Effect of Transcranial Random Noise (tRNS) for Early Alzheimer's Disease

Study Overview
=================
Brief Summary
-----------------
To investigate the treatment effect of Transcranial random noise (tRNS) on Alzheimer patients, and the underlying neural mechanism by EEG.

Detailed Description
-----------------
All patients underwent a medical evaluation that included physical examination and routine laboratory studies before and after Transcranial random noise (tRNS) treatment. Upon meeting the inclusion criteria and providing informed consent, each participant will complete a series of cognitive assessments and tRNS treatments at the First Affiliated Hospital of AnHui medical university. Patients were randomly allocated to tRNS group and the sham group. There are about 20 patients in each group. For the all patients, allocation was by coin toss. Patients were studied using a double-blind design. Study participants, clinical raters, and all personnel responsible for the clinical care of the patient remained masked to allocated condition and allocation parameters. Only tRNS administrators had access to the randomization list; they had minimal contact with the patients, and no role in cognitive and synptom assessments. Each patient would be treated for continuous 14 days by tRNS. The stimulation electrodes were arranged in a 4 × 1 ring at AFz, FCz, F7, C5 and F3, with the central electrode producing a random alternating current of 1.5ma and the surrounding 4 electrodes producing 1/4 of the current of the central electrode. At 100-640 Hz tRNS, participants had a mean interpeak-to-peak stimulation intensity of 1.5mA. Under the sham conditions, 100-640 Hz tRNS were delivered only during the ascent and descent phases (30 seconds); No current was transmitted during the 30-minute intervention. The tRNS stimulation lasted for 30 minutes, which is common in cognitive neuroscience research. Before the tRNS treatment, a series of cognitive assessments and neuropsychological tests were obtained by a trained investigator to assess baseline. Each assessment will involve a set of assessment tools, the associative memory as the primary outcome measure and various other tasks and questionnaires to measure cognition(including MoCA,MMSE, DS, Stroop test, TMT, BNT-30, VFT, CDT,JLOT. Form H,HVOT), memory (CAVLT, LMT), emotion(HAMA-17,HAMD-14,GDS-30), behavioral and psychological symptoms(NPI), and treatment tolerability. All the tests are conducted in two days. The patient received resting EEG data collection. After the last treatment, the MoCA, and associative memory were obtained, as well as the Global Index of Safety to assess adverse events of the treatment. Patients were instructed to focus their answers on the past 14 days. The patients had also receiving a battery measure of neuropsychological tests, resting EEG. Two month after the last treatment, participants were interviewed to obtain the same assessment as before. They were instructed to focus their answers on the past months.

Official Title
-----------------
Investigating the Effect of Transcranial Random Noise (tRNS) add-on Treatment for Early Alzheimer's Disease

Conditions
-----------------
Transcranial Random Noise, Electroencephalography, Alzheimer Disease

Intervention / Treatment
-----------------
* Device: High frequency transcranial random noise
* Device: Sham high frequency transcranial random noise


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject diagnosed with early Alzheimer's disease or related diseases according to NINCDS-ACDRADA criteria. Subjects must have a MMSE score between 10 and 27,indicating mild cognitive impairment or dementia CDR score ≤ 2 Subject under treatment by IAChE for at least 3 months. psychotropic treatments are tolerated if they were administered and unchanged for at least 3 months Exclusion Criteria: CDR > 2 Any history or clinical signs of other severe psychiatric illnesses (like major depression,psychosis or obsessive compulsive disorder). History of head injury,stroke,or other neurologic disease. Organic brain defects on T1 or T2 images. History of seizures or unexplained loss of consciousness. Implanted pacemaker,medication pump,vagal stimulator,deep brain stimulator. Family history of medication refractory epilepsy. History of substance abuse within the last 6 months.

Ages Eligible for Study
-----------------
Minimum Age: 45 Years
Maximum Age: 80 Years

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

Accepts Healthy Volunteers
-----------------
No

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Transcranial random noise-Real<br>Participants will receive real tRNS once daily for two weeks | Device: High frequency transcranial random noise<br>* High frequency tRNS is described as a non-invasive form of brain stimulation that uses a low-intensity, alternating current applied directly to the head through scalp electrodes.<br>|
| Sham Comparator: Transcranial random noise-Sham<br>Participants will receive sham tRNS once daily for two weeks | Device: Sham high frequency transcranial random noise<br>* In the sham condition, tRNS was delivered only during the ramp-up and ramp-down periods (30s); no current was delivered during the 30-minute intervention.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Alzheimers Disease Assessment Scale Cognitive section(ADAS-Cog) | The changes in Alzheimers Disease Assessment Scale Cognitive section (ADAS-Cog) will constitute the major research outcome measure used to assess response to Transcranial Random Noise (tRNS). The ADAS-Cog scale is a scale used for clinical assessment of dementia patients with some memory efficiency tests, which can be used as an objective assessment of memory. The scale is considered a tool capable of providing a specific assessment of the severity of cognitive and non-cognitive behavioral impairments in people with Alzheimer's disease or dementia. The advantage of the ADAS-Cog compared to other scales used in the same clinical area is that its score quantifies clinical and impressionistic aspects of the patient assessed by the examiner, as well as objectively defined cognitive characteristics. The higher the ADAS-Cog score, the worse the cognitive function. The minimum value is 0 and the maximum is 86. | baseline, 2 weeks and 8 weeks after treatment | 
| Associative Memory | The changes in Associative Memory will constitute the major research outcome measure used to assess response to tRNS. The associative memory test uses facial cue word recall. The subjects memorized 20 photos of faces displayed on a screen in gray scale for 4 seconds each. When each card was presented, a common word appeared alongside the face. The subjects had to remember associations between faces and words by association. After a delay of about a minute after the study ended, the subjects were shown 12 of the same faces in different random orders, instructing them to recall the words that appeared with each face during the study. Recorded the correct number of words each face recalled. The faces were taken from a database of 24 amateur models. Each test format included only male or female faces. | baseline, 2 weeks and 8 weeks after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The changes in MMSE(Mini Mental State Examination) | The changes in MMSE will constitute the secondary research outcome. The full name of MMSE is mini-mental state examination, and the scale consists of 30 subject, include the following seven aspects: time orientation, place orientation,immediate memory,attention and calculation,delay memory,language, visual space. One point is awarded for each question correctly answered during MMSE evaluation. If subject give the wrong answer or don't know answe he/she awarded 0 score, scope of scale score of 0 to 30 points. The higher the score, the better. In this study, changes in MMSE scores before and after treatment were used as secondary observations,we hoped that scores would increase after treatment. | baseline, 2 weeks and 8 weeks after treatment | 
| DST (Digital Span Test; Forward and Backward) | The changes in DST will constitute the secondary research outcome. Digital span test (DST) was commonly used to evaluate attention ability and instantaneous memory ability. There are two types of test: forward(0-14) and backward(0-13). In the forward test, the subjects were asked to retell the the digits immediately after hearing it untilthey could not be repeated correctly.In backward test, the subjects were asked to repeat a set of numbers in reverse order until they could not be repeated correctly. The length of the last set of Numbers correctly repeated by the subjects was the final score, forward and backward are counted separately. The higher the score, the better. In this study, we hoped that scores would increase after treatment. | baseline, 2 weeks and 8 weeks after treatment | 
| TMT (Trail Making Test) | The changes in TMT will constitute the secondary research outcome. The Trail Making Test (TMT) is divided into two parts, part A and part B. Part A requires the subject to connect 25 Numbers on the paper in sequence, and partB requires the subject to connect 25 Numbers of different colors alternately in sequence. The time it takes for the subject to complete all the Numbers is the subject's final score.In this study, we hoped that scores would decrease after treatment. | baseline, 2 weeks and 8 weeks after treatment | 
| HAMD (Hamilton Depression Scale) | The changes in HAMD will constitute the secondary research outcome. Hamilton Depression Scale (HAMD) compiled by Hamilton in 1960, is the most common clinical to assess Depression Scale. In this study, 17 versions were selected, and there were 17 questions. The subjects were assessed for their depression in the past week. Each question scored between 0 and 4 points.Higher scores indicate more depressive symptoms. The severity of the disease and the therapeutic effect can be evaluated after treatment. In this study, we hoped that scores would decrease after treatment | baseline, 2 weeks and 8 weeks after treatment | 
| HAMA (Hamilton Anxiety Scale) | The changes in HAMA will constitute the secondary research outcome. Hamilton Anxiety Scale (HAMA) was compiled by Hamilton in 1959.It was one of the most commonly used scales in psychiatric clinic, including 14 items. It is often used in clinical diagnosis and degree classification of anxiety disorder. The subjects were assessed for their anxiety in the past week. Each question scored between 0 and 4 points. The higher the score, the more symptoms of anxiety. The severity of the disease and the therapeutic effect can be evaluated after treatment. In this study, we hoped that scores would decrease after treatment. | baseline, 2 weeks and 8 weeks after treatment | 
| NPI (Neuropsychiatric Inventory) | The changes NPI will constitute the secondary research outcome. The Neuropsychology Scale (NPI) evaluates 12 neuropsychiatric disorders which included 10 neuropsychiatric symptoms and 2 autonomic neurological symptoms based on the caregiver's perception of the patient's behavior and the perceived distress. Each item was evaluated for its occurrence frequency (1-4 points) and severity (1-3 points). The frequency and severity were multiplied to obtain the score (0-12 points) of each item.The patient's assessment rating ranges from 0 to 144, and the caregiver's distress rating score is 0 to 60. The lower the score, the lighter the symptoms, and we expect the score to go down after treatment. | baseline, 2 weeks and 8 weeks after treatment | 
| changes in Montreal Cognitive Assessment (MoCA) | The changes in MoCA will constitute assess response to tRNS the secondary research outcome measure used to.MoCA was developed by Nasreddine et al. based on clinical experience and reference to the MMSE cognitive items and scores, and the final version was finalized in November 2004. We adopted a localized version (Mandarin version#includes 2 alternative versions) in line with the Chinese cultural background.It includes 11 inspection items in 8 cognitive fields, including visual structure skills, executive function, naming, attention and calculation, language, abstract thinking, memory, and orientation. With a total score of 30 or more than 26, it is normal. Anyone who has been education for less than 12 years will need to add one point to his final score. The final score of the higher the better, and we hope the subjects' scores will improve after treatment | baseline, 2 weeks and 8 weeks after treatment | 
| GDS(Geriatric depression scale) | The changes in GDS will constitute assess response to tRNS the secondary research outcome measure.The Geriatric Depression Scale (GDS) was created in 1982 by Brank et al. and is dedicated to screening for depression in the elderly. The most suitable feelings for the elderly in the past week were evaluated.There are 30 items in the scale, the total score is 30 points. The higher the score, the more obvious the depressive symptoms. It is generally considered that less than 10 points is normal.And we hope the subjects' scores will decrease after treatment. | baseline, 2 weeks and 8 weeks after treatment | 
| JLOT(Judgment of line Judgment of line orientation test orientation test) | The changes in JLOT (Judgment of line Judgment of line orientation test orientation test) will constitute assess response to tRNS the secondary research outcome measure.The JLOT test was determined by Benton et al. in 1994. There are two versions of H and V. The difference is that the order in which the pictures are presented is different. Each version contains 35 images, of which the official test consists of 30 images, and the other 5 images are for the participants to learn. The final score is the correct number of subjects to answer, the full score is 30 points, the higher the score, the better the space perception ability of the subject.We hope the subjects' scores will improve after treatment. | baseline, 2 weeks and 8 weeks after treatment | 
| HVOT(Hooper visual organization test Hooper visual organization test) | The changes in HVOT(Hooper visual organization test Hooper visual organization test) will constitute assess response to tRNS the secondary research outcome measure.HVOT is a cognitive test used to evaluate the perceived structure of the subject. It consists of 30 items#and each question is 1 point and the total score is 30 points. The final score is the correct number of subjects to answer, the full score is 30 points, the higher the score, the better the space perception ability of the subject.We hope the subjects' scores will improve after treatment. | baseline, 2 weeks and 8 weeks after treatment | 
| The Stroop color test | The changes in The Stroop color test will constitute assess response to tRNS the secondary research outcome measure.The Stroop color word test was developed by Stroop in 1935 and is used to evaluate the attention function of the subject. The subject is required to correctly read the target color on the stimulus card and record the completion time. The final completion time is the score of the participant. The shorter the time used, the better the performance of the subjects. We expect the participants to spend less time after the real stimulation. | baseline, 2 weeks and 8 weeks after treatment | 
| EEG power in the typical spectral bands | EEG recordings were obtained from each subject based on 64 electrode locations of the International 10-20 system (sampling frequency 1000Hz). The recorded EEG data were filtered with a second order band-pass Butterworth filter with cutoff frequencies of 0.5 and 60 Hz. For each testing condition, data with muscular, ocular and other types of artifacts were manually discarded and 60 seconds of stationary EEG signal were selected. Only these segments were accepted for further analysis. The analysis in the frequency domain was performed using Welch's periodogram method. Recordings were segmented into tracts of 10 seconds each, windowed with a Hanning window, with 50% overlap. The relative powers of the spectral components in the typical spectral bands delta (δ: 0.5-4 Hz), theta (θ: 4-8 Hz), alpha1 (α1: 8-10.5 Hz), alpha2 (α2: 10.5-13 Hz), beta1 (β1: 13-20 Hz), beta2 (β2: 20-30 Hz) and gamma (γ: 30-60 Hz) were computed by dividing the absolute power in each band by the total power. | baseline, 2 weeks and 8 weeks after treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Transcranial random noise, electroencephalography, Alzheimer Disease