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 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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		<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>
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		<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>
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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