Translational Psychiatry最新文献

Gamma-aminobutyric acid (GABA) and glutamate are implicated in the antidepressant effects of repetitive transcranial magnetic stimulation (rTMS), though findings from magnetic resonance spectroscopy (MRS) are inconsistent. Furthermore, the relationship between GABA_A-receptor availability and rTMS outcomes remains largely unexplored. In this study, GABA and glutamate levels in the dorsal anterior cingulate cortex (dACC) were measured using a ¹H-MRS MEGA-PRESS sequence in 42 patients with bipolar or unipolar depression, both before and after a sham-controlled, double-blind clinical trial involving intermittent theta-burst stimulation (iTBS) over the dorsomedial prefrontal cortex. A subset of 28 patients also underwent [¹¹C]flumazenil positron emission tomography (PET) to measure whole-brain GABA_A-receptor availability and mean receptor availability in the nucleus accumbens and dACC. Depressive symptoms were assessed using the self-rated Montgomery Åsberg Depression Rating Scale (MADRS-S). The results indicated no significant changes in neurotransmitter levels or GABA_A-receptor availability post-iTBS in either the active or sham conditions. However, changes in MADRS-S scores after active iTBS were positively correlated with changes in GABA levels in the dACC (r(13) = 0.54, p = 0.04) and baseline GABA_A-receptor availability in the nucleus accumbens (r(11) = 0.66, p = 0.02). These correlations were absent in the sham group. The findings suggest that a reduction in GABA within targeted frontostriatal circuits can be part of the antidepressant mechanism of iTBS, challenging previous research. Additionally, they indicate a potential predictive role for frontostriatal GABA_A-receptor availability in the treatment of depression using dorsomedial prefrontal iTBS.

Dependence is a hallmark of alcohol use disorder characterized by excessive alcohol intake and withdrawal symptoms. The central nucleus of the amygdala (CeA) is a key brain structure underlying the synaptic and behavioral consequences of ethanol dependence. While accumulating evidence suggests that astrocytes regulate synaptic transmission and behavior, there is a limited understanding of the role astrocytes play in ethanol dependence. The present study used a combination of viral labeling, super resolution confocal microscopy, 3D image analysis, and slice electrophysiology to determine the effects of chronic intermittent ethanol (CIE) exposure on astrocyte plasticity in the CeA. During withdrawal from CIE exposure, we observed increased GABA transmission, an upregulation in astrocytic GAT3 levels, and an increased proximity of astrocyte processes near CeA synapses. Furthermore, GAT3 levels and synaptic proximity were positively associated with voluntary ethanol drinking in dependent rats. Slice electrophysiology confirmed that the upregulation in astrocytic GAT3 levels was functional, as CIE exposure unmasked a GAT3-sensitive tonic GABA current in the CeA. A causal role for astrocytic GAT3 in ethanol dependence was assessed using viral-mediated GAT3 overexpression and knockdown approaches. However, GAT3 knockdown or overexpression had no effect on somatic withdrawal symptoms, dependence-escalated ethanol intake, aversion-resistant drinking, or post-dependent ethanol drinking in male or female rats. Moreover, intra-CeA pharmacological inhibition of GAT3 did not alter dependent ethanol drinking. Together, these findings indicate that ethanol dependence induces GABAergic dysregulation and astrocyte plasticity in the CeA. However, these changes in astrocytic GAT3 do not appear to be necessary for the drinking related phenotypes associated with dependence.

This study aims to uncover the mechanisms and quantitative dose response relationships among sleep quality, anxiety, depression and miscarriage, as well as develop a comprehensive predictive model for the miscarriage rate. In this study, 1058 pregnant women in mainland China were recruited. We utilized both univariate, multivariate analyses and sensitivity analysis to investigate the relationship between sleep quality, anxiety, depression, and miscarriage. Then, we used mediation analysis and directed acyclic graph to explore how anxiety and sleep quality mediate the relationship between depression and miscarriage. We employed restricted cubic spline (RCS) to examine the dose-response relationship between these variables and constructed a nomogram model for predicting the occurrence of miscarriages. During our investigation, 16.4% of the participant had a miscarriage. Our results showed a significant association between sleep quality, anxiety, depression and miscarriage both unadjusted and multivariable multinomial logistic regression. Dose-response relationships showed that the miscarriage rate slowly increases with increasing PSQI, SAS and SDS scores at first. However, when a certain threshold is reached, even slight increases in the scores will lead to a sharp rise in the miscarriage rate. Anxiety mediated the effect of depression on miscarriage by 44% and sleep quality had a similar mediation effect (16%). The quantitative dose response relationships between PSQI, SAS, SDS, and the miscarriage rate are all positive. In the impact of depression on the miscarriage rate, anxiety and sleep quality also play significant mediating roles. By revealing high-risk pregnant women, early intervention can be provided, aiming to reduce the miscarriage rate.

Cerebrospinal fluid (CSF) biomarkers have been widely adopted in Alzheimer's disease (AD) diagnosis. However, no studies focused on the application of CSF biomarkers in the clinical practice of complex and atypical patients with cognitive impairment in China. This study aimed to evaluate the added value of CSF AD biomarkers in cognitively impaired patients with complex conditions in a memory clinical setting. A total of 633 participants were included from the National Center for Neurological Disorders in Shanghai, China. The CSF AD biomarkers were measured with ELISA. Cutoff values were firstly identified using Youden's index. The neurologists proposed etiology diagnosis with a percentage estimate of their confidence and prescribed medication before and after CSF disclosure. Changes in etiological diagnosis, diagnostic confidence, and management plan were compared across the groups. Of the 633 patients (mean [SD] age, 61.1 [11.3] years; 295 males [46.6%]), 372 (58.8%) were diagnosed with dementia, 103 (16.3%) with mild cognitive impairment, and 158 (24.9%) with subjective cognitive decline. Using those pre-defined cutoffs, we categorized patients into 3 groups: Alzheimer's continuum (68.1%), non-AD pathologic change (11.1%), and normal AD biomarkers (20.8%). After CSF disclosure, the proposed etiology changed in 158 (25.0%) participants and the prescribed medication changed in 200 (31.6%) patients. Mean diagnostic confidence increased from 69.5-83.0% (+13.5%; P < 0.001). In conclusion, CSF AD biomarkers significantly impacted the diagnosis, diagnostic confidence, and treatment plans for Chinese patients with complex cognitive impairment. CSF AD biomarkers are a useful tool for clinicians beyond routine clinical assessment.

Use of antipsychotic medication is related to thinning of the cerebral cortex, but the underlying mechanisms of this effect remain largely unknown. Here, we investigated potential mechanisms across multiple levels of description by comparing antipsychotic medication related cortical thinning to atlases of normative neurotransmitter distributions, structural and functional organization of the brain, and meta-analyses of functional activation from the Neurosynth database. We first analyzed a single-site discovery sample of patients (N = 131) with early psychosis for whom antipsychotic related cortical thinning was estimated based on lifetime exposure to antipsychotics. Findings were replicated using data from a large (N ≥ 2168) ENIGMA meta-analysis on schizophrenia patients. We discovered that antipsychotic related cortical thinning is associated with a number of neurotransmitter systems, most notably the serotonin system, as well as physiological measures, functional networks and neural oscillatory power distributions typical for regions subserving higher cognition. At the functional level, antipsychotic related cortical thinning affects regions involved in executive function and motivation, but not perception. These results show how molecular, physiological, and large-scale functional patterns may underlie antipsychotic related cortical thinning.

Despite increasing mental health problems among young people, few studies have examined associations between plasma proteins and mental health. Interactions between proteins and metabolites in association with mental health problems remain underexplored. In 730 twins, we quantified associations between plasma proteins measured at age 22 with 21 indicators of either depressive symptoms or the p-factor and tested for interactions with metabolites. Symptoms were collected from questionnaires and interviews completed by different raters (e.g., self-report, teachers) through adolescence to young adulthood (12 to 22 years). We found 47 proteins associated with depressive symptoms or the p-factor (FDR < 0.2), 9 being associated with both. Two proteins, contactin-1 and mast/stem cell growth factor receptor kit, positively interacted with valine levels in explaining p-factor variability. Our study demonstrates strong associations between plasma proteins and mental health and provides evidence for proteome-metabolome interactions in explaining higher levels of mental health problems.

Despite substantial efforts to unravel cognitive heterogeneity in ADHD, the examination of motivational variability, particularly delay aversion, remains limited. This study aimed to identify homogeneous delay-averse profiles in children with ADHD to understand motivational deficits. Delay-averse profiles were examined in a clinically well-characterized sample of 43 children with ADHD and 47 control participants using cluster analyses on an experiential delay discounting task. External validation analyses included parents' and teachers' clinical ratings, and fNIRS-based resting-state functional connectivity (rsFC) from the frontoparietal (FPN) and the default mode (DMN) networks. A five-profile solution best fit the data. Two clusters, labeled Conventional and Conventional-steeper, exhibited a conventional reward discount with increased delay but differed in the discounting slope. Three clusters demonstrated altered discounting: Steep discounting (abrupt devaluation of the reward), Shallow discounting (shallow discounting), and Zero discounting (no devaluation across delay durations). 77.78% of ADHD-C children clustered into steep discounting profiles, while 41.67% of ADHD-IN children were found in Shallow and Zero profiles, showing a significant disparity in the distribution of categorical presentations. External validation showed no differences in clinical ratings. However, clusters showing Zero and Shallow discounting demonstrated hypoconnectivity within and between FPN and DMN nodes. Delay aversion in ADHD spans a continuum from decreased to increased discounting rather than being solely defined by steeper discounting. These findings highlight the relevance of dimensional approaches in capturing ADHD's motivational heterogeneity and identifying distinct neurobiological substrates, with implications for improving diagnostic protocols and intervention strategies through the incorporation of behavioral measures of reward processing.

Selective vulnerability of nerve cells is a feature of neurodegenerative disease. To date, animal models have been limited to examining pathogenic protein expression in broad or heterogeneous neuronal populations. Consequently, noted pathological hallmarks represent an average of disease phenotypes over multiple neuron types, rather than exact measures of individual responses. Here we targeted gene expression to small, precisely defined and homogenous neuronal populations in the Drosophila melanogaster central nervous system (CNS), allowing dissection of selective vulnerability of single types of neurons with single-neuron resolution. Using cellular degeneration as a readout for vulnerability, we found while all neurons were affected by tau some neuron types were more affected (vulnerable) than others (resilient). The tau-mediated pathogenic effects fell on a spectrum, demonstrating that neurons in the fly CNS are differentially vulnerable to tau pathology. Mechanistically, total tau levels did not correlate with vulnerability; rather, the best correlatives of degeneration were significant age-dependent increases in phospho-tau levels in the same neuron type, and tau mislocalisation into dendrites. Lastly, we found that tau phosphorylation in vulnerable neuron types correlated with downstream vesicular and mitochondrial trafficking defects. However, all vulnerable neuron types did not show the same pattern, suggesting multiple paths to degeneration. Beyond highlighting the heterogeneity of neuronal responses to tau in determining vulnerability, this work provides a new, high-resolution, tractable model for studying the age-dependent effects of tau, or any pathogenic protein, on postmitotic neurons with sub-cellular resolution.

Histamine H₃ receptor (H₃R) antagonists regulate histamine release that modulates neuronal activity and cognitive function. Although H₃R is elevated in Alzheimer's disease (AD) patients, whether H₃R antagonists can rescue AD-associated neural impairments and cognitive deficits remains unknown. Pitolisant is a clinically approved H₃R antagonist/inverse agonist that treats narcolepsy. Here, we find that pitolisant reverses AD-like pathophysiology and cognitive impairments in an AD mouse model. Behavioral assays and in vivo wide-field Ca²⁺ imaging revealed that recognition memory, learning flexibility, and slow-wave impairment were all improved following the 15-day pitolisant treatment. Improved recognition memory was tightly correlated with slow-wave coherence, suggesting slow waves serve as a biomarker for treatment response and for AD drug screening. Furthermore, pitolisant reduced amyloid-β deposition and dystrophic neurites surrounding plaques, and enhanced neuronal lysosomal activity, inhibiting which blocked cognitive and slow-wave restoration. Our findings identify pitolisant as a potential therapeutic agent for AD treatments.

There are significant sex differences in the prevalence, symptom presentation, treatment response and brain abnormalities of patients with late-life depression (LLD). The functional connectivity of the habenula has been associated with depressive symptoms and cognitive impairments in patients with LLD. However, sex differences in habenular functional connectivity patterns among LLD patients remain unclear. One hundred and fourteen patients with LLD and 75 healthy controls (HCs) were included in the present study. Resting-state functional magnetic resonance imaging was used to analyse the static and dynamic functional connectivity (sFC and dFC) of the habenula. There were significant interactions between diagnosis (LLD vs. HCs) and sex for the dFC of the left habenula with the left insula, precentral gyrus, angular gyrus, and middle frontal gyrus and for the right habenula with the right middle temporal gyrus. Pairwise comparisons revealed a trend of HC males > HC females and LLD males < HC males for the connections between the left habenula and the left precentral gyrus, angular gyrus and middle frontal gyrus. Conversely, a trend of HC males < HC females and LLD males > HC males was found for the connections between the right habenula and right middle temporal pole. Furthermore, there was a significant interaction for the sFC of the right habenula with the right fusiform gyrus, with trends of HC males > HC females, LLD males < HC males, and LLD females > HC females. Regression analysis revealed that left habenular-left insular dFC was associated with long-delay memory in females and working memory in males; right habenular-right middle temporal pole dFC was associated with information processing speed in females. Sex moderated the relationships between cognitive function (global cognition, delay-recalled memory and working memory) and dFC between the left habenula and left insula. In conclusions, this study revealed sex-specific alterations in the functional connectivity patterns of the habenula in LLD patients, and these alterations were associated with various cognitive functions in a sex-specific manner. These findings provide a neurobiological basis for understanding sex differences in LLD patients.