Back to Journals » Nature and Science of Sleep » Volume 17

Revolutionizing Sleep Science: A Narrative Review of the Historical Origins and Current Applications of Sleep Neuroimaging
Authors Kay DB, Duraccio KM, Michels L, Siclari F, Karim HT, Davis EB, Wilkins IJ
Received 2 September 2024
Accepted for publication 30 March 2025
Published 26 May 2025 Volume 2025:17 Pages 1079—1099
DOI https://doi.org/10.2147/NSS.S492585
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Prof. Dr. Ahmed BaHammam
Daniel B Kay,1 Kara McRae Duraccio,1 Lars Michels,2,3 Francesca Siclari,4,5 Helmet T Karim,6,7 Elijah B Davis,8 Isaac J Wilkins1
1Department of Psychology, Brigham Young University, Provo, UT, USA; 2Department of Neuroradiology, University Hospital Zürich, University of Zürich, Zürich, Switzerland; 3Center for MR Research, University Children’s Hospital Zürich, University of Zürich, Zürich, Switzerland; 4Département de Médecine, Lausanne University Hospital, Lausanne, Switzerland; 5Netherlands Institute for Neuroscience, Amsterdam, The Netherlands; 6Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA; 7Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA; 8Department of Neuroscience, Stanford University, Stanford, CA, USA
Correspondence: Daniel B Kay, Brigham Young University, 1090 KMBL, Provo, UT, 84602, USA, Tel +1 801-422-7949, Email [email protected]
Abstract: Sleep neuroimaging is a subfield of sleep science that goes beyond polysomnography by combining neuroimaging techniques with validated sleep research methods to characterize sleep-wake states and investigate sleep-related processes across the 24-hour day. In this article, we review the historical advancements and applications that grew out of somnography leading to current sleep neuroimaging methods. We highlight the power of somnoimages to help visualize sleep research results and communicate complex information about sleep processes. We also suggest several ways in which applying neuroimaging during sleep has opened new avenues to more fully capture the nature of sleep, uncovered mechanisms of sleep-wake regulation, and increased understanding of sleep-related processes. Current applications and future directions of sleep neuroimaging are also discussed.
Plain Language Summary: Sleep neuroimaging is an advanced area of research that combines brain imaging techniques with other validated sleep measures to better understand sleep. This article reviews how sleep research has evolved from basic monitoring techniques like polysomnography to modern multimodal sleep neuroimaging methods. It highlights how these new approaches provide clearer insights into sleep processes and have led to discoveries about sleep that were previously inaccessible. The article also discusses future directions for using neuroimaging to further explore sleep and its related neuronal, behavioral, and experiential processes.
Keywords: sleep neuroimaging, sleep fMRI, EEG-fMRI, somnoimages, somnoimaging
Introduction
It is said that a picture tells a thousand words; in sleep science graphs, polysomnography (PSG) and the hypnograms in particular, have dominated as the scientific depiction of sleep and for nearly a century have likewise governed its conceptualization and classification. With advances in neuroimaging technology, a clearer picture of sleep is coming to light. Studies that combine neuroimaging techniques with polysomnography and other validated sleep methods have been called by various names, including “sleep fMRI” (functional magnetic resonance imaging) and somnoimaging. In this paper we use the term sleep neuroimaging, which we define as a subfield of sleep science and sleep medicine that layers structural and functional neuroimaging with sleep methods including PSG to characterize sleep-wake states and study constructs across those states. Sleep and sleep-related constructs, such as sleep quality, daytime sleepiness, and circadian preference, are theoretical concepts not directly observable but are inferred from empirical indicators. The images generated from sleep neuroimaging studies are referred to as somnoimages, as they vividly capture the regional dynamics of sleep-wake states in the brain in ways graphs alone cannot depict. Somnoimages are powerful depictions of regional dynamics of sleep-wake states. The aims of this narrative review are to provide the history of sleep neuroimaging from its deep roots in somnography (defined below), current methods, advantages/disadvantages of common neuroimaging modalities, highlighting their contributions to understanding sleep regulation and future research directions. Our objectives are to revisit the historical progression of sleep research from the earliest probes of brain processes to modern neuroimaging techniques, provide examples of how neuroimaging has enhanced our understanding of sleep processes and regulatory mechanisms, and to discuss future directions and potential advancements in neuroimaging applications for sleep research.
Methods
This narrative review synthesizes key literature in sleep neuroimaging, emphasizing historical context and expert insights to trace the origins, developments, and applications of neuroimaging modalities in sleep science. PubMed searches, citation tracking, and the lead author’s years of compiled relevant sources, including gray literature and translated non-English manuscripts informed this narrative review. The review grouped studies thematically, highlighting the earliest applications of each modality and samples of current applications. While not exhaustive, the review prioritizes foundational studies and key advancements. Unlike systematic reviews, which aim to comprehensively answer specific questions, this narrative review focuses on providing an integrative overview of historical, theoretical, and methodological developments, allowing flexibility in study selection. We acknowledge that where we give precedence for a major advancement in sleep neuroimaging, there may be contributions we are unaware of or that were presented in outlets beyond the scope of our search. We welcome updates to this timeline should such information come to light. Such corrections to the history are natural and would not alter the main point message this review aims to communicate. Though this approach acknowledges potential biases and limited scope, it offers a nuanced synthesis to educate readers and foster scholarly dialogue on sleep neuroimaging’s past, present, and future. A timeline of the various advancements in sleep neuroimaging is provided in Table 1, which corresponds by year with sample images presented in Figure 1.
![]() |
Table 1 Historical Timeline of Sleep Neuroimaging |
![]() |
Figure 1 This figure is a timeline showing the major advancements made over the past 150 years in visualizing and communicating knowledge about sleep. This birds-eye view of the timeline shows the evolution of somnography into sleep neuroimaging moving from black and white somnochart and graphs, to colorful 3D somnoimages produced today. A description of each chart, graph, or image depicted in this timeline can be found in Table 1 corresponding by date. A description of each symbol in the figure is beyond the scope and purpose of this review. Notes: 1930s image: Reprinted from Berger H. Uber das Elektrenkephalogramm des Menschen. III. Mitteilung. Archiv fur Psychiatrie und Nervenkrankheiten. 1931;94:16–60.7 1935 image: Loomis AL, Harvey EN, Hobart G. Potential rhythms of the cerebral cortex during sleep. Science. 1935;81(2111):5978.8 1955 image: Reprinted from Mangold R, Sokoloff L, Conner E, Kleinerman J, Therman PO, Kety SS. The effects of sleep and lack of sleep on the cerebral circulation and metabolism of normal young men. J Clin Invest. 1955;34(7, Part 1):1092–1100. Creative Commons.9 1968 images: Reprinted from Reivich M, Isaacs G, Evarts E, Kety S. The effect of slow wave sleep and REM sleep on regional cerebral blood flow in cats. J Neurochem. 1968;15(4):301–30612 and Rechtschaffen A, Kales A. A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. Bethesda, Md: U.S. Dept. of Health, Education, and Welfare; 1968. Creative Commons.13 1969 image: Risberg LG J, Ingvar DH. Regional Cerebral Blood Volume During Paradoxical Sleep. Cerebral Blood Flow. Berlin: Springer; 1969:101–103, Springer Nature.14 1985 image: Reprinted from Brain Res, volume 327(1-2), Heiss WD, Pawlik G, Herholz K, Wagner R, Wienhard K. Regional cerebral glucose metabolism in man during wakefulness, sleep, and dreaming. 1362–366, copyright 1985, with permission from Elsevier.15 1991 image: Reprinted from Madsen PL, Holm S, Vorstrup S, Friberg L, Lassen NA, Wildschiodtz G. Human regional cerebral blood flow during rapid-eye-movement sleep. J Cerebral Blood Flow Metab. 1991;11(3):502–507. With permission from Sage Publication.16 1992 image: Reprinted from Electroencephalogr Clin Neurophysiol, volume: 82(3), Lu ST, Kajola M, Joutsiniemi SL, Knuutila J, Hari R. Generator sites of spontaneous MEG activity during sleep. 182–196. Copyright 1992, with permission from Elsevier.19 1999 image: Reprinted from Neuron, volume28(3), Portas CM, Krakow K, Allen P, Josephs O, Armony JL, Frith CD. Auditory processing across the sleep-wake cycle: simultaneous EEG and fMRI monitoring in humans. 991–999, Copyright 2000, with permission from Elsevier.21 2001 images: Reprinted from Hoshi Y, Mizukami S, Tamura M. Dynamic features of hemodynamic and metabolic changes in the human brain during all-night sleep as revealed by near-infrared spectroscopy. Brain Res. 1994;652(2):257-6222 and Igawa M, Atsumi Y, Takahashi K, Shiotsuka S, Hirasawa H, Yamamoto R, et al. Activation of visual cortex in REM sleep measured by 24-channel NIRS imaging. Psychiatry Clin Neurosci. 2001;55(3):187-8. Creative Commons.23 2002 image: Reprinted from Dehaene-Lambertz G, Pena M Electrophysiological evidence for automatic phonetic processing in neonates. Neuroreport. 12(14):3155–3158. Available from: https://www.science.org/doi/10.1126/science.1077066.26 2025 image: Reprinted from Chen JE, Lewis L, Coursey S, et al. Simultaneous EEG-PET-MRI identifies temporally coupled, spatially structured hemodynamic and metabolic dynamics across wakefulness and NREM sleep. bioRxiv. 2025. Creative Commons.27Abbreviations: PET, Positron Emission Tomography; hd-EEG, high-density electroencephalography; fMRI, Functional Magnetic Resonance Imaging; SPECT, Single Photon Emission Computed Tomography; MEG, Magnetoencephalography; fNRIS, Functional Near-Infrared Spectroscopy. |
History of Somnography
Somnography refers to the recording and study of sleep patterns and processes during sleep, with graphs as the primary vehicle for representing and communicating this knowledge. Conceptually, sleep neuroimaging grew out of somnography that emerged in the 19th century, as the brain’s role in sleep and consciousness became more evident and a topic of scientific study. Definitions of sleep prior to the introduction of somnographs were largely based on personal experience, clinical judgments, and behavioral observations. Some of the first systematic and empirical depictions of sleep were represented in somnocharts, including those anonymously collected throughout the year 1755 in daily diaries, among other daily variables.1 At the dawn of modern sleep science in the early 1860s, Ernst Kohlschütter produced the first somnographs of auditory threshold across the night demonstrating that exteroception varies over the course of sleep.2,3 The somnograph of the auditory threshold from sleep produced by Kohlschütter represented a major innovation, helping to convey the patterns of sleep data more clearly than accompanying somnocharts. Making headlines in 1875, Richard Caton used the galvanometer to document electrophysiological changes in the brains of animals, empirically observing for the first neurophysiological changes across states, including reports of increased currents during sleep.28–31 Using a different modality to investigate the brain changes associated with sleep (ie, plethysmography), Angelo Mosso produced the first neurophysiological somnographs of human sleep in 1876.4 Mosso pioneered a method to measure brain pulsations in patients with skull defects, providing indirect access to volume, which he applied across sleep-wake states. His findings generally showed decreased and more uniform hemodynamic activity during sleep. Mosso also invented a weighted table upon which was shown to tip down toward the feet during behavioral sleep compared to wakefulness and toward the head during stimulation, suggesting cerebral blood flow (CBF) decreased during sleep.32,33 Laying the groundwork for noninvasive brain activity studies, some consider these inventions to be the first rudimentary neuroimaging approach, and by exertion is a forerunner to sleep neuroimaging. At the time, the finding of lower pulsations and lower brain weight during sleep seemed to support the vascular theory of sleep that argued anemia marked by decreased CBF caused sleep. His finding aligns with modern sleep neuroimaging studies showing overall lower metabolic activity during non-rapid eye movement (NREM) sleep34 and his observation of periodic increases in brain pulsations— which he speculated might correspond to dreaming—predated the discovery of EEG defined rapid eye movement (REM) sleep by over 50 years.10,11 In hindsight these results could have suggested that reduced blood flow was not a prerequisite for sleep and the presence of multiple sleep states exist. However, the overall historical interpretation of his results were, regrettably, deemed unconvincing and inconclusive by some.35 Somnographs of sleep phenominology and physiology produced by Kohlschütter and Mosso represented a major innovation, helping to convey the patterns of sleep data more clearly than text or somnocharts and by the early 20th century, graphical depictions of physiology came to dominate the conceptualization and study of sleep. Somnographs were rapidly created for every conceivable physiological process known at the time, including brain weight, cranial pressure, CBF, heart activity, muscle tone, respiration, pupillometry, skin conductance, salivation, digestion, body temperature, and eye movements.32,36 This time period was a Renaissance in sleep science and the widespread adoption and use of somnographic methods in sleep research and clinical practice highlights the power of graphical depictions in portraying and communicating sleep patterns to other researchers and the public. None of these graphs, however, generated as much interest or electrified the field of sleep science like electroencephalography (EEG).
Hans Berger is widely credited with first measuring human brain activity using EEG.37 Less well known was his application of EEG, electrocardiography (ECG), and respiration patterns to study sleep in the early 1930s, thereby creating the first human PSG using EEG. The published images corresponding to his observations of a flattening in alpha EEG waves during sleep seemed to further confirm prior beliefs that sleep is a quiescent state of brain activity.7,31,38 This overly simplistic conclusion, based on somnographs from limited electrophysiological measures (ie, few electrodes), using limited modes of measurement (ie, behavioral observation and electrophysiology), over a limited timeframe (ie, minutes to hours) reveals the persisting problem of PSG—its poor content validity in capturing the complexity of sleep-wake dynamics, incuding regional brain processes.
Mitigating this limitation, Loomis et al soon published more detailed images of EEG signals across sleep wake states in humans by using multiple EEG electrodes and recording sleep in varying conditions.8 Their graphical depictions of characteristic sleep-related brain-wave patterns, “undoubtedly of cortical origin” including the K-complex that occurred in response to knocking on the door and sleep spindles, are important representations of their revolutionary work toward characterizing sleep stages. An important step forward in measuring and representing sleep-wake states was achieved by Gibbs et al who combined thermo-electric blood flow recorders with other physiological measures of sleep.39 Their multimodal somnographs showing maintained CBF during sleep demonstrated that reduced blood flow was not a viable mechanism of sleep onset, effectively putting to rest the vascular theory of sleep.39 Although they doubted that regional changes in blood flow to a “sleep center” was involved in sleep, they acknowledged the limited regional specificity of their method prevented comment on this theory. The somnographs produced by these early EEG investigations helped challenge conceptualizations of sleep as a quiescent physiological state for the body and demonstrated convincingly that the brain is endogenously active and dynamically reactive during sleep.
Despite early advances in CBF measurement across sleep-wake states, electrophysiology ultimately came to dominate the measurement and conceptualizations of sleep. Indeed, advancements in other brain measures of sleep were largely overshadowed by PSG within the emerging field of sleep and dream research following the discovery of REM sleep in the 1950s.10,11 Compared to electrophysiological measures, alternative measures of sleep proved to be less accessible, technical, and expensive. Human brain measures also tended to yield less reliable or clear results. Nevertheless, the application of neuroimaging to study sleep remained an important subscript in the history of sleep science. For example, in 1955, Mangold et al conducted an early multimodal sleep study in young men by combining EEG with the Kety-Schmidt method to study CBF and global cerebral metabolic rate of oxygen during sleep states, defined by the presence of sleep spindles and slow-wave activity.9 The Kety-Schmidt method involved having participants breathe low concentrations of nitrous oxide while researchers took blood measurements from the internal jugular bulb and the femoral artery to calculate N2O uptake and estimate CBF and oxygen metabolism.40 Their approach, though indirect, showed increased CBF during sleep compared to wakefulness and failed to find significant sleep-wake differences in oxygen metabolism. Although higher blood flow during sleep has subsequently been isolated to REM sleep, the results of this early CBF study demonstrated that reduced cerebral metabolism is neither necessary nor sufficient for sleep states to occur, which challenged contemporary sleep theories that sleep is caused by reduced gross nutrition or metabolism. Ultimately, this study demonstrated that multimodal brain measurement is needed to advance the field beyond what could be achieved with electroencephalography alone.
After the discovery of REM, the field of sleep research further emphasized electrophysiological measures of brain, body, eye, and heart movements. Standardizing PSG criteria for scoring sleep-wake stages became a priority for early sleep and dream researchers, particularly Allan Rechtschaffen, who outlined it as a key objective of the newly formed Association for the Psychophysiological Study of Sleep.41 Before settling on specific electrophysiological measures to define sleep based on global rather than regional brain activity, the field of sleep medicine struggled to account for discrepancies across units of measurement. Some argued for a decoupling of CBF, metabolic rate, and electrophysiology across sleep-wake states, while others sought agreement across units of analysis. Well known discrepancies between self-reported sleep and electrophysiological measures were largely ignored and disregarded as subjective “misperceptions” on the part of the sleepers. By 1968, manualized PSG became a rallying point around which sleep researcher and clinicians could call “objective”, which provided the footing the field needed to advance, particularly in sleep medicine. The polysomnogram became the “gold standard” graphical representation of sleep.13 Initially, produced with ink scratching on football fields worth of paper per night, digital PSG signals have become the image of scientific sleep to the present day. Although lacking the spatial resolution to characterize the subtle regional dynamics of global sleep-wake states suggested by contemporary animal research and sleep neuroimaging studies (described below), the establishment of a reference point in which neuroimaging results could be interpreted represented a major advancement in sleep science. The manualized Rechtschaffen and Kales (R&K) PSG staging criteria provided reliability and clarity to early brain studies, helping to reconcile contradictory findings of increased, decreased, or unchanged CBF and metabolism during sleep.42 Although PSG has yielded important advances, like somnocharts, somnographs have failed to fully capture the complexity of the sleep’s phenominology, behavior, and physiology needed to test sleep theories that have been debated for nearly two centuries.
Birth of Sleep Neuroimaging
The history of sleep neuroimaging is tied to theoretical debates over whether sleep is a local or global phenomena and whether there exist hypnogenic centers of the brain. In the modern age, local sleep theory was proposed by Robert Macnish.43 His regrettable use of phrenology, a discredited and widely derided theory, to outline his version of local sleep may have contributed to its subsequent difficulties in gaining wide acceptance. Conducting the first experimental study on sleep deprivation, Marie de Manacéïne argued that sleep was localized to the higher brain centers and observed that the cortex was most affected by sleep loss.44 Debate around sleep centers of the brain was revitalized by Ivan Pavlov in the early 1900s whose theory rejected the existence of a sleep center in favor of the view that every cell in the brain sleeps, some as a result of use, others as a result of chemical signaling that spread inhibition originating in the exhausted cells (Reviewed in 25). Nathaniel Kleitman, a sleep scientist whose views have had a much greater influence in the field of sleep research, panned Pavlov’s sleep theory in favor of a whole brain theory of sleep.45 Although concepts of local versus global sleep, sleep centers, and sleep systems continue to be debated, sleep neuroimaging has proved a powerful tool in settling these theoretical disputes.
Our knowledge of human sleep neurophysiology is largely derived from invasive animal research protocols. It is perhaps, therefore, not surprising that sleep neuroimaging was first developed and applied in animal models before its application in human sleep research. Using implantable EEG, thermistors, and autoradiography techniques, Reivich et al convincingly demonstrated regional differences in brain activity across sleep-wake states in the cat model.12,46 To our knowledge, these studies produced the first published somnoimages. Subsequently, sleep neuroimaging methods using fMRI have been developed for use in basic animal studies,47–49 making it a valuable tool for studying sleep physiology.
Sleep neuroimaging in humans began in the late-1960s, with the earliest human somnoimages being mere crude hand drawings produced by Risberg et al, who combined neuroimaging methods (ie, intravenous [131I] scintigraphy) with PSG in human, showing state-specific regional dynamics in cerebral blood volume.14 In 1973, Townsend et al used the xenon-133 inhalation method with PSG to investigate CBF across the recently developed R&K criteria for wake, NREM sleep, and REM sleep.13 Applying the xenon approach, participants inhaled xenon-133 during sleep while extracranial scintillation detectors around the head measured CBF, revealing decreased flow during slow-wave sleep and increased flow during REM sleep compared to wakefulness.50 Diagrams of the brain with accompanying plots of regional brain activity patterns were published, but a clear somnoimage was lacking. Nevertheless, the combination of neuroimaging with validated PSG criteria provided a clear picture of CBF during sleep and provided a possible solution to explain contradictory CBF findings in prior studies—inclusion of REM sleep.
Subsequent advances in xenon methods (eg, stable xenon methods that allowed for local CBF measures) demonstrated in humans that which was also being found in autoradiography studies in animals46,51–53—that there are regional changes in CBF and glucose metabolism during NREM and REM sleep.16,54–58 Blood flow was shown to be lower in stage 1 sleep in the bilateral frontal cortex, left parietal lobe, bilateral inferior temporal, right Sylvian opercular, right posterior temporal cortex, cerebellum, and brainstem relative to wakefulness but reductions became more diffuse throughout the brain as sleep deepened into stage 3 and 4.57 These subsequent human studies also provided hand-drawn somnoimages with statistics and plots positioned over regions showing differences in blood flow across sleep-wake states.
The first computer-generated somnoimage in humans was published in 1985 by Heiss et al, who used 2-deoxy-D-[2-aSF]glucose positron emission tomography (FDG-PET) with EEG to investigate regional cerebral metabolism during a nap compared to wakefulness.15 Although lacking R&K staging criteria, their investigation in 4 male participants demonstrated that sleep typically involves widespread reductions in glucose metabolism. However, in one volunteer who reported having a nightmare during the sleep period, regional increases in glucose metabolism were observed. In addition, these early studies showed the potential power of using sleep neuroimaging to elucidate regional dynamics of dreaming, state-specific regional differences in sleep disorders,59 and other neuropsychiatric disorders. For example, using the xenon 133 method, Gozakirmizi et al demonstrated that while good sleepers experience a reduction in CBF during NREM sleep, patients with complex partial seizures show increased CBF in the temporal lobe during paroxysmal activity than occurs during NREM sleep and that increased blood flow occurs beyond the lateralized temporal lobe showing paroxysmal EEG activity.54
In a pioneering application of this technique, Greisen et al utilized 133-Xenon clearance after intravenous injection to explore sleep-wake shifts in 15 healthy preterm infants.60 The team utilized concurrent biparietal EEG, heart rate, respiration, and clinical observation to investigate quiet and active sleep. They showed that in these infants active sleep was associated with lower CBF, comparable to the reductions seen in quiet sleep. They concluded that physiological and metabolic mechanisms governing REM sleep, typically characterized by greater neural activity, might not be fully developed in preterm infants. The first somnoimage in infants was published in 2002 by Dehaene-Lambertz et al who used sleep fMRI.26 Sleep fMRI has proved to be a powerful tool for studying early life development.61–63 These studies emphasized the crucial role sleep neuroimaging can play in elucidating the nuances of sleep physiology and development, particularly in vulnerable populations like preterm infants.
Although the basic approach was employed 2 years earlier,64 the first to publish a somnoimage of R&K-defined NREM and REM sleep states was Buchsbaum et al in 1989.65 Using the FDG-PET method, the authors demonstrated that NREM sleep involves widespread reductions in glucose metabolism compared to wakefulness, with the greatest reductions in the medial frontal cortex. They also showed that REM sleep involves lower glucose metabolism in some brain regions. In a subsequent re-analysis of these data, the authors published somnoimages that contrasted brain activity across states (activity during REM sleep compared to that occurring during NREM sleep).66 The FDG-PET method proved to be a powerful sleep neuroimaging approach bringing a higher degree of reliability and detail than were possible in prior human research methods. As described below, PET methods continue to have place in the rapidly evolving field of sleep neuroimaging.
Current Sleep Neuroimaging Methods
Modern sleep neuroimaging methods include high-density EEG (hd-EEG), magnetoencephalography (MEG), single-photon emission computed tomography (SPECT), PET, functional near-infrared spectroscopy (fNIRS), and various MRI sequences, and multimodal imaging techniques, including EEG-fMRI.19,42,65,67–81 Just as neuroimaging does not require the production of an actual image, the ability to measure brain functioning at a level capable of visualization is where the power lies in sleep neuroimaging. By combining dynamic neuroimaging (eg, fMRI, perfusion) with high-resolution structural scans, detailed somnoimages are now being produced that form a powerful communication tool for sleep science. Below we describe the major sleep neuroimaging modalities, outline their strengths and weakness (Table 2), and their applications in sleep science.
![]() |
Table 2 Strengths Limitations and Recommendations for Current Sleep Neuroimaging Modalities |
Hd-EEG
Almost immediately after EEG was applied to record human sleep, the natural evolution was to record multiple EEG signals simultaneously. With multiple simultaneous recordings, clues to local sleep patterns have challenged the prevailing view that sleep is a whole brain event. To overcome limitations in spatial resolution of standard PSG, hd-EEG utilizes 64+ electrode channels with computational modeling to provide real-time measurement of regional electrical brain activity and potential sources localization.80 Since its introduction in the 1990s,82 hd-EEG has become the most widely used sleep neuroimaging modality. This modality was first applied to study neural processes during sleep in infants and was soon applied to study sleep more broadly.24 Although it takes more time and expense to set up than PSG, hd-EEG has emerged as a versatile and powerful sleep neuroimaging technique used to investigate regional dynamics of sleep,83–85 source of neural changes in sleep,86,87 sleep deprivation,87–89 sleep disorders,83,90–93 dreams,94,95 sleep and learning/memory,25 sleep development,96 consciousness74,97 and numerous other sleep-related constructs (eg, concepts, phenomena, outcomes) across sleep-wake states, including mental illness.95,98,99
Like other sleep neuroimaging modalities, its introduction to the sleep community was met with some skepticism about its ability to measure naturally occurring sleep. The initial studies in adults were conducted in a testing room environment in which participants were reclined in a chair. Due to discomfort of the cap recording of sleep were limited to just a few hours.25 Advancements in laboratory sleep methods and technology now allow for all night records that address most of the early criticisms. Hd-EEG nets often include the standard 10–20 electrodes or can be easily supplemented with additional lead, which allows for systematic placement, measurement, and scoring of sleep states. Ensuring consistent placement of the cap, particularly when making recordings across multiple nights is essential for correct localization. Low profile electrodes, soft pillows, and plush-pile pads allow participants to sleep more comfortably in a bed during recordings, providing a more naturalistic gauge of regional brain activity in the laboratory setting than can be obtained using other neuroimaging modalities (as described below). Hd-EEG has traditionally had relatively poor spatial resolution compared to other modalities such as fMRI, particularly for deep brain activity. Advances in source localization, however, are beginning to overcome spatial limitation.100,101 Its advantages make it an ideal modality for combination with the other sleep neuroimaging methods described below.
MEG
MEG measures changes in the magnetic fields generated by electrical activity generated along dendritic clusters of neurons aligned perpendicular to the MEG sensors, primarily in superficial cortical layers. Early applications of MEG to sleep research in the 1970s measured concurrent EEG to pinpoint the maximal location of sleep spindles.18,102 Using simultaneous multichannel measures, MEG is now able to generate topographic images and localize magnetic changes associated with sleep onset, stages, saccades, consciousness, and depth.79,103 MEG has been combined with evoked response potential to map the flow of information through the sleeping brain and to investigate other sleep-related processes, including the regional impact of sleep deprivation on the brain.104 Compared to hd-EEG, MEG offers higher spatial resolution, especially for tangential oriented sources,105 increased signal sensitivity, and the ability to measure some deep brain activity while retaining exceptional temporal resolution. Limitations of MEG include the necessity of sleeping in the MEG helmet that prevents naturalistic measures of sleep, reliance on source localization for deeper brain structures that prevents access to many deep structure, and high expense for both the machine and requirements for a dedicated shielded room to eliminate external magnetic interference. MEG can be combined with hd-EEG to allow for standard sleep scoring. Their combined signals can help improve accuracy of source localization. Optically pumped MEG (OPM-MEG) is an emerging technology that may overcome several limitations of traditional MEG and holds promise for sleep research. It is a cost-effective, wearable system capable of simultaneously recording neuronal activity with both high temporal and spatial resolution over extended periods.106,107 OPM-MEG has already been combined with EEG and fNIRS,108 making it a potentially valuable tool for multimodal sleep neuroimaging. While optimal data quality requires a magnetically shielded room, ongoing advancements are improving its accessibility and usability.
SPECT
SPECT is a neuroimaging method that uses radioactive tracers to measure regional CBF. SPECT provides information about patterns of brain activity and has been applied to show differences in regional CBF across sleep stages, investigate regional dynamics of sleep deprivation, characterized abnormalities in sleep disorders,71,72,109 and study sleep-bound seizures.110 Compared to fMRI and PET, SPECT has higher radiation exposure and worse temporal and spatial resolution. While tracers can be injected during sleep and scanned later, SPECT provides only snapshots rather than continuous data. Although its use in sleep neuroimaging is more limited, SPECT remains clinically available, is more affordable than PET, and has unique tracers. Advances in image processing and camera technology continue to enhance its role in studying sleep disorders.
PET
To study metabolic activity and CBF across sleep-wake states, PET scans have been widely employed in sleep research. FDG-PET and water-PET (H2O-PET) allow for the quantitative analysis of changes in brain activity across the brain and have been used to study sleep stages,111 sleep disorders,34 and sleep deprivation.112 For the FDG-PET method, a stable electrophysiological state is confirmed prior to and following the injection of the radioactive tracer, whereupon active neurons take up the glucose homologue.113 Scans taken after the uptake period produce snapshot images reflecting the brain activity that occurred during the uptake period. In contrast, the shorter half-life of [15O]H2O-PET, these scans typically happen while the participant is sleeping in the scanner. This comes with higher temporal resolution but at the cost of ecological validity as the participant is not able to sleep quietly in a bed during the uptake period. PET offers typically higher spatial resolutions compared to SPECT, in addition to lower radiation exposure. Other PET methods have been used to measure neurotransmitter receptor activity, which provide a valuable window into regional molecular activity associated with sleep, sleep disorders, and sleep-related constructs.114,115 However, PET scans have limitations including higher radiation exposure, high expense, and relatively low temporal and spatial resolution compared to most alternatives except SPECT.
Assessing sleep using these methods has shown preliminary evidence that local sleep processes are associated with daytime outcomes. For example, Nofzinger et al studied healthy and depressed individuals using FDG-PET to show that increased glucose metabolism in the ventromedial prefrontal cortex and right lateral occipital cortex during sleep is associated with greater arousal and worse self-reported sleep quality, particularly in individuals who were clinically depressed.116 Inversely, PET scans can help us better understand existing differences in individuals with mental health disorders. For example, Germain et al found that veterans with posttraumatic stress disorder experienced more REM sleep and had more activity in arousal areas of the brainstem, limbic and cortical regions compared to veterans with major depressive disorder.117 These and other FDG-PET studies demonstrate the utility of this method as a sleep neuroimaging technique for identifying the role of sleep in mental health disorders and symptom presentation. In addition, PET radio-isotopes are an active area of research with new and exciting tracers being developed for inflammation, dopamine, serotonin, membrane-bound proteins (VMAT2), norepinephrine, amyloid, tau, GABA, nicotinic acetylcholine receptors that hold promise in future sleep neuroimaging studies. New hybrid imaging systems combine PET with MRI within a single machine that allow for simultaneous acquisition of structural, functional, and molecular data. The knowledge gained from sleep neuroimaging studies that use this these technologies will undoubtedly inform future psychiatric intervention efforts.
FNIRS
Multi-channel fNIRS utilizes near-infrared light to measure hemodynamics and oxygenation in underlying brain tissue.78 As a sleep neuroimaging technique, it has been used to study sleep disorders, the neurophysiology of cognitive performance following sleep deprivation, and resting brain connectivity across sleep-wake states in adults and infants.81,118–121 fNIRS enables measurement of cortical hemodynamic activity during sleep without requiring participants to sleep in an fMRI scanner.78 However, fNIRS has limitations including low spatial resolution, poor depth specificity, and bulky optical fibers, sources/detector optodes.78 This makes the somnoimages it produces somewhat less detailed than other modalities. Nevertheless, its high temporal resolution, low cost, and rapid engineering advances make fNIRS a promising sleep neuroimaging approach.
Nuclear Magnetic Resonance Modalities: FMRI, Magnetic Resonance Spectroscopy Imaging (MRSI), and Perfusion
Nuclear magnetic resonance is a non-invasive technique used to study the molecular and structural properties of materials, including biological tissues. It offers several powerful tools for studying sleep, including a host of scan sequences capable of tapping into many domains of brain physiology including fMRI, MRSI, and perfusion.
FMRI
fMRI is a particularly versatile sleep neuroimaging technique that measures brain activity by detecting the differential magnetic properties of oxyhemoglobin, deoxyhemoglobin, and total hemoglobin within brain tissues, enabling detection of cerebral cortex activity.122 fMRI can be co-registered with high-resolution structural MRI images collected in the same scanning session, which offer high spatial resolution. Task-based fMRI can be conducted across sleep-wake states by introducing a stimulus (eg, auditory, visual, olfactory) and measuring hemodynamic brain responses.21,123,124 Furthermore, as with resting-state scans, fMRI can continuously measure brain signals during sleep over extended periods, making it ideal for characterizing and imaging state-specific hemodynamics across sleep-wake state.122 Functional connectivity analysis to assess brain network interactions125 has been of particular interest but other measures used in sleep research include regional homogeneity to examine local synchronization of neural activity,126 amplitude of low-frequency fluctuations and fractional low-frequency fluctuations to measure spontaneous brain activity,127 degree centrality to identify hub regions in brain networks,128 graph theory-based network analysis to map topological changes,129 entropy-based methods to capture signal complexity,130 ultraslow fMRI to investigate long-range neural communication, global brain state transitions, cerebrospinal fluid (CSF) dynamics,131 and ultrafast functional MRI to investigate rapid sleep-state transitions, microstates, and brain fluid dynamics across sleep-wake states.132
fMRI has limitations including motion sensitivity, slower temporal resolution compared to EEG and MEG, scanner noise, constrained sleep positions, and lower rate of data sampling.122 Still, carefully applied, fMRI has provided valuable insights into regional sleep dynamics, as ways for prospective motion processing improved over the last decade.133 Although early sleep fMRI studies lacked concurrent EEG, EEG is recommended when investigating sleep-wake states, as discussed in the next section.134 Nevertheless, as a standalone modality, fMRI continues to have utility in investigating sleep disorders and other sleep-related constructs during the wake state. In these conditions, we recommend using tasks that require behavioral responses and eye tracking to ensure wakefulness, or at least require that eyes remain open and fixed on a cross during resting state scan, due to high rates of sleep occurrence in eyes-closed conditions.125 fMRI is also a valuable sleep neuroimaging method in cases where concurrent EEG is not feasible, for example studies in some patient populations or studying sleep in the human fetus.63,135 In such cases, behavioral measures may prove useful in helping determine the presence or absence of sleep. Machine learning may also be a viable alternative for staging sleep using fMRI in the absence of PSG, with the tantalizing possibility of one day untethering sleep neuroimaging from reliance on PSG staging criteria.125
MRSI
An exciting MR method of neuroimaging is MRSI, which measures stable changes in several metabolites, precursors and neurotransmitters, eg assessing the excitation-inhibition balance and oxidative stress within the human body.136 MRSI is a promising approach capable of uncovering the regional chemical patterns involved in sleep regulation, processes, and disorders but has several limitations including long acquisition sequences with limited coverage of the brain, requiring focus on specific regions of interest and insensitivity to subtle chemical changes associated with sleep. To date, this approach has been used to study neurochemical differences associated with acute sleep loss and sleep disorders.137,138 Sequences are now available on 3T scanners but high field (>3T) is recommended for greater spatial resolution and higher signal-to-noise ratio.139 Functional MSRI, combines fMRI with MRSI to assess metabolic changes in the brain during functional tasks or in response to external stimuli that has merit as a sleep neuroimaging approach.
Perfusion
Perfusion refers to the delivery of blood to brain tissue, facilitating the supply of oxygen and nutrients while aiding in the removal of metabolic waste, with CBF serving as a key measure of this process. CBF is tightly regulated by cerebral autoregulation, which maintains stable perfusion despite fluctuations in systemic blood pressure. CBF can be assessed with several other neuroimaging modalities including PET, SPECT, transcranial Doppler Ultrasound (TCD), and arterial spin labeling (ASL). TCD has many advantages for indirectly assessing CBF based on velocity-based flow measures, including relatively low cost, portability for bedside assessment of sleep, ability to combine with PSG, no need for radioactive tracers, and high temporal resolution. Highlighting its utility, one computer-assisted pulsed Doppler system together with simultaneous PSG showed that middle cerebral artery blood flow velocity changes across sleep stages, suggesting that factors other than metabolic mechanisms contribute to the regulation of cerebral perfusion during human NREM sleep.140 fMRI sequences sensitive to perfusion, such as ASL, have key advantages for sleep research: it is the only tool that provides a direct measure of absolute quantification of perfusion (without using a contrast agent) and provides better spatial resolution than these other options. Few studies have examined CBF changes using combined ASL perfusion and EEG measurements. Tüshaus et al (2017) found a dynamic relationship of CBF with slow-wave activity corroborated vigilance state specific (ie, wake, NREM sleep stages N1-N3, wake after sleep) differences of CBF, eg in the posterior cingulate, basal ganglia, and thalamus, indicating their role in sleep-wake regulation and sleep processes.134 The authors concluded that some of these brain areas – known to be affected in disorders of consciousness – might also contribute to the emergence of consciousness. ASL perfusion can be used in a time series to monitor CBF changes across sleep-wake states or averaged over a window of time to provide snapshots of specific states, providing unique information about cerebral activity on a timescale in between the temporal resolution offered by PET and fMRI.
EEG-fMRI
Simultaneous EEG-fMRI emerged as a multimodal neuroimaging approach in the 1990s and was initially used to localize seizures in epilepsy patients.20,21,77 Studies of epilepsy-related sleep patterns revealed a posterior-to-anterior shift in slow-wave activity in children141 and age-related thalamic hemodynamic changes in healthy volunteers.142,143 Since that time, EEG-fMRI has been used to advance sleep research considerably.144,145 This approach allows researchers to simultaneously capture the electrical activity of the brain and its hemodynamic responses, providing a comprehensive view of brain function across sleep-wake states. One of the key advantages of dual modality is its ability to correlate the temporal resolution of EEG with the spatial resolution of fMRI enabling investigation into the intricate dynamics of sleep stages, such as REM and NREM sleep, and their associated neural correlates. Moreover, EEG-fMRI can help identify biomarkers for various sleep-related conditions, facilitating early diagnosis and targeted interventions. As sleep is crucial for cognitive processes, emotional regulation, and physical health, understanding its neural underpinnings through EEG-fMRI could lead to improved therapeutic strategies. Studies have shown that stimulus-induced BOLD decreases during NREM sleep correlate with EEG synchronization, suggesting cortical deactivation protects against arousing stimuli.146 Research on sleep spindles found increased fMRI signals in the middle temporal gyrus during N2 compared to N3, with spindle-related activation negatively associated with N2 sleep duration.147 Memory consolidation studies have linked slow wave–spindle coupling to task-specific brain reactivations, confined to the learning hemisphere, while uncoupled spindles were associated with sensory processing and sleep maintenance.148 Additionally, EEG-fMRI has helped examine fatigue in insomnia, showing altered thalamic-cerebellar connectivity correlated with fatigue severity.149 EEG-fMRI has been used to examine changes in CSF and blood flow that are coupled in time to slow waves during sleep, providing important evidence for potential role of sleep in brain clearance in humans.150 A systematic review of EEG-fMRI studies is beyond the scope of this article but would be of great value and benefit to the field.
Despite its advantages, EEG-fMRI has several limitations that have been well characterized elsewhere, including considerable noise imposed on EEG in the MRI environment and potential distortions in MRI introduced by EEG electrodes.151,152 The considerations noted above for hd-EEG and fMRI above generally apply when combined and present additional challenges. For artifact reduction, Bullock recommended using additional hardware not often included on commercial products that synchronize clocks, and directly record artifact at the head, including motion, reparation, vibration, ballistocardiogram, and eye blinks. In their review of the EEG-fMRI sleep field, Czisch and Wehrle outline several logistical and technical challenges of this method when applied to sleep including reduced signal quality over the time course of sleep, increased movement artifact during sleep compared to wakefulness, inability of a minority of participants to sleep in the MR environment, disruption to sleep (particularly suppression of REM) in the MR acoustic environment, limited control over sleep-wake states, and limited ability to capture more than 1–2 sleep cycles.151 They suggest that habituating participants to the scanner environment, using sleep deprivation prior to sleep scans and using real-time scoring to confirm sleep-wake states may help overcome some of these challenges.
Although sleep deprivation may be advisable for nap protocols, prior studies indicate that most participants can sleep in the scanner at night without prior sleep deprivation, with 62% obtaining more than 10 minutes of N2 and/or N3 within a one-hour scan.153,154 Our data align with these findings, as 85% of participants self-reported sleeping during partial-night scans conducted at habitual bedtime. To help participants habituate to the scanner, we conduct a morning scan before the evening sleep scan and instructed participants to avoid napping during the day to help them feel sleepy that night. Many participants (~50%) in our simultaneous EEG-fMRI studies report experiencing pain due to the electrode cap and sleeping on the scanner bed after about 2 hours in the scanner. The added bulk of the EEG cap prevents the use of a comfortable pillow when using a high-channel MR head coil. Individual foam disks placed around the EEG electrodes on the back of the head or weaving gauze padding around electrodes provides some comfort . The EEG cap presents changes in securing the head in the coil without disrupting the EEG electrodes and introducing additional discomfort. In the fMRI scanner environment, artifacts associated with the magnetic field, movement, compromised electrode impedances, and time-varying gradient fields can comprise EEG-fMRI recordings during longer (sleep-related) sessions and make real time observation and subsequent scoring for sleep stages more difficult. Several postprocessing option are currently available to remove scanner artifacts which are impressive but the resulting EEG signals are different from those typically seen in PSG studies making processing the EEG data to the quality needed to score for sleep staging challenging. Nevertheless, advances in sleep neuroimaging and technology are rapidly overcoming these limitations. Requiring participants to shower (without conditioner) before the scan, utilizing a hd-EEG cap (64+ channels), and sampling at higher rates (≥5000 hz) can provide better postprocessing outcomes. Full-night fMRI-EEG studies have demonstrated that NREM-REM cycles occur in the scanner, with deep sleep typically emerging in the first part of the night (40–240 min), and sleep stage scoring during MRI scans has been validated.153,154 Multimodal fMRI-EEG has recently been combined with PET to reveal the complex regional interplay of neuronal, hemodynamic, and metabolic dynamics that occur across sleep-wake states.27 Sleep neuroimaging using fMRI-EEG is rapidly evolving and a white paper on best practices is needed.
Unlocking the Power of Sleep Neuroimaging
Human sleep researchers face a fundamental dilemma: prioritize temporal resolution to capture sleep patterns over time or use an unnaturalistic sleep environment to obtain the high spatial resolution needed to identify localized brain processes associated with sleep. While laboratory PSG balances these considerations, it lacks spatial resolution to localize sleep-related brain activity, fails to capture key aspects of sleep (eg, consciousness), and does not provide a fully naturalistic sleep setting. By comparison, neuroimaging techniques such as fMRI and PET offer detailed insights into sleep-related neural mechanisms but are constrained to controlled, short-term studies in an even more unnatural sleep environment than PSG. By integrating neuroimaging with sleep research methods, sleep neuroimaging leverages their respective strengths. When possible, we recommend conducting simultaneous PSG during scanning, supplemented by a post-scan sleep diary documenting participants’ sleep experience in the scanner. Although we have emphasized the power of multimodal approaches, sleep neuroimaging also recognizes the importance of integrating multiple units of analysis into sleep research. Collecting a detailed clinical sleep history, self-reported sleep including daily sleep diaries for at least one week, psychological and cognitive variables, overnight PSG sleep study outside the scanner, and wearable data (eg, actigraphy) can provide valuable context needed to interpret the neuroimaging results. The field of modern sleep science began with graphing the phenomenology of sleep and incorporating valid measures of self-reported sleep and sleep related experience is critical. Just as the emergence of polysomnography revolutionized sleep science’s conceptualization of sleep as well as the ability to directly measure sleep-related outcomes, we believe that sleep neuroimaging is the next revolutionary methodology that will advance the field of sleep science. The potential of sleep neuroimaging as a research and clinical tool truly feels unbounded, though our minds are drawn immediately to several direct applications of this method, including advancing our understanding of sleep neurophysiology including its most challenging aspects (ie, consciousness and dreaming), gaining insights into sleep disorders and mental health, and enhancing treatment strategies.
Sleep neuroimaging has significantly advanced our understanding of sleep mechanisms and disorders, resolving long-standing debates such as whether sleep is a whole-brain or localized process. Furthermore, neuroimaging provides crucial insights into the pathophysiology, diagnosis, and treatment of sleep disorders.155 A prime example is in insomnia research. Our sleep neuroimaging research has shown that insomnia is not merely a “misperception” of sleep but is linked to altered brain activity.156,157 Similarly, studies using hd-EEG have shown that the feeling of being awake during sleep correlated with increased localized high-frequency (ie, sigma and beta power) EEG activity in good sleepers and with more widespread changes in insomnia patients.92,158,159 Using FDG-PET, we have also shown that individuals with insomnia exhibit reduced sleep-wake differences in glucose metabolism in regions involved in conscious awareness, executive control, and affective processing, which may underlie both nighttime sleep difficulties and daytime impairments.34 Follow-up research demonstrated that sleep restriction lowers glucose metabolism in these regions during recovery sleep, for both individuals with insomnia and good sleepers, suggesting that sleep restriction therapy may enhance local sleep drive in areas of the brain involved in consciousness, sensory, and affective processing.112,160 Using real-time fMRI neurofeedback training (of the amygdala) to enhance positive autobiographical memory, Li et al were able to alter resting state brain activity to improve sleep in individuals with insomnia disorder.161 Collectively, these findings challenge the global hyperarousal model of insomnia and reinforce that sleep difficulties in these patients are not merely subjective experiences but involve a dynamic brain process across sleep-wake states.
Sleep neuroimaging also opens the door to investigate the neural mechanisms underlying dreaming and consciousness.151 Historically, these phenomena were difficult to measure, either due to methodological challenges or a focus on phenomenology. However, sleep neuroimaging now enables physiological assessments of these processes, overcoming past concerns in dreaming and consciousness research. For instance, Siclari et al (2017) identified neural correlates of dreaming across sleep stages, revealing local EEG activations associated with dream experiences despite globally distinct REM and NREM profiles.95 Additionally, high-frequency activity in these regions correlated with specific dream content. Using EEG-fMRI, neural differences between lucid and non-lucid dreaming have been demonstrated,162 offering insights into conscious experiences during sleep. These findings could establish a new domain of dream imaging research, challenging traditional views on consciousness and altered states.
Beyond dreaming, sleep neuroimaging plays a pivotal role in understanding individual variability in responses to sleep disruption.163,164 We have proposed that sleep may become disturbed regionally resulting in brain specific impairments during the day.165 We are excited about the potential of sleep neuroimaging to test this “local sleep deprivation hypotheses” and provide greater insights into how sleep restores cognitive and affective functions and the local mechanisms through which sleep disturbance impacts subsequent daytime functioning, physical health, and risk for mental illness. Emerging applications, including fMRI and fNIRS, now allow researchers to study glymphatic function, a critical sleep process.166 These sleep neuroimaging modalities may help us finally establish the functions of sleep.
Overall, sleep neuroimaging has transformed our understanding of sleep physiology, cognitive and behavioral functions, and its evolutionary significance.48 Its continued advancement holds immense potential for refining sleep medicine, developing targeted therapies, and unraveling the complexities of human sleep health.
Challenges and Future Directions
Sleep neuroimaging confronts several challenges that need to be addressed before this method can be fully utilized. These include the high cost and limited accessibility of certain neuroimaging techniques, the need for standardization in data acquisition and analysis, and the potential for artifacts due to head movement. Emerging technologies, such as mobile EEG systems and wearable fNIRS, offer promising solutions by allowing for more naturalistic, at-home sleep monitoring while maintaining neurophysiological precision. Additionally, advancements in motion-correction algorithms and machine learning-based artifact detection may help mitigate movement-related distortions in neuroimaging data. Perhaps the most important recommendation for future use of EEG-fMRI in sleep neuroimaging, is for researchers to fully report their methods according to best practices,152,167 hardware/software parameters, and artifact reduction procedures enable reproducibility and cross-study validation, thereby strengthening the reliability and advancement of sleep neuroimaging findings.
Beyond technical challenges, ethical considerations must also be addressed, especially when studying children, individuals with neurodevelopmental disorders, or patients with severe sleep disturbances. Ensuring informed consent, minimizing discomfort, and balancing scientific benefits with patient well-being are critical concerns. When conducting studies in these populations, we recommend designing the study around their specific needs. Future research should focus on refining sleep neuroimaging methods to be less disruptive to sleep and more adaptable to real-world settings, enhancing both the validity and ethical application of these techniques. The continuous evolution of sleep neuroimaging underscores the need for further interdisciplinary collaborations amongst neuroscientists, sleep researchers, MR-physicists, bioengineers, computer scientists, and clinicians to devise innovative methods for data collection and analysis. Such synergy will undoubtedly refine our understanding of the structural and functional aspects of sleep, eventually guiding the development of effective diagnostic and therapeutic strategies for sleep disorders, offering enhanced quality of life for affected individuals.
Conclusion
From the pioneering work of Angelo Mosso in the 19th century to the contemporary use of high-resolution techniques, the field of sleep science has made notable strides in elucidating the intricacies of sleep, whether in pathological samples, animal studies, or in unraveling the complexities of sleep disorders such as insomnia, obstructive sleep apnea, narcolepsy, restless legs syndrome, and REM sleep behavior disorder. The emergence and evolution of sleep neuroimaging have profoundly transformed our understanding of sleep and its related constructs. By leveraging advanced neuroimaging methods, sleep research has shed light on the neural mechanisms underpinning sleep patterns, disorders, and the consequences of sleep deprivation. For example, neuroimaging studies have identified disrupted thalamocortical connectivity in insomnia, providing potential biomarkers that may improve diagnostic accuracy. In the case of narcolepsy, fMRI and PET imaging have been used to assess hypocretin/orexin deficiencies, leading to a better understanding of its pathophysiology and informing pharmacological treatments. Additionally, sleep neuroimaging has provided insights into the cognitive impairments associated with sleep deprivation, which has influenced the development of interventions such as cognitive training and neurofeedback therapies to mitigate these deficits.
Modern sleep neuroimaging studies have enriched our knowledge of sleep-wake regulation66,168 and the pathophysiology of sleep disorders,72,109,169 providing a level of detail that surpasses traditional sleep staging. As machine learning and AI-driven neuroimaging analyses continue to evolve, sleep-related brain changes are being explored as potential early indicators of neurodegenerative diseases, such as Alzheimer’s disease. These advancements hold promise for developing predictive tools for early intervention and personalized treatments for sleep disorders. This revolution in sleep science is poised to redefine our understanding of the sleep-wake cycle, improve diagnostic precision, advance therapeutic strategies, and deepen our knowledge of the relationship between sleep, health, and overall well-being.
Acknowledgments
We acknowledge input from Drs. Ruth Tuura and Gawon Cho for their review of the manuscript, expertise, and editorial comments. We thank the undergraduate students who helped find citations for this review including Eric S. Cheney, Carter J. Chugg, and Michael G. Gnatiko and Sarah Brewer for checking for typos in the final proof.
Disclosure
The authors report no conflicts of interest in this work.
References
1. A Personal Diary of Consumption of Solids and Fluids, Exercise, Sleep, Amount of Urine Voided, Meteorological Observations. Hamburg: Etc. for One Year; 1755:1755–1756.
2. Kohlschütter E Messung der Festigkeit des Schlafes [dissertation]. Leipzig, Germany: Universität Leipzig; 1862.
3. Kohlschütter EOH. Messungen der Festigkeit des Schlafes. Zeitschrift fuer rationelle Medicin, Dritte Reihe. 1863;17:209–253.
4. Mosso A. Ueber den Kreislauf des Blutes im menschlichen Gehirn. Leipzig: Veit & comp. Leipzig; 1881.
5. de Manacéïne M. Quelques observations experimentales sur l’influence de l’insomnie absolue. Arch Ital Biol. 1894;21:322–325.
6. Patrick GTW, Gilbert JA Studies from the psychological laboratory of the University of Iowa: on the effects of loss of sleep. Psychological Rev. 1896;3:469–483.
7. Berger H. Uber das Elektrenkephalogramm des Menschen. III. Mitteilung. Archiv fur Psychiatrie und Nervenkrankheiten. 1931;94:16–60. doi:10.1007/BF01835097
8. Loomis AL, Harvey EN, Hobart G. Potential rhythms of the cerebral cortex during sleep. Science. 1935;81(2111):5978. doi:10.1126/science.81.2111.597
9. Mangold R, Sokoloff L, Conner E, Kleinerman J, Therman PO, Kety SS. The effects of sleep and lack of sleep on the cerebral circulation and metabolism of normal young men. J Clin Invest. 1955;34(7, Part 1):1092–1100. doi:10.1172/JCI103158
10. Aserinsky E, Kleitman N. Regularly occurring periods of eye motility, and concomitant phenomena, during sleep. Science. 1953;118(3062):273–274. doi:10.1126/science.118.3062.273
11. Dement W, Kleitman N. The relation of eye movements during sleep to dream activity: an objective method for the study of dreaming. J Exp Psychol. 1957;53(5):339–346. doi:10.1037/h0048189
12. Reivich M, Isaacs G, Evarts E, Kety S. The effect of slow wave sleep and REM sleep on regional cerebral blood flow in cats. J Neurochem. 1968;15(4):301–306. doi:10.1111/j.1471-4159.1968.tb11614.x
13. Rechtschaffen A, Kales A. A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. Bethesda, Md: U.S. Dept. of Health, Education, and Welfare; 1968.
14. Risberg J, Gustavsson L, Ingvar DH, et al. Regional Cerebral Blood Volume During Paradoxical Sleep. In: Brock M, Fieschi C, Ingvar DH, Lassen NA, Schürmann K, editors. Cerebral Blood Flow: Clinical and Experimental Results. Berlin, Heidelberg: Springer Berlin Heidelberg; 1969:101–103.
15. Heiss WD, Pawlik G, Herholz K, Wagner R, Wienhard K. Regional cerebral glucose metabolism in man during wakefulness, sleep, and dreaming. Brain Res. 1985;327(1–2):362–366. doi:10.1016/0006-8993(85)91537-9
16. Madsen PL, Holm S, Vorstrup S, Friberg L, Lassen NA, Wildschiodtz G. Human regional cerebral blood flow during rapid-eye-movement sleep. J Cerebral Blood Flow Metab. 1991;11(3):502–507. doi:10.1038/jcbfm.1991.94
17. Lydic R, Baghdoyan HA, Hibbard L, Bonyak EV, DeJoseph MR, Hawkins RA Regional brain glucose metabolism is altered during rapid eye movement sleep in the cat: a preliminary study. J Comp Neurol. 1991;304(4):517–529.
18. Hughes JR, Hendrix DE, Cohen J, et al. Relationship of the magnetoencephalogram to the electroencephalogram. Normal wake and sleep activity. Electroencephalogr Clin Neurophysiol. 1976;40(3):261–278. doi:10.1016/0013-4694(76)90150-4
19. Lu ST, Kajola M, Joutsiniemi SL, Knuutila J, Hari R. Generator sites of spontaneous MEG activity during sleep. Electroencephalogr Clin Neurophysiol. 1992;82(3):182–196. doi:10.1016/0013-4694(92)90166-F
20. Lövblad KO, Thomas R, Jakob PM, et al. Silent functional magnetic resonance imaging demonstrates focal activation in rapid eye movement sleep. Neurology. 1999;53(9):2193–2195. doi:10.1212/WNL.53.9.2193
21. Portas CM, Krakow K, Allen P, Josephs O, Armony JL, Frith CD. Auditory processing across the sleep-wake cycle: simultaneous EEG and fMRI monitoring in humans. Neuron. 2000;28(3):991–999. doi:10.1016/S0896-6273(00)00169-0
22. Hoshi Y, Mizukami S, Tamura M. Dynamic features of hemodynamic and metabolic changes in the human brain during all-night sleep as revealed by near-infrared spectroscopy. Brain Res. 1994;652(2):257–262.
23. Igawa M, Atsumi Y, Takahashi K, Shiotsuka S, Hirasawa H, Yamamoto R, et al. Activation of visual cortex in REM sleep measured by 24-channel NIRS imaging. Psychiatry Clin Neurosciences. 2001;55(3):187–188.
24. Dehaene-Lambertz G, Pena M Electrophysiological evidence for automatic phonetic processing in neonates. Neuroreport. 12(14):3155–3158. PMID: 11568655. doi:10.1097/00001756-200110080-00034
25. Huber R, Ghilardi MF, Massimini M, Tononi G. Local sleep and learning. Nature. 2004;430(6995):78–81. doi:10.1038/nature02663
26. Dehaene-Lambertz G, Dehaene S, Hertz-Pannier L. Functional neuroimaging of speech perception in infants. Science. 2002;298(5600):2013–2015. doi:10.1126/science.1077066
27. Chen JE, Lewis L, Coursey S, et al. Simultaneous EEG-PET-MRI identifies temporally coupled, spatially structured hemodynamic and metabolic dynamics across wakefulness and NREM sleep. bioRxiv. 2025. doi:10.1101/2025.01.17.633689
28. Caton R. The electric currents of the brain. British Med J. 1875;2:278.
29. Canton R. Researches on electrical phenomena of cerebral gray matter. Electroencephalogr Clin Neurophysiol. 1951;3(2):140. doi:10.1016/0013-4694(51)90002-8
30. Caton R. Pioneer electrophysiologist. Proc R Soc Med. 1842-1926 Aug;52(8):645–651. doi:10.1177/003591575905200816
31. Berger H. Uber das Elektrenkephalogramm des Menschen. II. Mitteilung. Journal Fur Psychologie Und Neurologie. 1930;40:160–179.
32. Sandrone S, Bacigaluppi M, Galloni MR, et al. Weighing brain activity with the balance: Angelo Mosso’s original manuscripts come to light. Brain. 2014;137(Pt 2):621–633. doi:10.1093/brain/awt091
33. James W. The Principles of Psychology. Vol. I. London: Macmillan; 1907.
34. Kay DB, Karim HT, Soehner AM, et al. Sleep-wake differences in relative regional cerebral metabolic rate for glucose among patients with insomnia compared with good sleepers. Sleep. 2016;39(10):1779–1794. doi:10.5665/sleep.6154
35. Stevenson L, Christensen BE, Wortis SB. Some experiments on intracranial pressure in man during sleep and under certain other conditions. In: Eldberg CA, Riley HA, Davis TK, Frantz AM, editors. The Intracranial Pressure in Health and Disease: An Investigation of the Most Recent Advances.
36. Kleitman N. Sleep and Wakefulness as Alternating Phases in the Cycle of Existence. Chicago: University of Chicago Press; 1939.
37. Berger H. Über das elektroenkephalogramm des menschen. Archiv für Psychiatrie und Nervenkrankheiten. 1929;87(1):527–570. doi:10.1007/BF01797193
38. Berger H. Uber das Elektrenkephalogramm des Menschen. V. Mitteilung. Archiv fur Psychiatrie und Nervenkrankheiten. 1932;98:231–254. doi:10.1007/BF01814645
39. Gibbs FA, Gibbs EL, Lennox WG. The cerebral blood flow during sleep in man. Brain. 1935;58(1):44–48. doi:10.1093/brain/58.1.44
40. Kety SS, Schmidt CF. The nitrous oxide method for the quantitative determination of cerebral blood flow in man: theory, procedure and normal values. J Clin Invest. 1948;27(4):476–483. doi:10.1172/JCI101994
41. Webb WB. Association for the Psychophysiological Study of Sleep Records. Hanna Holborn Gray Special Collections Research Center, University of Chicago Library; 1961. Box 1, Folder 5.
42. Madsen PL, Schmidt JF, Holm S, Vorstrup S, Lassen NA, Wildschiodtz G. Cerebral oxygen metabolism and cerebral blood flow in man during light sleep (stage 2). Brain Res. 1991;557(1–2):217–220. doi:10.1016/0006-8993(91)90137-K
43. Macnish R. The Philosophy of Sleep. Erscheinungsort Nicht Ermittelbar. Forgotten Books; 2012.
44. de Manacéïne M. Quelques observations experimentales sur l’influence de l’insomnie absolue. Arch Ital Biol. 1894;21:322–325.
45. Kleitman N. Sleep and Wakefulness. Oxford, England: Univ. Chicago Press; 1963:viii, 552–viii.
46. Reivich M, Isaacs G, Evarts E, Kety S. Regional cerebral blood flow during REM and slow wave sleep. Transactions Ame Neurol Assoc. 1967;92:70–74.
47. Khubchandani M, Jagannathan NR, Mallick HN, Mohan Kumar V. Functional MRI shows activation of the medial preoptic area during sleep. Neuroimage. 2005;26(1):29–35. doi:10.1016/j.neuroimage.2005.01.002
48. Ungurean G, Behroozi M, Böger L, et al. Wide-spread brain activation and reduced CSF flow during avian REM sleep. Nat Commun. 2023;14(1):3259. doi:10.1038/s41467-023-38669-1
49. Khubchandani M, Mallick HN, Jagannathan NR, Mohan Kumar V. Stereotaxic assembly and procedures for simultaneous electrophysiological and MRI study of conscious rat. Magnetic Resonance Med. 2003;49(5):962–967. doi:10.1002/mrm.10441
50. Townsend RE, Prinz PN, Obrist WD. Human cerebral blood flow during sleep and waking. J Appl Physiol. 1973;35(5):620–625. doi:10.1152/jappl.1973.35.5.620
51. Kennedy C, Gillin JC, Mendelson W, et al. Local cerebral glucose utilization in slow-wave sleep. Transact Ame Neurol Assoc. 1981;106:25–28.
52. Kennedy C, Gillin JC, Mendelson W, et al. Local cerebral glucose utilization in non-rapid eye movement sleep. Nature. 1982;297(5864):325–327. doi:10.1038/297325a0
53. Nakamura RK, Kennedy C, Gillin JC, et al. Hypnogenic center theory of sleep: no support from metabolic mapping in monkeys. Brain Res. 1983;268(2):372–376. doi:10.1016/0006-8993(83)90507-3
54. Gozukirmizi E, Meyer JS, Okabe T, Amano T, Mortel K, Karacan I. Cerebral blood flow during paroxysmal EEG activation induced by sleep in patients with complex partial seizures. Sleep. 1982;5(4):329–342. doi:10.1093/sleep/5.4.329
55. Meyer JS, Hayman LA, Amano T, et al. Mapping local blood flow of human brain by CT scanning during stable xenon inhalation. Stroke. 1981;12(4):426–436. doi:10.1161/01.STR.12.4.426
56. Meyer JS, Ishikawa Y, Hata T, Karacan I. Cerebral blood flow in normal and abnormal sleep and dreaming. Brain Cognition. 1987;6(3):266–294. doi:10.1016/0278-2626(87)90127-8
57. Sakai F, Meyer JS, Karacan I, Derman S, Yamamoto M. Normal human sleep: regional cerebral hemodynamics. Ann Neurol. 1980;7(5):471–478. doi:10.1002/ana.410070514
58. Sakai F, Meyer JS, Karacan I, Yamaguchi F, Yamamoto M. Narcolepsy: regional cerebral blood flow during sleep and wakefulness. Neurology. 1979;29(1):61–67. doi:10.1212/WNL.29.1.61
59. Meyer JS, Sakai F, Karacan I, Derman S, Yamamoto M. Sleep apnea, narcolepsy, and dreaming: regional cerebral hemodynamics. Ann Neurol. 1980;7(5):479–485. doi:10.1002/ana.410070515
60. Greisen G, Hellstrom-Vestas L, Lou H, Rosen I, Svenningsen N. Sleep-waking shifts and cerebral blood flow in stable preterm infants. Pediatric Research. 1985;19(11):1156–1159. doi:10.1203/00006450-198511000-00008
61. Redcay E, Kennedy DP, Courchesne E. fMRI during natural sleep as a method to study brain function during early childhood. Neuroimage. 2007;38(4):696–707. doi:10.1016/j.neuroimage.2007.08.005
62. Pierce K. Early functional brain development in autism and the promise of sleep fMRI. Brain Res. 2011;1380:162–174. doi:10.1016/j.brainres.2010.09.028
63. Pollatou A, Filippi CA, Aydin E, et al. An ode to fetal, infant, and toddler neuroimaging: chronicling early clinical to research applications with MRI, and an introduction to an academic society connecting the field. Dev Cogn Neurosci. 2022;54:101083. doi:10.1016/j.dcn.2022.101083
64. Franck G, Salmon E, Poirrier R, Sadzot B, Franco G. Study of regional cerebral glucose metabolism, in man, while awake or asleep, by positron emission tomography. Revue d’electroencephalographie et de neurophysiologie clinique. 1987;17(1):71–77. doi:10.1016/S0370-4475(87)80116-8
65. Buchsbaum MS, Gillin JC, Wu J, et al. Regional cerebral glucose metabolic rate in human sleep assessed by positron emission tomography. Life Sci. 1989;45(15):1349–1356. doi:10.1016/0024-3205(89)90021-0
66. Buchsbaum MS, Hazlett EA, Wu J, Bunney WE Jr. Positron emission tomography with deoxyglucose-F18 imaging of sleep. Neuropsychopharmacology. 2001;25(5 Suppl):S50–6. doi:10.1016/S0893-133X(01)00339-6
67. Nofzinger EA, Mintun MA, Price J, et al. A method for the assessment of the functional neuroanatomy of human sleep using FDG PET. Brain Res Brain Res Protoc. 1998;2(3):191–198. doi:10.1016/S1385-299X(97)00042-1
68. Maquet P, Dive D, Salmon E, et al. Cerebral glucose utilization during sleep-wake cycle in man determined by positron emission tomography and [18F]2-fluoro-2-deoxy-D-glucose method. Brain Res. 1990;513(1):136–143. doi:10.1016/0006-8993(90)91099-3
69. Asenbaum S, Zeithofer J, Saletu B, et al. Technetium-99m-HMPAO SPECT imaging of cerebral blood flow during REM sleep in narcoleptics. J Nucl Med. 1995;36(7):1150–1155.
70. Brayet P, Petit D, Baril AA, et al. Brain perfusion during rapid-eye-movement sleep successfully identifies amnestic mild cognitive impairment. Sleep Med. 2017;34:134–140. doi:10.1016/j.sleep.2017.01.025
71. Dang-Vu TT, Zadra A, Labelle MA, Petit D, Soucy JP, Montplaisir J. Sleep deprivation reveals altered brain perfusion patterns in somnambulism. PLoS One. 2015;10(8):e0133474. doi:10.1371/journal.pone.0133474
72. Desjardins ME, Baril AA, Soucy JP, et al. Altered brain perfusion patterns in wakefulness and slow-wave sleep in sleepwalkers. Sleep. 2018;41(5). doi:10.1093/sleep/zsy039.
73. Leslie WD, Wali S, Kryger M. Blood flow of the middle cerebral artery with sleep-disordered breathing: correlation with obstructive hypopneas. Stroke. 1999;30(1):188–190. doi:10.1161/str.30.1.188/a
74. Massimini M, Ferrarelli F, Huber R, Esser SK, Singh H, Tononi G. Breakdown of cortical effective connectivity during sleep. Science. 2005;309(5744):2228–2232. doi:10.1126/science.1117256
75. Ueno S, Iramina K. Modeling and source localization of MEG activities. Brain Topogr. 1990;3(1):151–165. doi:10.1007/BF01128872
76. Kubota Y, Takasu NN, Horita S, et al. Dorsolateral prefrontal cortical oxygenation during REM sleep in humans. Brain Res. 2011;1389:83–92. doi:10.1016/j.brainres.2011.02.061
77. Czisch M, Wetter TC, Kaufmann C, Pollmacher T, Holsboer F, Auer DP. Altered processing of acoustic stimuli during sleep: reduced auditory activation and visual deactivation detected by a combined fMRI/EEG study. Neuroimage. 2002;16(1):251–258. doi:10.1006/nimg.2002.1071
78. Uchitel J, Blanco B, Collins-Jones L, et al. Cot-side imaging of functional connectivity in the developing brain during sleep using wearable high-density diffuse optical tomography. NeuroImage. 2023;265:119784. doi:10.1016/j.neuroimage.2022.119784
79. Ioannides AA, Liu L, Poghosyan V, Kostopoulos GK. Using MEG to understand the progression of light sleep and the emergence and functional roles of spindles and K-complexes. Front Hum Neurosci. 2017;11:313. doi:10.3389/fnhum.2017.00313
80. Lustenberger C, Huber R. High density electroencephalography in sleep research: potential, problems, future perspective. Front Neurol. 2012;3:77. doi:10.3389/fneur.2012.00077
81. Pan Y, Borragán G, Peigneux P. Applications of functional near-infrared spectroscopy in fatigue, sleep deprivation, and social cognition. Brain Topogr. 2019;32(6):998–1012. doi:10.1007/s10548-019-00740-w
82. Nunez PL, Silberstein RB, Shi Z, et al. EEG coherency II: experimental comparisons of multiple measures. Clin Neurophysiol. 1999;110(3):469–486. doi:10.1016/S1388-2457(98)00043-1
83. Riedner BA, Goldstein MR, Plante DT, et al. Regional patterns of elevated alpha and high-frequency electroencephalographic activity during nonrapid eye movement sleep in chronic insomnia: a pilot study. Sleep. 2016;39(4):801–812. doi:10.5665/sleep.5632
84. Baird B, Castelnovo A, Riedner BA, et al. Human rapid eye movement sleep shows local increases in low-frequency oscillations and global decreases in high-frequency oscillations compared to resting wakefulness. eNeuro. 2018;5(4). doi:10.1523/ENEURO.0293-18.2018.
85. Bernardi G, Betta M, Ricciardi E, Pietrini P, Tononi G, Siclari F. Regional delta waves in human rapid eye movement sleep. J Neurosci. 2019;39(14):2686–2697. doi:10.1523/JNEUROSCI.2298-18.2019
86. Brancaccio A, Tabarelli D, Bigica M, Baldauf D. Cortical source localization of sleep-stage specific oscillatory activity. Sci Rep. 2020;10(1):6976. doi:10.1038/s41598-020-63933-5
87. Bersagliere A, Pascual-Marqui RD, Tarokh L, Achermann P. Mapping slow waves by EEG topography and source localization: effects of sleep deprivation. Brain Topogr. 2017;31:257–269. doi:10.1007/s10548-017-0595-6
88. Hung CS, Sarasso S, Ferrarelli F, et al. Local experience-dependent changes in the wake EEG after prolonged wakefulness. Sleep. 2013;36(1):59–72. doi:10.5665/sleep.2302
89. Bernardi G, Siclari F, Yu X, et al. Neural and behavioral correlates of extended training during sleep deprivation in humans: evidence for local, task-specific effects. J Neurosci. 2015;35(11):4487–4500. doi:10.1523/JNEUROSCI.4567-14.2015
90. Cataldi J, Stephan AM, Haba-Rubio J, Siclari F. Shared EEG correlates between non-REM parasomnia experiences and dreams. Nat Commun. 2024;15(1):3906. doi:10.1038/s41467-024-48337-7
91. Castelnovo A, Riedner BA, Smith RF, Tononi G, Boly M, Benca RM. Scalp and source power topography in sleepwalking and sleep terrors: a high-density EEG study. Sleep. 2016;39(10):1815–1825. doi:10.5665/sleep.6162
92. Lecci S, Cataldi J, Betta M, Bernardi G, Heinzer R, Siclari F. Electroencephalographic changes associated with subjective under- and overestimation of sleep duration. Sleep. 2020;43(11). doi:10.1093/sleep/zsaa094
93. Cataldi J, Stephan AM, Marchi NA, Haba-Rubio J, Siclari F. Abnormal timing of slow wave synchronization processes in non-rapid eye movement sleep parasomnias. Sleep. 2022;45(7). doi:10.1093/sleep/zsac111
94. Perogamvros L, Baird B, Seibold M, Riedner B, Boly M, Tononi G. The phenomenal contents and neural correlates of spontaneous thoughts across wakefulness, NREM sleep, and REM sleep. J Cogn Neurosci. 2017;29(10):1766–1777. doi:10.1162/jocn_a_01155
95. Siclari F, Baird B, Perogamvros L, et al. The neural correlates of dreaming. Nat Neurosci. 2017;20(6):872–878. doi:10.1038/nn.4545
96. Kurth S, Ringli M, Geiger A, LeBourgeois M, Jenni OG, Huber R. Mapping of cortical activity in the first two decades of life: a high-density sleep electroencephalogram study. J Neurosci. 2010;30(40):13211–13219. doi:10.1523/JNEUROSCI.2532-10.2010
97. Massimini M, Ferrarelli F, Murphy M, et al. Cortical reactivity and effective connectivity during REM sleep in humans. Cogn Neurosci. 2010;1(3):176–183.
98. Pisarenco I, Caporro M, Prosperetti C, Manconi M. High-density electroencephalography as an innovative tool to explore sleep physiology and sleep related disorders. Int J Psychophysiol. 2014;92(1):8–15. doi:10.1016/j.ijpsycho.2014.01.002
99. Plante DT, Cook JD, Barbosa LS, et al. Establishing the objective sleep phenotype in hypersomnolence disorder with and without comorbid major depression. Sleep. 2019;42(6). doi:10.1093/sleep/zsz060.
100. Bréchet L, Brunet D, Perogamvros L, Tononi G, Michel CM. EEG microstates of dreams. Sci Rep. 2020;10(1):17069. doi:10.1038/s41598-020-74075-z
101. Michels L, Muthuraman M, Anwar AR, et al. Changes of functional and directed resting-state connectivity are associated with neuronal oscillations, ApoE genotype and amyloid deposition in mild cognitive impairment. Front Aging Neurosci. 2017;9:304. doi:10.3389/fnagi.2017.00304
102. Nakasato N, Kado H, Nakanishi M, et al. Magnetic detection of sleep spindles in normal subjects. Electroencephalogr Clin Neurophysiol. 1990;76(2):123–130. doi:10.1016/0013-4694(90)90210-B
103. Ioannides AA, Corsi-Cabrera M, Fenwick PB, et al. MEG tomography of human cortex and brainstem activity in waking and REM sleep saccades. Cereb Cortex. 2004;14(1):56–72. doi:10.1093/cercor/bhg091
104. Boonstra TW, Daffertshofer A, Beek PJ. Effects of sleep deprivation on event-related fields and alpha activity during rhythmic force production. Neurosci Letters. 2005;388(1):27–32. doi:10.1016/j.neulet.2005.06.045
105. Ahlfors SP, Han J, Belliveau JW, Hämäläinen MS. Sensitivity of MEG and EEG to source orientation. Brain Topogr. 2010;23(3):227–232. doi:10.1007/s10548-010-0154-x
106. Pedersen M, Abbott DF, Jackson GD. Wearable OPM-MEG: a changing landscape for epilepsy. Epilepsia. 2022;63(11):2745–2753.
107. Hussain Z, Sheng QZ, Zhang WE, Ortiz J, Pouriyeh S. Non-invasive techniques for monitoring different aspects of sleep: a comprehensive review. ACM Transactions Computing Healthcare. 2022;3(2):1–26. doi:10.1145/3491245
108. Ru X, He K, Lyu B, et al. Multimodal neuroimaging with optically pumped magnetometers: a simultaneous MEG-EEG-fNIRS acquisition system. NeuroImage. 2022;259:119420. doi:10.1016/j.neuroimage.2022.119420
109. Bassetti C, Vella S, Donati F, Wielepp P, Weder B. SPECT during sleepwalking. Lancet. 2000;356(9228):484–485. doi:10.1016/S0140-6736(00)02561-7
110. Siclari F, Nobili L, Lo Russo G, et al. Stimulus-induced, sleep-bound, focal seizures: a case report. Sleep. 2011;34(12):1727–1730. doi:10.5665/sleep.1448
111. Kajimura N, Uchiyama M, Takayama Y, et al. Activity of midbrain reticular formation and neocortex during the progression of human non-rapid eye movement sleep. J Neurosci. 1999;19(22):10065–10073. doi:10.1523/JNEUROSCI.19-22-10065.1999
112. Kay DB, Karim HT, Hasler BP, et al. Impact of acute sleep restriction on cerebral glucose metabolism during recovery non-rapid eye movement sleep among individuals with primary insomnia and good sleeper controls. Sleep Med. 2019;55:81–91. doi:10.1016/j.sleep.2018.12.007
113. 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. doi:10.1176/appi.ajp.161.11.2126
114. Lin YS, Lange D, Baur DM, et al. Repeated caffeine intake suppresses cerebral grey matter responses to chronic sleep restriction in an A(1) adenosine receptor-dependent manner: a double-blind randomized controlled study with PET-MRI. Sci Rep. 2024;14(1):12724. doi:10.1038/s41598-024-61421-8
115. Doppler CEJ, Seger A, Farrher E, et al. Glutamate signaling in patients with Parkinson disease with REM sleep behavior disorder. Neurology. 2024;102(9):e209271.
116. Nofzinger EA, Price JC, Meltzer CC, et al. Towards a neurobiology of dysfunctional arousal in depression: the relationship between beta EEG power and regional cerebral glucose metabolism during NREM sleep. Psychiatry Res. 2000;98(2):71–91. doi:10.1016/S0925-4927(00)00045-7
117. Germain A, James J, Insana S, et al. A window into the invisible wound of war: functional neuroimaging of REM sleep in returning combat veterans with PTSD. Psychiatry Res. 2013;211(2):176–179. doi:10.1016/j.pscychresns.2012.05.007
118. Wang K, Ji X, Li T. Gender difference in functional activity of 4-months-old infants during sleep: a functional near-infrared spectroscopy study. Front Psychiatry. 2022;13:1046821. doi:10.3389/fpsyt.2022.1046821
119. Lee OW, Mao D, Savkovic B, et al. The use of heart rate responses extracted from functional near-infrared spectroscopy data as a measure of speech discrimination ability in sleeping infants. Ear Hear. 2023;44(4):776–786. doi:10.1097/AUD.0000000000001325
120. Nguyen T, Babawale O, Kim T, Jo HJ, Liu H, Kim JG. Exploring brain functional connectivity in rest and sleep states: a fNIRS study. Sci Rep. 2018;8(1):16144. doi:10.1038/s41598-018-33439-2
121. Oniz A, Inanc G, Taslica S, Guducu C, Ozgoren M. Sleep is a refreshing process: an fNIRS study. Front Hum Neurosci. 2019;13:160. doi:10.3389/fnhum.2019.00160
122. Uji M, Tamaki M. Sleep, learning, and memory in human research using noninvasive neuroimaging techniques. Neurosci Res. 2023;189:66–74. doi:10.1016/j.neures.2022.12.013
123. Born AP, Law I, Lund TE, et al. Cortical deactivation induced by visual stimulation in human slow-wave sleep. Neuroimage. 2002;17(3):1325–1335. doi:10.1006/nimg.2002.1249
124. Rasch B, Büchel C, Gais S, Born J. Odor cues during slow-wave sleep prompt declarative memory consolidation. Science. 2007;315(5817):1426–1429. doi:10.1126/science.1138581
125. Tagliazucchi E, Laufs H. Decoding wakefulness levels from typical fMRI resting-state data reveals reliable drifts between wakefulness and sleep. Neuron. 2014;82(3):695–708. doi:10.1016/j.neuron.2014.03.020
126. Dai X-J, Gong -H-H, Wang Y-X, et al. Gender differences in brain regional homogeneity of healthy subjects after normal sleep and after sleep deprivation: a resting-state fMRI study. Sleep Med. 2012;13(6):720–727. doi:10.1016/j.sleep.2011.09.019
127. Chen W, Wang H, Sun T, et al. Dynamic changes in fractional amplitude of low-frequency fluctuations in patients with chronic insomnia. Front Neurosci. 2022;16:1050240. doi:10.3389/fnins.2022.1050240
128. Wang H, Li H, Liu Z, et al. Abnormal sensory processing cortex in insomnia disorder: a degree centrality study. Brain Imaging Behav. 2025;19:302–312. doi:10.1007/s11682-024-00958-8
129. Song Y, Wang K, Wei Y, Zhu Y, Wen J, Luo Y. Graph theory analysis of the cortical functional network during sleep in patients with depression. Front Physiol. 2022;13:858739. doi:10.3389/fphys.2022.858739
130. Kung YC, Li CW, Hsiao FC, et al. Cross-scale dynamicity of entropy and connectivity in the sleeping brain. Brain Connect. 2022;12(9):835–845. doi:10.1089/brain.2021.0174
131. Gonzalez-Castillo J, Fernandez IS, Handwerker DA, Bandettini PA. Ultra-slow fMRI fluctuations in the fourth ventricle as a marker of drowsiness. Neuroimage. 2022;259:119424. doi:10.1016/j.neuroimage.2022.119424
132. Tuunanen J, Helakari H, Huotari N, et al. Cardiovascular and vasomotor pulsations in the brain and periphery during awake and NREM sleep in a multimodal fMRI study. Front Neurosci. 2024;18:1457732. doi:10.3389/fnins.2024.1457732
133. Maziero D, Rondinoni C, Marins T, Stenger VA, Ernst T. Prospective motion correction of fMRI: improving the quality of resting state data affected by large head motion. Neuroimage. 2020;212:116594. doi:10.1016/j.neuroimage.2020.116594
134. Tüshaus L, Omlin X, Tuura RO, et al. In human non-REM sleep, more slow-wave activity leads to less blood flow in the prefrontal cortex. Sci Rep. 2017;7(1):14993. doi:10.1038/s41598-017-12890-7
135. Ji L, Majbri A, Hendrix CL, Thomason ME. Fetal behavior during MRI changes with age and relates to network dynamics. Human Brain Mapping. 2023;44(4):1683–1694. doi:10.1002/hbm.26167
136. Uji M, Tamaki M. Sleep, learning, and memory in human research using noninvasive neuroimaging techniques. Neurosci Res (N Y). 2023;189:66–74.
137. Urrila AS, Hakkarainen A, Heikkinen S, et al. Preliminary findings of proton magnetic resonance spectroscopy in occipital cortex during sleep deprivation. Psychiatry Res. 2006;147(1):41–46. doi:10.1016/j.pscychresns.2006.01.010
138. Winkelman JW, Buxton OM, Jensen JE, et al. Reduced brain GABA in primary insomnia: preliminary data from 4T proton magnetic resonance spectroscopy (1H-MRS). Sleep. 2008;31(11):1499–1506. doi:10.1093/sleep/31.11.1499
139. Otazo R, Mueller B, Ugurbil K, Wald L, Posse S. Signal-to-noise ratio and spectral linewidth improvements between 1.5 and 7 Tesla in proton echo-planar spectroscopic imaging. Magn Reson Med. 2006;56(6):1200–1210. doi:10.1002/mrm.21067
140. Klingelhöfer J, Hajak G, Matzander G, et al. Dynamics of cerebral blood flow velocities during normal human sleep. Clin Neurol Neurosurg. 1995;97(2):142–148. doi:10.1016/0303-8467(95)00030-N
141. Bergamo D, Handjaras G, Petruso F, et al. Maturation-dependent changes in cortical and thalamic activity during sleep slow waves: insights from a combined EEG-fMRI study. Sleep Med. 2024;113:357–369. doi:10.1016/j.sleep.2023.12.001
142. Lüchinger R, Michels L, Martin E, Brandeis D. EEG-BOLD correlations during (post-)adolescent brain maturation. Neuroimage. 2011;56(3):1493–1505. doi:10.1016/j.neuroimage.2011.02.050
143. Lüchinger R, Michels L, Martin E, Brandeis D. Brain state regulation during normal development: intrinsic activity fluctuations in simultaneous EEG-fMRI. Neuroimage. 2012;60(2):1426–1439. doi:10.1016/j.neuroimage.2012.01.031
144. Bagshaw AP, Hale JR, Campos BM, et al. Sleep onset uncovers thalamic abnormalities in patients with idiopathic generalised epilepsy. Neuroimage Clin. 2017;16:52–57. doi:10.1016/j.nicl.2017.07.008
145. Hsiao FC, Tsai PJ, Wu CW, et al. The neurophysiological basis of the discrepancy between objective and subjective sleep during the sleep onset period: an EEG-fMRI study. Sleep. 2018;41(6). doi:10.1093/sleep/zsy056
146. Czisch M, Wehrle R, Kaufmann C, et al. Functional MRI during sleep: BOLD signal decreases and their electrophysiological correlates. Eur J Neurosci. 2004;20(2):566–574. PMID: 15233766. doi:10.1111/j.1460-9568.2004.03518.x
147. Shao Y, Guo Y, Chen Y, et al. Increased spindle-related brain activation in right middle temporal gyrus during N2 than N3 among healthy sleepers: initial discovery and independent sample replication. Neuroimage. 2025;305:120976. doi:10.1016/j.neuroimage.2024.120976
148. Baena D, Gabitov E, Ray LB, Doyon J, Fogel SM. Motor learning promotes regionally-specific spindle-slow wave coupled cerebral memory reactivation. Commun Biol. 2024;7(1):1492. doi:10.1038/s42003-024-07197-z
149. Guo Y, Chen Y, Shao Y, et al. Thalamic network under wakefulness after sleep onset and its coupling with daytime fatigue in insomnia disorder: an EEG-fMRI study. J Affect Disord. 2023;334:92–99. doi:10.1016/j.jad.2023.04.100
150. Fultz NE, Bonmassar G, Setsompop K, et al. Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Science. 2019;366(6465):628–631. doi:10.1126/science.aax5440
151. Czisch M, Wehrle R. Sleep. Available from. Cham, Switzerland: Springer;2022. https://app.kortext.com/borrow/2141916.
152. Bullock M, Jackson GD, Abbott DF. Artifact reduction in simultaneous EEG-fMRI: a systematic review of methods and contemporary usage. Front Neurol. 2021;12:622719. doi:10.3389/fneur.2021.622719
153. Moehlman TM, de Zwart JA, Chappel-Farley MG, et al. All-night functional magnetic resonance imaging sleep studies. J Neurosci Methods. 2019;316:83–98. doi:10.1016/j.jneumeth.2018.09.019
154. Song C, Boly M, Tagliazucchi E, Laufs H, Tononi G. fMRI spectral signatures of sleep. Proceedings Nat Acad Sci. 2022;119(30):e2016732119. doi:10.1073/pnas.2016732119
155. Dang-Vu TT, Desseilles M, Petit D, Mazza S, Montplaisir J, Maquet P. Neuroimaging in sleep medicine. Sleep Med. 2007;8(4):349–372. doi:10.1016/j.sleep.2007.03.006
156. Levenson JC, Kay DB, Buysse DJ. The pathophysiology of insomnia. Chest. 2015;147(4):1179–1192. doi:10.1378/chest.14-1617
157. Kay DB, Buysse DJ. Hyperarousal and beyond: new insights to the pathophysiology of insomnia disorder through functional neuroimaging studies. Brain Sci. 2017;7(3):23. doi:10.3390/brainsci7030023
158. Stephan AM, Lecci S, Cataldi J, Siclari F. Conscious experiences and high-density EEG patterns predicting subjective sleep depth. Curr Biol. 2021;31(24):5487–500.e3. doi:10.1016/j.cub.2021.10.012
159. Stephan AM, Siclari F. Reconsidering sleep perception in insomnia: from misperception to mismeasurement. J Sleep Res. 2023;32(6):e14028. doi:10.1111/jsr.14028
160. Kay DB, Karim HT, Soehner AM, et al. Subjective-objective sleep discrepancy is associated with alterations in regional glucose metabolism in patients with insomnia and good sleeper controls. Sleep. 2017;40(11):zsx155. doi:10.1093/sleep/zsx155
161. Li X, Li Z, Zou Z, et al. Real-time fMRI neurofeedback training changes brain degree centrality and improves sleep in chronic insomnia disorder: a resting-state fMRI study. Front Mol Neurosci. 2022;15:825286. doi:10.3389/fnmol.2022.825286
162. Dresler M, Wehrle R, Spoormaker VI, et al. Neural correlates of dream lucidity obtained from contrasting lucid versus non-lucid REM sleep: a combined EEG/fMRI case study. Sleep. 2012;35(7):1017–1020. doi:10.5665/sleep.1974
163. Drummond S, Brown G, Gillin J, et al. Altered brain response to verbal learning following sleep deprivation. Nature. 2000;403:655–657. doi:10.1038/35001068
164. Dzierzewski JM, Donovan EK, Kay DB, Sannes TS, Bradbrook KE. Sleep inconsistency and markers of inflammation. Front Neurol. 2020;11:1042. doi:10.3389/fneur.2020.01042
165. McCrae CS, Curtis AF, Kay DB. Pathophysiological mechanisms underlying the insomnia-fibromyalgia association: an overview for clinicians. In: Incayawar M, Maldonado Bouchard S, editors. Overlapping Pain and Psychiatric Syndromes: Global Perspectives. New York, NY: Oxford University Press; 2020:203–220.
166. Taga G, Neurovascular WH. Metabolic, and Glymphatic Dynamics of the Brain Measured with fNIRS. Adv Exp Med Biol. 2023;1438:197–202.
167. Pernet C, Garrido MI, Gramfort A, et al. Issues and recommendations from the OHBM COBIDAS MEEG committee for reproducible EEG and MEG research. Nat Neurosci. 2020;23(12):1473–1483. doi:10.1038/s41593-020-00709-0
168. Braun AR, Balkin TJ, Wesenten NJ, et al. Regional cerebral blood flow throughout the sleep-wake cycle. An H2(15)O PET Study. Brain. 1997;120(Pt 7):1173–1197.
169. Nofzinger EA, Buysse DJ, Germain A, et al. Increased activation of anterior paralimbic and executive cortex from waking to rapid eye movement sleep in depression. Arch Gen Psych. 2004;61(7):695–702. doi:10.1001/archpsyc.61.7.695
© 2025 The Author(s). This work is published and licensed by Dove Medical Press Limited. The
full terms of this license are available at https://www.dovepress.com/terms.php
and incorporate the Creative Commons Attribution
- Non Commercial (unported, 4.0) License.
By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted
without any further permission from Dove Medical Press Limited, provided the work is properly
attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.