Title of the research project. Actigraphic assessment of sleep/wake behaviour and circadian pattern of motor activity in multiple sclerosis.
Theoretical background. Multiple sclerosis (MS) is a neurodegenerative demyelinating disorder which determines an impairment of motor and cognitive performance (Noseworthy et al., 2000). MS patients are also characterized by a high prevalence of sleep disorders (e.g., Attarian et al., 2004), although these are often undetected or untreated (Brass et al., 2014). A recent review by Braley and Boudreau (2016) has pointed out that actigraphy, based on the use of accelerometer technology, is a potential screening tool for sleep problems in MS. However, although some actigraphic sleep studies in MS have been carried out (e.g., Attarian et al., 2004), none have detected the combination of nighttime and daytime actigraphic parameters that largely distinguishes between these patients and healthy controls (HCs). Besides its potential in the screening of sleep disorders, actigraphy is able to provide a description of the circadian pattern of motor activity, and thus highlight a chronobiological marker of the disorder within the theoretical framework of the two-process model of sleep regulation (Borbely et al., 2016), the prevalent conceptual model in the sleep research field. To date only one study (Kos et al., 2007) has examined the circadian pattern of motor activity in MS, but without comparing that of HCs, thus preventing the authors from detecting a disease marker. Therefore, it is yet unknown whether MS is characterized by an altered balance between the homeostatic and circadian processes (Borbely et al., 2016).
Aims/Hypotheses. The present study has three main aims. The first is to ascertain whether actigraphy is a useful technique to characterize sleep/wake behaviour in MS patients through a comparison with HCs, and whether a specific combination of actigraphic parameters, that may characterize MS patients compared to HCs, exists. The second aim is similar, but refers to a comparison between MS patients with sleep complaints and those without. The third aim is to explore the features of the minute-by-minute circadian pattern of motor activity of MS patients through a comparison with that of HCs, within the theoretical framework of the two-process model of sleep regulation. As regards the first aim, since actigraphy has proved reliable in the differentiation of patients with sleep disorders such as primary insomnia (Natale et al., 2009; Natale et a., 2014b) and narcolepsy (Filardi et al., 2015) from HCs, and considering that these sleep disorders have been reported in MS (Brass et al., 2010), we may also reasonably expect it to be a useful technique to differentiate MS patients from HCs. Regarding the second aim, in line with the suggestion by Braley and Boudreau (2016), actigraphy may be able to properly characterize the features of sleep/wake behaviour in MS patients with sleep complaints in comparison with those without such complaints. With reference to the third aim, since no previous similar studies are available, no clear-cut hypothesis can be put forward at this stage.
Methods.
– Participants. Sixty adult MS patients of both genders will be enrolled in the present study. The recruitment of patients will be carried out at the “Centro UOSI Riabilitazione Sclerosi Multipla dell’IRCCS” (Bellaria Hospital, Bologna). The inclusion criteria are: age ranging between 18 and 64 years; definite diagnosis of MS according to the current diagnostic criteria (Polman et al., 2011).
Sixty adult HCs of both genders will be recruited at the Laboratory of Applied Chronopsychology of the University of Bologna. HCs should range between 18 and 64 years of age and should not have sleep problems or diurnal symptoms due to unsatisfactory sleep.
MS patients and HCs will be age and gender matched.
- Tools. Micro Motionlogger® Watch actigraph (Ambulatory Monitoring, Inc, Ardsley, NY) will be used in the present study. The actigraph will be initialized through the WatchWare software to collect and store motor activity data in 1-min epochs. Sleep-wake behaviour will be analyzed through Action W 2 – version 2.71 software, to acquire information on both nighttime (e.g., sleep onset latency, the interval in minutes between light off and sleep start) and daytime (e.g., number of sleep episodes lasting more than 5 consecutive minutes) periods. Row motor activity data per minute will be extracted using Action 4 software.
The Mini Sleep Questionnaire (MSQ) (Natale et al., 2014a; Zomer et al., 1985), which includes 10 questions on sleep quality and daytime sleepiness, referring to the past week, will be compiled by all participants.
- Procedure. Participants will be requested to wear an actigraph around the non-dominant wrist (Kos et al., 2007) for seven consecutive days (Taphoorn et al., 1993), during both daytime and nighttime, and to press the mark-event button on the actigraph to signal bedtime and get-up time. At the end of the actigraphic recording week, participants will fill in the MSQ. On the basis of their replies, the MS patients will be assigned to one of two groups: patients with and patients without sleep complaints.
- Statistical analyses. With reference to both the first (two groups: MS patients and HCs) and the second (two groups: MS patients with and without sleep complaints) aims, the following statistical analyses will be performed. In order to verify the balance between groups for demographic characteristics, gender (Pearson’s chi-squared test) and age (independent samples t-test) of groups will be compared. For each actigraphic measure an independent samples t-test will be performed to compare groups, and the Bonferroni correction will be applied. A stepwise multiple discriminant analysis with Wilks’s Lambda method, including the actigraphic measures that significantly differed between groups in the previous statistical analyses, will then be carried out to detect the best combination of actigraphic parameters in differentiating the two groups. As regards the third aim, raw motor activity data per minute will be processed with R statistical software to apply functional linear modeling (Wang et al., 2011).
Expected results and implications. Concerning the first and second aim, the main expected result is to highlight which combination of actigraphic parameters is most able to discriminate between MS patients and HCs, and MS patients with and without sleep complaints, respectively. The main implication of these two expected results will be the opportunity to implement the use of actigraphy as an objective screening tool of sleep problems in MS (Braley & Boudreau, 2016). With reference to the third aim, if the results indicate a chronobiological marker of MS, this could improve the understanding of the disease and, as a result, have consequences on coadjuvant treatment.
References
Attarian HP, Brown KM, Duntley SP, et al. (2004). The relationship of sleep disturbances and fatigue in multiple sclerosis. Arch Neurol. 61:525-28.
Borbély AA, Daan S, Wirz-Justice A, et al. (2016). The two-process model of sleep regulation: a reappraisal. J Sleep Res. 25:131-43.
Braley TJ, Boudreau EA. (2016). Sleep disorders in multiple sclerosis. Curr Neurol Neurosci Rep. 16:50.
Brass SD, Duquette P, Proulx-Therrien J, et al. (2010). Sleep disorders in patients with multiple sclerosis. Sleep Med Rev. 14:121-9.
Brass SD, Li CS, Auerbach S. (2014). The underdiagnosis of sleep disorders in patients with multiple sclerosis. J Clin Sleep Med. 10:1025-31.
Filardi M, Pizza F, Martoni M, et al. (2015). Actigraphic assessment of sleep/wake behavior in central disorders of hypersomnolence. Sleep Med. 16:126-30.
Kos D, Nagels G, D’Hooghe MB, et al. (2007). Measuring activity patterns in multiple sclerosis. Chronobiol Int. 24:345-56.
Natale V, Fabbri M, Tonetti L, et al. (2014a). The psychometric goodness of the Mini-Sleep Questionnaire. Psychiatry Clin Neurosci. 68:568-73.
Natale V, Léger D, Martoni M, et al. (2014b). The role of actigraphy in the assessment of primary insomnia: a retrospective study. Sleep Med. 15:111-5.
Natale V, Plazzi G, Martoni M. (2009). Actigraphy in the assessment of insomnia: A quantitative approach. Sleep .32:767-71.
Noseworthy JH, Lucchinetti C, Rodriguez M, et al. (2000). Multiple sclerosis. N Engl J Med. 343:938-52.
Polman CH, Reingold SC, Banwell B, et al. (2011). Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 69:292-302.
Taphoorn MJB, van Someren E, Snoek FJ, et al. (1993). Fatigue, sleep disturbances and circadian rhythm in multiple sclerosis. J Neurol. 240:446-8.
Wang J, Xian H, Licis A, et al. (2011). Measuring the impact of apnea and obesity on circadian activity patterns using functional linear modeling of actigraphy data. Journal of Circadian Rhythms. 9:11.
Zomer J, Peder R, Rubin AH, et al. (1985). Mini Sleep Questionnaire for screening large populations for EDS complaints. In: Koella WP, Ruther E, Schulz H, editors. Sleep ’84. Stuttgart: Gustav Fischer Verlag; p. 467-470.
Plan of activities
MS patients and HCs will be selected according to the established criteria. The following tools will be prepared, delivered to each participant and then collected after the recording week: actigraph, MSQ and instructions to correctly use the actigraph and fill in the questionnaire. Data scoring and data entry will then be performed, followed by statistical analyses. Afterwards, a documented report of the work performed and results achieved will be written in English. Finally, the results of the research project will be submitted to international peer-reviewed journals for potential publication in the form of manuscripts.
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