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.

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 processes37,56 and the specific targets by which the declarative memory system may influence procedural motor control and learning in healthy21,36,37,38 and previously concussed populations75.
The are several advantages to the assessment of sensorimotor integration outlined here. First, the protocol moves beyond the standard evaluation of SAI using PA-induced current. SAI studies have almost exclusively employed PA-induced current when assessing SAI55,76. However, PA-induced current likely only recruits a subset of sensorimotor circuits in the motor cortex36,37,56,77, thus yielding an incomplete picture of the ongoing sensorimotor processes and the brain-behavior associations55. Second, the protocol employs variable pulse widths to enhance the specificity of the interneuron population recruited by the TMS stimulus77. The fixed pulse widths of conventional monophasic TMS stimulators, typically between 70-82 &#181;s59,60, can recruit a mix of sensorimotor circuits within a particular current direction56,77,78. Using cTMS to manipulate the pulse width during SAI assessments can enhance the understanding of the functional significance of the different sensorimotor loops that govern corticospinal output in healthy56,78,79 and clinical populations75. Lastly, in this work, the SAI assessments were conducted at rest and were time-locked to a specific process during a concurrent behavior. Such an approach is relatively rare in the sensorimotor control and learning SAI literature14,19,20,21,36,37,80. More common is to assess SAI and sensorimotor performance/learning separately34,81,82,83,84,85,86. However, resting assessments of SAI rely on the correlation of behavior and physiological measurements measured at different points in time. Further, assessing the influences on cortical spinal output at rest likely does not capture their task-related significance. Assessing SAI at rest may only make sense for quantifying baseline differences between groups or evaluating the effects of a fundamental change in brain structure/function in a clinical population, such as in individuals with Parkinson&#39;s disease26,27,28, Alzheimer&#39;s disease87,88, and focal hand dystonia29.
Users should also carefully consider several critical elements of the described SAI protocol. First, the stimulus intensity required to elicit a 1mV MEP using AP current with a given pulse width is consistently higher than the equivalent PA current16,36,37,38,56. Higher thresholds increase the probability that the stimulus intensity required to achieve a 1 mV MEP exceeds the stimulator ability for a subset of individuals, especially when using AP current with short pulse widths59. In such cases, the researcher must decide whether to exclude the participant or determine another stable threshold. For a conventional stimulator with a fixed pulse width of ~80 &#181;s, the magnitude of the AP SAI is not influenced by test stimulus MEP amplitudes ranging from 0.5 mV to 2 mV16. Second, the protocol outlined above requires participants to maintain a minimal contraction (5%-10% of maximal voluntary contraction) of the FDI. The slight contraction enhances the selectivity of the interneuron population recruited by various AP pulse widths by reducing the required stimulus intensity56,78. However, whether a slight contraction should be employed for PA-induced currents is questionable. Slight contraction does not enhance the selectivity of PA-induced currents of varying pulse widths78, and contraction-related sensory gating89 could mask other functional contributions of the PA-sensitive circuits during some task states. Moving forward, it may make sense to assess PA SAI at rest but AP SAI, especially at short pulse widths, with a slight contraction. Finally, the external validity of the reductionist approach of the SAI protocol described here is debatable. The described protocol targets one task-relevant muscle in a controlled task involving selective finger responses. The reductionist approach outlined here can provide substantial insight into the specific mechanisms at a given point of a sensorimotor behavior. However, the association between SAI in a specific motor representation and the sensorimotor behavior may vary across different elements of a complex task (e.g., planning versus motor execution). Further, the association between SAI and behavior may be less apparent as the complexity of the sensorimotor behavior increases. Assessing SAI across many muscles in a multivariate approach may be necessary to account for interactions between adjacent agonist, synergist, and antagonist motor representations as the task complexity increases.
Conventional TMS assessments have linked SAI to several movement and psychiatric disorders. The increased selectivity of cTMS-SAI could facilitate the identification of increasingly reliable biomarkers of sensorimotor and psychiatric disorders. A preliminary report highlighted the potential of cTMS, suggesting that AP30 SAI may be a marker of persistent latent cognitive-motor abnormalities in young adults with a concussion history75. However, the diagnostic utility of cTMS-SAI in movement and psychiatric disorders such as chronic concussion, Parkinson&#39;s disease, Alzheimer&#39;s disease, mild cognitive impairment, dystonia, and stroke is yet to be explored. One significant limitation to the clinical application of cTMS-SAI in the movement disorder domain is the need for larger scale studies to establish the reliability and normative ranges, as has been done for SAI assessed with a fixed width PA pulse90,91,92,93. Further, clinical applications would benefit from an enhanced understanding of how the different sensorimotor loops probed by cTMS-SAI interact with other facilitatory and inhibitory pathways converging on the motor cortical pyramidal neurons. For example, conventional TMS studies of SAI suggest that the probed sensorimotor loops may complement the function of short-interval cortical facilitation (SICF)74, SICI66,94, and long-interval cortical inhibition (LICI)67 inhibitory pathways. However, the functional significance of such interactions is not clear.
One exciting prospect is combining cTMS-SAI with electroencephalography (EEG). EEG can be used to quantify the effect of afferent projections on the pyramidal output evoked by TMS over motor77,95 and non-motor areas95, known as TMS-evoked potentials (TEP). Assessing SAI in the frontal cortex, rather than the motor cortex, provides a unique opportunity to directly evaluate the integrity of cholinergic function in the neural substrates that mediate cognitive function. For example, reductions in the afferent inhibition of the N100 TEP elicited by conventional TMS over the prefrontal cortex correlate with reduced executive function in older adults96 and schizophrenic patients97. Employing cTMS-SAI with EEG could help determine if the cholinergic profile of executive function decline in healthy aging and neuropsychiatric disorders involves the same prefrontal circuitry.
cTMS is still a relatively nascent technology. Like any new technique, there are limitations and unknowns. However, the early evidence from cTMS-SAI studies that vary induced current direction and pulse widths demonstrate exciting possibilities for better understanding the functional significance of various convergent sensorimotor circuits in ongoing behaviors in healthy and clinical populations.

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.

<table><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>&amp;lrm;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&amp;eacute;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&amp;eacute;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&amp;eacute;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)&amp;nbsp;</td></tr><tr><td>Peripheral electrical stimulator</td><td>Digitimer, Hertfordshire, UK</td><td>DS7R&amp;nbsp;</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&amp;eacute;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).

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-induced current for the same participant.
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 for the conditioned compared to unconditioned MEPs and SAI ratios of less than 1. The longer MEP onset latency for the AP30 SAI reflects the longer latency of the input to the corticospinal neuron.
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/65212/65212fig03.jpg" /> 
Figure 3: Exemplar MEP traces and peak-to-peak amplitudes for unconditioned (solid trace) and conditioned (dashed trace) stimuli using PA120- (top) and AP30- (bottom) induced current. (A) Examples of the raw MEP waveforms elicited by PA120- and AP30-induced current during a validly cued index finger trial. (B) The average peak-to-peak amplitude of the unconditioned and conditioned MEPs for PA120- and AP30-induced current during a validly cued index finger trial. The error bars represent the standard error. (C) Top: The conditioned to unconditioned MEP amplitude ratio (e.g., SAI) for PA120- and AP30-induced current during a validly cued index finger trial. Bottom: The onset latencies of the unconditioned MEPs elicited by PA120- and AP30-induced current during a validly cued index finger trial. The MEP onset latency is not impacted by the cue validity. Abbreviations: TMS = transcranial magnetic stimulation; MNS = median nerve stimulus; MEP = motor-evoked potential; SAI = short-latency afferent inhibition; PA = posterior-anterior; AP = anterior-posterior. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/65212/65212fig03large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
Figure 4 demonstrates the differential effects of a conditioning stimulus for the PA120 and AP30 TMS stimuli based on the validity of the informational cue for a single participant. The top-left and top-right panels depict the PA120 SAI and AP30 SAI during a validly cued index finger response and an invalidly cued index finger response in which the participants had to remap their response to a non-index finger. The bottom left and bottom panels depict the PA120 SAI and AP30 SAI during a validly cued non-index finger response and an invalidly cued non-index finger response in which the participants had to remap their response to the index finger.
In this participant, the PA120 SAI was similarly enhanced for an index finger response regardless of whether the participant was cued to the index finger (top left panel) or required to remap their response to the index finger following an invalid cue to a non-index finger (bottom left panel). In contrast, the AP30 SAI appears to be differentially modulated based on whether the invalid cue required a remap away (top-right panel) or toward the index finger (bottom-right panel).
<img alt="Figure 4" class="xfigimg" src="/files/ftp_upload/65212/65212fig04.jpg" /> 
Figure 4: SAI for valid and invalid cue types depending upon the cued finger (index vs. non-index) separated by PA120- and AP30-induced current. Top left: PA120 SAI for a correctly cued index finger response and an incorrectly cued response that required remapping to respond using a non-index finger. Top right: AP30 SAI for a correctly cued index finger response and an incorrectly cued response that required remapping to respond using a non-index finger. Bottom left: PA120 SAI for a correctly cued non-index finger response and an incorrectly cued response that required remapping to respond with the index finger. Bottom right: AP30 SAI for a correctly cued non-index finger response and an incorrectly cued response that required remapping to respond with the index finger. Abbreviations: SAI = short-latency afferent inhibition; PA = posterior-anterior; AP = anterior-posterior. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/65212/65212fig04large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

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

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.

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 ...

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

Nanyang Technological University

Research

JoVE Journal

Neuroscience

2.5K Views.  University of Waterloo. Deze techniek geeft inzicht in hoe sensorische informatie wordt geïntegreerd in motorische planning en uitvoering. De implementatie van controleerbare pulsparameter TMS stelt ons in staat om specifieke sensorische naar motorische paden te identificeren en hoe deze paden kunnen worden verstoord bij neurologische aandoeningen. Motorische schaalverwerving en -prestaties vereisen een fijne balans tussen het bewuste declaratieve en onbewuste procedurele proces.Afferente remming met korte l...

Video: Auteur in de schijnwerpers: gecombineerde perifere zenuwstimulatie en regelbare pulsparameter transcraniële magnetische stimulatie om sensomotorische controle en leren te onderzoeken  

A Novel Approach for Documenting Phosphenes Induced by Transcranial Magnetic Stimulation

Stimulation of the human visual cortex produces a transient perception of light, known as a phosphene. Phosphenes are induced by invasive electrical stimulation of the occipital cortex, but also by non-invasive Transcranial Magnetic Stimulation (TMS)1 of the same cortical regions. The intensity at which a phosphene is induced (phosphene threshold) is a well established measure of visual cortical excitability and is used to study cortico-cortical interactions, functional organization 2, susceptibility to pathology 3,4 and visual processing 5-7. Phosphenes are typically defined by three characteristics: they are observed in the visual hemifield contralateral to stimulation; they are induced when the subject s eyes are open or closed, and their spatial location changes with the direction of gaze 2. Various methods have been used to document phosphenes, but a standardized methodology is lacking. We demonstrate a reliable procedure to obtain phosphene threshold values and introduce a novel system for the documentation and analysis of phosphenes. We developed the Laser Tracking and Painting system (LTaP), a low cost, easily built and operated system that records the location and size of perceived phosphenes in real-time. The LTaP system provides a stable and customizable environment for quantification and analysis of phosphenes.

Phosphenes are transient percepts of light that can be induced by applying Transcranial Magnetic Stimulation (TMS) to visually sensitive regions of cortex. We demonstrate a standard protocol for determining the phosphene threshold value and introduce a novel method for quantifying and analyzing perceived phosphenes.

Stimulation of the human visual cortex produces a transient perception of light, known as a phosphene. Phosphenes are induced by invasive electrical ...

Combining Transcranial Magnetic Stimulation and fMRI to Examine the Default Mode Network

The default mode network is a group of brain regions that are active when an individual is not focused on the outside world and the brain is at "wakeful rest."1,2,3 It is thought the default mode network corresponds to self-referential or "internal mentation".2,3
It has been hypothesized that, in humans, activity within the default mode network is correlated with certain pathologies (for instance, hyper-activation has been linked to schizophrenia 4,5,6 and autism spectrum disorders 7 whilst hypo-activation of the network has been linked to Alzheimer's and other neurodegenerative diseases 8). As such, noninvasive modulation of this network may represent a potential therapeutic intervention for a number of neurological and psychiatric pathologies linked to abnormal network activation. One possible tool to effect this modulation is Transcranial Magnetic Stimulation: a non-invasive neurostimulatory and neuromodulatory technique that can transiently or lastingly modulate cortical excitability (either increasing or decreasing it) via the application of localized magnetic field pulses.9
In order to explore the default mode network's propensity towards and tolerance of modulation, we will be combining TMS (to the left inferior parietal lobe) with functional magnetic resonance imaging (fMRI). Through this article, we will examine the protocol and considerations necessary to successfully combine these two neuroscientific tools.

In this article, we examine the methodology and considerations relevant to the combination of TMS and fMRI to examine the effects of brain stimulation on the default network.

The default mode network is a group of brain regions that are active when an individual is not focused on the outside world and the brain is at "wakeful ...

State-Dependency Effects on TMS:  A Look at Motive Phosphene Behavior

Transcranial magnetic stimulation (TMS) is a non-invasive neurostimulatory and neuromodulatory technique that can transiently or lastingly modulate cortical excitability (either increasing or decreasing it) via the application of localized magnetic field pulses.1,2 Within the field of TMS, the term state dependency refers to the initial, baseline condition of the particular neural region targeted for stimulation. As can be inferred, the effects of TMS can (and do) vary according to this primary susceptibility and responsiveness of the targeted cortical area.3,4,5

In this experiment, we will examine this concept of state dependency through the elicitation and subjective experience of motive phosphenes. Phosphenes are visually perceived flashes of small lights triggered by electromagnetic pulses to the visual cortex. These small lights can assume varied characteristics depending upon which type of visual cortex is being stimulated. In this particular study, we will be targeting motive phosphenes as elicited through the stimulation of V1/V2 and the V5/MT+ complex visual regions.6

In this article, we examine the effects of visually relevant state dependency on TMS induced motive phosphenic presentations.

Transcranial magnetic stimulation (TMS) is a non-invasive neurostimulatory and neuromodulatory technique that can transiently or lastingly modulate ...

Utilizing Transcranial Magnetic Stimulation to Study the Human Neuromuscular System

Transcranial magnetic stimulation (TMS) has been in use for more than 20 years 1, and has grown exponentially in popularity over the past decade. While the use of TMS has expanded to the study of many systems and processes during this time, the original application and perhaps one of the most common uses of TMS involves studying the physiology, plasticity and function of the human neuromuscular system. Single pulse TMS applied to the motor cortex excites pyramidal neurons transsynaptically 2 (Figure 1) and results in a measurable electromyographic response that can be used to study and evaluate the integrity and excitability of the corticospinal tract in humans 3. Additionally, recent advances in magnetic stimulation now allows for partitioning of cortical versus spinal excitability 4,5. For example, paired-pulse TMS can be used to assess intracortical facilitatory and inhibitory properties by combining a conditioning stimulus and a test stimulus at different interstimulus intervals 3,4,6-8. In this video article we will demonstrate the methodological and technical aspects of these techniques. Specifically, we will demonstrate single-pulse and paired-pulse TMS techniques as applied to the flexor carpi radialis (FCR) muscle as well as the erector spinae (ES) musculature. Our laboratory studies the FCR muscle as it is of interest to our research on the effects of wrist-hand cast immobilization on reduced muscle performance6,9, and we study the ES muscles due to these muscles clinical relevance as it relates to low back pain8. With this stated, we should note that TMS has been used to study many muscles of the hand, arm and legs, and should iterate that our demonstrations in the FCR and ES muscle groups are only selected examples of TMS being used to study the human neuromuscular system.

Transcranial magnetic stimulation (TMS) is a non-invasive tool to gain insight on the physiology and function of the human nervous system. Here, we present our TMS techniques to study cortical excitability of the upper limb and lumbar musculature.

Transcranial magnetic stimulation (TMS) has been in use for more than 20 years 1, and has grown exponentially in popularity over the past decade.  While ...

Medicine

Electrode Positioning and Montage in Transcranial Direct Current Stimulation

Transcranial direct current stimulation (tDCS) is a technique that has been intensively investigated in the past decade as this method offers a non-invasive and safe alternative to change cortical excitability2. The effects of one session of tDCS can last for several minutes, and its effects depend on polarity of stimulation, such as that cathodal stimulation induces a decrease in cortical excitability, and anodal stimulation induces an increase in cortical excitability that may last beyond the duration of stimulation6. These effects have been explored in cognitive neuroscience and also clinically in a variety of neuropsychiatric disorders &#x2013; especially when applied over several consecutive sessions4. One area that has been attracting attention of neuroscientists and clinicians is the use of tDCS for modulation of pain-related neural networks3,5. Modulation of two main cortical areas in pain research has been explored: primary motor cortex and dorsolateral prefrontal cortex7. Due to the critical role of electrode montage, in this article, we show different alternatives for electrode placement for tDCS clinical trials on pain; discussing advantages and disadvantages of each method of stimulation.

Transcranial direct current stimulation (tDCS) is an established technique to modulate cortical excitability1,2. It has been used as an investigative tool in neuroscience due to its effects on cortical plasticity, easy operation, and safe profile. One area that tDCS has been showing encouraging results is pain alleviation 3-5.

Transcranial direct current stimulation (tDCS) is a technique that has been intensively investigated in the past decade as this method offers a ...

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 ...

Non-Invasive Modulation and Robotic Mapping of Motor Cortex in the Developing Brain

Mapping the motor cortex with transcranial magnetic stimulation (TMS) has potential to interrogate motor cortex physiology and plasticity but carries unique challenges in children. Similarly, transcranial direct current stimulation (tDCS) can improve motor learning in adults but has only recently been applied to children. The use of tDCS and emerging techniques like high&#8211;definition tDCS (HD-tDCS) require special methodological considerations in the developing brain. Robotic TMS motor mapping may confer unique advantages for mapping, particularly in the developing brain. Here, we aim to provide a practical, standardized approach for two integrated methods capable of simultaneously exploring motor cortex modulation and motor maps in children. First, we describe a protocol for robotic TMS motor mapping. Individualized, MRI-navigated 12x12 grids centered on the motor cortex guide a robot to administer single-pulse TMS. Mean motor evoked potential (MEP) amplitudes per grid point are used to generate 3D motor maps of individual hand muscles with outcomes including map area, volume, and center of gravity. Tools to measure safety and tolerability of both methods are also included. Second, we describe the application of both tDCS and HD-tDCS to modulate the motor cortex and motor learning. An experimental training paradigm and sample results are described. These methods will advance the application of non-invasive brain stimulation in children.

We demonstrate protocols for the modulation (tDCS, HD-tDCS) and mapping (robotic TMS) of the motor cortex in children.

Mapping the motor cortex with transcranial magnetic stimulation (TMS) has potential to interrogate motor cortex physiology and plasticity but carries ...

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 ...

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.

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 ...

Combined Intervention Training for Children with Spastic Cerebral Palsy 

Repeated Transcranial Magnetic Stimulation Combined with Action Observation Training in Children with Spastic Cerebral Palsy

This study presents the results of a randomized controlled trial utilizing a 2 x 2 factorial design, comparing the effects of repeated transcranial magnetic stimulation (rTMS) and action observation training (AOT) intervention methods on spasticity, balance function, and motor function in children with spastic cerebral palsy (SCP). The study aimed to investigate whether the combination of the two interventions produces greater improvement than either treatment alone or conventional treatment.
Subject children in this study, in accordance with the random number table, were randomly divided into four groups: conventional group, rTMS group, AOT group, and combined intervention group. All the children in the four groups received conventional rehabilitation treatment, on the basis of which they were given different therapeutic programs of rehabilitation measures. The conventional group had no other treatment while the rTMS group received rTMS, the AOT group received AOT and the combined intervention group was given a combined intervention of rTMS and AOT. They were trained five days per week for 12 weeks. Changes in scores of spasticity, balance function, walking ability, and gross motor function were assessed at the onset of the training program and upon completion of 12 weeks of treatment.
A total of 64 Children with SCP completed the study, and their results were analyzed. The total gross motor function efficiency of 87.50% in the experimental group was significantly higher than that of 25.00% in the conventional group, 62.50% in the rTMS group, and 68.75% in the AOT group. The preliminary results showed that combined intervention of rTMS and AOT could effectively improve the balance function and motor function of children, and the therapeutic effect of the combined intervention was better than that of conventional treatment, rTMS or AOT alone. Finally, clinical efficacy and optimal treatment parameters of the combined intervention were clarified to provide a clinical basis for therapists to conduct lower limb function rehabilitation for children with SCP.

Author Spotlight: Repetitive Transcranial Magnetic Stimulation Combined with Movement Observation in Cerebral Palsy

Children with spastic cerebral palsy (SCP) have limb spasticity, movement disorders, and abnormal posture due to injury to the cerebral cortex motor area, resulting in inability to stand and walk normally. Therefore, alleviating limb spasticity and enhancing gross motor function in children with SCP have become important therapeutic goals.

This study presents the results of a randomized controlled trial utilizing a 2 x 2 factorial design, comparing the effects of repeated transcranial ...

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

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