The authors acknowledge funding from the Natural Sciences and Engineering Research Council (NSERC), the Canada Foundation for Innovation (CFI), and the Ontario Research Fund (ORF) awarded to S.K.M.

The following protocol can be applied to various experiments. The information provided details an experiment in which SAI is used to quantify sensorimotor integration during a finger response to a validly or invalidly cued probe. In this protocol, SAI is assessed without a task, then concurrently during the cued sensorimotor task, and then again without a task. The cTMS stimulator can be replaced by any commercially available conventional TMS stimulator. However, the pulse width of the conventional TMS stimulator would b...

Combined Peripheral Nerve Stimulation and Controllable Pulse Parameter TMS

The authors have nothing to disclose.

The SAI method described here probes a subset of neural pathways that play a role in sensorimotor performance and learning. Assessing SAI while participants perform controlled sensorimotor tasks is critical for disentangling the complex contributions of the numerous sensorimotor loops that converge on the motor corticospinal neurons to shape the motor output in healthy and clinical populations. For example, a similar methodology has been used to identify the cerebellar influence over procedural motor control processes<su...

Multiple sensorimotor loops converge in the motor cortex to shape pyramidal tract projections to spinal motor neurons and interneurons1. However, how these sensorimotor loops interact to shape corticospinal projections and motor behavior remains an open question. Short-latency afferent inhibition (SAI) provides a tool to probe the functional properties of convergent sensorimotor loops in motor cortex output. SAI combines motor cortical transcranial magnetic stimulation (TMS) with electrical stimulation of the corresponding peripheral afferent nerve.
TMS is a non-invasive method to safely stimulate pyramidal motor neurons trans-synaptically in the human brain2,3. TMS involves passing a large, transient electric current through a coiled wire placed on the scalp. The transient nature of the electrical current creates a rapidly changing magnetic field that induces an electric current in the brain4. In the case of a single TMS stimulus, the induced current activates a series of excitatory inputs to the pyramidal motor neurons5-7. If the strength of the generated excitatory inputs is sufficient, the descending activity elicits a contralateral muscular response known as the motor-evoked potential (MEP). The latency of the MEP reflects the corticomotor conduction time8. The amplitude of the MEP indexes the excitability of the corticospinal neurons9. The single TMS stimulus that elicits the MEP can also be preceded by a conditioning stimulus10,11,12. These paired-pulse paradigms can be used to index the effects of various interneuron pools on the corticospinal output. In the case of SAI, the peripheral electrical conditioning stimulus is used to probe the impact of the afferent volley on the motor cortical excitability11,13,14,15. The relative timing of the TMS stimulus and peripheral electrical stimulation aligns the action of the TMS stimulus on the motor cortex with the arrival of the afferent projections to the motor cortex. For SAI in the distal upper limb muscles, the median nerve stimulus typically precedes the TMS stimulus by 18-24 ms11,13,15,16. At the same time, SAI increases as the strength of the afferent volley induced by the peripheral stimulus increases13,17,18.
Despite its strong association with the extrinsic properties of the afferent projection to the motor cortex, SAI is a malleable phenomenon implicated in many motor control processes. For example, SAI is reduced in task-relevant muscles before an impending movement19,20,21 but is maintained in adjacent task-irrelevant motor representations19,20,22. The sensitivity to task relevancy is hypothesized to reflect a surround inhibition mechanism23 that aims to reduce unwanted effector recruitment. More recently, it was proposed that the reduction in SAI in the task-relevant effector may reflect a movement-related gating phenomenon designed to suppress expected sensory afference21 and facilitate corrections during sensorimotor planning and execution24. Regardless of the specific functional role, SAI is correlated with reductions in manual dexterity and processing efficiency25. Altered SAI is also associated with an increased risk of falling in older adults26 and compromised sensorimotor function in Parkinson&#39;s disease26,27,28 and individuals with focal hand dystonia29.
Clinical and pharmacological evidence indicates that the inhibitory pathways mediating SAI are sensitive to central cholinergic modulation30. For example, administering the muscarinic acetylcholine receptor antagonist scopolamine reduces SAI31. In contrast, increasing the half-life of acetylcholine via acetylcholinesterase inhibitors enhances SAI32,33. Consistent with pharmacological evidence, SAI is sensitive to several cognitive processes with central cholinergic involvement, including arousal34, reward35, the allocation of attention21,36,37, and memory38,39,40. SAI is also altered in clinical populations with cognitive deficits associated with the loss of cholinergic neurons, such as Alzheimer&#39;s disease41,42,43,44,45,46,47, Parkinson&#39;s disease (with mild cognitive impairment)48,49,50, and mild cognitive impairment47,51,52. The differential modulation of SAI by various benzodiazepines with differential affinities for various &#947;-aminobutyric acid type A (GABAA) receptor subunit types suggests that the SAI inhibitory pathways are distinct from pathways mediating other forms of paired-pulse inhibition30. For example, lorazepam decreases SAI but enhances short-interval cortical inhibition (SICI)53. Zolpidem reduces SAI but has little effect on SICI53. Diazepam increases SICI but has little impact on SAI53. The reduction in SAI by these positive allosteric modulators of GABAA receptor function, coupled with the observation that GABA controls the release of acetylcholine in the brain stem and cortex54, has led to the hypothesis that GABA modulates the cholinergic pathway that projects to the sensorimotor cortex to influence SAI55.
Recently, SAI has been used to investigate interactions between the sensorimotor loops that set procedural motor control processes and those that align procedural processes to explicit top-down goals and cognitive control processes21,36,37,38. The central cholinergic involvement in SAI31 suggests that&#160;SAI may index an executive influence over procedural sensorimotor control and learning. Importantly, these studies have begun to identify the unique effects of cognition on specific sensorimotor circuits by assessing SAI using different TMS current directions. SAI studies typically employ posterior-anterior (PA) induced current, while only a handful of SAI studies have employed anterior-posterior (AP) induced current55. However, using TMS to induce AP compared with PA current during SAI assessment recruits distinct sensorimotor circuits16,56. For example, AP-sensitive, but not PA-sensitive, sensorimotor circuits are altered by cerebellar modulation37,56. Furthermore, AP-sensitive, but not PA-sensitive, sensorimotor circuits are modulated by attention load36. Finally, attention and cerebellar influences may converge on the same AP-sensitive sensorimotor circuits, leading to maladaptive alterations in these circuits37.
Advances in TMS technology provide additional flexibility to manipulate the configuration of the TMS stimulus employed during single-pulse, paired-pulse, and repetitive applications57,58. Controllable pulse parameter TMS (cTMS) stimulators are now commercially available for research use worldwide, and these provide flexible control over the pulse width and shape57. The increased flexibility arises from controlling the discharge duration of two independent capacitors, each responsible for a separate phase of the TMS stimulus. The biphasic or monophasic nature of the stimulus is governed by the relative discharge amplitude from each capacitor, a parameter called the M-ratio. cTMS studies have combined pulse width manipulation with different current directions to demonstrate that the fixed pulse widths used by conventional TMS stimulators (70-82 &#181;s)59,60 likely recruit a mix of functionally distinct sensorimotor circuits during SAI56. Therefore, cTMS is an exciting tool to disentangle further the functional significance of various convergent sensorimotor loops in sensorimotor performance and learning.
This manuscript details a unique SAI approach to studying sensorimotor integration that integrates peripheral electrical stimulation with cTMS during sensorimotor behaviors. This approach improves on the typical SAI approach by assessing the effect of afferent projections on select interneuron populations in the motor cortex that govern the corticospinal output during ongoing sensorimotor behavior. Although relatively new, cTMS provides a distinct advantage in studying sensorimotor integration in typical and clinical populations. Furthermore, the current approach can be easily adapted for use with conventional TMS stimulators and to quantify other forms of afferent inhibition and facilitation, such as long-latency afferent inhibition (LAI)13 or short-latency afferent facilitation (SAF)15.

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	<tbody>
		<tr>
			<td>Acquisition software (for EMG)</td>
			<td>AD Instruments, Colorado Springs, CO, USA</td>
			<td>PL3504/P</td>
			<td>LabChart Pro version 8</td>
		</tr>
		<tr>
			<td>Alcohol prep pads</td>
			<td>Medline Canada Corporation, Mississauga, ON, Canada</td>
			<td>211-MM-05507</td>
			<td>Alliance Sterile Medium, Antiseptic Isopropyl Alcohol Pad (200 per box)</td>
		</tr>
		<tr>
			<td>Amplifier (for EMG)</td>
			<td>AD Instruments, Colorado Springs, CO, USA</td>
			<td>FE234</td>
			<td>Quad Bio Amp</td>
		</tr>
		<tr>
			<td>Cotton round</td>
			<td>Cliganic, San Francisco, CA, USA</td>
			<td>&#8206;CL-BE-019-6PK</td>
			<td>Premium Cotton Rounds (6-pack, 90 per package)</td>
		</tr>
		<tr>
			<td>cTMS coils</td>
			<td>Rogue Research, Montr&#233;al, QC, Canada</td>
			<td>COIL70F80301</td>
			<td>70 mm Medium Inductance Figure-8 coil</td>
		</tr>
		<tr>
			<td>cTMS coils</td>
			<td>Rogue Research, Montr&#233;al, QC, Canada</td>
			<td>COIL70F80301-IC</td>
			<td>70 mm Medium Inductance Figure-8 coil (Inverted Current)</td>
		</tr>
		<tr>
			<td>cTMS stimulator</td>
			<td>Rogue Research, Montr&#233;al, QC, Canada</td>
			<td>CTMSMU0101</td>
			<td>Elevate cTMS stimulator</td>
		</tr>
		<tr>
			<td>Data acquisition board (for EMG)</td>
			<td>AD Instruments, Colorado Springs, CO, USA</td>
			<td>PL3504</td>
			<td>PowerLab 4/35</td>
		</tr>
		<tr>
			<td>Digital to analog board</td>
			<td>National Instruments, Austin, TX, USA</td>
			<td>782251-01</td>
			<td>NI USB-6341, X Series DAQ Device with BNC Termination</td>
		</tr>
		<tr>
			<td>Dispoable adhesive electrodes (for EMG)</td>
			<td>Covidien, Dublin, Ireland</td>
			<td>31112496</td>
			<td>Kendal 130 Foam Electrodes</td>
		</tr>
		<tr>
			<td>Electrogel</td>
			<td>Electrodestore.com</td>
			<td>E9</td>
			<td>Electro-Gel for Electro-Cap (16 oz jar)</td>
		</tr>
		<tr>
			<td>Nuprep</td>
			<td>Weaver and Company, Aurora, CO, USA</td>
			<td>10-30</td>
			<td>Nuprep skin prep gel (3-pack of 4 oz tubes)&#160;</td>
		</tr>
		<tr>
			<td>Peripheral electrical stimulator</td>
			<td>Digitimer, Hertfordshire, UK</td>
			<td>DS7R&#160;</td>
			<td>DS7R High Voltage Constant Current Stimulator</td>
		</tr>
		<tr>
			<td>Reusable bar electrode</td>
			<td>Electrodestore.com</td>
			<td>DDA-30</td>
			<td>Black Bar Electrode, Flat, Cathode Distal</td>
		</tr>
		<tr>
			<td>Software (for behaviour and stimulator triggering)</td>
			<td>National Instruments, Austin, TX, USA</td>
			<td>784503-35</td>
			<td>Labview 2020</td>
		</tr>
		<tr>
			<td>TMS stereotactic coil guidance system</td>
			<td>Rogue Research, Montr&#233;al, QC, Canada</td>
			<td>KITBSF0404</td>
			<td>BrainSight Neuronavigation System</td>
		</tr>
		<tr>
			<td>Transpore tape</td>
			<td>3M, Saint Paul, MN, USA</td>
			<td>50707387794571</td>
			<td>Transpore Medical Tape (1 in x 10 yds)</td>
		</tr>
	</tbody>
</table>

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  

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

This technique provides insight into how sensory information is integrated into motor planning and execution. The implementation of controllable pulse parameter TMS enables us to identify specific sensory to motor pathways and how these pathways may be disrupted in neurological disorders. Motor scale acquisition and performance requires a fine balance between the conscious declarative and subconscious procedural process.Short latency afferent inhibition is a potential marker of how cognition may shape different procedural sensory motor circuits in the motor cortex of healthy and clinical populations. afferent inhibition quantifies the impact of afferent inputs on motor cortical output as elicited by transcranial magnetic stimulation. As a measure of sensory motor integration, it compliments functional magnetic resonance imaging and on electroencephalography by probing the contributions of specific neuronal populations on global hemodynamic and electrical responses elicited by skilled motor behavior.The lock parameters of magnetic stimuli generated by traditional transcranial magnetic stimulators recruit a mixture of sensory motor circuits. On the other hand, controllable pulse parameter transcranial magnetic stimulators unlock several stimulus parameters, enhancing the specificity of sensory motor circuits probed by afferent inhibition during skilled behavior. Assessing sensory motor inhibition during performance is critical to establishing markers of skilled and unskilled motor execution.Reliable and valid markers are an important step in developing enhanced models of motor control that will enhance or boost best practices in healthy populations, as well as minimize the impact of movement disorders through effective clinical interventions. Enhanced modeling of sensory motor circuits and the factors that influence their function can help provide objective markers of function and dysfunction that will inform best practices for motor performance, skill acquisition, and rehabilitation in both healthy and neurological populations. Continued definition of psychomotor and pharmacological influences over sensory motor circuits converging in motor cortex is critical.Combining afferent inhibition with electroencephalography provides an exciting opportunity to quantify afferent inhibition in non-motor areas as a marker of movement disorders and neuropsychiatric disorders.

Figure 3 illustrates examples of unconditioned and conditioned MEPs from a single participant elicited in the FDI muscle during the sensorimotor task using PA120- and AP30- (subscript denotes pulse width) induced current. The bar graphs in the middle column illustrate the raw average peak-to-peak MEP amplitudes for the unconditioned and conditioned trials. The bar graphs to the right show the SAI and MEP onset latencies for the PA120- and AP30-indu...

Watch this Scientific Journal Video about Combined Peripheral Nerve Stimulation and Controllable Pulse Parameter Transcranial Magnetic Stimulation to Probe Sensorimotor Control and Learning at JoVE.co

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 ...

combined-peripheral-nerve-stimulation-controllable-pulse-parameter

Research

JoVE Journal

Neuroscience

﻿Participant Screening for Transcranial Magnetic Stimulation

Participant Screening for Transcranial Magnetic Stimulation  

To begin, screen the participant for any contraindications to transcranial magnetic stimulation, or TMS. Inform the participant about the study objectives and procedures. Review the risks outlined in the institution's ethics review board-approved consent document.Answer any questions about the potential risks and obtain written, informed consent before beginning any study procedures.

Electromyography (EMG) Electrode Placement

To begin, instruct the participant to sit in the experimental chair with their elbows resting on the arms of the chair and bent to allow the wrist or hand to rest comfortably on the desk workplace. Adjust the height of the chair and desk workplace as needed. Clean the skin over the abductor pollicis brevis or APB, first dorsal interosseous, or FDI and the ulnar styloid process, using a mildly abrasive cream placed on a round cotton pad.Wipe away any residue using an alcohol prep pad. For each muscle, place one disposable silver silver chloride adhesive electrode over the muscle belly. Place a second electrode on a nearby bony landmark as a reference.Finally, place one additional silver silver chloride adhesive electrode on the ulnar styloid process to serve as a ground. Connect each pair of electrodes and the ground to the electromyography or EMG amplifier and data acquisition system. Use channel one for the first dorsal interosseous and channel two for the abductor pollicis brevis.

Peripheral Electrical Stimulator Electrode Placement

To begin, use a mildly abrasive cream to clean the skin inside the forearm. Start from the wrist flexion crease, and extend to six centimeters proximal approximately. Extend cleaning to the area from the wrist midline to the radial side of the forearm.Wipe away any residue using an alcohol prep pad. Next, apply the conducting gel to a reusable stimulating bar electrode. Use enough gel to cover the metal discs of the anodal and cathodal contact points.Place the stimulating electrode on the Palmer side of the wrist with the cathode proximal to the anode. Place the cathode slightly medial and proximal to the radial styloid process. On the peripheral stimulator, set the stimulus type selector two monophasic, stimulus duration to 200 microseconds, and select an appropriate voltage and amperage, double checking any multiplication factors, While holding the stimulating electrode, deliver a single electrical stimulus by depressing the trigger switch on the constant current stimulator.Then visually inspect the abductor pollicis brevis, or APB muscle, and the electromyography, or EMG display, for evidence of a muscle contraction. The muscle contraction, also known as the M wave, is elicited by direct activation of the motor axon by the electrical stimulus and should occur between six and nine milliseconds after the peripheral electrical stimulus artifact. If there is no evidence of a muscle contraction, then ask the participant if they felt a tingling sensation radiating toward the fingers or immediately underneath the electrode.If the participant reports no sensation or is restricted to the skin immediately below the electrode, then increase the amperage in increments of 0.05 until the participant reports a tingling sensation radiating up to the fingers or thumb. If the participant reports a radiating sensation in a digit other than the thumb, reposition the electrode by moving it radially until the feeling radiates to the thumb. Once the optimal position of the stimulating electrode is determined, secure the electrode to the wrist using three pieces of tape.Position the first piece over the middle of the electrode, and then use the second and third pieces to secure the top and bottom of the electrode. After securing the electrode, ask the participant to assume the desired limb orientation to be used during TMS stimulation. Check to make sure a thumb twitch is still elicited.

Determination of Median Nerve Stimulus Intensity and Optimal Coil Trajectory for TMS

Determine the peripheral stimulus threshold, the first amperage value where the M-wave exceeds 0.2 millivolts. If the M-wave exceeds the desired 0.2 millivolts target amplitude on three successive stimuli, then decrease the amperage. To determine the optimal coil trajectory for transcranial magnetic stimulation, or TMS, set an initial coil position by placing the coil on the participant's head and recording the coil trajectory.Ensure that the center surface of the coil is tangential to the scalp. Align the midline of the coil at 45 degrees to the mid-sagittal plane of the participant's head. On the CTMS stimulator, set the pulse type selector to monophasic positive to induce a PA current in the underlying neural tissue.Next, set the M ratio to 0.2 and the stimulus intensity to 30%of the maximal stimulator output. Finally, set the pulse width to 120 microseconds. Deliver three to five TMS stimuli while the participant maintains a slight contraction of the first dorsal interosseous, of FDI, muscle.If no motor evoked potential, or MEP, elicits, increase the stimulator intensity by 10%and deliver three to five additional TMS stimuli. Increase the stimulator intensity until an MEP of at least 0.2 millivolts is consistently elicited to every stimulus or until the stimulator intensity reaches 60 to 70%of the maximal stimulator output. If no reliable MEP elicits, keep the stimulation parameters constant and move the TMS stimulator in a circle with an approximately two centimeter diameter around the original stimulation site.Once a reliable MEP elicits, record the coil position. Confirm the FDI motor hotspot by keeping the stimulation parameters constant and moving the TMS stimulator two centimeters north, east, south, and west of the current coil location. Record the new coil position and trajectory if a consistently larger MEP elicits at any of the four quadrants.Use the new coil position and trajectory as the cortical motor hotspot.

Short-Latency Afferent Inhibition (No Task Baseline)

Attach the coil that will induce the PA current in the brain to the CTMS stimulator. Set the pulse type to monophasic positive, the pulse width to 120 microseconds, and M-ratio to 0.2. Finally, set the stimulus intensity to the one millivolt threshold.After setting the peripheral electrical stimulus intensity, launch the no task software routine on a personal computer or PC 1. Next, set the inter stimulus interval between the peripheral electrical and TMS stimuli to 21 milliseconds. Position the TMS coil over the first dorsal interosseous or FDI motor hotspot and ask the participant to hold a slight contraction of the FDI muscle.Next, run the no task software on PC 1 to trigger the peripheral and CTMS stimulators. Repeat the procedure for the AP 30 current configuration using the coil that induces AP current in the brain.

Short-Latency Afferent Inhibition (Sensorimotor Task)

Attach the coil that will induce the PA current in the brain to the CTMS stimulator. Set the pulse type to monophasic positive, the pulse width to 120 microseconds, and M ratio to 0.2. Finally, set the stimulus intensity to the one millivolt threshold.After setting the peripheral electrical stimulus intensity, launch the sensory motor task software routine on a personal computer or PC1. Next, set the interstimulus interval between the peripheral electrical and TMS stimuli to 21 milliseconds. Position the TMS coil over the first dorsal interosseous, or FDI, motor hotspot and ask the participant to hold a slight contraction of the FDI muscle.Keep the desired number of unconditioned and conditioned trials between eight and 24 stimuli per condition. Run the sensory motor task software routine to control the sensory motor task and send the behavior locked digital triggers to the peripheral and CTMS stimulators. Repeat the procedure for the AP30 current configuration using the coil that induces AP current in the brain.The average effect of the peripheral electrical conditioning stimulus is to suppress the corticospinal output elicited by the TMS stimulus as shown by the smaller raw, average, peak-to-peak MEP amplitudes in the conditioned MEPs compared to the unconditioned MEPs and short-latency afferent inhibition, or SAI, ratios of less than one. The longer MEP onset latency for the AP30 SAI reflects the longer latency of the input to the corticospinal neuron. In differential effects, the PA120 SAI was similarly enhanced for an index finger response regardless of whether the participant was queued to the index finger or required to remap their response to the index finger following an invalid queue to a non-index finger.In contrast the AP30 SAI appears to be differentially modulated based on whether the invalid queue required a remap away or toward the index finger.

1.2K Views.  University of Waterloo.  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. 

Combined Peripheral Nerve Stimulation and Controllable Pulse Parameter TMS

Summary