BackgroundPost-COVID-19 condition (PCC), commonly called long COVID, is a prevalent sequela of SARS-CoV-2 infection and can affect multiple organ systems. Cognitive dysfunction is one of the most common symptoms in PCC, with a prevalence of 22%. It can persist for years and significantly reduce patients’ quality of life. The brain network is the neural basis underlying human cognitive processes. Diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) studies have revealed that cognitive impairments across attention, memory, executive function, and language are associated with alterations in network characteristics for PCC. Currently, there is no accepted therapy for cognitive impairment in PCC. Acupuncture has the potential to improve cognitive deficits in PCC. This trial aims to investigate the effect of acupuncture on cognitive functions in patients with PCC, and to explore the underlying mechanism of its effects on cognition in this condition using DTI and fMRI.MethodsIn this three-armed, randomized controlled trial, 117 PCC patients with cognitive symptoms will be randomly assigned in a 1:1:1 ratio to verum acupuncture (VA), sham acupuncture (SA), or a waitlist control group. Participants in the VA and SA groups will receive three sessions of treatment per week for 8 weeks. The primary outcome measures are the changes in Addenbrooke’s Cognitive Examination-III (ACE-III) total score and phonemic fluency test score at week 8. The secondary outcome measures include the Digit Span Test (DST), Symbol Digit Modality Test (SDMT), Trail Making Test (TMT), Rey’s Auditory Verbal Learning Test (RAVLT), Rey-Osterrieth Complex Figure Test (RCFT), Stroop Color Word Test (SCWT), category fluency test, action fluency test, and Boston Naming Test (BNT-30), as well as global and regional topological measures of structural and functional brain networks constructed from DTI and fMRI data. Additionally, the Fatigue Severity Scale (FSS), the Generalized Anxiety Disorder-7 (GAD-7), the 24-item Hamilton Depression Scale (HAMD-24), and the MOS 36-item Short Form Health Survey (SF-36) will also be measured.DiscussionThe results of this study will reveal the effect of acupuncture treatment on cognitive functions for PCC and provide insights into the mechanisms by which acupuncture may improve cognition in PCC.Clinical trial registrationClinicalTrials.gov (www.clinicaltrials.gov), identifier: NCT07355751.

Aberrant microglial activation and impaired adult hippocampal neurogenesis play critical roles in the pathogenesis of depression. Although electroacupuncture (EA) has demonstrated clinical antidepressant efficacy, the underlying mechanisms by which it modulates microglial activity and promotes neurogenesis remain unclear. Male C57BL/6 J mice were subjected to chronic unpredictable mild stress (CUMS) for three weeks. Following this period, the mice were divided into groups receiving either EA at the Yintang (GV29) and Baihui (GV20) acupoints, imipramine (IMI) as a positive control, or no treatment (vehicle control) for an additional 3 weeks. To evaluate depressive-like behaviors, we conducted the sucrose preference test, forced swimming test, and tail suspension test. Anxiety-like behaviors were assessed using the open field test and elevated plus maze. We employed immunofluorescence, Golgi staining, Western blotting, and real-time quantitative PCR (qRT-PCR) to elucidate the effects of EA on microglia-driven hippocampal neurogenesis and BDNF signaling. Notably, loss-of-function experiments utilizing PLX5622 for microglial ablation and ANA-12 for TrkB blockade demonstrated the necessity of both microglia and BDNF signaling for the therapeutic efficacy of EA. EA treatment significantly alleviated CUMS-induced anxiodepressive behaviors. This behavioral recovery was associated with a phenotypic shift in microglia towards a pro-neurogenic state in the hippocampus. Importantly, microglia were essential for the therapeutic effects of EA, as evidenced by their ablation with PLX5622. Furthermore, EA enhanced neurogenesis by orchestrating a multi-step augmentation of BDNF signaling, which involved PKA activation, subsequent release from MeCP2-mediated transcriptional repression, and ultimately increased maturation of BDNF. Our findings demonstrate that EA exerts antidepressant effects by promoting a pro-neurogenic transformation of microglia. Mechanistically, these microglia enhance BDNF function via the PKA/MeCP2/BDNF pathway, thereby facilitating hippocampal neurogenesis and restoring synaptic plasticity, which collectively alleviate depressive symptoms.

Background:Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a common sequela following COVID-19. Although cognitive dysfunction is one of the most debilitating symptoms in ME/CFS, effective therapies are limited. Acupuncture is an important complementary and alternative therapy for ME/CFS and has been shown to have positive effects on cognitive dysfunction in other diseases. However, the effect and mechanism of acupuncture in treating cognitive dysfunction in post-COVID-19 ME/CFS(PCME/CFS) remain unclear. In this study, we designed a randomized controlled trial to evaluate the efficacy of acupuncture treatment in improving cognitive function in PCME/CFS and to investigate the neural mechanisms of acupuncture using multimodal magnetic resonance imaging (MRI) techniques. Methods:A total of 129 patients and 30 healthy controls (HCs) will be enrolled. The 129 patients with PCME/CFS will be randomly assigned in a 1:1:1 ratio to a verum acupuncture (VA), sham acupuncture (SA), or a waitlist control group. Participants in the VA and SA groups will receive three sessions of treatment per week for 8 weeks, while patients in the waitlist control group will be treated after the 8-week waiting period. The primary outcome is the change in the Symbol Digit Modalities Test (SDMT) score from baseline to week 8. The secondary outcome measures include changes from baseline to endpoint (week 8) in cognitive performance as assessed by the Digit Span Test (DST), Trail Making Test (TMT), Rey Auditory Verbal Learning Test (RAVLT), Rey-Osterrieth complex figure test (RCFT), Stroop Color and Word Test (SCWT), phonemic fluency test, category fluency test, action fluency test, and 30-item Boston Naming Test (BNT-30). In addition, changes in hippocampal metabolites and resting-state functional connectivity(RSFC) will be examined using 1H-magnetic resonance spectroscopy(1H-MRS) and functional MRI (fMRI), respectively. Moreover, the Multidimensional Fatigue Inventory (MFI-20), Pittsburgh Sleep Quality Index (PSQI), Generalized Anxiety Disorder 7-item scale (GAD-7), 24-item Hamilton Depression Scale (HAMD-24), and 36-Item Short Form Survey (SF-36) will also be assessed at baseline and week 8. Discussion:The results of this study will provide preliminary evidence regarding the efficacy of acupuncture therapy in improving cognitive function in PCME/CFS and will explore whether acupuncture improves cognitive function in this disease by modulating metabolism and RSFC in the hippocampus. Clinical trial registration:www.clinicaltrials.gov, identifier: NCT07357688.

Background: Electroconvulsive therapy (ECT) provides rapid relief of depressive symptoms. However, the relationship between intracranial electric field (E-field) distribution, dosage, and antidepressant outcomes remains underexplored. Methods: Thirty patients with depressive episodes received bifrontal ECT. Clinical symptoms were assessed using the 17-Item Hamilton Rating Scale for Depression at baseline and post-ECT treatment. Magnetic resonance imaging was performed at baseline to calculate E-field strength and intracranial E-field dosage. Results: No significant associations were found between accumulated or average E-field dosage and overall antidepressant outcomes. However, significant associations were observed between antidepressant outcomes and Efield dosage during the initial ECT session in key brain regions, including the amygdala, anterior cingulate cortex, cerebellum, hippocampus, medial para-hippocampal cortex, postcentral gyrus, thalamus, and superior frontal lobe (P all < 0.05). Conclusions: While no significant associations were found between cumulative or average E-field dosage and antidepressant outcomes of ECT, significant associations were observed between E-field dosage in key brain regions and antidepressant outcomes during the initial ECT session. These findings suggest that individualized ECT protocols, tailored to patient-specific neuroanatomy and E-field dosage in specific brain regions, may enhance ECT's therapeutic efficacy. Future research should explore personalized ECT protocols using computer-modeled E-field distribution and ECT parameters.

Background Aberrant microglial activation and impaired adult hippocampal neurogenesis are critically involved in depression pathogenesis. Although electroacupuncture (EA) demonstrates clinical antidepressant efficacy, its mechanisms in modulating microglia and promoting neurogenesis remain unclear. Methods Male C57BL/6J mice were subjected to chronic mild stress (CMS) for 3 weeks, then divided into groups for subsequent intervention. The groups received either EA at the Yintang (GV29) and Baihui (GV20) acupoints, imipramine (IMI) administration as a positive control, or no treatment/vehicle control for an additional 3 weeks. Anxiety- and depression-like behaviors were assessed using a battery of behavioral tests, including the sucrose preference test (SPT), forced swim test (FST), tail suspension test (TST), elevated plus maze (EPM), and open field test (OFT). The status of microglia and neurogenesis were detected with immunofluorescence imaging. Structural changes in synapses were quantified using Golgi staining. The underlying molecular mechanisms were probed by examining brain-derived neurotrophic factor (BDNF)-related signaling pathways via Western blotting and quantitative real-time PCR. Microglia were depleted using colony-stimulating factor-1 receptor (CSF-1R) antagonist PLX5622, and BDNF-TrkB signaling was blocked by ANA-12. Results We found that EA treatment significantly alleviated CMS-induced anxiodepressive behaviors. Crucially, EA induced a shift towards a pro-neurogenic microglial phenotype in the hippocampus. Furthermore, EA enhanced adult hippocampal neurogenesis and synaptic plasticity. Mechanistically, EA augmented BDNF function through promoting BDNF maturation, repressing MeCP2-mediated transcriptional inhibition, and activating PKA expression. Critically, microglial depletion by PLX5622 or TrkB inhibition by ANA-12 abolished EA-induced neurogenesis and behavioral improvements. Conclusions Our findings demonstrate that EA alleviates depression by driving a pro-neurogenic transformation of microglia. These reprogrammed microglia, in turn, enhance BDNF function via the coordinated multiple convergent pathways, ultimately promoting hippocampal neurogenesis and restoring synaptic plasticity.

OBJECTIVES:Depersonalisation-derealization disorder (DPD) is a dissociative disorder that impairs cognitive function and occupational performance. Emerging evidence indicate the levels of tumour necrosis factor-α and interleukin associated with the dissociative symptoms. In this study, we aimed to explore the role of the immune system in the pathology of DPD. METHODS:We screened the protein expression in serum samples of 30 DPD patients and 32 healthy controls. Using a mass spectrometry-based proteomic approach, we identified differential proteins that were verified in another group of 25 DPD patients and 30 healthy controls using immune assays. Finally, we performed a correlation analysis between the expression of differential proteins and clinical symptoms of patients with DPD. RESULTS:We identified several dysregulated proteins in patients with DPD compared to HCs, including decreased levels of C-reactive protein (CRP), complement C1q subcomponent subunit B, apolipoprotein A-IV, and increased levels of alpha-1-antichymotrypsin (SERPINA3). Moreover, the expression of CRP was positively correlated with visuospatial memory and the ability to inhibit cognitive interference of DPD. The expression of SERPINA3 was positively correlated with the ability to inhibit cognitive interference and negatively correlated with the perceptual alterations of DPD. CONCLUSIONS:The dysregulation of the immune system may be the underlying biological mechanism in DPD. And the expressions of CRP and SERPINA3 can be the potential predictors for the cognitive performance of DPD.

Objectives: Schizophrenia is associated with impairment in theory of mind (ToM), which is defined as the ability to make judgments about mental states and is related to medial prefrontal cortical activity. Ziprasidone, but not haloperidol, is known to have a protective effect in the medial prefrontal cortex. Thus, we hypothesized that these 2 drugs would have different efficacy in improving ToM task performance in patients with schizophrenia. Methods: Patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnosis of schizophrenia matched for sex, duration of illness, and education were randomized to receive ziprasidone (n=30) or haloperidol (n=30). All patients were assessed using the Positive and Negative Syndrome Scale and the Personal and Social Functioning Scale. ToM was assessed using a first-order false belief task, a second-order false belief task, the faux-pas task, and the Reading the Mind in the Eyes Task, in order of developmental complexity and difficulty. The primary outcome was change in ToM performance from baseline to 16 weeks of treatment. Results: For the first-order false belief task, there were no significant differences between the groups ( P >0.05). For the second-order false belief task, the interaction effect was significant ( P <0.05), and the simple effect of time showed a significant difference only in the ziprasidone group ( P <0.001). For the faux-pas task, the interaction effect was not significant ( P >0.05). For the Reading the Mind in the Eyes Task, the interaction effect was significant ( P <0.05), and the simple effect of time showed a significant difference only in the ziprasidone group ( P <0.001). The Positive and Negative Syndrome Scale results were similar between the groups. The ziprasidone group performed better than the haloperidol group on the Personal and Social Functioning Scale. There were no major safety concerns or adverse events. Conclusions: The findings of this study suggest that ziprasidone could improve ToM and might be superior to haloperidol for improving complex ToM as well as personal and social functioning in patients with schizophrenia. Trial Registration Chinese Clinical Trial Register: ChiCTR2200060542.

Introduction:Abnormalities of the cerebellum have been displayed to be a manifestation of schizophrenia (SCH) which is a detrimental psychiatric disorder. It has been recognized that the cerebellum contributes to motor function, sensorimotor function, cognition, and other brain functions in association with cerebral functions. Multiple studies have observed that abnormal alterations in cerebro-cerebellar functional connectivity (FC) were shown in patients with SCH. However, the FC of cerebellar networks in SCH remains unclear. Methods:In this study, we explored the FC of cerebellar networks of 45 patients with first-episode SCH and 45 healthy control (HC) subjects by using a defined Yeo 17 network parcellation system. Furthermore, we performed a correlation analysis between cerebellar networks' FC and positive and negative symptoms in patients with first-episode SCH. Finally, we established the classification model to provide relatively suitable features for patients with first-episode SCH concerning the cerebellar networks. Results:We found lower between-network FCs between 14 distinct cerebellar network pairs in patients with first-episode SCH, compared to the HCs. Significantly, the between-network FC in N2-N15 was positively associated with positive symptom severity; meanwhile, N4-N15 was negatively associated with negative symptom severity. Besides, our results revealed a satisfactory classification accuracy (79%) of these decreased between-network FCs of cerebellar networks for correctly identifying patients with first-episode SCH. Conclusion:Conclusively, between-network abnormalities in the cerebellum are closely related to positive and negative symptoms of patients with first-episode SCH. In addition, the classification results suggest that the cerebellar networks can be a potential target for further elucidating the underlying mechanisms in first-episode SCH.

Electroconvulsive therapy (ECT) has been widely used in many countries and diverse patient populations [1,2]. However, there are no reports on the safety and efficacy of ECT in patients living above 2500 m (8250 feet) or high altitude (HA) areas where arterial oxygen saturation levels begin to fall compared to low altitude (LA) areas. Residents living in HA areas adapt to the decreased oxygen saturation through genetic and physiologic changes including ventilatory responsiveness [3,4] and increased hemoglobin (Hb) concentrations [5].

Investing in early childhood development is an effective way to enhance human capital accumulation. Caregivers' mental health is one of the most important factors influencing children's development. Previous studies have found that mental health issues in caregivers are widespread all over the world, especially in low- and middle-income countries. In this study, we explored the effects of the "Integrated Program for Early Childhood Development" on the mental health of female caregivers in Southwest China through a randomized intervention trial, with infants aged 5-25 months and their caregivers as the target subjects. The heterogeneity of the effects of different characteristics of the caregivers and the mechanism of the intervention effect were also analyzed. Primary caregivers were provided comprehensive early development interventions for the children in the treatment group via bi-weekly home visiting activities and monthly family group activities. The results showed that the prevalence of depression, anxiety, and stress symptoms among female caregivers in this rural area were 32%, 42%, and 30%, respectively. Whether the child was breastfed, parent's age, parent's education level, primary caregiver type, the ratio of the number of months the mother was at home full time to the child's age, the grandmother's rearing ability, and the family asset index were the factors influencing the mental health of female caregivers. The intervention significantly increased the proportion of depressive symptoms in 28% of the grandmothers. It significantly reduced the anxiety symptoms of daughters-in-law not from the local town, while the social interactions of both local and non-local daughters-in-law were significantly improved.

The hypothalamus critically regulates innate social interactions, but how hypothalamic neurons transducing sex-related sensory signals emitted by conspecifics to trigger appropriate behaviors remains largely unknown. We addressed this issue by identifying specific hypothalamic neurons involved in perceiving conspecific male cues relevant to inter-male aggression. By in vivo recording of neuronal activities in behaving mice, we showed that neurons expressing dopamine transporter (DAT+) in the ventral premammillary nucleus (PMv) of the hypothalamus responded specifically to male urine cues in a vomeronasal organ (VNO)-dependent manner in naive males. Retrograde trans-synaptic tracing further revealed a specific group of neurons in the bed nucleus of the stria terminalis (BNST) that convey male-relevant signals from VNO to PMv. Moreover, ablation of PMvDAT+ neurons blocked the preference for male urine cues and reduced inter-male attacks. Thus, PMvDAT+ neurons exemplify the function of specific hypothalamic neurons responsible for transforming sex-related sensory signals into perception and behaviors.

OBJECTIVE: To determine differences in cerebral activity evoked by acupuncture and conventional stroke treatment, and identify the treatment targets.METHODS: In total, 21 patients were randomly divided into two groups. Group A(11 patients) received both acupuncture and conventional treatment, while group B(10 patients) received conventional treatment only. Resting-state functional magnetic resonance imaging(f MRI) was performed on each participant before and after treatment. Regional homogeneity analysis was performed to investigate the potential mechanism of acupuncture treatment by comparing differences in cerebral activity between treatments.RESULTS: Group A showed higher Re Ho in the frontal lobe(BA6, BA46), supra-marginal gyrus(BA40),middle temporal gyrus(BA21), cerebellum, and insula. Group B showed higher Re Ho in the frontal lobe(BA6) and parietal lobe(BA3, BA7).CONCLUSION: Acupuncture and conventional treatment triggered relatively different clinical efficacy and brain responses. Acupuncture treatment more significantly improved the symptoms of stroke patients. More marked changes in sensory,emotional, and motor areas(including the frontal lobe, middle temporal gyrus, cerebellum, and insula) might reflect the specific acupuncture mechanism.