Physiological Responses in Experimentally Induced Cognitive Fatigue in People With Multiple Sclerosis (MS)

Study Overview
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Brief Summary
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The current study will add to the current knowledge by combining several electrophysiological techniques to examine the relationship between physiological responses and cognitive fatigue and daily activity performance in a stress- and fatigue-inducing protocol. The aims of this study are: 1) to evaluate the feasibility and usability of assessing physiological responses in an experimental set-up and 2) to investigate the association between physiological outcomes, experimentally induced stress and cognitive fatigue in people with multiple sclerosis (MS) and healthy controls.

Detailed Description
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In an experimental set-up participants (20 people with MS and 20 healthy controls) will perform a high-challenging cognitive protocol to provoke stress and (cognitive) fatigue. Physiological responses (heart rate variability, skin conductance, body temperature) and brain activity (EEG) will be measured while resting (resting baseline), while speaking as normal (speaking baseline), during protocol performance and following the protocol (post-protocol). Demographic and clinical characteristics, as well as levels of perceived fatigue, stress, pain, daily activity performance, quality of life and anxiety and depression will be assessed using medical records and questionnaires. Feasibility and usability will be assessed in participants and researcher(s) by standardized questionnaires.

Official Title
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Physiological Responses in Experimentally Induced Cognitive Fatigue in People With Multiple Sclerosis (MS): a Feasibility Study

Conditions
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Fatigue, Multiple Sclerosis, Stress

Intervention / Treatment
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* Behavioral: High-challenging cognitive protocol to provoke stress and (cognitive) fatigue


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: diagnosis MS, Relapsing Remitting (RR) type (MS group) Expanded Disability Status Scale (EDSS) <6 (MS group) Dutch speaking normal or corrected vision feasible use of computer Exclusion Criteria: relapse < 3 months (MS group) pregnancy relevant comorbidity (thyroid disease, diabetes, other neurological disorders, metabolic diseases, neuro-endocrine tumor(s) severe cognitive disability

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Multiple Sclerosis (MS)<br>People with MS diagnosis, aged 18-55 years, Relapsing Remitting type, EDSS < 6.0, normal vision (if necessary corrected), Dutch speaking. | Behavioral: High-challenging cognitive protocol to provoke stress and (cognitive) fatigue<br>* Baseline measurement is done in two parts: 1) resting for five minutes (no talking, no movement) and 2) speaking at normal pace (2 minutes). This is immediately followed by a measurement of the physiological response variables during the testing, in which the following protocol is performed in the order presented: 1) SDMT-NBack task-SDMT*-NBacktask**, 2) NBack task-SDMT-NBack task-SDMT. Participants will run either sequence to check for effects of the previous testing. During the conduct of the study, it will be ensured that half of the participants in each group followed Sequence 1 and the other half of the group followed Sequence 2. During all these measurements, the participant will sit at a table with a computer on which the tests are performed. *SDMT: Symbol Digit Modalities Test: see description in outcome measures **N-Back Task: see description in outcome measures<br>|
| Healthy Controls (HC)<br>Healthy controls without relevant health conditions (diabetes, thyroid diseases, neurological disorders), non-pregnant, aged 18-55 years, normal vision (if necessary corrected), Dutch speaking. | Behavioral: High-challenging cognitive protocol to provoke stress and (cognitive) fatigue<br>* Baseline measurement is done in two parts: 1) resting for five minutes (no talking, no movement) and 2) speaking at normal pace (2 minutes). This is immediately followed by a measurement of the physiological response variables during the testing, in which the following protocol is performed in the order presented: 1) SDMT-NBack task-SDMT*-NBacktask**, 2) NBack task-SDMT-NBack task-SDMT. Participants will run either sequence to check for effects of the previous testing. During the conduct of the study, it will be ensured that half of the participants in each group followed Sequence 1 and the other half of the group followed Sequence 2. During all these measurements, the participant will sit at a table with a computer on which the tests are performed. *SDMT: Symbol Digit Modalities Test: see description in outcome measures **N-Back Task: see description in outcome measures<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in heart rate variability (time-domain) | ECG monitoring will be done using the MindMedia NEXUS-10MKII.- Heart Rate Variability will be studied in a time- and frequency domain. For the time-domain following measures are studied: 1) the average normal-normal interval; 2) the standard deviation of normal-normal (SDNN); 3) the Root Mean Square of Successive Differences (RMSSD); 4) the percentage of adjacent normal-normal intervals with differences of more than 50miliseconds. (PNN50). | immediately post protocol (approx. 2 hours after baseline) | 
| Change in heart rate variability (frequency-domain) | ECG monitoring will be done using the MindMedia NEXUS-10MKII.- Heart Rate Variability will be studied in a time- and frequency domain. For the frequency domain, the changes in the high frequency (HF) and low frequency (LF) will be studied and analysed. | immediately post protocol (approx. 2 hours after baseline) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Visual Analogue Scale (VAS) Momentary fatigue | Momentary fatigue experienced following the protocol using Visual Analogue Scale (VAS) (minimum 0- maximum 10), higher scores indicate higher fatigue. | immediately post protocol (approx. 2 hours after baseline) | 
| Change in Visual Analogue Scale (VAS) Momentary pain | Momentary pain experienced following the protocol using Visual Analogue Scale (minimum 0- maximum 10), higher scores indicate higher pain. | immediately post protocol (approx. 2 hours after baseline) | 
| Usefulness, Satisfaction, and ease of use Questionnaire (USE) | The USE is a self-report questionnaire in which 30 items in four dimensions (usefulness, ease of use, ease of learning and satisfaction) are answered on a 7-point Likert scale (1 = disagree, 7 = fully agree) and one not -answer option. Higher scores indicate higher satisfaction and usefulness. | post protocol (approx. 2 hours after baseline) | 
| NASA Task Load Index (NASA-TLX) | The NASA-TLX is a self-report questionnaire that measures perceived work-related stress using six dimensions with a focus on mental stress: mental, physical and time-related stress, frustration and execution. The dimensions are assessed on the basis of a semantic differential scale (0-10). The six individual scores are converted to a global score by means of a paired comparison task in which comparison cards are used prior to the assessment. Higher scores indicate higher task load. | post protocol (approx. 2 hours after baseline) | 
| Galvanic Skin Response (GSR) | For the monitoring of the GSR, the Mind Media NEXUS-10MKII will be used. Two electrodes will be placed on the palmar side of the left manus. The first electrode is positioned on the phalanx medialis of the index, the second electrode is positioned on the phalanx medialis of the digitus annulare. As the participants will not be exposed to abrupt changes in stimulus presentation, and no expected or unexpected changes in the environment will be present, the tonic Skin Conductance Level (SCL) will be analysed. | baseline | 
| Galvanic Skin Response (GSR) | For the monitoring of the GSR, the Mind Media NEXUS-10MKII will be used. Two electrodes will be placed on the palmar side of the left manus. The first electrode is positioned on the phalanx medialis of the index, the second electrode is positioned on the phalanx medialis of the digitus annulare. As the participants will not be exposed to abrupt changes in stimulus presentation, and no expected or unexpected changes in the environment will be present, the tonic Skin Conductance Level (SCL) will be analysed, using mean microsiemens. | during protocol (approx. 1 hour after baseline) | 
| Galvanic Skin Response (GSR) | For the monitoring of the GSR, the Mind Media NEXUS-10MKII will be used. Two electrodes will be placed on the palmar side of the left manus. The first electrode is positioned on the phalanx medialis of the index, the second electrode is positioned on the phalanx medialis of the digitus annulare. As the participants will not be exposed to abrupt changes in stimulus presentation, and no expected or unexpected changes in the environment will be present, the tonic Skin Conductance Level (SCL) will be analysed, using mean microsiemens. | immediately post protocol (approx. 2 hours after baseline) | 
| Brain activity | • Electroencephalography (EEG): EEG monitoring will be done using the MindMedia NEXUS-10MKII. Ten20 conductive paste for EEG is used in combination with Ag/AgCl disc electrodes. A positive electrode will be placed on Cz according to the international 10-20 system, a negative electrode will be placed on the left earlobe, and the ground electrode for EEG and ECG measurement will be placed on the right earlobe. EEG measures: - The impact of the cognitive fatigue and stress inducing protocol on alpha, beta, delta, and there frequency bands will be studied. | baseline | 
| Brain activity | • Electroencephalography (EEG): EEG monitoring will be done using the MindMedia NEXUS-10MKII. Ten20 conductive paste for EEG is used in combination with Ag/AgCl disc electrodes. A positive electrode will be placed on Cz according to the international 10-20 system, a negative electrode will be placed on the left earlobe, and the ground electrode for EEG and ECG measurement will be placed on the right earlobe. EEG measures: - The impact of the cognitive fatigue and stress inducing protocol on alpha, beta, delta, and there frequency bands will be studied. | during protocol (approx. 1 hour after baseline) | 
| Brain activity | • Electroencephalography (EEG): EEG monitoring will be done using the MindMedia NEXUS-10MKII. Ten20 conductive paste for EEG is used in combination with Ag/AgCl disc electrodes. A positive electrode will be placed on Cz according to the international 10-20 system, a negative electrode will be placed on the left earlobe, and the ground electrode for EEG and ECG measurement will be placed on the right earlobe. EEG measures: - The impact of the cognitive fatigue and stress inducing protocol on alpha, beta, delta, and there frequency bands will be studied. | immediately post protocol (approx. 2 hours after baseline) | 
| Respiration | Respiration set up: The mind media NEXUS-10 MKII will be used for respiration measurement. An elastic band with sensor will be worn around the trunk at height of the umbilicus. Respiration measures: Data will solely cover mechanical aspects of breathing. Only the respiration rate will be taken into analyses to study relations with previous neurophysiological measures. Also the breathing rate (BRPM) per minute will be analysed. | baseline | 
| Respiration | Respiration set up: The mind media NEXUS-10 MKII will be used for respiration measurement. An elastic band with sensor will be worn around the trunk at height of the umbilicus. Respiration measures: Data will solely cover mechanical aspects of breathing. Only the respiration rate will be taken into analyses to study relations with previous neurophysiological measures. Also the breathing rate (BRPM) per minute will be analysed. | during protocol (approx. 1 hour after baseline) | 
| Respiration | Respiration set up: The mind media NEXUS-10 MKII will be used for respiration measurement. An elastic band with sensor will be worn around the trunk at height of the umbilicus. Respiration measures: Data will solely cover mechanical aspects of breathing. Only the respiration rate will be taken into analyses to study relations with previous neurophysiological measures. Also the breathing rate (BRPM) per minute will be analysed. | immediately post protocol (approx. 2 hours after baseline) | 
| Decline in Symbol Digit Modalities Test | The Symbol Digit Modalities Test (SDMT) Performance The SDMT is frequently used in the normal treatment and follow up of people with MS. Therefore, a customized version for this study is developed. Participants are shown one file with at the top a row as example consisting of symbols with related numbers. Beneath this row, a couple of rows with symbols are shown. The participant has to link the number to the specific symbol according to the example row. This as fast as possible within 90 seconds. Scores A total score consisting of the total amount of correct answers will be determined. The SDMT will be divided in three equal parts of 30 seconds. For part1 part2, and part3 a correct score will be determined. Additionally, a cognitive fatigability score is determined: the difference between part3 versus part1. | immediately post protocol (approx. 2 hours after baseline) | 
| Decline in N-Back Task | The N-Back Task (NBT) Performance: The participants are shown a presentation of a series of letters. The participants have to respond with 'yes' whenever the same letter appeared as two letters previously. The participants perform two versions of this: with a 2- and 1-second interstimulus interval. Scores: A total score consisting of the total amount of correct answers is determined. The NBT is then divided in three equal parts. For part1, part2, and part3, a total correct score is determined. Additionally, a cognitive fatigability score (i.e. difference between part3 and part1) is determined. | immediately post protocol (approx. 2 hours after baseline) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fatigability, cognitive fatigue, cognitive fatigability