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Numerous studies have investigated the impacts of common types of chronic pain (CP) on patients’ cognitive function and observed that CP was associated with later dementia. More recently, there is a growing recognition that CP conditions frequently coexist at multiple body sites and may bring more burdens on patients’ overall health. However, whether and how multisite CP (MCP) contributes to an increased risk of dementia, compared to single-site CP (SCP) and pain-free (PF), is largely unclear. In the current study, utilizing the UK Biobank cohort, we first investigated dementia risk in individuals (n = 354,943) with different numbers of coexisting CP sites using Cox proportional hazards regression models. We then applied generalized additive models to investigate whether MCP leads to excessive deterioration of participants’ (n = 19,116) cognition and brain structure. We found that individuals with MCP were associated with significantly higher dementia risk, broader and faster cognitive impairment, and greater hippocampal atrophy than both PF individuals and those with SCP. Moreover, the detrimental effects of MCP on dementia risk and hippocampal volume aggravated along with the number of coexisting CP sites. Mediation analyses further revealed that the decline of fluid intelligence in MCP individuals was partially mediated by hippocampal atrophy. Our results suggested that cognitive decline and hippocampal atrophy interact biologically and may underlie the increased risk of dementia associated with MCP.

Previous coronavirus pandemics were associated elevated post-traumatic stress symptoms (PTSS), but the self-report and neurological basis of PTSS in patients who survived coronavirus disease 2019 (COVID-19) are largely unknown. We conducted a two-session study to record PTSS in the COVID-19 survivors discharged from hospitals for a short (i.e., about 3 months, Session 1) to a medium period (i.e., about 6 months, Session 2), as well as brain imaging data in Session 2. The control groups were non-COVID-19 locals. Session 1 was completed for 126 COVID-19 survivors and 126 controls. Session 2 was completed for 47 COVID-19 survivors and 43 controls. The total score of post-traumatic stress disorder (PTSD) checklist for DSM-5 (PCL-5) score was significantly higher in COVID-19 survivors compared with controls in both sessions. The PCL-5 score in COVID-19 survivors was positively correlated with the duration after discharge (r = 0.27, p = 0.003 for Session 1), and increased by 20% from Session 1 to Session 2 for the survivors who participated both sessions. The increase was positively correlated with individual’s test-retest duration (r = 0.46, p = 0.03). Brain structural volume and functional activity in bilateral hippocampus and amygdala were significantly larger in COVID-19 survivors compared with controls. However, the volumes of the left hippocampus and amygdala were negatively correlated with the PCL-5 score for the COVID-19 survivors. Our study suggests that COVID-19 survivors might face possible PTSS deteriorations, and highlights the importance of monitoring mental wellness of COVID-19 survivors.

Thalamocortical dysrhythmia is a key pathology of chronic neuropathic pain, but few studies have investigated thalamocortical networks in chronic low back pain (cLBP) given its non-specific etiology and complexity. Using fMRI, we propose an analytical pipeline to identify abnormal thalamocortical network dynamics in cLBP patients and validate the findings in two independent cohorts. We first identify two reoccurring dynamic connectivity states and their associations with chronic and temporary pain. Further analyses show that cLBP patients have abnormal connectivity between the ventral lateral/posterolateral nucleus (VL/VPL) and postcentral gyrus (PoCG) and between the dorsal/ventral medial nucleus and insula in the less frequent connectivity state, and temporary pain exacerbation alters connectivity between the VL/VPL and PoCG and the default mode network in the more frequent connectivity state. These results extend current findings on thalamocortical dysfunction and dysrhythmia in chronic pain and demonstrate that cLBP pathophysiology and clinical pain intensity are associated with distinct thalamocortical network dynamics. Thalamocortical dysrhythmia is a key pathology of chronic pain. Here, the authors propose an analytical pipeline to study dynamic fMRI brain networks and demonstrate that chronic low back pain pathophysiology and clinical pain intensity are associated with distinct thalamocortical network dynamics.

Pain perception varies widely among individuals due to the varying degrees of biological, psychological, and social factors. Notably, sex differences in pain sensitivity have been consistently observed in various experimental and clinical investigations. However, the neuropsychological mechanism underlying sex differences in pain sensitivity remains unclear. To address this issue, we quantified pain sensitivity (i.e., pain threshold and tolerance) using the cold pressure test and negative emotions (i.e., pain-related fear, pain-related anxiety, trait anxiety, and depression) using well-established questionnaires and collected magnetic resonance imaging (MRI) data (i.e., high-resolution T1 structural images and resting-state functional images) from 450 healthy subjects. We observed that, as compared to males, females exhibited lower pain threshold and tolerance. Notably, sex differences in pain sensitivity were mediated by pain-related fear and anxiety. Specifically, pain-related fear and anxiety were the complementary mediators of the relationship between sex and pain threshold, and they were the indirect-only mediators of the relationship between sex and pain tolerance. Besides, structural MRI data revealed that the amygdala subnuclei (i.e., the lateral and basal nuclei in the left hemisphere) volumes were the complementary mediators of the relationship between sex and pain-related fear, which further influenced pain sensitivity. Altogether, our results provided a comprehensive picture of how negative emotions (especially pain-related negative emotions) and related brain structures (especially the amygdala) contribute to sex differences in pain sensitivity. These results deepen our understanding of the neuropsychological underpinnings of sex differences in pain sensitivity, which is important to tailor a personalized method for treating pain according to sex and the level of pain-related negative emotions for patients with painful conditions.

Background Migraine is a neurological disease with a significant genetic component and is characterized by recurrent and prolonged episodes of headache. Previous epidemiological studies have reported a higher risk of dementia in migraine patients. Neuroimaging studies have also shown structural brain atrophy in regions that are common to migraine and dementia. However, these studies are observational and cannot establish causality. The present study aims to explore the genetic causal relationship between migraine and dementia, as well as the mediation roles of brain structural changes in this association using Mendelian randomization (MR). Methods We collected the genome-wide association study (GWAS) summary statistics of migraine and its two subtypes, as well as four common types of dementia, including Alzheimer’s disease (AD), vascular dementia, frontotemporal dementia, and Lewy body dementia. In addition, we collected the GWAS summary statistics of seven longitudinal brain measures that characterize brain structural alterations with age. Using these GWAS, we performed Two-sample MR analyses to investigate the causal effects of migraine and its two subtypes on dementia and brain structural changes. To explore the possible mediation of brain structural changes between migraine and dementia, we conducted a two-step MR mediation analysis. Results The MR analysis demonstrated a significant association between genetically predicted migraine and an increased risk of AD (OR = 1.097, 95% CI = [1.040, 1.158], p  = 7.03 × 10 − 4 ). Moreover, migraine significantly accelerated annual atrophy of the total cortical surface area (-65.588 cm 2 per year, 95% CI = [-103.112, -28.064], p  = 6.13 × 10 − 4 ) and thalamic volume (-9.507 cm 3 per year, 95% CI = [-15.512, -3.502], p  = 1.91 × 10 − 3 ). The migraine without aura (MO) subtype increased the risk of AD (OR = 1.091, 95% CI = [1.059, 1.123], p  = 6.95 × 10 − 9 ) and accelerated annual atrophy of the total cortical surface area (-31.401 cm 2 per year, 95% CI = [-43.990, -18.811], p  = 1.02 × 10 − 6 ). The two-step MR mediation analysis revealed that thalamic atrophy partly mediated the causal effect of migraine on AD, accounting for 28.2% of the total effect. Discussion This comprehensive MR study provided genetic evidence for the causal effect of migraine on AD and identified longitudinal thalamic atrophy as a potential mediator in this association. These findings may inform brain intervention targets to prevent AD risk in migraine patients.

Human pain perception is not solely driven by sensory input but is dynamically modulated by what we expect to feel and how confident we are in those expectations. Yet, the temporal mechanisms through which evolving expectations shape pain remain poorly understood. Here, we combined a probabilistic cueing paradigm with computational modeling and EEG to dissociate two core components of expectation: strength (a recency-weighted estimate of predicted pain) and precision (the inverse variability of recent predictions). Trial-wise strength estimates closely tracked subjective expectations and outperformed static cue labels, validating the model’s psychological relevance. Expectation strength and precision exerted dissociable effects on pain processing: strength enhanced, whereas precision suppressed, pain-evoked responses. Critically, anticipatory α-band activity mediated these effects via distinct topographical patterns—expectation strength reduced fronto-central α power (reflecting heightened vigilance), while precision increased contralateral sensorimotor α-synchronization (supporting sensory gating). Source-level mediation analyses identified a right-lateralized dorsolateral prefrontal–sensorimotor cortices (DLPFC-SM1) integrating both components, with strength-specific engagement of the medial prefrontal cortex (mPFC). These effects were supported by Bayesian inference and pooled mega-analyses, underscoring their robustness. Together, these findings highlight cortical α-oscillations as dual-control mechanisms for predictive integration, with DLPFC–SM1 as a shared expectation hub and mPFC as a strength-specific node. By moving beyond static cue-based models, this framework captures the adaptive dynamics of expectation and provides a neurocomputational foundation for targeted interventions in chronic pain.

Placebo and nocebo effects are salubrious benefits and negative outcomes attributable to non-specific symbolic components. Leveraging advanced experimental and analytical approaches, recent studies have elucidated complicated neural mechanisms that may serve as a solid basis for harnessing the powerful self-healing and self-harming capacities and applying these findings to improve medical practice and minimize the unintended exacerbation of symptoms in medical practice. We review advances in employing psychosocial, pharmacological, and neuromodulation approaches to modulate/harness placebo and nocebo effects. While these approaches show promising potential, translating these research findings into clinical settings still requires careful methodological, technical, and ethical considerations.

BackgroundDysfunction of the thalamocortical connectivity network is thought to underlie the pathophysiology of the migraine. This current study aimed to explore the thalamocortical connectivity changes during 4 weeks of continuous transcutaneous vagus nerve stimulation (taVNS) treatment on migraine patients.Methods70 migraine patients were recruited and randomized in an equal ratio to receive real taVNS or sham taVNS treatments for 4 weeks. Resting-state functional MRI was collected before and after treatment. The thalamus was parceled into functional regions of interest (ROIs) on the basis of six priori-defined cortical ROIs covering the entire cortex. Seed-based functional connectivity analysis between each thalamic subregion and the whole brain was further compared across groups after treatment.ResultsOf the 59 patients that finished the study, those in the taVNS group had significantly reduced number of migraine days, pain intensity and migraine attack times after 4 weeks of treatment compared with the sham taVNS. Functional connectivity analysis revealed that taVNS can increase the connectivity between the motor-related thalamus subregion and anterior cingulate cortex/medial prefrontal cortex, and decrease the connectivity between occipital cortex-related thalamus subregion and postcentral gyrus/precuneus.ConclusionOur findings suggest that taVNS can relieve the symptoms of headache as well as modulate the thalamocortical circuits in migraine patients. The results provide insights into the neural mechanism of taVNS and reveal potential therapeutic targets for migraine patients.

Pain is a multidimensional subjective experience with biological, psychological, and social factors. Whereas acute pain can be a warning signal for the body to avoid excessive injury, long-term and ongoing pain may be developed as chronic pain. There are more than 100 million people in China living with chronic pain, which has raised a huge socioeconomic burden. Studying the mechanisms of pain and developing effective analgesia approaches are important for basic and clinical research. Recently, with the development of brain imaging and data analytical approaches, the neural mechanisms of chronic pain have been widely studied. In the first part of this review, we briefly introduced the magnetic resonance imaging and conventional analytical approaches for brain imaging data. Then, we reviewed brain alterations caused by several chronic pain disorders, including localized and widespread primary pain, primary headaches and orofacial pain, musculoskeletal pain, and neuropathic pain, and present meta-analytical results to show brain regions associated with the pathophysiology of chronic pain. Next, we reviewed brain changes induced by pain interventions, such as pharmacotherapy, neuromodulation, and acupuncture. Lastly, we reviewed emerging studies that combined advanced machine learning and neuroimaging techniques to identify diagnostic, prognostic, and predictive biomarkers in chronic pain patients.

Both attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are neurodevelopmental disorders with a high prevalence. They are often comorbid and both exhibit abnormalities in sustained attention, yet common and distinct neural patterns of ASD and ADHD remain unidentified.AimsTo investigate shared and distinct functional connectivity patterns in a relatively large sample of boys (7- to 15-year-olds) with ADHD, ASD and typical development matched by age, gender and IQ. We applied machine learning techniques to investigate patterns of surface-based brain resting-state connectivity in 86 boys with ASD, 83 boys with ADHD and 125 boys with typical development. We observed increased functional connectivity within the limbic and somatomotor networks in boys with ASD compared with boys with typical development. We also observed increased functional connectivity within the limbic, visual, default mode, somatomotor, dorsal attention, frontoparietal and ventral attention networks in boys with ADHD compared with boys with ASD. In addition, using a machine learning approach, we were able to discriminate typical development from ASD, typical development from ADHD and ASD from ADHD with accuracy rates of 76.3%, 84.1%, and 79.3%, respectively. Our results may shed new light on the underlying mechanisms of ASD and ADHD and facilitate the development of new diagnostic methods for these disorders.Declaration of interestJ.K. holds equity in a startup company, MNT.