Primer on Neurobiology and Neuropsychiatry of Sleep – Application to Clinical Practice

THE PHYSIOLOGY OF SLEEP-WAKE REGULATION

Sleep is regulated by two processes: process S and process C. [Borbély et al., 2016]

Process S (Homeostatic Process):

• Process-S reflects the increase in sleep pressure, or drowsiness, and is a function of the duration of wakefulness which starts accumulating after waking up in the morning.
• Sleep pressure increases during prolonged wakefulness and reduces during sleep.
• This sleep pressure or drowsiness is reflected as frontal theta activity, a slow EEG rhythm.
• This slow theta activity builds up during the day and gradually declines during sleep.

Process C (Circadian Process):

• Process C is a circadian process controlled by a circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus.
• The SCN is the ‘master circadian clock’ that generates and regulates the body’s circadian rhythms (biological clock) and synchronises them to the environmental 24-h light-dark cycle (circa – approximately; dies- day).
• Each tissue and cell has its molecular clock, known as the peripheral clock, which is also controlled and synchronised daily by the SCN.
• The SCN influences many internal systems, such as body temperature, endocrine functions, and blood pressure.
• The SCN is also synchronised to the external environment through zeitgebers (time givers), e.g. environmental temperature, daylight, food availability and socialisation.
• Day-light intensity reaching the eye’s retina is a crucial zeitgeber giving the SCN information about the time of the day, thereby leading to photoentrainment (coupling of light with circadian rhythm) of the internal clock system.

Circadian System: [Carpenter et al., 2021]

• In addition to rods and cones (for night and colour vision), the retina has the melanopsin-producing (M1-type) intrinsically photosensitive retinal ganglion cells (ipRGCs), which modulate, the pupillary reflex, the release of melatonin and dopamine, and project via the retinohypothalamic tract to the SCN.
• When light enters the eye and is translated via the retinohypothalamic tract to the SCN within the hypothalamus, SCN signals the pineal gland to turn off melatonin production.
• The photopigment melanopsin in these ipRGCs is most sensitive to blue light wavelengths (high energy short wavelength).
• When melanopsin is activated by the short wavelength component of light (e.g. blue light), it suppresses melatonin synthesis, e. g. during daylight.
• When daylight intensity is diminished and its colour spectrum shifts from blue to red, the SCN signals the pineal gland to produce melatonin.
• In addition to projection to the SCN, the ipRGCs also project to sleep-promoting neurons in the ventrolateral preoptic nucleus (VLPO) and superior colliculus.
• Melatonin and dopamine (DA) release are also closely linked. DA is released during the daytime and inhibits melatonin secretion, and this relationship reverses in the evening as exposure to light decreases.
• The rise of endogenous melatonin concentration is often used as the phase marker of the circadian rhythm.
• Dim-Light Melatonin onset: The time of the day when the melatonin concentration in saliva reaches the threshold of 3 -5 pg/ml is termed the dim-light melatonin onset (DLMO). [Pandi-Perumal et al., 2007]
• Sleep is typically initiated 2–3 h after the time of DLMO.

A recent study showed that:

• Greater night light exposure was associated with greater odds of major depressive disorder (MDD), generalised anxiety disorder (GAD), bipolar disorder, post-traumatic stress disorder (PTSD), self-harm behaviour and psychotic experiences.
• Conversely, greater daytime light exposure was associated with lower odds of MDD, PTSD, self-harm behaviour and psychotic experiences. There was no significant association between daylight exposure with GAD or bipolar disorder.

Avoiding light at night and seeking light during the day may be a simple and effective, non-pharmacological means of broadly improving mental health. [Burns et al., 2022]

The Glymphatic system (The garbage truck of the brain): [Reddy and van der Werf, 2020] 

• The glymphatic system constantly filters toxins from the brain and is active during sleep and deactivated during wakefulness.  [Jessen et al., 2015]
• During natural sleep, noradrenaline (NA) levels reduce, expanding the brain’s extracellular space, resulting in decreased fluid flow resistance.
• This is reflected by improved cerebrospinal fluid (CSF) infiltration along the perivascular spaces.
• These expansions and increases in CSF production decrease resistance and increase perfusion, leading to a further boost in removing metabolic waste products from the brain.
• This increase in clearance happens specifically during non-rapid eye movement sleep (N3) or slow-wave sleep (SWS), which is characterised by slow oscillatory brain waves, creating a flux of CSF within the interstitial cavities, increasing glymphatic clearance to 80–90% relative to the waking state.
• Impaired glymphatic clearance has been linked to neurodegenerative diseases.

SLEEP STRUCTURE

Normal sleep consists of several consecutive sleep stages that occur in a cyclic pattern of approximately 90 -120min per sleep cycle.

The first one or two sleep cycles are therefore regarded as ‘restorative’ sleep (NREM), while the last sleep cycles are more dominated by dreaming (REM sleep).

Approximately 75% of sleep is spent in the NREM stages (N1-N3).

From the start to the end of a night’s sleep, the relative amount of time spent in NREM- N3 (deep) sleep declines per cycle, while the relative duration of REM sleep increases over the sleep cycles.

Stages of sleep:

REM (Rapid Eye Movement):

• Low-amplitude, high-frequency EEG characterises REM sleep
• Characterised by muscle atonia
• Dream phase of sleep
• 25% of sleep.

NREM (Non-rapid eye movement sleep):

N1–N3 are graded from light to deep sleep, respectively. In the above diagram, they correspond to stages 2,3 and 4.

Characteristics of different sleep stages:

NREM Sleep:

N1 (non-REM stage 1):

• Associated with both alpha and theta waves.
• The early portion produces low-frequency, high-amplitude alpha waves (8–13 Hz) associated with a relaxed yet awake state. Later stages of this phase, as sleep progresses, are characterised by an increase in theta wave activity,  which are lower frequency, higher amplitude waves.
• 1 to 5 minutes (5% of total sleep time).

N2 (non-REM stage 2)

• The transition phase from N1 to N3.
• Characterised by N1 EEG signal with theta waves still dominating, plus short bouts of high amplitude (sleep spindles and K-complexes).
• 25 minutes in the first cycle, lengthening with each successive cycle (45% of total sleep).
• Stage of sleep where bruxism (teeth grinding) occurs.

N3 (non-REM stage 3):

• The deep sleep phase is characterised by high-amplitude slow-wave EEG (delta waves)
• 25% of total sleep.
• The stage when sleepwalking, night terrors, and bedwetting occur.

NEUROBIOLOGY OF SLEEP-WAKE REGULATION

NEUROTRANSMITTERS IN SLEEP-WAKE CYCLE

Role of Dopamine: [España and Scammell., 2011], [Perlis et al, 2009]

• Wake-active DA neurons in the vPAG promote wakefulness by acting on D1 and D2 receptors inhibiting the sleep-promoting neurons in the VLPO and stimulating the wake-promoting cell groups.
• D1 receptors enhance wakefulness and are excitatory.
• D2 receptors stimulation in the cortex likely stimulates wakefulness, while D2 action in the striatum promotes sleep.
• Thus, DA in the extra-basal ganglia circuitry promotes wakefulness. This network may also be responsible for the arousal effects of psychostimulants.
• DA also has circadian-like activities in the retina, olfactory bulb, striatum, midbrain, and hypothalamus.
• Activation of the DA system during sleep is linked to the emotional and hallucinatory aspects of dreaming.
• Dreaming is mediated by mesolimbic DA release (see later), which plays an integral part in reward experience and motivational drive.

Dreams as a Reward State:

There are different theories with regard to the functions of dreams. The 3 main theories are: [Nir & Tononi, 2010]

1. Psychodynamic
2. Activation-input-modulation (AIM) model
3. Neurocognitive

Interestingly the concept of sleep as a reward has similarities with the psychoanalytic dream theory of wish fulfilment (reward), with motivation acting as a significant contributor to dreaming: [Boag, 2017]

“Psychoanalysis is founded upon the analysis of dreams…”  [Freud, 1912]

Freud accordingly writes, “[s]ince a dream that shows a wish as fulfilled is believed during sleep, it does away with the wish and makes sleep possible” [Freud, 1901]

According to psychoanalytic dream theory, dreaming occurs because unconscious infantile wishes, which are easily suppressed during waking, become active in sleep. When the ego is off duty, the id becomes unruly. To the rescue of the sleeping ego come the defensive forces of disguise and censorship. They bowdlerize the kinky id forces and make them look non-sensical and meaningless whereas, in fact, they are masquerades for viciously potent entities that would overwhelm consciousness if admitted to that realm undisguised. [Hobson, 2014]

Further evidence that dreams may represent a reward experience underpinned by a motivational drive comes from studies of individuals with sensory and motor impairments: [Siclari et al., 2020]

• Individuals who had paraplegia since birth walked,  ran, danced, swam, bicycled, skied, gardened, and played basketball, pointing to a cerebral walking programme (possibly developed via mirror neurons) being reactivated during sleep.
• Most dreams of individuals who are deaf do not contain sensory limitations. Many patients speak in their dreams, and others can hear and understand spoken language.
• Participants with late-onset (>2·5 years) blindness report visual images in dreams, although tactile and auditory content is more frequent.
• Up to 21% of individuals with congenital blindness report some visual impressions in dreams when they still have light perception.
• Individuals with amputations continue to dream of being physically unharmed, even years after the amputation and even when the physical disability is congenital.

Activation of the DA system during sleep may be linked to creativity and problem-solving in artists and scientists. [Perogamvros et al., 2013]

It is said that Robert Louis Stevenson came up with the plot of Strange Case of Dr Jekyll and Mr Hyde during a dream and that Mary Shelley’s Frankenstein was also inspired by a dream at Lord Byron’s villa. Paul McCartney purportedly discovered the tune for the song “Yesterday” in a dream and was inspired to write “Yellow Submarine” after hypnagogic auditory hallucinations. Otto Loewi (1873–1961), a German-born physiologist, dreamed of the experiment that ultimately allowed him to prove chemical synaptic transmission, and was later awarded the Nobel Prize. [Perogamvros et al., 2013]

Role of Noradrenaline (NA): [Osorio-Forero et al, 2022]

• The primary source of NA to the forebrain is the LC.
• NA helps generate arousal during conditions that require high attention, or conditions that need responding to a behaviourally important stimulus, or activation of the sympathetic nervous system.

Goldilocks effect of NA activity for optimal PFC functioning: 

• An optimal level of NA is required for optimal attention and arousal. [Read here]
• If LC activity is too low, the individual may be drowsy and inattentive.
• If LC activity is too high, they may be distractible and anxious.
• LC neurons fire most rapidly during wakefulness.
• LC neurons are less active during NREM sleep.

REM sleep and NA:

• Restful (Sound) REM sleep is associated with a “time-out” of NA, i.e. the LC is silenced.
• Silencing of NA is associated with synaptic plasticity in limbic brain circuits activated during REM sleep.
• Restless REM sleep indicates insufficient LC silencing, and this prevents an NA-time-out which disrupts or alters synaptic plasticity in limbic circuits.

Orexin (ORX):

• The excitatory neuropeptides ORX-A and B (also known as hypocretin-1 and 2) are synthesised by neurons in the lateral and posterior hypothalamus.
• The ORX neurons heavily innervate all the arousal regions with particularly dense innervation of the LC (NA) and TMN (HA) and stimulate target neurons through the OX1 and OX2 receptors.
• ORX neurons fire mainly during wakefulness and are silent during NREM and REM sleep.
• ORX helps sustain wakefulness throughout the day and increases arousal in motivating conditions.
• ORX also promotes arousal responses to drive motivated behaviours such as seeking food. The ORX system is an essential link between metabolic function and sleep regulation.
• ORX activates the mesolimbic reward pathways, and ORX antagonists can reduce the motivation to seek drugs of abuse.
• Patients with narcolepsy with cataplexy have a severe (85% to 95%) loss of the orexin neurons and deficient ORX-A CSF levels.

Acetylcholine (ACh):

• LDT/PPT release ACh to excite neurons in the thalamus, hypothalamus, and brainstem, increasing wakefulness.
• Cholinergic neurons in the LDT/PPT are mainly active during wakefulness and REM sleep.
• Agents that reduce ACh signalling, including the muscarinic antagonists scopolamine and atropine, produce immobility and EEG slow waves.

Histamine (HA):

• The TMN neurons are the sole source of HA in the brain, with projections to the forebrain and brainstem.
• TMN firing rates and HA release are highest during wakefulness, lower during NREM sleep and lowest during REM sleep.
• Administration of HA or an H1-receptor agonist increases cortical activation and wakefulness while reducing NREM and REM sleep.
• In contrast, drugs that reduce HA signalling, such as the H1 receptor antagonists diphenhydramine, and low-dose doxepin, increase NREM and REM sleep.

Serotonin (5-HT):

• 5-HT is produced mainly by DRN neurons, which innervate the preoptic area, BF, hypothalamus, and thalamus.
• 5-HT promotes wakefulness and suppresses REM sleep. Without turning off serotonin transmission, neither initiation nor maintenance of REM sleep is possible.
• Suppression of NREM is carried out mainly by inhibition of VLPO neurons mediated by the 5-HT1A receptor.
• The firing rates of DRN and extracellular 5-HT levels are highest during wakefulness, much lower during NREM sleep, and lowest during REM sleep (similar to that of the NA and HA systems).

GABA and Galanin:  

• GABA neurons are inhibitory and are widely scattered across the cortex and play an essential role in sleep.
• The VLPO and MNPO neurons in the preoptic area contain the inhibitory neurotransmitter GABA (and galanin). They project to all the arousal-promoting regions, including the LDT/PPT, LC, DR, TMN, and orexin neurons.
• By inhibiting the arousal regions during REM and NREM sleep, the VLPO and MNPO promote sleep.
• The LHA has many REM sleep-active neurons that produce GABA.
• The BF and LHA contain scattered GABAergic neurons that are active during NREM sleep. Some of these cells may directly innervate the cortex and promote slow-wave activity.
• The sublaterodorsal (SLD) nucleus (subcoeruleus, or LCα) is a small group of cells ventral to the LC that produce GABA or glutamate.
• The SLD neurons are active during REM sleep and project to the ventromedial medulla and ventral horn of the spinal cord, inhibiting motor neurons.
• Activation of the SLD region elicits atonia and REM sleep-like EEG activity, while inhibition of the SLD promotes wakefulness and reduces REM sleep.
• Transitions between NREM and REM sleep are mediated by a mutually inhibitory circuit connecting the vPAG/LPT and SLD.

Melanin-concentrating hormone (MCH):

• The LHA has many REM sleep-active neurons that produce MCH (and GABA).
• These cells innervate nearly all the same target regions as the orexin neurons, including the DRN and LC, with inhibitory effects.
• MCH neurons fire at a high rate during REM sleep, with much less firing during NREM sleep and complete inactivity during wakefulness.

Adenosine (AD):

• AD is a byproduct of the breakdown of ATP and cAMP, with AD levels influenced by neuronal activity.
• With prolonged neuronal activity during wakefulness, ATP accumulates in the extracellular space and is degraded by 5′-EN to adenosine leading to the homeostatic pressure to sleep.
• Adenosine can be thought of as the homeostatic accumulator of the need to sleep. [Reichert et al., 2022]
• During sleep, AD levels decrease in the cortex, BF, hypothalamus, and brainstem, with AD acting specifically within the basal forebrain to influence the sleep/waking state by reducing the activity of most wake-promoting neurons and disinhibiting VLPO neurons.
• AD may also affect the circadian clock and the interaction between the circadian clock and sleep homeostatic mechanisms.
• Caffeine is an AD receptor antagonist, and ~200 mg of caffeine ingested in the early evening delays the endogenous melatonin rhythm by roughly 40 min, nearly half of the delay caused by bright light exposure at bedtime. [Burke et al., 2015]
• AD agonists increase slow wave activity (SWA) or delta power (deep sleep).

Cytokines:

• Inflammatory signals between the brain and periphery are mediated by vagal afferents (80%) to the Nucleus tractus solitarius (Hypothalamus), while vagal efferents (20%) have anti-inflammatory actions mediated by ACh receptor activation.
• Inflammation via the effect of cytokines differentially affects circadian rhythms by impacting the SCN. [Zielinski and Gibbons, 2022]

Effects of cytokines on sleep architecture: [Zielinski and Gibbons, 2022]

• IL-1 beta (IL-1β) and Tumour necrosis factor-alpha (TNF-α) are two pro-inflammatory cytokines that regulate sleep and interact with the circadian system.
• IL-1β and TNF-α flatten the diurnal rhythm of activity.
• IL-6 reduces SWS.
• The NLRP3 inflammasome is somatogenic and promotes NREM sleep during inflammation.
• In animal studies, TNF promotes NREM sleep in higher doses suppressing REM.
• Alterations in sleep architecture (REM suppression and NREM increase) might facilitate fever: energy is spared through long NREM, whereas shorter time spent in REM allows for shivering.
• IL-6 may lead to sleep disorders such as RLS. It induces hepcidin production in hepatocytes, which decreases iron absorption in the intestines and inhibits iron release from the macrophage, leading to hypoferremia, which is associated with fatigue, irritability, and RLS.

Prostaglandin:

• Prostaglandin D2 (PGD2) may contribute to the sleepiness seen with inflammation.
• PGD2  promotes sleep by acting through adenosine signalling pathways in the VLPO nuclei. [Nagata & Urade, 2012]

NEUROCHEMISTRY, NEUROPHYSIOLOGY AND NEUROBIOLOGY OF SLEEP PHASES

 [España and Scammell., 2011],[Perlis et al, 2009] ,[Morin et al., 2015] , [Van Someren, 2021]

REM sleep:

The REM sleep cerebral biochemical environment is unique.

• Complete absence of ORX (hypocretin) and monoamines – 5-HT, NA and HA, except DA (the concentration may sometimes even exceed that in wakefulness).
• High levels of ACh, DA, Glu and galanin.

GABA lock:

The release of GABA is high in areas of the ORX (LHA), HA (TMN), 5-HT (DR) and NA (LC) neurons, inhibiting the activity of these activating neurons during the entire period of REM sleep (GABA Lock), but in general GABA release is significantly reduced. [Kovalzon, 2021]

MCH peptide:

• Mediates the hypothalamo-pontine level of REM sleep regulation.

Functional aspects of REM sleep: [Pace-Schott & Picchioni, 2005]

• REM sleep is the key sleep phase associated with dreaming.
• The LDT/PPT cholinergic neurons activation promotes ACh release, which depolarises thalamic neurons resulting in cortical activation responsible for the complex dreams of REM sleep.
• Stimulation of limbic and prefrontal reward networks by dopaminergic projections from the midbrain VTA generates motivational impulses that initiate dreaming. [Solms, 1997]
• DA stimulation of the cortex during REM, in the absence of waking’s inhibitory 5-HT and NA modulation, allows the emergence of psychotomimetic (psychosis-like) aspects of dream consciousness. [Gottesmann, 2002]

Emotional aspects of dreaming: [Perogamvros et al., 2013]

• Increased activity and blood flow in limbic and paralimbic areas (amygdaloid complexes, hippocampal formation, and anterior cingulate cortex

Visual aspects of dreams: [Perogamvros et al., 2013]

• Activation of Posterior temporo-occipital cortices.

Reduced control over dreams: [Perogamvros et al., 2013]

• Reduction of frontoparietal associative and vigilance networks via the activation of emotional/motivational circuits
• Sleep and dreaming assist in reprocessing emotions and associative learning, improving memory organisation, waking emotion regulation, social skills, and creativity.

REM sleep can be divided into Restful and Restless REM sleep: [Van Someren, 2021]

• REM sleep is characterised by low-amplitude, high-frequency EEG and by high cholinergic and low NA modulation.
• REM sleep is associated with the activation of the amygdala–the hippocampus–medial prefrontal cortex circuit, which regulates the REM-ON neurons, the key to emotional processing, fear memory, and valence consolidation.
• Increased activity in the amygdala and across mesolimbic DA regions during REM sleep is likely to promote the consolidation of memory traces with high emotional/motivational value. [Perogamvros et al., 2013]

Clinical Implications of Restful REM sleep:

• Aids in “forgetting” the emotional tone and somatic arousal associated with initial emotional experiences.
• High REM h-activity on EEG is linked to low LC activity (NA neurons) and restful REM sleep. It is associated with less intrusive re-experiencing. [Sopp et al., 2019]
• Restful REM sleep leads to limbic circuit overnight adaptation (synaptic plasticity), resolving the burden of emotional memories by making them milder.
• The REM sleep-induced cessation of norepinephrine and serotonin release, by maintaining the optimal functioning of these receptors, would improve the organism’s ability to process information in wakefulness. [Siegel, 1990]

Clinical Implications of Restless REM Sleep:

• Interferes with emotional memory processing; if persistent, these adverse consequences may have a long-lasting impact on brain function.
• Restless REM sleep is also a biomarker of vulnerability to MDD. [Pillai et al., 2011]
• Prevents the reset of LC activity after entering sleep, resulting in ongoing hyperarousal, worsened significantly during REM sleep.
• Restless REM sleep is one of the most distinguishing sleep characteristics of insomnia.
• In conditions where the amygdala is hyperactivated, REM sleep may be significantly affected.
• People with insomnia show an enhanced amygdala response to insomnia-related stimuli and a lack of overnight attenuation of the amygdala response to emotional stimuli. [Van Someren, 2021]
• Strong, generally positive emotional stimuli, which might activate the amygdala, are known to trigger cataplexy in narcolepsy-cataplexy patients.
• Restless REM sleep can be targeted via medication that blocks NA receptors (e.g., β-blockers) or suppresses LC activity (e.g., guanfacine, clonidine, prazosin). 

REM Atonia:[Scammell et al, 2017]

• REM sleep is associated with decreased postural muscle tone.
• During wakefulness, ORX activates monoaminergic neurons, the vlPAG/LPT, and the vlPAG/LPT inhibits the SLD via GABAergic neurons, which prevents muscular atonia and REM sleep.
• During REM sleep, the vlPAG/LPT may be inhibited by MCH and GABA neurons, leading to SLD neurons activating GABA neurons in the ventromedial medulla and spinal cord that inhibit spinal and brainstem motor neurons during REM sleep leading to atonia.

• The hypoglossal (XII) motoneurons innervate the genioglossus, and both NA and 5-HT activate these motoneurons. The pontine NA neuron groups, which project to the XII motoneurons, have a state-dependent activity, maximal during active wakefulness and minimal or absent during REM sleep.
• The reduced activity of NA and 5-HT brainstem neurons during SWS and cessation of firing during REM sleep contribute to sleep-related upper airway hypotonia.
• Thus, atonia during REM sleep is probably due to a combination of inhibition (GABA and glycine) and a loss of excitation (NA and 5-HT). [Kubin, 2016]

NREM Sleep:

• NREM sleep may contribute to the selective strengthening of memories for important events.
• GABA increases with the deepening of NREM sleep, and the peptide galanin is co-localised with GABA. [Kovalzon, 2021]
• During NREM sleep, the circuit’s hippocampus–medial prefrontal cortex part is activated without the amygdala’s involvement.
• EEG shows high amplitude, low-frequency slow waves and spindles, and reduced cholinergic and NA transmission.

STRUCTURAL CORRELATES IN SLEEP-WAKE REGULATION

PFC and Sleep deprivation:

• The Frontoparietal network (FPN), which is the alerting network and the default mode network (DMN) activated during tasks that do not need significant attention, i.e. resting state, e.g. mind wandering, abstraction (DMN), are affected by sleep deprivation.
• The dorsolateral prefrontal cortex (DLPFC), thalamus, medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC) are differentially altered by sleep loss. [Krause et al., 2017]
• Prefrontal hypoactivation is assumed to be associated with daytime fatigue, and reduced recruitment of the caudate head is thought to be related to arousal regulation. [Morin et al., 2015]

PFC and Adolescence:

Adolescence represents a formative period for the emergence of higher-order cognitive networks with pronounced changes in multiple aspects of PFC development. [Anastasiades et al., 2022]

Sleep deprivation can significantly affect PFC development during adolescence and may have an enduring impact.

A state of limbic predominance characterises adolescence:

• In adolescence, glutamatergic synapse density is significantly reduced, while limbic connectivity peaks to produce a developmental phase where the limbic system has considerable influence over the PFC.
• Transitioning to adulthood is characterised by stabilising PFC circuitry, with the long-range coupling of the DMN and FPN (at the expense of local connections), as we transition to adulthood.
• ADHD is characterised by decoupling DMN and FPN, resulting in a weaker negative correlation between DMN and FPN. [Mills et al., 2018]
• ADHD is particularly relevant due to the high rates of co-morbid sleep dysfunction, which may be both cause and effect. [Shanahan et al, 2021]
• Reduced sleep duration decreases PFC inhibitory control of amygdala activity and PFC excitatory drive to the striatum, impacting the normal development of crucial corticolimbic circuits.

Role of Globus Pallidus:

In the striatum, the Globus pallidus, as part of the cortico-striatal-thalamic cortical network, is a critical area that regulates the sleep-wake cycle. [Vetrivelan et al., 2010]

Globus Pallidus Interna (GPi):

• The GPi has both glutamatergic and GABAergic neurons.
• D2 receptor action on postsynaptic receptors may promote wakefulness via GPi neurons (excitatory).

Globus Pallidus Externa (GPe)

• The GPe has mainly GABAergic neurons.
• Activating the presynaptic D2 receptors on GABAergic striatopallidal neurons in the GPe promotes sleep via an inhibitory action on striatopallidal neurons. [Vetrivelan et al., 2010]

The CSTC has direct (excitatory) and indirect (inhibitory) pathways:

Direct / Excitatory pathway:

• Neurons of the direct pathway express excitatory D1R and inhibitory A1R, which promote wakefulness.

Indirect / Inhibitory Pathway:

• Express inhibitory D2R and excitatory A2R, which promote sleep. [Bijlenga et al., 2019]

 Role of the Mesolimbic system: [Oishi & Lazarus, 2017]

• The mesolimbic DA system (reward pathway) also controls sleep and wakefulness.
• AD regulates the activity of NAc neurons that induce sleep because A1R and A2R are expressed in the NAc neurons on direct and indirect pathways.
• Nucleus accumbens (NAc) D1R neurons regulate wakefulness, whereas NAc D2R/A2R neurons regulate sleep.
• Activating A2R receptor-expressing GABAergic neurons in the NAc (ventral striatum) promotes NREM sleep via the indirect pathway. Activation of this indirect pathway in the dorsal striatum plays a role in motor suppression.
• The activity of the NAc indirect pathway neurons is sufficient and necessary for slow-wave sleep generation under baseline conditions.

APPLICATION OF NEUROBIOLOGY TO CLINICAL PRACTICE

Abnormalities of Process S and C as aetiological contributors to insomnia:

• Misalignment of the circadian process leading to phase delays or advances (prolonged sleep-onset latency)
• Delayed or advanced melatonin secretion.
• Dysfunction of the homeostatic process.
• Maladaptive behaviours reducing the homeostatic process.

Insomnia – Neurobiology | Pathophysiology | Assessment and Management

Neurobiological correlates of Hyperarousal:

• The hyperarousal model of insomnia is associated with increased activation of cognitive-emotional, behavioural, and autonomic processes during waking and sleeping hours.

• Amygdala overactivity can impede PFC function via activation of alpha-1 receptors resulting in reduced top-down inhibition of the amygdala and impaired daytime cognition.
• Frightening dreams are suggestive of increased amygdala activation during REM sleep.
• Dopaminergic dysfunction can impair top-down inhibition of PFC and striatum on limbic hyperarousal.
• Alterations in the salience network are linked to the hyperarousal and affective symptoms of people with insomnia. Increased salience network activity may be a trans-diagnostic marker of insomnia severity. [Van Someren, 2021]
• Preventing REM sleep for even a few hours can increase NA tone, causing hyperactivity of the affective salience network innervated by the LC.
• Co-morbid psychological or medical issues and genetic vulnerabilities exacerbate this imbalance between arousal and sleep-inducing brain activity.
• Adults with insomnia are more likely to re-engage limbic circuits during the recall of emotional memories, similar to the limbic-dominated adolescent, which can result in the persistence of hyperarousal, inadequate processing of emotional memories impeding the process of fear extinction and increasing negative valence on everyday events leading to impaired decision making, defensive and avoidance behaviours.[Wassing et al., 2019], [Pignatelli and Beyeler, 2019]

Clinical features in insomnia and their neurobiological correlates:  

Fronto-striato-limbic dysfunction: [Perlis et al., 2012]

• Abnormal activity within the basal ganglia may be associated with ruminations and worry.
• Insufficient caudate activation could result in cortical hyper-responsiveness, which may subjectively be experienced as hyperarousal. [Morin et al., 2015]
• Reduced activation of the OFC may be associated with ruminations and complaints of being unable to ‘‘turn their minds off” in patients with insomnia.
• The DLPFC is deactivated during REM sleep with increased activity of subcortical structures, which results in dreaming.
• In insomnia, increased activation of DLPFC is associated with worry and rumination that may interfere with sleep initiation and maintenance.
• Dysregulation of motivational and emotional processes due to sleep dysfunction can be a risk factor for reward-related disorders, such as mood disorders, and increased risk-taking and compulsive behaviours. [Oishi & Lazarus, 2017]

REM sleep without atonia and REM sleep behaviour disorder:

• REM disinhibition of atonia may indicate brainstem dysfunction, specifically the involvement of the impairments in the vPAG/ LDT -SLD network, g., in REM sleep behaviour disorder (RBD)
• RBD is associated with neuronal loss in the SLD nucleus in the pons.
• 93% of patients with REM sleep behaviour disorder report enacted dreams.
• 60% of patients with Parkinson’s disease have REM sleep behaviour disorder.
• In the early stages of Parkinson’s disease, REM sleep behaviour disorder is a significant determinant of the later development of hallucinations, psychosis, and dementia.
• Parkinsonism disappears during REM sleep behaviour disorder-associated complex behaviours [Siclari et al., 2020]

Have you ever been told, or suspected yourself, that you seem to ‘act out your dreams’ while asleep (for example, punching, flailing your arms in the air, making running movements, etc.)?

This question is sensitive and specific for distinguishing patients with REM sleep behaviour disorder from healthy controls and patients with obstructive sleep apnoea but not from sleepwalking or sleep terrors.

Sleep and Hunger:

• Decreased activity in decision-regulating frontal cortex regions following sleep deprivation, combined with enhanced subcortical mesolimbic sensitivity, leads to an increased desire for and selection of high-calorie food items.
• Experimental sleep restriction increases calorie consumption and promotes weight gain. [Krause et al., 2017]

NREM parasomnias: [Siclari et al., 2020]

• Dreaming can also occur in NREM sleep, but these differ from REM sleep dreams.

NREM dreams are:

• Shorter
• Less dreamlike
• Less vivid
• More conceptual
• Less bizarre
• Less emotional
• Under greater volitional control
• More related to current concerns

NREM parasomnias can be associated with dream enactment.

• Dreamlike experiences in NREM parasomnia are short, often of a single visual scene, associated with negative emotions (e.g. apprehension, fear, or terror.)
• The content involves misfortunes and disasters with imminent death, in which the patient has to escape from a closed location (e.g., a narrow room, elevator, labyrinth, grave, or moving walls, or seeing the ceiling collapse or being buried) or a danger (e.g., trains, cars, fires, snakes). [Siclari et al., 2020]
• Clinicians should be mindful not to equate sleep terrors with nightmares because patients sometimes use the terms nightmares or awake nightmares to refer to their parasomnia episodes. [Siclari et al., 2020]

Obstructive sleep apnoea (OSA):

• Patients with a higher apnoea-hypopnea index, specifically in REM sleep, tend to have more nightmares.
• After starting positive airway pressure therapy, patients with both nightmares and sleep apnoea report a reduction in nightmares.

Obstructive Sleep Apnea and Depression – Pathophysiology & Management

Restless Legs Syndrome (RLS):

• Iron deficiency is linked to Restless legs syndrome (RLS).
• Iron is a cofactor for tyrosine hydroxylase, the rate-limiting enzyme responsible for dopamine synthesis, which also influences the dopamine pathway directly.
• Inhibitory A1R downregulation is involved in the hyperarousal of RLS.
• With normal brain iron conditions, extracellular AD concentrations keep an inhibitory AD presynaptic tone on Glu and DA transmission, mediated by A1R, which results in a relatively low activation of the direct and indirect DA pathways.
• Downregulation of A1R induced by brain iron deficiency leads to hypersensitive Glu terminals, to disinhibition of Glu and DA release, to striatal hyperdopaminergic and hyperglutamatergic states, leading to an increase and decrease in the activity of the direct and indirect striatal medium spiny neurons (MSN), respectively. [Ferré et al., 2018]

Clinical application of neurotransmitter dysfunction in insomnia:

• Reduced GABAergic activity or ORX over-activity.
• ORX deficiency underpins narcolepsy sleepiness (culminating in sleep attacks), cataplexy, and sleep-onset REM periods.
• Loss of the ORX neurons in narcolepsy with cataplexy results in persistent sleepiness, frequent transitions between sleep states, and odd states such as cataplexy and hypnagogic hallucinations in which elements of REM sleep mix into wakefulness. [España and Scammell., 2011]
• Insufficient silencing of the LC NA neurons leads to restless REM sleep.
• Extensive cholinergic deficits may cause visual hallucinations of Lewy body dementia.

PSYCHOTROPICS AND SLEEP

[España and Scammell., 2011], [Siclari et al., 2020], [Nicolas, 2020]

Effects of medications on sleep:

Selective serotonin reuptake inhibitors (SSRIs): [Hutka et al., 2021]

• SSRIs increase 5-HT in the synaptic cleft by inhibiting SERT.
• 5-HT inhibits REM sleep-producing neurons suppressing REM sleep mediated via the activation of postsynaptic 5HT1A, 5HT2A/C, 5HT3 and 5HT7 receptors. [Kovalzon, 2021]
• This reduction/suppression of REM sleep can benefit some patients by reducing nightmares, dream recall frequency and hyperarousal.
• SSRIs are also associated with sleep fragmentation.
• Increased 5-HT can also increase hyperarousal and worsen sleep in some patients. This effect may not subside, and clinicians should rule out the presence of a mixed state.
• SSRIs are associated with night sweats by blocking muscarinic receptors and/or by increasing NA release. Thus, there is evidence that alpha adrenergic blockers can reduce night sweats in those taking SSRIs. [Mold & Holtzclaw , 2015]
• Other option for SSRI or SNRI induced sweating are beta blockers, serotonergic antagonists like cyproheptadine (5-HT2A) blockade in the hypothalamic region. Since sweat glands uniquely have cholinergic neurons as part of the sympathetic postganglionic innervation, anticholinergics like benztropine van also be useful. [Mold & Holtzclaw , 2015]
• Downregulation of 5HT2C receptors within parts of the limbic circuit contributes to the reduction of hyperarousal.
• Fluoxetine is distinctive amongst SSRIs and increases dream intensity, dream recall frequency and nightmare recall. (possibility linked to 5HT2C antagonism, which increases DA in PFC and can have an activating effect in early stages)

Tricyclic antidepressants :

• TCAs increase 5-HT and NA, which inhibit REM sleep-producing neurons leading to decreased REM sleep.
• Clomipramine is effective in cataplexy and can be very effective at doses as low as 25 mg/day (morning or evening). Still, 75 mg/day is typically needed, with a maximum of 150 mg/day.

SNRI:

• SNRIs increase 5-HT and NA, leading to nightmares and REM sleep behaviour disorder.
• Venlafaxine and its metabolite, desvenlafaxine, also tend to modify the dream content, with a significant increase of “abnormal dreams” reported in desvenlafaxine withdrawal in depressed patients.
• Duloxetine effectively reduces PTSD nightmares and has a similar effect on sleep as venlafaxine.
• SNRIs are associated with reduced length of REM sleep, fragmented sleep, and an increase in periodic limb movement.
• SNRIs are effective in treating cataplexy. [Barateau & Dauvilliers, 2019]

Important aspects of Serotonergic agents:

Sudden discontinuation of antidepressant drugs which suppress REM sleep can lead to a prolonged rebound REM sleep replacement, with increased tension, dread and a reduction of sleep quality. This REM rebound can increase the risk of relapse, worsen withdrawal symptoms and /or lead to depression or anxiety morphing into a more severe agitated melancholic depression. [Siclari et al., 2020]

• In clinical practice, early morning awakening is a clue towards the more severe agitated depression from a sleep perspective. Patients describe significant psychomotor agitation immediately upon awakening, in contrast to the normal awakening process.
• From a neurobiological perspective, reduced 5HT (a feature of REM sleep), impaired 5HT2A (5HT2A normally activates GABAergic neurons in the amygdala resulting in an inhibitory effect ), and 5HT2C activity (excitatory effect on the amygdala and anxiogenic) results in a reduced GABAergic tone and increased LC (NA) activity.
• This combination lowers the intrinsic threshold of the amygdala circuitry in response to stressful events resulting in an amygdala that is hyperresponsive to traumatic reminders and even innocuous stimuli [Sengupta and Holmes, 2019]

The long pre-morning periods of REM sleep become especially dangerous since they can reduce the level of cerebral serotonin below a certain critical level, the threshold for disruption of general serotonergic transmission and the occurrence of emotional disorders. This approach is confirmed by the subjective reports of patients reporting the appearance of the first feelings of depression even during the experience of morning dreams and reaching their maximum severity immediately upon awakening. However, by the evening (as cerebral serotonin accumulates in the course of a vigorous state), the patient’s condition gradually improves, depressive symptoms go away by themselves, and he/she feels completely healthy … until a new period of sleep comes!. It is clear that against the background of a low, near-threshold level of cerebral serotonin, even immersions in NREM sleep causing a decrease in serotonin release can re-launch pathological processes in the brain.[Kovalzon, 2021]

• Antidepressants can induce acute REM sleep behaviour disorder (RBD) (SNRIs, MAOIs, TCAs and especially serotonin reuptake inhibitors (SSRI). [Arnaldi et al., 2015]
• Serotonergic antidepressants may unmask a subclinical RBD associated with a neurodegenerative process. . Clinicians should consider a neurological opinion and an organic evaluation in such a clinical constellation. [Postuma et al., 2013]

Agomelatine:

• Agomelatine is a novel antidepressant medication with M1 & M2 agonist activity, and 5HT2C antagonism is postulated to improve SWS and delta distribution through the night with no effect on REM sleep. [Quera-Salva et al., 2010]
• In RBD, agomelatine decreases dream enactment behaviours and REM sleep without atonia (RSWA).
• Agomelatine could be especially beneficial for use in RBD patients with depression. [Bonakis et al., 2012]

Vortioxetine: [Adamo et al., 2021]

• Vortioxetine increases NREM sleep duration through 5HT3 antagonism.
• Vortioxetine reduces REM sleep via 5HT7 and 5HT1D antagonism.

Mirtazapine:

• Mirtazapine improves SWS via 5HT2A and 5HT2C antagonism.
• Mirtazapine can treat nightmares in PTSD.
• Some patients, however, can report new onset or an increase in existing nightmares. [Buschkamp et al, 2017]
• Mirtazapine may induce restless legs syndrome in as many as 28% of patients. [Rottach et al., 2008]

Trazodone: 

• Used in insomnia at lower doses (50-100 mg with 100 mg dosage as most effective to improve sleep.)
• Acts via the 5HT2A receptor, H1 receptor, and alpha-1-adrenergic receptors. [Hutka et al., 2021]
• Useful for insomnia in depression and PTSD.

Amphetamine-like stimulants (Methylphenidate, Dexamphetamine):

• Increased DA and NA signalling leads to increased wakefulness.
• Used in the treatment of narcolepsy.

Wake-promoting, non-traditional stimulants (Modafinil, Armodafinil)

• Increased DA and ORX signalling.
• Increased wakefulness.
• Useful in narcolepsy.
• Armodafinil and modafinil are evidence-based in treating OSA and in OSA with comorbid depression.

Psychostimulants are not always associated with dream enhancement (they may occur as activating effects in some patients with significant hyperarousal or other comorbidities).

DA dream effects may depend on the dosage, receptor type, and location. [Pace-Schott & Picchioni, 2005]

Benzodiazepines: 

• Enhance GABA signalling via GABA-A receptors which inhibits the arousal systems.
• Benzodiazepines have been reported to increase β -power in the sleep EEG which does not suggest an optimal natural arousal reduction.

Clonazepam

• Increase in GABA.
• Reduces nightmares and behaviours in patients with REM sleep behaviour disorder.
• Clonazepam is efficacious and well tolerated by most patients afflicted by RBD and should be considered as initial treatment. [Gagnon et al., 2006]

Non-benzodiazepine receptor agonists (eg, zolpidem, zaleplon, zopiclone, eszopiclone)

• Enhance GABA signalling via GABAA receptors which inhibits the arousal systems.
• Nightmares; dream-like hallucinations; dream-related and sleep-related behaviours (e.g., automatism-amnesia syndrome)

Classic antihistamines:

• Block H1 receptors and reduce HA signalling in the TMN nucleus inhibiting the arousal pathway and leading to a hypnotic action.
• Low-dose doxepin has a very high selectivity for H1 receptors. It binds to HA receptors 100 times more than that NA and 5-HT  receptors.
• A low dose of doxepin (1, 3, 6 mg) can produce selective H1 blockade and be an effective treatment for insomnia. [Katwala et al., 2013]

Orexin (hypocretin) receptor antagonists: 

• Suvorexant is a novel pharmacological treatment that blocks both ORX-A and B receptors, thus suppressing 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 that is effective for treating insomnia disorder, with significant benefits on sleep onset and maintenance. Lemborexant is an effective option for patients who cannot tolerate the most commonly prescribed medications for insomnia, such as benzodiazepines and sedative-hypnotics (Z drugs). It may be instrumental in geriatric patients sensitive to side effects. [Waters, 2022]

Antipsychotics:

First- or second-generation antipsychotic drugs are generally sedative and improve the continuity of sleep without significantly altering the internal structure of sleep.

Typical antipsychotics:

• Reduced DA signalling can lead to increased sleep which is dose-dependent.
• Higher doses are more likely to lead to somnolence.

Atypical antipsychotics

• Reduced DA signalling can lead to increased sleep.
• Atypical antipsychotics (SGAs), including clozapine, olanzapine and paliperidone, may ameliorate insomnia in patients with schizophrenia by significantly reducing sleep latency (SL), increasing total sleep time (TST), sleep efficiency (SE) and SWS. Olanzapine augments both SWS and REM sleep. [Monti et al., 2017]
• Agents with antihistaminergic activity, e.g. olanzapine, and quetiapine, are helpful for significant insomnia in patients with psychosis, bipolarity or severe depression.
• Olanzapine, risperidone, aripiprazole and brexpiprazole may target nightmares in PTSD. (to be used when comorbid agitation or severe depression is present at low doses). [Nicolas & Ruby, 2020]
• Higher doses of antipsychotic medications resulting in D2 receptor blockade can disrupt sleep architecture and lead to daytime sedation and fatigue.

Cyproheptadine:

• 5-HT and H1 antagonist with anticholinergic effects.
• Reduced nightmares at 16-24 mg nocte.
• The antagonistic effect at the serotonin autoreceptor (5HT1A) results in increased serotonin outflow at the midbrain raphe resulting in the REM suppression effect common to SSRIs.
• Cyproheptadine also possesses strong anticholinergic properties, which have been linked to reduced REM sleep.
• Cyproheptadine is associated with anti-H1, anticholinergic side effects that can affect tolerability. Hepatotoxicity is a less well-known but severe side effect; hence, cyproheptadine should not be prescribed in patients with prior liver disease. [El-Solh, 2018].  [Bertrand et al, 2021].

Montelukast (leukotriene receptor antagonist):

• Leukotriene receptor antagonist for the treatment of asthma.
• The most frequently reported side effect was nightmares that cease after the drug’s cessation. [Cereza et al., 2012]
• Quick recovery after montelukast withdrawal in most cases.

β-blockers (e.g., propranolol, metoprolol):

• Reduces NA (β) and melatonin.
• Nightmares, disturbing dreams, and vivid dreams are more likely with lipophilic β-blockers(e.g., propranolol, metoprolol) due to improved cerebrovascular permeability and passage through the BBB.
• Nightmares induced by the beta-blockers result from reduced melatonin and disinhibition of cholinergic-brainstem REM-generating mechanisms.
• Only one β-blocker Nebivolol, which also has a strong lipophilic profile, has been shown to have improved sleep quality.

Efavirenz:

• Increased 5- HT leading to 5HT2 activation.
• Abnormal, vivid, or unusual dreams.

Mefloquine:

• Decrease in 5HT and GABA.
• Blockade of gap junctions.
• Increase in dreaming, vivid dreams, abnormal dreams.

Pramipexole:

• Increase in DA activity.
• Vivid dreams.

Levodopa:

• Increase in DA activity.
• Vivid dreams, nightmares.

Varenicline: 

• Partial agonist of nicotinic α4β2 receptors.
• Increase in ACh.
• Increase dream recall, abnormal dreams, and dream-related and sleep-related behaviours.

Nicotine patches: 

• Increase in ACh (nicotinic) activity and increase in DA activity.
• Abnormal dreams.

Cholinesterase inhibitors (e.g., galantamine, donepezil)

• Increased ACh.
• Increased lucid dreams, dream recall, sensory vividness and complexity of dreams (in healthy participants); nightmares.
• Induce REM sleep with dreaming.
• Increase in nightmares and hypnagogic hallucinations.

Melatonin: 

• Acts on melatonin receptors
• Reduction in bad dreams and RBD behaviours
• In patients at risk of falls who have cognitive impairment or who have obstructive sleep apnoeas, melatonin may be a good alternative to clonazepam in RBD.
• Read melatonin receptor agonists. 

Nabilone: [El-Solh, 2018]

• Acts on cannabinoid receptors (CB1 and CB2) 
• It can reduce nightmares in PTSD, but recurrence can occur post-cessation.
• Dose in PTSD: 5 mg 1 hour before bedtime and titrated up to 4.0 mg.
• Tolerability has been mixed.
• Longer-term safety has not been established.
• Caution in patients with psychosis or BPAD.

Alpha (α2) agonists and Alpha (α1) antagonist:

• The α2 agonists clonidine or guanfacine produced a reduction of REM sleep and an increase in NREM sleep. At the same time, the α2 antagonist idazoxan increased the time spent in wake and reduced the time in REM sleep.
• Clonidine decreased peripheral NA levels during sleep, consistent with suppressing an active LC during sleep. [Osorio-Forero et al., 2022]
• May increase glymphatic system clearance by reducing NA tone and hence promoting SWS.
• Dramatic clearance of prion protein and amelioration of astrocytosis in the dexmedetomidine- and clonidine-treated prion-infected mice at 5 months post-injection. [Kim et al., 2021]
• The disturbed sleep in PTSD has been proposed to involve enhanced responsiveness of α1R specifically.
• Prazosin (α1R antagonist) improved subjective sleep, polysomnographically recorded sleep and increased both the continuity and total duration of REM sleep.

CONCLUSION

Distinct processes mediate sleep in the brain. The sleep-wake cycle is sensitive to internal and external stimuli that interact with the arousal and sleep pathways in the brain.

Understanding the neurobiology of sleep is essential in psychiatric practice, as sleep dysfunction is a transdiagnostic indicator of dysfunction common to all psychiatric disorders.

Sleep dysfunction may point to specific neuropsychiatric abnormalities from a diagnostic perspective.

Treating insomnia and sleep deprivation can improve mood, activity, cognition, and immune and metabolic health.

Recognising the various neurotransmitters involved in sleep-wake regulation helps the clinician choose appropriate psychopharmacological and psychological interventions for sleep dysfunction leading to better clinical outcomes.