Treating Comorbid Depression of Patients With Narcolepsy by Intermittent Theta Burst Stimulation

Treating Comorbid Depression of Patients With Narcolepsy by Intermittent Theta Burst Stimulation: A Preliminary Study

Narcolepsy is a chronic brain disorder. The mechanism is the impairment of brain controlling of sleep and wakefulness. The cause of this disease is still unclear, but common symptoms include excessive day time sleepiness, cataplexy, hypnogogic hallucination, sleep paralysis, and sleep disturbance. Because these symptoms are easily confused together in many situations, it is difficult for doctors to make the diagnosis. Therefore, medical treatment for patients is always delayed. According to previous research report, narcoleptic patients are often delay diagnosis for 10 to 15 years after the onset of the disease. Clearly, to make the diagnosis of narcolepsy is very difficult. Another cause for the delay is the method for diagnosing narcolepsy, which mainly rely on sleep examination instruments and the testing of hypocretin concentration in the cerebrospinal fluid. However, these tests are difficult to carry out in many areas, and diagnosing narcolepsy is still difficult in many countries. To the patients and their families, developing a fast and accurate method or tool for diagnosing narcolepsy is of the utmost importance.

The purposes of this study are as follows: (1) To collect comprehensive narcolepsy and non-narcolepsy brain imaging data. The difference between the two groups will be analyzed. To find the difference between the Type 1 and Type 2 narcolepsy by brain imaging characteristics. Use these data to find the special parameter by "machine learning" and build a predictive model; (2)To collect comprehensive narcolepsy and non-narcolepsy HLA typing data. Attempt to understand the HLA profile of narcoleptic patients and their parents in Taiwan. To analyze the difference between the two groups of Type 1 and Type 2 narcolepsy. Use these data of HLA typing characteristics to find the special parameter by "machine learning" and to establish a predictive model; and (3) categorize and group narcolepsy clinical data, sleep examination data, and the aforementioned data based on machine learning concept and build a predictive model as the basis for developing a fast and accurate" narcolepsy diagnostic tool or model" in the future. Research method: This is a case control study. There are 400 subjects (age 9 - 45) will be collected. These subjects will be divided into the three following groups: (1) experimental group (narcolepsy Type 1, 200 subjects); (2) experimental group (narcolepsy Type 2, 100 subjects); and (3) control group (age and gender matched non-narcolepsy subjects, 100). The investigators will collect all the clinical data for each subject, including clinical characteristics, sleep examination data, actigraphy, HLA typing, and brain imaging data. Data analysis method: the narcolepsy clinical data, sleep examination data, and the aforementioned data were categorized and grouped through data analysis based on computer machine learning, neural network, and predictive model effectiveness analysis concepts. Then the investigators will built a predictive model based on the results.

hypersomnia, narcolepsy, depression, transcranial magnetic stimulation, neurocognitive function, quality of life

Stimulate with Double 70mm Alpha Coil figure of 8 stimulator (8-shaped stimulator) (Magstim Company, UK, high frequency magnetic stimulator with force power booster), each treatment will give subjects 1800 pulses, including 60 TBS Section stimulation, each section has 2 seconds of stimulation (30 pulses) and 8 seconds of interval, a total stimulation time of 10 minutes.

iTBS is a new treatment method for depression. It uses the principle of magnetoelectricity to intermittently stimulate local brain nerves. In recent years, domestic and foreign studies have confirmed its efficacy and safety for depression. In addition, research has also It shows that iTBS has better therapeutic effect and efficiency than the previous regular rTMS.

he Beck Depression Inventory (BDI) is a 21-item, self-report rating inventory that measures characteristic attitudes and symptoms of depression. Below 10 points are non-depressed, 10-18 are mild depression, 19-29 are moderate depression, 30-63 are severe depression.

a 21-question method developed by Aaron T. Beck. A multiple-choice self-administered scale designed to measure levels of clinical anxiety that can be used to measure anxiety severity. Takes 5 to 10 minutes to complete. Each answer is scored on a scale of 0 (not at all) to 3 (serious). A higher total score indicates more severe anxiety symptoms. Normalized cut-off values are: 0-7: minimal; 8-15: mild; 16-25: Moderate.

The Conners Continuous Performance Test is a computer administered test that is designed to assess problems with attention.Many statistics are computed including omission errors , commission errors, hit reaction time, hit reaction time standard error, detectability, response style, perseverations , hit reaction time by block, standard error by block, reaction time by ISI , and standard error by ISI. These statistics are converted to T-scores and can be interpreted in terms of various aspects of attention including inattention, impulsivity, and vigilance.Higher rates of correct detections indicate better attentional capacity.

The Wisconsin Card Sorting Test (WCST) is a neuropsychological test that is frequently used to measure such higher-level cognitive processes as attention, perseverance,working memory, abstract thinking and set shifting.

Epworth Sleepoiness Scale (ESS) assesses the responder's propensity to doze or fall asleep during 8 common daily activities, such as: sitting and reading; sitting inactive in a public place; sitting and talking to someone; sitting quietly after a lunch without alcohol; or in a car, while stopped for a few minutes in traffic. An ESS score >10 suggests excessive daytime sleepiness (EDS); ESS score ≥16 suggests a high level of EDS.

36-Item Short-Form Health Survey (SF-36) includes 11 major questions that evaluate eight components (0-100), with higher scores indicating better outcome.These components include physical functioning, role limitations due to physical health, role limitations due to emotional problems, energy/fatigue, emotional wellbeing, social functioning, pain, and general health.

To explore the improvement and difference of narcolepsy and depression symptoms in patients with narcolepsy comorbid depression after rTMS treatment, and to explore the pathological and physiological mechanisms.

Nine main questions assess eight sleep components. Assessments included subjective sleep quality, time to sleep, sleep duration, sleep efficiency, sleep disturbances, use of sleeping pills, daytime dysfunction, and global Pittsburgh Sleep Quality Index scores, with higher scores indicating poorer sleep quality. Each indicator is scored between 0 and 3. The final composite score is made up of seven combined scores, with a total score ranging from 0 to 21, with lower scores representing healthier sleep quality.

Assess the changes in each follow-up of daytime sleepiness and cataplexy symptoms, and the higher the score, the more severe the daytime sleepiness or cataplexy. no (0-4 mm), mild (5-44 mm), moderate (45-74 mm), and severe (75-100 mm)

Inclusion Criteria: Meet the diagnosis of Type 1 or Type 2 sleep disorder, and comorbid with depression. The age is introduced between 18-60 years old, regardless of gender. Those who agree to participate in the trial and sign the subject's consent form. Exclusion Criteria: Combined with epilepsy, brain injury or severe organic brain disease or serious heart disease. Combined with serious other mental disorders, such as bipolar disorder, mental retardation or addiction disorders. Not willing to participate in this study or not willing to fill out the consent form. Those who are not suitable to enter the experiment after being evaluated by PI and co PI.

Arand D, Bonnet M, Hurwitz T, Mitler M, Rosa R, Sangal RB. The clinical use of the MSLT and MWT. Sleep. 2005 Jan;28(1):123-44. doi: 10.1093/sleep/28.1.123.

Barbey AK, Koenigs M, Grafman J. Dorsolateral prefrontal contributions to human working memory. Cortex. 2013 May;49(5):1195-205. doi: 10.1016/j.cortex.2012.05.022. Epub 2012 Jun 16.

Buskova J, Kemlink D, Ibarburu V, Nevsimalova S, Sonka K. Antidepressants substantially affect basic REM sleep characteristics in narcolepsy-cataplexy patients. Neuro Endocrinol Lett. 2015;36(5):430-3.

Blouin AM, Thannickal TC, Worley PF, Baraban JM, Reti IM, Siegel JM. Narp immunostaining of human hypocretin (orexin) neurons: loss in narcolepsy. Neurology. 2005 Oct 25;65(8):1189-92. doi: 10.1212/01.wnl.0000175219.01544.c8. Epub 2005 Aug 31.

Brooks S, Black J. Novel therapies for narcolepsy. Expert Opin Investig Drugs. 2002 Dec;11(12):1821-7. doi: 10.1517/13543784.11.12.1821.

Corbetta M, Shulman GL. Control of goal-directed and stimulus-driven attention in the brain. Nat Rev Neurosci. 2002 Mar;3(3):201-15. doi: 10.1038/nrn755.

Dauvilliers Y, Arnulf I, Mignot E. Narcolepsy with cataplexy. Lancet. 2007 Feb 10;369(9560):499-511. doi: 10.1016/S0140-6736(07)60237-2.

Nardone R, Bergmann J, Lochner P, Caleri F, Kunz A, Staffen W, Tezzon F, Ladurner G, Trinka E, Golaszewski S. Modafinil reverses hypoexcitability of the motor cortex in narcoleptic patients: a TMS study. Sleep Med. 2010 Oct;11(9):870-5. doi: 10.1016/j.sleep.2010.05.007.

Huang YS, Liu FY, Lin CY, Hsiao IT, Guilleminault C. Brain imaging and cognition in young narcoleptic patients. Sleep Med. 2016 Aug;24:137-144. doi: 10.1016/j.sleep.2015.11.023. Epub 2016 Jan 19.

Huang YS, Hsiao IT, Liu FY, Hwang FM, Lin KL, Huang WC, Guilleminault C. Neurocognition, sleep, and PET findings in type 2 vs type 1 narcolepsy. Neurology. 2018 Apr 24;90(17):e1478-e1487. doi: 10.1212/WNL.0000000000005346. Epub 2018 Mar 30.

Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet. 2000 Jan 1;355(9197):39-40. doi: 10.1016/S0140-6736(99)05582-8.

Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991 Dec;14(6):540-5. doi: 10.1093/sleep/14.6.540.

Kales A, Cadieux RJ, Soldatos CR, Bixler EO, Schweitzer PK, Prey WT, Vela-Bueno A. Narcolepsy-cataplexy. I. Clinical and electrophysiologic characteristics. Arch Neurol. 1982 Mar;39(3):164-8. doi: 10.1001/archneur.1982.00510150034008.

Kedzior KK, Gierke L, Gellersen HM, Berlim MT. Cognitive functioning and deep transcranial magnetic stimulation (DTMS) in major psychiatric disorders: A systematic review. J Psychiatr Res. 2016 Apr;75:107-15. doi: 10.1016/j.jpsychires.2015.12.019. Epub 2015 Dec 22.

Lee SA, Kim MK. Effect of Low Frequency Repetitive Transcranial Magnetic Stimulation on Depression and Cognition of Patients with Traumatic Brain Injury: A Randomized Controlled Trial. Med Sci Monit. 2018 Dec 4;24:8789-8794. doi: 10.12659/MSM.911385.

Li CT, Cheng CM, Chen MH, Juan CH, Tu PC, Bai YM, Jeng JS, Lin WC, Tsai SJ, Su TP. Antidepressant Efficacy of Prolonged Intermittent Theta Burst Stimulation Monotherapy for Recurrent Depression and Comparison of Methods for Coil Positioning: A Randomized, Double-Blind, Sham-Controlled Study. Biol Psychiatry. 2020 Mar 1;87(5):443-450. doi: 10.1016/j.biopsych.2019.07.031. Epub 2019 Aug 9.

Mignot E, Hayduk R, Black J, Grumet FC, Guilleminault C. HLA DQB1*0602 is associated with cataplexy in 509 narcoleptic patients. Sleep. 1997 Nov;20(11):1012-20.

Lai JB, Han MM, Xu Y, Hu SH. Effective treatment of narcolepsy-like symptoms with high-frequency repetitive transcranial magnetic stimulation: A case report. Medicine (Baltimore). 2017 Nov;96(46):e8645. doi: 10.1097/MD.0000000000008645.

Naumann A, Daum I. Narcolepsy: pathophysiology and neuropsychological changes. Behav Neurol. 2003;14(3-4):89-98. doi: 10.1155/2003/323060.

Ohayon MM. Narcolepsy is complicated by high medical and psychiatric comorbidities: a comparison with the general population. Sleep Med. 2013 Jun;14(6):488-92. doi: 10.1016/j.sleep.2013.03.002. Epub 2013 May 3.

Ohayon MM, Priest RG, Caulet M, Guilleminault C. Hypnagogic and hypnopompic hallucinations: pathological phenomena? Br J Psychiatry. 1996 Oct;169(4):459-67. doi: 10.1192/bjp.169.4.459.

Posner MI, Petersen SE. The attention system of the human brain. Annu Rev Neurosci. 1990;13:25-42. doi: 10.1146/annurev.ne.13.030190.000325. No abstract available.

Sonmez AI, Kucuker MU, Lewis CP, Kolla BP, Doruk Camsari D, Vande Voort JL, Schak KM, Kung S, Croarkin PE. Improvement in hypersomnia with high frequency repetitive transcranial magnetic stimulation in depressed adolescents: Preliminary evidence from an open-label study. Prog Neuropsychopharmacol Biol Psychiatry. 2020 Mar 8;97:109763. doi: 10.1016/j.pnpbp.2019.109763. Epub 2019 Oct 18.

Tsai PS, Wang SY, Wang MY, Su CT, Yang TT, Huang CJ, Fang SC. Psychometric evaluation of the Chinese version of the Pittsburgh Sleep Quality Index (CPSQI) in primary insomnia and control subjects. Qual Life Res. 2005 Oct;14(8):1943-52. doi: 10.1007/s11136-005-4346-x.

Vijayakumari AA, Khan FR, Varma RP, Radhakrishnan A. Can transcranial magnetic stimulation be used to evaluate patients with narcolepsy? Neurol Sci. 2013 Aug;34(8):1411-20. doi: 10.1007/s10072-012-1253-0. Epub 2012 Nov 29.

Wang W, Chair SY, Thompson DR, Twinn SF. A psychometric evaluation of the Chinese version of the Hospital Anxiety and Depression Scale in patients with coronary heart disease. J Clin Nurs. 2009 Jul;18(13):1908-15. doi: 10.1111/j.1365-2702.2008.02736.x.

Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992 Jun;30(6):473-83.

Yang CM, Huang YS, Song YC. Clinical utility of the Chinese version of the Pediatric Daytime Sleepiness Scale in children with obstructive sleep apnea syndrome and narcolepsy. Psychiatry Clin Neurosci. 2010 Apr;64(2):134-40. doi: 10.1111/j.1440-1819.2009.02054.x. Epub 2010 Feb 1.