Insomnia is a prevalent and disabling condition whose treatment is not always effective. This pilot study explores the feasibility and effects of closed-loop auditory stimulation (CLAS) as a potential non-invasive intervention to improve sleep, its subjective quality, and memory consolidation in patients with insomnia. A total of 27 patients with chronic insomnia underwent a crossover, sham-controlled study with 2 nights of either CLAS or sham stimulation. Polysomnography was used to record sleep parameters, while questionnaires and a word-pair memory task were administered to assess subjective sleep quality and memory consolidation. The initial analyses included 17 patients who completed the study, met the inclusion criteria, and received CLAS. From those, 10 (58%) received only a small number of stimuli. In the remaining seven (41%) patients with sufficient CLAS, we evaluated the acute and whole-night effect on sleep. CLAS led to a significant immediate increase in slow oscillation (0.5-1 Hz) amplitude and activity, and reduced delta (1-4 Hz) and sigma/sleep spindle (12-15 Hz) activity during slow-wave sleep across the whole night. All these fundamental sleep rhythms are implicated in sleep-dependent memory consolidation. Yet, CLAS did not change sleep-dependent memory consolidation or sleep macrostructure characteristics, number of arousals, or subjective perception of sleep quality. Results showed CLAS to be feasible in patients with insomnia. However, a high variance in the efficacy of our automated stimulation approach suggests that further research is needed to optimise stimulation protocols to better unlock potential CLAS benefits for sleep structure and subjective sleep quality in such clinical settings.

3rd Faculty of Medicine Charles University Prague Czech Republic

Center for Brain Behaviour and Metabolism University of Lübeck Lübeck Germany

Department of Physiology Faculty of Science Charles University Prague Prague Czech Republic

Department of Psychology University of Essex Colchester UK

Department of Psychology University of Lübeck Lübeck Germany

Faculty of Biomedical Engineering Czech Technical University Prague Prague Czech Republic

National Institute of Mental Health Klecany Czech Republic

School of Medicine Medical Sciences and Nutrition University of Aberdeen Aberdeen Scotland

See more in PubMed

American Academy of Sleep Medicine . (2007). The AASM manual for the scoring of sleep and associated events: Rules, terminology and technical specifications (1st ed.). American Academy of Sleep Medicine.

Atkin, T. , Comai, S. , & Gobbi, G. (2018). Drugs for insomnia beyond benzodiazepines: Pharmacology, clinical applications, and discovery. Pharmacological Reviews, 70(2), 197–245. 10.1124/pr.117.014381 PubMed DOI

Backhaus, J. , Junghanns, K. , Born, J. , Hohaus, K. , Faasch, F. , & Hohagen, F. (2006). Impaired declarative memory consolidation during sleep in patients with primary insomnia: Influence of sleep architecture and nocturnal cortisol release. Biological Psychiatry, 60(12), 1324–1330. 10.1016/j.biopsych.2006.03.051 PubMed DOI

Baglioni, C. , Battagliese, G. , Feige, B. , Spiegelhalder, K. , Nissen, C. , Voderholzer, U. , Lombardo, C. , & Riemann, D. (2011). Insomnia as a predictor of depression: A meta‐analytic evaluation of longitudinal epidemiological studies. Journal of Affective Disorders, 135(1–3), 10–19. 10.1016/j.jad.2011.01.011 PubMed DOI

Baglioni, C. , Regen, W. , Teghen, A. , Spiegelhalder, K. , Feige, B. , Nissen, C. , & Riemann, D. (2014). Sleep changes in the disorder of insomnia: A meta‐analysis of polysomnographic studies. Sleep Medicine Reviews, 18(3), 195–213. 10.1016/j.smrv.2013.04.001 PubMed DOI

Beck, A. T. , Epstein, N. , Brown, G. , & Steer, R. (1988). Beck anxiety inventory. APA PsycTests. 10.1037/t02025-000. DOI

Beck, A. T. , Ward, C. H. , Mendelson, M. , Mock, J. , & Erbaugh, J. (1961). An inventory for measuring depression. Archives of General Psychiatry, 4, 561–571. 10.1001/archpsyc.1961.01710120031004 PubMed DOI

Berens, P. (2009). CircStat: A MATLAB toolbox for circular statistics. Journal of Statistical Software, 31(10), 1–21. 10.18637/jss.v031.i10 DOI

Cellini, N. , de Zambotti, M. , Covassin, N. , Sarlo, M. , & Stegagno, L. (2014). Impaired off‐line motor skills consolidation in young primary insomniacs. Neurobiology of Learning and Memory, 114, 141–147. 10.1016/j.nlm.2014.06.006 PubMed DOI

Debellemaniere, E. , Chambon, S. , Pinaud, C. , Thorey, V. , Dehaene, D. , Léger, D. , Chennaoui, M. , Arnal, P. J. , & Galtier, M. N. (2018). Performance of an ambulatory dry‐EEG device for auditory closed‐loop stimulation of sleep slow oscillations in the home environment. Frontiers in Human Neuroscience, 12, 88. 10.3389/fnhum.2018.00088 PubMed DOI PMC

Diep, C. , Ftouni, S. , Manousakis, J. E. , Nicholas, C. L. , Drummond, S. P. A. , & Anderson, C. (2019). Acoustic slow wave sleep enhancement via a novel, automated device improves executive function in middle‐aged men. Sleep, 43(1), zsz197. 10.1093/sleep/zsz197 PubMed DOI

Dudysová, D. , Fajnerová, I. , Nekovářová, T. , Ngo, H. V. V. , & Kopřivová, J. (2016). Czech version of paired associative learning test – a pilot study. Psychiatrie, 20(4), 174–177.

Feige, B. , Baglioni, C. , Boehm, P. , Heinrich, A. , Trumm, S. , Benz, F. , Nissen, C. , Domschke, K. , Frase, L. , & Riemann, D. (2021). Event‐related potentials in insomnia reflect altered perception of sleep. Sleep, 44(10), zsab137. 10.1093/sleep/zsab137 PubMed DOI

Feige, B. , Nanovska, S. , Baglioni, C. , Bier, B. , Cabrera, L. , Diemers, S. , Quellmalz, M. , Siegel, M. , Xeni, I. , Szentkiralyi, A. , Doerr, J. P. , & Riemann, D. (2018). Insomnia‐perchance a dream? Results from a NREM/REM sleep awakening study in good sleepers and patients with insomnia. Sleep, 41(5), 1–11. 10.1093/sleep/zsy032 PubMed DOI

Ferrarelli, F. , Huber, R. , Peterson, M. J. , Massimini, M. , Murphy, M. , Riedner, B. A. , … Tononi, G. (2007). Reduced sleep spindle activity in schizophrenia patients. The American Journal of Psychiatry, 164(3), 483–492. 10.1176/ajp.2007.164.3.483 PubMed DOI

Geiser, T. , Hertenstein, E. , Fehér, K. , Maier, J. G. , Schneider, C. L. , Züst, M. A. , Wunderlin, M. , Mikutta, C. , Klöppel, S. , & Nissen, C. (2020). Targeting arousal and sleep through noninvasive brain stimulation to improve mental health. Neuropsychobiology, 79(4–5), 284–292. 10.1159/000507372 PubMed DOI

Hogan, S. E. , Delgado, G. M. , Hall, M. H. , Nimgaonkar, V. L. , Germain, A. , Buysse, D. J. , & Wilckens, K. A. (2020). Slow‐oscillation activity is reduced and high frequency activity is elevated in older adults with insomnia. Journal of Clinical Sleep Medicine, 16(9), 1445–1454. 10.5664/jcsm.8568 PubMed DOI PMC

Horne, J. A. , & Ostberg, O. (1976). A self‐assessment questionnaire to determine morningness‐eveningness in human circadian rhythms. International Journal of Chronobiology, 4(2), 97–110. PubMed

Johns, M. W. (1991). A new method for measuring daytime sleepiness: The Epworth sleepiness scale. Sleep, 14(6), 540–545. 10.1093/sleep/14.6.540 PubMed DOI

Knoblauch, V. , Kräuchi, K. , Renz, C. , Wirz‐Justice, A. , & Cajochen, C. (2002). Homeostatic control of slow‐wave and spindle frequency activity during human sleep: Effect of differential sleep pressure and brain topography. Cerebral Cortex, 12(10), 1092–1100. 10.1093/cercor/12.10.1092 PubMed DOI

Kyle, S. D. , Miller, C. B. , Rogers, Z. , Siriwardena, A. N. , Macmahon, K. M. , & Espie, C. A. (2014). Sleep restriction therapy for insomnia is associated with reduced objective total sleep time, increased daytime somnolence, and objectively impaired vigilance: Implications for the clinical management of insomnia disorder. Sleep, 37(2), 229–237. 10.5665/sleep.3386 PubMed DOI PMC

Leminen, M. M. , Virkkala, J. , Saure, E. , Paajanen, T. , Zee, P. C. , Santostasi, G. , Hublin, C. , Müller, K. , Porkka‐Heiskanen, T. , Huotilainen, M. , & Paunio, T. (2017). Enhanced memory consolidation via automatic sound stimulation during non‐REM sleep. Sleep, 40(3), zsx003. 10.1093/sleep/zsx003 PubMed DOI PMC

Mander, B. A. , Rao, V. , Lu, B. , Saletin, J. M. , Lindquist, J. R. , Ancoli‐Israel, S. , Jagust, W. , & Walker, M. P. (2013). Prefrontal atrophy, disrupted NREM slow waves and impaired hippocampal‐dependent memory in aging. Nature Neuroscience, 16(3), 357–364. 10.1038/nn.3324 PubMed DOI PMC

Maris, E. , & Oostenveld, R. (2007). Nonparametric statistical testing of EEG‐ and MEG‐data. Journal of Neuroscience Methods, 164(1), 177–190. 10.1016/j.jneumeth.2007.03.024 PubMed DOI

Marshall, L. , Molle, M. , Hallschmid, M. , & Born, J. (2004). Transcranial direct current stimulation during sleep improves declarative memory. The Journal of Neuroscience, 24(44), 9985–9992. 10.1523/JNEUROSCI.2725-04.2004 PubMed DOI PMC

Murtagh, D. R. , & Greenwood, K. M. (1995). Identifying effective psychological treatments for insomnia: A meta‐analysis. Journal of Consulting and Clinical Psychology, 63(1), 79–89. 10.1037//0022-006x.63.1.79 PubMed DOI

Ngo, H. V. , Martinetz, T. , Born, J. , & Molle, M. (2013). Auditory closed‐loop stimulation of the sleep slow oscillation enhances memory. Neuron, 78(3), 545–553. 10.1016/j.neuron.2013.03.006 PubMed DOI

Ngo, H. V. , Miedema, A. , Faude, I. , Martinetz, T. , Molle, M. , & Born, J. (2015). Driving sleep slow oscillations by auditory closed‐loop stimulation‐a self‐limiting process. The Journal of Neuroscience, 35(17), 6630–6638. 10.1523/JNEUROSCI.3133-14.2015 PubMed DOI PMC

Nissen, C. , Kloepfer, C. , Feige, B. , Piosczyk, H. , Spiegelhalder, K. , Voderholzer, U. , & Riemann, D. (2011). Sleep‐related memory consolidation in primary insomnia. Journal of Sleep Research, 20(1 Pt 2), 129–136. 10.1111/j.1365-2869.2010.00872.x PubMed DOI

Ohayon, M. M. (2002). Epidemiology of insomnia: What we know and what we still need to learn. Sleep Medicine Reviews, 6(2), 97–111. 10.1053/smrv.2002.0186 PubMed DOI

Okajima, I. , Komada, Y. , & Inoue, Y. (2011). A meta‐analysis on the treatment effectiveness of cognitive behavioral therapy for primary insomnia. Sleep and Biological Rhythms, 9(1), 24–34. 10.1111/j.1479-8425.2010.00481.x DOI

Oostenveld, R. , Fries, P. , Maris, E. , & Schoffelen, J. M. (2011). FieldTrip: Open source software for advanced analysis of MEG, EEG, and invasive electrophysiological data. Computational Intelligence and Neuroscience, 2011, 156869. 10.1155/2011/156869 PubMed DOI PMC

Papalambros, N. A. , Santostasi, G. , Malkani, R. G. , Braun, R. , Weintraub, S. , Paller, K. A. , & Zee, P. C. (2017). Acoustic enhancement of sleep slow oscillations and concomitant memory improvement in older adults. Frontiers in Human Neuroscience, 11, 109. 10.3389/fnhum.2017.00109 PubMed DOI PMC

Pathak, V. , Juan, E. , Goot, R. V. D. , & Talamini, L. M. (2021). The looping lullaby: closed‐loop neurostimulation decreases sleepers' sensitivity to environmental noise. bioRxiv, 1–38. 10.1101/2021.08.07.455505 DOI

Payne, J. D. , Tucker, M. A. , Ellenbogen, J. M. , Wamsley, E. J. , Walker, M. P. , Schacter, D. L. , & Stickgold, R. (2012). Memory for semantically related and unrelated declarative information: The benefit of sleep, the cost of wake. PLoS One, 7(3), e33079. 10.1371/journal.pone.0033079 PubMed DOI PMC

Piorecky, M. , Koudelka, V. , Piorecka, V. , Strobl, J. , Dudysova, D. , & Koprivova, J. (2021). Real‐time excitation of slow oscillations during deep sleep using acoustic stimulation. Sensors (Basel), 21(15), 5169. 10.3390/s21155169 PubMed DOI PMC

Riemann, D. , Baglioni, C. , Bassetti, C. , Bjorvatn, B. , Dolenc Groselj, L. , Ellis, J. G. , Espie, C. A. , Garcia‐Borreguero, D. , Gjerstad, M. , Gonçalves, M. , Hertenstein, E. , Jansson‐Fröjmark, M. , Jennum, P. J. , Leger, D. , Nissen, C. , Parrino, L. , Paunio, T. , Pevernagie, D. , Verbraecken, J. , … Spiegelhalder, K. (2017). European guideline for the diagnosis and treatment of insomnia. Journal of Sleep Research, 26(6), 675–700. 10.1111/jsr.12594 PubMed DOI

Riemann, D. , Spiegelhalder, K. , Feige, B. , Voderholzer, U. , Berger, M. , Perlis, M. , & Nissen, C. (2010). The hyperarousal model of insomnia: A review of the concept and its evidence. Sleep Medicine Reviews, 14(1), 19–31. 10.1016/j.smrv.2009.04.002 PubMed DOI

Schneider, J. , Lewis, P. A. , Koester, D. , Born, J. , & Ngo, H.‐V. V. (2020). Susceptibility to auditory closed‐loop stimulation of sleep slow oscillations changes with age. Sleep, 43(12), zsaa111. 10.1093/sleep/zsaa111 PubMed DOI PMC

Spiegelhalder, K. , Regen, W. , Feige, B. , Holz, J. , Piosczyk, H. , Baglioni, C. , Riemann, D. , & Nissen, C. (2012). Increased EEG sigma and beta power during NREM sleep in primary insomnia. Biological Psychology, 91(3), 329–333. 10.1016/j.biopsycho.2012.08.009 PubMed DOI

Stanyer, E. C. , Baniqued, P. D. E. , Awais, M. , Kouara, L. , Davies, A. G. , Killan, E. C. , & Mushtaq, F. (2022). The impact of acoustic stimulation during sleep on memory and sleep architecture: A meta‐analysis. Journal of Sleep Research, 31(3), e13385. 10.1111/jsr.13385 PubMed DOI

Svetnik, V. , Snyder, E. S. , Ma, J. , Tao, P. , Lines, C. , & Herring, W. J. (2017). EEG spectral analysis of NREM sleep in a large sample of patients with insomnia and good sleepers: Effects of age, sex and part of the night. Journal of Sleep Research, 26(1), 92–104. 10.1111/jsr.12448 PubMed DOI

Thacher, P. V. , Pigeon, W. R. , & Perlis, M. L. (2006). Do patients with sleep maintenance insomnia have a problem with sleep maintenance? Behavioral Sleep Medicine, 4(4), 203–218. 10.1207/s15402010bsm0404_1 PubMed DOI

Wassing, R. , Benjamins, J. S. , Talamini, L. M. , Schalkwijk, F. , & Van Someren, E. J. W. (2019). Overnight worsening of emotional distress indicates maladaptive sleep in insomnia. Sleep, 42(4), 1–8. 10.1093/sleep/zsy268 PubMed DOI

Weiner, O. M. , & Dang‐Vu, T. T. (2016). Spindle oscillations in sleep disorders: A systematic review. Neural Plasticity, 2016, 7328725. 10.1155/2016/7328725 PubMed DOI PMC

Wittchen, H. U. , Jacobi, F. , Rehm, J. , Gustavsson, A. , Svensson, M. , Jonsson, B. , Olesen, J. , Allgulander, C. , Alonso, J. , Faravelli, C. , Fratiglioni, L. , Jennum, P. , Lieb, R. , Maercker, A. , van Os, J. , Preisig, M. , Salvador‐Carulla, L. , Simon, R. , & Steinhausen, H. C. (2011). The size and burden of mental disorders and other disorders of the brain in Europe 2010. European Neuropsychopharmacology, 21(9), 655–679. 10.1016/j.euroneuro.2011.07.018 PubMed DOI

Wunderlin, M. , Züst, M. A. , Hertenstein, E. , Fehér, K. D. , Schneider, C. L. , Klöppel, S. , & Nissen, C. (2021). Modulating overnight memory consolidation by acoustic stimulation during slow‐wave sleep: A systematic review and meta‐analysis. Sleep, 44(7), 1–11. 10.1093/sleep/zsaa296 PubMed DOI

Zhao, W. , Van Someren, E. J. W. , Li, C. , Chen, X. , Gui, W. , Tian, Y. , Liu, Y. , & Lei, X. (2021). EEG spectral analysis in insomnia disorder: A systematic review and meta‐analysis. Sleep Medicine Reviews, 59, 101457. 10.1016/j.smrv.2021.101457 PubMed DOI