Open research questions in Sleep and Wakefulness Research

What the literature leaves open

• Hippocampal sharp wave ripples (SWRs) coordinate hippocampal and neocortical interactions for memory consolidation, yet how cortical GABA signaling is organized around SWRs remains unclear.

  Cortical GABAergic dynamics around hippocampal sharp-wave ripples · 2026 · DOI

• Background: Chronic sleep restriction (CSR) impairs cognitive function, but its effects on the cortical dynamics underlying active motor performance remain poorly understood.

  Cortical Activity During Sustained Isometric Ankle Contractions Following Chronic Sleep Restriction: A High-Density EEG Study · 2026 · DOI

• Even though this is a prominent feature of HAT, the connection between parasite neuroinvasion, neuroinflammation, circadian dysfunction, and neurological impairment is not fully understood.

  Sleep–Wake Dysregulation in Human African Trypanosomiasis: From Neuroinvasion to Neuronal Dysfunction · 2026 · DOI

• Neurological and neuropsychiatric conditions affect 43% of the global population, many shaped by modifiable lifestyle exposures, yet their relationship to cortical haemodynamics is poorly characterised.

  Prefrontal activation predicts response latency and is shaped by age and lifestyle · 2026 · DOI

• Working memory (WM) allows recently encountered information to be maintained over short periods, yet neural mechanisms supporting this short-term accessibility remain debated.

  Sleep spindles enhance latent working memory representations · 2026 · DOI

• Immunomodulatory treatments have shown encouraging results in isolated reports but have not been tested rigorously in controlled trials (46). Comorbidities such as depression, obesity, metabolic dysregulation, autonomic instability and chronic pain remain under-recognized in routine care, despite robust evidence of their contribution to disability and reduced quality of life. Important gaps in the evidence base impede progress. Epidemiological estimates remain uncertain, with prevalence varying dramatically across global populations, likely reflecting differences in genetic susceptibility, infectious exposures and environmental triggers (36).

  Narcolepsy as an immune-associated hypothalamic encephalopathy: orexin dysfunction and implications for precision sleep medicine · 2026 · DOI

• Significance StatementTime-restricted eating - targeting food intake to a defined window during the circadian active phase - confers well-established metabolic benefits, but its impact on sleep is largely underexplored.

  Time Restricted Feeding Mitigates High-Fat-Diet Induced Sleep Disruption and Amplifies NREM Substates · 2026 · DOI

• In conclusion, TMR applied during a 2-hour nap did not enhance motor retention, but the changes in sleep physiological features could be linked to a possible underlying effect on memory processing that warrants further investigation.

  Targeted memory reactivation during sleep modulates spindle and slow wave density, but not motor memory consolidation, in Parkinson's disease · 2026 · DOI

• Although nocturnal awakenings are thought to facilitate the encoding and later retrieval of dream experiences, it remains unclear whether dream recall is shaped primarily by awakening frequency or by more specific awakening characteristics, including duration, sleep stage, and timing within the night.

  How Awakenings Shape Dream Recall: A Multilevel Study · 2026 · DOI

• Ramelteon, a selective MT1/MT2 receptor agonist, has been reported to possess cognitive-enhancing properties; however, its impact on the fine-scale dynamics of hippocampal ripples remains unclear.

  Ramelteon facilitates hippocampal ripple occurrence and amplitude in mice · 2026 · DOI

• The results should be interpreted with the understand- ing that the categorical distinction between phases and between physical, emotional, and mental aspects repre- sents a methodological simplification. In actual expe- rience, these dimensions cannot be strictly separated. Rather, they are closely interwoven and mutually influ- ential processes that interact with the environment [54]. The example of Floatation-REST illustrates the extent to which cognitive processes are embedded in bodily- sensory perceptions, thereby highlighting the funda- mental unity of body, mind, and environment in human experience [55]. The data analysis was conducted by the interviewer, which may be regarded as a methodological limitation. At the same time, the interviewer’s in-depth familiarity with the subject matter facilitated a nuanced interpretation of the data. Reliability of the analysis was ensured by reflecting each step of the analysis in the team. Describing experiences of ASC presents a challenge and deviates considerably from everyday modes of com- munication [56]. The analysis revealed varying degrees of data saturation depending on the specific content of the ASC: mental activity was described in the greatest detail, whereas physical sensations and emotions were articulated less extensively. This discrepancy may be attributable to limitations in expressive capacity. Other micro-phenomenological studies (e.g. Schmidt et al. [57]) have therefore deliberately recruited verbally adept par- ticipants with meditation experience. In contrast, the present study intentionally included participants without prior experience, which may have resulted in less precise verbal accounts. To ensure interpretative richness (or ‘thickness’), even infrequently mentioned categories were incorporated into the semantic networks. In micro-phenomenological analysis, even rarely occurring themes are considered rel- evant, as they can reveal subtle or unconscious content and contribute to the overall density and depth of the data [58]. A common critique of micro-phenomenological meth- ods concerns the potential for cognitive distortion in retrospective reports [59]. In the present study, such memory distortion was minimized by conducting the interviews immediately following the Floatation-REST session. Particularly salient or unusual experiences, such as ASC, are known to be well retained in memory (Poynter, 1983). The “evocation” technique employed at the beginning of the interviews served to activate epi- sodic memory through sensory re-experiencing pro- cesses, thereby supporting authentic and valid recall [59, 60]. Micro-phenomenological indicators of success- ful recall include among others slowed speech, pauses, and detailed descriptions accompanied by gestures [59], which were evaluated using a interview quality checklist prior to analysis. A potential influence of prior experience and expec- tations on the experience of ASC warrants discussion. Whereas prior float experience ranged from one to five sessions, a substantial number of participants had exten- sive contemplative practice, which may limit the gen- eralizability of the float-related findings to the broader population. We relied on a typical convenience sample and did not specifically recruit individuals with contem- plative experience. In a university city—and particularly in Freiburg—many people practice meditation. Such indi- viduals are also more likely to be interested in trying and participating in a flotation study. However, Norlander et al. [12] found no effect of contemplative background on ASC experiences, the present study similarly supports this finding: All participants, regardless of prior experi- ence, reported ASC phenomena. Participants’ expectations regarding the Floatation- REST session were not assessed in this study, which could be addressed in future research. A possible concern is that some experiences reported during flotation could be influenced by increased suggestibility or self-suggest- ibility brought on by the environment. This underscores a Hruby et al. BMC Complementary Medicine and Therapies (2026) 26:200 broader issue in altered states of consciousness research: separating true effects of an intervention from those shaped by expectations or contextual factors.

  The micro-phenomenology of Floatation-REST · 2026 · DOI

• An important next step will be to clarify the limits and flexibility of residual environmental monitoring during sleep. Current evidence suggests that preserved processing is not fixed, but varies with stimulus salience, sleep microstructure, and the timing of permissive windows across sleep cycles. How these effects extend beyond auditory, highly controlled paradigms to more ecological and multimodal contexts remains to be established. The influence of prior experience, environmental context, and individual traits on this selectivity is also still insufficiently understood. A further challenge is to determine when transient environmental access remains adaptive and compatible with sleep continuity, consolidation, and restorative functions, and when it becomes disruptive. This issue is especially relevant given recent attempts to use externally timed stimulation to reinforce sleep-dependent processes. Determining when external input is beneficial, compatible, or maladaptive therefore remains an important challenge.

  Guarded Slumber: Dynamic Disconnection, Selective Monitoring, and the Balance of Information Processing during Sleep · 2026 · DOI

• Future studies should prioritize several key research priorities. First, well-designed randomized controlled trials combining exercise inter- vention with sleep manipulation (e.g., sleep extension, selective sleep deprivation and pharmacological sleep regulation) were required to verify whether exercise-induced cognitive improvements were mediated by sleep architecture changes, while accounting for potential bidirec- tional and reciprocal interactions (10). Second, longitudinal repeated- measures designs with multi-timepoint assessments of sleep architecture, physical activity and executive function helped clarify temporal causality and distinguish unidirectional, bidirectional and reciprocal relationships (66). Third, closed-loop intervention strategies that adjusted real-time exercise prescriptions based on wearable device-monitored sleep param- eters (e.g., switching to low-intensity mind–body exercise after poor sleep) optimized the synergistic effects of exercise and sleep regulation (67). Moreover, multimodal approaches integrating functional magnetic resonance imaging, electroencephalography and actigraphy, combined with computational modeling, facilitated the construction of individual- ized response prediction models for combined intervention (68). Finally, the development of feasible, population-tailored intervention protocols (e.g., morning light-exercise combined therapy, midday short napping and evening relaxation training) and their translational application in community settings remained critical for clinical implementation. Several limitations constrain the interpretability of this review. First, most cited studies are cross-sectional or observational, precluding causal inference and leaving unmeasured confounding unresolved. Second, the hypothesized pathway in which sleep architecture is involved in exercise effects on executive function lacks direct testing; no randomized controlled trial has manipulated sleep architecture within an exercise intervention to examine whether altering sleep archi- tecture changes the cognitive outcomes, which would be necessary to support a causal role. Third, mechanistic evidence, particularly for the glymphatic system and lactate signaling, derives primarily from animal models, limiting direct translation to aging humans due to species dif- ferences. Fourth, individual differences (e.g., genetic background, cog- nitive reserve, comorbidities) in middle-aged and older adults and considerable heterogeneity in the operationalization of sleep architec- ture and executive function across studies further complicate synthesis.

  The interplay of sleep architecture and exercise in executive function of middle-aged and older adults · 2026 · DOI

• In particular, it remains unclear whether the observed dysregulation of sleep-related neu- ronal dynamics mirrors the E/I imbalance present during wakefulness, or instead reflects compensatory processes aimed at counteracting such dysregulation. Further research is needed to determine whether the sleep-stage-dependent alterations observed in ASD reflect adaptive or maladaptive mechanisms, and to establish more direct associations between atypical sleep EEG pat- terns and E/I imbalance.

  Aperiodic and periodic neural activity during sleep in autism spectrum disorders · 2026 · DOI

• A main limitation of the study is the reduced statistical power due to the limited sample size, which was a direct consequence of strict inclusion criteria: specifically, the inclusion of only participants not undergoing pharmaco- logical treatment, which is highly prevalent among adults with ASD. Furthermore, several recording segments and participants had to be excluded due to corrupted or incomplete PSG data, primarily resulting from partici- pant discomfort. Another potential limitation is the use of a single-night recording session without an adaptation night, as implemented in some previous studies. This may have affected participants’ comfort and familiarity with the sleep setting, potentially influencing sleep qual- ity. However, the use of a single-night PSG also prevented any carry-over effects of discomfort or distress from a prior night, which could have altered sleep architecture in subsequent recordings. Finally, we acknowledge that the limited number of EEG electrodes, used to reduce participant discomfort during sleep, may have impacted the spatial resolution of the EEG results. Nonetheless, this approach is consistent with most previous PSG stud- ies in similar populations.

  Aperiodic and periodic neural activity during sleep in autism spectrum disorders · 2026 · DOI

• The pathophysiological mechanisms distinguishing idiopathic hypersomnia with long sleep from narcolepsy type 1 remain incompletely understood beyond hypocretin/orexin deficiency. Novel research on alternative neurochemical pathways, neural circuit dysfunction, and genetic mechanisms specific to idiopathic hypersomnia subtypes is explicitly noted as necessary but lacks detailed specification of which pathways should be prioritized.

  Bedřich Roth: pioneer in sleep medicine · 2020 · DOI

• While Roth's clinical observations from the 1950s regarding narcolepsy type 2 similarity to monosymptomatic hypersomnia have been validated conceptually, prospective longitudinal studies tracking patients with narcolepsy type 2 and idiopathic hypersomnia without long sleep over extended periods are needed to establish natural history, progression patterns, and long-term clinical outcomes in these merged diagnostic categories.

  Bedřich Roth: pioneer in sleep medicine · 2020 · DOI

• The Polygraphic Score of Sleepiness introduced by Roth as an alternative quantification method for excessive daytime sleepiness has not been systematically compared against contemporary measures in large cohorts of narcolepsy and idiopathic hypersomnia patients. Validation studies comparing this scoring method's sensitivity and specificity relative to the MSLT and other objective sleepiness measures in different hypersomnia subtypes are needed.

  Bedřich Roth: pioneer in sleep medicine · 2020 · DOI

• The paper identifies an urgent need for biological markers in idiopathic hypersomnia and narcolepsy type 2 diagnosis, as current diagnostic polysomnographic criteria require continuous readjustment. Specific biomarkers beyond the hypocretin/orexin deficiency identified in narcolepsy type 1 need to be established to differentiate idiopathic hypersomnia from narcolepsy type 2 and to enable objective classification of these separate disease entities.

  Bedřich Roth: pioneer in sleep medicine · 2020 · DOI

• Even though REM sleep was only identified as a distinct behavioural state in the early 1950s, considerable progress has been made in understanding its mechanisms and functions, with most of this headway being made within the past decade. And while it is undeniable that many of these advances in our understanding of REM sleep biology link to the development of new technologies (e.g., chemo- and opto-genetics), we would argue that it is the combinatorial application of these newer techniques with more classical approaches (e.g., functional anatomy, unit recording, and cellular imaging) that has truly enabled the effective probing and elucidation of the delimited circuits that drive REM sleep and, in turn, revealed how these circuits influence the function and activity of brain structures associated with learning, memory and motor control. Although scientists have made important progress in identiits fying REM sleep mechanisms and elucidating some of biological functions, many important questions remain. For example, is REM sleep actually present in all animals? While many biologists believe that sleep is a universal behaviour, we have only studied and identified sleep in a small fraction of all existing animal species. Understanding sleep biology across species, is important because such insight could provide new clues about the potential functions of REM sleep. For example, does REM sleep serve the same function in all animals? including differences, Although REM sleep appears important for certain types of learning and memory, it remains virtually unknown how REM sleep actually facilitates plasticity and learning. While recent evidence indicates that theta activity during REM sleep (Figure 1) is critical for facilitating motor learning, it remains unknown how or why theta activity promotes memory-related plasticity. It also remains unclear if REM sleep serves the same biological function(s) across the lifespan. For example, why are REM sleep amounts typically higher in young and developing animals than in older ones? These age-related differences in REM sleep amounts suggest that REM sleep function may vary across an animal’s lifespan, but what those potential functions are remains unclear. While some of the circuits underlying REM sleep generation have been identified, the full extent of REM sleep circuits remains R1244 Current Biology 27, R1237–R1248, November 20, 2017 unidentified. For example, it was only within the last several years that neuroscientists identified that structures beyond the brainstem (e.g., MCH cells in the hypothalamus) also play a critical role in modulating REM sleep. It also remains unclear how circuits that control REM sleep communicate with those that promote wakefulness and non-REM sleep. And this is a critical question in science and medicine because changes in REM sleep control are associated with some of the symptoms in narcolepsy (e.g., cataplexy).

  The Biology of REM Sleep · 2017 · DOI

• However, comparatively little is known about that occurs in other sensory modalities, such as olfactory, gustatory (taste), tactile, thermal, kinesthetic, bodily and synesthetic sensations, plus sensations of a presence (Leaning, 1925; Mavromatis, 1987; Schacter, 1976).

  A Web Survey of the Content, Sensory Modalities, and Interpretation of Hypnagogic and Hypnopompic experiences/Una Encuesta En la Red Sobre Contenido, Modalidades Sensoriales, E Interpretacion De Experiencia Hipnagogicas E hipnopompicas/Un Sondage Enligne Du Contenu, Des Modalites Sensorielles et De L'interpretation Des Experiences Hypnagogiques et hypnopompiques/Eine Webbasierte Umfrage Uber Inhalte · 2012

• Over the years science has tried to provide a consistent explanation of the etiopathogenesis and physiopathology of SB, although the pathophysiological mechanisms are even now not yet fully understood.

  Sleep bruxism. Conceptual review and update · 2011 · DOI

• Following commands and the subsequent fMRI activations indicate that the subject had recovered to at least the level of MCS, even though behavioral evidence was lacking.

  Shades of Gray: New Insights into the Vegetative State · 2006 · DOI

• From a consideration of these facts, it seems reasonable to conclude that in sleep those operations of the mind are suspended which depend on our volition; for if it be certain that before we fall asleep we must withhold, as much as we are able, the exercise of all our different powers, it is scarcely to be imagined that, as soon as sleep commences, these powers should again begin to be exerted.

  Dreaming: From Elements of the Philosophy of the Human Mind (1794) · 2004 · DOI

• The absence of REM sleep in the Enchidna and in two species of dolphins (that have relatively large brains) suggests that REM may allow the brain to be smaller than if REM were lacking.

  REM sleep and neural nets · 1986

Most-cited papers in Sleep and Wakefulness Research

• Bruxism physiology and pathology: an overview for clinicians* · Journal of Oral Rehabilitation · 2008 · 646 citations
• Sleep Disturbances as the Hallmark of PTSD: Where Are We Now? · American Journal of Psychiatry · 2012 · 536 citations
• N<scp>eurobiological</scp> M<scp>echanisms</scp> I<scp>nvolved in</scp> S<scp>leep</scp> B<scp>ruxism</scp> · Critical Reviews in Oral Biology & Medicine · 2003 · 403 citations
• The Biology of REM Sleep · Current Biology · 2017 · 324 citations
• Macro and micro sleep architecture and cognitive performance in older adults · Nature Human Behaviour · 2020 · 147 citations
• Memory and Sleep: How Sleep Cognition Can Change the Waking Mind for the Better · Annual Review of Psychology · 2020 · 136 citations
• A neuron–glia lipid metabolic cycle couples daily sleep to mitochondrial homeostasis · Nature Neuroscience · 2024 · 128 citations
• Effect of Age on the Circadian Pattern of Sleep and Wakefulness in the Mouse · Journal of Gerontology · 1986 · 110 citations
• Infraslow noradrenergic locus coeruleus activity fluctuations are gatekeepers of the NREM–REM sleep cycle · Nature Neuroscience · 2024 · 105 citations
• Sleep Disturbances in Posttraumatic Stress Disorder: Updated Review and Implications for Treatment · Psychiatric Annals · 2016 · 102 citations

Most recent work

• Contrasting effects of global and local cortical activity on the regulation of sleep · bioRxiv · 2026
• SARS-CoV-2 infection is associated with hypothalamic orexin suppression and persistent cortical NeuN attenuation · Journal of Neuroinflammation · 2026
• Peripheral metabolic dysfunction drives sleep disruption in TDP-43 proteinopathy · bioRxiv · 2026
• Treatment of chronic insomnia in elderly adults with dual orexin receptor antagonists: A systematic review and meta-analysis · SLEEP · 2026
• Modulating sleep: slow oscillation and spindle stimulation effects on physiology and memory · npj Science of Learning · 2026
• The biopsychosocial model of bruxism · CRANIO® · 2026
• Aperiodic and periodic neural activity during sleep in autism spectrum disorders · BMC Medicine · 2026
• Practical Guidance for Initiation and Management of Patients on Once-Nightly Sodium Oxybate for Narcolepsy Treatment: Modified Delphi Panel Consensus Recommendations · Neurology and Therapy · 2026
• Narcolepsy as an immune-associated hypothalamic encephalopathy: orexin dysfunction and implications for precision sleep medicine · Frontiers in Psychiatry · 2026
• Wavelength-dependent sleep state manipulation using light pulses in Pogona vitticeps · Communications Biology · 2026

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