How sleep timing relates to thinking skills and brain activity, with possible effects around surgery

Sleep chronotype, also as known as circadian preference, refers to individuals' subjective preference for their own sleep–wake cycle, often showing significant individual variation, and is part of circadian rhythm (Adan et al., 2012). Defined as individual differences of the preferred timing of the sleep–wake cycle (Zavada et al., 2005), reflect the properties of an individual's circadian phase (Levandovski et al., 2013), which reveals how active an individual is throughout the day in terms of body state, hormone levels, core body temperature, cognition function, diet, and sleep quality.

Recent studies commonly divide chronotype into three (or five) types: morning chronotype (moderate morning chronotype and definite morning chronotype), evening chronotype (moderate evening chronotype and definite evening chronotype), and intermediate chronotype (Horne and Ostberg, 1976).

(1) Morning type: Also known as early chronotype or larks. Morning type individuals are more active in the morning, they usually prefer to go to bed early and get up early. In the early part of the day after waking up, they achieve peak physical and mental performance.

(2) Evening type: Also called late chronotype or owls, prefer to be active in the evening and sleep and wake up late. Contrary to the morning type, evening chronotype individuals have the best mental and physical performance before sleeping.

(3) Intermediate type: Also regarded as neutral or neither type. This type of crowd has no preference for morning or evening.

Chronotype can be evaluated using self-reported questionnaires, the following scales are the most widely used: Morningness-Eveningness Questionnaire (MEQ) (Horne and Ostberg, 1976), Composite Scale of Morningness (CSM) (Smith et al., 1989), Munich Chronotype Questionnaire (MCTQ) (Roenneberg et al., 2003), and recently improved scale—Morningness-Eveningness-stability Scale (MESSi).

Other relative objective physiological indexes can evaluate chronotype, including dim light melatonin onset (DLMO), the serum cortisol and core body temperature. In addition, it can also use polysomnography (PSG) and actigraphy to record sleep chronotype.

Due to the high cost and complex operation of objective methods, their application in large-scale research is limited. In contrast, using subjective scales to assess sleep chronotype is easier and more feasible, so they can be used in large-scale clinical researches and epidemiological investigations. One of the most widely used questionnaires is MEQ and MEQ-5, which uses a statistical modal to extract five items of MEQ. It has been proved by researches that MEQ-5 has good psychometric characteristics (Danielsson et al., 2019). At the same time, the chronotype obtained by the objective measurement of sleep–wake cycle using the actigraphy are basically consistent with the results of the self-assessment questionnaires (Thun et al., 2012).

Gender has been proven to correlated with chronotype. In adults, morningness predominates among females (Vink et al., 2001), and high levels of testosterone seem to lead to a stronger tendency toward eveningness among males (Randler et al., 2012), although the difference disappears in menopause or elderly age. In addition, the changes in the propensity toward preferring the morning and the evening that occur with advancing age are perhaps due to changes in hormone secretion (Hagenauer et al., 2011).

Melatonin, also known as the pineal hormone, is an indole-like neuroendocrine hormone secreted by the pineal gland (Guo et al., 2023). Melatonin has widespread effects on the body and acts as a neuroendocrine transducer and circadian signal, is used as one of the biological markers of morningness-eveningness. Morning types have an advance in the melatonin secretion rhythm phase compared to evening types (Allada and Bass, 2021): compared with the evening type, the onset, acrophase, and offset of the melatonin profiles occurs approximately 3 h earlier in morning type, with no differences in amplitude. Because the evening type has higher melatonin levels at 9 a.m. than morning type, previous studies have shown that serum melatonin concentrations measured at 9 a.m. may help distinguish different sleep chronotype. At noon, the serum melatonin level typically does not show any differences between morning types and evening types anymore (Morera-Fumero et al., 2013).

Apart from melatonin, which clearly reaches its peak plasma concentration between 2 and 4 a.m., the nocturnal oscillations of other hormones also play a significant role in the generation and regulation of sleep patterns. Cortisol shows a characteristic rhythm of a peak in the morning and a trough at night. Among sex hormones, the level of testosterone is similar to that of cortisol, being the highest in the early morning and the lowest at night. Growth hormone is mainly secreted in a pulsatile manner during slow-wave sleep and is most vigorously secreted in the first sleep cycle at night (Begemann et al., 2025). These hormones, which have distinct circadian rhythms in production and secretion, are the core regulatory factors for maintaining normal circadian rhythms and sleep chronotype, and have a profound impact on various pathological and physiological processes in the human body. Although more extensive research is still needed to describe the connection between circadian clock and skin wound healing, an existing study have shown that in female Siberian hamsters, wounds incurred at night take longer to recover by 50% than wounds incurred at day (Cable et al., 2017).

Suprachiasmatic nucleus neurons contain N-methyl-d-aspartic acid (NMDA) and γ-aminobutyric acid (GABA) receptors, and the activation of these receptors affects the expression of clock genes and the synchronization between the internal clock and the exogenous clock. Most of the drugs of anesthesia are NMDA receptors' antagonists and GABA receptors' agonists. Clinical observational researches have found that anesthesia and surgery can cause delays in the endogenous rhythm of plasma melatonin levels and melatonin metabolite excretion (Gögenur et al., 2007). In addition, glucocorticoids, which are used in surgery, could mimic endogenous cortisol and have a strong effect on the molecular clock (Oster et al., 2017). Numerous studies have assessed effects of anesthesia and surgery on circadian rhythm; however, research on how does anesthesia/surgery affect perioperative chronotype is scarce.

Clock genes, including core regulators CLOCK, BMAL1, and feedback components Period (PER) and Cryptochrome (CRY), orchestrate circadian rhythms through a transcription-translation feedback loop (TTFL). The CLOCK/BMAL1 heterodimer activates downstream targets (e.g., Rev-reba, Dbp) via E-box binding, while PER/CRY proteins inhibit CLOCK/BMAL1 activity, establishing 24-h rhythmicity. Genetic studies reveal that the CLOCK genes' polymorphism is associated with delayed sleep phase (Jones et al., 2019). BMAL1 knockout models exhibit sleep fragmentation and reduced NREM sleep underscoring clock genes' direct role in chronotype regulation (Qiu et al., 2019).

Ion channels are not only the output pathways of the biological clock but also can feedback regulate the core clock mechanism. Data collected in the last decade, including different model organisms, support a central role for metal ions in regulating gene expression rhythms of core clock genes, both at the transcription and translation level (Stangherlin, 2023). Studies have shown that I_Ca(L) and fast delayed rectifier K⁺ currents [I_K(FDR)] inhibition affect firing during the day, when their respective current magnitudes are larger, and I_BK inhibition affects firing at night, when its current magnitude is larger (Harvey et al., 2020). This ion current rhythm with diurnal periodic changes is also very likely to be the basis of sleep chronotype, but further research is still needed.

In addition to the aforementioned metal ion channels, another type of ion channel has been discovered to serve as a bridge between body temperature and the circadian rhythm—transient receptor potential (TRP) channels. This is a molecular mechanism whereby external light and temperature are able to communicate sleep and wakefulness through multiple clock genes and TRP channels located throughout the body including muscle cells, neuronal cells and peripheral nerves sending cues as to time of day (Woodard et al., 2024).

Social jetlag (SJL) is a proxy for circadian misalignment quantifying the discrepancy between social and biological time (Roenneberg et al., 2019). Chronic SJL induces circadian phase delay and amplitude dampening, disrupting sleep homeostasis and metabolic regulation. The interplay between SJL and clock genes exacerbates chronotype disruption. Genome-wide association studies (GWAS) demonstrate that carriers of the CRY1 rs2287161 risk allele exhibit aggravated melatonin rhythm dysregulation under chronic SJL, with dose-dependent correlations to subjective sleep quality deterioration.

Differences between sleep chronotype can cause circadian rhythm sleep–wake disorders (CRSWDs), advanced sleep–wake phase disorders (ASWPD) and delayed sleep–wake phase disorders (DSWPD) all three of these clinical diagnoses (Facer-Childs et al., 2019). Patients with DSWPD tend to shorten the length of their sleep because of social constraints (such as work/school regulations), leading to the accumulation of sleep debt, which leads to excessive daytime sleepiness and impaired cognitive function, many of which are similar to those of evening type individuals.

Previous studies have shown that different sleep chronotypes in univariate analysis have significant effects on the occurrence of depressive symptoms and anxiety, and after controlling other influencing factors, further multivariate logistic regression analysis shows that evening types is one of risk factors for both depression and anxiety. This may be due to the differences in activities and functional connections in brain regions involved in emotional processing. Morphometric studies of the brain have identified associations of sleep chronotype with various subcortical structures and hippocampal subfields. The evening chronotype group exhibited notable reductions in the right caudate and the left strata radiatum/lacunosum/moleculare (SR-SL-SM). Additionally, the amplitude scale of the Chronotype Questionnaire (CHQ-AM) demonstrated significant positive and negative correlations with the volumes of the left thalamus and amygdala, respectively (Alhazmi, 2025). Moreover, evidence indicates that patients with major depressive disorder (MDD) exhibit dysregulated expression of clock genes in the dorsolateral prefrontal cortex, hippocampus, amygdala, nucleus accumbens, and cerebellum (Li et al., 2013). The amygdala is an important response organ in the limbic system of the brain, and its activation can be used as an indicator of the emotional intensity of an individual under stress (Frank et al., 2014).

With the increasing complexity of social relations and the increasing pressure of life, the incidence of depression disorders is rising day by day. Depressive disorders are characterized by significant and persistent depressive symptoms as the primary clinical feature, often accompanied by the rhythmical fluctuation of mood and high morbidity, heavy burden, and great social attention. Many researches have shown that evening-type individuals are significantly associated with depression, one of the recent meta analyses of 43 studies revealed a reliable association between a preference for night sleep patterns and depression symptoms (Norbury, 2021).

Bipolar disorders (BD), including BD-I and BD-II, are mood disorders. Previous studies have confirmed the association between chronotype and BD after measuring sleep chronotype using subjective methods (such as questionnaires) and objective methods (such as actigraphy) (Gershon et al., 2018; Kaufmann et al., 2018). However, other researches have found no significant correlation between chronotype and the two BD subtypes. In conclusion, sleep chronotype may be a risk factor for BD because of its more severe symptoms and more complications. Nevertheless, the current evidence is insufficient and the underlying mechanism is not clear. In the future, a large number of relevant studies are still needed to pay attention to the relationship between chronotype and BD.

With regard to brain structure, it is well known that brain regions are connected and innervated via white matter (WM) bundles, so the structure of WM is essential for coordinating brain function. In one study, after exploring the microstructures of WM through diffusion tensor imaging (DTI), it was found that the frontal lobe, temporal lobe, corpus callosum and other regions showed significant differences in the WM integrity structure of different chronotypes, as manifested in the following aspects: Compared with early chronotypes and intermediate chronotypes, evening chronotypes in the left anterior cingulate gyrus (ACC) at the bottom of the WM showed a significantly lower of the fractional anisotropy (FA) and lower fiber count (FC) values in WM below the right frontal lobe (Rosenberg et al., 2014). By the way, WM microstructure underlying the frontal lobes has been associated with disturbances in motor movements and cognitive functions, e.g., attention (Kiernan and Hudson, 1994).

Brain lateralization denotes the functional asymmetry between the cerebral hemispheres in cognitive, sensory, and motor processing. Research on this topic dates back to the mid-19th century (Güntürkün et al., 2020). Recent evidence reveals marked hemispheric asymmetries in individuals with different sleep chronotype. Employing voxel-based morphometry (VBM) and vertex-wise cortical thickness (CTh) analysis, Rosenberg et al. noted that early chronotypes showed significantly lower gray matter volumes in the right lingual gyrus, occipital fusiform gyrus and the occipital pole as compared to intermediate chronotype. Furthermore, lower gray matter volumes for early chronotypes in the left anterior insula, precuneus, inferior parietal cortex, and right pars triangularis than for late chronotypes (Rosenberg et al., 2018). Another study published in 2025 similarly demonstrated that a notable leftward hemispheric laterality of the subiculum was found in the early chronotype group compared to the late chronotype group (Alhazmi, 2025). These findings may reveal the basis for chronotype differences in brain function and shed how sleep chronotype affects brain lateralization.

Regarding the basis of brain imaging, both morning and evening chronotypes are significantly associated with functional connectivity of the default mode network and frontoparietal network (DMN-FPN), and the more early morning type individuals tend to have stronger functional connectivity (Hodkinson et al., 2014). The correlation between the morning chronotype and the functional connection of the left dorsolateral superior frontal-left inferior parietal marginal angular gyrus may mainly reflect the role of internal circadian rhythm. The negative correlation between evening chronotype and functional connection between left angular gyrus and right frontal middle gyrus may mainly express the components of homeostasis process.

The chronotype and the functional connection of brain's resting state can be used to predict human's cognitive performance (Facer-Childs et al., 2019). Salehinejad et al. (2021) conducted a successful trial using non-invasive brain stimulation (NIBS) and transcranial direct current stimulation (tDCS) to monitor people with different sleep chronotypes and found that motor learning and cognitive performance (working memory, and attention) along with their electrophysiological components are significantly enhanced at the circadian-preferred, compared to the non-preferred time. This outperformance is associated with enhanced cortical excitability (prominent cortical facilitation, diminished cortical inhibition), and long-term potentiation/depression-like (LTP/LTD) plasticity (Salehinejad et al., 2021). For cortical-related electrophysiological changes, at the circadian-preferred time, intracortical facilitation is enhanced predominantly by increased activity of glutamatergic synapses. Conversely, cortical inhibition is significantly pronounced at the circadian non-preferred time presumably through enhanced GABAergic activation. In the second place, for the regulation of neuroplasticity, this study found that LTP/LTD-like neuroplasticity also depends on glutamatergic and GABAergic systems and is driven by NMDA receptors. This is consistent with the evidence from primary motor cortex modals in humans and animals (Castañeda et al., 2004; Albus et al., 2005; Langel et al., 2018).

At the same time, another research has found that compared with the morning chronotype, the cognitive ability and emotional experience of the evening chronotype are more likely to be impaired. And then after the intervention based on light and sleep homeostasis pressure, the cognitive ability, emotional problems, sleep quality and sleep structure of the evening chronotype subjects were significantly improved. It may be that the prolonged sleep duration after the intervention causes the regulation of neurotrophic factors, improves the glucose metabolism in the brain, down-regulates the adenosine concentration, and then attenuates the negative effects of homeostasis sleep stress to improve cognitive function (Arnal et al., 2015).