Translational Psychiatry最新文献

Introduction: Major depressive disorder (MDD) is a prevalent and debilitating mental disorder that shares symptoms, genetics, and molecular changes in the brain with other psychiatric disorders, such as schizophrenia and bipolar disorder. Decreased brain pH, associated with increased lactate levels due to altered energy metabolism and neuronal hyperexcitation, has been consistently observed in schizophrenia and bipolar disorder. We recently demonstrated similar brain alterations in various animal models of neuropsychiatric disorders, including MDD. However, our understanding of brain pH alterations in human patients with MDD remains limited.

Methods: We conducted meta-analyses to assess postmortem brain pH in patients with MDD compared to control subjects, examining its relationships with recurrence of depressive episodes and illness duration, utilizing publicly available demographic data. Studies reporting individual raw pH data were identified through searches in the Stanley Medical Research Institute database, NCBI GEO database, PubMed, and Google Scholar. The data were analyzed using the random effects model, ANOVA, and ANCOVA.

Results: The random effects model, using 39 curated datasets (790 patients and 957 controls), indicated a significant decrease in brain pH in patients with MDD (Hedges' g = -0.23, p = 0.0056). A two-way ANCOVA revealed that the effect of diagnosis on pH remained significant when considering covariates, including postmortem interval, age at death, and sex. Patients with recurrent episodes, but not a single episode, showed significantly lower pH than controls in both females and males (256 patients and 279 controls from seven datasets). Furthermore, a significant negative correlation was observed between brain pH and illness duration (115 patients from five datasets). Female preponderance of decreased pH was also found, possibly due to a longer illness duration and a higher tendency of recurrent episodes in females.

Conclusion: This study suggests a decrease in brain pH in patients with MDD, potentially associated with recurrent episodes and longer illness duration. As suggested from previous animal model studies, altered brain energy metabolism, leading to decreased pH, may serve as a potential transdiagnostic endophenotype for MDD and other neuropsychiatric disorders.

The use of repetitive Transcranial Magnetic Stimulation (rTMS) in treating major depressive disorder (MDD) is increasingly being explored in precision medicine. However, there's a notable lack of understanding of the underlying neurobiological effects, which limits our ability to correlate specific imaging features with treatment efficacy. As one possible neurobiological mechanism, clinical research has already shown that in MDD, lower norepinephrine release in the locus coeruleus (LC) triggers depressive symptoms, and pharmacological approaches that block norepinephrine reuptake boost its levels, easing depression. Surprisingly, the LC has not received a more pronounced focus in contemporary rTMS research. This study investigates the role of the LC in MDD and its response to high-frequency (HF)-rTMS using ¹⁸FDG-PET imaging. We compared LC metabolic connectivity between MDD patients (n = 43) and healthy controls (n = 32). Additionally, we evaluated the predictive value of LC connectivity for HF-rTMS treatment outcomes and examined post-treatment changes in LC metabolic connectivity. Our findings revealed significant differences in LC metabolic connectivity between MDD patients and controls. Baseline LC metabolic connectivity did not predict HF-rTMS treatment outcomes. However, post-treatment analyses showed a significant correlation between improved clinical outcomes and attenuation of LC metabolic connectivity in regions associated with cognitive control and the default mode network. Notably, a reduction in state anxiety moderated this relationship, highlighting the role of anxiety in HF-rTMS efficacy for MDD treatment. Our findings suggest that LC metabolic connectivity, influenced by state anxiety levels, may be crucial in HF-rTMS efficacy, offering further insights for personalized MDD treatment strategies.

Mild cognitive impairment (MCI) is a prodromal stage in aging to possible progression to Alzheimer's disease and related dementia (ADRD), where co-occurrence of major depressive disorder (MDD) accelerates the progression. Metabolic and mitochondrial abnormalities in ADRD and other neurodegenerative disorders have been widely suggested, while possible mitochondrial dysfunction has been associated with etiopathology of both MCI and MDD. Hence, investigation of mitochondrial markers in MCI, MDD, and presence of both conditions is warranted. In total, 332 older adult participants were included: 168 with MCI, 108 with MCI plus remitted MDD (rMDD), and 56 with rMDD but without MCI. We measured plasma circulating mitochondrial DNA (ccf-mtDNA), lactate, and extracted nuclear mitochondrial encoded (NMt) single-nucleotide variants (SNVs) (n = 312). Non-parametric statistical tests on ccf-mtDNA and lactate levels were performed on the diagnosis, clinical and cardiometabolic variables. Binary sequence kernel association test (SKAT-O) and burden test were performed on NMt-SNV, adjusted for age, race, gender, type II diabetes, and APOE genotype. Lower level of lactate was observed in MCI (KW χ² = 14.8, P = 0.0024), more specifically, significant differences of lower plasma lactate between MCI only and rMDD, but not between MCI+rMDD and MCI were found, suggesting potential roles in MCI driving lactate lower levels. While higher levels of ccf-mtDNA were observed in APOE-ε4 carrier (χ² = 5.04, P = 0.05). This relationship was present only in MCI (P = 0.043) and MCI+rMDD groups (P = 0.023). No significant nuclear-encoded mitochondrial gene associations were observed with MCI or MDD. The results suggest decreased level of plasma lactate in individuals with MCI and MCI+rMDD, with inverse correlation with ccf-mtDNA, in addition to effect of APOE-ε4 in further increasing ccf-mtDNA specifically in participants with cognitive impairment. These findings contribute to a deeper understanding of the mitochondrial markers in MCI and MDD, warranting further research to explore the precise roles of mitochondrial abnormalities in the development and progression of MCI.

tDCS is widely assumed to cause neuromodulation via the electric field in the cortex acting directly on cortical neurons. However, recent evidence suggests that tDCS may indirectly influence brain activity through cranial nerve pathways, notably the trigeminal nerve, but these neuromodulatory pathways remain unexplored. To investigate the first stages in this potential pathway we developed an animal model to study the effect of trigeminal nerve direct current stimulation (TN-DCS) on neuronal activity in the principal sensory nucleus (NVsnpr) and the mesencephalic nucleus of the trigeminal nerve (MeV). We conducted experiments on twenty-four male Sprague Dawley rats (n = 10 NVsnpr, n = 10 MeV during anodic stimulation, and n = 4 MeV during cathodic stimulation). DC stimulation, ranging from 0.5 to 3 mA, targeted the trigeminal nerve's marginal branch. Concurrently, single-unit electrophysiological recordings were obtained using a 32-channel silicon probe, encompassing three 1-min intervals: pre, during, and post-stimulation. Xylocaine trigeminal nerve blockage served as a control. TN-DCS increased neuronal spiking activity in both NVsnpr and MeV, returning to baseline during the post-stimulation phase. The 3 mA DC stimulation of the blocked trigeminal nerve failed to induce increased spiking activity in the trigeminal nuclei. These findings provide empirical support for trigeminal nuclei modulation via TN-DCS, suggesting the cranial nerve pathways could play a role in mediating the tDCS effects in humans.

Cognitive impairment and symptoms of psychiatric disorders have been reported frequently as features of post-acute sequelae of SARS-CoV-2 infection. This study aims to investigate subjective memory complaints in COVID-19 survivors and determine if these are more strongly associated with objective cognitive impairment related to sequelae of SARS-CoV-2 infection or with symptoms of psychiatric conditions. A total of 608 COVID-19 survivors were evaluated in-person 6-11 months after hospitalization, with 377 patients assigned to a "no subjective memory complaint (SMC)" group and 231 patients assigned to an SMC group based on their Memory Complaint Scale scores. Follow-up evaluations included an objective cognitive battery and scale-based assessments of anxiety, depression, and post-traumatic stress symptoms. We found the perception of memory impairment in COVID-19 survivors to be more strongly associated to core symptoms of psychiatric conditions rather than to primary objective cognitive impairment. Univariate analysis indicated significant differences between the "no SMC" and SMC groups, both for the psychiatric symptom evaluations and for the cognitive evaluations (p < 0.05); however, the psychiatric symptoms all had large partial eta-squared values (ranging from 0.181 to 0.213), whereas the cognitive variables had small/medium partial eta-squared values (ranging from 0.002 to 0.024). Additionally, multiple regression analysis indicated that only female sex and depressive and post-traumatic stress symptoms were predictors of subjective memory complaints. These findings may help guide clinical evaluations for COVID-19 survivors presenting with memory complaints while also serving to expand our growing understanding of the relationship between COVID-19, subjective memory complaints, and the risk of cognitive decline.

Childhood adversity is associated with various clinical dimensions in psychosis; however, how genetic vulnerability shapes the adversity-associated psychopathological signature is yet to be studied. We studied data of 583 First Episode Psychosis (FEP) cases from the EU-GEI FEP case-control study, including Polygenic risk scores for major depressive disorder (MDD-PRS), bipolar disorder (BD-PRS) and schizophrenia (SZ-PRS); childhood adversity measured with the total score of the Childhood Trauma Questionnaire (CTQ); and positive, negative, depressive and manic psychopathological domains from a factor model of transdiagnostic dimensions. Genes and environment interactions were explored as a departure from a multiplicative effect of PRSs and total CTQ on each dimension. Analyses were adjusted for age, sex, 10 PCA, site of recruitment and for medication. A childhood adversity and PRS multiplicative interaction was observed between A) the CTQ and MDD-PRS on the predominance of positive (β = 0.42, 95% CI = [0.155, 0.682], p = 0.004); and depressive (β = 0.33, 95% CI = [0.071, 0.591], p = 0.013) dimensions; B) between the CTQ and BD-PRS on the positive dimension (β = 0.45, 95% CI = [0.106, 0.798], p = 0.010), and C) with the CTQ and SZ-PRS on the positive dimension (β = -0.34, 95% CI = [-0.660, -0.015], p = 0.040). Bonferroni corrected p-value of significance was set at 0.0125. In conclusion, despite being underpowered, this study suggests that genetic liability for MDD and BD may have a moderating effect on the sensibility of childhood adversity on depressive and positive psychotic dimensions. This supports the hypothesis of an affective pathway to psychosis in those exposed to childhood adversity.

Altered fear conditioning and extinction learning are discussed as key etiological features in anxiety disorders. Women have an increased risk for anxiety disorders and fear conditioning has been shown to be influenced by the menstrual cycle phase and circulating gonadal hormones. The objective of our study was to investigate the effects of separate and combined estradiol and progesterone administration on fear extinction in healthy women. We conducted a placebo-controlled, randomized study in healthy women, who completed a fear conditioning paradigm on three consecutive days: fear acquisition training on day 1, fear extinction training on day 2, and return of fear test on day 3. Skin conductance responses (SCRs) served as main outcome variable. Two hours before testing on day 2, participants received pills containing either placebo, estradiol (2 mg), progesterone (400 mg) or the combination of both. We examined 116 women (mean age 25.7 ± 6.0 years), who showed significantly stronger conditioned SCRs to the CS+ than CS- during fear acquisition training indicating successful fear learning. At the beginning of the fear extinction training, estradiol administration reduced the differentiation between the conditioned stimuli. In the return of fear test, the estradiol groups showed heightened SCR responses to the previously extinguished stimulus, i.e., impaired extinction recall. Administration of progesterone did not have any significant influence on SCRs. There were also no effects on fear potentiated startle response. In our interpretation, exogenous estradiol administration affected the extinction of the conditioned fear response which led subsequently to a stronger return of fear. From a clinical perspective our findings suggest that estradiol levels may have an influence on the success of exposure therapy and could be taken into consideration when planning exposure sessions.

Previous studies have revealed morphologic alterations in patients with major depressive disorder (MDD) with experiences of childhood trauma. However, the underlying neural mechanisms remain largely unknown. This study aims to explore the brain structural changes and their possible mediation role in the relationship between childhood maltreatment and psychological resilience in drug-naïve adolescents with first-episode MDD. A total of 57 adolescents with first-episode MDD and 36 healthy controls (HCs) completed the T1-weighted magnetic resonance imaging scan. The adverse childhood experiences and current psychological resilience were assessed using the Childhood Trauma Questionnaire-Short Form and the Connor Davidson Resilience Scale, respectively. The voxel-based morphometry approach was applied to examine changes in the gray matter volume (GMV). Compared with the HCs, adolescents with MDD had significantly reduced GMV volumes in the left fusiform gyrus, right orbitofrontal gyrus, right superior temporal gyrus, right calcarine cortex, right middle frontal gyrus, left angular gyrus, right precuneus, right posterior cingulate gyrus, and right posterior central gyrus, as well as significantly increased GMV volumes in the left lenticular putamen and right lenticular pallidum. The GMV of the right calcarine cortex was found to be negatively correlated with the severity of emotional abuse and positively correlated with the level of psychological resilience. Moreover, the GMV of the right calcarine cortex might partially mediate the relationship between childhood maltreatment and psychological resilience. The present study provided further evidence for structural impairments in adolescents with MDD. Our findings also confirmed the important role of depression-related GMV changes in childhood growth experiences and psychological resilience characteristics during adolescent brain maturation.

The exposure to aversive experiences during early-life affects brain maturation and induces changes in behavior. Additionally, when these experiences coincide with subtle neurodevelopmental alterations, they may contribute to the emergence of psychiatric disorders, such as schizophrenia. Studies in patients and animal models have identified changes in parvalbumin (PV) expressing inhibitory neurons, highlighting their significance in the etiology of this disorder. Most studies have been focused on the cortex, but PV+ neurons also provide inhibitory input to diencephalic regions, particularly to the thalamus (through cells in the thalamic reticular nucleus, TRN) and the habenula. Remarkably, alterations in both nuclei have been described in schizophrenia. Some of these changes in PV+ cells may be mediated by perineuronal nets (PNN), specialized regions of the extracellular matrix that often surround them and regulate their synaptic input and activity. Interestingly, the physiological maturation and integration of PV+ neurons, which involves the assembly of PNN, occurs during early postnatal life. Plasticity molecules associated to inhibitory neurons, such as PSA-NCAM, or NMDA receptors (NMDAR) can also influence the structure and function of these cells. Growing evidence also indicates that glial cells regulate the physiology of PV+ neurons by influencing their maturation and modulating their synaptic connectivity. To explore the impact of early-life aversive experiences and concomitant subtle neurodevelopmental alterations on diencephalic PV+ cells, we analyzed adult male mice subjected to a double-hit model (DHM) of schizophrenia, combining a single injection of an NMDAR antagonist at P7 and post-weaning social isolation. We observed that exploratory behavior, PV+ neurons and their associated PNN, as well as PSA-NCAM and NMDAR expression and glial cells, in the TRN and the habenula were affected by the DHM or one of its factors. To our knowledge, this is the first report on such alterations in these diencephalic structures in an animal model combining neurodevelopmental alterations and early-life stress during adolescence. Our findings complement previous work on PV+ neurons in cortical regions and underscore the importance of studying diencephalic inhibitory networks and their intricate interactions with aversive experiences and neurodevelopmental alterations during early life in the context of schizophrenia.