Persistent brain network signatures in psychosis: implications for diagnosis, prognosis, and treatment
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Functional brain network dynamics mediate the relationship between female reproductive aging and interpersonal adversity
Premature reproductive aging is linked to heightened stress sensitivity and psychological maladjustment across the life course. However, the brain dynamics underlying this relationship are poorly understood. Here, to address this issue, we analyzed multimodal data from female participants in the Adolescent Brain and Cognitive Development (longitudinal, N = 441; aged 9–12 years) and Human Connectome-Aging (cross-sectional, N = 130; aged 36–60 years) studies. Age-specific intrinsic functional brain network dynamics mediated the link between reproductive aging and perceptions of greater interpersonal adversity. The adolescent profile overlapped areas of greater glutamatergic and dopaminergic receptor density, and the middle-aged profile was concentrated in visual, attentional and default mode networks. The two profiles showed opposite relationships with patterns of functional neural network variability and cortical atrophy observed in psychosis versus major depressive disorder. Our findings underscore the divergent patterns of brain aging linked to reproductive maturation versus senescence, which may explain developmentally specific vulnerabilities to distinct disorders.
Dopaminergic modulation and dosage effects on brain state dynamics and working memory component processes in Parkinson’s disease
Parkinson’s disease (PD) is primarily diagnosed through its characteristic motor deficits, yet it also encompasses progressive cognitive impairments that profoundly affect quality of life. While dopaminergic medications are routinely prescribed to manage motor symptoms in PD, their influence extends to cognitive functions as well. Here we investigate how dopaminergic medication influences aberrant brain circuit dynamics associated with encoding, maintenance and retrieval working memory (WM) task-phases processes. PD participants, both on and off dopaminergic medication, and healthy controls, performed a Sternberg WM task during fMRI scanning. We employ a Bayesian state-space computational model to delineate brain state dynamics related to different task phases. Importantly, a within-subject design allows us to examine individual differences in the effects of dopaminergic medication on brain circuit dynamics and task performance. We find that dopaminergic medication alters connectivity within prefrontal-basal ganglia-thalamic circuits, with changes correlating with enhanced task performance. Dopaminergic medication also restores engagement of task-phase-specific brain states, enhancing task performance. Critically, we identify an “inverted-U-shaped” relationship between medication dosage, brain state dynamics, and task performance. Our study provides valuable insights into the dynamic neural mechanisms underlying individual differences in dopamine treatment response in PD, paving the way for more personalized therapeutic strategies.
Preventing psychosis in people at clinical high risk: an updated meta-analysis by the World Psychiatric Association Preventive Psychiatry section
Recently published large-scale randomised controlled trials (RCTs) have questioned the efficacy of preventive interventions in individuals at clinical high risk for psychosis (CHR-P). We conducted a systematic review and meta-analysis to include this new evidence and provide future directions for the field. We followed the PRISMA guidelines and a pre-registered protocol, with a literature search conducted from inception to November 2023. We included RCTs that collected data on psychosis transition (the primary outcome) in CHR-P. Secondary outcomes were symptoms severity and functioning. Investigated time points were 6,12,24,36, and +36 months. We used odd ratios (ORs) and standardised mean differences (SMD) as summary outcomes. Heterogeneity was estimated with the Higgins I2. Twenty-four RCTs, involving 3236 CHR-P individuals, were included. Active interventions were Cognitive Behavioural Therapy (CBT), family-focused therapy, Integrated Psychological Therapy, antipsychotics, omega-3 fatty acids, CBT plus risperidone, minocycline, and other non-pharmacological approaches (cognitive remediation, sleep-targeted therapy, brain stimulation). Results showed no evidence that any of the investigated active interventions had a sustained and robust effect on any of the investigated outcomes in CHR-P, when compared to control interventions, including CBT on transition to psychosis at 12 months (9 RCTs; OR: 0.64; 95% CI: 0.39–1.06; I2: 21%; P = 0.08). These results highlight the need for novel treatment approaches in CHR-P. Future studies should consider the heterogeneity of this clinical population and prioritise stratification strategies and bespoke treatments.
Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia
X-linked hypophosphataemia (XLH) is a rare metabolic bone disorder caused by pathogenic variants in the PHEX gene, which is predominantly expressed in osteoblasts, osteocytes and odontoblasts. XLH is characterized by increased synthesis of the bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23), which results in renal phosphate wasting with consecutive hypophosphataemia, rickets, osteomalacia, disproportionate short stature, oral manifestations, pseudofractures, craniosynostosis, enthesopathies and osteoarthritis. Patients with XLH should be provided with multidisciplinary care organized by a metabolic bone expert. Historically, these patients were treated with frequent doses of oral phosphate supplements and active vitamin D, which was of limited efficiency and associated with adverse effects. However, the management of XLH has evolved in the past few years owing to the availability of burosumab, a fully humanized monoclonal antibody that neutralizes circulating FGF23. Here, we provide updated clinical practice recommendations for the diagnosis and management of XLH to improve outcomes and quality of life in these patients.
Baicalein inhibits cell proliferation and induces apoptosis in brain glioma cells by downregulating the LGR4-EGFR pathway
Patients diagnosed with brain glioma have a poor prognosis and limited therapeutic options. LGR4 is overexpressed in brain glioma and involved in the tumorigenesis of many tumors. Baicalein (BAI) is a kind of flavonoid that has exhibited anti-tumor effects in various tumors. Nevertheless, the functions and associations of BAI and LGR4 in brain glioma remain unclear. In this study, Gene Expression Profiling Interactive Analysis and Human Protein Atlas databases were used to perform expression and survival analysis of LGR4 in brain glioma patients. Subsequently, the significance of LGR4-EGFR in brain glioma cells (HS683 and KNS89) and brain glioma animal models was explored by RNA interference and subcutaneous transplantation. Additionally, brain glioma cells were treated with BAI to explore the roles and mechanisms of BAI in brain glioma. The results showed that LGR4 was highly expressed in brain glioma and was related to a poor prognosis. LGR4 knockdown repressed the proliferation and EGFR phosphorylation but induced apoptosis in brain glioma cells. However, these effects were reversed by EGFR overexpression and CBL knockdown. In contrast, both in vitro and in vivo experiments revealed that LGR4 overexpression facilitated brain glioma cell malignant behavior and promoted tumor development, but these effects were rescued by BAI and an EGFR inhibitor. Furthermore, si-LGR4 accelerated EGFR protein degradation, while oe-LGR4 exhibited the opposite effect. Without affecting normal cellular viability, BAI inhibited malignant behavior, interacted with LGR4, and blocked the LGR4-EGFR pathway for brain glioma cells. In conclusion, our data suggested that BAI inhibited brain glioma cell proliferation and induced apoptosis by downregulating the LGR4-EGFR pathway, which provides a novel strategy and potential therapeutic targets to treat brain glioma.
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