Role In Pathophysiology Of Schizophrenia Research Articles

White matter microstructure alterations of the posterior limb of internal capsule in first-episode drug naive schizophrenia patients

ObjectivesPrevious studies have shown that microstructural alterations in white matter (WM) could contribute to the symptom manifestation and support the dysconnectivity hypothesis in schizophrenia patients. These alterations were pervasive, non-specific, and reported inconsistently across the literature. This study aimed to specifically investigate the microstructure alterations of the posterior limb of the internal capsule (PLIC) in first-episode, drug-naive schizophrenia patients. Utilizing a multicompartmental biophysical model, we further explored the correlation between these alterations and syndrome scale scores. MethodsThirty-two individuals with first-episode, drug-naive schizophrenia (FES) and thirty demographically matched healthy controls were enrolled. High-resolution multi-shell diffusion MRI data were collected, followed by the application of a three-compartment Neurite Orientation Dispersion and Density Imaging (NODDI) model to scrutinize the alterations in white matter microstructure. Changes in sensory and motor fibers within the PLIC were specifically focused on. Additionally, the correlation between these pathological changes and scores on the Positive and Negative Syndrome Scale (PANSS) was investigated. ResultsThe Neurite density index (NDI) in the left PLIC was significantly lower in FES patients compared to healthy individuals, and positively correlated with PANSS positive syndrome scores (r = 0.0379, p = 0.046). In the sensory component (left superior thalamic radiation within PLIC, STR_P), the NDI was significantly elevated (p < 0.0001). Conversely, the NDI in the motor component (left corticospinal tract within PLIC, CST_P) was reduced (p = 0.007) in FES patients compared to healthy individuals, and strongly correlated with PANSS positive syndrome scores (p < 0.020) and PANSS total scores (p < 0.045). Moreover, the NDI deviation of STR from total PLIC (fSTR_P) and NDI deviation in STR_P and CST_P compared to PLIC region (fPLIC) were significantly higher in FES patients than in healthy controls (p < 0.00001), with an area under the curve (AUC) of fPLIC reaching 0.872. ConclusionThe study’s findings provided new insights into the discrepancy of white matter microstructure changes associated with the sensory and motor fibers in the PLIC region in FES patients. These results contribute to the growing body of evidence suggesting that WM microstructural alterations play a critical role in schizophrenia pathophysiology.

Schizophrenia and Glutathione: A Challenging Story.

Schizophrenia (SZ) is a devastating mental illness with a complex and heterogeneous clinical state. Several conditions like symptoms, stage and severity of the disease are only some of the variables that have to be considered to define the disorder and its phenotypes. SZ pathophysiology is still unclear, and the diagnosis is currently relegated to the analysis of clinical symptoms; therefore, the search for biomarkers with diagnostic relevance is a major challenge in the field, especially in the era of personalized medicine. Though the mechanisms implicated in SZ are not fully understood, some processes are beginning to be elucidated. Oxidative stress, and in particular glutathione (GSH) dysregulation, has been demonstrated to play a crucial role in SZ pathophysiology. In fact, glutathione is a leading actor of oxidative-stress-mediated damage in SZ and appears to reflect the heterogeneity of the disease. The literature reports differing results regarding the levels of glutathione in SZ patients. However, each GSH state may be a sign of specific symptoms or groups of symptoms, candidating glutathione as a biomarker useful for discriminating SZ phenotypes. Here, we summarize the literature about the levels of glutathione in SZ and analyze the role of this molecule and its potential use as a biomarker.

Exploring the Association between Schizophrenia and Cardiovascular Diseases: Insights into the Role of Sigma 1 Receptor.

Contemporary society is characterized by rapid changes. Various epidemiological, political and economic crises represent a burden to mental health of nowadays population, which may at least partially explain the increasing incidence of mental disorders, including schizophrenia. Schizophrenia is associated with premature mortality by at least 13-15 years. The leading cause of premature mortality in schizophrenia patients is high incidence of cardiovascular diseases. The specific-cause mortality risk for cardiovascular diseases in schizophrenia patients is more than twice higher as compared to the general population. Several factors are discussed as the factor of cardiovascular diseases development. Intensive efforts to identify possible link between schizophrenia and cardiovascular diseases are made. It seems that sigma 1 receptor may represent such link. By modulation of the activity of several neurotransmitter systems, including dopamine, glutamate, and GABA, sigma 1 receptor might play a role in pathophysiology of schizophrenia. Moreover, significant roles of sigma 1 receptor in cardiovascular system have been repeatedly reported. The detailed role of sigma 1 receptor in both schizophrenia and cardiovascular disorders development however remains unclear. The article presents an overview of current knowledge about the association between schizophrenia and cardiovascular diseases and proposes possible explanations with special emphasis on the role of the sigma 1 receptor.

L-Carnitine Prevents Behavioural Alterations in Ketamine-Induced Schizophrenia in Mice: Possible Involvement of Oxidative Stress and Inflammation Pathways.

Schizophrenia is a chronic mental complaint known as cognitive impairment. There has been evidence that inflammation and oxidative stress play a main role in schizophrenia pathophysiology. This study aimed to investigate the effects of l-carnitine, as a potent antioxidant, on the treatment of behavioural and biochemical disturbances in mice with ketamine-induced schizophrenia. In this study, schizophrenia was induced in mice by ketamine (25 mg/kg/day, i.p). Before induction of schizophrenia, mice were treated with l-carnitine (100, 200, and 400 mg/kg/day, i.p). Then, behavioural impairments were evaluated by open field (OF) assessment and social interaction test (SIT). After brain tissue isolation, reactive oxygen species (ROS), glutathione concentration (GSH), lipid peroxidation (LPO), protein carbonyl oxidation, superoxide dismutase activity (SOD), and glutathione peroxidase activity (GPx) were assessed as oxidative stress markers. Furthermore, inflammatory biomarkers such as tumour necrosis factor alpha (TNF-α) and nitric oxide (NO) were evaluated in brain tissue. Our results showed ketamine increased inflammation and oxidative damage in brain tissue that was similar to behaviour disorders in mice. Interestingly, l-carnitine significantly decreased oxidative stress and inflammatory markers compared with ketamine-treated mice. In addition, l-carnitine prevented and reversed ketamine-induced alterations in the activities of SOD and GPx enzymes in mice's brains. Also, improved performance in OFT (locomotor activity test) and SIT was observed in l-carnitine-treated mice. These data provided evidence that, due to the antioxidant and anti-inflammatory effects of l-carnitine, it has a neuroprotective effect on mice model of schizophrenia.

Modulation of Hippocampal Network Oscillation by PICK1-Dependent Cell Surface Expression of mGlu3 Receptors.

Metabotropic glutamate receptor Type 3 (mGlu3) controls the sleep/wake architecture, which plays a role in the glutamatergic pathophysiology of schizophrenia. Interestingly, mGlu3 receptor expression is decreased in the brain of schizophrenic patients. However, little is known about the molecular mechanisms regulating mGlu3 receptors at the cell membrane. Subcellular receptor localization is strongly dependent on protein-protein interactions. Here we show that mGlu3 interacts with PICK1 and that this scaffolding protein is important for mGlu3 surface expression and function in hippocampal primary cultures. Disruption of their interaction via an mGlu3 C-terminal mimicking peptide or an inhibitor of the PDZ domain of PICK1 altered the functional expression of mGlu3 receptors in neurons. We next investigated the impact of disrupting the mGlu3-PICK1 interaction on hippocampal theta oscillations in vitro and in vivo in WT male mice. We found a decreased frequency of theta oscillations in organotypic hippocampal slices, similar to what was previously observed in mGlu3 KO mice. In addition, hippocampal theta power was reduced during rapid eye movement sleep, non-rapid eye movement (NREM) sleep, and wake states after intraventricular administration of the mGlu3 C-terminal mimicking peptide. Targeting the mGlu3-PICK1 complex could thus be relevant to the pathophysiology of schizophrenia.SIGNIFICANCE STATEMENT Dysregulation of the glutamatergic system might play a role in the pathophysiology of schizophrenia. Metabotropic glutamate receptors Type 3 (mGlu3) have been proposed as potential targets for schizophrenia. Understanding the molecular mechanisms regulating mGlu3 receptor at the cell membrane is critical toward comprehending how their dysfunction contributes to the pathogenesis of schizophrenia. Here we describe that the binding of the signaling and scaffolding protein PICK1 to mGlu3 receptors is important for their localization and physiological functions. The identification of new proteins that associate specifically to mGlu3 receptors will advance our understanding of the regulatory mechanisms associated with their targeting and function and ultimately might provide new therapeutic strategies to counter these psychiatric conditions.

Magnetic resonance imaging of the dopamine system in schizophrenia - A scoping review.

For decades, aberrant dopamine transmission has been proposed to play a central role in schizophrenia pathophysiology. These theories are supported by human in vivo molecular imaging studies of dopamine transmission, particularly positron emission tomography. However, there are several downsides to such approaches, for example limited spatial resolution or restriction of the measurement to synaptic processes of dopaminergic neurons. To overcome these limitations and to measure complementary aspects of dopamine transmission, magnetic resonance imaging (MRI)-based approaches investigating the macrostructure, metabolism, and connectivity of dopaminergic nuclei, i.e., substantia nigra pars compacta and ventral tegmental area, can be employed. In this scoping review, we focus on four dopamine MRI methods that have been employed in patients with schizophrenia so far: neuromelanin MRI, which is thought to measure long-term dopamine function in dopaminergic nuclei; morphometric MRI, which is assumed to measure the volume of dopaminergic nuclei; diffusion MRI, which is assumed to measure fiber-based structural connectivity of dopaminergic nuclei; and resting-state blood-oxygenation-level-dependent functional MRI, which is thought to measure functional connectivity of dopaminergic nuclei based on correlated blood oxygenation fluctuations. For each method, we describe the underlying signal, outcome measures, and downsides. We present the current state of research in schizophrenia and compare it to other disorders with either similar (psychotic) symptoms, i.e., bipolar disorder and major depressive disorder, or dopaminergic abnormalities, i.e., substance use disorder and Parkinson’s disease. Finally, we discuss overarching issues and outline future research questions.

Multimodal Magnetic Resonance Imaging Depicts Widespread and Subregion Specific Anomalies in the Thalamus of Early-Psychosis and Chronic Schizophrenia Patients.

Although the thalamus has a central role in schizophrenia pathophysiology, contributing to sensory, cognitive, and sleep alterations, the nature and dynamics of the alterations occurring within this structure remain largely elusive. Using a multimodal magnetic resonance imaging (MRI) approach, we examined whether anomalies: (1) differ across thalamic subregions/nuclei, (2) are already present in the early phase of psychosis (EP), and (3) worsen in chronic schizophrenia (SCHZ). T1-weighted and diffusion-weighted images were analyzed to estimate gray matter concentration (GMC) and microstructural parameters obtained from the spherical mean technique (intra-neurite volume fraction [VFINTRA)], intra-neurite diffusivity [DIFFINTRA], extra-neurite mean diffusivity [MDEXTRA], extra-neurite transversal diffusivity [TDEXTRA]) within 7 thalamic subregions. Compared to age-matched controls, the thalamus of EP patients displays previously unreported widespread microstructural alterations (VFINTRA decrease, TDEXTRA increase) that are associated with similar alterations in the whole brain white matter, suggesting altered integrity of white matter fiber tracts in the thalamus. In both patient groups, we also observed more localized and heterogenous changes (either GMC decrease, MDEXTRA increase, or DIFFINTRA decrease) in mediodorsal, posterior, and ventral anterior parts of the thalamus in both patient groups, suggesting that the nature of the alterations varies across subregions. GMC and DIFFINTRA in the whole thalamus correlate with global functioning, while DIFFINTRA in the subregion encompassing the medial pulvinar is significantly associated with negative symptoms in SCHZ. Our data reveals both widespread and more localized thalamic anomalies that are already present in the early phase of psychosis.

Cannabis Use in Autism: Reasons for Concern about Risk for Psychosis.

Being particularly vulnerable to the pro-psychotic effects of cannabinoid exposure, autism spectrum individuals present with an increased risk of psychosis, which may be passed on to their own children. More specifically, cannabis exposure among autism spectrum individuals seems to exert disruptive epigenetic effects that can be intergenerationally inherited in brain areas which play a critical role in schizophrenia pathophysiology. Additionally, because of such cannabinoid-induced epigenetic effects, autism candidate genes present with bivalent chromatin markings which make them more vulnerable to subsequent disruption, possibly leading to psychosis onset later in life. Thus, findings support a developmental trajectory between autism and psychosis, as per endocannabinoid system modulation. However, such evidence has not received the attention it deserves.

Free Papers Compiled

Background:Schizophrenia is a chronic disease. It is characterized by disorders of thought, perceptions, sense of self and behavior. It was found that stress play an important role in pathophysiology of schizophrenia. It is time to know regarding particular type of stress experienced by schizophrenic patient.AIMS:Aim of our study was to find out perceived stress in patient with schizophrenia and correlation with psychopathology.METHODS:We had assessed total 100 participants (50 patients with schizophrenia and 50 healthy controls). We applied PANSS to assess psychopathology and we applied students stress dimension questionnaire (SSDQ) to assess stress loading. Correlation between Psychopathology and stress was analyzed by using Pearson’s correlation.RESULTS:Mean of PANSS score among patients with schizophrenia was 65.56 (SD 13.58). Mean of cumulative stress loading on SSDQ was 341.23 (SD 77.61) in patients with schizophrenia and 226.97 (SD 69.14) in healthy control. We found that there was negative correlation between PANSS and cumulative stress loading. Pearson’s correlation coefficient between PANSS and cumulative stress loading was r : 0.522 ( p value .000).CONCLUSION:Positive correlation between Psychopathology and stress is found. It clears that it’s time to address stress in patient with schizophrenia and non pharmacotherapy for stress must be included in patient with schizophrenia.

Shared Biological Pathways between Antipsychotics and Omega-3 Fatty Acids: A Key Feature for Schizophrenia Preventive Treatment?

Schizophrenia typically emerges during adolescence, with progression from an ultra-high risk state (UHR) to the first episode of psychosis (FEP) followed by a chronic phase. The detailed pathophysiology of schizophrenia and the factors leading to progression across these stages remain relatively unknown. The current treatment relies on antipsychotics, which are effective for FEP and chronic schizophrenia but ineffective for UHR patients. Antipsychotics modulate dopaminergic and glutamatergic neurotransmission, inflammation, oxidative stress, and membrane lipids pathways. Many of these biological pathways intercommunicate and play a role in schizophrenia pathophysiology. In this context, research of preventive treatment in early stages has explored the antipsychotic effects of omega-3 supplementation in UHR and FEP patients. This review summarizes the action of omega-3 in various biological systems involved in schizophrenia. Similar to antipsychotics, omega-3 supplementation reduces inflammation and oxidative stress, improves myelination, modifies the properties of cell membranes, and influences dopamine and glutamate pathways. Omega-3 supplementation also modulates one-carbon metabolism, the endocannabinoid system, and appears to present neuroprotective properties. Omega-3 has little side effects compared to antipsychotics and may be safely prescribed for UHR patients and as an add-on for FEP patients. This could to lead to more efficacious individualised treatments, thus contributing to precision medicine in psychiatry.

Chapter 8 - The implications of hypothalamic abnormalities for schizophrenia

Until a few years ago, the hypothalamus was believed to play only a marginal role in schizophrenia pathophysiology. However, recent findings show that this rather small brain region involved in many pathways found disrupted-in schizophrenia. Gross anatomic abnormalities (volume changes of the third ventricle, the hypothalamus, and its individual nuclei) as well as alterations at the cellular level (circumscribed loss of neurons) can be observed. Further, increased or decreased expression of hypothalamic peptides such as oxytocin, vasopressin, several factors involved in the regulation of appetite and satiety, endogenous opiates, products of schizophrenia susceptibility genes as well as of enzymes involved in neurotransmitter and neuropeptide metabolism have been reported in schizophrenia and/or animal models of the disease. Remarkably, although profound disturbances of the hypothalamus-pituitary-adrenal axis, hypothalamus-pituitary-thyroid axis, and the hypothalamus-pituitary-gonadal axis are typical signs of schizophrenia, there is currently no evidence for alterations in the expression of hypothalamic-releasing and inhibiting factors that control these hormonal axes. Finally, the implications of hypothalamus for disease-related disturbances of the sleep-wakefulness cycle and neuroimmune dysfunctions in schizophrenia are outlined.

The origin of NMDA receptor hypofunction in schizophrenia.

N-methyl-d-aspartate (NMDA) receptor (NMDAR) hypofunction plays a key role in pathophysiology of schizophrenia. Since NMDAR hypofunction has also been reported in autism, Alzheimer's disease and cognitive dementia, it is crucial to identify the location, timing, and mechanism of NMDAR hypofunction for schizophrenia for better understanding of disease etiology and for novel therapeutic intervention. In this review, we first discuss the shared underlying mechanisms of NMDAR hypofunction in NMDAR antagonist models and the anti-NMDAR autoantibody model of schizophrenia and suggest that NMDAR hypofunction could occur in GABAergic neurons in both models. Preclinical models using transgenic mice have shown that NMDAR hypofunction in cortical GABAergic neurons, in particular parvalbumin-positive fast-spiking interneurons, in the early postnatal period confers schizophrenia-related phenotypes. Recent studies suggest that NMDAR hypofunction can also occur in PV-positive GABAergic neurons with alterations of NMDAR-associated proteins, such as neuregulin/ErbB4, α7nAChR, and serine racemase. Furthermore, several environmental factors, such as oxidative stress, kynurenic acid and hypoxia, may also potentially elicit NMDAR hypofunction in GABAergic neurons in early postnatal period. Altogether, the studies discussed here support a central role for GABAergic abnormalities in the context of NMDAR hypofunction. We conclude by suggesting potential therapeutic strategies to improve the function of fast-spiking neurons.

ECT-Induced Effects on Hippocampal Structure and Function and Its Differences in Schizophrenia Remission and Non-Remission Patients

Background: Modified electroconvulsive therapy (MECT) is considered as a treatment option in drug-resistant schizophrenia (SZ). But approximately one-third of patients do not benefit from MECT in clinic. Thus it is high significance to investigate differences between MECT responders and non-responders. Accumulated evidence indicated that one of MECT action regions is the hippocampus, which also plays an important role in SZ pathophysiology. To date, no studies have investigated the differences of MECT effects to hippocampus between treatment responders and non-responders. Methods: This study recruited twenty-one SZ patients treated by four-weeks MECT (MSZ, n=21) and twenty-one SZ patients who received pharmaceutical therapy (DSZ, n=21). The MSZ was further classified to responders (MSR, n=10) or non-responders (MNR, n=11) according to treatment outcomes by the criterion of 50% PANSS total reductive ratio. Using structural and resting-state functional MRI, we measured the hippocampal volume and functional connectivity (FC) in all SZ patients (before and after treatment) and 23 healthy controls. Results: Contrast to pharmaceutical therapy, MECT induced bilateral hippocampal volume increases in MSZ. Both of MSR and MNR exhibited a hippocampus expansion after MECT, whereas a lesser baseline volume at one of hippomcapal subfield (hippocampus-amygdala transition area) was found in MNR. After MECT, increased FC between the hippocampus and brain networks associated with cognitive functions was only observed in MSR. Conclusions: MECT action mechanism in schizophrenia is complex. A combination of baseline impairment level, MECT-introduced morphological changes and post-ECT FC increases at the hippocampus may jointly contribute to the post-ECT symptom improvements in SZ. Funding Statement: This study was funded by grants from the National Nature Science Foundation of China (grant number: 81861128001, 61761166001, 81471638, 81771822, 81571759, 81660233, 81671332), the Program for Changjiang Scholars and Innovative Research Team Project (IRT0910), the ‘111’ Project (B12027) and grants from Ministry of Science and Technology of China (2016YFC1306800) and SHSMU-ION Research Center for Brain Disorders (2015NKX001). Declaration of Interests: The authors state: There is no conflict of interest. Ethics Approval Statement: The Ethics Committee of SMHC approved the study protocol. Written informed consent was obtained from all subjects prior to study participation.

Early enriched environment prevents cognitive impairment in an animal model of schizophrenia induced by MK-801: Role of hippocampal BDNF

Early life experience has long-lasting effects on brain and behaviour. This study aims to investigate the long-term effects of enriched environment (EE), which was imposed during the animals’ development, on their recognition memory as well as hippocampal levels of brain-derived neurotrophic factor (BDNF), in an animal model of schizophrenia induced by chronic postnatal administration of MK-801. Forty male and female rat pups were separated in four distinct groups for each sex (n = 10). The rats were injected with MK-801 (1 mg/kg) or saline (1 cc/kg) on their postnatal days (P) 6–10. MK-801 and Control rats were maintained in standard or enriched cages (containing toys, tunnels, running wheels, and climbing frame), from their birth up to the time of behavioral experiments at P60. Neonatal challenge with MK-801 significantly impaired novel object recognition (NOR) in both male and female animals. EE exposure reversed the recognition memory only in male rats. MK-801 resulted in decreased levels of BDNF in the hippocampus, and EE exposure restored the decreased level. Our results provide evidence that BDNF plays an important role in pathophysiology of schizophrenia in the present animal model, and is a possible mechanism through which early EE can enhance the cognitive functions.

Antipsychotic Drug Responsiveness and Dopamine Receptor Signaling; Old Players and New Prospects.

Antipsychotic drugs targeting dopamine neurotransmission are still the principal mean of therapeutic intervention for schizophrenia. However, about one third of people do not respond to dopaminergic antipsychotics. Genome wide association studies (GWAS), have shown that multiple genetic factors play a role in schizophrenia pathophysiology. Most of these schizophrenia risk variants are not related to dopamine or antipsychotic drugs mechanism of action. Genetic factors have also been implicated in defining response to antipsychotic medication. In contrast to disease risk, variation of genes coding for molecular targets of antipsychotics have been associated with treatment response. Among genes implicated, those involved in dopamine signaling mediated by D2-class dopamine receptor, including DRD2 itself and its molecular effectors, have been implicated as key genetic predictors of response to treatments. Studies have also reported that genetic variation in genes coding for proteins that cross-talk with DRD2 at the molecular level, such as AKT1, GSK3B, Beta-catenin, and PPP2R2B are associated with response to antipsychotics. In this review we discuss the relative contribution to antipsychotic drug responsiveness of candidate genes and GWAS identified genes encoding proteins involved in dopamine responses. We also suggest that in addition of these older players, a deeper investigation of new GWAS identified schizophrenia risk genes such as FXR1 can provide new prospects that are not clearly engaged in dopamine function while being targeted by dopamine-associated signaling molecules. Overall, further examination of genes proximally or distally related to signaling mechanisms engaged by medications and associated with disease risk and/or treatment responsiveness may uncover an interface between genes involved in disease causation with those affecting disease remediation. Such a nexus would provide realistic targets for therapy and further the development of genetically personalized approaches for schizophrenia.

Common increased hippocampal volume but specific changes in functional connectivity in schizophrenia patients in remission and non-remission following electroconvulsive therapy: A preliminary study.

Electroconvulsive therapy (ECT) is considered a treatment option in patients with drug-resistant schizophrenia (SZ). However, approximately one-third of patients do not benefit from ECT in the clinic. Thus, it is critical to investigate differences between ECT responders and non-responders. Accumulated evidence has indicated that one region of ECT action is the hippocampus, which also plays an important role in SZ pathophysiology. To date, no studies have investigated differences in ECT effects in the hippocampus between treatment responders and non-responders. This study recruited twenty-one SZ patients treated for four weeks with ECT (MSZ, n = 21) and twenty-one SZ patients who received pharmaceutical therapy (DSZ, n = 21). The MSZ group was further categorized into responders (MSR, n = 10) or non-responders (MNR, n = 11) based on treatment outcomes by the criterion of a 50% reduction in the Positive and Negative Syndrome Scale total scores. Using structural and resting-state functional MRI, we measured the hippocampal volume and functional connectivity (FC) in all SZ patients (before and after treatment) and 23 healthy controls. In contrast to pharmaceutical therapy, ECT induced bilateral hippocampal volume increases in the MSZ. Both the MSR and MNR exhibited hippocampal expansion after ECT, whereas a lower baseline volume in one of hippocampal subfield (hippocampus-amygdala transition area) was found in the MNR. After ECT, increased FC between the hippocampus and brain networks associated with cognitive function was only observed in the MSR. The mechanism of action of ECT in schizophrenia is complex. A combination of baseline impairment level, ECT-introduced morphological changes and post-ECT FC increases in the hippocampus may jointly contribute to the post-ECT symptom improvements in patients with SZ.

Functional and Structural Connectivity of the Cerebellar Nuclei With the Striatum and Cerebral Cortex in First-Episode Psychosis.

Evidence suggests that the cortico-striatal-thalamo-cortical circuitry plays an important role in schizophrenia pathophysiology. Cerebellar contribution from deep cerebellar nuclei to the circuitry has not yet been examined. The authors investigated resting-state functional connectivity (RSFC) of cerebellar output nuclei with striatal-thalamic-cortical regions in relation to white-matter integrity and regional gray-matter volumes in first-episode psychosis (FEP). Methods: Forty FEP patients and 40 age- and gender-matched healthy control subjects (HCs) participated. RSFC between cerebellar nuclei and striatal-thalamic-cortical regions was examined. Diffusion tensor imaging and volumetric scans were examined for possible structural constraints on RSFC. The authors also examined relationships between neuroimaging variables and cognitive and clinical measures. Results: FEP patients, compared with HCs, exhibited decreased RSFC between the left fastigial nucleus and right putamen, which was associated with poor letter fluency performance and lower global assessment of functioning scores. By contrast, patients showed widespread increased accumbens network connectivity in the left nucleus. The authors further observed both hypo- and hyper-RSFC between the cerebellar nuclei and fronto-parietal areas in patients, independent of striatal activity. Finally, the authors found impaired integrity of the left superior cerebellar peduncle and decreased bilateral putamen volume in patients, whereas structural-functional relationships found in HCs were absent in patients. Conclusions: This study provides evidence of disordered RSFC of cerebellar output nuclei to the striatum and neocortex at the early stage of schizophrenia. Furthermore, dysfunctional cerebellar influences on fronto-parietal areas that are independent of striatal dysfunction in patients with FEP were observed. The results suggest that cortico-striatal abnormalities in patients with FEP are produced by abnormal cerebellar influences.

Plasma levels of IL-1Ra are associated with schizophrenia.

Although peripheral low-grade inflammation and brain-derived neurotrophic factor (BDNF) levels have been implicated in schizophrenia (SCZ), the interactions between them remain to be fully revealed. We aimed to compare BDNF and cytokines in patients with SCZ and healthy controls (HC). Additionally, we aimed to investigate the association between peripheral levels of cytokines and BDNF in patients with SCZ. Plasma levels of BDNF, interferon gamma, interleukin (IL)-10, IL-12, IL-1, IL-6, IL-8, tumor necrosis factor alpha, macrophage migration inhibitory factor, IL-1 receptor antagonist (IL-1Ra), and CD40 Ligand were compared in 45 SCZ patients and 38 HC using Luminex technology. Compared to HC, patients had significantly higher IL-1Ra levels (P = 0.031). We found a strong positive association between BDNF and CD40 Ligand in the patient group (rho = 0.858, P < 0.001) as well as in the HC group (rho = 0.822, P < 0.001), respectively. Furthermore, there was a negative association between BDNF and tumor necrosis factor alpha in patients (rho = -0.429, P = 0.030) as well as in HC (rho = -0.649, P < 0.001). These results suggest that the cytokine IL-1Ra may play a role in SCZ pathophysiology. Additionally, the interaction between cytokines and BDNF levels further indicated the diverse actions of these cytokines.

Association of CCL11 promoter polymorphisms with schizophrenia in a Korean population

BackgroundImmunological alterations and dysregulation of the inflammatory response have been suggested to play a crucial role in schizophrenia pathophysiology. Growing evidence supports the involvement of chemokines in brain development, thus many chemokines have been studied in relation with schizophrenia. The C-C motif chemokine ligand 11 (CCL11) has been shown to be related with synaptic plasticity and neurogenesis. Moreover, altered levels of CCL11 have been observed in schizophrenia patients. Therefore, we examined whether single nucleotide polymorphisms (SNPs) of the CCL11 in the promoter region contribute to susceptibility to schizophrenia. MethodsFour promoter SNPs [rs17809012 (-384T>C), rs16969415 (-426C>T), rs17735961 (-488C>A), and rs4795896 (576G>A)] were genotyped in 254 schizophrenia patients and 405 control subjects using Fluidigm SNPtype assays. ResultsThe genotype frequency of CCL11 rs4795896 (-576G>A) showed significant association with schizophrenia in a recessive model (AA vs. GG/AG, p < 0.0001) and in a log-additive model (AG vs. AA vs. GG, p < 0.0001). The allele frequency of rs4795896 also showed a significant association with schizophrenia (p < 0.0001). Furthermore, haplotype analysis revealed that GCT, ACT, and GCC haplotypes containing rs4795896, rs17735961 and rs17809012 were significantly associated with schizophrenia (p = 0.0044, p < 0.0001, and p < 0.0001, respectively). ConclusionOur results suggest that CCL11 promotor polymorphism is associated with increased risk for the development of schizophrenia in a Korean population.

Evaluaton of regional cerebral blood flow alterations by limbic activation in patients with schizophrenia

The aim of study is to evaluate the functions of limbic system in schizophrenia by performing procaine administration and using single photon emission computed tomography (SPECT). 22 patients and 19 controls were included in the study. Patients were evaluated with Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), Hamilton Rating Scale for Depression (HAM-D) and Hamilton Rating Scale for Anxiety (HAM-A), Calgary Depression Rating Scale for Schizophrenia (CDSS) and the controls were evaluated with BPRS, HAM-D and HAM-A. The regional cerebral blood flow (rCBF) values were measured by SPECT. The rCBF following placebo and the alteration ratios of the rCBF following procaine of patients compared to controls. The rCBF following placebo in bilateral frontal, bilateral superior temporal, bilateral parahippocampus, thalamus, insula and alteration ratios of rCBF following procaine in bilateral anterior cingulate cortex (ACC) and left thalamus of patients were lower. Poor limbic activation to procaine was observed in the ACC and left thalamus of patients with schizophrenia. These findings support that the ACC and thalamus are crucial role in pathophysiology of schizophrenia.