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What is sleep, and why is it important?
The role of circadian rhythms in sleep onset
Neurological mechanisms in sleep transition
Current strategies to improve sleep onset
Future research trends in sleep onset
Further reading

Sleep is essential for physical and psychological performance.1 Since millions of individuals worldwide deal with sleep-related problems, scientists have focused on understanding the mechanisms associated with sleep and wakefulness. This could help alleviate the issues linked to sleep disorders and improve overall quality of life.

Image Credit: PeopleImages.com - Yuri A/Shutterstock.com

Image Credit: PeopleImages.com – Yuri A/Shutterstock.com

What is sleep, and why is it important?

Sleep is a complex process that can be defined as reduced responsiveness to environmental stimuli when compared to wakefulness.2 Sleep quality can be explained by an individual’s level of self-satisfaction after sleep. This can be assessed through sleep efficiency, sleep duration, sleep latency, and wake after sleep onset.3

Good sleep quality has a positive effect on a person’s physiological and psychological factors. Multiple studies have shown that sleep influences aging, body mass index, circadian rhythm, Rapid Eye Movement (REM), and Non-Rapid Eye Movement (NREM). Furthermore, sleep is also linked with stress, depression, and anxiety. Poor sleep quality leads to fatigue, daytime dysfunction, irritability, increased caffeine/alcohol intake, and slowed responses. Good sleep is also positively associated with human relationships.4

Sleep is critical for waking cognition and is associated with one’s ability to think efficiently, be alert, and sustain attention. It has been observed that vigilant attention declines considerably after more than sixteen hours of continuous wakefulness.5 Partial sleep deprivation accumulates over time and leads to a steady deterioration of alertness. Furthermore, sleep plays a vital role in emotional regulation, metabolic processes, and body healing. Memories are also consolidated during sleep.6

The role of circadian rhythms in sleep onset

Circadian rhythm can be described as the 24-hour internal clock of our brain that regulates the cycles of alertness and sleepiness in accordance with environmental changes.7 The homeostatic physiology of the circadian rhythm processes sleep/wake cycles. Over the years, the biological circadian system has evolved to help humans adapt to environmental changes, such as temperature, radiation, and food availability. In the absence of an endogenous circadian clock, humans would fail to optimize energy expenditure without hampering internal physiological functions.

Circadian rhythms utilize positive and negative molecular feedback loops to regulate their expression. Several clock genes have been identified, including CRY1/CRY2, PER1/PER2/PER3, BMAL1/BMAL2, and CLOCK, that regulate genetic transcription and translation.8

The expression of clock genes inside a cell influences many signaling pathways that allow the cell to identify specific times of day and, accordingly, conduct essential functions. Phosphorylation of core clock proteins helps manage 24-hour sleep/wake cycles.9 A disruption of the circadian cycle has many health implications associated with immune, skeletal, renal, cardiac, gastrointestinal, and endocrinal functions. 

Neurological mechanisms in sleep transition

The transition between sleep and wakefulness involves changes in motor control, brain activity, cognition, and consciousness. Sleep and wake states can be determined through electromyogram (EMG) and electroencephalogram (EEG) recordings. These analytical tools measure the muscular and global cortical activity, respectively.10 Wake state has shown significant heterogeneity with variable muscle activity and desynchronized EEG oscillations of low amplitude and mixed frequencies.

Image Credit: vetre/Shutterstock.com

Image Credit: vetre/Shutterstock.com

The active state is rich in theta and gamma EEG frequency ranges, while quiet wakefulness displays slower EEG frequencies. Both EEG and EMG recordings are used to distinguish two distinct states of sleep, i.e., REM and NREM, which alternate cyclically across sleep.11

Brain nuclei that control the sleep/wake states display heterogeneity and are composed of intermingled neuronal populations that support differentially activated states. Complex interactions of subcortical neuromodulatory neurons in the hypothalamus, brainstem, midbrain, thalamus, basal forebrain (BF), and the cortex are responsible for the differential physiological behavioral, and electrocortical sleep/wake states.12

Both the dorsal and the ventral pathways are activated during wakefulness. Here, the dorsal pathway of the thalamus mediates the transmission of sensory information to the cortex. The ventral pathway associated with the BF, hypothalamus, and other forebrain structures synergistically excite the cortex.13 

Monoaminergic and cholinergic-producing neurons are inherently associated with the regulation of arousal states. Recent studies have also highlighted the role of gamma-aminobutyric acid (GABA) and glutamate neurotransmission in the regulation of the sleep-wake cycle. GABAergic cells promote sleep by inhibiting cells that are involved in arousal functions. Inhibition of neurons containing histamine, serotonin, glutamate, norepinephrine, and hypocretin promotes sleep.14 

GABAergic sleep-active neurons also inhibit cholinergic neurons in the basal forebrain. Since the cholinergic system is one of the key players in the wakefulness of the brain, its inhibition deactivates the cortex and promotes sleep.

Current strategies to improve sleep onset

Sleep onset latency is the time it takes to go from complete wakefulness to sleeping. Sleep latency and the time required to reach REM sleep are two factors that determine the amount and quality of sleep.

A normal person’s sleep latency is between 10 and 20 minutes. Several factors, such as the number of naps, alcohol consumption, sleep time of the preceding week, and age, could impact sleep latency. 

Both pharmacological and non-pharmacological strategies have been developed to alleviate sleeping disorders, such as insomnia.15 Epidemiologic research has shown that regular light to vigorous exercise improves sleep quality and reduces the risk of insomnia. 

Cognitive behavioral treatment for insomnia (CBT-I) encompasses sleep hygiene, which entails maintaining a conducive sleep environment by keeping the bedroom dark, cool, and quiet. The CBT-I strategy also entails reduced consumption of nicotine, caffeine, and alcohol, particularly close to bedtime. Exposure to bright light negatively affects an individual’s circadian rhythms.

Several pharmacologic therapies, such as melatonin receptor agonists, benzodiazepines, selective histamine H1 antagonists, orexin antagonists, antipsychotics, non‐selective antihistamines, anticonvulsants, and antipsychotics, have also been formulated to improve sleep onset. It is important to note that these pharmacological interventions can only be prescribed by physicians.

Future research trends in sleep onset

Circadian rhythm disturbances and sleep disorders are commonly found in patients with Alzheimer’s Disease. Typically, sleep-related issues manifest in the early phase of AD onset. It is important to develop better strategies or combinational treatments with drug and non-drug interventions to improve the sleep quality of these patients.

More research is required to regulate the mechanisms that control the biological clock and the neural circuits involved in sleep. It is also important to understand the extent of sleep disorders that influence the onset and progression of neurodegenerative disease. More studies are required to elucidate the biological changes associated with sleep disorders in the elderly population.


  1. Charest J, Grandner MA. Sleep and Athletic Performance: Impacts on Physical Performance, Mental Performance, Injury Risk and Recovery, and Mental Health. Sleep Med Clin. 2020;15(1):41-57.
  2. Biabani N, Birdseye A, Higgins S, et al. The neurophysiologic landscape of the sleep onset: a systematic review. J Thorac Dis. 2023;15(8):4530-4543.
  3. Nelson KL, Davis JE, Corbett CF. Sleep quality: An evolutionary concept analysis. Nurs Forum. 2022;57(1):144-151.
  4. Zhang J, Jin X, Li R, Gao Y, Li J, Wang G. Influence of rapid eye movement sleep on all-cause mortality: a community-based cohort study. Aging (Albany NY). 2019;11(5):1580-1588.
  5. Worley SL. The Extraordinary Importance of Sleep: The Detrimental Effects of Inadequate Sleep on Health and Public Safety Drive an Explosion of Sleep Research. P T. 2018;43(12):758-763.
  6. Rasch B, Born J. About sleep’s role in memory. Physiol Rev. 2013;93(2):681-766.
  7. Reddy S, Reddy V, Sharma S. Physiology, Circadian Rhythm. In: StatPearls. Treasure Island (FL): StatPearls Publishing; May 1, 2023.
  8. Jiang Y, Shen X, Fasae MB, et al. The Expression and Function of Circadian Rhythm Genes in Hepatocellular Carcinoma. Oxid Med Cell Longev. 2021;2021:4044606.
  9. Ode KL, Ueda HR. Phosphorylation Hypothesis of Sleep. Front Psychol. 2020;11:575328.
  10. Saper CB. et al. Sleep State Switching. Neuron. 2010; 68(6), 1023-1042.
  11. Eban-Rothschild A, Appelbaum L, de Lecea L. Neuronal Mechanisms for Sleep/Wake Regulation and Modulatory Drive. Neuropsychopharmacology. 2018;43(5):937-952.
  12. Scammell TE, Arrigoni E, Lipton JO. Neural Circuitry of Wakefulness and Sleep. Neuron. 2017;93(4):747-765.
  13. Des Champs de Boishebert L, Pradat P, Bastuji H, Ricordeau F, Gormand F, Le Cam P, Stauffer E, Petitjean T, Peter-Derex L. Microsleep versus Sleep Onset Latency during Maintenance Wakefulness Tests: Which One Is the Best Marker of Sleepiness? Clocks & Sleep. 2021; 3(2):259-273.
  14. Siegel JM. The neurotransmitters of sleep. J Clin Psychiatry. 2004;65 Suppl 16(Suppl 16):4-7
  15. Chun W, Chao D, Qi H, Dongliang Z, Zhenmei L, Jia L. Pharmacological and non-pharmacological treatments for insomnia: A protocol for a systematic review and network meta-analysis. Medicine (Baltimore). 2021;100(31):e26678.

Further Reading


Do you think you may suffer from Sleep Issues and live in Florida, California or New York?

If so, please consider scheduling a proper virtual online Sleep Disorder and Anxiety diagnosis with one of our physicians. Although we have an online ADHD and Anxiety diagnosis tool, a proper diagnosis from a Board-Certified Medical Doctor will help you know for sure. If appropriate, a customized treatment program will be recommended at the conclusion of that initial visit.

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