|Year : 2022 | Volume
| Issue : 1 | Page : 27-32
Understanding the pathophysiology of insomnia (Anidra) with special reference to primary insomnia using neurotransmitter sleep theories: a narrative review
Shruti Jhawar1, G Gopala Krishna1, Umesh Chikkanna2
1 Department of PG Studies in Kayachikitsa, Sri Sri College of Ayurvedic Science and Research, Bengaluru, Karnataka, India
2 Department of Integrative Medicine, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
|Date of Submission||29-Aug-2021|
|Date of Decision||14-Jan-2022|
|Date of Acceptance||27-Jan-2022|
|Date of Web Publication||31-Mar-2022|
Dr. Shruti Jhawar
Sri Sri College of Ayurvedic Research, 21st km, Kanakapura Road, Udayapalya P.O., Bengaluru 560082, Karnataka.
Source of Support: None, Conflict of Interest: None
Sleep is a primordial requirement for human sustenance and its role in health is inevitable. Despite its importance, inadequate sleep is one of the most common complaints across the globe. Ayurveda identifies Nidra (sleep) as one of the three supporting pillars of life and attributes its maintenance not only to health but also to longevity and prosperity; in contrast, Anidra (disturbed sleep) is one of the contributing factors for disease. Ayurveda clearly identifies the factors in Anidra which are vitiation of Pitta or Vata (fundamental humors of the body), Manasantapa (psycho-social stress), Kshaya (debilitating factors), or Abhighata (injury/trauma). Insomnia is characterized by reduced quality or quantity of sleep and has effects on the quality of life of the affected individual. It can be the difficulty of sleep initiation, sleep maintenance, or early morning awakening, which can have a significant impact on the daily activity of the individual. The contemporary science is yet to give a definite theory for the physiology of sleep and the pathophysiology of insomnia. The most widely accepted and researched concept is the role of neurotransmitters such as gamma-aminobutyric acid, serotonin, acetylcholine, dopamine, norepinephrine, melatonin and their effects in the regulation of sleep–wake cycle. These neurotransmitters and their effect on sleep physiology and pathology of insomnia need to be further explored in order to improve its management strategies. Hence, this review aims to determine the possible relation between the concepts of Nidra (sleep) and Anidra (disturbed sleep) mentioned in Ayurveda and these neurotransmitter sleep theories. This will help in improving the understanding of the pathophysiology of insomnia, developing Ayurveda management protocols for insomnia, and also in explaining the pharmacodynamics of Ayurveda drugs better. The method used for review is by sourcing and analyzing the available data from Ayurveda and contemporary literature on the topic in discussion.
Keywords: Anidra, insomnia, neurotransmitters, Nidra
|How to cite this article:|
Jhawar S, Gopala Krishna G, Chikkanna U. Understanding the pathophysiology of insomnia (Anidra) with special reference to primary insomnia using neurotransmitter sleep theories: a narrative review. J Indian Sys Medicine 2022;10:27-32
|How to cite this URL:|
Jhawar S, Gopala Krishna G, Chikkanna U. Understanding the pathophysiology of insomnia (Anidra) with special reference to primary insomnia using neurotransmitter sleep theories: a narrative review. J Indian Sys Medicine [serial online] 2022 [cited 2023 Apr 2];10:27-32. Available from: https://www.joinsysmed.com/text.asp?2022/10/1/27/342314
| Introduction|| |
Nidra, one among the Trayopastambha (three pillars of life), mentioned in Ayurveda is one of the most important parts of human physiology. It is responsible for the restoration and rejuvenation of the body. Hence, disturbed Nidras are said to result in serious derangements in the physiology over time. Even in contemporary medical world sleep is given utmost importance as it has effects on the nervous system and as well as other bodily functions such as endocrine and digestive systems. Most adults require 7–8 h of sleep to ensure a productive or healthy following day, although the timing, duration, and internal structure of sleep may vary among healthy individuals. Due to the multiple factors of today’s world that can affect the sleep cycle, insomnia is one among the most common health complaints across the globe. Insomnia is the complaint of difficulty in initiation and maintenance of sleep. India is estimated to have an insomnia prevalence of about 9% in the general population, with a prevalence of occasional insomnia in 30% of the population. This makes insomnia a burning issue and its management the need of the hour.
In the Ayurveda treatises, the causes of Anidra have been explained as: Pitta (increase of Pitta dosha), Vata (increase of Vata dosha), Manasantapa (stress and other psycho-social factors), Kshaya (debilitating factors), or Abhighata (trauma/injury). Factors such as Karya (physical or mental activity that keeps one awake), Kala (diurnal changes, seasonal changes, and age-related changes), Vikara (diseases/conditions affecting sleep), Prakruti (natural variations in sleep patterns constitutionally), and Vata (impaired Vata dosha) are said to affect its physiology and pathology.
Even in the allied science, various researches have tried to establish the possible elements affecting sleep physiology and pathology. The various sleep theories postulated have one common link, i.e., influence of different neurotransmitters acting as sleep-promoting or sleep-inhibiting agents. Owing to the limited understanding of sleep and its physiology and the possible pathology of insomnia, there is also a limitation in the scope of management of insomnia in the contemporary science. The current modalities of treatment adopted in the contemporary science have been able to manage insomnia only to a certain degree but there are several drawbacks associated with them. There is a higher incidence of drug dependence and day-time impairments on long-term usage, and these modalities have not been successful to restore natural sleep in the patients. Also the use of pharmacological interventions alone cannot be sufficient in the management of insomnia as it also requires a multi-dimensional lifestyle intervention. Thus it is the need of the hour to venture into inter-disciplinary avenues in the management of insomnia.
Hence, this article aims to understand the neurotransmitter sleep theories and the pathophysiology of insomnia using the Ayurveda concepts of Nidra and Anidra in order to develop possible measures for its management.
| Materials and Methods|| |
The literary data for the present study were collected from Ayurveda classical textbooks, textbooks of modern medical science, reputed journals, and studies conducted on related works, credible internet, and other sources.
| Results|| |
The information was collected from the above sources under the following categories: the concept of Nidra and Anidra as explained in Ayurveda along with the contemporary understanding of sleep and insomnia and the various research works carried out on the probable role of neurotransmitters on sleep and their effect in the pathophysiology of insomnia. The obtained data were scrutinized and analyzed to draw probable conclusions to substantiate the current topic.
| Ayurveda Understanding of Nidra and Anidra|| |
Ayurveda gives utmost importance to sleep and mentions the various factors responsible for its maintenance. It emphasizes the importance of sleep not only in the regulation of health but also attributes several other benefits such as happiness, growth, strength, virility, and longevity to it. The physiology of sleep manifestation is credited largely to four factors, which may vary according to the different authors. They are Kapha Dosha (one of the three humoral factors), Tamoguna (entity of mind responsible for inertia), Shrama (exertion both physically and mentally), and Svabhava (natural phenomenon). The same is explained in [Table 1].
It is important to understand that Ayurveda also has examined Nidra as a naturally occurring complex phenomenon with varied interdependent factors that regulate its physiology. Even though there is a difference of opinion in the causes of sleep according to different authors and different contexts, it should be understood that all the above four factors work in synergy to produce natural sleep in an individual.
Acharya Charaka and Sushruta have each given a set of factors that can affect the sleep physiology. These factors could be observed in both physiological and pathological disturbance of sleep. Acharya Sushruta explains the pathological causes of Anidra, whereas the factors mentioned by Acharya Charaka can be understood in both physiology and pathology. The causes are explained in [Table 2].
| Contemporary Sleep Theories|| |
Numerous theories are postulated to explain the physiology of sleep, of which the most widely accepted are the ones explaining the role of neurotransmitters in brain functioning. These neurotransmitters act either as sleep-promoting or sleep-inhibiting agents in the normal physiology and when affected it can act as causes to insomnia. They are as follows.
Gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the brain, and the activation of their receptors causes inhibition of neuronal activity responsible for sleep production. It was proven that when the GABAergic transmission was increased in the specific areas of the mid-brain, it resulted in the increase of wakefulness and decreased sleep. This implies that endogenous increase in the GABA levels in the central pons area increases wakefulness, making it a wake-promoting neurotransmitter.
It is found via extensive imaging research that the most prominent stimulation area for inducing habitual sleep is the raphe nuclei in lower half of the pons and medulla. This area contains serotonergic nerves that spread across in the mid-brain and also extend to several areas of the cerebrum affecting large portion of the brain’s functional activity. These neurons secrete serotonin which promotes sleep. It is also proven that drugs and foods that inhibit the secretion of serotonin render the patient sleepless and increases nocturnal awakenings. Hence, it can be understood that serotonin is a sleep-promoting neurotransmitter.
The noradrenergic neurons associated with locus ceruleus have shown to play an important role in controlling sleep patterns. Drugs that increase the activity of these neurons have shown a marked reduction in the REM sleep and resulted in increased wakefulness. It is a wake-promoting neurotransmitter.
Brain acetylcholine is speculated to be increased during REM sleep, which is usually seen during wakefulness when the person is active. These spurts of acetylcholine released intermittently during sleep could be responsible for breaking the slow wave sleep cycle with the REM sleep. Cholinergic neurons and drugs stimulating them have hence shown to promote cortical activation during REM sleep and wakefulness. It regulates REM and NREM sleep patterns and when in excess it causes wakefulness.
Several researches show that dopamine has an alerting effect. Increase in dopamine concentration in brain tends to produce arousal and wakefulness, wherein dopamine blockers increase sleep time. Hence, it is a wake-promoting neurotransmitter.
Melatonin secretion from the pineal gland is inhibited by bright light, so the lowest serum melatonin levels occur in the day. The secretion of melatonin trains the brain into a 24-h sleep–wake cycle. It is also shown to have three physiologic effects, which are promotion of sleep onset, maintenance of sleep, and phase shifting of the circadian rhythms.
Apart from these neurotransmitters, there are other substances responsible for maintaining the sleep–wake cycle. One such factor is adenosine which is a nucleoside formed with the breakdown of ATP. With prolonged wakefulness, an increase in the adenosine levels is observed which acts through the adenosine A1 receptors to directly inhibit the arousal-promoting brain regions. It also promotes sleep by blocking the adenosine A2 receptors. Also peptides such as hypocretin-1 and 2, leptin, and ghrelin play a major role in the maintenance of the sleep–wake cycle [Table 3].
From the above table, it can be understood that different neurotransmitters and several other factors affect the production of sleep, but their precise interdependence and functioning are yet to be completely understood. The exact physiology of sleep−wake is yet to be postulated by these neurotransmitter sleep theories, which can be expected to be closest to the explanation.
Insomnia can be of varied causes as enlisted under the Classification of Insomnia by the 2nd edition of International Classification of Sleep Disorders, where the common factor lies in their presentation. Insomnia is characterized by the complaint of sleep initiation, maintenance, or early morning awakening, which causes significant day-time impairments in the individual, for a significant duration of time (at least three nights per week for at least 3 months). This sleep disturbance causes clinically significant distress or impairment in social, occupational, educational, academic, behavioral, or other important areas of functioning. It is the complaint of poor sleep quality, quantity, or both. Although the direct causes of insomnia are variable, certain risk and prognostic factors have been enlisted that help in its pathogenesis. They are as follows: temperamental—anxiety or worry-prone personalities, increased arousal tendencies; environmental—noise, light, uncomfortably high or low temperature, and high altitude; genetic and physiological—female gender and advancing age, familial disposition; course modifiers—deleterious course modifiers include poor sleep hygiene practices (e.g., excessive caffeine use, irregular sleep schedules). Even though insomnia and its pathophysiology cannot be generalized due to its varied causes, most of these factors when evaluated show a link to the above-explained neurotransmitters; hence, they can be assumed to be the primary cause in the manifestation of insomnia.
| Discussion|| |
On comparing the data available from the allied sciences as well as Ayurveda, various connections can be drawn in the physiology and pathology of sleep and insomnia, as explained by contemporary science and Ayurveda, respectively.
Nidra and Sleep Physiology
There is a striking similarity in the factors responsible for Nidra as explained in Ayurveda as well as the factors responsible for the maintenance of the sleep–wake cycle as mentioned by the contemporary sciences. Kapha and Tamas mentioned as the cause for sleep can be understood in the context of serotonin, which induces sleep in an individual. An individual with a Kaphaprakriti or a Tamasika Prakriti also has a tendency of indulging more into sleep. This can also be supported by the observation that when selective serotonin reuptake inhibitors anti-depressants are prescribed to an individual, there is an increase in the levels of serotonin in the brain and the subject experiences excessive drowsiness and sleep. Another cause for Nidra is mentioned as Shrama or fatigue. This can be correlated to the increase of adenosine in the brain that accumulates on physical and mental activity and induces sleep. It is also proven that exercise induces stimulatory effects on the serotonergic pathways and thus helps improving sleep. Similarly, the other cause of Nidra is Svabhava, i.e., initiation of sleep naturally on approaching of night time. This can be understood via the melatonin theory of sleep as its secretions increase by night due to the absence of bright light and induce sleep [Table 4].
With the above explanation, it can be estimated that even though the understanding of both sciences to explain the process of sleep generation may vary, the basic elements remain similar. The sleep-promoting neurotransmitters and their effects are found to be similar to the factors inducing sleep according to Ayurveda. Hence, this similarity can be extended to the causes of Anidra and the pathophysiology of insomnia.
Anidra and Neurotransmitter Theories
In ayurveda, Acharya mentions different causes of Anidra in which the role of these sleep- and wake-promoting factors can be correlated. Vata and Pitta Vriddhi mentioned as the cause for Anidra can be correlated to the increase of wake-promoting factors such as GABA, noradrenaline, and acetylcholine. Factors such as Ati Vyayama (excessive exertion), Vyavaya (sexual activity), Ratri Jagarana (improper sleep hygiene), Krodha (anger), Ati-Upavasa (fasting), which are the usual causes of Vata–Pitta Prakopa, have shown to exert altering effects on these neurotransmitters. Hence, it can speculated that the Vata and Pitta Vriddhi in an individual stimulates the wake-promoting factors and renders the subject sleepless. Similarly, Manastapa (mental and emotional stress) acts as a cause for insomnia by directly acting on the dopamine and serotonin mechanisms in the brain. This has been proven by extensive research in both Ayurveda and contemporary sciences. Kala (time or age) and Kshaya (debilitating factors) have been mentioned as the cause for Anidra can once again point toward the functions of these neurotransmitters. It is found that melatonin production physiologically reduces with age, which can be considered as Kala Parinama Anidra (loss of sleep due to advancing age). Serotonin and dopamine levels also reduce gradually with advancing decades, which result in Kalaja Anidra. These neurotransmitters have an atrophic effect on the brain, which could be correlated to Kshaya acting as a cause for Anidra. Karya or excessive indulgence in activity results in increased dopamine levels, which has an alerting effect on the brain and inhibits sleep. It is also proven in cross-sectional studies that people working in shift works end up having altered serotonergic pathways, resulting in desynchronization of the circadian rhythm which in turn results in insomnia. Abhighata or injury can be understood as both local injury to the sleep-promoting areas of the brain which would directly hamper the sleep–wake cycle and injury to any part of the body resulting in pain which might disturb sleep. Although the relation between pain mechanism and sleep is still under study, there are various researches carried out that speculate the involvement of dopamine, serotonin as well as melatonin in this pathology, which would in turn affect sleep [Table 5].
The above factors of Anidra and their probable effect on neurotransmitters give a clear understanding to the fact that the causes mentioned are affecting the neurotransmitters invariably. Therefore, it can be believed that the Ayurveda concepts of management of Anidra should definitely have an effect on these neurotransmitters and help in the management of insomnia.
Probable Role of Ayurveda Treatment on Neurotransmitters Regulating Sleep–Wake Cycle
Based on the above results and discussion, a relation between the contemporary sleep theories and Anidra can be drawn. This gives way to explore the various measures told in the management of Anidra in Ayurveda to discover their role on these neurotransmitters and in turn production of sleep. Drugs such as Ashwagandha [Withania somnifera (L.)],Jatamansi [Nardostachys jatamamsi (D.Don) DC], and Shankhapushpi (Convolvulus pluricalis, Choisy) and their formulations are being used in the management of insomnia or Anidra. These drugs are said to be Vata–Pitta Shamaka and have Sheeta-Ushna Veerya and Medhya properties. They are also proven to have an effect on sleep neurotransmitters such as serotonin, dopamine, and acetylcholine.,, It is reassuring that the drugs which are explained in Ayurveda to be effective in Anidra due to their Rasa Panchaka (individual drug properties according to Ayurveda) are proven to be having effect on these neurotransmitters, according to the contemporary research. Similarly, other drugs, Ayurveda therapies (Shirodhara, Abhyanga, Nasya) as well as diet and regimen (Madhura, Snigdha Ahara, Vyayama, etc.) protocols, which are told for the management of Anidra, could be explored for their possible effects on these neurotransmitters. There are several measures in Ayurveda that can serve in addition to the existing protocols of management of insomnia and should be expounded upon. For example, drugs or therapies which are said to be Medhya (acting on mind) can be used to manage conditions of insomnia occurring due to stress or Manasantapa, drugs which improve the strength of an individual (Balya) can be used to manage insomnia due to old age (Kala/Kshaya).
| Conclusion|| |
There is a surprising commonality in the factors of Anidra and contemporary sleep theories as discussed earlier. It can be assumed that the neurotransmitter sleep theories that are being explained today have been understood by Ayurveda Acharya centuries ago. This also reflects in the drugs, therapies, and regimen told for the maintenance of sleep in Ayurveda. In contrast, even though the contemporary science has developed various classes of drugs for the management of insomnia, they have been observed to have varied drawbacks and are being augmented every day. This is due to the lack of complete understanding of the physiology and pathophysiology of sleep and insomnia. respectively. And only when the pathophysiology is understood thoroughly can we start to make comprehensive treatment modalities. Hence, this article aimed to contribute toward the development of an overall management protocol for insomnia from Ayurveda by understanding this relation between the factors of Anidra and the pathophysiology of insomnia.
| Scope for Future Study|| |
Quantifiable assessment of Anidra Nidana (causes) and their probable effect on sleep neurotransmitters;
Drug discovery and development of Ayurveda drugs for their probable effects on sleep neurotransmitters;
Assessment of Dosha on sleep neurotransmitters.
| Take Away Message|| |
There is an important role of Ayurveda concepts of Nidra and Anidra in the better understanding of neurotransmitter sleep theories.
Aid can be given from Ayurveda management protocols to contribute in the management of insomnia.
There is a need to further explore the Ayurveda therapies, drugs, diet, and regimen on the sleep neurotransmitters.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Vagbhatta A, Hemadri AH Pt Hari Sadasiva Sastri Paradakara Bhisagacharya, Sutra Sthana 7/53. Varanasi: Chaukhambha Orientalia; 2010. p. 140.
Ksaper DL Sleep disorders. In: Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, editors. Harrison’s Principles of Internal Medicine. 20th ed. New York: McGraw Hill Education Medical; 2016. 172p.
Panda S, Taly AB, Sinha S, Gururaj G, Girish N, Nagaraja D Sleep-related disorders among a healthy population in South India. Neurol India 2012;60:68-74.
Sushruta D Sushruta Samhita, Vaidya Yadavji Trikamji. Shareera Sthana 4/42, Varanasi: Chawkhamba Krishnadas Academy; 2004. p. 359.
Agnivesha C, Dridhabala C Charaka Samhita, Vaidya Yadavji Trikamji Acharya. Sutra Sthana 21/58, Varanasi: Chaukhamba Surbharati Prakashan; 2009. p. 119.
Sushruta D Sushruta Samhita, Vaidya Yadavji Trikamji Acharya. Shareera Sthana 4/34, Varanasi: Chawkhamba Krishnadas Academy; 2004. p. 358.
Vagbhatta S Ashtanga Sangraha. Dr. Shailaja Srivastava, Sutra Sthana 9/29, Varanasi: Chaukhambha Orientalia; 2006. p. 183.
Harita. Harita Samhita. Vaidya Jaimini Pandey, Shareera Sthana 1/53–54, Varanasi: Chaukhamba Visvabharati; 2010. p. 421.
Agnivesha C, Dridhabala C Charaka Samhita, Vaidya Yadavji Trikamji Acharya. Sutra Sthana 21/35, Varanasi: Chaukhamba Surbharati Prakashan; 2009. p. 118.
Watson CJ, Baghdoyan HA, Lydic R Neuropharmacology of sleep and wakefulness. Sleep Med Clin 2010;5:513-28.
Monti JM, Jantos H The roles of dopamine and serotonin, and of their receptors, in regulating sleep and waking. Prog Brain Res 2008;172:625-46.
Sadock BJ, Sadock VA, Ruiz P Kaplan and Sadock’s Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry. 11th ed. Philadelphia: Wolters Kluwer Medknow Publications; 2015. p. 538.
Sadock BJ, Sadock VA, Ruiz P Kaplan and Sadock’s Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry. 11th ed. Philadelphia: Wolters Kluwer Medknow Publications; 2015. p. 542.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013. p. 365-6.
Chu A, Wadhwa R Selective serotonin reuptake inhibitors. [Updated 2021 May 10]. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554406/.
Meeusen R, Watson P, Hasegawa H, Roelands B, Piacentini MF Central fatigue: The serotonin hypothesis and beyond. Sports Med 2006;36:881-909.
Melancon MO, Lorrain D, Dionne IJ Exercise and sleep in aging: Emphasis on serotonin . Pathol Biol 2014;62:276-83.
Costello RB, Lentino CV, Boyd CC, O’Connell ML, Crawford CC, Sprengel ML, et al
. The effectiveness of melatonin for promoting healthy sleep: A rapid evidence assessment of the literature. Nutr J 2014;13:106.
Finan PH, Goodin BR, Smith MT The association of sleep and pain: An update and a path forward. J Pain 2013;14:1539-52.
Shastri VD Bhavaprakasha Nighantu. 9th ed. New Delhi: Motilal Banarasidas; 2002. p. 219.
Shastri VD Bhavaprakasha Nighantu. 9th ed. New Delhi: Motilal Banarasidas; 2002. p. 127.
Shastri VD Bhavaprakasha Nighantu. 9th ed. New Delhi: Motilal Banarasidas; 2002. p. 261.
Singh N, Bhalla M, de Jager P, Gilca M An overview on ashwagandha: A rasayana (rejuvenator) of Ayurveda. Afr J Tradit Complement Altern Med 2011;8:208-13.
Rahman H, Shaik H, Madhavi P, Chinna M A review: Pharmacognostics and pharmacological profiles of Nardastachys jatamansi DC. Elixir Pharm 2011;6:5017-20.
Sethiya N, Nahata A, Mishra SH, Dixit V An update on Shankhpushpi, a cognition boosting Ayurvedic medicine. J Chin Integr Med 2009;7:1001-22. Doi:10.3736/jcim20091101.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]