Insomnia Neurobiology and Therapy

Abstract

Insomnia is highly prevalent in clinical practice and can present independently or alongside other medical and mental health disorders. Insomnia is a risk factor for the development and exacerbation of medical and mental health conditions. Behavioral and pharmacological treatments for insomnia are available. In this article, we review important mechanisms associated with insomnia including the hyperarousal model of insomnia and the neurobiology of insomnia. We then review the treatment approaches and management strategies for insomnia including cognitive behavioral therapy for insomnia, transcranial magnetic stimulation, pharmacologic treatment, and adjunctive treatments for insomnia.

Keywords

insomnia - cognitive behavioral therapy - sleep - hyperarousal

Publication History

Article published online:
26 June 2025

• References

• 1 Perlis ML, Pigeon WR, Grandner MA. et al. Why treat insomnia?. J Prim Care Community Health 2021; 12: 21 501327211014084
• 2 Laugsand LE, Vatten LJ, Platou C, Janszky I. Insomnia and the risk of acute myocardial infarction: a population study. Circulation 2011; 124 (19) 2073-2081
• 3 Edinger JD, Arnedt JT, Bertisch SM. et al. Behavioral and psychological treatments for chronic insomnia disorder in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med 2021; 17 (02) 255-262
• 4 Fernandez-Mendoza J, Vgontzas AN, Liao D. et al. Insomnia with objective short sleep duration and incident hypertension: the Penn State Cohort. Hypertension 2012; 60 (04) 929-935
• 5 Mayer G, Jennum P, Riemann D, Dauvilliers Y. Insomnia in central neurologic diseases—occurrence and management. Sleep Med Rev 2011; 15 (06) 369-378
• 6 Baglioni C, Battagliese G, Feige B. et al. Insomnia as a predictor of depression: a meta-analytic evaluation of longitudinal epidemiological studies. J Affect Disord 2011; 135 (1-3): 10-19
• 7 Kucharczyk ER, Morgan K, Hall AP. The occupational impact of sleep quality and insomnia symptoms. Sleep Med Rev 2012; 16 (06) 547-559
• 8 Martin SA, Aikens JE, Chervin RD. Toward cost-effectiveness analysis in the diagnosis and treatment of insomnia. Sleep Med Rev 2004; 8 (01) 63-72
• 9 Léger D, Guilleminault C, Bader G, Lévy E, Paillard M. Medical and socio-professional impact of insomnia. Sleep 2002; 25 (06) 625-629
• 10 Roy AN, Smith M. Prevalence and cost of insomnia in a state Medicaid fee-for-service population based on diagnostic codes and prescription utilization. Sleep Med 2010; 11 (05) 462-469
• 11 Ekirch AR. Segmented sleep in preindustrial societies. Sleep 2016; 39 (03) 715-716
• 12 Moreno CRC, Conway SG, Assis M. et al. COVID-19 pandemic is associated with increased sleep disturbances and mental health symptoms but not help-seeking: a cross-sectional nation-wide study. Sleep Sci 2022; 15 (01) 1-7
• 13 Hurley D. . Sleep Neurologists Call It “COVID-Somnia”—Increased Sleep Disturbances Linked to the Pandemic. Accessed June 6, 2025 at: https://journals.lww.com/neurotodayonline/fulltext/2020/07090/sleep_neurologists_call_it.1.aspx
• 14 Murthy VH. Together: The Healing Power of Human Connection in a Sometimes Lonely World. Harper; 2020
• 15 Jahrami H, Trabelsi K, Vitiello MV, BaHammam AS. The tale of orthosomnia: I am so good at sleeping that I can do it with my eyes closed and my fitness tracker on me. Nat Sci Sleep 2023; 15: 13-15
• 16 Espie CA. Insomnia: conceptual issues in the development, persistence, and treatment of sleep disorder in adults. Annu Rev Psychol 2002; 53: 215-243
• 17 Riemann D, Spiegelhalder K, Feige B. et al. The hyperarousal model of insomnia: a review of the concept and its evidence. Sleep Med Rev 2010; 14 (01) 19-31
• 18 Zhang J, Lam SP, Li SX. et al. A community-based study on the association between insomnia and hypothalamic-pituitary-adrenal axis: sex and pubertal influences. J Clin Endocrinol Metab 2014; 99 (06) 2277-2287
• 19 Bonnet MH, Arand DL. Heart rate variability in insomniacs and matched normal sleepers. Psychosom Med 1998; 60 (05) 610-615
• 20 Lushington K, Dawson D, Lack L. Core body temperature is elevated during constant wakefulness in elderly poor sleepers. Sleep 2000; 23 (04) 504-510
• 21 Bonnet MH, Arand DL. 24-Hour metabolic rate in insomniacs and matched normal sleepers. Sleep 1995; 18 (07) 581-588
• 22 Nofzinger EA, Buysse DJ, Germain A, Price JC, Miewald JM, Kupfer DJ. Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry 2004; 161 (11) 2126-2128
• 23 Freedman RR, Sattler HL. Physiological and psychological factors in sleep-onset insomnia. J Abnorm Psychol 1982; 91 (05) 380-389
• 24 Perlis ML, Merica H, Smith MT, Giles DE. Beta EEG activity and insomnia. Sleep Med Rev 2001; 5 (05) 363-374
• 25 Kutscher S, Juang C. Insomnia. Continuum (Minneap Minn) 2023; 29 (04) 1167-1187
• 26 Wassing R, Schalkwijk F, Lakbila-Kamal O. et al. Haunted by the past: old emotions remain salient in insomnia disorder. Brain 2019; 142 (06) 1783-1796
• 27 Spielman AJ, Caruso LS, Glovinsky PB. A behavioral perspective on insomnia treatment. Psychiatr Clin North Am 1987; 10 (04) 541-553
• 28 Lind MJ, Gehrman PR. Genetic pathways to insomnia. Brain Sci 2016; 6 (04) 64
• 29 Bouvette-Turcot A-A, Pluess M, Bernier A. et al; MAVAN research team. Effects of genotype and sleep on temperament. Pediatrics 2015; 136 (04) e914-e921
• 30 Brummett BH, Krystal AD, Ashley-Koch A. et al. Sleep quality varies as a function of 5-HTTLPR genotype and stress. Psychosom Med 2007; 69 (07) 621-624
• 31 Brummett BH, Krystal AD, Siegler IC. et al. Associations of a regulatory polymorphism of monoamine oxidase-A gene promoter (MAOA-uVNTR) with symptoms of depression and sleep quality. Psychosom Med 2007; 69 (05) 396-401
• 32 Li J, Huang C, Lan Y, Wang Y. A cross-sectional study on the relationships among the polymorphism of period2 gene, work stress, and insomnia. Sleep Breath 2015; 19 (04) 1399-1406
• 33 Brower KJ, Wojnar M, Sliwerska E, Armitage R, Burmeister M. PER3 polymorphism and insomnia severity in alcohol dependence. Sleep 2012; 35 (04) 571-577
• 34 Ziv-Gal A, Flaws JA, Mahoney MM, Miller SR, Zacur HA, Gallicchio L. Genetic polymorphisms in the aryl hydrocarbon receptor-signaling pathway and sleep disturbances in middle-aged women. Sleep Med 2013; 14 (09) 883-887
• 35 Wang CC, Lung FW. The role of PGC-1 and Apoε4 in insomnia. Psychiatr Genet 2012; 22 (02) 82-87
• 36 Goel N, Banks S, Mignot E, Dinges DF. Dopaminergic polymorphisms associated with sleep and circadian phenotypes. Sleep 2011; 34 (05) 513-520
• 37 Holzman JB, Bridgett DJ, Green MJ. Personality and catechol-O-methyltransferase (COMT) genotype interact to predict insomnia symptoms. Pers Individ Dif 2018; 120: 250-256
• 38 Killgore WDS, Jankowski S, Henderson-Arredondo K. et al. Functional connectivity of the default mode network predicts subsequent polysomnographically measured sleep in people with symptoms of insomnia. Neuroreport 2023; 34 (14) 734-740
• 39 Salas RE, Galea JM, Gamaldo AA. et al. Increased use-dependent plasticity in chronic insomnia. Sleep 2014; 37 (03) 535-544
• 40 Nofzinger EA, Buysse DJ, Germain A, Price JC, Miewald JM. Kupfer DJ. Functional neuroimaging evidence for hyperarousal in insomnia. Am. J Psychiatry 2004; 161 (11) 2126-2128
• 41 Pejovic S, Vgontzas AN. Neurobiological disturbances in insomnia: clinical utility of objective measures of sleep. In: Sateia JM, Buysse D. eds Insomnia. Boca Raton, FL: CRC Press; 2010: 65-76
• 42 Johns Hopkins University. Accessed June 6, 2025 at: https://doi-org.proxy1.library.jhu.edu/10.1111/jsr.14032
• 43 Carskadon MA, Brown ED, Dement WC. Sleep fragmentation in the elderly: relationship to daytime sleep tendency. Neurobiol Aging 1982; 3 (04) 321-327
• 44 Stepanski E, Lamphere J, Badia P, Zorick F, Roth T. Sleep fragmentation and daytime sleepiness. Sleep 1984; 7 (01) 18-26
• 45 Finan PH. Richards JM, Gamaldo CE. et al. Validation of a wireless, self-application, ambulatory electroencephalographic sleep monitoring device in healthy volunteers. J Clin Sleep Med 2016; 12 (11) 1443-1451
• 46 Baglioni C, Regen W, Teghen A. et al. Sleep changes in the disorder of insomnia: a meta-analysis of polysomnographic studies. Sleep Med Rev 2014; 18 (03) 195-213
• 47 Feige B, Al-Shajlawi A, Nissen C. et al. Does REM sleep contribute to subjective wake time in primary insomnia? A comparison of polysomnographic and subjective sleep in 100 patients. J Sleep Res 2008; 17 (02) 180-190
• 48 Riemann D, Spiegelhalder K, Nissen C, Hirscher V, Baglioni C, Feige B. REM sleep instability—a new pathway for insomnia?. Pharmacopsychiatry 2012; 45 (05) 167-176
• 49 Parrino L, Milioli G, De Paolis F, Grassi A, Terzano MG. Paradoxical insomnia: the role of CAP and arousals in sleep misperception. Sleep Med 2009; 10 (10) 1139-1145
• 50 Christensen JAE, Wassing R, Wei Y. et al. Data-driven analysis of EEG reveals concomitant superficial sleep during deep sleep in insomnia disorder. Front Neurosci 2019; 13: 598
• 51 Feige B, Baglioni C, Spiegelhalder K, Hirscher V, Nissen C, Riemann D. The microstructure of sleep in primary insomnia: an overview and extension. Int J Psychophysiol 2013; 89 (02) 171-180
• 52 Blanken TF, Benjamins JS, Borsboom D. et al. Insomnia disorder subtypes derived from life history and traits of affect and personality. Lancet Psychiatry 2019; 6 (02) 151-163
• 53 Terzano MG, Parrino L, Smerieri A. [Neurophysiological basis of insomnia: role of cyclic alternating patterns]. Rev Neurol (Paris) 2001; 157 (11 Pt 2): S62-S66
• 54 Van Someren EJW. Brain mechanisms of insomnia: new perspectives on causes and consequences. Physiol Rev 2021; 101 (03) 995-1046
• 55 Swift KM, Gross BA, Frazer MA. et al. Abnormal locus cooeruleus sleep activity alters sleep signatures of memory consolidation and impairs place cell stability and spatial memory. Curr Biol 2018; 28 (22) 3599-3609.e4
• 56 Van Someren EJW. Brain mechanisms of insomnia: new perspectives on causes and consequences. Physiol Rev 2021; 101 (03) 995-1046
• 57 Porosnicu Rodriguez KA, Salas RME, Schneider L. Insomnia: personalized diagnosis and treatment options. Neurol Clin 2023; 41 (01) 1-19
• 58 Ziegelstein RC. Personomics: the missing link in the evolution from precision medicine to personalized medicine. J Pers Med 2017; 7 (04) 11
• 59 Perez MN, Salas RME. Insomnia. Continuum (Minneap Minn) 2020; 26 (04) 1003-1015
• 60 Beaulieu-Bonneau S, Ivers H, Guay B, Morin CM. Long-term maintenance of therapeutic gains associated with cognitive-behavioral therapy for insomnia delivered alone or combined with zolpidem. Sleep 2017; 40 (03) zsx002
• 61 Castronovo V, Galbiati A, Sforza M. et al. Long-term clinical effect of group cognitive behavioral therapy for insomnia: a case series study. Sleep Med 2018; 47: 54-59
• 62 Mitchell MD, Gehrman P, Perlis M, Umscheid CA. Comparative effectiveness of cognitive behavioral therapy for insomnia: a systematic review. BMC Fam Pract 2012; 13: 40
• 63 van Straten A, van der Zweerde T, Kleiboer A, Cuijpers P, Morin CM, Lancee J. Cognitive and behavioral therapies in the treatment of insomnia: a meta-analysis. Sleep Med Rev 2018; 38: 3-16
• 64 Brasure M, Fuchs E, MacDonald R. et al. Psychological and behavioral interventions for managing insomnia disorder: an evidence report for a clinical practice guideline by the American College of Physicians. Ann Intern Med 2016; 165 (02) 113-124
• 65 Qaseem A, Kansagara D, Forciea MA, Cooke M, Denberg TD. Clinical Guidelines Committee of the American College of Physicians. Management of chronic insomnia disorder in adults: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2016; 165 (02) 125-133
• 66 Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med 2017; 13 (02) 307-349
• 67 Wilson S, Anderson K, Baldwin D. et al. British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders: an update. J Psychopharmacol 2019; 33 (08) 923-947
• 68 Mansfield D, Grima NA, Bei B. Insomnia management. Aust J Gen Pract 2019; 48 (04) 198-202
• 69 Espie CA, Broomfield NM, MacMahon KM, Macphee LM, Taylor LM. The attention-intention-effort pathway in the development of psychophysiologic insomnia: a theoretical review. Sleep Med Rev 2006; 10 (04) 215-245
• 70 Harvey AG. A cognitive model of insomnia. Behav Res Ther 2002; 40 (08) 869-893
• 71 Valero-Cabré A, Amengual JL, Stengel C, Pascual-Leone A, Coubard OA. Transcranial magnetic stimulation in basic and clinical neuroscience: a comprehensive review of fundamental principles and novel insights. Neurosci Biobehav Rev 2017; 83: 381-404
• 72 van Dijk KD, Møst EI, Van Someren EJ, Berendse HW, van der Werf YD. Beneficial effect of transcranial magnetic stimulation on sleep in Parkinson's disease. Mov Disord 2009; 24 (06) 878-884
• 73 Sánchez-Escandón O, Arana-Lechuga Y, Terán-Pérez G. et al. Effect of low-frequency repetitive transcranial magnetic stimulation on sleep pattern and quality of life in patients with focal epilepsy. Sleep Med 2016; 20: 37-40
• 74 Gao X, Wang L, Liu X, Yan T. The effect of repetitive transcranial magnetic stimulation on sleep: a meta-analysis. Sleep Med Rev 2020; 49: 101225
• 75 Berlim MT, Van den Eynde F, Jeff Daskalakis Z. Clinically meaningful efficacy and acceptability of low-frequency repetitive transcranial magnetic stimulation (rTMS) for treating primary major depression: a meta-analysis of randomized, double-blind and sham-controlled trials. Neuropsychopharmacology 2013; 38 (04) 543-551
• 76 Cheng Y, Xue T, Dong F. et al. Abnormal functional connectivity of the salience network in insomnia. Brain Imaging Behav 2022; 16 (02) 930-938
• 77 Jiang CG, Zhang T, Yue FG, Yi ML, Gao D. Efficacy of repetitive transcranial magnetic stimulation in the treatment of patients with chronic primary insomnia. Cell Biochem Biophys 2013; 67 (01) 169-173
• 78 Jiang B, He D, Guo Z, Mu Q, Zhang L. Efficacy and placebo response of repetitive transcranial magnetic stimulation for primary insomnia. Sleep Med 2019; 63: 9-13
• 79 Song P, Lin H, Li S. et al. Repetitive transcranial magnetic stimulation (rTMS) modulates time-varying electroencephalography (EEG) network in primary insomnia patients: a TMS-EEG study. Sleep Med 2019; 56: 157-163
• 80 Kryger MH, Roth T, Dement WC. Principles and Practice of Sleep Medicine. 5th ed.. Elsevier/Saunders; 2011. :xlii, 1723 p
• 81 Smith MT, Perlis ML, Park A. et al. Comparative meta-analysis of pharmacotherapy and behavior therapy for persistent insomnia. Am J Psychiatry 2002; 159 (01) 5-11
• 82 Nowell PD, Mazumdar S, Buysse DJ, Dew MA, Reynolds III CF, Kupfer DJ. Benzodiazepines and zolpidem for chronic insomnia: a meta-analysis of treatment efficacy. JAMA 1997; 278 (24) 2170-2177
• 83 Michelson D, Snyder E, Paradis E. et al. Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, double-blind, placebo-controlled trial. Lancet Neurol 2014; 13 (05) 461-471
• 84 Riemann D, Spiegelhalder K. Orexin receptor antagonists: a new treatment for insomnia?. Lancet Neurol 2014; 13 (05) 441-443
• 85 Riemann D, Espie CA, Altena E. et al. The European Insomnia Guideline: an update on the diagnosis and treatment of insomnia 2023. J Sleep Res 2023; 32 (06) e14035
• 86 Gong H, Ni CX, Liu YZ. et al. Mindfulness meditation for insomnia: a meta-analysis of randomized controlled trials. J Psychosom Res 2016; 89: 1-6
• 87 Rusch HL, Rosario M, Levison LM. et al. The effect of mindfulness meditation on sleep quality: a systematic review and meta-analysis of randomized controlled trials. Ann N Y Acad Sci 2019; 1445 (01) 5-16
• 88 Ong J, Sholtes D. A mindfulness-based approach to the treatment of insomnia. J Clin Psychol 2010; 66 (11) 1175-1184
• 89 Riedel A, Benz F, Deibert P. et al. The effect of physical exercise interventions on insomnia: a systematic review and meta-analysis. Sleep Med Rev 2024; 76: 101948
• 90 Bernstein AM, Allexandre D, Bena J. et al. “Go! to sleep”: a Web-based therapy for insomnia. Telemed J E Health 2017; 23 (07) 590-599
• 91 Saldaña KS, McGowan SK, Martin JL. Acceptance and commitment therapy as an adjunct or alternative treatment to cognitive behavioral therapy for insomnia. Sleep Med Clin 2023; 18 (01) 73-83
• 92 Curry G, Cheung T, Zhang SD. et al. Repeated electrical vestibular nerve stimulation (VeNS) reduces severity in moderate to severe insomnia; a randomised, sham-controlled trial; the modius sleep study. Brain Stimul 2024; 17 (04) 782-793