Repetitive Transcranial Magnetic Stimulation as Therapy for Apathy in Amyotrophic Lateral Sclerosis

Study Overview
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Brief Summary
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of central and peripheral motor neurons. ALS leads to death usually within 3 to 5 years from the onset of the symptoms. Available treatment can prolong the disease duration but cannot modify the disease course. Apathy is a frequent complication of ALS, affecting up to 30% of patients and affecting negatively the survival. Repetitive Transcranial Magnetic Stimulation (rTMS) is a noninvasive method of modulation of brain plasticity with confirmed beneficial effect on apathy in several neurologic and psychiatric conditions. The purpose of this study is to compare the effectiveness of rTMS in improving the apathy in patients with ALS with placebo stimulation.

Detailed Description
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of central and peripheral motor neurons. ALS leads to death usually within 3 to 5 years from the onset of the symptoms. Available treatment can prolong the disease duration but cannot modify the disease course. Apathy is a frequent complication of ALS, which negatively influences quality of life (caga et al. 2018) and is an independent poor prognostic factor for survival (Caga et al. 2016). Similarly, the depression is also a frequent complication of ALS. Repetitive Transcranial Magnetic Stimulation (rTMS) is a noninvasive method of modulation of brain plasticity with confirmed beneficial effect on apathy in several neurologic and psychiatric conditions like mild cognitive impairment (Padala et al. 2018), stroke (Sasaki et al. 2017), Alzheimer disease (Nguyen et al. 2017) and schizophrenia (Prikryl et al. 2013). The purpose of this study is to compare the effectiveness of rTMS in improving the apathy in patients with ALS with placebo stimulation and - as a secondary outcome - depression in patients with ALS. Intervention will include ten daily sessions of rTMS. In each session 3000 magnetic pulses will be administered over the left dorsolateral prefrontal cortex. Stimulation intensity will equal 120% of the motor threshold value for the right first dorsal interosseus. Assessment of apathy and of depression and daily functioning will be made before and after therapy, as well as two and four weeks later.

Official Title
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A Pilot Study of Repetitive Transcranial Magnetic Stimulation for Improvement of Apathy in Amyotrophic Lateral Sclerosis

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Device: rTMS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of definite or probable ALS according to el Escorial criteria (Brooks et al. 2000) Moderate or severe depression defined as the score in Beck's Depression Inventory ≥20 Mini-Mental State Examination score ≥26 Exclusion Criteria: Psychiatric symptoms, which may negatively influence patient's tolerance and adherence to therapy Respiratory insufficiency and other complications od advanced stages of ALS, which may compromise patient's ability to undergo the study procedure Contraindications for rTMS as listed by the Guidelines of the International Federation of Clinical Neurophysiology (Rossi et al. 2009) i.e. seizure in the past, epilepsy, presence of magnetic material in the reach of magnetic field, pregnancy, likelihood to get pregnant, intracranial electrodes, cardiac pacemaker or intracardiac lines, frequent syncopes

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomly assigned to real or placebo (sham) stimulation.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active rTMS<br>10 hertz (Hz) rTMS will be administered over the left dorsolateral prefrontal cortex. Therapy will include 10 daily sessions (on consecutive week days). In every sessions 3000 magnetic pulses of 120% of the resting motor threshold intensity will be elicited. | Device: rTMS<br>* High frequency rTMS to induce the long term potentiation in the left dorsolateral prefrontal cortex.<br>|
| Sham Comparator: Sham rTMS<br>Sham stimulation will mimic the active one except that the stimulating coil will be held perpendicularly to the scalp, which assures similar impression as the active stimulation but prevents that significant magnetic field will reach brain tissue. | Device: rTMS<br>* High frequency rTMS to induce the long term potentiation in the left dorsolateral prefrontal cortex.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Apathy Evaluation Scale Clinical Version after rTMS, total score, range 18 to 72 with higher values representing a worse outcome | Change from baseline score in Apathy Evaluation Scale Clinical Version to the measurement taken directly after finishing rTMS. | Baseline rTMS, directly (on the same 1 day) after finishing rTMS | 
| Apathy Evaluation Scale Clinical Version first follow up, total score, range 18 to 72 with higher values representing a worse outcome | Change from baseline score in Apathy Evaluation Scale Clinical Version to the measurement taken two weeks after finishing rTMS. | Baseline rTMS, two weeks after finishing rTMS | 
| Apathy Evaluation Scale Clinical Version second follow up, total score, range 18 to 72 with higher values representing a worse outcome | Change from baseline score in Apathy Evaluation Scale Clinical Version to the measurement taken four weeks after finishing rTMS | Baseline rTMS, four weeks after finishing rTMS | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lateral Sclerosis Functional Rating Scale-Revised after rTMS, total score, range 0 to 40 with higher values representing a better outcome | Change from baseline score in Lateral Sclerosis Functional Rating Scale-Revised to the measurement taken directly after finishing rTMS. | Baseline rTMS, directly (on the same 1 day) after finishing rTMS | 
| Lateral Sclerosis Functional Rating Scale-Revised first follow up, total score, range 0 to 40 with higher values representing a better outcome | Change from baseline score in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised to the measurement taken two weeks after finishing rTMS. | Baseline rTMS, two weeks after finishing rTMS | 
| Lateral Sclerosis Functional Rating Scale-Revised second follow up, total score, range 0 to 40 with higher values representing a better outcome | Change from baseline score in Lateral Sclerosis Functional Rating Scale-Revised to the measurement taken directly after finishing rTMS | Baseline rTMS, four weeks after finishing rTMS | 
| Beck's Depression Inventory ater rTMS, total score, range 0 to 63, with higher values representing a worse outcome | Change from baseline score in the Beck's Depression Inventory to the measurement taken directly after finishing rTMS. | Baseline rTMS, directly (on the same 1 day) after finishing rTMS | 
| Beck's Depression Inventory first follow up, total score, range 0 to 63, with higher values representing a worse outcome | Change from baseline score in the Beck's Depression Inventory to the measurement taken two weeks after finishing rTMS. | Baseline rTMS, two weeks after finishing rTMS | 
| Beck's Depression Inventory second follow up, total score, range 0 to 63, with higher values representing a worse outcome | Change from baseline score in the Beck's Depression Inventory to the measurement taken four weeks after finishing rTMS. | Baseline rTMS, four weeks after finishing rTMS | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amyotrophic Lateral Sclerosis, rTMS, apathy, depression