The Role of Circadian Factors in Regulation of Neuroplasticity in Ischemic Stroke (Interventional)

Federal State Budgetary Institution, V. A. Almazov Federal North-West Medical Research Centre, of the Ministry of Health

There is a lack of complex studies which could establish the association between genetic circadian factors with the features and short-term outcomes of ischemic stroke, as well as the effects of various auxiliary therapies for circadian rhythm modulation for neuroplasticity enhancement and improvement of short-term outcomes in ischemic stroke. The main research hypothesis is that circadian factors influence the recovery from ischemic stroke via sleep-mediated regulation of synaptic plasticity. The project aims at the investigation of the influence of combined melatonin therapy and blue light exposure on molecular circadian biomarkers, sleep characteristics, neuroplasticity markers and stroke outcome in acute stroke patients. This study is a prospective, interventional, randomized placebo-controlled trial.

The study will investigate the influence of combined blue light exposure and melatonin therapy on molecular biomarkers of circadian rhythms, sleep characteristics and stroke outcome in acute stroke patients This study is designed as a prospective study in acute stroke patients (approx 80 patients) admitted to the Stroke Unit. After initial assessment, the participants will be randomly assigned in 4 groups (the treatment or control) with approx.20 participants in each group. In all participants, the following parameters will be assessed: medical records, stroke characteristics, sleep characteristics, cardiovascular circadian rhythms and blood samples for the evaluation of circadian molecular biomarkers at baseline and 14 days after inclusion. Stroke outcomes will be reassessed at 3-month follow-up. The following associations will be assessed: the role of blue light exposure and melatonin treatment for stroke outcome the role of blue light exposure and melatonin treatment in the modulation of sleep parameters in acute stroke the association of molecular biomarkers of circadian rhythms with stroke outcome (the difference in neurological and functional deficit from admission to 14 and 90 days after study inclusion), with stroke characteristics (stroke subtype and neuroimaging stroke parameters, routine protocol) and with sleep characteristics. the association of sleep characteristics with stroke outcome (the difference in neurological and functional deficit from admission to 14 and 90 days after stroke) and with stroke characteristics (stroke subtype and neuroimaging stroke parameters, routine protocol).

The participants will receive the combination of blue light exposure according to the protocol described by Killgore et al. (2020) and 3 mg of melatonin 1 hour before going to sleep (approximately at 20:00) (Ramos et al 2020) for 14 days

The participants will receive 3 mg of melatonin 1 hour before going to sleep (approximately at 20:00) (Ramos et al 2020) and the morning placebo-light exposure according to the protocol described by Killgore et al. (2020) for 14 days

The participants will receive the morning blue light exposure according to the protocol described by Killgore et al. (2020) for 14 days and placebo pill 1 hour before going to sleep (approximately at 20:00)

The participants will receive placebo light exposure in the morning (lamp turned off) and placebo pill treatment in the evening for 14 days

3 mg Melatonin pill will be given 1 hour before going to bed. Blue light exposure will be performed during 30-minute sessions with the use of the lamps (Lumie/Vitamin L) in the morning.

Blue light exposure will be performed during 30-minute sessions with the use of the lamps (Lumie/Vitamin L) in the morning.

Placebo light exposure will be performed by using lamp turned off; and placebo pill will be given in the evening

Change in the value of National Institutes of Health Stroke Scale from baseline to 14 days after inclusion

National Institutes of Health Stroke Scale (NIHSS) is a tool used to objectively quantify the impairment caused by a stroke, 0-42 scores, higher scores characterize worse impairment

Stroke-related disability assessed by the change in modified Rankin scale from baseline to 14 days after treatment initiation

values of modified Rankin scale (scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke, from 0 (no symptoms) to 6 (dead) points)

Stroke-related disability assessed by the change in Rivermead Mobility Index from baseline to 14 days after treatment initiation

Rivermead Mobility Index (a standardized scale used to assess mobility in patients with neurological deficits, a maximum of 15 points is possible; higher scores indicate better mobility performance)

Stroke-related disability assessed by the change in Barthel Index from baseline to 14 days after treatment initiation

Barthel Index (a common scale used to measure performance in activities of daily living, 0-100 scores, higher scores define better performance)

Change in Psychomotor vigilance task (mean reaction time) from baseline to 14 days after treatment initiation

The psychomotor vigilance task is a sustained-attention, reaction-timed task that measures the speed with which subjects respond to a visual stimulus, the outcome (mean reaction time) is measured in msec

The psychomotor vigilance task is a sustained-attention, reaction-timed task that measures the speed with which subjects respond to a visual stimulus, the outcome (mean reaction time) is measured in msec

Kraepelin test is the test in which the examinee performs a simple single-digit addition. The outcome is the number of correct and incorrect addition operations per each 30 sec and during the whole task, performance index (number of correct addition operations during second part of task / number of correct addition operations during first part of task)

Kraepelin test is the test in which the examinee performs a simple single-digit addition. The outcome is the number of correct and incorrect addition operations per each 30 sec and during the whole task, performance index (number of correct addition operations during second part of task / number of correct addition operations during first part of task)

Trails Making Test (Trails) is a neuropsychological test of visual attention and task switching. It can provide information about visual search speed, scanning, speed of processing, mental flexibility, as well as executive functioning

Trails Making Test (Trails) is a neuropsychological test of visual attention and task switching. It can provide information about visual search speed, scanning, speed of processing, mental flexibility, as well as executive functioning. Execution time will be assessed (in msec)

Victoria Stroop is a neuropsychological test extensively used to assess the ability to inhibit cognitive interference. Execution time will be measured. (in msec)

Victoria Stroop is a neuropsychological test extensively used to assess the ability to inhibit cognitive interference. Execution time will be measured. (in msec)

Hopkins Verbal Learning Test - Revised brief assessment of immediate recall, delayed recall and delayed recognition. The number of words recalled will be assessed.

Hopkins Verbal Learning Test - Revised brief assessment of immediate recall, delayed recall and delayed recognition. The number of words recalled will be assessed.

Change in Brief Visuospatial Memory Test (Revised) from baseline to 14 days after treatment initiation

Brief Visuospatial Memory Test (Revised)is a commonly used, commercialized, assessment tool to measure visuospatial learning and memory abilities across research and clinical settings. The number of figures will be assessed.

Brief Visuospatial Memory Test (Revised)is a commonly used, commercialized, assessment tool to measure visuospatial learning and memory abilities across research and clinical settings. The number of figures will be assessed.

Wechsler Memory Scale - Revised is a neuropsychological test designed to measure different memory functions in a person. A composite score will be assessed.

Wechsler Memory Scale - Revised is a neuropsychological test designed to measure different memory functions in a person. A composite score will be assessed.

The Corsi block-tapping test is a psychological test that assesses visuo-spatial short term working memory. The visual span raw score will be assessed.

The Corsi block-tapping test is a psychological test that assesses visuo-spatial short term working memory. The visual span raw score will be assessed.

Change in emotional outcome assessed by Hospital anxiety and depression scale from baseline to 90 days after inclusion

Hospital anxiety and depression scale is used to determine the levels of anxiety and depression. It is a 14-item scale; Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 and 21 for either anxiety or depression, higher scores indicate worse situation

Change in emotional outcome assessed by Hospital anxiety and depression scale from baseline to 14 days after treatment initiation

Hospital anxiety and depression scale is used to determine the levels of anxiety and depression. It is a 14-item scale; Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 and 21 for either anxiety or depression, higher scores indicate worse situation

Assessment of mood by change in Visual Analogue Mood Scale from baseline to 14 days after treatment initiation

Visual Analogue Mood Scale is a reliable and valid measure of eight specific mood states: Afraid, Confused, Sad, Angry, Energetic, Tired, Happy, and Tense. The score for each mood ranges from 0 to 100 (100 mm vertical line), with 100 representing a maximal level of that mood and zero representing a minimal level (or absence) of that mood

Visual Analogue Mood Scale is a reliable and valid measure of eight specific mood states: Afraid, Confused, Sad, Angry, Energetic, Tired, Happy, and Tense. The score for each mood ranges from 0 to 100 (100 mm vertical line), with 100 representing a maximal level of that mood and zero representing a minimal level (or absence) of that mood

Change in the value of National Institutes of Health Stroke Scale from baseline to 90 days after inclusion

National Institutes of Health Stroke Scale (NIHSS) is a tool used to objectively quantify the impairment caused by a stroke, 0-42 scores, higher scores characterize worse impairment

values of modified Rankin scale (scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke, from 0 (no symptoms) to 6 (dead) points)

Rivermead Mobility Index (a standardized scale used to assess mobility in patients with neurological deficits, a maximum of 15 points is possible; higher scores indicate better mobility performance)

Barthel Index (a common scale used to measure performance in activities of daily living, 0-100 scores, higher scores define better performance)

Pittsburgh Sleep Quality Index is a self-rated questionnaire which assesses subjective sleep quality and disturbances over a 1-month time interval, Each of the sleep components yields a score ranging from 0 to 3, with 3 indicating the greatest dysfunction. The sleep component scores are summed to yield a total score ranging from 0 to 21 with the higher total score indicating worse sleep quality

Epworth Sleepiness Scale is a common tool to assess sleepiness; 0-24 points, higher score indicate greater sleepiness

Fatigue severity Scale is a common 9-item tool used to determine and quantify fatigue as subjective feeling of exhaustion, persisting lack of energy and rapid inanition, 9-63 points, higher score indicates more severe fatigue

Insomnia severity index is a 7-item tool to assess the severity of insomnia, 0-5 points per each item, higher score indicates more severe insomnia

Sensorimotor assessment of upper limbs by Fugl-Meyer is a stroke-specific, performance-based impairment index. The total possible scale score is 226

salivary melatonin levels samples collected every 3 hours for 24 hours at study inclusion and at 14 days after study inclusion

salivary cortisol sampled every 3 hours for 24 hours at study inclusion and at 14 days after study inclusion

Change from baseline in circadian brain-derived neurotrophic factor messenger ribonucleic acid (mRNA) expression

Brain-derived neurotrophic factor messenger ribonucleic acid (mRNA) expression will be measured in blood samples taken every 4 hours for 24 hours at study inclusion and at 14 days after study inclusion

clock gene CLOCK messenger ribonucleic acid (mRNA) expression will be measured in blood samples taken every 4 hours for 24 hours at study inclusion and at 14 days after study inclusion

clock gene Bmal1 messenger ribonucleic acid (mRNA) expression will be measured in blood samples taken every 4 hours for 24 hours at study inclusion and at 14 days after study inclusion

Melatonin receptor messenger ribonucleic acid (mRNA) expression will be measured in blood samples taken every 4 hours for 24 hours at study inclusion and at 14 days after study inclusion

Change in psychophysiological state: heart rate variability assessed by biofeedback method from baseline to 14 days

heart rate variability assessed by electrocardiogram (maximum heart rate - minimum heart rate, beats per minute)

Change in psychophysiological state: heart rate variability assessed by biofeedback method from baseline to 90 days after inclusion

heart rate variability assessed by electrocardiogram (maximum heart rate - minimum heart rate, beats per minute)

Change in psychophysiological state: respiratory movement amplitude assessed by biofeedback method - from baseline to 14 days

Change in psychophysiological state: respiratory movement amplitude assessed by biofeedback method- from baseline to 90 days

Change in psychophysiological state: alpha-rhythm index assessed by biofeedback method - from baseline to 14 days after treatment initiation

Change in psychophysiological state: beta-rhythm index assessed by biofeedback method - from baseline to 14 days after treatment initiation

Change in psychophysiological state: alpha-rhythm index assessed by biofeedback method - from baseline to 90 days after inclusion

Change in psychophysiological state: beta-rhythm index assessed by biofeedback method - from baseline to 90 days after inclusion

Number of participants with treatment-related adverse events assessed according to the protocol-specified adverse effects

Number of participants with treatment-related adverse events assessed according to the Toronto Side Effects Scale

Inclusion Criteria: acute (symptom onset to admission <1 days) ischemic stroke ischemic stroke affecting the branches of anterior cerebral artery, middle cerebral artery and posterior cerebral artery age 18-80 years moderate or severe stroke (National Institutes of Health Stroke Scale, NIHSS>=5) intravascular stroke treatment with thrombolysis or thrombectomy leading to satisfactory reperfusion (if applicable) informed consent Exclusion Criteria: secondary parenchymal hemorrhage (>hemorrhage index (HI)-2) clinically unstable or life-threatening conditions previous stroke in the last 6 months known progressive neurological diseases known psychiatric diseases concomitant benzodiazepine medication drug or alcohol abuse pregnancy inability to participate in the study severe sensory aphasia melatonin intake at/before admission light therapy use at/before admission blindness severe sleep-disordered breathing (apnea-hypopnea index >=30/h) contraindications to light therapy (severe retinopathy, epilepsy, porphyria, intake of drugs with photosensitizing effects) contraindications to melatonin intake (severe bronchial asthma, severe autoimmune disorders, chronic kidney disease 3b stage and higher, leukosis) congestive heart failure with reduced ejection fraction (<=45%) or New York Heart Association (NYHA) classification III-IV functional class.

Korostovtseva L. Ischemic Stroke and Sleep: The Linking Genetic Factors. Cardiol Ther. 2021 Dec;10(2):349-375. doi: 10.1007/s40119-021-00231-9. Epub 2021 Jun 30.

Bochkarev MV, Korostovtseva LS, Medvedeva EA, Rotar OP, Sviryaev YV, Zhernakova YV, Shalnova SA, Konradi AO, Chazova IE, Boitsov SA, Shlyakhto EV. [Sleep disorders and stroke: data of the esse-rf study]. Zh Nevrol Psikhiatr Im S S Korsakova. 2019;119(4. Vyp. 2):73-80. doi: 10.17116/jnevro201911904273. Russian.