EEG and TMS-based Biomarkers of ALS, MS and FTD

Study Overview
=================
Brief Summary
-----------------
The purpose of this observational study is to improve understanding of the biology of why ALS, MS and FTD have different effects on different people and facilitate better measurement of the disease in future drug testing. To do this, brain and spinal cord neural network functionality will be measured over time, in addition to profiling of movement and non-movement symptoms, in large groups of patients, as well as in a population-based sample of the healthy population. Patterns of dysfunction which relate to patients' diagnosis and coinciding and future symptoms which align with categories of patients with similar prognoses will be investigated and their ability to predict incident patients' symptoms in future will be measured.

Detailed Description
-----------------
The aim of this project is to characterize spatiotemporal patterns of central nervous system dysfunction that correlate with clinical features of ALS, MS and FTD, to provide non-invasive electrophysiological measurements that can be used in a clinical setting to inform stratification of patients in clinical trials, and to provide data driven diagnostic and prognostic biomarkers and objective clinical trial outcome measures. Such dysfunction will be investigated by recording single- and paired-pulse transcranial magnetic stimulation (TMS)-associated electromyography (EMG) during rest and by recording electroencephalography (EEG) during rest and during cognitive-motor tasks.

Official Title
-----------------
Investigation of EEG and TMS-based Biomarkers of Amyotrophic Lateral Sclerosis, Multiple Sclerosis and Frontotemporal Dementia

Conditions
-----------------
Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Multiple Sclerosis

Intervention / Treatment
-----------------
* Procedure: 128 electrode electroencephalography (EEG)
* Procedure: Transcranial magnetic stimulation (TMS)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Age >18 years and able to give informed written or verbal (in the presence of two witnesses) consent. In the case of non-control subjects, a clinical diagnosis of: (i) Probable frontotemporal dementia (FTD) including behavioural variant FTD, semantic dementia or primary progressive aphasia) with supportive brain imaging or known FTD causing genetic mutation (ii) Multiple sclerosis (MS) according to the McDonald criteria (Polman et al., 2011) or (iii) Possible, probable or definite amyotrophic lateral sclerosis (ALS) according to the El Escorial Criteria Revised (Brooks et al. 2000) Exclusion criteria: Any diagnosed neurological/muscular disease other than ALS, MS or FTD Use of neuro- or myo-modulatory medications except riluzole Inability to participate due to disease-related motor symptoms (e.g. inability to sit for the required time or click the mouse to respond) Upper body metallic implants History of seizure disorders in the participant or immediate family members Anxiety-induced fainting Regular migraine Evidence of significant respiratory insufficiency Sleep time >2 hours below normal and/or alcohol consumption the night before data collection (in which case, recording session will be rescheduled).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Controls<br>Individuals from the Irish population with no psychiatric, psychological, neurological or muscular disease diagnosis | Procedure: 128 electrode electroencephalography (EEG)<br>* 128 electrode EEG will be non-invasively recorded from electrodes placed in a montage over the scalp while the participant is resting or performing tasks designed to engage specific cortical motor networks of interest (cognitive, behavioural, motor and sensory)<br>Procedure: Transcranial magnetic stimulation (TMS)<br>* Single and paired pulse TMS protocol will be delivered while surface bipolar EMG is recorded over hand muscles to interrogate corticospinal tract function and cortical motor network component functions<br>|
| Amyotrophic lateral sclerosis patients<br> | Procedure: 128 electrode electroencephalography (EEG)<br>* 128 electrode EEG will be non-invasively recorded from electrodes placed in a montage over the scalp while the participant is resting or performing tasks designed to engage specific cortical motor networks of interest (cognitive, behavioural, motor and sensory)<br>Procedure: Transcranial magnetic stimulation (TMS)<br>* Single and paired pulse TMS protocol will be delivered while surface bipolar EMG is recorded over hand muscles to interrogate corticospinal tract function and cortical motor network component functions<br>|
| Multiple sclerosis patients<br> | Procedure: 128 electrode electroencephalography (EEG)<br>* 128 electrode EEG will be non-invasively recorded from electrodes placed in a montage over the scalp while the participant is resting or performing tasks designed to engage specific cortical motor networks of interest (cognitive, behavioural, motor and sensory)<br>Procedure: Transcranial magnetic stimulation (TMS)<br>* Single and paired pulse TMS protocol will be delivered while surface bipolar EMG is recorded over hand muscles to interrogate corticospinal tract function and cortical motor network component functions<br>|
| Frontotemporal dementia patients<br> | Procedure: 128 electrode electroencephalography (EEG)<br>* 128 electrode EEG will be non-invasively recorded from electrodes placed in a montage over the scalp while the participant is resting or performing tasks designed to engage specific cortical motor networks of interest (cognitive, behavioural, motor and sensory)<br>Procedure: Transcranial magnetic stimulation (TMS)<br>* Single and paired pulse TMS protocol will be delivered while surface bipolar EMG is recorded over hand muscles to interrogate corticospinal tract function and cortical motor network component functions<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diagnosis-related difference in EEG or TMS measurements | Differences in single or paired pulse TMS measures or time and/or frequency domain EEG characteristics between those within each patient cohort and controls | Baseline recording | 
| Prognosis-related EEG or TMS measurements | Patient cohort single or paired pulse TMS measures or time and/or frequency domain EEG characteristics which show significant correlation to cognitive, behavioural, motor and/or sensory task performance, to disease duration or to survival time | Baseline recording | 
| Diagnosis-related changes in EEG or TMS measurements | Differences in rate of change (slope) across time of single or paired pulse TMS measures or time and/or frequency domain EEG characteristics between those within each patient cohort relative to controls | Baseline to final visit assessed up to 2 years after baseline | 
| Prognosis-related changes in EEG or TMS measurements | Rates of change (slope) across time of patient cohort single or paired pulse TMS measures or time and/or frequency domain EEG characteristics which show significant correlation to cognitive, behavioural, motor and/or sensory task performance, to disease duration or to survival time | Baseline to final visit assessed up to 2 years after baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diagnosis-specific changes in EEG or TMS measurements | Differences in rate of change (slope) across time of single or paired pulse TMS measures or time and/or frequency domain EEG characteristics between patient cohorts | Baseline to final visit assessed up to 2 years after baseline | 
| Diagnosis-specific difference in EEG or TMS measurements | Differences in single or paired pulse TMS measures or time and/or frequency domain EEG characteristics between patient cohorts | Baseline recording | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
EEG, TMS, Neurodegeneration, Network, Electrophysiology, Biomarkers, Cognitive, Behavioural, Motor