Progress in Neuro-Psychopharmacology & Biological Psychiatry最新文献

Background: Psychosis is characterized by both genetic and neurostructural abnormalities. However, the mechanisms linking genetic risk to brain structural alterations remain unclear. This study investigates associations between polygenic risk scores (PRS) and brain structural measures in individuals experiencing a first-episode psychosis (FEP) and healthy controls (HC).

Methods: A total of 241 participants (130 FEP, 111 HC, mean age = 24.8 years, 34.9% females) underwent structural magnetic resonance imaging (MRI) and genotyping. PRS for schizophrenia, educational attainment, brain cortical thickness, and surface area were computed using PRS continuous shrinkage (PRS-CS). MRI data provided measures of cortical thickness, surface area, subcortical volumes, and hippocampal subfields. Associations between PRS and brain measures were assessed using generalized linear models within each group.

Results: FEP participants had significantly higher PRS for schizophrenia (p.adj = 1.56e^-6) and lower PRS for educational attainment (p.adj = 0.006) compared to HC, but groups did not differ in neurostructural PRS. Neuroimaging revealed trend-level reductions in left hippocampal volume (p = 0.040, p.adj = 0.280) and significant reductions in specific hippocampal subfields in FEP. In PRS-brain structure analyses, significant associations were observed only in HC, while in FEP, educational attainment PRS showed nominal associations with multiple hippocampal subfields.

Conclusion: By incorporating polygenic scores for brain structural traits, our study shows that neurostructural genetic risk does not differ between FEP and HC, even as FEP participants exhibit significant reductions in specific hippocampal subfields. Genetic influences on brain structure in early psychosis appear subtle and region-specific, underscoring the complex interplay between distinct genetic domains and neurodevelopment in psychosis.

Cannabidiol (CBD) is a non-intoxicating Cannabis sativa plant compound with some preclinical studies reporting efficacy for the treatment of psychiatric disorders, including schizophrenia and substance abuse. Considering that there are high rates of substance use in individuals with schizophrenia, CBD may be effective in the simultaneous treatment of both disorders. However, this exciting possibility has not been investigated preclinically, and CBD has only been evaluated for substance use treatment in healthy animals. Thus, to address this question thereby focusing on cocaine as an example for substance use, we used a mouse model of genetic risk for schizophrenia, heterozygous transmembrane domain neuregulin 1 mice (Nrg1 TM HET), which importantly show addiction-like responses to cocaine and altered schizophrenia-relevant behaviours to cannabinoids. We examined the efficacy of intraperitoneal administration of selected doses of CBD in reducing cocaine-induced conditioned place preference and locomotion (at a dose of 10 mg/kg) as well as in decreasing cocaine self-administration (at a dose of 20 mg/kg) in male Nrg1 TM HET and wildtype-like controls. The effects of prior CBD administration on the cessation and relapse-like behaviour for cocaine self-administration were also determined. The selected dose of CBD reduced cocaine place preference, cocaine locomotion and cocaine self-administration in wildtype-like littermates. However, CBD was ineffective in reducing these behaviours in Nrg1 TM HET mice. Furthermore, prior CBD treatment did not affect cessation of cocaine self-administration or relapse-like behaviour in either genotype, indicating that acute CBD administration may be needed to reduce these behaviours. Together, our findings show that CBD at the dose chosen can reduce cocaine reward, locomotion and self-administration in healthy animals. Importantly, the selected CBD treatment design may not be effective in reducing cocaine-induced mouse behaviours in the presence of schizophrenia risk mutations including mutant Nrg1 TM. These findings advocate for research evaluating CBD's efficacy in models of substance use susceptibility or other psychiatric disorders, to determine the circumstances and treatment design under which CBD is and is not effective for substance use treatment.

Excessive self-blaming emotions are commonly observed in anxiety disorders, with qualitatively similar symptomatology reported in subclinical populations. Interpretation of moral information requires assessing the social conceptual information, a process overseen by the superior anterior temporal lobe (sATL). Feelings of self-blame evoke interactions of sATL and socio-affective regions, and previous research shows that subclinical anxiety modulates the organisation of the self-blame circuitry. This study aimed to extend these findings by exploring links of trait-anxiety with (i) self-blaming emotions and associated behaviours in an experimental task, and (ii) self-blame-dependent neural activity and connectivity, as observed during reliving of autobiographical guilt memories. We also explored the role of resting-state fMRI in linking these phenomena. Increased anxiety was linked to stronger self-blaming emotions, and more pronounced self-attacking and hiding. When experiencing negative emotions about themselves (i.e. shame and self-anger), anxious individuals were also less likely to disengage from self-focused thoughts. These behavioural findings were paralleled by enhanced self-blame-related connectivity between the left sATL and bilateral posterior subgenual cingulate cortex. Distinct patterns of activity and connectivity within the ATL-related circuitry were furthermore linked to individual differences in intensity of the self-blaming emotions and approach-avoidance motivation towards the guilt memories. As such, the results of the current study link stronger self-blaming emotions in anxious individuals with specific maladaptive patterns of behaviour. Furthermore, the work provides robust evidence for the important role of ATL-related circuitry in self-blame processing, supporting its broader involvement in social conceptual processing and its alterations in subclinical anxiety.

Fragile X syndrome (FXS) is the most prevalent X-linked dominant autism spectrum disorder, causing a range of developmental problems, notably characterized by mild-severe mood/cognitive dysfunctions. NLX-101 is a highly selective and fully efficacious biased agonist at post-synaptic 5-HT_1A receptors, and has shown efficacy for reversal of sensory hypersensitivity and EEG anomalies in transgenic mouse models of FXS. Presently, we examined the ability of NLX-101 to "normalize" (i.e., restore to levels observed in wild-type mice) several aspects of behavioral anomalies displayed by adult male FMR1 KO2 mice, a transgenic murine model of FXS. FMR1 KO2 mice were treated with NLX-101 (0.64 or 2.5 mg/kg intraperitoneally) and tested sequentially in 1) the open-field test to study hyperactivity and stereotypies (self-grooming), 2) the three chamber partition test (social memory), 3) the nesting behavior test (daily living), 4) the novel object recognition test (working memory) and 5) the hyponeophagia (novelty suppression feeding) test (anxiety). Each test was separated by a three-day wash-out period. NLX-101 normalized hyperactivity and excessive self-grooming at both 0.64 and 2.5 mg/kg, whereas hyponeophagia, and deficits in working and social memory, were partially (0.64 mg/kg) or fully (2.5 mg/kg) normalized. Abnormal nest building was partially normalized at 2.5 mg/kg. In conclusion, NLX-101 exerts beneficial and dose-dependent activity against several behavioral and mood/cognitive deficits displayed by FMR1 KO2 mice. These results highlight the therapeutic potential of using a selective post-synaptic 5-HT_1A receptor biased agonist as a novel strategy to treat FXS, for which there is currently no approved efficacious and safe pharmacotherapy.

Aims: Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising intervention for autism spectrum disorder (ASD). However, the neurophysiological mechanisms driving its therapeutic effects, particularly regarding the complex reorganization of brain network dynamics, remain largely uncharacterized. This study aimed to elucidate the multidimensional network reconfiguration induced by low-frequency rTMS and identify specific electrophysiological predictors of clinical response in young children with ASD.

Methods: In a randomized, sham-controlled trial, 44 young children with ASD were assigned to receive either active (1 Hz, left dorsolateral prefrontal cortex) or sham rTMS for 20 sessions. Resting-state EEG data were acquired at baseline and post-intervention. We employed a comprehensive analytical framework integrating static Low- and High-Order Functional Connectivity (LOFC/HOFC), graph theoretical topology, dynamic Network State Entropy (NSE), and between-frequency coupling to assess network reconfiguration. Clinical efficacy was evaluated using the Autism Behavior Checklist (ABC).

Results: Active rTMS yielded significant improvements in sensory behavior and total behavioral scores compared to sham stimulation. Neurophysiologically, rTMS induced a "restorative" reorganization characterized by: (1) the suppression of pathological hyper-connectivity in the delta band and the enhancement of long-range synchronization in the alpha band; (2) the optimization of network topology, evidenced by increased global and local efficiency in the alpha band; (3) the modulation of dynamic flexibility, manifested as stabilized low-frequency dynamics and enhanced high-frequency metastability; and (4) the decoupling of aberrant cross-frequency interactions, specifically reducing pathological δ-β coupling. Crucially, the increase in delta network segregation and the reduction in pathological delta-beta coupling were significantly correlated with the magnitude of clinical symptom alleviation.

Conclusions: Low frequency rTMS promotes a systemic reorganization of brain networks in children with ASD, shifting the neural architecture from a disorganized, hyper-connected state towards an optimized, hierarchically structured system. Despite the limited spatial resolution of portable EEG, the rigorous multidimensional analysis revealed robust temporal dynamic changes. The direct link between network segregation, cross-frequency decoupling, and sensory-behavioral gains highlights multidimensional EEG metrics as potential biomarkers for monitoring therapeutic responses in early ASD intervention.

Heart failure (HF) is a complex systemic syndrome with major neuropsychiatric consequences. Cognitive impairment (e.g., dementia) and depression are common among HF patients, worsening prognosis, increasing hospital admissions, and impairing quality of life. Despite their prevalence, the neurobiological basis of these comorbidities is not yet fully understood. This review uniquely discusses converging neuroendocrine, inflammatory, and neuroplastic mechanisms linking HF, depression, and dementia inside an integrative heart-brain axis highlighting brain-derived neurotrophic factor (BDNF) as an important modulator of synaptic plasticity, neurogenesis, and stress resilience. Understanding the interactions between HF-induced hypothalamic-pituitary-adrenal axis activation, systemic inflammation, and impaired BDNF signaling may contribute to the development of novel multimodal therapeutic strategies targeting neurotrophic pathways and improving cognitive and mental health outcomes in HF.

Insomnia disorder (ID) is often accompanied by cognitive deficits and disturbances in brain networks and metabolism. As a potential marker of central metabolism and oxidative stress, the role of 27-hydroxycholesterol (27-OHC) in ID pathophysiology and dCBT-I-induced neuroplasticity remains unclear. This study investigated the relationships among alterations in brain function, 27-OHC levels, and the therapeutic effects of dCBT-I. We collected resting-state fMRI data and serum samples from 32 ID patients (at baseline and after six weeks of dCBT-I) and 32 healthy controls. We compared group differences in spontaneous anterior cingulate cortex (ACC) activity and resting-state functional connectivity (rsFC), and assessed whether changes in brain function and 27-OHC levels were associated with dCBT-I effects. Results showed that ID patients exhibited decreased spontaneous activity in the right ACC and enhanced rsFC within the sensorimotor network. Serum 27-OHC concentrations were significantly elevated and positively correlated with rsFC strength of the supplementary motor area. After dCBT-I, 27-OHC levels significantly decreased, and the treatment reversed aberrant activity in several brain regions. Post-treatment changes in dysfunctional beliefs about sleep were closely associated with normalized activity in the left putamen and left middle temporal gyrus. In summary, elevated serum 27-OHC and its aberrant coupling with the sensorimotor network jointly constitute an important biological basis for hyperarousal in ID. dCBT-I not only alleviates peripheral metabolic stress but also reshapes patients' cognition by inducing neuroplasticity within the striatum (especially the putamen and caudate).

Previous studies have revealed the presence of brain network abnormalities in structural and functional connectivity in migraineurs. However, the underlying mechanisms of structural and functional connectivity (SC-FC) coupling in migraineurs remain unclear. This study is the first to explore the mechanisms of SC-FC coupling in migraineurs using resting-state functional magnetic resonance imaging and diffusion kurtosis imaging methods. We collected multimodal magnetic resonance imaging data from 54 healthy controls and 72 migraineurs. We compared SC-FC coupling at the regional level and at the network level between the two groups, and we correlated the differential SC-FC coupling signals with clinical scales and neurotransmitter profiles. Significant differences in regional diffusion tensor SC-FC coupling in the Right_ContB_IPL_2 and Right_SomMotB_S2_2 regions were observed in migraineurs compared to healthy controls. Compared to healthy controls, there were significant differences in diffusion kurtosis SC-FC coupling at the network level of the somatomotor network, frontoparietal control network and default mode network in migraineurs. Diffusion kurtosis SC-FC coupling in the dorsal attention network and anxiety scores were significantly correlated in migraineurs. Differences between the two groups in the diffusion tensor SC-FC coupling were significantly associated with 5-hydroxytryptamine 2a. Our results suggest the presence of an abnormal pattern of SC-FC coupling in migraineurs that is associated with mental behavior and neurotransmission. Diffusion kurtosis SC-FC coupling and diffusion tensor SC-FC coupling provide different perspectives for exploring the coupling mechanisms of brain networks.