Name: a protocol for the use of remotely-supervised transcranial direct current stimulation (tdcs) in multiple sclerosis (ms)
Uploaded: 2015-12-26T13:00:00
Duration: 8 min 18 s
Description: Watch this Scientific Journal Video about A Protocol for the Use of Remotely-Supervised Transcranial Direct Current Stimulation tDCS in Multiple Sclerosis MS at JoVE.com

Supported by The Lourie Foundation, Inc.

Ethics Statement: Stony Brook University Institutional Review Board (IRB) approved this protocol on February 10, 2015.
1. Recruitment of Participants for Remotely-Supervised tDCS
<ol>
	<li>Provide recruited study participants with information on the device and the ten day study protocol.</li>
</ol>
2. Inclusion/Exclusion Criteria
<ol>
	<li>Health
	<ol>
		<li>Ensure that a clinician has provided medical clearance for all enrolled participants at the baseline visit.</li>
	</ol>
	</li>
	<li>tDCS tolerability and laptop aptitude
	<ol>
		<li>Ensure that participants are familiar with the basic functioning of a laptop computer and how to connect the computer to Wi-Fi internet. For both the use of the laptop, and the setup of the tDCS device, ensure that participants (or a proxy), have the dexterity to complete the procedures.</li>
		<li>Beyond setup, at baseline visits, give participants a 1 min trial dose of 1.5 mA of tDCS to determine tolerability. If participants cannot tolerate this session, a lower dose of 1.0 mA can be applied. If neither is tolerated, exclude the participant.</li>
	</ol>
	</li>
	<li>Environmental
	<ol>
		<li>Confirm that participants have access to a distraction-free, well lit, clean environment with a safe area to store the device and device kit.</li>
	</ol>
	</li>
	<li>Compliance
	<ol>
		<li>If a participant does not adhere to the scheduled video conference session in a timely fashion, exclude that participant.</li>
	</ol>
	</li>
	<li>Stop Criteria
	<ol>
		<li>At each participant interaction, review a series of predetermined &#34;stop criteria&#34; to ensure that participants tolerate the session, adhere to the study schedule, and safely operate the device without adverse effects. Should any of these be met, exclude the participant from the study (Figure 1).</li>
	</ol>
	</li>
</ol>
3. Materials
Note: As recommended in the published guidelines for remotely-supervised use16, precise electrode preparation and placement must mirror the clinic protocol with respect to dose control and ongoing monitoring.
<ol>
	<li>Device Kit
	<ol>
		<li>Prepare the same materials for every remote tDCS participant. This includes a study provided laptop computer with secure video conferencing software, the device, and a device kit.</li>
		<li>Design the device kit for ease of use and organize it by day (Figure 2).</li>
		<li>Prepare the kit with twenty wrapped sponge pockets of size 5x5cm with a perforation at the top (two per day required for a 10-day study) , twenty syringes pre-filled with 6 mL of saline solution for each sponge pocket, a wash bottle filled with extra saline, spare batteries for the device, and a handheld mirror for headset application.</li>
		<li>In addition, require that study users have a portable home phone or mobile phone at their workspace for each session.</li>
	</ol>
	</li>
	<li>Device
	<ol>
		<li>Choose a tDCS device that only releases a session through a one-time use unlock code. Ensure that the study device has functionality whereby participants can only administer a session after being provided the code by the study technician. In addition, ensure that in the selection of a study device, contact quality is continually monitored to ensure safe and proper use.</li>
	</ol>
	</li>
	<li>Video Monitoring
	<ol>
		<li>Choose a secure video conferencing software to allow for remote supervision of the proper setup of the device, optimal contact quality, and that the intended user is applying the session.</li>
		<li>Use the video conferencing software as another method of training. Instruct users how to turn the device on, read their contact quality, troubleshoot poor contact quality, enter a one-time use unlock code, and safely remove the device after shutdown.</li>
	</ol>
	</li>
	<li>Headgear
	<ol>
		<li>Design the headgear for simple and robust electrode positioning. Use a single-position headgear to eliminate room for user error, and to help conserve the placement of the montage. Configure a cap-like design, with clearly labeled sponge markers to enhance the reliability of placement in the single-position headgear with the anodal electrode placed on the left side.</li>
	</ol>
	</li>
</ol>
4. Training
Note: Complete the majority of participant training during the first baseline session of the remote study. Roughly 1-2 hr of the baseline visit should be spent on training. Allow participants to view an instructional tDCS video as their first instruction.
<ol>
	<li>Instructional video
	<ol>
		<li>Set up the instructional video to play for the participant following the baseline visit. During the viewing, allow the participant to have access to the device and device kit and to follow along at each step.</li>
		<li>Prepare the video to first introduce the participant to the materials and then transition into a step-by-step guide that mimics the flow of an actual study session.</li>
		<li>Present the setup of the tDCS headset slowly and clearly (and make it available for replay), should the user need clarification. Also provide a participant view so that the study participant can gain a sense of what device screens to expect and how the device display will appear when providing certain readings.</li>
	</ol>
	</li>
	<li>Video sections 
	Note: Remote technicians will not provide unlock codes for devices unless appropriate contact quality is achieved.
	<ol>
		<li>Design the instructional video to detail the means of troubleshooting poor contact quality, including applying pressure and moistening the sponge pockets. Ensure that the video also provides information on the safe usage of study materials, as well as the protocol to follow in order to end a session.</li>
		<li>Instruct participants on procedures to terminate a session and require participants to maintain phone access throughout the duration of the session, ensuring that a level of in-clinic safety is maintained in the case of emergency,</li>
		<li>Following the video, allow the participant to attempt their own set up with the aid of a study technician.</li>
	</ol>
	</li>
	<li>Instruction manual
	<ol>
		<li>Prepare a transcript of the information presented in the video, as well as photographs and diagrams of the materials, device screenshots, and laptop information, in the form of a manual.</li>
	</ol>
	</li>
	<li>In-person training
	<ol>
		<li>Monitor the participant as they begin the set-up.</li>
		<li>Coach the participant through each step (moisten sponge pockets, insert electrode into the sponge, fasten sponges on to the headset, place headset on head, center the headset, confirm with study technician, and turn device on).</li>
		<li>Clarify the procedure or equipment where necessary.</li>
	</ol>
	</li>
	<li>Troubleshooting for participants that experience setup difficulty
	<ol>
		<li>If participants struggle with the set-up, repeat the demonstration of the method.</li>
		<li>If participants are unable to complete the set up after repeated attempts, terminate the session. This is defined as a study &#34;stop&#34; criteria.</li>
	</ol>
	</li>
</ol>
5. Participant Preparation for Study Session
<ol>
	<li>Instruct participants to set up their study laptop, mobile phone, device kit, device and headset in a clean, well lit area. Inform participants to pull hair back and minimize distractions.</li>
	<li>Allow participants to refer to the instructional video or manual for a step by step guide of the protocol.</li>
	<li>First initiate web conference with the study participant before beginning setup so that there is ongoing monitoring for compliance16.</li>
</ol>
6. Device Setup during Study Session
<ol>
	<li>After the video conference is initiated, instruct the participant to begin set up.</li>
	<li>Open the sponge pockets and moisten using the 6 mL syringes (one syringe per sponge pocket). About 3 mL can be used to moisten each side of the sponge pocket.</li>
	<li>Apply carbon-rubber electrodes to carry current from the tDCS stimulator. Encase the electrodes in sponge pockets. Insert each carbon rubber electrode into the sponge pocket fully. Note: Since direct skin contact with rubber electrodes is painful, electrodes are encased in sponge pockets.</li>
	<li>Ensure the red cable is connected to red receiver plug labeled &#39;anode&#39; on the device. Ensure the black cable is connected to black receiver plug labeled &#39;cathode&#39; on the device. These cables are never removed from the device.</li>
	<li>Connect the sponge pockets and electrodes to the headset using the common bilateral dorsolateral prefrontal cortex (DLPC), with the anodal electrode (one connected to the red wire) placed on the left side. Note: Label the headset with red and black to ensure proper electrode placement.</li>
	<li>Fasten the headset using buttons on the sponge pockets that fit into grooves on the headset. The smooth side of the sponge pocket always faces in toward the forehead. 
	Note: This offers ease of reliable electrode placement and wide therapeutic applications.</li>
	<li>After the sponge pockets are fastened, position the headset on the head. Tuck the back strap beneath the groove in the back of the head and align the center button with the nasion. This can be confirmed using the handheld mirror supplied in the device kit and by the study technician through video conferencing software.</li>
	<li>At this point, instruct the participant to read aloud the contact quality on the device display. Note: A moderate or optimal reading is required for session code administration.</li>
	<li>If contact quality needs to be improved, instruct participants to follow pre-set troubleshooting procedures. First, recommend applying pressure to the sponge pockets. If this does not prove successful, give participants the option to apply a small amount of saline solution to the sponge pockets using the wash bottle (paper towels are provided for any spillage).</li>
	<li>Once proper contact quality is achieved, administer a one-time use unlock code for the sessions. Note: These codes are pre-programmed by study staff for the set amount of time and amplitude.</li>
</ol>
7. Session completion
Note: After the participant enters the unlock code, the screen of the device will show a timer that counts down the minutes until the end of the session. The device will also indicate the contact quality of the electrodes throughout the session. When 1 min remains on the timer, a countdown in seconds will occur.
<ol>
	<li>If contact quality falls below &#34;moderate&#34; provide instructions on how to improve it using the troubleshooting steps in 6.9.</li>
	<li>Remind the participant to not to remove the headset until the seconds have fully counted down to zero and the device shuts off (confirmed with a beeping noise).</li>
	<li>Instruct the participant to remove the headset when the device beeps.</li>
	<li>Direct the participant to remove sponge pockets from the device and discard them. Syringes are one time use as well and should also be discarded.</li>
	<li>Ensure that the participant stores the device and headset in the kit.</li>
	<li>Remind the participant to safely store the laptop, device, and all materials for the next session.</li>
</ol>
8. End of Study Analyses
<ol>
	<li>Assess each study participant using a participant tracker. This serves as a method of recording study compliance, adverse events, and session completion. At the end of study, review each participant&#39;s data to determine study success. For the purpose of this protocol, study success will be defined by 80% of participants having completed 80% of study sessions24.</li>
	<li>Validate session success through records of daily session attendance, review of daily pain scales and before and after stimulation questionnaires for adverse events Please see Supplemental Code Files for sample questionnaire. 
	Note: Validation that the 20 min&#160;of stimulation were fully delivered can be reviewed at study end. The study technician can access the device for completion codes as confirmation.</li>
</ol>

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CUNY has patents with Marom Bikson as inventor. Marom Bikson has equity in Soterix Medical Inc. CUNY has patents with Abhishek Datta as inventor. Abhishek Datta has equity in Soterix Medical Inc.

Critical steps within the protocol 
As remotely-supervised tDCS is administered away from the direct supervision of a clinician, inclusion and exclusion criteria are designed to ensure that the participant has no contraindicated health conditions or environmental distractions, and are fully capable to use a laptop computer (including those with adaptive technology) for communication with the research team. In addition, participants must be able to tolerate a tDCS session and commit to the scheduled session time for the duration of the study.
While remote tDCS offers a convenience to the study and administration of the therapy, self-directed participant use is not advisable due to both safety concerns and the inability to monitor and standardize the stimulation that is delivered. Instead, our protocol follows the standards and guidelines for remotely-supervised tDCS16 to extend clinic standards through delivery in a remote location. The guidelines ensure that research staff are properly trained for participant interactions, that users have proper ability to participate in remote tDCS, and that there are ongoing training materials as well as assessments made of the participant at each step of the study. The stimulation was uniform and reproducible with exactly 20 min&#160;of 1.5 mA delivered at every session without any interruption or variation across sessions or individuals.
Modifications to the protocol and troubleshooting tips
The protocol includes several small modifications. Firstly, we expanded the use of this protocol to MS participants that have an EDSS score above 6.5 in the instance where there is a proxy accessible to administer each dose. In addition, we have implemented a procedure whereby we remotely access the participant&#39;s study provided laptop to initiate the web conference for those who need extra support and review measures of tolerability and study experiences through a shared document. A future modification to the current protocol includes allowing various degrees of remote supervision so that participants who prove most competent with the technique would only require early supervision to confirm device set up and to receive the unlock code.
Limitations of the technique 
While our preliminary results support the feasibility of this protocol, the sample size is limited. As enrollment expands, analyses will be made for gaps in training, ways to streamline sessions, enhance the instructional video, and make the technique more accessible to those with motor impairment (i.e., adaptive mice for computer usage, sponge pocket/headset modification to further ease application). Some participants in the EDSS range below 6.5 (not requiring proxy), may still experience some difficulty in headset preparation and troubleshooting computer related issues. Furthermore, while this study recommends full remote monitoring of participants throughout all sessions, future studies may deem some participants sufficiently trained to operate the device without supervision for the entirety of a session.
Significance of the method with respect to existing methods 
These initial results demonstrate the feasibility of our protocol for remotely-supervised tDCS delivery for clinical trials, following a set of guidelines and standards that must be employed to safely, and effectively administer tDCS under remote supervision. The protocol was designed to have a decision-tree series of checkpoints with &#34;stop&#34; criteria (section 2.5.1 above) that must be cleared in order to proceed at each step (see Figure 1). These checkpoints addressed tolerability (experiences of pain or adverse effects to the treatment) and compliance (timely session attendance and proper technique). For each session 1 through 10, participants completed brief adverse event reports before and after their sessions (with items derived from a list of the most common tDCS side-effects in previous trials). In addition, participants completed the self-report measures to address tolerability (before and after the session) and can complete symptom inventories as well. This study is significant in that it establishes a technique to examine a therapy in MS with adequate power while also providing broader access to tDCS treatment.
Future applications of the technique
Once the method for remotely-supervised tDCS has been fully piloted in the MS population, a larger, randomized controlled trial can be initiated to target symptom management. Through the use of the instructional training materials and structure around daily participant interactions, remotely-supervised tDCS can be accessed by a wider range of patient populations and expand clinical study of the technique.

tDCS is a relatively recent therapy that operates through the use of low amplitude (2.0 mA or less) direct current to modulate cortical excitability 1. Hundreds of clinical trials have demonstrated tDCS to be safe and well-tolerated2-4. tDCS is easier to use, lower in cost, and better tolerated when compared to other methods such as transcranial magnetic stimulation (e.g., tDCS has not been associated with the development of seizures 5,6). Multiple tDCS sessions are required for benefit, especially when administered with the goal of enhancing rehabilitation outcomes.7-10
It is not yet known how many tDCS sessions are necessary or optimal, but the effects are cumulative with little evidence that tDCS over a single session produces behaviorally meaningful changes.2,11 For example, studies of depression have found 30 or more sessions needed for full benefit in some participants. 12,13 Multiple sessions are especially important when pairing tDCS with a behavioral therapy, which only occurs with rigorous repetition across many sessions. 14
For many patients and caregivers, traveling to the outpatient facility to receive repeated tDCS treatment sessions is a major obstacle in terms of time, cost and travel arrangements. This real-world limitation has resulted in studies with small sample sizes and without adequate power or design to draw conclusions that can lead to clinical use.15 Remote tDCS delivery would allow for participation in study protocols from home or other locations, and reach those patients who otherwise would not have access to these trials. Further, it allows the possibility for testing "on-demand" application for indications such as epilepsy and migraines. 
We have worked with a diverse group of clinical investigators interested in remotely-supervised tDCS to develop guidelines and standards for remotely-supervised tDCS delivery including specialized equipment and specific training requirements both for staff and study participants16. Here, we developed a protocol to follow these guidelines and test for feasibility in patients with multiple sclerosis (MS), a disorder where tDCS may be a useful tool for the management of its symptoms. 11,17-23

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			<td height="42" style="height:42px;width:184px;">Mini-CT transcranial direct current stimulation device</td>
			<td style="width:71px;">Soterix</td>
			<td style="width:119px;"></td>
			<td style="width:419px;">Device to deliver direct current stimultion in a remote manner</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:184px;">Study Kit&#160;</td>
			<td style="width:71px;">NA</td>
			<td style="width:119px;"></td>
			<td>Provided to participant with all required setup items - device, headset, sponge pockets, pre-filled syringes, Kleenex, handheld mirro, spare batteries&#160;</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:184px;">Laptop&#160;</td>
			<td style="width:71px;">NA</td>
			<td style="width:119px;"></td>
			<td>Provided to allow secure video conferecing during device setup and headset placement</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:184px;">Instruction Manual&#160;</td>
			<td style="width:71px;">NA</td>
			<td style="width:119px;"></td>
			<td>Transcription of instructional video and detailed instructions for protocol&#160;</td>
		</tr>
	</tbody>
</table>

a protocol for the use of remotely-supervised transcranial direct current stimulation (tdcs) in multiple sclerosis (ms)

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that uses low amplitude direct currents to alter cortical excitability. With well-established safety and tolerability, tDCS has been found to have the potential to ameliorate symptoms such as depression and pain in a range of conditions as well as to enhance outcomes of cognitive and physical training. However, effects are cumulative, requiring treatments that can span weeks or months and frequent, repeated visits to the clinic. The cost in terms of time and travel is often prohibitive for many participants, and ultimately limits real-world access. 
Following guidelines for remote tDCS application, we propose a protocol that would allow remote (in-home) participation that uses specially-designed devices for supervised use with materials modified for patient use, and real-time monitoring through a telemedicine video conferencing platform. We have developed structured training procedures and clear, detailed instructional materials to allow for self- or proxy-administration while supervised remotely in real-time. The protocol is designed to have a series of checkpoints, addressing attendance and tolerability of the session, to be met in order to continue to the next step. The feasibility of this protocol was then piloted for clinical use in an open label study of remotely-supervised tDCS in multiple sclerosis (MS). This protocol can be widely used for clinical study of tDCS.

We have adapted this protocol for use in MS. We targeted the delivery of ten tDCS stimulation sessions delivered over two weeks. 9,10 The first two sessions of the ten were in-person training sessions and the following eight were remotely supervised (Figure 3). The second session consists of an environmental suitability assessment where study technicians visited the participant&#39;s home to confirm appropriate set-up.
To complete the following remotely-supervised sessions, participants were provided with the tDCS device specially-designed for remote use and a headset that was modified for ease of use to guide accurate electrode placement. A device kit was provided and included the device and headset, one-time use sponge pockets for electrodes and syringes filled with the measured amount of saline required for each sponge, with all items individually labeled by day and organized for ease of use. Electrodes were placed in the bilateral dorsolateral prefrontal cortex (DLPC) position with the anodal electrode placed on the left side. 10 This offers ease of reliable electrode placement, wide therapeutic applications.9,10 Based on prior studies we targeted 1.5 mA for 20 min&#160;sessions. The protocol 9,10allowed for a current reduction to 1.0 mA at baseline if this improves overall subject tolerability.
Participants were given a study-provided laptop computer configured for the study, including the easily accessible instructional video and link for secure video conference connection with the study technician. The laptop also included a program for remote monitoring of all computer activity, and a program to remotely access the computer for technical support. Detailed manuals for operation were used by both the participant and study technician, and a binder for self-report measures was provided.
A total of n=20 MS participants have completed the study. Inclusion criteria specified an Expanded Disability Status Scale (EDSS)25 * of 6.0 or below OR 6.5 or above with proxy to ensure minimal motor requirements to operate the device. Enrollment has been representative of a range of impairment in MS (motor impairment, cognitive impairment, or both). All 20 participants, n=4 with proxy, were successfully trained to self-apply a tDCS session and 192 total sessions were completed. As shown in Figure 4, 40 of the192 sessions included training; the remaining 152 were exclusively remotely-supervised sessions. Of the remotely-supervised sessions, 100% were executed correctly with successfully placement of electrodes, device operation and well-tolerated delivery of stimulation.
<img alt="Figure 1" src="/files/ftp_upload/53542/53542fig1.jpg" /> 
Figure 1.&#160;Stop Criteria Flowchart. The chart details the various criteria that indicate a participant can no longer proceed or participate in a remotely-supervised tDCS study. <a href="https://www.jove.com/files/ftp_upload/53542/53542fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 2" src="/files/ftp_upload/53542/53542fig2.jpg" /> 
Figure 2.&#160;Device Kit.&#160;This view demonstrates the device kit with individually wrapped sponge pockets, one saline-filled syringe per sponge per day, a handheld mirror a device holder, spare saline solution, and the device with headgear. <a href="https://www.jove.com/files/ftp_upload/53542/53542fig2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 3" src="/files/ftp_upload/53542/53542fig3.jpg" /> 
Figure 3. Participant study timeline. This timeline demonstrates a way to cycle study kits and devices through each 10 day participant enrollment in the study. <a href="https://www.jove.com/files/ftp_upload/53542/53542fig3large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 4" src="/files/ftp_upload/53542/53542fig4.jpg" /> 
Figure 4.&#160;Self-applied tDCS sessions across n=20 participants. This figure demonstrates the completed, self-applied sessions across n=20 participants enrolled in the study. The initial session is completed in-clinic while the remaining nine sessions are completed through remote supervision in the participant&#39;s home. <a href="https://www.jove.com/files/ftp_upload/53542/53542fig4large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

Watch this Scientific Journal Video about A Protocol for the Use of Remotely-Supervised Transcranial Direct Current Stimulation tDCS in Multiple Sclerosis MS at JoVE.com

A Protocol for the Use of Remotely-Supervised Transcranial Direct Current Stimulation tDCS in Multiple Sclerosis MS

The goal of this pilot study is to describe a protocol for the remotely-supervised delivery of transcranial direct current stimulation (tDCS) so that the procedure maintains standards of in-clinic practice, including safety, reproducibility, and tolerability. The feasibility of this protocol was tested in participants with multiple sclerosis (MS).

A Protocol for the Use of Remotely-Supervised Transcranial Direct Current Stimulation (tDCS) in Multiple Sclerosis (MS)

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that uses low amplitude direct currents to alter cortical ...

a-protocol-for-use-remotely-supervised-transcranial-direct-current

Research

JoVE Journal

Medicine

A Protocol for Comprehensive Assessment of Bulbar Dysfunction in Amyotrophic Lateral Sclerosis (ALS)

Improved methods for assessing bulbar impairment are necessary for expediting diagnosis of bulbar dysfunction in ALS, for predicting disease progression across speech subsystems, and for addressing the critical need for sensitive outcome measures for ongoing experimental treatment trials. To address this need, we are obtaining longitudinal profiles of bulbar impairment in 100 individuals based on a comprehensive instrumentation-based assessment that yield objective measures. Using instrumental approaches to quantify speech-related behaviors is very important in a field that has primarily relied on subjective, auditory-perceptual forms of speech assessment1. Our assessment protocol measures performance across all of the speech subsystems, which include respiratory, phonatory (laryngeal), resonatory (velopharyngeal), and articulatory. The articulatory subsystem is divided into the facial components (jaw and lip), and the tongue. Prior research has suggested that each speech subsystem responds differently to neurological diseases such as ALS. The current protocol is designed to test the performance of each speech subsystem as independently from other subsystems as possible. The speech subsystems are evaluated in the context of more global changes to speech performance. These speech system level variables include speaking rate and intelligibility of speech.
The protocol requires specialized instrumentation, and commercial and custom software. The respiratory, phonatory, and resonatory subsystems are evaluated using pressure-flow (aerodynamic) and acoustic methods. The articulatory subsystem is assessed using 3D motion tracking techniques. The objective measures that are used to quantify bulbar impairment have been well established in the speech literature and show sensitivity to changes in bulbar function with disease progression. The result of the assessment is a comprehensive, across-subsystem performance profile for each participant. The profile, when compared to the same measures obtained from healthy controls, is used for diagnostic purposes. Currently, we are testing the sensitivity and specificity of these measures for diagnosis of ALS and for predicting the rate of disease progression. In the long term, the more refined endophenotype of bulbar ALS derived from this work is expected to strengthen future efforts to identify the genetic loci of ALS and improve diagnostic and treatment specificity of the disease as a whole. The objective assessment that is demonstrated in this video may be used to assess a broad range of speech motor impairments, including those related to stroke, traumatic brain injury, multiple sclerosis, and Parkinson disease.

A Protocol for Comprehensive Assessment of Bulbar Dysfunction in Amyotrophic Lateral Sclerosis ALS

Objective assessments of the physiological mechanisms that support speech are needed to monitor disease onset and progression in persons with ALS and to quantify treatment effects in clinical trials. In this video, we present a comprehensive, instrumentation-based protocol for quantifying speech motor performance in clinical populations.

Improved methods for assessing bulbar impairment are necessary for expediting diagnosis of bulbar dysfunction in ALS, for predicting disease progression ...

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 ...

Clinical Testing and Spinal Cord Removal in a Mouse Model for Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder resulting in progressive degeneration of motoneurons. Peak of onset is around 60 years for the sporadic disease and around 50 years for the familial disease. Due to its progressive course, 50% of the patients die within 30 months of symptom onset. In order to evaluate novel treatment options for this disease, genetic mouse models of ALS have been generated based on human familial mutations in the SOD gene, such as the SOD1 (G93A) mutation. Most important aspects that have to be evaluated in the model are overall survival, clinical course and motor function. Here, we demonstrate the clinical evaluation, show the conduction of two behavioural motor tests and provide quantitative scoring systems for all parameters. Because an in depth analysis of the ALS mouse model usually requires an immunohistochemical examination of the spinal cord, we demonstrate its preparation in detail applying the dorsal laminectomy method. Exemplary histological findings are demonstrated. The comprehensive application of the depicted examination methods in studies on the mouse model of ALS will enable the researcher to reliably test future therapeutic options which can provide a basis for later human clinical trials.

Clinical Testing and Spinal Cord Removal in a Mouse Model for Amyotrophic Lateral Sclerosis ALS

A mouse model for amyotrophic lateral sclerosis (ALS) is examined clinically and behaviorally. As a prerequisite for an accompanying immunohistological analysis the preparation of the spinal cord is depicted in detail.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder resulting in progressive degeneration of motoneurons. Peak of onset is around 60 ...

Utilizing Repetitive Transcranial Magnetic Stimulation to Improve Language Function in Stroke Patients with Chronic Non-fluent Aphasia

Transcranial magnetic stimulation (TMS) has been shown to significantly improve language function in patients with non-fluent aphasia1. In this experiment, we demonstrate the administration of low-frequency repetitive TMS (rTMS) to an optimal stimulation site in the right hemisphere in patients with chronic non-fluent aphasia. A battery of standardized language measures is administered in order to assess baseline performance. Patients are subsequently randomized to either receive real rTMS or initial sham stimulation. Patients in the real stimulation undergo a site-finding phase, comprised of a series of six rTMS sessions administered over five days; stimulation is delivered to a different site in the right frontal lobe during each of these sessions. Each site-finding session consists of 600 pulses of 1 Hz rTMS, preceded and followed by a picture-naming task. By comparing the degree of transient change in naming ability elicited by stimulation of candidate sites, we are able to locate the area of optimal response for each individual patient. We then administer rTMS to this site during the treatment phase. During treatment, patients undergo a total of ten days of stimulation over the span of two weeks; each session is comprised of 20 min of 1 Hz rTMS delivered at 90% resting motor threshold. Stimulation is paired with an fMRI-naming task on the first and last days of treatment. After the treatment phase is complete, the language battery obtained at baseline is repeated two and six months following stimulation in order to identify rTMS-induced changes in performance. The fMRI-naming task is also repeated two and six months following treatment. Patients who are randomized to the sham arm of the study undergo sham site-finding, sham treatment, fMRI-naming studies, and repeat language testing two months after completing sham treatment. Sham patients then cross over into the real stimulation arm, completing real site-finding, real treatment, fMRI, and two- and six-month post-stimulation language testing.

We explore the use of repetitive transcranial magnetic stimulation (rTMS) to improve language abilities in patients with chronic stroke and non-fluent aphasia. After identifying a site in the right frontal gyrus for each patient that responds optimally to stimulation, we target this site during ten days of rTMS treatment.

Transcranial magnetic stimulation (TMS) has been shown to significantly improve language function in patients with non-fluent aphasia1. In this ...

Technique and Considerations in the Use of 4x1 Ring High-definition Transcranial Direct Current Stimulation (HD-tDCS)

High-definition transcranial direct current stimulation (HD-tDCS) has recently been developed as a noninvasive brain stimulation approach that increases the accuracy of current delivery to the brain by using arrays of smaller "high-definition" electrodes, instead of the larger pad-electrodes of conventional tDCS. Targeting is achieved by energizing electrodes placed in predetermined configurations. One of these is the 4x1-ring configuration. In this approach, a center ring electrode (anode or cathode) overlying the target cortical region is surrounded by four return electrodes, which help circumscribe the area of stimulation. Delivery of 4x1-ring HD-tDCS is capable of inducing significant neurophysiological and clinical effects in both healthy subjects and patients. Furthermore, its tolerability is supported by studies using intensities as high as 2.0 milliamperes for up to twenty minutes.
Even though 4x1 HD-tDCS is simple to perform, correct electrode positioning is important in order to accurately stimulate target cortical regions and exert its neuromodulatory effects. The use of electrodes and hardware that have specifically been tested for HD-tDCS is critical for safety and tolerability. Given that most published studies on 4x1 HD-tDCS have targeted the primary motor cortex (M1), particularly for pain-related outcomes, the purpose of this article is to systematically describe its use for M1 stimulation, as well as the considerations to be taken for safe and effective stimulation. However, the methods outlined here can be adapted for other HD-tDCS configurations and cortical targets.

Technique and Considerations in the Use of 4x1 Ring High-definition Transcranial Direct Current Stimulation HD-tDCS

High-definition transcranial direct current stimulation (HD-tDCS), with its 4x1-ring montage, is a noninvasive brain stimulation technique that combines both the neuromodulatory effects of conventional tDCS with increased focality. This article provides a systematic demonstration of the use of 4x1 HD-tDCS, and the considerations needed for safe and effective stimulation.

High-definition transcranial direct current stimulation (HD-tDCS) has recently been developed as a noninvasive brain stimulation approach that increases ...

The Multiple Sclerosis Performance Test (MSPT): An iPad-Based Disability Assessment Tool

Precise measurement of neurological and neuropsychological impairment and disability in multiple sclerosis is challenging. We report a new test, the Multiple Sclerosis Performance Test (MSPT), which represents a new approach to quantifying MS related disability. The MSPT takes advantage of advances in computer technology, information technology, biomechanics, and clinical measurement science. The resulting MSPT represents a computer-based platform for precise, valid measurement of MS severity. Based on, but extending the Multiple Sclerosis Functional Composite (MSFC), the MSPT provides precise, quantitative data on walking speed, balance, manual dexterity, visual function, and cognitive processing speed. The MSPT was tested by 51 MS patients and 49 healthy controls (HC). MSPT scores were highly reproducible, correlated strongly with technician-administered test scores, discriminated MS from HC and severe from mild MS, and correlated with patient reported outcomes. Measures of reliability, sensitivity, and clinical meaning for MSPT scores were favorable compared with technician-based testing. The MSPT is a potentially transformative approach for collecting MS disability outcome data for patient care and research. Because the testing is computer-based, test performance can be analyzed in traditional or novel ways and data can be directly entered into research or clinical databases. The MSPT could be widely disseminated to clinicians in practice settings who are not connected to clinical trial performance sites or who are practicing in rural settings, drastically improving access to clinical trials for clinicians and patients. The MSPT could be adapted to out of clinic settings, like the patient&#8217;s home, thereby providing more meaningful real world data. The MSPT represents a new paradigm for neuroperformance testing. This method could have the same transformative effect on clinical care and research in MS as standardized computer-adapted testing has had in the education field, with clear potential to accelerate progress in clinical care and research.

The Multiple Sclerosis Performance Test MSPT: An iPad-Based Disability Assessment Tool

Precise measurement of neurological and neuropsychological impairment and disability in multiple sclerosis is challenging. We report methodologic details on a new test, the Multiple Sclerosis Performance Test (MSPT). This new approach to the objective of quantification of MS related disability provides a computer-based platform for precise, valid measurement of MS severity.

Precise measurement of neurological and neuropsychological impairment and disability in multiple sclerosis is challenging. We report a new test, the ...

A Method of Trigonometric Modelling of Seasonal Variation Demonstrated with Multiple Sclerosis Relapse Data

This report describes a novel Stata-based application of trigonometric regression modelling to 55 years of multiple sclerosis relapse data from 46 clinical centers across 20 countries located in both hemispheres. Central to the success of this method was the strategic use of plot analysis to guide and corroborate the statistical regression modelling. Initial plot analysis was necessary for establishing realistic hypotheses regarding the presence and structural form of seasonal and latitudinal influences on relapse probability and then testing the performance of the resultant models. Trigonometric regression was then necessary to quantify these relationships, adjust for important confounders and provide a measure of certainty as to how plausible these associations were. Synchronization of graphing techniques with regression modelling permitted a systematic refinement of models until best-fit convergence was achieved, enabling novel inferences to be made regarding the independent influence of both season and latitude in predicting relapse onset timing in MS. These methods have the potential for application across other complex disease and epidemiological phenomena suspected or known to vary systematically with season and/or geographic location.

Combining plot analysis with trigonometric regression is a robust method for exploring complex, cyclical phenomena such as relapse onset timing in multiple sclerosis (MS). This method enabled unbiased characterisation of seasonal trends in relapse onset permitting novel inferences around the influence of seasonal variation, ultraviolet radiation (UVR) and latitude.

This report describes a novel Stata-based application of trigonometric regression modelling to  55 years of multiple sclerosis relapse data from 46 ...

Adapted Resistance Training Improves Strength in Eight Weeks in Individuals with Multiple Sclerosis

Hip weakness is a common symptom affecting walking ability in people with multiple sclerosis (MS). It is known that resistance strength training (RST) can improve strength in individuals with MS, however; it remains unclear the duration of RST that is needed to make strength gains and how to adapt hip strengthening exercises for individuals of varying strength using only resistance bands. This paper describes the methodology to set up and implement an adapted resistance strength training program, using resistance bands, for individuals with MS. Directions for pre- and post-strength tests to evaluate efficacy of the strength-training program are included. Safety features and detailed instructions outline the weekly program content and progression. Current evidence is presented showing that significant strength gains can be made within 8 weeks of starting a RST program. Evidence is also presented showing that resistance strength training can be successfully adapted for individuals with MS of varying strength with little equipment.

Hip weakness is a common symptom affecting walking ability in people with multiple sclerosis. Isolated muscle strengthening is a useful method to target specific weaknesses. This protocol describes a progressive resistance-training program using exercise bands to increase hip muscle strength.

Hip weakness is a common symptom affecting walking ability in people with multiple sclerosis (MS). It is known that resistance strength training (RST) can ...

Bioluminescence and Near-infrared Imaging of Optic Neuritis and Brain Inflammation in the EAE Model of Multiple Sclerosis in Mice

Experimental autoimmune encephalomyelitis (EAE) in SJL/J mice is a model for relapsing-remitting multiple sclerosis (RRMS). Clinical EAE scores describing motor function deficits are basic readouts of the immune-mediated inflammation of the spinal cord. However, scores and body weight do not allow for an in vivo assessment of brain inflammation and optic neuritis. The latter is an early and frequent manifestation in about 2/3 of MS patients. Here, we show methods for bioluminescence and near-infrared live imaging to assess EAE evoked optic neuritis, brain inflammation, and blood-brain barrier (BBB) disruption in living mice using an in vivo imaging system. A bioluminescent substrate activated by oxidases primarily showed optic neuritis. The signal was specific and allowed the visualization of medication effects and disease time courses, which paralleled the clinical scores. Pegylated fluorescent nanoparticles that remained within the vasculature for extended periods of time were used to assess the BBB integrity. Near-infrared imaging revealed a BBB leak at the peak of the disease. The signal was the strongest around the eyes. A near-infrared substrate for matrix metalloproteinases was used to assess EAE-evoked inflammation. Auto-fluorescence interfered with the signal, requiring spectral unmixing for quantification. Overall, bioluminescence imaging was a reliable method to assess EAE-associated optic neuritis and medication effects and was superior to the near-infrared techniques in terms of signal specificity, robustness, ease of quantification, and cost.

We show a technique for in vivo live bioluminescence and near-infrared imaging of optic neuritis and encephalitis in the experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis in SJL/J mice.

Experimental autoimmune encephalomyelitis (EAE) in SJL/J mice is a model for relapsing-remitting multiple sclerosis (RRMS). Clinical EAE scores describing ...

Home-Based Transcranial Direct Current Stimulation Device Development: An Updated Protocol Used at Home in Healthy Subjects and Fibromyalgia Patients

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation (NIBS) method, which modulates the membrane potential of neurons in the cerebral cortex by a low-intensity direct current. tDCS is a low-cost technique with minimal adverse effects and easy application. This neurostimulation method has a promising future to improve pain therapy, treatment of neuropsychiatric disorders, and physical rehabilitation.
Current studies demonstrate the benefits of using tDCS over consecutive multiple sessions. However, the daily displacement to the specialized centers, travel costs, and disruptions to daily activities are some of the difficulties faced by patients. Thus, to be more comfortable, easy-to-use, and not disrupt daily commitments, a home-based tDCS was designed. Therefore, the objective of this study was to evaluate the feasibility of a portable tDCS device for home use in healthy subjects and fibromyalgia patients.
Despite increased tDCS use and a reasonably large body of research on the effects across a range of clinical conditions, there is a limited amount of research on developing secure devices that guarantee the dose and contain a block system to avoid excessive use. Therefore, we used a tDCS device with a security system to permit daily use for 20 minutes with a minimal interval of 12 hours between sessions. A programmer preconfigures the equipment, which has a neoprene cap that allows the electrode positions in any assembly, according to individualized protocols for treatments or research. After, researchers can assess the effectiveness of treatment, and its adherence using information kept in the device software.
Results suggest that the device is feasible for home use, with proper monitoring of adherence and contact impedance. There were reports of a few adverse effects, which do not differ from those reported in the literature in studies with the treatment under direct supervision.

This study provides an updated home-based tDCS protocol that enables subjects to receive the beneficial effects of tDCS at home with an easy to use device with settings to control the use and dosage, enhancing the feasibility for long-term use at home.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation (NIBS) method, which modulates the membrane potential of neurons in the ...