ADHD: Allostatic load is key in understanding ADHD comorbidity

Living life without an adequate functioning autoregulatory system in place comes with a high price – allostatic load. Allostasis is the (predictive) system of the human body, which in cooperation with Homeostasis (reactive) are the autonomous systems which are tasked with keeping all of our body (and mind) in the best shape possible. But people with ADHD suffers from Circadian Disruption, a breakdown in the natural sleep/wake phases, which in turn have massive implications for our habitual well-being. This article will focus on the stress part of this equation.

TOPIC: CIRCADIAN RHYTHMS IN ENDOCRINOLOGY AND METABOLISM

Overview of the Circadian Rhythms
The outer circle represents the chronotype Owl (late riser) and the inner circle represents the Lark chronotype (early riser). The table to the right shows the various brainwaves states and neurotransmitters, hormones, and psychological trait associated with each circadian phase.

Introduction

Circadian rhythms are a prominent and critical feature of cells, tissues, organs, and behavior that help an organism function most efficiently and anticipate things such as food availability. Therefore, it is not surprising that disrupted circadian rhythmicity, a prominent feature of modern-day society, promotes the development and/or progression of a wide variety of diseases, including inflammatory, metabolic, and alcohol-associated disorders (Voigt et al. (2013)

CIRCADIAN DISRUPTION: Circadian rhythms are a prominent and critical feature of cells, tissues, organs, and behavior that help an organism function most efficiently and anticipate things such as food availability. Therefore, it is not surprising that disrupted circadian rhythms or misalignment between central and peripheral circadian rhythms predispose and/or exacerbate a wide variety of diseases, including alcohol-associated disorders.

Voigt et al., (2013)

Circadian Disruption has massive implications for ADHD, directly through timing issues related to neurodevelopment and early childhood, but likewise across the lifespan, as the desynchrony between the “outside time” and the “inside time” causes internal chronic stress leads to allostatic load, and ultimately to allostatic stress, a condition where the predictive management systems of the body simply gives up and all is left to the reactive, homeostatic system to sort out the mayhem.

The result is a long list of both mental and somatic comorbid diseases and illnesses (Instanes et al., 2018) which not only reduce quality of life, but also shortens the life expectancy by 12.7 years according to a study by Barkley et al. (2018)

Circadian Disruption and Society

The circadian clock is a sophisticated mechanism that functions to synchronize (i.e., entrain) endogenous systems with the 24-hour day in a wide variety of organisms, from simple organisms such as fungi up to the complex mammalian systems (Voigt et al., 2013).

Circadian rhythms control a variety of biological processes, including sleep/wake cycles, body temperature, hormone secretion, intestinal function, metabolic glucose homeostasis, and immune function. Functional consequences of modern-day society, such as late-night activity, work schedules that include long-term night shifts and those in which employees change or rotate shifts (i.e., shift work), and jetlag are substantial environmental disruptors of normal circadian rhythms (Voigt et al., 2013).

Fifteen percent of American workers perform shift work (Bureau of Labor Statistics 2005), indicating the pervasiveness of circadian disruption as a normal part of modern-day society. This change from the diurnal lifestyle of our ancestors to one that is more prominently nocturnal results in misalignment between natural rhythms based on the 24-hour day and behavioral activity patterns (i.e, circadian misalignment) (Voigt et al., 2013).

Circadian misalignment has a significant detrimental effect on cell, tissue, and whole-organism function. These alterations can manifest in humans as chronic health conditions, such as metabolic syndrome, diabetes, cardiovascular disease, cancer, and intestinal disorders (Voigt et al., 2013).

The increased prevalence of diseases associated with circadian disruption underscores the need to better understand how circadian disruption can wreak havoc in so many different ways throughout the body (Voigt et al., 2013).

What are the consequences of Circadian Disruption?

Millions of individuals worldwide do not obtain sufficient sleep for healthy metabolic function, and many participate in shift work and social activities at times when the internal physiological clock is promoting sleep (McHill et al., 2017).

These behaviours predispose an individual for poor metabolic health by promoting excess caloric intake in response to reduced sleep, food intake at internal biological times when metabolic physiology is not prepared, decreased energy expenditure when wakefulness and sleep are initiated at incorrect internal biological times, and disrupted glucose metabolism during short sleep and circadian misalignment (McHill et al., 2017).

In addition to the traditional risk factors of poor diet and exercise, disturbed sleep and circadian rhythms represent modifiable risk factors for prevention and treatment of metabolic disease and for promotion of healthy metabolism (McHill et al., 2017).

The circadian clock is a complex and highly specialized network of the human organism and is key for metabolic health. Circadian rhythms are modulated by behavioral patterns, physical activity, food intake as well as sleep loss and sleep disorders. Furthermore, an altered expression of clock genes (e. g. PERIOD1 and 2) can alter circadian rhythms (Meyhöfer et al., 2019)

Chronodisruption, i. e. the alteration of circadian rhythms, is associated with a variety of mental and physical illnesses. Recent studies show a significant association between quantitative and qualitative sleep rhythm disturbances and an increasing prevalence of obesity (Meyhöfer et al., 2019)

Furthermore, reduced sleep quality and duration lead to decreased glucose tolerance and insulin sensitivity, thus increasing the risk of developing type 2 diabetes. In addition to the core components of the metabolic syndrome, there are also changes in hormonal and neuronal signaling pathways impinging on human energy metabolism (Meyhöfer et al., 2019)

Insufficient and disrupted sleep and energy metabolism

Because of time demands of modern society with work, school and social schedules, insufficient sleep is common amongst both adults and adolescents. Epidemiological evidence has produced numerous associations of short sleep and obesity (McHill et al., 2017).

However, it would seem somewhat paradoxical that short sleep would result in weight gain, as wakefulness increases energy expenditure (McHill et al., 2017).

Thus, if energy intake was stable, the increased amount of wakefulness and associated increase in energy expenditure would lead to a negative shift in energy balance and consequent weight loss over time (McHill et al., 2017).

When sleep is restricted in humans and food is provided ad libitum, participants have been shown to increase their food intake far beyond the amount of calories needed to meet the energy needs of extended wakefulness and thus enter a state of positive energy balance. If maintained over time, this positive energy balance will result in weight gain (McHill et al., 2017).

Furthermore, the response of increased caloric intake and subsequent weight gain during sleep restriction appears to be aconsistent response within an individual under repeated exposures of sleep restriction (McHill et al., 2017).

Insufficient sleep also impacts the resulting body composition during caloric restriction-induced weight loss. Overweight individuals exhibit similar weight loss during caloric restriction regardless of sleep, but calorically restricted individuals under insufficient sleep conditions showed a higher loss of fat-free mass whereas calorically restricted individuals under adequate sleep conditions showed higher loss of fat mass. These data indicate that healthy sleep results in a healthier body composition when dieting (McHill et al., 2017).

Circadian misalignment and energy metabolism

As reviewed previously, the circadian system and energy metabolism are tightly integrated to promote energy intake during the day. In the modern 24-h society, however, people often choose to partake in these behaviours at inappropriate biological times. This misalignment is often accompanied with poor health. Night shift workers have a higher risk of gastrointestinal disorders, obesity, cardiovascular disease and diabetes (McHill et al., 2017).

In rodent models, allowing mice to eat only during their habitual sleep time – thereby inducing a circadian misalignment as the mice must be awake to eat – increases body mass as compared with mice eating during habitual wake time even though caloric intake or locomotor activity was similar (McHill et al., 2017).

In humans, sleeping during the biological day and wakefulness and eating during the biological night in a shift work model decreased 24-h energy expenditure. The latter may help to explain a potential contributing mechanism as to why the rodent models and shift workers eating during the biological night gain weight in the absence of higher caloric intake or energy expenditure differences (McHill et al., 2017).

The Human Stress Response

The human stress response has evolved to maintain homeostasis under conditions of real or perceived stress. This objective is achieved through autoregulatory neural and hormonal systems in close association with central and peripheral clocks (Russell et al., 2019).

The hypothalamic–pituitary–adrenal axis is a key regulatory pathway in the maintenance of these homeostatic processes. The end product of this pathway — cortisol — is secreted in a pulsatile pattern, with changes in pulse amplitude creating a circadian pattern. During acute stress, cortisol levels rise and pulsatility is maintained (Russell et al., 2019).

Although the initial rise in cortisol follows a large surge in adrenocortico­tropic hormone levels, if long-term inflammatory stress occurs, adrenocorticotropic hormone levels return to near basal levels while cortisol levels remain raised as a result of increased adrenal sensitivity. In chronic stress, hypothalamic activation of the pituitary changes from corticotropin-releasing hormone-dominant to arginine vasopressin-dominant, and cortisol levels remain raised due at least in part to decreased cortisol metabolism. Acute elevations in cortisol levels are beneficial to promoting survival of the fittest as part of the fight-or-flight response (Russell et al., 2019).

However, chronic exposure to stress results in reversal of the beneficial effects, with long-term cortisol exposure becoming maladaptive, which can lead to a broad range of problems including the metabolic syndrome, obesity, cancer, mental health disorders, cardiovascular disease and increased susceptibility to infections (Russell et al., 2019).

Definition of Allostatic and Homeostatic Stress

In response to a stressor, the body activates multiple coordinated and dynamic processes to restore homeostasis, preserve life and ultimately achieve evolutionary success for the species (Russell et al., 2019).

HOMEOSTASIS: is the tendency to resist change in order to maintain a stable, relatively constant internal environment.

Interestingly, anticipation of these threats is itself a very potent activator of these systems. Homeostatic processes also interact with internal and external Zeitgebers such as the light–dark cycle and internal body clocks. These internal clocks enable the body to anticipate regular changes in the environment to ensure optimal fitness across the 24 h and thus the best chance for survival (Russell et al., 2019).

The human stress response is an additional homeostatic mechanism that provides a better chance of survival when the body is under threat and mobilizes neural and hormonal net works to optimize cognitive, cardiovascular, immuno logical and metabolic function (Russell et al., 2019).

ZEITGEBERS: Cues that entrain or syncronize the body’s 24-h cycle

Circadian Clocks

In the absence of internal or external stressors, the integrity of physiological systems is maintained in a dynamic fashion over 24 h by an internal circadian clock that antici pates the changes occurring over the 24h day. In the past, the neurocentric hierarchical view was that body rhythms were controlled from a master clock in the hypothalamic suprachiasmatic nucleus (SCN) (Russell et al., 2019).

Now, it is very clear that peripheral clocks also exist in most, if not all, tissues of the body, which have their own autonomous transcriptional autoregulatory feedback loops (Russell et al., 2019).

This rhythmicity is crucial for homeostasis. The body can only behave optimally when all biological rhythms are in synchrony (Russell et al., 2019).

However, with our increasingly chaotic lifestyles this orderly physiological regulation is steadily being disrupted, which can result in chronodisruption (Russell et al., 2019).

This desynchronization between cellular oscillators in the SCN and peripheral tissues can manifest as negative health outcomes in the form of cardiovascular, metabolic, cognitive and immune dysfunction (Russell et al., 2019).

HPA axis and circadian rhythmicity

The HPA axis is critical for life and is a major part of our homeostatic regulatory system. The output of this system is the endogenous glucocorticoid corticosterone (in rodents) or cortisol (in humans), which are collectively referred to as CORT (Russell et al., 2019).

Glucocorticoid: any steroid hormone that is produced by the adrenal gland and known particularly for its anti-inflammatory and immunosuppressive actions.

Glucocorticoids have diverse and far reaching effects, which is why they are such successful therapeutic agents; however, this diversity is a double edged sword and excess levels of glucocorticoids result in a myriad of unwanted adverse effects, including diabetes mellitus, hypertension, immune dysregulation and osteoporosis (Russell et al., 2019).

Glucocorticoids also interact with the major neurotransmitters and many secondary neuro peptidergic systems. As such, glucocorticoids modulate emotion and cognition, with key examples being learn ing ability, performance, emotional perception and mood. These interactions also exemplify how glucocorticoid therapy can result in multiple effects, including unwanted adverse effects such as depression (Russell et al., 2019).

NADIR: the lowest point in the fortunes of a person or organization.

CORT is a homeostatic anticipatory hormone that is secreted by the adrenal glands. Consequently, under basal conditions it is released with a characteristic circadian pattern of secretion with high levels just before waking (start of the active cycle), followed by a steady decline down to trough (or nadir) levels during the sleeping or inactive phase, hence anticipating the needs of the body (Russell et al., 2019).

These circadian fluctuations in activation of glucocorticoid receptors also have important interactions with multiple other crucial homeostatic processes, including the transcriptional activity of other genes that respond to glucocorticoids and their corresponding physiological outputs, such as physical activity and body temperature (Russell et al., 2019).

Stress Response

ACUTE STRESS: The acute response to stress is a dynamic process that changes over time, starting with stereotypic behaviours and then changing to goal-directed behaviours specific to the stressor, followed by activation of the SAM within seconds and finally recruitment of the HPA axis, with peak levels of cortisol occurring between 15 and 20 min after stress onset. These early responses provide increased energy resources and initiate longer term and slower genomic effects that restrain inflammatory and other potentially dangerous responses (Russell et al., 2019).

Obstructive sleep apnoea is a good example of chronic stress.

CHRONIC STRESS: In response to chronic stress, a dynamic change in the ratio of AVP to CRH in the hypothalamic PVN occurs as well as an associated decreased sensitivity to the glucocorticoid feedback. In sleep apnoea, there is a marked increase in the amount of cortisol released during each secretory pulse, which normalizes after continuous positive airway pressure treatment. In critical illness, the situation is somewhat different with the increased levels of cortisol produced by long term stress being present for the first few days secondary to increased adrenal sensitivity to ACTH and increased cortisol synthesis. During long term critical illness, a further change in HPA axis regulation occurs with reduced cortisol metabolism becoming an increasingly important factor in maintaining raised levels of plasma cortisol (Russell et al., 2019).

Sleep Deprivation and Circadian Disruption Stress, Allostasis, and Allostatic Load

Allostatic load/overload: refers to the cumulative wear and tear on body systems caused by too much stress and/or inefficient management of the systems that promote adaptation through allostasis.

(McEwen et al., 2015)
Fig. 1. Nonlinear network of mediators of allostasis involved in the stress response. Arrows indicate that each system regulates the others in a reciprocal manner, creating a nonlinear network. Moreover, there are multiple pathways for regulation (eg, inflammatory cytokine production is negatively regulated via anti-inflammatory cytokines as well as via parasympathetic and glucocorticoid pathways), whereas sympathetic activity increases inflammatory cytokine production. Parasympathetic activity, in turn, contains sympathetic activity. CNS, central nervous system; DHEA, dehydroepiandrosterone (McEwen et al., 2015)

Allostasis and Allostatic Overload

The maintenance of homeostasis, defined as those aspects of physiology that must remain stable to keep us alive (eg, oxygen tension, body temperature, pH), is an active process requiring coordinated action of many different systems, including the autonomic nervous system and neuroendocrine and immune systems (McEwen et al., 2015).

This active process is called “allostasis” or “maintaining stability through change.” Allostatic mediators work as a nonlinear, sometimes reciprocating, network (Fig. 1), meaning that too much or too little of each mediator can perturb the entire network, leading to harmful consequences (McEwen et al., 2015).

Take for example the relationship between cytokines and the glucocorticoids. Pro-inflammatory cytokines stimulate the production of cortisol, which then suppresses inflammatory cytokine production (McEwen et al., 2015).

Similarly, increased activity of the sympathetic nervous system increases pro-inflammatory cytokine production, whereas parasympathetic activity has the opposite effect (McEwen et al., 2015).

This balance is particularly important, as during an infection, the proinflammatory response that is essential to mounting an immune defense is normally contained by cortisol and also by parasympathetic activity (McEwen et al., 2015).

Inadequate containment can lead to septic shock and death. Treatment with cortisol, or elevation of parasympathetic activity, is a pathway that can reduce the exaggerated inflammatory response. However, at the opposite extreme, too much cortisol can suppress pro-inflammatory responses, thus compromising immune defenses (McEwen et al., 2015).

Allostatic overload, which is wear and tear produced by imbalances in the mediators of allostasis, is perfectly illustrated by these 2 examples: too much or too little activity of certain mediators of allostasis (McEwen et al., 2015).

Other examples of allostatic overload include conditions such as hypertension, atherosclerosis, diabetes, and the metabolic syndrome as well as stress-induced remodeling in brain regions that support memory, executive function, and anxiety (McEwen et al., 2015).

One of the key mediators of allostasis is cortisol (corticosterone in rodent species), and conditions in which corticosteroid balance is affected lead to many such changes in physiologic function and brain structure (McEwen et al., 2015).

Circadian Disruption and Allostatic Load and Overload

When exploring how the brain and body are affected by stress, it is often overlooked that they may be directly regulated by time of day. All of the systems that are modulators of allostasis show rhythms of activity over the sleep-wake cycle (McEwen et al., 2015).

It is posited that if efficient regulation of the HPA axis is a hallmark of a “healthy” response, then disrupted circadian patterns (or, in this case, a lack of a pattern) can result in an unhealthy regulation of the HPA and thus could contribute to allostatic load (McEwen et al., 2015).

Thus, both disruption of the HPA axis and disruption of circadian rhythms could have interacting effects and contribute to shifts in resilience and vulnerability (McEwen et al., 2015).

Both descriptive and epidemiologic studies show that individuals who suffer from repeated chronic circadian misalignment show negative physiologic, neural, and behavioral effects (McEwen et al., 2015).

The specific mechanisms by which disrupted circadian clocks cause changes in brain, behavior, and peripheral physiology remain unknown (McEwen et al., 2015).

One hypothesis is that disrupted light-dark cycles lead to a gradual loss of cohesion between circadian clocks in the brain (eg, the SCN) and those in the body (eg, liver) (McEwen et al., 2015).

This loss of cohesion results in central and peripheral oscillators eventually becoming out of phase with each other, creating internal desynchrony (McEwen et al., 2015).

In the brain, this could lead to changes in synchrony between various nodes of a neural circuit (eg, the prefrontal cortex and amygdala drifting out of phase). Over many cycles, such loss of cohesion could lead to changes in neurobehavioral function (McEwen et al., 2015).

In addition to long-term, chronic Circadian Disruption (CD), shorter durations of CD could lead to changes in these circuits that make them more vulnerable to further insult and could be a more insidious mechanism of circuit level disruption, setting the stage for other stressors (eg, metabolic stress, immune stress) to overwhelm an already compromised network (McEwen et al., 2015).

Extending this model to the periphery, disruption of peripheral body clocks could lead to changes in the way the stress system responds to environmental or psychological stressors (McEwen et al., 2015).

Together, this model illustrates how CD could lead to neural circuits becoming more vulnerable to insult as well as pathways by which disruption could compromise allostatic responses engaged to help an organism adapt to environmental challenge (McEwen et al., 2015).

In this schema, CD effects may be similar to the diathesis-stress models, which could explain many of the epidemiologic findings of increased risk for development of psychiatric, cardiovascular, or other physiologic syndromes in populations undergoing chronic CD, such as shift workers (McEwen et al., 2015).

Neural Responses to Sleep Deprivation

The brain is the master regulator of the neuroendocrine, autonomic, and immune systems. It is important to remember that it is also the master regulator of behaviors that contribute to unhealthy or healthy lifestyles, which, in turn, influence the physiologic processes of allostasis. Therefore, chronic stress can therefore have direct and indirect effects on cumulative allostatic overload (McEwen et al., 2015).

There are many disparate changes driven by allostatic overload resulting from chronic stress. In animal models, chronic stress causes atrophy of neurons in the prefrontal cortex and hippocampus, brain regions involved in executive function, selective attention, and memory. On the other hand, chronic stress leads to hypertrophy of neurons in the amygdala, a region involved in fear, anxiety, and aggression (McEwen et al., 2015).

Thus, chronic stress compromises the ability of an organism to learn, remember, and make decisions, as well as increases levels of anxiety and aggression (McEwen et al., 2015).

The neural mechanisms of the effects of sleep deprivation on behavior are still not understood. Recently, clear effects of sleep and sleep deprivation on hippocampal function has been demonstrated, showing that hippocampal network activity changes during sleep-dependent memory consolidation, and that sleep deprivation can affect hippocampal synaptic plasticity during defined timeframes. Work in the visual cortex also shows that sleep affects memory consolidation, suggesting these effects are not merely limited to the hippocampus (McEwen et al., 2015).

Circadian Disruption and Sleep

Sleep is thought to be a neural state during which consolidation of declarative memories takes place.

The vast influences of Circadian Disruption on Quality of Life.

Sleep deprivation, even for the course of the active period of the day in diurnal animals, increases the homeostatic drive to sleep, with resulting changes in pro-inflammatory cytokines and glycogen levels (McEwen et al., 2015).

Relatively brief deprivation of sleep promotes an exacerbation of these processes with progressively more severe physiologic, neurobiological, and behavioral consequences as the sleep deprivation is prolonged (McEwen et al., 2015).

CD is a broader aspect of the problem of sleep disruption, with disruption of the circadian clock contributing to changes in sleep patterns, and sleep patterns potentially influencing the circadian clock (McEwen et al., 2015).

Shift work and jet lag are 2 common practices that have measurable effects on the brain and body. For instance, long distance air travel with short turnaround has been reported to be associated with smaller volume of the temporal lobe and impaired performance on a visual-spatial cognitive task (McEwen et al., 2015).

The long-term consequences of sleep deprivation and CD constitute a form of allostatic load, with consequences involving hypertension, reduced parasympathetic tone, increased proinflammatory cytokines, increased oxidative stress, and increased evening cortisol and insulin. (McEwen et al., 2015).

As noted above, reduced sleep and CD are associated with increased chances of cardiovascular disease and diabetes. Indeed, shorter sleep times have been associated with increased obesity (McEwen et al., 2015).

Moreover, diabetes is associated with impaired hippocampal function, decreased hippocampal volume and increased risk for Alzheimer disease are observed. In addition to the inflammatory and cardiometabolic changes that are observed, depressive illness is almost universally associated with disturbed sleep (McEwen et al., 2015).

Thus, there are not only linkages between the multiple, interacting mediators that are involved in allostasis and allostatic load/overload, as summarized in Fig. 1, but also overlaps (ie, comorbidities) between disorders, such as diabetes, hypertension, cardiovascular disease, and depression, that are associated with excessive stress and with the dysregulation of the systems that normally promote allostasis and successful adaptation (McEwen et al., 2015).

Sleep has important functions in maintaining homeostasis and sleep deprivation. Sleep deprivation or other forms of circadian disruption are stressors that have consequences for the brain as well as many body systems. Whether the sleep deprivation or circadian disruption is due to anxiety, depression, jetlag, shift work, or other aspects of a hectic lifestyle, there are consequences that contribute to allostatic load throughout the body. Taken together, these changes in brain and body are further evidence that circadian disruption predisposes an individual to altered responses to stressors as well as impaired cognitive function and metabolic dysregulation. Sleep deprivation can be described as a chronic stressor that can cause allostatic overload, including mood and cognitive impairment and autonomic and metabolic dysregulation (McEwen et al., 2015).

ADHD, Circadian Disruption and Comorbidity

Circadian Disruption is a major contributor to both mental and somatic disorders, and ADHD as a neurodevelopmental, chronic and lifelong illness, is linked to all parts of this complex causilty, as shown in the vast evidence for comorbid disorders, known to be associated with ADHD.

Therefore it is logical to link this evidence together, and conclude that ADHD is either causing Circadian Disruption (due to the developmental delay of the phsycial brain structures) or that Circadian Disruption is causing comorbidity in persons with ADHD.

Multiple lines of evidence in the past couple of years, have repeatedly shown indirect proof of the link between ADHD and Circadian Disruption. According to recent study on ADHD and Circadian Rhythms showed that upwards of 80% of all suffering from ADHD, also suffers from a sleep disorder (Biljenga et al. 2019).

In a pivotal Norwegian study on ADHD and comorbidity, a comprehensive list of comorbidities where linked to ADHD via meta-analyses of published studies on ADHD and specific comorbidity, see table for a complete list (Instanes et al., 2018).

ADHD and Circadian Disruption

Attention-deficit/hyperactivity disorder (ADHD) is highly associated with the delayed sleep phase disorder, a circadian rhythm sleep–wake disorder, which is prevalent in 73–78% of children and adults with ADHD. Besides the delayed sleep phase disorder, various other sleep disorders accompany ADHD, both in children and in adults. ADHD is either the cause or the consequence of sleep disturbances, or they may have a shared etiological and genetic background (Biljenga et al., 2019).

The functional and neuroanatomical overlap between brain regions involved in attention, arousal, and sleep regulation reflects the complex relationship between ADHD and sleep. Sleep problems may be causes, effects, or intrinsic features of ADHD (Biljenga et al., 2019).

For instance, in young children we are all familiar with the hyperactive, ‘high-spirited’ behavior when they are very tired. These children compensate for their fatigue with hyperactive behavior. In this example, hyperactivity is caused by sleepiness and is regarded as a vigilance autostabilization behavior (i.e., keeping yourself awake by moving/talking) (Biljenga et al., 2019).

A healthy adult experiencing drowsiness at home near bedtime will feel sleepy and will decide to ‘withdraw,’ seeking an environment with low external stimulation, thus increasing the probability of falling asleep. However, when this same healthy adult is driving a car experiencing the same drowsiness, he will try to avoid further drowsiness by turning up the volume of the radio, open the window and lower the temperature by turning down the heating, and so on. Hence, this healthy person will exhibit autostabilization or externalizing behavior in order to stay awake (Biljenga et al., 2019).

This autostabilization behavior can thus be either adaptive (i.e., keeping oneself awake while driving a car) or maladaptive (i.e., the hyperactivity in children with ADHD and the constant mind wandering in adults with ADHD), depending on the circumstance and chronicity (Biljenga et al., 2019).

A child exhibiting hyperactive behavior in the evening may seem full of energy and thus postpone bedtime. Also, adults may experience internal hyperactivity such as internal restlessness, many thoughts, or rumination that keeps them awake (Biljenga et al., 2019).

Another link between sleep and ADHD is that sleep disorders may also lead to symptoms, behaviors or functional impairments that mimic those in ADHD, such as concentration problems, learning impairment, problematic behavior, and emotion dysregulation (Biljenga et al., 2019).

This points to the direction that sleep problems and ADHD share intrinsic features. In a recent study among healthy individuals, the trait impulsivity was associated with objective measures of phase delay, lower sleep quality and sleep efficiency (Biljenga et al., 2019).

Furthermore, medical treatment of ADHD also impacts sleep, with limited evidence for both positive effects in children and adults, and negative effects in children. Moreover, children with ADHD with a longer sleep duration before the start of their treatment have a higher chance of better treatment response (Biljenga et al., 2019).

The delayed circadian rhythm and ADHD have genetic associations and shared environmental factors, and may have shared etiology. Symptoms of ADHD, a delayed circadian rhythm, and sleep disorders are thus intertwined by various pathways. They seem to share a genetic and etiological background and may profit from a common treatment. However, results from studies investigating such common treatment are yet scarce (Biljenga et al., 2019).

Time to redefine ADHD?

There are multiple indications that treating those sleep problems reduces ADHD symptoms. The main current scientific consensus is that a dopamine and/or norepinephrine deficit is the neurochemical basis of ADHD that is associated with the main clinical problems of hyperactive, impulsive, and inattentive behavior (Biljenga et al., 2019).

However, ADHD might be better conceptualized as a ‘heterogenous’ disorder from the neurobiological perspective, where at least several subtypes with different etiology exist, most clearly evidenced by the fact that none of the current neurobiological treatments have perfect efficacy (Biljenga et al., 2019).

In line with this notion of neurobiological heterogeneity, it makes more sense to aim to explain this neurobiological heterogeneity, in order to develop more specific treatments (Biljenga et al., 2019).

We therefore propose a novel hypothesis: ADHD symptoms resulting from a chronic sleep disorder, with most evidence for the delayed sleep phase disorder, in a large group of patients with ADHD. Chronic circadian sleep disorders that may have a large genetic component, almost always lead to poor sleep quality and/or quantity, with presumed suboptimal development or function of the dopaminergic system and thus to ADHD-like symptoms such as concentration problems, inattention, impulsivity, and hyperactivity (Biljenga et al., 2019).

This may also be true for other sleep disorders, but those have been studied less. However, it is yet unknown whether the (chronic) sleep problems are the sole cause of ADHD symptoms, if there are other underlying mechanisms to the ADHD symptoms, or if the causation in patients is heterogeneous (i.e., the etiology of the ADHD symptoms is different across patients). More research is needed to disentangle these issues and to verify our hypothesis (Biljenga et al., 2019).

Conclusion from Biljenga et al., 2019: In summary, our plea for a redefinition of part of the ADHD symptoms as the result of a chronic sleep disorder is based on the following pieces of evidence that have been discussed throughout this manuscript:

  1. The consistent findings of increased prevalences of various sleep disorders in ADHD populations across studies.
  2. Solid scientific evidence for a strong relationship between symptoms of ADHD and a delayed circadian, with 73–78% of patients with ADHD having a delayed circadian rhythm.
  3. Sleep restriction studies and cross-sectional studies show that shorter sleep is associated with impaired sustained attention and executive functioning.
  4. Genetic associations between ADHD and a delayed circadian rhythm.
  5. A higher ADHD prevalence in countries and geographical areas with lower solar intensities and thus less entrainment to the day and night by the central biological clock.
  6. Possible indications of a lower functioning of photosensitive retinal cells that are key for optimal entrainment of the circadian rhythm to the natural day and night cycle.
  7. Indications of an effect of light therapy both on a phase advance of the circadian rhythm and on the symptoms of ADHD.
  8. The central role of dopamine in ADHD, sleep, and retinal circadian alignment.
  9. First indications of the short- and long-term effects of sleep improvement (by sleep hygiene measures, melatonin, light therapy, and SMR neurofeedback in delayed sleep; adenotonsillectomy in sleep apnea, and drug treatment in restless legs syndrome) on the reduction of the severity of ADHD symptoms.

Finally, we propose some scientific direction for future studies:

  1. The longitudinal relationship between sleep and ADHD over the lifespan.
  2. The functioning of the retinal photosensitive cells of ADHD patients.
  3. The additive effect of chronotherapy for the delayed sleep phase disorder to an existing ADHD treatment regime.
  4. The effect of treatments for other sleep disorders on ADHD symptomatology.

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