Review
The neurobiology, investigation, and treatment of chronic insomnia

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Summary

Chronic insomnia is defined by difficulties in falling asleep, maintaining sleep, and early morning awakening, and is coupled with daytime consequences such as fatigue, attention deficits, and mood instability. These symptoms persist over a period of at least 3 months (Diagnostic and Statistical Manual 5 criteria). Chronic insomnia can be a symptom of many medical, neurological, and mental disorders. As a disorder, it incurs substantial health-care and occupational costs, and poses substantial risks for the development of cardiovascular and mental disorders, including cognitive deficits. Family and twin studies confirm that chronic insomnia can have a genetic component (heritability coefficients between 42% and 57%), whereas the investigation of autonomous and central nervous system parameters has identified hyperarousal as a final common pathway of the pathophysiology, implicating an imbalance of sleep–wake regulation consisting of either overactivity of the arousal systems, hypoactivity of the sleep-inducing systems, or both. Insomnia treatments include benzodiazepines, benzodiazepine-receptor agonists, and cognitive behavioural therapy. Treatments currently under investigation include transcranial magnetic or electrical brain stimulation, and novel methods to deliver psychological interventions.

Introduction

In 2002, about 6% of the adult population in high-income countries had chronic insomnia.1 If acute insomnia is considered, the diagnostic prevalence rises to almost 50% of the population. Thus, as a transient phenomenon, insomnia is commonplace and frequently remits spontaneously. In its chronic form, insomnia is associated with several negative health outcomes and a severely reduced quality of life.2 In a 2009 longitudinal study,3 181 out of 244 individuals who fulfilled the DSM-IV diagnostic criteria for at least 4 weeks, still had insomnia 1 year later. Gender has a strong effect on the prevalence of insomnia, with women having insomnia more frequently than men at a ratio of 1·4:1.1 This difference becomes even more pronounced after the age of 45 years, reaching a ratio of 1·7:1. Epidemiological data from a British sleep survey indicate that the inability to relax or unwind (a racing mind) is reported as the main reason for inability to sleep.

Prospective longitudinal studies have shown that individuals with insomnia show a heightened risk for developing acute myocardial infarction (relative risk 1·5; 95% CI 1·2–1·8).4 An important mediator for this association might be the short sleep duration, which has been linked to cardiovascular disease both when assessed subjectively5 or polysomnographically.6 Insomnia also arises frequently in the context of neurological disorders. Mayer and colleagues report that insomnia as a symptom ranges in prevalence from 25% to 60% in patients with multiple sclerosis, Parkinson's disease, Alzheimer's disease, stroke, traumatic brain injury, or epilepsy.7 Moreover, insomnia is involved in the development of cognitive impairment,8 and a cross-sectional correlation between poor sleep quality and cortical atrophy has been shown in community dwelling elderly adults.9

The epidemiological literature describing the association between insomnia and mental disorders, especially depression, shows a particularly strong correlation. One meta-analysis10 showed that insomnia independently confers a two times increased risk of development of depression in subsequent years. In other meta-analyses, insomnia also specifically conferred a two times increased risk for suicidal ideation and behaviour, although this risk was not moderated by depression.11, 12 Insomnia is increasingly regarded as an independent risk factor for work disability, sick leave, and reduced work performance.13 These data are complemented by economically driven analyses concluding that insomnia is associated with high direct and indirect costs for the health-care system and society.14

In this Review, we aim to summarise the basic research on sleep–wake regulatory mechanisms that are of relevance for the understanding of chronic insomnia. These findings will be contextualised within evidence from clinical studies. This approach is expected to help provide a conceptualisation of insomnia as a disorder of the brain with long-lasting negative consequences for somatic and mental health. Our introductory overview regarding the epidemiology, diagnosis, and public health effects underscores the necessity to develop a comprehensive psycho-neurobiological understanding of insomnia. This Review will focus only on chronic insomnia with duration of at least 3 months, and not on acute or transient insomnia.15

Section snippets

Diagnostic classification of insomnia

With respect to diagnostic classifications, an important change in the way insomnia is diagnosed was recently defined in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders16 and the third edition of the International Classification of Sleep Disorders.17 Instead of classification of insomnia into primary or secondary forms, this distinction was removed in favour of an umbrella category for insomnia disorder which could be used in cases when insomnia is comorbid with

Sleep–wake regulation

The basic tenets of sleep–wake regulation have been formulated in the two-process model.20 According to this model, two major processes govern sleep–wake rhythms: a circadian (chronobiological) process and a homoeostatic process. The circadian process reflects the fact that, from the cellular to the system level, the variation in intrinsic activity over 24 h follows a sinusoidal curve. This activity is controlled by an internal clock located in the suprachiasmatic nuclei and synchronised to the

Genetics and epigenetics of insomnia

Family studies undertaken in infants, adolescents, and adults have provided solid evidence for a familial aggregation of insomnia.40, 41 In afflicted individuals, between 35% and 55% of first-degree relatives also have insomnia, which is a substantially higher rate of insomnia than that seen in first-degree relatives of good sleepers. To separate genetic and environmental factors, several twin studies have been done yielding heritability coefficients between 42% and 57%.42, 43, 44 Moreover, a

Pathophysiological markers of insomnia

The pathophysiology of insomnia has been mainly investigated from the perspective of the hyperarousal model.53 This approach is based on a long-standing history of clinical observation and empirical findings that patients with insomnia display signs of increased arousal either on a cognitive-emotional', behavioural, autonomous, or central nervous system level. A substantial number of cross-sectional case-control studies have been undertaken to investigate the hypothalamic-pituitary-adrenal axis

Insomnia treatment

Despite striking progress in the understanding of the neurobiology of sleep–wake regulation, primary treatments for insomnia such as cognitive behavioural therapy for insomnia (CBT-I), benzodiazepines, and benzodiazepine-receptor agonists were all introduced into clinical practice at least three decades ago. About 40% of patients with chronic insomnia do not reach sustained remission with these treatments.92

At present, CBT-I is the first-line treatment for chronic insomnia.93 This treatment

Conclusions and future directions

This Review aimed to delineate neurobiological aspects of chronic insomnia, thus adding to and complementing the existing literature on psychological aspects of the disorder. Whereas the psychological aspects can be considered as a top-down perspective in the understanding of chronic insomnia, the search for neurobiological origins is a bottom-up approach. The reviewed evidence suggests a genetic component for the development of insomnia, probably in the form of an inherited vulnerability

Search strategy and selection criteria

We identified studies on the neurobiology of chronic insomnia through a search of PubMed with the term “insomnia” linked to any of the following terms: “neurobiology”, “brain”, “central nervous system”, “genetics”, “cortisol”, “heart rate variability”, “power spectral analysis”, “polysomnography”, “MRI”, “fMRI”, “PET”, “SPECT”, “spectroscopy”, “treatment”, or “therapy”. We searched Pubmed from Jan 1, 1980 to Jan 31, 2015. Further relevant studies were found by examination of reference lists of

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