TITLE : INFLUENCE OF SOCIOECONOMIC STATUS AND STRESS OVER QUALITY OF SLEEP : A SYSTEMATIC REVIEW 1-Faustin

REVIEW 1Faustin Armel Etindele Sosso, PhD, Research Center of Neurosciences, Center for Advanced Studies in Sleep Medicine, Hopital du Sacré-Coeur de Montreal, Montreal, Québec, Canada a 2Aarti Jagannath, PhD, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom b 3Fabricio Ferreira De Oliveira, PhD, Department of Neurology and Neurosurgery, Universidade Federal de São Paulo, Sao Paulo, Brazil c 4Salim R. Surani, PhD, Department of Medicine, Texas A&M University System Health Science Center, Bryan, Texas, United States d 5Vincent Mysliwiec, MD, Pulmonary and Sleep Medicine, Madigan Army Medical Center, Tacoma, Washington, United States e


INTRODUCTION
Sleep is a physiological state that corresponds to one-third of a human life.Much more than just a passive state, sleep plays a major role in physical and psychological health 1 .Indeed, acute or chronic disruption of sleep can have major consequences on alertness, learning ability, mood, cardiovascular health, the immune system and weight regulation 2 .Sleep is a natural state of loss of consciousness of the external world that does not exclude the reception of sensory information but is accompanied by a progressive reduction of muscle tone and recurs in regular intervals.
The timing of the sleep-wake cycle is driven by two factors, the homeostatic build-up of sleep need and the circadian rhythm (CR) which defines the appropriate temporal niche for sleep 3,4 .Organization of the circadian cycle (CC) leads to alternation between the day before and sleep.Organization of ultradian cycles leads to alternation between slow sleep and paradoxical sleep 5,6 .The primary circadian pacemaker of the human brain is the suprachiasmatic nucleus of the hypothalamus, indirectly connected to the ventrolateral preoptic area (VLPO), a hypothalamic structure made up of GABAergic neurons which inhibit the arousal systems, therefore supporting sleep 7 .These processes are supported and maintained by various neurotransmitters like adenosine and histamine 8 .The CC, regulated by internal biological clocks, is aligned with the dawn-dusk cycle (the nychthemeral rhythm) by external synchronizing factors [8][9][10] .The nychthemeral rhythm leads to lower body temperature due to the action of melatonin, a cerebral hormone that is synthesized by the pineal body during the night.The scheduled secretion of this hormone partly depends upon genetic factors but is also modulated by epigenetic interactions through external stimuli such as luminosity, food supply, social relationships and the production of heat 9,10 .The molecular mechanisms at the origin of this homeostatic process are not fully understood.The result is a nightly sequence of three to five cycles of approximately 90-minutes of sleep, each one composed of several distinct phases, starting with the slow wave sleep and ending with the paradoxical sleep (when dreams start).It was recently shown that exposure to natural light improves symptoms related to disorders of the cycles of sleep, but research associating melatonin therapy with better sleep is continuously discussed as melatonin shows limited potency and is only applicable in some populations 9 .
During sleep, many neuronal networks are rebuilt, and this mechanism could have explanations and implications for energy processing, metabolism and memory 9,11 .Consolidation of the information received during the wake phase of the day is carried out during sleep, due to inhibition of the cerebral activity supporting processes of homeostatic plasticity of the different neural networks 12,13 .The need for sleep (often termed sleep debt) varies from person to person, but also with cultural influences, geographical location and the practices of life.The ideal mean length of sleep for an adult would be eight hours per day, but it usually varies between six and ten hours per night, also affected by factors that may predispose to sleep disorders (such as age, the presence of a neurological disease and the exposure to intense psychological or environmental stress).
Sleep disturbances or sleep disorders (SD) have many and varied causes, such as stress, mood disorders (MD), lifestyle habits, living conditions, diseases or aging 14,15 ; and they are often associated with some clinical outcomes such as cognitive impairment and breathing abnormalities 8,16 .The spatial distribution of SD within a population is influenced by sociodemographic variables like age, sex, profession and comorbidities 17,18 .Socioeconomic status (SES), and thus living conditions, lifestyle habits, stress, physical and mental health and aging 14,16,[19][20][21][22] can all influence the development and progression of SD.The variations in SES within the population correspond to variations in the level of access to different conditions and resources favorable to health [22][23][24] .While SES is an important determinant of health, its role in the development and maintenance of SD is not well studied.SES may induce some form of stress, often complex to figure out mainly because of the difficulty to evaluate the direction of this relationship 25,26 .This chronic accumulation of stress becomes a progressive burden (known as allostatic load); and correlation or association between the socioeconomic factors inducing psychological and environmental stress and the trajectory of SD remains unclear.This review explains the recent theories about environmental and psychological stress in the context of different SD documented in current literature.Following that, the review gives a detailed synthesis of existing interactions among allostatic load, SD, SES and clinical outcomes like cancer, metabolic diseases, neurodegenerative diseases and circadian rhythm disturbances.
Finally, the authors provide a theoretical model explaining how this interaction works, emerging from the current state of the knowledge and how researchers may improve current practice.

METHOD
Using PRISMA (Preferred reporting items for systematic reviews and meta-analyses) guidelines, a comprehensive literature search was performed on articles published in peer-reviewed journals from June 1974 until March 2018, according to the following types of studies: clinical, experimental, quasi-experimental and epidemiological.The databases used for this review were the following: PubMed, Web of Science, PsycINFO.We crossed the term "socioeconomic" with "social class" (55415 articles found).
After that, the results were associated with the term "sleep" (623 articles found), then this syntax was crossed with the term "stress" (101 articles found).The final items were screened and reviewed in combination with Google Scholar, allowing us to identify the fulltext manuscripts.Google Scholar was also useful to identify the most relevant references for our subject.The inclusion criteria upon which the studies were selected were: (i) the inclusion of empirically collected data (ii), an assessment of SD in some form (iii), the inclusion of human participants aged from 18 to 90 years old in the sample (iv), articles published in peer-reviewed journals (v), fulltext availability (vi), an assessment of SES and SC in some form (vii), an assessment of stress, cortisol, anxiety and depression (vii) and (viii) written in either English or French.Methodological papers, editorials, opinion articles, policy and commentary papers were excluded.Papers focusing on one disease only (obesity, heart failure, etc.) in association or in correlation with sleep disturbances without assessing SES, or articles reporting only sleep disturbances without association or correlation with socioeconomic or sociodemographic factors were excluded.Research reporting stress or sleep problems related to natural disasters and stressful life events such as death of a close relative or moving from a location to another were also excluded.Articles on SES reporting associations, correlations or influence of psychological and social stressors on sleep problems were retained.Following this rigorous literature compilation, 23 empirical studies met the inclusion criteria.After reading and analyzing full texts and extracting data, 19 articles were considered interesting for the topic and selected for review.

Relation between allostatic load and sleep
Experiences from our environment stimulate our perception and our training capabilities.These training capabilities are improved by quality and length of our sleep 46,47 .Recent results showed that repetitive stimuli trigger cortical neurons and their mechanisms of synaptic plasticity, mediating training and consolidation during sleep 12,13 .SD such as insomnia, narcolepsy and sleepwalking are frequently associated with cognitive impairment, both in healthy people and in those with neurological disorders such as parkinsonian syndromes or MD 48,49 .Such SD may result from MD or neurodegenerative diseases at an early stage, and may be the initial manifestations of neuropsychiatric syndromes 17,18,50 .Insomnia (e.g.frequent and early alarm clocks, difficulty sustaining sleep) and excessive diurnal somnolence (e.g.attacks of sleep, frequent drowsiness lasting the day) are important examples of disordered brain function and may have several different causes like some forms of parkinsonism, medications and psychiatric disorders 6,51 .
Stress is an important feature associated with SD.Environmental stress results from exposure to multiple environmental stressors (e.g.housing, income, social relationships) and varies according to SES, and needs to be distinguished from psychological stress in the development of MD such as anxiety and depression 15,[52][53][54] .In older people, the level of exposure to environmental stressors influences psychological stress.Thus, development of SD may be affected by several external factors (environmental and socioeconomic) and biological factors (hormones, circadian cycle, practices of life, medical history, medication) 6,15,[51][52][53][54] .
Current literature describes the rise of psychological, environmental and socioeconomic factors in several populations 55,56 .The combined interaction of socioeconomic and psychobiological factors over SD has not been studied in depth.As much as the prevalence of SD is higher in the population over 50 years-old, these issues have not been addressed in much depth in younger adults.
Current epidemiological data also show higher incidence of neurological diseases and mental illness for elders, compared to adults under 40 years-old 54,57 .It is important to understand the simultaneous effects of environmental stimuli and psychological profiles on the evolution of SD according to different age ranges, because stressors are the same and probably start to affect people at an early age.The allostatic load is a manifestation of this long exposure to stress, and people in the same community are affected differently even with the same stressors [58][59][60] .

Relation between socioeconomic status, sleep and mood disorders
As is the case with any biological feature, health status is highly variable for any person in a given population.Certain individuals die at a very early age; others have chronic diseases, and many live up until a very advanced age.Health differences may be analyzed according to geographic region, race, age ranges, and according to SES 60,61 .These factors reveal systematic trends in the distribution of health so that, from birth, each person is not as likely as the other to live in good health for a long time.The SES indicates the position that a person holds in the community.One cannot measure this status directly, but there are some indirect indicators, for example, income, education, occupation, household or the social class (SC) 60,61 .Whatever the indicator used, there is a universal tendency for people from lower socioeconomic groups to die younger and to get sick more often during their lives.The concept of "socioeconomic groups" is identical to the term "socioeconomic category".A socioeconomic category is generally defined as a class in which members of a community or a population have similar features in common, such as professional indicators, age, sex, social position, income, education, environmental stress and psychological stressors 61 .
Social position and economic disparity are strong predictors of health inequalities.Exposure to low income, low levels of education and precarious employment status may impair indicators of health in a population by way of several indirect mechanisms that limit access to better lifestyles and proper healthcare 23,60,62 .
Predisposing risk factors are recurring elements that increase the odds of development of a disease, usually present in the environment or being part of the lifestyle 61,63 .Such risk factors may be environmental, 63 biological and psychosocial 62,64,65 .Among biopsychosocial risk factors we have metabolic heredity, tobacco addiction, sedentarism, and diseases such as diabetes mellitus, obesity, arterial hypertension, hypercholesterolemia, and stress 1,20,66 .Arterial hypertension is the most important risk factor for stroke, whereas environmental and psychological stress are major psychosocial risk factors for MD (depression and anxiety) and SD such as insomnia.When several risk factors are present, the risk may result from the product of them rather than the sum.
Certain risk factors (genetic or environmental) or unforeseen events in our daily lives often escape our control.There is a pressing need for more research on prevention, pharmacological therapy and rehabilitation of patients with SD.SD are usually progressive and strongly correlated with living conditions 53 .SES is considered in the diagnosis and in the response to therapy of SD by way of psychological stress, which is a mediator of environmental stress 67,68 .
In older people, the level of exposure to the environmental stressors exerts an influence on psychological stress 54,69 .There is a strong relation between environmental stress and SD, but also between environmental stress and MD such as depression and anxiety 2,25 .A similar relation would also exist between stress and cognition, more importantly for young adults.Young adults are more prone to psychological stressors, therefore prone to MD and cognitive disorders, incidentally more frequent in people under 40 years 20,70 .
MD usually impair academic performance, social and professional relationships.
Psychological stress, moderated by MD, would be a mediator of the effect of environmental stress over SD, which can become chronic 25,26,59,[71][72][73] .Physical and emotional balance are required for proper functionality.Manifestations of stress are associated with the appearance or aggravation of MD and SD 74,75 .Psychological stress induced by some professional (for example night shift work, building jobs, customer relations) or academic environments (for example graduated studies, medical school) results in a combination of risk factors which worsen cognitive impairments and SD 18,50,76 .The risk of cognitive impairment is more important for people who have difficulty to fall asleep.People with cognitive disorders often have reduced length of sleep, but also difficulty falling asleep, cardiovascular and respiratory dysfunction, and neurological impairment including memory dysfunction 17 .Cognitive disorders may also worsen when neuropsychiatric conditions are present (anxiety, depression, general discomfort) and result in light sleep disturbances 9,10 .Overall, cognitive decline is accelerated when there is a disturbance of the quality and the duration of sleep.MD probably play a central role in the cognition of young adults who, however, do not have as many comorbidities or diagnoses of neurodegenerative diseases as older people; and reduced psychological stress will, hypothetically, lead to decreased incidence or aggravation of cognitive disorders 1,17,18 .Improved living conditions (including professional environments, psychosocial and financial support) would reduce the devastating effects of stress on cognition.In this context, SD would be indicators of cognitive decline well before the diagnoses of depression and anxiety 77,78 .In the current state of knowledge and scientific findings, the most recurrent psychological and social stressors related to sleep disturbances are the following: ethnicity, well-being, households, obesity, social ties and support, discrimination, education, low-SC or low-incomes and multiple comorbidities 1,15,16,20,40,55,63,67,79 .Overall, the risk of SD increases when an individual has a lower SES, one or multiple comorbidities (like obesity and mood disorders), and is exposed to permanent stressors (i.e.discrimination, lack of social support, low income) in his environment leading to allostatic load.In the same logic, an individual living in relatively good conditions (i.e.healthy habits, no chronic diseases) with a satisfactory income (middle and higher SES) and very little stress in his environment has a small risk of SD in his lifetime (except when induced by physiological dysfunctions).Figure 2 summarizes these interactions, with their influences one by one or in association with sleep.

Relation between socioeconomic status and circadian rhythms
CRs are 24h cycles in physiology and behaviour that are driven by an internal molecular clock.The molecular mechanism underlying this rhythm is the cell autonomous transcription-translation feedback loop (TTFL).In mammals, the transcription factors CLOCK and BMAL1 drive the expression of Period (Per1/2) and Cryptochrome (Cry1/2), whose protein products repress the function of CLOCK and BMAL1 80 .CLOCK and BMAL1 bind to DNA elements known as E-boxes that lie within the promoters of about 1/3 of the genome, which as result, can oscillate with a 24h rhythm to regulate tissue-specific metabolic and physiological functions.This molecular clock exists within most cells of the body, which are maintained in synchrony by a master pacemaker, the SCN, residing within the hypothalamus.The SCN receives direct input on the environmental light dark cycle from the retinohypothalamic tract, thus ensuring that internal time is coordinated with the external world 81 .The SCN then synchronises peripheral circadian clocks throughout the body through multiple signals, with the hypothalamic pituitary adrenal axis, through the hormone cortisol, providing one of the most powerful synchronising signals.As the circadian clock regulates on average about 15% of the transcriptome of any tissue [82][83][84] , it has a profound effect on the function of that tissue, resulting in appropriately timed physiology.It is therefore no surprise that sleep and CR disruption, that occurs for example as a consequence of stressors such as shift-work or jet-lag, can contribute to the development of a range of disorders.Much of our evidence comes from the study of night shift workers and offshore workers, where CRs of cortisol can be dampened and shifted 85,86 , and resulting in comorbidity with insomnia, anxiety and depression 87 , and impacting normal metabolism, incidence of cancer and mental health disorders 88,89 .
Fig. 3: Theoretical relation between circadian rhythms, socioeconomic status, lifestyle and metabolic disorders.

FUTURE DIRECTIONS AND CONCLUSIONS
SD have been under intense study in the last two decades and remain a subject of interest at the borders of several disciplines such as psychology, neurology and psychiatry.Incidence and prevalence of SD are increasing, while their determinants as well as their associated psychopathological mechanisms are not well understood.More than the other external factors, the interaction between the SES and sleep must be understood better.Living conditions strongly influence the trajectory of SD by inducing allostatic load which affects differently adolescents, adults and older people, in an unknown speed and for a non-determined period.The combined effects of environmental and psychological stressors seem noxious for mood disorders and sleep.Future work should identify the combined effect of psychological factors, stress and lifestyle on the development and progression of SD, such that behavioural and pharmacological interventions, including those promoting a healthy lifestyle, can be implemented to reduce the incidence of SD and develop novel therapies.This would be effective when a full definition of SES is known, allowing researchers of different fields to understand each other and apply mixed methodologies to assess collected data, which can be used by everyone.

Practice Points
 Socioeconomic status affects the development of sleep disorders in low-income populations, independently of gender, age, education and country. Socioeconomic status can induce allostatic load through daily stressors, sleep disorders and MD. Sleep disorders can be a consequence of MD but may also be indicators of high levels of stress. Circadian rhythms and circadian cycle are affected by socioeconomic status and their influences vary from one individual to another inside the same community. Socioeconomic status and circadian disruption are associated with metabolic diseases such as diabetes and cancer. Socioeconomic status has almost no effect on SD in the normal aging population but increase SD symptoms of older people suffering from neurodegenerative diseases. The most widely correlated measures of socioeconomic status related to sleep disorders are social class, discrimination, ethnicity, low-income, occupation, education, obesity, neurodevelopmental and motor disabilities and households. The most well-studied sleep disorders in association with socioeconomic status are insomnia, sleepiness, circadian rhythms sleep disorders, obstructive sleep apnea and sleep disorders induced by some substance (caffeine, opioid, nicotine, etc..)

Research Agenda
It will be worthy for future generations of researchers to think about the following points:  A clear and conventional definition of socioeconomic status should be developed to allow crosscomparisons between different studies. A novel mixed methodology to assess level of stress without cortisol. Development of fundamental theories and biomedical applications of an index of measure of sleep disorders related to socioeconomic status. Wide investigations of prevalence and incidence of other sleep disorders in low-and middleincome countries and their populations should be performed in the future. Associations between circadian rhythm and metabolic syndromes should be deeply explored. Development of mixed-programs to increase socioeconomic status and sleep disorders should be considered by leaders, as tools to prevent public health crises.

Table 1 :
Details of studies included in the results