Exploring the Use of Non-invasive Neuromodulation Combined With Exercise in People With Advanced Multiple Sclerosis (MS)

• Sponsor: University of Wisconsin, Madison (Other)
• Overall Status: Completed
• CT.gov ID: NCT02252666
• Collaborator: (none)
• Enrollment: 6
• Location: 1
• Arm: 1
• Duration (Months): 39.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The investigators hypothesis is that electrical stimulation to the tongue that directly stimulates two cranial nerve nuclei (Trigeminal and Facial Nerve Nuclei), will excite neural impulses to the brainstem and cerebellum. The investigators call this cranial nerve non-invasive neuromodulation (CN-NINM). The activation of these structures induces neuroplasticity when combined with specific physical exercises, can reduce symptoms of advanced MS, targeting primarily postural stability (sitting and standing), upper extremity movement, and ability to perform self-transfers.

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis	Device: Neuromodulation Rehabilitation	N/A

Detailed Description

The intervention will be similar to that used in the investigators previous work with movement disorders, and will be tailored to the address issues unique to individuals with advanced MS.

The study will enroll a total of 6 subjects having advanced MS that present with significant seated and standing balance, posture, or movement control deficits due to MS.

Subjects will complete twice-daily lab training for two weeks (5 days/week). Each lab training (morning and afternoon) includes 1.5 to 2 hours of instruction in balance, posture and gait activities; therapeutic exercise for isolated muscle control; transfer training; and relaxation training.

Activities are performed in 20-minute sessions with concomitant electrical stimulation of the tongue. The intervention is customized according to each subject's particular symptoms and tolerance. If a subject is not able to perform this amount of training, the training will be adapted to a level that is tolerable.

After these 2 weeks, subjects will continue to perform these same intervention activities at home for 4 weeks. They will return to the lab for 1 week of training and testing, then perform home training for 4 weeks. This cycle is repeated for a total of 5 cycles.

After the 6 months have been completed, subjects may choose to participate in an optional second phase of the study. The second phase includes an additional 12 months of participation in which subjects perform the intervention activities at home training and return to the lab on time per month for 2 hours of testing and 2 hours of training.

If successful, this study would indicate that CN-NINM intervention may reduce the symptoms of advanced MS.

Study Design

• Study Type: Interventional
• Actual Enrollment: 6 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Exploring the Use of Non-invasive Neuromodulation Combined With Exercise in People With Advanced Multiple Sclerosis (MS)
• Study Start Date: Mar 1, 2014
• Actual Primary Completion Date: Jan 1, 2017
• Actual Study Completion Date: Jun 28, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Neuromodulation Rehabilitation Balance, posture and gait activities; therapeutic exercise for isolated muscle control; transfer training; and relaxation training using neurostimulation modulation. 2-week in lab intervention training, training at home and periodic return for follow-up testing and instruction on the next phase of the intervention.	Device: Neuromodulation Rehabilitation; CN-NINM uses sequenced patterns of electrical stimulation on the tongue. Our hypothesis is that CN-NINM induces neuroplasticity by noninvasive stimulation of two major cranial nerves: trigeminal, CN-V, and facial, CN-VII.; Other Names: Cranial Nerve Non-invasive Neuromodulation (CN-NINM) Portable Neuromodulation Stimulator (PoNS)

Outcome Measures

Primary Outcome Measures

1. Trunk Impairment Scale (TIS) [Change from Baseline at 2, 6, 11, 16, and 21 weeks]

   Static and dynamic sitting balance and trunk coordination are evaluated by a clinician. It is scored on a scale from 0-23, where the higher the score, the more improved the balance. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.

Secondary Outcome Measures

1. Static Standing Balance Test [Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks]

   Clinician measures standing balance for up to 30 seconds in each of 5 conditions: feet 10 cm apart, feet together, stride stance, tandem stance, and single leg stance with eyes open and eyes closed. Total score is the sum of all 5 conditions. Higher scores indicate better balance. Performance-based and tested in participants who possessed the ability to perform the assessment. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.

2. Impact of Visual Impairment Scale (IVIS) [Change from Baseline at 2, 6, 11, 16, and 21 weeks]

   A 5-item self-report questionnaire that assesses the extent to which various activities dependent upon vision are affected by MS-related visual problems. Scores range from 0-15, with higher scores indicating a greater impact of visual problems on daily activities. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.

3. Medical Outcomes Study (MOS) Pain Effects Scale (PES) [Change from Baseline at 2, 6, 11, 16, and 21 weeks]

   A self-report scale that assesses the ways in which pain and unpleasant sensation interfere with mood, ability to walk or move, sleep, work, recreation, and enjoyment of life. This assessment is used for subjects who have pain. Scores can range from 6-30. Items are scaled so that higher scores indicate a greater impact of pain on a patient's mood and behavior. Symptom specific test, only used for participants who presented symptom. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.

4. Bladder Control Scale (BLCS) [Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks]

   A 4-item self-report scale to evaluate the impact of bladder control on lifestyle. This assessment is used for subjects with bladder issues. Scores can range from 0-22, with higher scores indicating greater bladder control problems. Symptom specific test, only used for participants who presented symptom. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.

5. Bowel Control Scale (BWCS) [Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks]

   A 5-item self-report scale to evaluate the impact of bowel control on lifestyle. This assessment is used for subjects with bowel issues. Scores can range from 0-26, with higher scores indicating greater bowel control problems. Symptom specific test, only used for participants who presented symptom. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.

6. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) [Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks]

   A brief, clinician-administered test that helps determine the neuropsychological status of adults who have neurologic injury or disease such as dementia, head injury, and stroke. This tool consists of a battery of tests. Raw scores are transformed to a 0-120 scale, with a higher score indicating higher function. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.

7. Walking Distance [Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks]

   Clinician measures how far the individual can walk until fatigue requires him/her to stop. Longer distances demonstrate improvement. Performance-based and tested in participants who possessed the ability to perform the assessment. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.

8. Walking Speed [Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks]

   Assessed by timing the first 25 feet that the person walked. Performance-based and tested in participants who possessed the ability to perform the assessment. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.

9. 12-item MS Walking Scale (MSWS-12) [Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks]

   A 12-item self-report measure of the impact of MS on a person's walking. Raw scores are transformed to a 0-100 scale. A reduction in score indicates improvement. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.

10. Box & Blocks (B&B) Assessment - Right [Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks]

    A standardized clinical assessment of gross upper limb dexterity. Subjects move small blocks from one side of a box to the other within a time period (one minute). Each side is tested separately. The score is the number of blocks moved from 0-150. A higher score indicates improvement. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.

11. Box & Blocks (B&B) Assessment - Left [Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks]

    A standardized clinical assessment of gross upper limb dexterity. Subjects move small blocks from one side of a box to the other within a time period (one minute). Each side is tested separately. The score is the number of blocks moved from 0-150. A higher score indicates improvement. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.

12. Multiple Sclerosis Impact Scale (MSIS-29) - Physical [Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks]

    A 29-item self-report tool that measures the impact of MS on day-to-day life. There are 3 scores, physical, psychological, and total score. Raw scores are transformed to a 0-100 scale. A higher score indicates a greater impact of disease on daily function. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.

13. Multiple Sclerosis Impact Scale (MSIS-29) - Psychological [Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks]

    A 29-item self-report tool that measures the impact of MS on day-to-day life. There are 3 scores, physical, psychological, and total score. Raw scores are transformed to a 0-100 scale. A higher score indicates a greater impact of disease on daily function. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.

14. Modified Fatigue Impact Scale (MFIS) [Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks]

    A self-report tool that assesses the perceived impact of fatigue on daily activities. Consists of 21 items selected from the Fatigue Impact Scale. Scored on a 0-84 scale. A higher score indicates a greater impact of fatigue on daily activities. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.

15. Gross Motor Function Measure (GMFM) [Change from Baseline at 6, 11, 16, 21 and 27 weeks]

    The GMFM a standardized observational instrument that measures change in gross motor function. Subscales include lying & rolling; sitting; crawling & kneeling; standing; and walking, running & jumping. For the complete test, the raw scores are converted to a 0-100 scale, with higher scores indicating greater functional mobility. The items that we used were scored on a 0-3 scale and changes reported in percent improvement. Performance-based and tested in participants who possessed the ability to perform the assessment. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.

16. Slump Test [Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks]

    Measures and quantifies changes in trunk control during functional sitting. It was quickly determined that this test duplicated the TIS and was difficult to score objectively so the decision was made not to use it for the study. Performance-based and tested in participants who possessed the ability to perform the assessment.

17. Modified Rivermead Mobility Index [Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks]

    An 8 item assessment that quantifies the ability to perform transfers. It has been validated in persons with stroke and a mixed neurologic population (43% MS). Score is a 0-40 scale. A higher score indicates higher function. Performance-based and tested in participants who possessed the ability to perform the assessment. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.

Other Outcome Measures

1. Video Nystagmography (VNG) [Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks]

   VNG is a standardized eye tracking test used to measure static and dynamic eye movement control to detect oculomotor abnormalities typically associated with degenerative neurological disorders, particularly in the brainstem and cerebellum. The subject wears goggles while an infrared video camera monitors and records eye movement as the eyes follow a dot on a computer screen.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects must be age 18 or older.

• Subjects will have a score between 6.5 to 7.5 on the Kurtzke Expanded Disability Status Scale (EDSS). The EDSS is a method of quantifying disability in people with multiple sclerosis.

• Score of 6.5: needs constant bilateral support to walk 20 meters without resting.

• Score of 7.0: unable to walk beyond five meters even with aid, and is essentially restricted to a wheelchair; wheels self and transfers alone, and is active in wheelchair about 12 hours a day.

• Score of 7.5: unable to take more than a few steps and is restricted to wheelchair, and may need aid to transfer; wheels self, but may require a motorized chair for a full day's activities.

• Subjects will have reached a plateau in an MS focused physical rehabilitation program in the 6 months prior to enrollment.

• Requiring prior physical therapy will ensure that subjects have a core level of function that will allow them to participate in the study.

• Requiring that subjects have reached a plateau will ensure that subjects' response to the intervention is due to the use of the device and not to the physical exercises alone.

• Subjects who have participated in a physical rehabilitation program demonstrate that they are willing and able to commit to a rigorous training regimen.

• Subjects will have a maximum score of 20 on the Trunk Impairment Scale (TIS). The TIS assesses static dynamic sitting balance and trunk coordination in a sitting position. A score of 20 or lower indicates that their ability to adequately maintain sitting posture is affected.

• Subjects may have upper extremity involvement.

• Subjects may have additional symptoms of nystagmus, dysarthria, sensory disturbance, pain, and/or bowel and bladder function. As they present, we will use appropriate assessments at baseline and successive study test points.

• Subjects are their own legal guardians, and are able to understand and give informed consent.

Exclusion Criteria:

Subjects will have no major co-morbidities, especially neurological disorders, uncontrolled pain, hypertension or diabetes. All subjects, if on medications, will not have had any major changes in type or dosage in within 3 months of enrollment. Additionally, candidates will be excluded if they:

• have Functional Systems Scores (FSS) 4 or greater for pyramidal, cerebellar, brainstem, and sensory functions; 3 or greater for bowel and bladder function; and 2 or greater for cerebral function;

• are able to walk independently;

• use tobacco products (these activities tend to reduce tactile sensitivity in the oral cavity);

• have any oral abrasions, cuts, cold sores, piercings, tissue inflammation, or have had oral surgery within the previous 3 months;

• have a pacemaker, or are identified as at-risk for cardiovascular events;

• have a history of seizures;

• have a communicable disease;

• have a biomechanical prosthetic;

• are females who are pregnant.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	TCNL, 455 Science Drive, Suite 165	Madison	Wisconsin	United States	53711

Sponsors and Collaborators

• University of Wisconsin, Madison

Investigators

• Principal Investigator: Mitchell E Tyler, MS, University of Wisconsin, Madison

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Wisconsin, Madison
• ClinicalTrials.gov Identifier: NCT02252666
• Other Study ID Numbers: 2013-1060
• First Posted: Sep 30, 2014
• Last Update Posted: Jul 9, 2019
• Last Verified: Jun 1, 2019

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Keywords provided by University of Wisconsin, Madison: MS; balance; standing; control; movement
• Additional relevant MeSH terms: Multiple Sclerosis; Sclerosis

Study Results

Participant Flow

Arm/Group Title	Neuromodulation Rehabilitation
Arm/Group Description	Balance, posture and gait activities; therapeutic exercise for isolated muscle control; transfer training; and relaxation training using neurostimulation modulation. 2-week in lab intervention training, training at home and periodic return for follow-up testing and instruction on the next phase of the intervention. Neuromodulation Rehabilitation: Cranial-nerve non-invasive neuromodulation (CN-NINM) uses sequenced patterns of electrical stimulation on the tongue. The hypothesis is that CN-NINM induces neuroplasticity by noninvasive stimulation of two major cranial nerves: trigeminal, CN-V, and facial, CN-VII.
Period Title: Overall Study
STARTED	6
COMPLETED	6
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Neuromodulation Rehabilitation
Arm/Group Description	Balance, posture and gait activities; therapeutic exercise for isolated muscle control; transfer training; and relaxation training using neurostimulation modulation. 2-week in lab intervention training, training at home and periodic return for follow-up testing and instruction on the next phase of the intervention. Neuromodulation Rehabilitation: CN-NINM uses sequenced patterns of electrical stimulation on the tongue. The hypothesis is that CN-NINM induces neuroplasticity by noninvasive stimulation of two major cranial nerves: trigeminal, CN-V, and facial, CN-VII.
Overall Participants	6
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	5 83.3%
>=65 years	1 16.7%
Sex: Female, Male (Count of Participants)
Female	5 83.3%
Male	1 16.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 16.7%
Not Hispanic or Latino	5 83.3%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	5 83.3%
More than one race	0 0%
Unknown or Not Reported	1 16.7%
Region of Enrollment (participants) [Number]
United States	6 100%
Disease Chronicity (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	17.7 (7.4)
EDSS Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	7.0 (0.4)
MS Subtype (participants) [Number]
SPMS	5 83.3%
PPMS	1 16.7%

Outcome Measures

1. Primary Outcome

Title	Trunk Impairment Scale (TIS)
Description	Static and dynamic sitting balance and trunk coordination are evaluated by a clinician. It is scored on a scale from 0-23, where the higher the score, the more improved the balance. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.
Time Frame	Change from Baseline at 2, 6, 11, 16, and 21 weeks

Outcome Measure Data

Analysis Population Description

Effect sizes from baseline reported for 4 subjects with EDSS 6.5 - 7.0. It was postulated that the physical limitations of two subjects with EDSS score of 7.5 presented special challenges to measuring changes in function with the available assessment mechanisms for this clinical population.

Arm/Group Title	Neuromodulation Rehabilitation
Arm/Group Description	Balance, posture and gait activities; therapeutic exercise for isolated muscle control; transfer training; and relaxation training using neurostimulation modulation. 2-week in lab intervention training, training at home and periodic return for follow-up testing and instruction on the next phase of the intervention. Neuromodulation Rehabilitation: CN-NINM uses sequenced patterns of electrical stimulation on the tongue. The hypothesis is that CN-NINM induces neuroplasticity by noninvasive stimulation of two major cranial nerves: trigeminal, CN-V, and facial, CN-VII.
Measure Participants	4
Baseline to Week 2	0.82
Baseline to Week 6	2.58
Baseline to Week 11	1.47
Baseline to Week 16	1.63
Baseline to Week 21	3.06

2. Secondary Outcome

Title	Static Standing Balance Test
Description	Clinician measures standing balance for up to 30 seconds in each of 5 conditions: feet 10 cm apart, feet together, stride stance, tandem stance, and single leg stance with eyes open and eyes closed. Total score is the sum of all 5 conditions. Higher scores indicate better balance. Performance-based and tested in participants who possessed the ability to perform the assessment. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.
Time Frame	Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks

Outcome Measure Data

Analysis Population Description

Effect sizes from baseline reported for 4 subjects with EDSS 6.5 - 7.0. It was postulated that the physical limitations of two subjects with EDSS score of 7.5 presented special challenges to measuring changes in function with the available assessment mechanisms for this clinical population.

Arm/Group Title	Neuromodulation Rehabilitation
Arm/Group Description	Balance, posture and gait activities; therapeutic exercise for isolated muscle control; transfer training; and relaxation training using neurostimulation modulation. 2-week in lab intervention training, training at home and periodic return for follow-up testing and instruction on the next phase of the intervention. Neuromodulation Rehabilitation: CN-NINM uses sequenced patterns of electrical stimulation on the tongue. The hypothesis is that CN-NINM induces neuroplasticity by noninvasive stimulation of two major cranial nerves: trigeminal, CN-V, and facial, CN-VII.
Measure Participants	4
Baseline to Week 2	0.90
Baseline to Week 6	0.57
Baseline to Week 11	1.04
Baseline to Week 16	0.90
Baseline to Week 21	0.49
Baseline to Week 27	0.32

3. Secondary Outcome

Title	Impact of Visual Impairment Scale (IVIS)
Description	A 5-item self-report questionnaire that assesses the extent to which various activities dependent upon vision are affected by MS-related visual problems. Scores range from 0-15, with higher scores indicating a greater impact of visual problems on daily activities. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.
Time Frame	Change from Baseline at 2, 6, 11, 16, and 21 weeks

Outcome Measure Data

Analysis Population Description

Effect sizes from baseline reported for 4 subjects with EDSS 6.5 - 7.0. It was postulated that the physical limitations of two subjects with EDSS score of 7.5 presented special challenges to measuring changes in function with the available assessment mechanisms for this clinical population.

Arm/Group Title	Neuromodulation Rehabilitation
Arm/Group Description	Balance, posture and gait activities; therapeutic exercise for isolated muscle control; transfer training; and relaxation training using neurostimulation modulation. 2-week in lab intervention training, training at home and periodic return for follow-up testing and instruction on the next phase of the intervention. Neuromodulation Rehabilitation: CN-NINM uses sequenced patterns of electrical stimulation on the tongue. The hypothesis is that CN-NINM induces neuroplasticity by noninvasive stimulation of two major cranial nerves: trigeminal, CN-V, and facial, CN-VII.
Measure Participants	4
Baseline to Week 2	1.27
Baseline to Week 6	2.12
Baseline to Week 11	3.54
Baseline to Week 16	3.54
Baseline to Week 21	2.12

4. Secondary Outcome

Title	Medical Outcomes Study (MOS) Pain Effects Scale (PES)
Description	A self-report scale that assesses the ways in which pain and unpleasant sensation interfere with mood, ability to walk or move, sleep, work, recreation, and enjoyment of life. This assessment is used for subjects who have pain. Scores can range from 6-30. Items are scaled so that higher scores indicate a greater impact of pain on a patient's mood and behavior. Symptom specific test, only used for participants who presented symptom. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.
Time Frame	Change from Baseline at 2, 6, 11, 16, and 21 weeks

Outcome Measure Data

Analysis Population Description

Effect sizes from baseline reported for 4 subjects with EDSS 6.5 - 7.0. It was postulated that the physical limitations of two subjects with EDSS score of 7.5 presented special challenges to measuring changes in function with the available assessment mechanisms for this clinical population.

Arm/Group Title	Neuromodulation Rehabilitation
Arm/Group Description	Balance, posture and gait activities; therapeutic exercise for isolated muscle control; transfer training; and relaxation training using neurostimulation modulation. 2-week in lab intervention training, training at home and periodic return for follow-up testing and instruction on the next phase of the intervention. Neuromodulation Rehabilitation: CN-NINM uses sequenced patterns of electrical stimulation on the tongue. The hypothesis is that CN-NINM induces neuroplasticity by noninvasive stimulation of two major cranial nerves: trigeminal, CN-V, and facial, CN-VII.
Measure Participants	4
Baseline to Week 2	0.55
Baseline to Week 6	0.64
Baseline to Week 11	0.71
Baseline to Week 16	0.40
Baseline to Week 21	1.00

5. Secondary Outcome

Title	Bladder Control Scale (BLCS)
Description	A 4-item self-report scale to evaluate the impact of bladder control on lifestyle. This assessment is used for subjects with bladder issues. Scores can range from 0-22, with higher scores indicating greater bladder control problems. Symptom specific test, only used for participants who presented symptom. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.
Time Frame	Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks

Outcome Measure Data

Analysis Population Description

Effect sizes from baseline reported for 4 subjects with EDSS 6.5 - 7.0. It was postulated that the physical limitations of two subjects with EDSS score of 7.5 presented special challenges to measuring changes in function with the available assessment mechanisms for this clinical population.

Arm/Group Title	Neuromodulation Rehabilitation
Arm/Group Description	Balance, posture and gait activities; therapeutic exercise for isolated muscle control; transfer training; and relaxation training using neurostimulation modulation. 2-week in lab intervention training, training at home and periodic return for follow-up testing and instruction on the next phase of the intervention. Neuromodulation Rehabilitation: CN-NINM uses sequenced patterns of electrical stimulation on the tongue. The hypothesis is that CN-NINM induces neuroplasticity by noninvasive stimulation of two major cranial nerves: trigeminal, CN-V, and facial, CN-VII.
Measure Participants	4
Baseline to Week 2	0.30
Baseline to Week 6	0.30
Baseline to Week 11	0.13
Baseline to Week 16	0.41
Baseline to Week 21	0.62
Baseline to Week 27	0.27

6. Secondary Outcome

Title	Bowel Control Scale (BWCS)
Description	A 5-item self-report scale to evaluate the impact of bowel control on lifestyle. This assessment is used for subjects with bowel issues. Scores can range from 0-26, with higher scores indicating greater bowel control problems. Symptom specific test, only used for participants who presented symptom. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.
Time Frame	Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks

Outcome Measure Data

Analysis Population Description

Effect sizes from baseline reported for 4 subjects with EDSS 6.5 - 7.0. It was postulated that the physical limitations of two subjects with EDSS score of 7.5 presented special challenges to measuring changes in function with the available assessment mechanisms for this clinical population.

Arm/Group Title	Neuromodulation Rehabilitation
Arm/Group Description	Balance, posture and gait activities; therapeutic exercise for isolated muscle control; transfer training; and relaxation training using neurostimulation modulation. 2-week in lab intervention training, training at home and periodic return for follow-up testing and instruction on the next phase of the intervention. Neuromodulation Rehabilitation: CN-NINM uses sequenced patterns of electrical stimulation on the tongue. The hypothesis is that CN-NINM induces neuroplasticity by noninvasive stimulation of two major cranial nerves: trigeminal, CN-V, and facial, CN-VII.
Measure Participants	4
Baseline to Week 2	1.20
Baseline to Week 6	0.68
Baseline to Week 11	0.52
Baseline to Week 16	1.04
Baseline to Week 21	0.86
Baseline to Week 27	0.35

7. Secondary Outcome

Title	Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)
Description	A brief, clinician-administered test that helps determine the neuropsychological status of adults who have neurologic injury or disease such as dementia, head injury, and stroke. This tool consists of a battery of tests. Raw scores are transformed to a 0-120 scale, with a higher score indicating higher function. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.
Time Frame	Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks

Outcome Measure Data

Analysis Population Description

Effect sizes from baseline reported for 4 subjects with EDSS 6.5 - 7.0. It was postulated that the physical limitations of two subjects with EDSS score of 7.5 presented special challenges to measuring changes in function with the available assessment mechanisms for this clinical population.

Arm/Group Title	Neuromodulation Rehabilitation
Arm/Group Description	Balance, posture and gait activities; therapeutic exercise for isolated muscle control; transfer training; and relaxation training using neurostimulation modulation. 2-week in lab intervention training, training at home and periodic return for follow-up testing and instruction on the next phase of the intervention. Neuromodulation Rehabilitation: CN-NINM uses sequenced patterns of electrical stimulation on the tongue. The hypothesis is that CN-NINM induces neuroplasticity by noninvasive stimulation of two major cranial nerves: trigeminal, CN-V, and facial, CN-VII.
Measure Participants	4
Baseline to Week 2	-0.12
Baseline to Week 6	0.39
Baseline to Week 11	0.24
Baseline to Week 16	0.78
Baseline to Week 21	1.94
Baseline to Week 27	0.51

8. Secondary Outcome

Title	Walking Distance
Description	Clinician measures how far the individual can walk until fatigue requires him/her to stop. Longer distances demonstrate improvement. Performance-based and tested in participants who possessed the ability to perform the assessment. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.
Time Frame	Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks

Outcome Measure Data

Analysis Population Description

Effect sizes from baseline reported for 4 subjects with EDSS 6.5 - 7.0. It was postulated that the physical limitations of two subjects with EDSS score of 7.5 presented special challenges to measuring changes in function with the available assessment mechanisms for this clinical population.

Arm/Group Title	Neuromodulation Rehabilitation
Arm/Group Description	Balance, posture and gait activities; therapeutic exercise for isolated muscle control; transfer training; and relaxation training using neurostimulation modulation. 2-week in lab intervention training, training at home and periodic return for follow-up testing and instruction on the next phase of the intervention. Neuromodulation Rehabilitation: CN-NINM uses sequenced patterns of electrical stimulation on the tongue. The hypothesis is that CN-NINM induces neuroplasticity by noninvasive stimulation of two major cranial nerves: trigeminal, CN-V, and facial, CN-VII.
Measure Participants	4
Baseline to Week 2	0.89
Baseline to Week 6	0.75
Baseline to Week 11	0.76
Baseline to Week 16	0.69
Baseline to Week 21	0.67
Baseline to Week 27	0.26

9. Secondary Outcome

Title	Walking Speed
Description	Assessed by timing the first 25 feet that the person walked. Performance-based and tested in participants who possessed the ability to perform the assessment. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.
Time Frame	Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks

Outcome Measure Data

Analysis Population Description

Effect sizes from baseline reported for 4 subjects with EDSS 6.5 - 7.0. It was postulated that the physical limitations of two subjects with EDSS score of 7.5 presented special challenges to measuring changes in function with the available assessment mechanisms for this clinical population.

Arm/Group Title	Neuromodulation Rehabilitation
Arm/Group Description	Balance, posture and gait activities; therapeutic exercise for isolated muscle control; transfer training; and relaxation training using neurostimulation modulation. 2-week in lab intervention training, training at home and periodic return for follow-up testing and instruction on the next phase of the intervention. Neuromodulation Rehabilitation: CN-NINM uses sequenced patterns of electrical stimulation on the tongue. The hypothesis is that CN-NINM induces neuroplasticity by noninvasive stimulation of two major cranial nerves: trigeminal, CN-V, and facial, CN-VII.
Measure Participants	4
Baseline to Week 2	0.77
Baseline to Week 6	0.84
Baseline to Week 11	1.00
Baseline to Week 16	1.01
Baseline to Week 21	-0.41
Baseline to Week 27	-0.94

10. Secondary Outcome

Title	12-item MS Walking Scale (MSWS-12)
Description	A 12-item self-report measure of the impact of MS on a person's walking. Raw scores are transformed to a 0-100 scale. A reduction in score indicates improvement. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.
Time Frame	Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks

Outcome Measure Data

Analysis Population Description

Effect sizes from baseline reported for 4 subjects with EDSS 6.5 - 7.0. It was postulated that the physical limitations of two subjects with EDSS score of 7.5 presented special challenges to measuring changes in function with the available assessment mechanisms for this clinical population.

Arm/Group Title	Neuromodulation Rehabilitation
Arm/Group Description	Balance, posture and gait activities; therapeutic exercise for isolated muscle control; transfer training; and relaxation training using neurostimulation modulation. 2-week in lab intervention training, training at home and periodic return for follow-up testing and instruction on the next phase of the intervention. Neuromodulation Rehabilitation: CN-NINM uses sequenced patterns of electrical stimulation on the tongue. The hypothesis is that CN-NINM induces neuroplasticity by noninvasive stimulation of two major cranial nerves: trigeminal, CN-V, and facial, CN-VII.
Measure Participants	4
Baseline to Week 2	-0.50
Baseline to Week 6	0.43
Baseline to Week 11	0.87
Baseline to Week 16	0.50
Baseline to Week 21	1.33
Baseline to Week 27	-0.42

11. Secondary Outcome

Title	Box & Blocks (B&B) Assessment - Right
Description	A standardized clinical assessment of gross upper limb dexterity. Subjects move small blocks from one side of a box to the other within a time period (one minute). Each side is tested separately. The score is the number of blocks moved from 0-150. A higher score indicates improvement. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.
Time Frame	Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks

Outcome Measure Data

Analysis Population Description

Effect sizes from baseline reported for 4 subjects with EDSS 6.5 - 7.0. It was postulated that the physical limitations of two subjects with EDSS score of 7.5 presented special challenges to measuring changes in function with the available assessment mechanisms for this clinical population.

Arm/Group Title	Neuromodulation Rehabilitation
Arm/Group Description	Balance, posture and gait activities; therapeutic exercise for isolated muscle control; transfer training; and relaxation training using neurostimulation modulation. 2-week in lab intervention training, training at home and periodic return for follow-up testing and instruction on the next phase of the intervention. Neuromodulation Rehabilitation: CN-NINM uses sequenced patterns of electrical stimulation on the tongue. The hypothesis is that CN-NINM induces neuroplasticity by noninvasive stimulation of two major cranial nerves: trigeminal, CN-V, and facial, CN-VII.
Measure Participants	4
Baseline to Week 2	0.52
Baseline to Week 6	0.45
Baseline to Week 11	0.47
Baseline to Week 16	1.17
Baseline to Week 21	0.21
Baseline to Week 27	4.95

12. Secondary Outcome

Title	Box & Blocks (B&B) Assessment - Left
Description	A standardized clinical assessment of gross upper limb dexterity. Subjects move small blocks from one side of a box to the other within a time period (one minute). Each side is tested separately. The score is the number of blocks moved from 0-150. A higher score indicates improvement. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.
Time Frame	Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks

Outcome Measure Data

Analysis Population Description

Effect sizes from baseline reported for 4 subjects with EDSS 6.5 - 7.0. It was postulated that the physical limitations of two subjects with EDSS score of 7.5 presented special challenges to measuring changes in function with the available assessment mechanisms for this clinical population.

Arm/Group Title	Neuromodulation Rehabilitation
Arm/Group Description	Balance, posture and gait activities; therapeutic exercise for isolated muscle control; transfer training; and relaxation training using neurostimulation modulation. 2-week in lab intervention training, training at home and periodic return for follow-up testing and instruction on the next phase of the intervention. Neuromodulation Rehabilitation: CN-NINM uses sequenced patterns of electrical stimulation on the tongue. The hypothesis is that CN-NINM induces neuroplasticity by noninvasive stimulation of two major cranial nerves: trigeminal, CN-V, and facial, CN-VII.
Measure Participants	4
Baseline to Week 2	0.07
Baseline to Week 6	0.50
Baseline to Week 11	0.80
Baseline to Week 16	0.58
Baseline to Week 21	-0.04
Baseline to Week 27	0.00

13. Secondary Outcome

Title	Multiple Sclerosis Impact Scale (MSIS-29) - Physical
Description	A 29-item self-report tool that measures the impact of MS on day-to-day life. There are 3 scores, physical, psychological, and total score. Raw scores are transformed to a 0-100 scale. A higher score indicates a greater impact of disease on daily function. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.
Time Frame	Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks

Outcome Measure Data

Analysis Population Description

Effect sizes from baseline reported for 4 subjects with EDSS 6.5 - 7.0. It was postulated that the physical limitations of two subjects with EDSS score of 7.5 presented special challenges to measuring changes in function with the available assessment mechanisms for this clinical population.

Arm/Group Title	Neuromodulation Rehabilitation
Arm/Group Description	Balance, posture and gait activities; therapeutic exercise for isolated muscle control; transfer training; and relaxation training using neurostimulation modulation. 2-week in lab intervention training, training at home and periodic return for follow-up testing and instruction on the next phase of the intervention. Neuromodulation Rehabilitation: CN-NINM uses sequenced patterns of electrical stimulation on the tongue. The hypothesis is that CN-NINM induces neuroplasticity by noninvasive stimulation of two major cranial nerves: trigeminal, CN-V, and facial, CN-VII.
Measure Participants	4
Baseline to Week 2	1.58
Baseline to Week 6	0.61
Baseline to Week 11	0.94
Baseline to Week 16	0.89
Baseline to Week 21	1.46
Baseline to Week 27	-0.71

14. Secondary Outcome

Title	Multiple Sclerosis Impact Scale (MSIS-29) - Psychological
Description	A 29-item self-report tool that measures the impact of MS on day-to-day life. There are 3 scores, physical, psychological, and total score. Raw scores are transformed to a 0-100 scale. A higher score indicates a greater impact of disease on daily function. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.
Time Frame	Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks

Outcome Measure Data

Analysis Population Description

Effect sizes from baseline reported for 4 subjects with EDSS 6.5 - 7.0. It was postulated that the physical limitations of two subjects with EDSS score of 7.5 presented special challenges to measuring changes in function with the available assessment mechanisms for this clinical population.

Arm/Group Title	Neuromodulation Rehabilitation
Arm/Group Description	Balance, posture and gait activities; therapeutic exercise for isolated muscle control; transfer training; and relaxation training using neurostimulation modulation. 2-week in lab intervention training, training at home and periodic return for follow-up testing and instruction on the next phase of the intervention. Neuromodulation Rehabilitation: CN-NINM uses sequenced patterns of electrical stimulation on the tongue. The hypothesis is that CN-NINM induces neuroplasticity by noninvasive stimulation of two major cranial nerves: trigeminal, CN-V, and facial, CN-VII.
Measure Participants	4
Baseline to Week 2	1.77
Baseline to Week 6	1.17
Baseline to Week 11	0.86
Baseline to Week 16	0.98
Baseline to Week 21	2.05
Baseline to Week 27	0.35

15. Secondary Outcome

Title	Modified Fatigue Impact Scale (MFIS)
Description	A self-report tool that assesses the perceived impact of fatigue on daily activities. Consists of 21 items selected from the Fatigue Impact Scale. Scored on a 0-84 scale. A higher score indicates a greater impact of fatigue on daily activities. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.
Time Frame	Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks

Outcome Measure Data

Analysis Population Description

Effect sizes from baseline reported for 4 subjects with EDSS 6.5 - 7.0. It was postulated that the physical limitations of two subjects with EDSS score of 7.5 presented special challenges to measuring changes in function with the available assessment mechanisms for this clinical population.

Arm/Group Title	Neuromodulation Rehabilitation
Arm/Group Description	Balance, posture and gait activities; therapeutic exercise for isolated muscle control; transfer training; and relaxation training using neurostimulation modulation. 2-week in lab intervention training, training at home and periodic return for follow-up testing and instruction on the next phase of the intervention. Neuromodulation Rehabilitation: CN-NINM uses sequenced patterns of electrical stimulation on the tongue. The hypothesis is that CN-NINM induces neuroplasticity by noninvasive stimulation of two major cranial nerves: trigeminal, CN-V, and facial, CN-VII.
Measure Participants	4
Baseline to Week 2	0.87
Baseline to Week 6	3.10
Baseline to Week 11	2.54
Baseline to Week 16	1.75
Baseline to Week 21	1.40
Baseline to Week 27	0.20

16. Secondary Outcome

Title	Gross Motor Function Measure (GMFM)
Description	The GMFM a standardized observational instrument that measures change in gross motor function. Subscales include lying & rolling; sitting; crawling & kneeling; standing; and walking, running & jumping. For the complete test, the raw scores are converted to a 0-100 scale, with higher scores indicating greater functional mobility. The items that we used were scored on a 0-3 scale and changes reported in percent improvement. Performance-based and tested in participants who possessed the ability to perform the assessment. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.
Time Frame	Change from Baseline at 6, 11, 16, 21 and 27 weeks

Outcome Measure Data

Analysis Population Description

Effect sizes from baseline reported for 4 subjects with EDSS 6.5 - 7.0. It was postulated that the physical limitations of two subjects with EDSS score of 7.5 presented special challenges to measuring changes in function with the available assessment mechanisms for this clinical population.

Arm/Group Title	Neuromodulation Rehabilitation
Arm/Group Description	Balance, posture and gait activities; therapeutic exercise for isolated muscle control; transfer training; and relaxation training using neurostimulation modulation. 2-week in lab intervention training, training at home and periodic return for follow-up testing and instruction on the next phase of the intervention. Neuromodulation Rehabilitation: CN-NINM uses sequenced patterns of electrical stimulation on the tongue. The hypothesis is that CN-NINM induces neuroplasticity by noninvasive stimulation of two major cranial nerves: trigeminal, CN-V, and facial, CN-VII.
Measure Participants	4
Baseline to Week 6	0.82
Baseline to Week 11	1.10
Baseline to Week 16	1.19
Baseline to Week 21	0.84
Baseline to Week 27	0.16

17. Secondary Outcome

Title	Slump Test
Description	Measures and quantifies changes in trunk control during functional sitting. It was quickly determined that this test duplicated the TIS and was difficult to score objectively so the decision was made not to use it for the study. Performance-based and tested in participants who possessed the ability to perform the assessment.
Time Frame	Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks

Outcome Measure Data

Analysis Population Description

The Slump Test was ultimately not used because the investigators decided to use the TIS instead. The TIS was realized to be the more appropriate assessment of the two, and the investigators wanted to avoid both data redundancy and test fatigue

Arm/Group Title	Neuromodulation Rehabilitation
Arm/Group Description	Balance, posture and gait activities; therapeutic exercise for isolated muscle control; transfer training; and relaxation training using neurostimulation modulation. 2-week in lab intervention training, training at home and periodic return for follow-up testing and instruction on the next phase of the intervention. Neuromodulation Rehabilitation: CN-NINM uses sequenced patterns of electrical stimulation on the tongue. The hypothesis is that CN-NINM induces neuroplasticity by noninvasive stimulation of two major cranial nerves: trigeminal, CN-V, and facial, CN-VII.
Measure Participants	0

18. Secondary Outcome

Title	Modified Rivermead Mobility Index
Description	An 8 item assessment that quantifies the ability to perform transfers. It has been validated in persons with stroke and a mixed neurologic population (43% MS). Score is a 0-40 scale. A higher score indicates higher function. Performance-based and tested in participants who possessed the ability to perform the assessment. Effect size is reported (quantified difference between baseline and time point). The larger the absolute value, the stronger the effect. Cohen's guidelines for social sciences indicate 0.10 as a "small" effect size, 0.30 as a "medium" effect size, and 0.50 as a "large" effect size.
Time Frame	Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks

Outcome Measure Data

Analysis Population Description

Effect sizes from baseline reported for 4 subjects with EDSS 6.5 - 7.0. It was postulated that the physical limitations of two subjects with EDSS score of 7.5 presented special challenges to measuring changes in function with the available assessment mechanisms for this clinical population.

Arm/Group Title	Neuromodulation Rehabilitation
Arm/Group Description	Balance, posture and gait activities; therapeutic exercise for isolated muscle control; transfer training; and relaxation training using neurostimulation modulation. 2-week in lab intervention training, training at home and periodic return for follow-up testing and instruction on the next phase of the intervention. Neuromodulation Rehabilitation: CN-NINM uses sequenced patterns of electrical stimulation on the tongue. The hypothesis is that CN-NINM induces neuroplasticity by noninvasive stimulation of two major cranial nerves: trigeminal, CN-V, and facial, CN-VII.
Measure Participants	4
Baseline to Week 2	1.01
Baseline to Week 6	1.21
Baseline to Week 11	0.94
Baseline to Week 16	1.44
Baseline to Week 21	1.15
Baseline to Week 27	0.38

19. Other Pre-specified Outcome

Title	Video Nystagmography (VNG)
Description	VNG is a standardized eye tracking test used to measure static and dynamic eye movement control to detect oculomotor abnormalities typically associated with degenerative neurological disorders, particularly in the brainstem and cerebellum. The subject wears goggles while an infrared video camera monitors and records eye movement as the eyes follow a dot on a computer screen.
Time Frame	Change from Baseline at 2, 6, 11, 16, 21 and 27 weeks

Outcome Measure Data

Analysis Population Description

The VNG was exploratory and opportunistic. The results are not available as the software to perform the quantitative data analysis is still under development.

Arm/Group Title	Neuromodulation Rehabilitation
Arm/Group Description	Balance, posture and gait activities; therapeutic exercise for isolated muscle control; transfer training; and relaxation training using neurostimulation modulation. 2-week in lab intervention training, training at home and periodic return for follow-up testing and instruction on the next phase of the intervention. Neuromodulation Rehabilitation: CN-NINM uses sequenced patterns of electrical stimulation on the tongue. The hypothesis is that CN-NINM induces neuroplasticity by noninvasive stimulation of two major cranial nerves: trigeminal, CN-V, and facial, CN-VII.
Measure Participants	0

Adverse Events

Arm/Group Title	Neuromodulation Rehabilitation
Arm/Group Description	Balance, posture and gait activities; therapeutic exercise for isolated muscle control; transfer training; and relaxation training using neurostimulation modulation. 2-week in lab intervention training, training at home and periodic return for follow-up testing and instruction on the next phase of the intervention. Neuromodulation Rehabilitation: CN-NINM uses sequenced patterns of electrical stimulation on the tongue. The hypothesis is that CN-NINM induces neuroplasticity by noninvasive stimulation of two major cranial nerves: trigeminal, CN-V, and facial, CN-VII.
All Cause Mortality
	Neuromodulation Rehabilitation
	Affected / at Risk (%)	# Events
Total	0/6 (0%)
Serious Adverse Events
	Neuromodulation Rehabilitation
	Affected / at Risk (%)	# Events
Total	0/6 (0%)
Other (Not Including Serious) Adverse Events
	Neuromodulation Rehabilitation
	Affected / at Risk (%)	# Events
Total	6/6 (100%)
General disorders
Fatigue	1/6 (16.7%)	1
Infections and infestations
Viral Infection	2/6 (33.3%)	2
Injury, poisoning and procedural complications
Injury	1/6 (16.7%)	1
Musculoskeletal and connective tissue disorders
Osteoarthritis Pain	1/6 (16.7%)	1
Nervous system disorders
Trigeminal Neuralgia (TN)	1/6 (16.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.