Journal of Psychiatry & Neuroscience最新文献

Background: Transcranial magnetic stimulation (TMS) is a noninvasive neurostimulation modality that has been used to study human synaptic plasticity. Leveraging work in ex vivo preparations, mechanistically informed pharmacological adjuncts to TMS have been used to improve our fundamental understanding of TMS-induced synaptic plasticity.

Methods: We systematically reviewed the literature pairing pharmacological adjuncts with TMS plasticity-induction protocols in humans. We searched MEDLINE, PsycINFO, and Embase from 2013 to Mar. 10, 2023. Studies published before 2013 were extracted from a previous systematic review. We included studies using repetitive TMS, theta-burst stimulation, paired associative stimulation, and quadripulse stimulation paradigms in healthy and clinical populations.

Results: Thirty-six studies met our inclusion criteria (28 in healthy and 8 in clinical populations). Most pharmacological agents have targeted the glutamatergic N-methyl-d-aspartate (NMDA; 15 studies) or dopamine receptors (13 studies). The NMDA receptor is necessary for TMS-induced plasticity; however, sufficiency has not been shown across protocols. Dopaminergic modulation of TMS-induced plasticity appears to be dose-dependent. The GABAergic, cholinergic, noradrenergic, and serotonergic neurotransmitter systems have small evidence bases supporting modulation of TMS-induced plasticity, as do voltage-gated calcium and sodium channels. Studies in clinical populations suggest that pharmacological adjuncts to TMS may rescue motor cortex plasticity, with implications for therapeutic applications of TMS and a promising clinical trial in depression.

Limitations: This review is limited by the predominance in the literature of studies with small sample sizes and crossover designs.

Conclusion: Pharmacologically enhanced TMS largely parallels findings from ex vivo preparations. As this area expands and novel targets are tested, adequately powered samples in healthy and clinical populations will inform the mechanisms of TMS-induced plasticity in health and disease.

Background: Environmental modification of genetic information (epigenetics) is often invoked to explain interindividual differences in the phenotype of schizophrenia. In clinical practice, such variability is most prominent in the symptom profile and the treatment response. Epigenetic regulation of immune function is of particular interest, given the therapeutic relevance of this mechanism in schizophrenia.

Methods: We analyzed the DNA methylation data of immune-relevant genes in patients with schizophrenia whose disease duration was less than 3 years, with previous lifetime antipsychotic treatment of no more than 2 weeks total.

Results: A total of 441 patients met the inclusion criteria. Core symptoms were consistently associated with 206 methylation positions, many of which had previously been implicated in inflammatory responses. Of these, 24 methylation positions were located either in regulatory regions or near the CpG islands of 20 genes, including the SRC gene, which is a key player in glutamatergic signalling. These symptom-associated immune genes were enriched in neuronal development functions, such as neuronal migration and glutamatergic synapse. Compared with using only clinical information (including scores on the Positive and Negative Syndrome Scale), integrating methylation data into the model significantly improved the predictive ability (as indicated by area under the curve) for response to 8 weeks of antipsychotic treatment.

Limitations: We focused on a small number of methylation probes (immune-centred search) and lacked nutritional data and direct brain-based measures.

Conclusion: Epigenetic modifications of the immune system are associated with symptom severity at onset and subsequent treatment response in schizophrenia.

Background: Susceptibility to schizophrenia is determined by interactions between genes and environment, possibly via epigenetic mechanisms. Schizophrenia has been associated with a restrictive epigenome, and histone deacetylase (HDAC) inhibitors have been postulated as coadjuvant agents to potentiate the efficacy of current antipsychotic drugs. We aimed to evaluate global histone posttranslational modifications (HPTMs) and HDAC expression and activity in the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia.

Methods: We used postmortem DLPFC samples of individuals with schizophrenia and controls matched for sex, age, and postmortem interval. Schizophrenia samples were classified into antipsychotic-treated or antipsychotic-free subgroups according to blood toxicology. Expression of HPTMs and HDAC was quantified by Western blot. HDAC activity was measured with a fluorometric assay.

Results: H3K9ac, H3K27ac, and H3K4me3 were globally enhanced in the DLPFC of individuals with schizophrenia (+24%-42%, p < 0.05). HDAC activity (-17%, p < 0.01) and HDAC4 protein expression (-20%, p < 0.05) were downregulated in individuals with schizophrenia. Analyses of antipsychotic-free and antipsychotic-treated subgroups revealed enhanced H3K4me3 and H3K27ac (+24%-49%, p < 0.05) and reduced HDAC activity in the antipsychotic-treated, but not in the antipsychotic-free subgroup.

Limitations: Special care was taken to control the effect of confounding factors: age, sex, postmortem interval, and storage time. However, replication studies in bigger cohorts might strengthen the association between permissive HPTMs and schizophrenia.

Conclusion: We found global HPTM alterations consistent with an aberrantly permissive epigenome in schizophrenia. Further studies to elucidate the significance of enhanced permissive HPTMs in schizophrenia and its association with the mechanism of action of antipsychotic drugs are encouraged.

Background: Depression is a prevalent nonmotor symptom in Parkinson disease and can greatly reduce the quality of life for patients; the dopamine receptors found in glutamatergic pyramidal cells in the medial prefrontal cortex (mPFC) play a role in regulating local field activity, which in turn affects behavioural and mood disorders. Given research showing that glial cell-derived neurotrophic factor (GDNF) may have an antidepressant effect, we sought to evaluate the impact of exogenous GDNF on depression-like behaviour in mouse models of Parkinson disease.

Methods: We used an established subacute model of Parkinson disease in mice involving intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), followed by brain stereotaxic injection of GDNF into the mPFC region. Subsequently, we assessed depression-like behaviour using the sucrose preference test, forced swimming test and tail suspension test, while also evaluating protein expression in the mPFC.

Results: We included 60 mice, divided into 3 groups, including a control group (saline injection), an MPTP plus saline injection group and an MPTP plus GDNF injection group. We found that exogenous GDNF injection into the mPFC led to an increase in dopamine receptor D1 (DRD1) protein levels. We also observed that activating the protein kinase A pathway through DRD1 produced a prolonged antidepressant response. Under GDNF stimulation, the expression of dopamine receptor D2 (DRD2) remained constant, suggesting that the DRD2 signal was ineffective in alleviating depression-like symptoms. Moreover, our investigation involved Golgi staining and Western blot techniques, which found enhanced synaptic plasticity, including increased dendritic branches, dendritic spines and retrograde protection after GDNF treatment in Parkinson disease models.

Limitations: A subtle motor phenotype became evident only toward the conclusion of the behavioural testing period. The study exclusively involved male mice, and no separate control group receiving only GDNF treatment was included in the experimental design.

Conclusion: Our findings support a positive effect of exogenous GDNF on synaptic plasticity, mediated by DRD1 signalling in the mPFC, which could facilitate depression remission in Parkinson disease.

Background: The interplay between state- and trait-related disruptions in structural networks remains unclear in bipolar disorder (BD), but graph theory can offer insights into global and local network changes. We sought to use diffusion-tensor imaging (DTI) and graph theory approaches to analyze structural topological properties across distinct mood states and identify high-risk individuals by examining state- and trait-related impairments in BD.

Methods: We studied changes in white matter network among patients with BD and healthy controls, exploring relationships with clinical variables. Secondary analysis involved comparing patients with BD with unaffected people at high genetic risk for BD.

Results: We included 152 patients with BD, including 52 with depressive BD (DBD), 64 with euthymic BD (EBD) and 36 with manic BD (MBD); we also included 75 healthy controls. Secondary analyses involved 27 unaffected people at high genetic risk for BD. Patients with DBD and MBD exhibited significantly lower global efficiencies than those with EBD and healthy controls, with patients with DBD showing the lowest global efficiencies. In addition, patients with DBD displayed impaired local efficiency and normalized clustering coefficient (γ). At a global level, γ correlated negatively with depression and anxiety. Compared with healthy controls, and across mood states, patients with BD showed abnormal shortest path lengths in the frontolimbic circuit, a trend mirrored among those at high genetic risk for BD.

Limitations: Considerations include medication effects, absence of recorded BD episode counts and the cross-sectional nature of the study.

Conclusion: Mood-specific whole-brain network metrics could serve as potential biomarkers in BD for transitions between mood states. Moreover, these findings contribute to evidence of trait-related frontolimbic circuit irregularities, shedding light on underlying pathophysiological mechanisms in BD.

Background: Deficits in prepulse inhibition may be a common feature in first-episode schizophrenia, bipolar disorder (BD) and major depressive disorder (MDD). We sought to explore the levels and viability of prepulse inhibition to differentiate first-episode schizophrenia, BD and MDD in patient populations.

Methods: We tested patients with first-episode schizophrenia, BD or MDD and healthy controls using prepulse inhibition paradigms, namely perceived spatial co-location (PSC-PPI) and perceived spatial separation (PSS-PPI).

Results: We included 53 patients with first-episode schizophrenia, 30 with BD and 25 with MDD, as well as 82 healthy controls. The PSS-PPI indicated that the levels of prepulse inhibition were smallest to largest, respectively, in the first-episode schizophrenia, BD, MDD and control groups. Relative to the healthy controls, the prepulse inhibition deficits in the first-episode schizophrenia group were significant (p < 0.001), but the prepulse inhibitions were similar between patients with BD and healthy controls, and between patients with MDD and healthy controls. The receiver operating characteristic curve analysis showed that PSS-PPI (area under the curve [AUC] 0.73, p < 0.001) and latency (AUC 0.72, p < 0.001) were significant for differentiating patients with first-episode schizophrenia or BD from healthy controls.

Limitations: The demographics of the 4 groups were not ideally matched. We did not perform cognitive assessments. The possible confounding effect of medications on prepulse inhibition could not be eliminated.

Conclusion: The level of prepulse inhibition among patients with first-episode schizophrenia was the lowest, with levels among patients with BD, patients with MDD and healthy controls increasingly higher. The PSS-PPI paradigm was more effective than PSC-PPI to recognize deficits in prepulse inhibition. These results provide a basis for further research on biological indicators that can assist differential diagnoses in psychosis.

Background: Numerous neuroimaging studies using surface-based morphometry analyses have reported altered cortical thickness among patients with schizophrenia, but the results have been inconsistent. We sought to provide a whole-brain meta-analysis, which may help enhance the spatial accuracy of identification.

Methods: We conducted a meta-analysis of whole-brain studies that explored cortical thickness alteration among adult patients with schizophrenia, including first-episode patients with schizophrenia, and patients with chronic schizophrenia, compared with healthy controls by using the seed-based d mapping with permutation of subject images (SDM-PSI) software.

Results: A systematic literature search identified 25 studies (33 data sets) of cortical thickness, including 2008 patients with schizophrenia and 2004 healthy controls. Overall, patients with schizophrenia showed decreased cortical thickness in the right inferior frontal gyrus (IFG) and bilateral insula extending to the superior temporal gyrus (STG). Subgroup meta-analysis reported that patients with chronic schizophrenia showed decreased cortical thickness in the right insula extending to the right IFG. There was no significant cortical thickness difference between first-episode patients with schizophrenia and healthy controls.

Limitations: The results of meta-regression analyses should be viewed cautiously since they were driven by a small number of studies or did not overlap with the between-group differences found in the primary analyses.

Conclusion: The meta-analysis suggested robust cortical thickness reduction in the IFG, insula and STG among adult patients with schizophrenia, particularly in those with chronic schizophrenia. The results provide useful insights to understanding the underlying pathophysiology of schizophrenia.

Background: Interhemispheric cooperation is one of the most prominent functional architectures of the human brain. In patients with schizophrenia, interhemispheric cooperation deficits have been reported using increasingly powerful neurobehavioural and neuroimaging measures. However, these methods rely in part on the assumption of anatomic symmetry between hemispheres. In the present study, we explored interhemispheric cooperation deficits in schizophrenia using a newly developed index, connectivity between functionally homotopic voxels (CFH), which is unbiased by hemispheric asymmetry.

Methods: Patients with schizophrenia and age- and sexmatched healthy controls underwent multimodal MRI, and whole-brain CFH maps were constructed for comparison between groups. We examined the correlations of differing CFH values between the schizophrenia and control groups using various neurotransmitter receptor and transporter densities.

Results: We included 86 patients with schizophrenia and 86 matched controls in our analysis. Patients with schizophrenia showed significantly lower CFH values in the frontal lobes, left postcentral gyrus and right inferior temporal gyrus, and significantly greater CFH values in the right caudate nucleus than healthy controls. Moreover, the differing CFH values in patients with schizophrenia were significantly correlated with positive symptom score and illness duration. Functional connectivity within frontal lobes was significantly reduced at the voxel cluster level compared with healthy controls. Finally, the abnormal CFH map of patients with schizophrenia was spatially associated with the densities of the dopamine D₁ and D₂ receptors, fluorodopa, dopamine transporter, serotonin transporter and acetylcholine transporter.

Conclusion: Regional abnormalities in interhemispheric cooperation may contribute to the clinical symptoms of schizophrenia. These CFH abnormalities may be associated with dysfunction in neurotransmitter systems strongly implicated in schizophrenia.