the operating room, and provides an alternative for patients not suitable for awake craniotomy. Non-invasive imaging methods like MRI, fMRI, MEG, and PET are currently applied in presurgical design and planning. Although anatomical and functional imaging can identify the brain regions involved in speech, they cannot determine whether these regions are critical for speech. Transcranial magnetic stimulation (TMS) non-invasively excites the cortical neuronal populations by means of electric field induction in the brain. When applied in its repetitive mode (rTMS) to stimulate a speech-related cortical site, it can produce speech-related errors analogous to those induced by intraoperative DCS. rTMS combined with neuronavigation (nrTMS) enables neurosurgeons to preoperatively assess where these errors occur and to plan the DCS and the operation to preserve the language function. A detailed protocol is provided here for non-invasive speech cortical mapping (SCM) using nrTMS. The proposed protocol can be modified to best fit the patient- and site-specific demands. It can also be applied to language cortical network studies in healthy subjects or in patients with diseases that are not amenable to surgery.

Navigated repetitive transcranial magnetic stimulation is a highly efficient non-invasive tool for mapping speech-related cortical areas. It helps in designing brain surgery and speeds up the direct cortical stimulation conducted during the surgery. This report describes how to perform speech cortical mapping reliably for preoperative evaluation and research.

The cortical areas involved in human speech should be characterized reliably prior to surgery for brain tumors or drug-resistant epilepsy. The functional ...

Conventional and Threshold-Tracking Transcranial Magnetic Stimulation Tests for Single-handed Operation

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