Insomnia – Neurobiology | Pathophysiology | Assessment and Management

NEUROBIOLOGY OF INSOMNIA

Research into the neurobiological basis of insomnia has not revealed any definitive answers yet. As previously described, the heterogeneity of the disorder makes it difficult to define a precise causal relationship. [Riemann D et al., 2015]

Detailed review on the Neurobiology and Neuropsychiatry of Sleep – Application to Clinical Practice

Two major processes govern the sleep-wake cycle.

1.Circadian process:

• The circadian process is linked to an internal clock located in the suprachiasmatic nuclei and synchronised to the time of day by external clues, mainly the light-dark cycle. Melatonin and adenosine regulate the sleep-wake cycle.
• All cells in the body contain this core clock.
• Melatonin is a hormone produced by the pineal gland, and its secretion is suppressed by light.  Its secretion starts at twilight and peaks during the middle of the night.  This is associated with the circadian rhythm.

• On the other hand, the neuropeptide adenosine has been identified as a sleep promoter. It can inhibit arousal by blocking activities of the orexin system, which is known to induce arousal and wakefulness.
• The endogenous rhythms are influenced by ‘zeitgebers’ (time-givers), with blue light being the most prominent zeitgeber in mammals. Other zeitgebers include eating, physical and social activity.
• Wrist-worn actigraphs are increasingly utilised to measure ambulatory activity rhythm and sleep patterns. [Slyepchenko A et al., 2019]

2. Homeostatic process:

• On the other hand, the homeostatic process, which is the need for sleep, is a function of the time since the last adequate sleep.

There are two systems of sleep-inducing and wake-inducing brain pathways that constitute a flip-flop switch that is responsible for the transition between sleep and wakefulness.

Wakefulness System: 

• The ascending reticular activating system consists of monoaminergic, cholinergic, histaminergic and glycinergic neurons in the brainstem.
• These structures project to the thalamus, basal forebrain and cerebral cortex and are involved in the generation of wakefulness.
• The neurons from the locus coeruleus project to the basal forebrain, pre-optic area, hypothalamus, thalamus and cortex and are instrumental in regulating arousal and awake state.

Sleep-promoting system

• The ventrolateral and medial preoptic nucleus inhibits the ascending reticular activating system, constituting the sleep-promoting system.

PATHOPHYSIOLOGY OF INSOMNIA

Individuals fluctuate between NREM stages 1 to 3 and REM periods in 90 to 120-minute cycles. [Riemann D et al., 2015]

5% of the night is spent in stage 1, 50% in stage 2, 20% in stage 3 and REM sleep, whereas 5% of the night is spent awake.

Characteristics of stages of sleep: [Carley D & Farabi S., 2016]

1. Drowsy wakefulness: associated with alpha waves (8- to 13-Hz)
2. Stage 1 NREM (N1):  loss of alpha rhythm and presence of theta waves (4–7 Hz).
3. Stage 2 NREM (N2): marked by the expression of spindles (burst-like trains of waves 11- to 16-Hz) and K-complexes (well-defined biphasic waves lasting ≥0.5 seconds and usually maximal over the frontal cortex).
4. Stage 3 NREM sleep (N3): Deep sleep is also associated with slow (0.5–3 Hz) waves known as delta waves.
5. REM sleep: associated with the lowest skeletal muscle tone and with either sharp theta waves (sawtooth waves) or wake-like EEG patterns

Normal Brain EEG waves

Insomnia may occur due to some neurobiological changes in the sleep-wake regulation mechanisms outlined below:

1. Misalignment of the circadian process leading to phase delays or advances (prolonged sleep-onset latency).
2. Delayed or advanced melatonin secretion.
3. Dysfunction of the homeostatic process.
4. Maladaptive behaviours reducing the homeostatic process.
5. Reduced GABAergic activity or orexigenic over-activity.
6. Over-activity in the hypothalamus, hippocampus, amygdala, and prefrontal cortices.
7. The hyperarousal model of insomnia (see diagram below) describes an increased activation of cognitive-emotional, behavioural, and autonomous processes during waking and sleeping hours. [Morin C et al., 2015]
8. Comorbid psychological or medical issues and genetic vulnerabilities also exacerbate this imbalance between arousal and sleep-inducing brain activity.

GENES ASSOCIATED WITH INSOMNIA [Riemann D et al., 2015]

1. GABRB3: Regulation of GABAergic inhibition
2. 3111T/C Clock: Timing of the circadian rhythm
3. 5-HTTLPR: Regulation of serotonin in the synapse
4. ROR1: Modulation of neurite growth and synapse formation
5. PLCB1: Regulation of calcium signalling
6. CACNA1C: Regulation of calcium signalling

ASSESSMENT OF INSOMNIA [Morin C et al., 2015]

Evaluation: A diagnosis requires the patient to have symptoms of insomnia for ≥3 nights per week and to be present for >3 months.

The 3P model [Spielman A et al., 1987] can help the clinician focus on a sleep history.

Predisposing factors: e.g. genetic and personality traits leading to physiological and cognitive hyperarousal.

Precipitating factors: triggers, e.g.  grief or stressors

Perpetuating factors: factors that allow insomnia to continue, even when the trigger is removed. e.g poor sleep hygeine

1.Insomnia Symptoms

• Age of onset, precipitating events sudden or gradual onset.
• Current symptoms including difficulty getting to sleep, problems staying asleep and waking up too early.
• Frequency of symptoms, every night, episodic shifts, specific nights, situation-specific or seasonal variation.
• Course since the onset of symptoms, e.g. changes in severity over time
• Perceived daytime consequences include fatigue, reduced energy, impaired attention concentration, disturbances and difficulty functioning in an academic or occupational setting.

2. Factors influencing insomnia symptoms

• Past and current treatment, including efficacy. (e.g. sleep specialist, hypnotics, cognitive behavioural therapy etc.)
• Factors that improve or reduce symptoms.
• Factors that exacerbate insomnia such as stress or schedule changes.
• Factors that maintain insomnia including behavioural factors, for example, going to bed too early, poor sleep hygiene, getting extra sleep on the weekends, drinking alcohol and unhelpful beliefs about sleep and worry.

3. Evaluation of co-morbidities

• Comorbid sleep disorders, e.g. restless legs syndrome, REM sleep movement disorder, obstructive sleep apnoea
• Pain and discomfort
• Alerting effects of medication
• Persistent pain, cardiac or respiratory conditions, chronic inflammatory conditions
• Mental health issues, e.g. depression, bipolar disorder, anxiety etc.
• Medications, e.g. antidepressants, adrenergic agonists, over the counter stimulant medications for cold containing pseudoephedrine/phenylephrine, corticosteroids and opioids
• A family history of insomnia
• Excessive stimulant use such as caffeine, energy drinks, nicotine
• Shift work or long working hours with little recovery time between sleep

4. Psychosocial Factors

• Perfectionistic traits
• Arriving home late without enough time to wind down
• Family and social responsibilities at night such as caretaking of a child or elderly person
• Stressful life event
• Sleeping with pets.

5. Risk Assessment

Sleepiness when driving or operating equipment

6. Validated Scales

• Epworth Sleepiness Scale
• Insomnia Severity Index
• Pittsburgh Sleep Quality Index

7. Tools for Assessment of Insomnia [Krystal A et al., 2019]

Sleep Diary: A sleep diary is a form compiled by the patient, usually for at least two consecutive weeks, in which the patient notes down

• the time patient went to bed
• the time of lights out
• time to sleep
• time and duration of awakenings overnight
• time awake in the morning
• time out of bed
• naps
• perceived duration of sleep
• quality and depth of sleep.

Actigraphy:

• Actigraphy is a device worn on the wrist that records movement and employs an algorithm to estimate sleep and wake periods.

• It has satisfactory reliability with the “gold standard” polysomnography in good sleepers who spend little time awake and still, but not in those with sleep difficulties where significant periods of waking stillness occur. It is often combined with a light sensor to estimate the latency from lights out to sleep onset.
• Actigraphy can be useful for a patient whose sleep history is unreliable or when circadian disorders are suspected.

Personal Monitoring devices:

• Commercial devices measuring sleep are available but do not accurately reflect sleep architecture, sleep efficiency or latency, and tend to overestimate sleep duration in normal sleepers.
• They are not recommended in making clinical decisions until rigorous studies are carried out.

Polysomnography:

• Polysomnography is the gold standard to distinguish sleep from wake.
• It can be helpful to rule out other possible explanations for poor sleep, such as sleep apnea or periodic leg movement disorder.

MANAGEMENT

It is important to distinguish between acute and chronic insomnia.

Key principles in managing chronic insomnia: [Buysse D et al., 2017]

• Address anxiety about sleep
• Address maladaptive behaviours around sleep
• Address fear of further disruption of sleep
• Consider predisposing factors
• Consider co-morbidities
• Cognitive behavioural therapy for insomnia (CBT-I) is recommended first-line treatment.
• Consider pharmacological options as an adjunct to CBT-I
• Use hypnotics as a short-term measure
• Refer to a sleep specialist if symptoms continue despite the above measures

COGNITIVE BEHAVIOURAL THERAPY FOR INSOMNIA (CBT-I)

Cognitive–behavioural therapy for insomnia (CBT-I) is a sleep-focussed strategy consisting of a package of treatments aimed at changing unhealthy sleep-scheduling behaviours by creating a comfortable sleep environment, keeping a regular sleep schedule as well as advice on not to clock-watch, and not to take naps close to your regular bedtime. [Cunnington, D & Junge, M. 2016 ]

A recent meta-analysis of studies of CBT-I showed that multicomponent CBT-I reduced time to sleep onset by 19 mins; the amount of wakefulness after sleep onset by 26 mins, and these effects were sustained to 12 months after treatment.

The therapy package consists of the following components:

Sleep restriction

• Strengthens the homeostatic sleep drive by restricting the sleep window to only the duration spent in bed. Over time the sleep window can be increased until an optimal balance is achieved.
• Set a strict bedtime and waking schedule, limited to average expected hours of sleep. Keep a fixed wake time regardless of actual sleep duration.

Stimulus control

• Instructions are to go to bed only when sleepy.
• If unable to get to or return to sleep within 15-20 mins, leave the bed and go to another room and do a non-stimulating activity.
• Return to bed only when comfortable to sleep again.
• Further to this, the bedroom becomes a room only for sleeping and not watching television, etc.
• Arise at the same time every morning
• No napping

Relaxation strategies

• Breathing, focused relaxation, visual imagery and meditation. Muscle relaxation to relieve muscle tension as well as how to reduce intrusive thoughts.
• Practice relaxation techniques at least daily. Take short relaxation periods (2-3 mins) several times during the day.

Cognitive therapy

• Identifies and targets beliefs about sleep that may be contributing to anxiety and distress about sleep.
• Addresses unhelpful beliefs about sleep such as the number of hours required each night, overestimating the power of sleeping tablets, underestimation of actual sleep and fear of threats to sleep.
• Changes thinking about and approach to sleep

Sleep hygiene education

• Avoid long naps during daytime
• Exercise regularly
• Maintain a regular sleep-wake cycle
• Avoid stimulants (caffeine and nicotine)
• Limit alcohol before bed
• Keep the bedroom quiet, dark, clean and comfortable

PHARMACOLOGICAL MANAGEMENT

For many patients that are experiencing acute insomnia, a pharmacological approach can be taken as a short-term treatment strategy. [Morin C et al., 2015]

For those, who are suffering from chronic insomnia, pharmacological agents can also be used in combination with CBT-I.

Benzodiazepines 

• Benzodiazepines promote sleep by acting on the GABA Type A receptor complex.
• Agents such as triazolam are indicated for sleep-onset insomnia whereas temazepam is indicated for both sleep-onset and sleep-maintenance insomnia.
• Alprazolam may be useful in treating sleep problems in patients with substantial anxiety at night. In Australia, alprazolam has been upgraded to a schedule 8 (restricted authority) drug.
• Clonazepam improves sleep in patients with Major Depressive Disorder (MDD) and insomnia
• Many other benzodiazepines have little to no data on efficacy and safety. All benzodiazepine agents come with abuse potential.

Non-benzodiazepines: 

• Agents such as zolpidem, eszopiclone, and zaleplon (The Z-Drugs) have a similar mechanism of action to benzodiazepines, enhancing GABA-mediated inhibition through allosteric modulation of the GABA-A complex but are part of a different chemical class.
• These agents have been approved by the FDA for the treatment of sleep-onset insomnia with eszopiclone also indicated for sleep-maintenance insomnia.
• Long term trials of eszopiclone and extended-release zolpidem have shown sustained response with no tolerance or dependence after 6 months of daily use.
• Zolpidem has been associated with parasomnias.

Melatonin receptor agonists:

• Melatonin has a good safety profile but data indicates that it has a greater benefit for those with delayed sleep-phase syndrome rather than insomnia.
• It has shown particular efficacy in treating insomnia in individuals > 55 years of age. It is available as an extended-release form as well.
• Ramelteon is an M1 and M2 receptor agonist and is indicated for sleep-onset insomnia. It has minimal abuse potential.

Selective histamine receptor antagonists:

• Doxepin, mirtazapine, amitriptyline and trazodone are used off label to treat insomnia.

Antidepressants and Antipsychotics:

• Agents such as amitriptyline, trazodone and mirtazapine have been suggested to have sedative qualities however there is little to no clinical data on the risk-benefit of these antidepressants as a treatment for insomnia.
• Olanzapine and quetiapine are used off label and there are no placebo-controlled trials in insomnia, hence their risk-benefit ratio remains unknown.
• There is a significant risk of daytime sedation along with many other common adverse effects already associated with these specific agents.

Prazosin

• Unique therapeutic effects on nightmares and sleep disturbance associated with PTSD
• Orthostatic hypotension as a main side effect
• Minimum abuse potential

Clonidine:

• Sleep deprivation is known to affect the clearance of metabolic waste products via increased locus coeruleus (NA neuron projections) activity resulting in reduced NREM sleep and increased periods of wakefulness impeding clearance of toxins by the glymphatic system which is mainly active during NREM sleep.
• Thus, manipulation of NA tone may enhance glymphatic clearance providing a neuroprotective effect for the brain.
• Clonidine is an α2 agonist (high affinity for all 3 α2 -receptor subtypes, α2A, α2B and α2C) which is known to increase NREM sleep. While low doses (e. g., 25 μg) have little effect on REM sleep, 150 mcg clonidine reduces REM sleep by about 50 %.
• Indications include primary insomnia in the paediatric population,  insomnia in the context of ADHD, ASD PTSD and Borderline personality disorder. [Nguyen et al., 2013], [Broese et al., 2012]
• Guanfacine is also an α2 agonist (specific α2A). Higher doses of about 2 mg can reduce REM sleep by 26 % which is less marked than clonidine.

Orexin (hypocretin) receptor antagonists: 

• Suvorexant is a novel pharmacological treatment that blocks both orexin-A and B receptors, thus suppresses stimulatory processes rather than enhancing the sleep drive like most other drugs. [Herring W et al., 2016]
• Suvorexant is indicated for treating sleep-onset and sleep maintenance issues.
• Clinical trials have shown a sustained response for a year without significant rebound insomnia and a favourable adverse effect profile.
• Lemborexant is a new orexin antagonist which is effective for treating insomnia disorder, with significant benefits on sleep onset and sleep maintenance. Lemborexant is an effective option for patients who cannot tolerate most commonly prescribed medications for insomnia, such as benzodiazepines and sedative-hypnotics (Z drugs). It may be particularly useful in geriatric patients sensitive to side effects. [Waters, 2022]

Herbal and alternative medications

• Valerian has the most evidence showing improvements in sleep latency.

A recent systematic review and meta-analysis showed: [De Crescenzo et al, 2022]

Eszopiclone and lemborexant had a favorable profile, but eszopiclone might cause substantial adverse events and safety data on lemborexant were inconclusive. Doxepin, seltorexant, and zaleplon were well tolerated, but data on efficacy and other important outcomes were scarce and do not allow firm conclusions. Many licensed drugs (including benzodiazepines, daridorexant, suvorexant, and trazodone) can be effective in the acute treatment of insomnia but are associated with poor tolerability, or information about long-term effects is not available. 

CONCLUSION

Insomnia is a subjectively heterogeneous disorder but is suggested to be a neurobiological imbalance in critical arousal and sleep-inducing networks in the brain.

Since insomnia is closely linked to mental health conditions, understanding circadian science and the drivers of the sleep-wake cycle is becoming increasingly important.

An exciting methodological trend is the elevation of 24-hour activity monitoring through actigraphy (a well-understood form of wearable technology, originally from sleep research). Actigraphy provides a face-valid, non-intrusive, potentially clinically informative signal of synchrony with the light/dark cycle and hence vulnerability to circadian disruption. [Murray G., 2019]

More research is required to help define the aetiology and pathophysiological basis of the disorder so that treatment strategies can be optimised and novel treatments can be explored and developed.

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