Understanding neurobiological mechanisms underlying changes in behavior and neural activity caused by early life stress (ELS) is essential for improving these adverse outcomes in individuals. ELS incited by exposure to maternal separation (MS) can be defined as a form of social pain, but little is known about the neural mechanism in adolescents with ELS-induced pain sensitization. Employing an MS-induced ELS paradigm in mice, we reported here that both male and female MS mice aged 1-2 months exhibited mechanical and thermal hyperalgesia using paw-withdrawal and hot/cold plate tests. The increased high gamma (γhigh) oscillations accompanied by the activation of parvalbumin-positive interneurons (PVINs) in the anterior insular cortex (AIC), but not the anterior cingulate cortex (ACC), were shown in MS mice. Moreover, ACC-driven AIC connectivity was enhanced in MS mice, characterized by amplified phase coherence in the delta (δ) and theta (θ) bands and an escalation in the coupling of the ACC θ phase and AIC γ amplitude. Chemogenetic inactivation of AIC PVINs relieved hyperalgesia and altered the ACC-AIC connectivity in MS mice. The observed increase in δ-θ synchronization and PVIN activation in the ACC-AIC circuit indicates this pathway is a therapeutic target for ELS-induced hyperalgesia.

To investigate whether functional radiomic features in bilateral hippocampi can identify the cognitively impaired patients from low-back-related leg pain (LBLP).

For this retrospective study, a total of 95 clinically definite LBLP patients (40 cognitively impaired patients and 45 cognitively preserved patients) were included, and all patients underwent functional MRI and clinical assessments. After calculating the amplitude of low-frequency fluctuations (ALFF), regional homogeneity (ReHo), voxel-mirrored homotopic connectivity (VMHC) and degree centrality (DC) imaging, the radiomic features (n = 819) of bilateral hippocampi were extracted from these images, respectively. After feature selection, machine learning models were trained. Finally, we further analyzed the relationship between the hippocampal functional radiomic features and clinical measures, to explore the clinical significance of these features.

The combined radiomic features model logistic regression algorithm superior performance in distinguishing cognitively impaired patients from LBLP (AUC = 0.970, accuracy = 92.3%, sensitivity = 92.3%, specificity = 92.3%) compared to the other models. Additionally, radiomic wavelet features were correlated with Montreal Cognitive Assessment (MoCA) and Hamilton Anxiety Scale, present pain intensity scores in cognitively impaired LBLP patients (P < 0.05, with Bonferroni correction).

Hippocampal functional radiomic features are valuable for diagnosing cognitively impaired patients from LBLP.

Chronic pain is a multidimensional experience that not only involves persistent nociception but is also frequently accompanied by significant emotional disorders, such as anxiety and depression, which complicate its management and amplify its impact. This review provides an in-depth exploration of the neurobiological mechanisms underlying the comorbidity of chronic pain and emotional disturbances. Key areas of focus include the dysregulation of major neurotransmitter systems (serotonin, gamma-aminobutyric acid, and glutamate) and the resulting functional remodeling of critical neural circuits implicated in pain processing, emotional regulation, and reward. Given the contribution of neuroimmune mechanisms to pain chronicity and mood disorders, we further conducted an in-depth investigation into the role of neuroimmune factors, including resident immune cells, infiltrating immune cells, and the release of inflammatory mediators. This review further discusses current therapeutic strategies, encompassing pharmacological interventions, neuromodulation, and integrative approaches, and emphasizes the necessity of targeted treatments that address both pain and emotional components. Finally, it identifies gaps in the current understanding and outlines future research directions aimed at elucidating the complex interplay between chronic pain and emotional disorders, thereby laying the foundation for more effective and holistic treatment paradigms.

Cognitive impairment is a common comorbidity of chronic pain, significantly disrupting patients' quality of life. Despite this comorbidity being clinically recognized, the underlying neuropathological mechanisms remain unclear. Recent preclinical studies have focused on the fundamental mechanisms underlying the coexistence of chronic pain and cognitive decline. Pain chronification is accompanied by structural and functional changes in the neural substrate of cognition. Based on the developments in electrophysiology and optogenetics/chemogenetics, we summarized the relevant neural circuits involved in pain-induced cognitive impairment, as well as changes in connectivity and function in brain regions. We then present the cellular and molecular alternations related to pain-induced cognitive impairment in preclinical studies, mainly including modifications in neuronal excitability and structure, synaptic plasticity, glial cells and cytokines, neurotransmitters and other neurochemicals, and the gut-brain axis. Finally, we also discussed the potential treatment strategies and future research directions.

It is known that humans and rodents are capable of transmitting stress to their naive partners via social interaction. However, a comprehensive understanding of transmitted stress, which may differ from authentic stress, thus revealing unique neural mechanisms of social interaction resulting from transmitted stress and the associated anxiety, is missing. We used, in the present study, maternal separation (MS) as a stress model to investigate whether MS causes abnormal behavior in adolescence. A key concern in the analysis of stress transmission is whether the littermates of MS mice who only witness MS stress ("Partners") exhibit behavioral abnormalities similar to those of MS mice themselves. Of special interest is the establishment of the neural mechanisms underlying transmitted stress and authentic stress. The results show that Partners, similar to MS mice, exhibit anxiety-like behavior and hyperalgesia after witnessing littermates being subjected to early-life repetitive MS. Electrophysiological analysis revealed that mice subjected to MS demonstrate a reduction in both the excitatory and inhibitory synaptic activities of parvalbumin interneurons (PVINs) in the anterior cingulate cortex (ACC). However, Partners differed from MS mice in showing an increase in the number and excitability of GABAergic PVINs in the ACC and in the ability of chemogenetic PVIN inactivation to eliminate abnormal behavior. Furthermore, the social transfer of anxiety-like behavior required intact olfactory, but not visual, perception. This study suggests a functional involvement of ACC PVINs in mediating the distinct neural basis of transmitted anxiety.SIGNIFICANCE STATEMENT The anterior cingulate cortex (ACC) is a critical brain area in physical and social pain and contributes to the exhibition of abnormal behavior. ACC glutamatergic neurons have been shown to encode transmitted stress, but it remains unclear whether inhibitory ACC neurons also play a role. We evaluate, in this study, ACC neuronal, synaptic and network activities and uncover a critical role of parvalbumin interneurons (PVINs) in the expression of transmitted stress in adolescent mice who had witnessed MS of littermates in infancy. Furthermore, inactivation of ACC PVINs blocks transmitted stress. The results suggest that emotional contagion has a severe effect on brain function, and identify a potential target for the treatment of transmitted anxiety.

Cognitive impairment, one of the most prevalent complications of trigeminal neuralgia, is troubling for patients and clinicians due to limited therapeutic options. Curcumin shows antinociception and neuroprotection pharmacologically, suggesting that it may have therapeutic effect on this complication. This study aimed to investigate whether curcumin alleviates orofacial allodynia and improves cognitive impairment by regulating hippocampal CA1 region synaptic plasticity in trigeminal neuralgia.

A mouse model of trigeminal neuralgia was established by partially transecting the infraorbital nerve (pT-ION). Curcumin was administered by gavage twice daily for 14 days. Nociceptive thresholds were measured using the von Frey and acetone test, and the cognitive functions were evaluated using the Morris water maze test. Dendritic spines and synaptic ultrastructures in the hippocampal CA1 area were observed by Golgi staining and transmission electron microscopy.

Curcumin intervention increased the mechanical and cold pain thresholds of models. It decreased the escape latency and distance to the platform and increased the number of platform crossings and dwell time in the target quadrant of models, and improved spatial learning and memory deficits. Furthermore, it partially restored the disorder of the density and proportion of dendritic spines and the abnormal density and structure of synapses in the hippocampal CA1 region of models.

Curcumin alleviates abnormal orofacial pain and cognitive impairment in pT-ION mice by a mechanism that may be related to the synaptic plasticity of hippocampal CA1, suggesting that curcumin is a potential strategy for repairing cognitive dysfunction under long-term neuropathic pain conditions.

This study aimed to reveal the influence of emotional valence and sensory modality on neural activity in response to multimodal emotional stimuli using scalp EEG. In this study, 20 healthy participants completed the emotional multimodal stimulation experiment for three stimulus modalities (audio, visual, and audio-visual), all of which are from the same video source with two emotional components (pleasure or unpleasure), and EEG data were collected using six experimental conditions and one resting state. We analyzed power spectral density (PSD) and event-related potential (ERP) components in response to multimodal emotional stimuli, for spectral and temporal analysis. PSD results showed that the single modality (audio only/visual only) emotional stimulation PSD differed from multi-modality (audio-visual) in a wide brain and band range due to the changes in modality and not from the changes in emotional degree. The most pronounced N200-to-P300 potential shifts occurred in monomodal rather than multimodal emotional stimulations. This study suggests that emotional saliency and sensory processing efficiency perform a significant role in shaping neural activity during multimodal emotional stimulation, with the sensory modality being more influential in PSD. These findings contribute to our understanding of the neural mechanisms involved in multimodal emotional stimulation.

The absence of clinically objective methods to evaluate adenomyosis-associated pain and the poor understanding of its pathophysiology lead to treatment limitations. We conducted a resting-state functional magnetic resonance imaging study with 49 patients with pain-related adenomyosis and 30 pain-free controls to investigate brain morphological alterations and regional dysfunctions in patients with pain-related adenomyosis. These patients had significantly higher scores for anxiety and depression than the control group (p < 0.05). They also had a lower gray matter volume (GMV) in the bilateral insula, left angular gyrus, precuneus, left inferior temporal gyrus, and left postcentral gyrus (p < 0.05, AlphaSim corrected). Similarly, decreased voxel-mirrored homotopic connectivity was observed in the bilateral insula, posterior cingulate cortex, middle frontal gyrus, and postcentral gyrus in the adenomyosis patient group (p < 0.05, AlphaSim corrected). Regional homogeneity showed significant differences mainly in the bilateral cerebellum, left inferior frontal gyrus, medial prefrontal cortex, and posterior cingulate gyrus. Correlation analysis showed that the degree of depression in patients with adenomyosis was negatively correlated with the GMV of the left angular gyrus. The results show that these patients exhibited changes in multiple brain regions associated with pain as well as emotion perception and processing.