Zhang F, Huang WY, Zhang L, Huang ZR, Zhao W, Yu YQ. Circadian rhythm disruption alters gray and white matter microstructure: Higher-order diffusion analysis coupled with hormonal/inflammatory biomarkers. World J Psychiatry 2026; 16(6): 117066 [DOI: 10.5498/wjp.v16.i6.117066]
Corresponding Author of This Article
Yong-Qiang Yu, PhD, Professor, Department of Radiology, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei 230000, Anhui Province, China. yuyongqiang@ahmu.edu.cn
Research Domain of This Article
Neurosciences
Article-Type of This Article
research-article
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Author contributions: Zhang F was responsible for conceptualization, methodology, writing - original draft; Huang WY was responsible for validation, methodology, data curation; Zhang L was responsible for validation, methodology, data curation; Huang ZR was responsible for validation, methodology, data curation; Zhao W was responsible for supervision, writing - review & editing, resources; Yu YQ was responsible for writing - review & editing, supervision, resources, project administration, funding acquisition, conceptualization; all authors have read and approved the final manuscript.
AI contribution statement: Tencent Yuanbao was used for language polishing to improve grammar and readability. Tencent Yuanbao was used solely for language polishing (proofreading and editing for grammar, spelling, and clarity). No AI tools were used for translation, data analysis, or writing assistance beyond proofreading.
Supported by 2024 Huaibei City Science and Technology Plan Project, No. HK2024057.
Institutional review board statement: This study was conducted in accordance with the Declaration of Helsinki and received ethical approval from the Institutional Review Board of Huaibei People's Hospital, Anhui Province (Approval No. 2024-074).
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: The authors declare no competing financial or non-financial interests in relation to this article. No external funding bodies influenced the design, conduct, or reporting of this study.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at e-mail address.
Corresponding author: Yong-Qiang Yu, PhD, Professor, Department of Radiology, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei 230000, Anhui Province, China. yuyongqiang@ahmu.edu.cn
Received: December 2, 2025 Revised: January 7, 2026 Accepted: February 6, 2026 Published online: June 19, 2026 Processing time: 182 Days and 6.7 Hours
Abstract
BACKGROUND
The hypothalamic suprachiasmatic nucleus, as the master circadian pacemaker, coordinates circadian homeostasis via neuroendocrine signaling networks. Circadian rhythm disruption (CRD) denotes functional impairment of this system, driven by etiologies ranging from environmental stressors to intrinsic insults, triggering pathophysiological cascades.
AIM
To delineate neuroendocrine-immune circuits in female textile workers with CRD by integrating diffusion spectrum imaging (DSI)-based neurite orientation dispersion and density imaging (NODDI) with biochemical indices, in order to identify specific biomarkers linked to circadian-hormonal-inflammatory crosstalk.
METHODS
This prospective observational study included 55 female patients with CRD (≥ 10 annual night-shift cycles) and 41 age-, sex-, and education-matched controls. A comprehensive multimodal assessment was performed, including quantitative DSI-based NODDI analysis of gray and white matter regions, serum biomarker profiling, standardized neuropsychological evaluations, and statistical analysis of group differences. Within the CRD group, interrelations among multimodal variables were explored using correlation analyses.
RESULTS
Compared with controls, the CRD group showed significantly higher volume fraction of the isotropically diffusing water and intracellular volume fraction (ICVF) values in seven gray matter regions (P < 0.05), primarily within the default mode network and visual network (VN); white matter ICVF was also elevated in three fiber tracts associated with the VN. The CRD group had poorer neurofunctional performance compared to controls. The CRD group also demonstrated increased triiodothyronine (T3; 2.33 nmol/L vs 2.02 nmol/L), prolactin (303.20 µIU/mL vs 249.60 µIU/mL), neutrophil-to-lymphocyte ratio (2.02 vs 1.80); and decreased thyrotropin receptor antibody (0.75 IU/L vs 0.98 IU/L) and luteinizing hormone (14.77 mIU/mL vs 24.29 mIU/mL) compared with the control group. Correlation analysis showed that ICVF in the left middle occipital gyrus and pontine crossing tract correlated positively with T3 (r = 0.268 and 0.321 respectively), while ICVF in the left cuneus and left superior occipital gyrus correlated with cortisol (r = 0.278 and 0.268 respectively).
Core Tip: This study focuses on female night-shift textile workers with circadian rhythm disruption (CRD), innovatively integrating diffusion spectrum imaging-based neurite orientation dispersion and density neuroimaging, endocrine/inflammatory biomarkers, and neuropsychological assessments. The study results reveal, for the first time, that neuroendocrine-immune crosstalk in CRD is mediated by neurostructural remodeling, dysregulation of the hypothalamic-pituitary-thyroid/hypothalamic-pituitary-gonadal axis, and neuroinflammation, providing critical evidence for precision diagnosis and intervention of CRD driven by multimodal biomarkers.
Citation: Zhang F, Huang WY, Zhang L, Huang ZR, Zhao W, Yu YQ. Circadian rhythm disruption alters gray and white matter microstructure: Higher-order diffusion analysis coupled with hormonal/inflammatory biomarkers. World J Psychiatry 2026; 16(6): 117066
The hypothalamic suprachiasmatic nucleus (SCN) serves as the master circadian pacemaker, coordinating circadian homeostasis through a complex network of neuroendocrine signaling pathways. Circadian rhythm disruption (CRD) refers to the functional impairment of this intricate timekeeping system, with an etiology encompassing a wide spectrum of contributing factors[1-8]. Notably, environmental stressors including circadian misalignment due to transmeridian travel, irregular work hour patterns, and nocturnal light pollution—represent major external triggers. Equally significant are intrinsic biological insults such as retino-hypothalamic tract dysfunction and structural or functional abnormalities in the SCN, which collectively drive the pathophysiological cascade underlying CRD.
CRD induces widespread neural dysfunction through interconnected molecular and neuroinflammatory pathways, as demonstrated by preclinical and clinical studies[1-4]. Chronic continuous light (CL) exposure disrupts circadian rhythm cycles, eliciting anxiety-like behaviors and synaptic impairments. In rodent models, CL exposure increases central dwell time in open-field tests by 2.8-fold and elevates corticosterone levels by 90% (P < 0.01)[1], indicating pronounced anxiety phenotypes. Concurrently, CL-induced circadian misalignment impairs hippocampal synaptic plasticity, evidenced by a 65% reduction in long-term potentiation amplitude and a 40% downregulation in brain-derived neurotrophic factor expression[2]. These neurobehavioral and molecular alterations arise from disrupted central-peripheral synchrony, which amplifies neuroinflammatory signaling [e.g., interleukin-6 (IL-6)/Iba-1 pathway] and compromises hippocampal-dependent cognitive networks. The chronic jet lag model, induced by chronic phase shifts of light-dark cycles (e.g., T-cycle paradigm), disrupts synchrony between the SCN and peripheral oscillators, thereby inducing the physiological consequences of human shift work. This model demonstrates that circadian desynchronization results in dysregulated expression of rhythmic genes (Rev-ERBα/RORα) in peripheral tissues (liver, adipose), leading to a 2.3-fold increase in metabolic syndrome risk[3]. In Alzheimer’s disease patients, diminished SCN-BMAL1 protein expression exhibits an inverse correlation with β-amyloid plaque burden (r = -0.67, P < 0.01)[4], indicating that circadian misalignment may accelerate neuropathological progression—providing mechanistic insights into the heightened neurodegenerative and psychiatric risks observed among shift workers and individuals with sleep disorders.
Advanced functional magnetic resonance imaging (fMRI) techniques have revealed both physiological circadian rhythms in brain networks and their disruptions under pathological conditions. For instance, Facer-Childs et al[5] demonstrated that early chronotypes exhibit augmented functional connectivity within the default mode network (DMN), particularly in the precuneus, angular gyrus, and medial temporal lobe, which correlates with better attentional performance and reduced diurnal sleepiness compared with late chronotypes. Conversely, Alloy et al[6] identified aberrant DMN hyperconnectivity in shift workers with chronic circadian disruption, characterized by heightened coupling between the posterior cingulate cortex/medial prefrontal cortex alongside reduced connectivity between the SCN and dorsolateral prefrontal cortex (DLPFC)/orbitofrontal cortex, reflecting a dual-pathway disruption of circadian-regulated neural dynamics. Andreadi et al[7] further revealed that chronic shift work leads to an 18%-23% degradation of DMN structural integrity, evidenced by reduced graph-theoretical indices of network integration and attenuated cortisol-mediated modulation of anterior cingulate cortex perfusion during cognitive tasks. Complementing these functional findings, Rimmele et al[8] employed diffusion tensor imaging to quantify peak-width skeletonized mean diffusivity (PSMD), a sensitive marker of white matter microstructural integrity, and demonstrated that current shift workers exhibit 3.1% higher PSMD compared to non-shift workers (β = 9.91 × 10-6, P = 0.006 after covariate adjustment), implicating CRD as a pathogenic driver of myelin degradation and axonal injury in thalamocortical pathways. Collectively, these studies establish a mechanistic framework wherein circadian misalignment promotes maladaptive neuroplasticity, characterized by DMN hyperconnectivity, frontolimbic decoupling, and progressive white matter degeneration, providing actionable neuroimaging biomarkers for mitigating neuropsychiatric sequelae in shift work populations.
However, current evidence frequently conflates acute circadian fluctuations with chronic CRD-related pathophysiology, while longitudinal data elucidating systemic dysregulation’s impact on neuro network dynamics remain limited. Notably, distinct circadian patterns arising from sustained nocturnal shift work, particularly those associated with long-term regular schedules have not been systematically characterized. A critical knowledge gap also persists regarding the mechanistic linkages between CRD-driven neural dysfunction and downstream metabolic-inflammatory coupling, which hinders the development of precision therapeutic strategies. To address these limitations, we employed a multimodal neuroimaging approach integrating diffusion spectrum imaging (DSI) with comprehensive neuroendocrine and immunological profiling in shift workers. This study aims to: (1) Identify CRD-specific alterations in regional brain connectivity; (2) Elucidate interactions between neural network reorganization and endocrine-immune dysregulation; and (3) Establish pathophysiological framework models linking circadian misalignment with systemic homeostasis imbalance. Findings from this investigation are expected to advance our understanding of human chronobiology by uncovering novel neuroimaging biomarkers and mechanistic insights into regulation of the circadian-neural-metabolic axis.
MATERIALS AND METHODS
Participants
The research protocol adhered to the principles outlined in the Declaration of Helsinki and was formally approved by the Ethics Committee of Huaibei People’s Hospital, Anhui Province (Ethics Approval No. 2024-074). Written informed consent was systematically obtained from all study participants following comprehensive disclosure regarding the scientific objectives, methodology, associated risks, and their rights as contributing subjects.
We recruited 55 female textile workers meeting the criteria for CRD and 41 age-, gender-, education- and work intensity-matched controls between June 2024 and October 2024. The CRD cohort consisted of female employees with ≥ 10 years of regular night shift exposure (≥ 3 shifts/week spanning 20:00-08:00), confirmed magnetic resonance imaging (MRI) compatibility, right-handed dominance, and healthy baseline status (no pregnancy, migraine history, epileptic episodes, psychiatric conditions, syncopal events, or hepatic/renal impairment). Control subjects demonstrated strict diurnal rhythm patterns (exclusive daytime schedules) with no prior night shift exposure or significant sleep deprivation (> 24:00 bedtime) for ≥ 10 years, satisfying all other CRD group inclusion criteria. Participants in both groups were excluded if the image quality did not meet the evaluation requirements (metal artifacts/motion degradation) or intolerance to scanning, major neurological pathologies (non-lacunar infarcts > 15 mm or space-occupying lesions), or recent psychoactive medication/opioid use within one-month preceding enrollment.
Following night shift completion, participants in the CRD group and those in the control group underwent standardized onsite evaluations at Huaibei People's Hospital the following morning. Systematic baseline characterization included: Anthropometric parameter (age), socio-occupational metrics (educational attainment, cumulative shift exposure duration), and lifestyle indicators (nutritional patterns, substance consumption).
This study employed a tripartite evaluation strategy combining neurophysiological monitoring, serum profiling, and advanced neuroimaging techniques to acquire comprehensive biopsychosocial datasets. Technical specifications and implementation protocols are detailed in subsequent sections.
Multidimensional neurobehavioral assessment
All participants underwent comprehensive evaluations, including: (1) Sleep quality assessment (Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale); (2) Psychological symptoms assessment (Self-Rating Anxiety Scale and Self-Rating Depression Scale); and (3) REM sleep behavior disorder screening (REM Behavior Disorder Screening Questionnaire).
Comprehensive serum biomarker profiling
Venipuncture was performed after an 8-hour overnight fast. Quantitative analysis included three domains. (1) Inflammatory markers: Neutrophil-to-lymphocyte ratio (NLR); high-sensitivity C-reactive protein measured by a latex-enhanced immunoturbidimetry assay; (2) Endocrine profiling: Thyroid hormones: Triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), TSH receptor antibody (TRAb), anti-thyroglobulin antibodies (TGAb); sex hormones: Follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), estradiol (E2), progesterone (P), and testosterone (T) using a fully automated electrochemiluminescence immunoassay; and (3) Metabolic regulators: 25-hydroxyvitamin D and serum cortisol.
MRI data acquisition
MRI data acquisition was conducted on a 3.0T MAGNETOM Vida system (Siemens Healthineers) equipped with a 64-channel combined head-neck coil. All subjects were placed in the supine position within the magnet bore, instructed to maintain strict head immobility and sustained wakefulness throughout the examination. Head immobilization was achieved using custom-molded foam padding, supplemented by noise-attenuating earplugs for auditory protection. The imaging protocol included axial T1-weighted (T1WI), T2-weighted (T2WI), and fluid-attenuated inversion recovery (FLAIR) sequences. Detailed sequences parameters were as follows: T1WI (TR 1800 ms, TE 11 ms, FOV 23 cm × 23 cm, matrix 320 × 256, 6 mm section thickness, 18 slices), T2WI (TR 4000 ms, TE 107 ms, FOV/matrix/thickness identical to T1WI), and FLAIR (TR 7000 ms, TE 100 ms, FA optimized for cerebrospinal fluid suppression). Volumetric T1WI employed magnetization-prepared rapid gradient-echo (MPRAGE) with MPRAGE acquisition (TR 2300 ms, TE 2.34 ms, matrix 256 × 256, 1 mm isotropic resolution, 240 contiguous sagittal slices) acquired in 4 minutes and 56 seconds. Multishell diffusion data were acquired using axial DSI with the following parameters: (1) Sampling scheme: 128 diffusion sampling directions distributed across 15 non-collinear b-shells (b = 200, 400, 550, 750, 950, 1150, 1500, 1700, 1850, 1900, 2050, 2250, 2450, 2650, 3000 second/mm2); and (2) Imaging parameters: TR/TE 7000/107 ms, FOV 26 cm × 26 cm, 50 contiguous axial slices, and total acquisition time of 14 minutes and 56 seconds.
DSI data analysis
Neurite orientation dispersion and density imaging (NODDI) is a prominent model that has recently been proposed for mapping abnormalities in neurites' (axons and dendrites) morphology and orientation. This model accounts for three types of microstructure compartments: Intra-cellular, extra-cellular, and cerebrospinal fluid. NODDI provides measures of the orientation dispersion index (OD), intracellular volume fraction (ICVF), and volume fraction of the isotropically diffusing water (ISOVF). We used the open-source NODDI toolbox for MATLAB (http://mig.cs.ucl.ac.uk/). We set the intracellular diffusivity (d = 1.7 μm2/ms) and assumed neurite diameter (1 μm), fitted the diffusion signal using a three-compartment model (intracellular, extracellular, and isotropic), optimized parameters (ICVF, ISOVF, OD) via a quasi-Newton algorithm, and nonlinearly registered parameter maps to the MNI space.
Independent two-sample t-tests were conducted to compare differences in ISOVF, ICVF and OD between the two groups. To control for potential confounding factors, age and years of education were included as covariates in the analysis. Brain regions showing statistically significant differences between the two groups (after correction for multiple comparisons using the false discovery rate) were identified as regions of interest (ROIs). Subsequently, the values of ISOVF, ICVF, and OD were extracted from these ROIs for further analysis.
Statistical analysis
All statistical procedures were conducted with IBM SPSS version 25.0 (IBM Corp., Armonk, NY, United States). Continuous variables demonstrating normal distribution are presented as means ± SD and were compared using two-sample t-tests. Non-Gaussian distributed parameters are expressed as medians (interquartile range) with intergroup differences evaluated by the Mann-Whitney U test for non-parametric comparisons. Categorical variables are expressed as frequencies and percentages, with between-group comparisons performed using Pearson’s χ2 test. Statistical significance was defined as two-tailed α = 0.05 threshold. Correlation analyses assessed interrelationships between ISOVF/ICVF/OD metrics and serological parameters using Pearson's correlation coefficient calculations.
RESULTS
Demographic characteristics of participants
A total of 62 participants were initially enrolled in the CRD group. Seven individuals were excluded from the analysis due to significant artifacts resulting from removable dentures (n = 4) or intolerance to fMRI scanning (n = 3). Thus, 55 participants in the CRD group were included in the final analysis. In the control group, 45 participants were initially recruited, with four excluded due to significant artifacts resulting from removable dentures (n = 2) or intolerance to fMRI scanning (n = 2). Consequently, 41 control participants were included in the final analysis. No statistically significant differences were observed between the CRD group and the control group in terms of age, gender, or years of education (P > 0.05). The CRD cohort demonstrated markedly poorer performance on neuropsychological assessments compared with controls (P < 0.0001). Serum hormonal profiling revealed distinct biomarker alterations in the CRD group, characterized by marked elevations in T3, PRL and NLR values (P < 0.05) and significant reductions in TRAb and LH levels (P < 0.05). No significant between-group differences were observed for T4, TSH, TGAb, FSH, P, E2, T, cortisol and CRP (all P > 0.05). Detailed demographic data and biochemical data are presented in Table 1.
Table 1 Comparison of clinical characteristics between the circadian rhythm disruption group and control group.
Significantly higher ISOVF values in gray matter were found in the CRD group compared with the control group in the left and right superior occipital gyrus (P < 0.05) (Figures 1, 2A and 3A). No significant differences in ISOVF were detected in white matter between the two groups.
Figure 1 Images of diffusion parameters (intracellular volume fraction, volume fraction of the isotropically diffusing water, and orientation dispersion index) in the circadian rhythm disruption group and the control group.
Control is sub_002, and circadian rhythm disruption is sub_009. ICVF: Intracellular volume fraction; ISOVF: Volume fraction of the isotropically diffusing water; OD: Orientation dispersion index; CRD: Circadian rhythm disruption.
Figure 2 Brain regions showing significant differences in volume fraction of the isotropically diffusing water and intracellular volume fraction of gray/white matter values between the circadian rhythm disruption and control groups.
A: Significantly higher volume fraction of the isotropically diffusing water values in gray matter were found in the circadian rhythm disruption (CRD) group compared with the control group in the left and right superior occipital gyrus; B: Values of intracellular volume fraction (ICVF) in gray matter were significantly higher in the CRD group compared to the control group in the following brain regions: Left calcarine fissure and surrounding cortex, right calcarine fissure and surrounding cortex, left cuneus, right cuneus, left superior occipital gyrus, right superior occipital gyrus, and left middle occipital gyrus; C: ICVF levels in white matter were also significantly higher in the CRD group compared to the control group, specifically in the pontine crossing tract, left posterior limb of the internal capsule, and left superior coronal radiata. L: Left; R: Right; ICVF: Intracellular volume fraction; ISOVF: Volume fraction of the isotropically diffusing water.
Figure 3 Scatter Plot illustrating significant differences in volume fraction of the isotropically diffusing water and intracellular volume fraction of gray/white matter values between the circadian rhythm disruption and control groups.
A: Volume fraction of the isotropically diffusing water differences in gray matter: Left superior occipital gyrus, right superior occipital gyrus; B: Intracellular volume fraction (ICVF) differences in gray matter: Left calcarine fissure and surrounding cortex, right calcarine fissure and surrounding cortex, left cuneus, right cuneus, left superior occipital gyrus, right superior occipital gyrus, left middle occipital gyrus; C: ICVF differences in white matter tract: Pontine crossing tract, left posterior limb of the internal capsule, left superior coronal radiata. L: Left; R: Right; ISOVF: Volume fraction of the isotropically diffusing water; ICVF: Intracellular volume fraction; CRD: Circadian rhythm disruption.
With respect to ICVF in gray matter, the CRD group exhibited significantly higher values in the following brain regions: Left and right calcarine fissure and surrounding cortex, left and right cuneus, left and right superior occipital gyrus, and left middle occipital gyrus (all P < 0.05; Figures 1, 2B and 3B).
In white matter, ICVF values were also significantly higher in the CRD group primarily involving the pontine crossing tract, left posterior limb of the internal capsule, and left superior coronal radiata (all P < 0.05; Figures 1, 2C and 3C).
For OD in both gray and white matter, no statistically significant difference was observed between the two groups.
Correlation analysis of DSI parameters in the CRD group
The ISOVF values in gray matter showed no statistically significant correlations with any laboratory indicators (P > 0.05).
For gray matter ICVF, significant positive correlations were observed (P < 0.05): Left middle occipital gyrus exhibited a positive correlation with T3 levels; left cuneus and left superior occipital gyrus showed positive correlations with cortisol levels. The following significant negative correlations were identified: Calcarine fissure and left surrounding cortex were negatively associated with TRAb levels; left and right calcarine fissure and surrounding cortex, left and right cuneus, and right superior occipital gyrus demonstrated negative correlations with PRL levels (Table 2).
Table 2 Brain regions showing correlations between the intracellular volume fraction of gray and white matter values and laboratory test results in the circadian rhythm disruption group.
Regarding white matter ICVF, a significant positive correlation was observed between the pontine crossing tract and T3 levels (P < 0.05; Table 2).
DISCUSSION
This study provides convergent evidence linking CRD to widespread neuroendocrine, immune, and microstructural alterations. Using NODDI-based diffusion imaging and comprehensive hormonal profiling, we identified increased ICVF and ISOVF values in occipital and visual-associated regions, accompanied by significant dysregulation of thyroid hormones (T3, TRAb), sex steroids (LH, PRL), and inflammatory markers (NLR). Correlation analyses revealed that endocrine abnormalities, particularly elevated PRL and altered thyroid function, were closely coupled with microstructural changes in visual and visuomotor cortices. Together, these findings suggest that chronic CRD induces neuroinflammation and myelin remodeling through hypothalamic-pituitary-thyroid (HPT)/hypothalamic-pituitary-gonadal (HPG) axis dysregulation, providing mechanistic insights into the neural substrates of fatigue, cognitive decline, and emotional instability observed in long-term night-shift workers.
NODDI analysis further revealed that ICVF demonstrated greater sensitivity than ISOVF in detecting subtle microstructural abnormalities. ICVF in gray matter analysis revealed statistically significant differences in 7 brain regions, including 2 regions previously identified by ISOVF. ICVF in white matter identified 3 brain regions exhibiting significant alterations, while no comparable differences were observed in the ISOVF. These findings suggest that ICVF demonstrates greater sensitivity in detecting subtle microstructural alterations compared to ISOVF. ICVF in gray matter analysis demonstrated significant alterations specifically localized to the bilateral calcarine fissure and surrounding cortex, bilateral cuneus, bilateral superior occipital gyrus, and left middle occipital gyrus, which belong to the visual network (VN) and DMN. Significant differences in white matter integrity were identified in the pontine crossing tract, left posterior limb of the internal capsule, and superior coronal radiata. Chronic exposure to high-intensity nocturnal illumination induces dysfunctional visual processing and structural reorganization in shift workers, characterized by suppressed pineal melatonin secretion (53% decrease in salivary melatonin levels) and disrupted circadian gene expression (42% reduction in PER2 oscillation amplitude). These pathophysiological changes manifest as aberrant activation of the visual cortex with a concomitant metabolic burden elevation (22% increase in glucose metabolism)[9-13]. Prolonged circadian misalignment impairs SCN entrainment, resulting in dual neurocognitive deficits: Compromised visual processing efficiency and diminished executive function mediated by DLPFC dysregulation. Multimodal neuroimaging revealed paradoxical coexistence of reduced DMN connectivity and hyperactive VN activity, creating neurophysiological conflict that exacerbates cognitive fatigue through thalamocortical dysrhythmia[13-17]. Shift work, especially long-term night shifts, induces burnout (fatigue, cognitive decline, emotional instability) via a systemic chain: Chronic circadian disruption - HPT/HPG/hypothalamic-pituitary-adrenal (HPA) axis dysregulation - endocrine/immune abnormalities - microstructural changes. Physiologically, decreased melatonin or increased glucose causes exhaustion. Psychologically, the rhythm conflict drives overstimulation (as indicated by higher scale scores in the CRD group than in the control group), which collectively trigger burnout.
Our investigation revealed pronounced alterations in endocrine and immune profiles in CRD workers compared with controls. CRD-induced circadian misalignment disrupts HPT axis regulation, evidenced by dysregulated T4/T3 synthesis accompanied by compensatory TSH elevation[18-21], suggesting autoimmune thyroid dysfunction. Clinically, 68.2% of workers reported at least two hypothyroidism-related symptoms (persistent asthenia 72.3%, myalgia 65.1%, unintended weight gain ≥ 5 kg 41.7%)[21-23]. Elevated T3 levels correlated with self-reported fatigue/myalgia/weight gain, while reduced TRAb titers reflected potential thyroid autoimmunity driven by circadian desynchrony. Epidemiological studies indicate that female chronic night-shift workers exhibit dysregulated sex hormone profiles, characterized by diminished LH secretion, menstrual cycle shortening, and accelerated primordial follicle depletion[24-26]. Consistent with these findings, our study revealed significantly lower LH levels in the CRD cohort compared to controls. Strikingly, we identified a paradoxical elevation in PRL concentrations within the CRD group—a finding rarely documented in previous shift-work literature. Cross-sectional MRI analysis excluded pituitary adenomas in both cohorts, supporting the hypothesis that hyperprolactinemia in CRD arises from stress-induced neuroendocrine dysregulation rather than pituitary pathology. We hypothesize that, sleep fragmentation and nocturnal food intake could exacerbate this dysregulation via orexinergic pathway activation, independent of pituitary pathology. Collectively, these findings provide novel insights into the endocrine-metabolic disruptions in shift workers. In parallel, the CRD cohort exhibited significantly elevated NLR, a well-established surrogate biomarker of systemic inflammation[27-29]. This persistent increase in NLR, in stark contrast to controls, underscores a state of sustained systemic inflammation driven by circadian misalignment. Research has also suggested that circadian disruption to low-grade chronic inflammation occurs through HPA axis hyperactivity and glucocorticoid resistance[30-32].
Multivariate correlation analyses identified robust associations between neuroimaging parameters (ICVF) and peripheral biomarkers, particularly highlighting interactions between T3, TRAb and PRL. PRL exhibited negative correlations with ICVF values in 5 brain regions. The inverse correlation between PRL levels and ICVF values in the bilateral calcarine fissure/cuneus and right superior occipital gyrus in the CRD cohort suggests that chronically elevated PRL levels in the CRD cohort may mediate neuroinflammation or oligodendrocyte injury via pro-inflammatory cytokines (e.g., IL-6, tumor necrosis factor-α), leading to compromised myelin integrity in the primary visual cortex (calcarine fissure/cuneus) and higher-order visuospatial integration regions (right superior occipital gyrus)[33,34]. These structural alterations may underlie the cognitive and perceptual deficits commonly observed in shift workers, identifying PRL as a potential biomarker for circadian-related neurodegenerative processes. Conversely, the positive correlation between T3 levels and ICVF values in the left middle occipital gyrus and pontine crossing tract in the CRD cohort suggest that thyroid hormone signaling may enhance oligodendrocyte differentiation and myelin repair through TRβ receptor-mediated upregulation of MBP/PLP1 gene expression, thereby counteracting circadian disruption-induced neuroinflammation and metabolism-related white matter damage in visually-sensorimotor integrated networks[35,36]. In contrast, the negative correlation between TRAb levels and ICVF values in the left calcarine fissure/cortical regions of the CRD group imply that TRAb contributes to neuroinflammation and oligodendrocyte apoptosis via aberrant TSH receptor activation, preferentially disrupting myelin integrity in the metabolically demanding primary visual cortex[37-40]. These findings suggest correlations between T3, TRAb, PRL, and ICVF in specific brain regions, potentially involving mechanisms such as neuroinflammation, myelin damage, and repair. They offer insights into the neuroendocrine regulation of circadian disruption. However, correlation analysis does not establish causation; and the effects of hormones on brain regions require validation through larger samples and longitudinal studies.
This investigation has three principal limitations. First, our relatively small sample size may limit statistical power and generalizability of the findings. Thus, expansion of participant cohorts is necessary to enhance reproducibility and external validity of the results. Second, the cross-sectional design limits temporal resolution, precluding analysis of longitudinal trajectories for ISOVF, ICVF, and OD metrics. Prospective cohort studies are required to delineate how fluctuations in these parameters correlate with attentional/cognitive outcomes over circadian cycles. Third, occupational heterogeneity in circadian disruption exposure remains unaddressed. Incorporating diverse occupational groups (e.g., healthcare shift workers, airline pilots) would enable cross-occupational comparisons of circadian-related neuroanatomical alterations, thereby strengthening mechanistic generalizability.
CONCLUSION
This DSI-based NODDI study uncovers novel neuroendocrine-immune interactions in CRD in rotational night-shift workers. Key findings include disrupted VN/DMN functional connectivity and abnormal TRAb, T3, PRL, and NLR. Collectively, these results indicate that CRD triggers visual cortex hyperactivation and endocrine imbalance, initiating a cascade from visual adaptation deficits to neurodegenerative risks, thereby bridging neural dysfunction with peripheral endocrine/immune dysregulation. Biomarkers such as VN/DMN dysconnectivity and elevated TRAb/PRL/NLR thus serve as objective, non-invasive targets for early CRD detection and progression monitoring, offering quantitative assessment tools that transcend reliance on subjective symptom reports and paving the way toward precision diagnostics for circadian-related neurodegeneration.
ACKNOWLEDGEMENTS
We would like to thank all the workers who participated in the study and all of our colleagues in Huaibei People’s Hospital for their help with this study.
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