Brain Stimulation for Neurological Patients

Study Overview
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Brief Summary
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This is a prospective double-blind randomized placebo-controlled crossover clinical trial

Official Title
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Brain Stimulation for Neurological Patients

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Device: NEUROLITH


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinically stable patients with probable Alzheimer's Disease (Diagnosis according to ICD-10 Criteria (F00)) At least 3 months of stable antidementive therapy or no antidementive therapy necessary Signed written informed consent Monthly pregnancy test for women in childbearing years Age >= 18 years Exclusion Criteria: Non-compliance with the protocol Pregnant or breastfeeding women Relevant intracerebral pathology unrelated to the Alzheimers's disease (e.g. Brain tumor) Hemophilia or other blood clotting disorders Cortisone treatment within the last 6 weeks before first treatment Thrombosis

Ages Eligible for Study
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Minimum Age: 18 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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>NEUROLITH Cycle 1: Active treatment Cycle 2: Sham treatment | Device: NEUROLITH<br>* transcranial pulse stimulation (TPS)<br>* Other names: TPS;|
| Experimental: Group B<br>NEUROLITH Cycle 1: Sham treatment Cycle 2: Active treatment | Device: NEUROLITH<br>* transcranial pulse stimulation (TPS)<br>* Other names: TPS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Consortium to Establish a Registry for Alzheimer's Disease (CERAD) - Corrected Total Score | CERAD stands for The Consortium to Establish a Registry for Alzheimer's Disease. The CERAD was funded by the National Institute on Aging in 1986 to develop standardized, validated measures for the assessment of Alzheimer's disease (Fillenbaum 2008). CERAD is a cognitive test battery which is normalized for age, gender and education (Morris 1988). The CERAD total score (Chandler 2005) is a good measure for Alzheimer's Disease (Ehrensperger 2010, Rossetti 2010, Seo 2010, Hallikainen 2013). The CERAD total score is a scale from 0 to 100 with 100 meaning normal cognitive ability and 0 meaning severe cognitive impairment. | month 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Alzheimer's Disease Assessment Scale (ADAS) | Cognitive test. The Alzheimer's Disease Assessment Scale (ADAS) was designed to evaluate the severity of cognitive and noncognitive behavioral dysfunctions characteristic of persons with Alzheimer's disease (Rosen 1984). It consists of 21 items. Its sensitivity seems limited in mild AD (Irizarry 2008) but it is commonly used with AD intervention studies. The ADAS total score (ADASUM) ranges from 0 to 120 and consists of two subscales, the ADAS-COG with 70 possible points and the ADAS-NonCog with 50 possible points. In both subscales and total scale 0 points means healthy and the highest score means severe impairment. The total score ADASUM is the sum of both subscales. Its cognition subscale (ADAS-COG) is a standard tool in pivotal clinical trials to detect therapeutic efficacy in cognition (Robert 2010). The ADAS-COG includes 11 items assessing the several cognitive domains. | immediately post-treatment | 
| Alzheimer's Disease Assessment Scale (ADAS) | Cognitive test. The Alzheimer's Disease Assessment Scale (ADAS) was designed to evaluate the severity of cognitive and noncognitive behavioral dysfunctions characteristic of persons with Alzheimer's disease (Rosen 1984). It consists of 21 items. Its sensitivity seems limited in mild AD (Irizarry 2008) but it is commonly used with AD intervention studies. The ADAS total score (ADASUM) ranges from 0 to 120 and consists of two subscales, the ADAS-COG with 70 possible points and the ADAS-NonCog with 50 possible points. In both subscales and total scale 0 points means healthy and the highest score means severe impairment. The total score ADASUM is the sum of both subscales. Its cognition subscale (ADAS-COG) is a standard tool in pivotal clinical trials to detect therapeutic efficacy in cognition (Robert 2010). The ADAS-COG includes 11 items assessing the several cognitive domains. | month 1 | 
| Alzheimer's Disease Assessment Scale (ADAS) | Cognitive test. The Alzheimer's Disease Assessment Scale (ADAS) was designed to evaluate the severity of cognitive and noncognitive behavioral dysfunctions characteristic of persons with Alzheimer's disease (Rosen 1984). It consists of 21 items. Its sensitivity seems limited in mild AD (Irizarry 2008) but it is commonly used with AD intervention studies. The ADAS total score (ADASUM) ranges from 0 to 120 and consists of two subscales, the ADAS-COG with 70 possible points and the ADAS-NonCog with 50 possible points. In both subscales and total scale 0 points means healthy and the highest score means severe impairment. The total score ADASUM is the sum of both subscales. Its cognition subscale (ADAS-COG) is a standard tool in pivotal clinical trials to detect therapeutic efficacy in cognition (Robert 2010). The ADAS-COG includes 11 items assessing the several cognitive domains. | month 3 | 
| Neuropsychological Test Battery Vienna (NTBV) | The Neuropsychological Test Battery Vienna (NTBV) ist a cognitive test, which was created to detect Alzheimer's Disease (Lehrner 2007). | immediately post-treatment | 
| Neuropsychological Test Battery Vienna (NTBV) | Cognitive test | month 1 | 
| Neuropsychological Test Battery Vienna (NTBV) | Cognitive test | month 3 | 
| CERAD | Cognitive test | immediately post-treatment | 
| CERAD | Cognitive test | month 1 | 
| CERAD | Cognitive test | month 3 | 
| Clock drawing test | The clock drawing test shows the visuoconstructive skills (Shulman 1986). The subject is asked to draw the face of a clock with all numbers and to set the hands for a specified time (hh:mm). Scores range from 0 (worst) to 7 (best). | immediately post-treatment | 
| Clock drawing test | Clock drawing test | month 1 | 
| Clock drawing test | Clock drawing test | month 3 | 
| Forgetfulness assessment inventory (FAI) | FAI stands for Forgetfulness Assessment Inventory. The Forgetfulness Assessment Inventory is a questionnaire. Kogler et al (2013) developed the forgetfulness assessment inventory FAI (German: Skala zur Erfassung der Gedächtnisleistung - SEG) to evaluate subjective complaints regarding everyday memory problems. Lehrner et al. (2014) validated the test. The FAI consists of 16 items to measure subjective memory problems in daily life based on a Likert scale. The FAI focuses on the subjective evaluation of memory problems, particularly in relation to episodic memory, which has been found to be very sensitive in the early detection of mild cognitive impairment and AD (Lehrner 2014). This questionnaire is supposed to be completed by the patient as well as by a person familiar with the patient. The total score ranges from 0 to 80. Higher scores reflect poorer subjective functioning and greater complaints. | immediately post-treatment | 
| Forgetfulness assessment inventory (FAI) | FAI stands for Forgetfulness Assessment Inventory. The Forgetfulness Assessment Inventory is a questionnaire. Kogler et al (2013) developed the forgetfulness assessment inventory FAI (German: Skala zur Erfassung der Gedächtnisleistung - SEG) to evaluate subjective complaints regarding everyday memory problems. Lehrner et al. (2014) validated the test. The FAI consists of 16 items to measure subjective memory problems in daily life based on a Likert scale. The FAI focuses on the subjective evaluation of memory problems, particularly in relation to episodic memory, which has been found to be very sensitive in the early detection of mild cognitive impairment and AD (Lehrner 2014). This questionnaire is supposed to be completed by the patient as well as by a person familiar with the patient. The total score ranges from 0 to 80. Higher scores reflect poorer subjective functioning and greater complaints. | month 1 | 
| Forgetfulness assessment inventory (FAI) | FAI stands for Forgetfulness Assessment Inventory. The Forgetfulness Assessment Inventory is a questionnaire. Kogler et al (2013) developed the forgetfulness assessment inventory FAI (German: Skala zur Erfassung der Gedächtnisleistung - SEG) to evaluate subjective complaints regarding everyday memory problems. Lehrner et al. (2014) validated the test. The FAI consists of 16 items to measure subjective memory problems in daily life based on a Likert scale. The FAI focuses on the subjective evaluation of memory problems, particularly in relation to episodic memory, which has been found to be very sensitive in the early detection of mild cognitive impairment and AD (Lehrner 2014). This questionnaire is supposed to be completed by the patient as well as by a person familiar with the patient. The total score ranges from 0 to 80. Higher scores reflect poorer subjective functioning and greater complaints. | month 3 | 
| Instrumental Activities of Daily Living Scale (IADL) - Patient | IADL stands for Instrumental Activities of Daily Living. Lawton's Instrumental Activities of Daily Living Scale (IADL) is an instrument to assess independent living skills (Lawton 1969). This questionnaire is supposed to be completed by the patient as well as by a person familiar with the patient. There are 8 domains of function measured with the Lawton IADL scale: Telephone, Shopping, Food preparation, Housekeeping, Laundry, Mode of transportation, Medication, Finances. The Total Score is a sum of all domains. The total score ranges from 0 (low function, dependent) to 8 (high function, independent). For male patients the highest possible score is 5 (due to expected zero scores for food preparation, housekeeping, and laundry). | immediately post-treatment | 
| IADL- Patient | IADL stands for Instrumental Activities of Daily Living. Lawton's Instrumental Activities of Daily Living Scale (IADL) is an instrument to assess independent living skills (Lawton 1969). This questionnaire is supposed to be completed by the patient as well as by a person familiar with the patient. There are 8 domains of function measured with the Lawton IADL scale: Telephone, Shopping, Food preparation, Housekeeping, Laundry, Mode of transportation, Medication, Finances. The Total Score is a sum of all domains. The total score ranges from 0 (low function, dependent) to 8 (high function, independent). For male patients the highest possible score is 5 (due to expected zero scores for food preparation, housekeeping, and laundry). | month 1 | 
| IADL- Patient | IADL stands for Instrumental Activities of Daily Living. Lawton's Instrumental Activities of Daily Living Scale (IADL) is an instrument to assess independent living skills (Lawton 1969). This questionnaire is supposed to be completed by the patient as well as by a person familiar with the patient. There are 8 domains of function measured with the Lawton IADL scale: Telephone, Shopping, Food preparation, Housekeeping, Laundry, Mode of transportation, Medication, Finances. The Total Score is a sum of all domains. The total score ranges from 0 (low function, dependent) to 8 (high function, independent). For male patients the highest possible score is 5 (due to expected zero scores for food preparation, housekeeping, and laundry). | month 3 | 
| Beck Depression Inventory (BDI) | BDI stands for the Beck Depression Inventory. The Beck Depression Inventory (BDI) measures the severity of depression (Beck 1961). It is a 21-item questionnaire for self-evaluation with 0-3 scores per item. The total score is the sum of all items. It ranges from 0 (normal state) to 63 (severe depression). | immediately post-treatment | 
| Beck Depression Inventory (BDI) | BDI stands for the Beck Depression Inventory. The Beck Depression Inventory (BDI) measures the severity of depression (Beck 1961). It is a 21-item questionnaire for self-evaluation with 0-3 scores per item. The total score is the sum of all items. It ranges from 0 (normal state) to 63 (severe depression). | month 1 | 
| Beck Depression Inventory (BDI) | BDI stands for the Beck Depression Inventory. The Beck Depression Inventory (BDI) measures the severity of depression (Beck 1961). It is a 21-item questionnaire for self-evaluation with 0-3 scores per item. The total score is the sum of all items. It ranges from 0 (normal state) to 63 (severe depression). | month 3 | 
| Prosopagnosia index (PI20) | PI20 stands for the 20-item prosopagnosia index. The PI20 is a self-report instrument for identifying developmental prosopagnosia, also called face blindness. Patients indicate the extent to which 20 statements describe their face recognition experiences. Each statement is scored on a five-point scale. The total score is the sum of all scores. It ranges from 0 to 100. Higher scores reflect impairment to recognize faces. | immediately post-treatment | 
| Prosopagnosia index (PI20) | PI20 stands for the 20-item prosopagnosia index. The PI20 is a self-report instrument for identifying developmental prosopagnosia, also called face blindness. Patients indicate the extent to which 20 statements describe their face recognition experiences. Each statement is scored on a five-point scale. The total score is the sum of all scores. It ranges from 0 to 100. Higher scores reflect impairment to recognize faces. | month 1 | 
| Prosopagnosia index (PI20) | PI20 stands for the 20-item prosopagnosia index. The PI20 is a self-report instrument for identifying developmental prosopagnosia, also called face blindness. Patients indicate the extent to which 20 statements describe their face recognition experiences. Each statement is scored on a five-point scale. The total score is the sum of all scores. It ranges from 0 to 100. Higher scores reflect impairment to recognize faces. | month 3 | 
| Neuropsychiatric Inventory (NPI) (Care Taker) | The NPI stands for Neuropsychiatric Inventory. It is a questionnaire for care taker. The Neuropsychiatric Inventory (NPI) was developed to provide a means of assessing neuropsychiatric symptoms and psychopathology of patients with Alzheimer's disease and other neurodegenerative disorders (Cummings 1997). Ten behavioral and two neurovegetative areas are included in the NPI. The NPI is based on responses from an informed caregiver, preferably one living with the patient. A caregiver can be defined as a person spending at least 4 hours per day at least 4 days per week with the patient and who is knowledgeable about the patient's daytime and nighttime behaviors. The total NPI score is the sum of all items. It varies from 0 to 120 for the behavioral domains and from 0 to 144 for all 12 domains. | immediately post-treatment | 
| Neuropsychiatric Inventory (NPI) (Care Taker) | The NPI stands for Neuropsychiatric Inventory. It is a questionnaire for care taker. The Neuropsychiatric Inventory (NPI) was developed to provide a means of assessing neuropsychiatric symptoms and psychopathology of patients with Alzheimer's disease and other neurodegenerative disorders (Cummings 1997). Ten behavioral and two neurovegetative areas are included in the NPI. The NPI is based on responses from an informed caregiver, preferably one living with the patient. A caregiver can be defined as a person spending at least 4 hours per day at least 4 days per week with the patient and who is knowledgeable about the patient's daytime and nighttime behaviors. The total NPI score is the sum of all items. It varies from 0 to 120 for the behavioral domains and from 0 to 144 for all 12 domains. | month 1 | 
| Neuropsychiatric Inventory (NPI) (Care Taker) | The NPI stands for Neuropsychiatric Inventory. It is a questionnaire for care taker. The Neuropsychiatric Inventory (NPI) was developed to provide a means of assessing neuropsychiatric symptoms and psychopathology of patients with Alzheimer's disease and other neurodegenerative disorders (Cummings 1997). Ten behavioral and two neurovegetative areas are included in the NPI. The NPI is based on responses from an informed caregiver, preferably one living with the patient. A caregiver can be defined as a person spending at least 4 hours per day at least 4 days per week with the patient and who is knowledgeable about the patient's daytime and nighttime behaviors. The total NPI score is the sum of all items. It varies from 0 to 120 for the behavioral domains and from 0 to 144 for all 12 domains. | month 3 | 
| IADL (Care Taker) | Questionnaire for care taker. IADL stands for Instrumental Activities of Daily Living. Lawton's Instrumental Activities of Daily Living Scale (IADL) is an instrument to assess independent living skills (Lawton 1969). This questionnaire is supposed to be completed by the patient as well as by a person familiar with the patient. There are 8 domains of function measured with the Lawton IADL scale: Telephone, Shopping, Food preparation, Housekeeping, Laundry, Mode of transportation, Medication, Finances. The Total Score is a sum of all domains. The total score ranges from 0 (low function, dependent) to 8 (high function, independent). For male patients the highest possible score is 5 (due to expected zero scores for food preparation, housekeeping, and laundry). | immediately post-treatment | 
| IADL (Care Taker) | Questionnaire for care taker. IADL stands for Instrumental Activities of Daily Living. Lawton's Instrumental Activities of Daily Living Scale (IADL) is an instrument to assess independent living skills (Lawton 1969). This questionnaire is supposed to be completed by the patient as well as by a person familiar with the patient. There are 8 domains of function measured with the Lawton IADL scale: Telephone, Shopping, Food preparation, Housekeeping, Laundry, Mode of transportation, Medication, Finances. The Total Score is a sum of all domains. The total score ranges from 0 (low function, dependent) to 8 (high function, independent). For male patients the highest possible score is 5 (due to expected zero scores for food preparation, housekeeping, and laundry). | month 1 | 
| IADL (Care Taker) | Questionnaire for care taker. IADL stands for Instrumental Activities of Daily Living. Lawton's Instrumental Activities of Daily Living Scale (IADL) is an instrument to assess independent living skills (Lawton 1969). This questionnaire is supposed to be completed by the patient as well as by a person familiar with the patient. There are 8 domains of function measured with the Lawton IADL scale: Telephone, Shopping, Food preparation, Housekeeping, Laundry, Mode of transportation, Medication, Finances. The Total Score is a sum of all domains. The total score ranges from 0 (low function, dependent) to 8 (high function, independent). For male patients the highest possible score is 5 (due to expected zero scores for food preparation, housekeeping, and laundry). | month 3 | 
| Bayer Activities of Daily Living Scale (B-ADL) | The B-ADL scale is used to assess deficits in the performance of everyday activities. The scale's main target group is community dwelling patients who suffer from mild cognitive impairment or mild-to-moderate dementia. It comprises 25 items. Each item is scored from 1 (no difficulties at all) to 10 (always difficulties). The global B-ADL score is the arithmetic mean of all items. | [ Time Frame: immediately post-treatment ] | 
| Bayer Activities of Daily Living Scale (B-ADL) | The B-ADL scale is used to assess deficits in the performance of everyday activities. The scale's main target group is community dwelling patients who suffer from mild cognitive impairment or mild-to-moderate dementia. It comprises 25 items. Each item is scored from 1 (no difficulties at all) to 10 (always difficulties). The global B-ADL score is the arithmetic mean of all items. | [ Time Frame: month 1 ] | 
| Bayer Activities of Daily Living Scale (B-ADL) | The B-ADL scale is used to assess deficits in the performance of everyday activities. The scale's main target group is community dwelling patients who suffer from mild cognitive impairment or mild-to-moderate dementia. It comprises 25 items. Each item is scored from 1 (no difficulties at all) to 10 (always difficulties). The global B-ADL score is the arithmetic mean of all items. | [ Time Frame: month 3 ] | 
| Geriatric Depression Scale - short form (GDS-15) | The Geriatric Depression Scale (GDS) is a questionnaire to assess depression in the elderly population. This scale generates self-evaluation scores concerning various aspects with relevance for the depressive disease (e.g. mood, drive, anxiety). The short form contains 15 items. The GDS-15 score ranges from 0 (normal state) to 15 (severe depression). | [ Time Frame: immediately post-treatment ] | 
| Geriatric Depression Scale - short form (GDS-15) | The Geriatric Depression Scale (GDS) is a questionnaire to assess depression in the elderly population. This scale generates self-evaluation scores concerning various aspects with relevance for the depressive disease (e.g. mood, drive, anxiety). The short form contains 15 items. The GDS-15 score ranges from 0 (normal state) to 15 (severe depression). | [ Time Frame: month 1 ] | 
| Geriatric Depression Scale - short form (GDS-15) | The Geriatric Depression Scale (GDS) is a questionnaire to assess depression in the elderly population. This scale generates self-evaluation scores concerning various aspects with relevance for the depressive disease (e.g. mood, drive, anxiety). The short form contains 15 items. The GDS-15 score ranges from 0 (normal state) to 15 (severe depression). | [ Time Frame: month 3 ] | 
| Leisure Behavior (FZV; German: Freizeitverhalten) | The leisure behavior questionnaire has 25 items covering the following activities: information / entertainment, active movement, social interactions, creative activities, church / cultural / educational activities. The frequency of each activity is rated on a Likert-Scale from 0 (never) to 6 (daily). The total score (0-6) is calculated as the average of all 25 items. | [ Time Frame: immediately post-treatment ] | 
| Leisure Behavior (FZV; German: Freizeitverhalten) | The leisure behavior questionnaire has 25 items covering the following activities: information / entertainment, active movement, social interactions, creative activities, church / cultural / educational activities. The frequency of each activity is rated on a Likert-Scale from 0 (never) to 6 (daily). The total score (0-6) is calculated as the average of all 25 items. | [ Time Frame: month 1 ] | 
| Leisure Behavior (FZV; German: Freizeitverhalten) | The leisure behavior questionnaire has 25 items covering the following activities: information / entertainment, active movement, social interactions, creative activities, church / cultural / educational activities. The frequency of each activity is rated on a Likert-Scale from 0 (never) to 6 (daily). The total score (0-6) is calculated as the average of all 25 items. | [ Time Frame: month 3 ] | 
| anatomical Magnetic Resonance Imaging (MRI) | 3 Tesla Magnetic Resonance Imaging (MRI) for safety reasons: no bleeding or anatomical changes to the brain. | immediately post-treatment | 
| functional Magnetic Resonance Imaging (fMRI) | 3 Tesla functional Magnetic Resonance Imaging (MRI) to analyze brain activation and connectivity after TPS. This will be done according to Sperling 2001. | immediately post-treatment |