Activity In Schizophrenia Research Articles

Effects of olanzapine during cognitive and emotional processing in schizophrenia: A review of functional magnetic resonance imaging findings.

Olanzapine is an atypical antipsychotic that is widely used in the treatment of schizophrenia and has shown some degree of efficacy on negative and cognitive symptoms. We aimed to review the effects of olanzapine treatment on brain regions that are directly involved in cognitive and emotional processing. We used the PubMed database to perform a bibliographic search on functional magnetic resonance imaging studies that investigated the effects of olanzapine treatment on neural activity in patients with schizophrenia during cognitive and emotional tasks. Despite the high variability of tasks and analysis methods employed, the weight of the evidence was consistent with the hypothesis that olanzapine treatment is associated with a normalization of brain activity in schizophrenia. Distinctive functional changes were found in frontal cortex and cingulate cortex activity during both cognitive and emotional tasks. During emotional processing, olanzapine treatment seems to specifically regulate the activity of the striatum and limbic system. The results of the reviewed studies suggest that in patients with schizophrenia, olanzapine treatment might lead to a more physiological brain activity coupled with regulation of dopamine release. Future studies should further corroborate these hypotheses using larger samples and homogeneous experimental tasks.

Abnormal Entropy Modulation of the EEG Signal in Patients With Schizophrenia During the Auditory Paired-Stimulus Paradigm.

The complexity change in brain activity in schizophrenia is an interesting topic clinically. Schizophrenia patients exhibit abnormal task-related modulation of complexity, following entropy of electroencephalogram (EEG) analysis. However, complexity modulation in schizophrenia patients during the sensory gating (SG) task, remains unknown. In this study, the classical auditory paired-stimulus paradigm was introduced to investigate SG, and EEG data were recorded from 55 normal controls and 61 schizophrenia patients. Fuzzy entropy (FuzzyEn) was used to explore the complexity of brain activity under the conditions of baseline (BL) and the auditory paired-stimulus paradigm (S1 and S2). Generally, schizophrenia patients showed significantly higher FuzzyEn values in the frontal and occipital regions of interest (ROIs). Relative to the BL condition, the normalized values of FuzzyEn of normal controls were decreased greatly in condition S1 and showed less variance in condition S2. Schizophrenia patients showed a smaller decrease in the normalized values in condition S1. Moreover, schizophrenia patients showed significant diminution in the suppression ratios of FuzzyEn, attributed to the higher FuzzyEn values in condition S1. These results suggested that entropy modulation during the process of sensory information and SG was obvious in normal controls and significantly deficient in schizophrenia patients. Additionally, the FuzzyEn values measured in the frontal ROI were positively correlated with positive scores of Positive and Negative Syndrome Scale (PANSS), indicating that frontal entropy was a potential indicator in evaluating the clinical symptoms. However, negative associations were found between the FuzzyEn values of occipital ROIs and general and total scores of PANSS, likely reflecting the compensation effect in visual processing. Thus, our findings provided a deeper understanding of the deficits in sensory information processing and SG, which contribute to cognitive deficits and symptoms in patients with schizophrenia.

Unsuccessful reduction of high-frequency alpha activity during cognitive activation in schizophrenia.

Electroencephalogram (EEG) alpha activity during resting state reflects the 'readiness' of an individual to respond to the environment; this includes the performance of cognitive processes. Alpha activity is reported to be attenuated in schizophrenia (SCZ). Understanding the interaction between alpha activity during rest and when cognitively engaged may provide insights into the neural circuitry, which is dysfunctional in SCZ. This study investigated the changes of alpha activity between resting state and cognitive engagement in SCZ patients. Thirty-four SCZ patients and 29 healthy controls (HC) were recruited. EEG was performed in the resting state and during an auditory P300 task. All experimental procedures followed the relevant institutional guidelines and regulations. In SCZ, high-frequency alpha activity was reduced in the resting state. High-frequency alpha source density was decreased in both the resting-state and a P300 task condition in patients, compared to HC. HC, but not SCZ patients, showed a reduction in high-frequency alpha source density during the P300 task compared to the resting state. The negative correlation between high-frequency alpha source density in the resting state and positive symptoms was significant. High-frequency alpha activity in SCZ patients and its unsuccessful reduction during cognitive processing may be biological markers of SCZ.

Reduced SNAP25 Protein Fragmentation Contributes to SNARE Complex Dysregulation in Schizophrenia Postmortem Brain

Recent studies associated schizophrenia with enhanced functionality of the presynaptic SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex. Altered degradation pathways of the three core SNARE proteins: synaptosomal-associated protein 25 (SNAP25), syntaxin-1 and vesicle-associated membrane protein (VAMP) could contribute to enhanced complex function. To investigate these pathways, we first identified a 15-kDa SNAP25 fragment (f-S25) in human and rat brains, highly enriched in synaptosomal extractions, and mainly attached to cytosolic membranes with low hydrophobicity. The presence of f-S25 is consistent with reports of calpain-mediated SNAP25 cleavage. Co-immunoprecipitation assays showed that f-S25 retains the ability to bind syntaxin-1, which might prevent VAMP and/or Munc18-1 assembly into the complex. Quantitative analyses in postmortem human orbitofrontal cortex (OFC) revealed that schizophrenia (n = 35), but not major depression (n = 15), is associated with lower amounts of f-S25 (−37%, P = 0.027), and greater SNARE protein–protein interactions (35%, P < 0.001), compared with healthy matched controls (n = 28). Enhanced SNARE complex formation was strongly correlated with lower SNAP25 fragmentation rates (R = 0.563, P < 0.001). Statistical mediation analyses supported the hypothesis that reduced f-S25 density could upregulate SNARE fusion events in schizophrenia. Cortical calpain activity in schizophrenia did not differ from controls. f-S25 levels did not correlate with total calpain activity, indicating that if present, schizophrenia-related calpain dysfunction might occur locally at the presynaptic terminals. Overall, the present findings suggest the existence of an endogenous SNARE complex inhibitor related to SNAP25 proteolysis, associated with enhanced SNARE activity in schizophrenia.

Where There’s Smoke, There’s Fire—But Who Is Lighting the Match? Bolstering Transcriptional Evidence for the Role of Nuclear Factor-κB in Neuroimmune Activation in Schizophrenia

Where There’s Smoke, There’s Fire—But Who Is Lighting the Match? Bolstering Transcriptional Evidence for the Role of Nuclear Factor-κB in Neuroimmune Activation in Schizophrenia

Multimodal neuroimaging evidence for looser lexico-semantic networks in schizophrenia:Evidence from masked indirect semantic priming

It has been hypothesized that schizophrenia is characterized by overly broad automatic activity within lexico-semantic networks. We used two complementary neuroimaging techniques, Magnetoencephalography (MEG) and functional Magnetic Resonance Imaging (fMRI), in combination with a highly automatic indirect semantic priming paradigm, to spatiotemporally localize this abnormality in the brain.Eighteen people with schizophrenia and 20 demographically-matched control participants viewed target words (“bell”) preceded by directly related (“church”), indirectly related (“priest”), or unrelated (“hammer”) prime words in MEG and fMRI sessions. To minimize top-down processing, the prime was masked, the target appeared only 140 ms after prime onset, and participants simply monitored for words within a particular semantic category that appeared in filler trials.Both techniques revealed a significantly larger automatic indirect priming effect in people with schizophrenia than in control participants. MEG temporally localized this enhanced effect to the N400 time window (300–500 ms) — the critical stage of accessing meaning from words. fMRI spatially localized the effect to the left temporal fusiform cortex, which plays a role in mapping of orthographic word-form on to meaning. There was no evidence of an enhanced automatic direct semantic priming effect in the schizophrenia group.These findings provide converging neural evidence for abnormally broad highly automatic lexico-semantic activity in schizophrenia. We argue that, rather than arising from an unconstrained spread of automatic activation across semantic memory, this broader automatic lexico-semantic activity stems from looser mappings between the form and meaning of words.

Rigidity in Motor Behavior and Brain Functioning in Patients With Schizophrenia and High Levels of Apathy.

The aim of this study was to investigate whether apathy in schizophrenia is associated with rigidity in behavior and brain functioning. To this end, we studied associations between variability in dynamic functional connectivity (DFC) in relevant functional brain networks, apathy, and variability in physical activity in schizophrenia. Thirty-one patients with schizophrenia, scoring high on apathy, were included and wore an actigraph. Activity variability was calculated on the activity counts using the root of the Mean Squared Successive Difference (MSSD). Furthermore, we calculated DFC on resting-state data as phase interactions between blood oxygen-level dependent (BOLD) signals of 270 brain regions per volume. Variability (MSSD) in DFC was calculated for 3 networks, including the default-mode network (DMN), frontoparietal network, and salience-reward network (SRN). Finally, we calculated correlations between these DFC estimates and apathy and activity variability. First, lower activity variability was associated with higher levels of apathy. Second, higher levels of apathy were associated with lower variability in DFC in the DMN and SRN. Third, higher activity variability was associated with higher variability in DFC in the SRN. In conclusion, patients with schizophrenia and more severe levels of apathy showed less variability in their physical activity and more rigid functional brain network behavior in the DMN and SRN. These networks have been shown relevant for self-reflection, mental simulation, and reward processing, processes that are pivotal for self-initiated goal-directed behavior. Functional rigidity of these networks may therefore contribute to reduced goal-directed behavior, which is characteristic for these patients.

The Role of the Nuclear Factor-κB Transcriptional Complex in Cortical Immune Activation in Schizophrenia

BackgroundTranscript levels for cytokines and the viral restriction factor interferon-induced transmembrane protein are markedly higher in the prefrontal cortex in schizophrenia. These gene products are regulated by the nuclear factor-κB (NF-κB) transcriptional complex. NF-κB activity, which requires the formation of NF-κB family member heterodimers, is regulated by activation receptors, kinases, and inhibitors. Whether any of these factors are altered in schizophrenia is not known. It is also unclear whether NF-κB-related disturbances reflect ongoing cortical immune activation or a long-lasting response to a prenatal immune-related insult. MethodsTranscript levels for NF-κB pathway markers were assessed using quantitative polymerase chain reaction in the prefrontal cortex from 1) 62 matched pairs of schizophrenia and unaffected comparison subjects, 2) antipsychotic-exposed monkeys, and 3) adult mice exposed prenatally to maternal immune activation or in adulthood to the immune stimulant polyinosinic-polycytidylic acid. ResultsIn schizophrenia subjects, but not antipsychotic-exposed monkeys, we found higher messenger RNA levels for 1) most NF-κB family members, 2) all NF-κB activation receptors, 3) several kinases, and 4) one inhibitor (IκBα) whose transcript level is itself regulated by NF-κB activity. A similar pattern of elevated NF-κB-related messenger RNA levels was seen in adult mice that received daily polyinosinic-polycytidylic acid injections, but not in adult mice subjected to maternal immune activation in utero. ConclusionsHigher NF-κB activity, evidenced by elevated transcript levels for NF-κB family members, activation receptors, and kinases, may contribute to increased markers of cortical immune activation in schizophrenia.

Altered Persistence of Brain Activity in Schizophrenia during Working Memory Tasks

We studied the dynamic properties of the blood oxygenation level-dependent (BOLD) time series of patients diagnosed with schizophrenia both at resting state and during working memory tasks, by computing a key measure from complexity science, the Hurst exponent (H), using Adaptive Fractal Analysis (AFA). 44 participants meeting the DSM-IV criteria for schizophrenia and 77 healthy controls underwent fMRI scanning at 3.0 T at resting state and during Paired associate Memory Task and Spatial Working Memory Task. Mean H for all the 116 brain regions extracted from Anatomical Automatic Labeling (AAL) template as well as the whole brain were generated and analyzed for each subject based on voxel by voxel time series. At resting state, 103 of 116 brain regions showed significantly reduced H, suggesting overwhelmingly less persistent spontaneous brain activity in patients with schizophrenia at whole brain level and region level. While performing working memory task, only prefrontal cortex (PFC), anterior cingulate cortex (ACC) presented significantly lower H. Either resting state or working memory tasks, H of healthy controls showed wide variation from region to region, while patients with schizophrenia were the opposite. The result provides evidence that brain activity of schizophrenia is associated with weaker persistence and more randomness in signal patterns compared to healthy controls at resting state; PFC and ACC are critical area for working memory; schizophrenia is characterized by limited resource allocation capability.

Effects of DISC1 Polymorphisms on Resting-State Spontaneous Neuronal Activity in the Early-Stage of Schizophrenia

Background: Localized abnormalities in the synchrony of spontaneous neuronal activity, measured with regional homogeneity (ReHo), has been consistently reported in patients with schizophrenia (SCZ) and their unaffected siblings. To date, little is known about the genetic influences affecting the spontaneous neuronal activity in SCZ. DISC1, a strong susceptible gene for SCZ, has been implicated in neuronal excitability and synaptic function possibly associated with regional spontaneous neuronal activity. This study aimed to examine the effects of DISC1 variations on the regional spontaneous neuronal activity in SCZ.Methods: Resting-state fMRI data were obtained from 28 SCZ patients and 21 healthy controls (HC) for ReHo analysis. Six single nucleotide polymorphisms (SNPs) of DISC1 gene were genotyped using the PCR and direct sequencing.Results: Significant diagnosis × genotype interactions were noted for three SNPs (rs821616, rs821617, and rs2738880). For rs821617, the interactions were localized to the precuneus, basal ganglia and pre-/post-central regions. Significant interactive effects were identified at the temporal and post-central gyri for rs821616 (Ser704Cys) and the inferior temporal gyrus for rs2738880. Furthermore, post-hoc analysis revealed that the DISC1 variations on these SNPs exerted different influences on ReHo between SCZ patients and HC.Conclusion: To our knowledge this is the first study to unpick the influence of DISC1 variations on spontaneous neuronal activity in SCZ; Given the emerging evidence that ReHo is a stable inheritable phenotype for schizophrenia, our findings suggest the DISC1 variations are possibly an inheritable source for the altered ReHo in this disorder.

F236. CLONIDINE NORMALIZES MMN IN SCHIZOPHRENIA PATIENTS ON STABLE MEDICATION

BackgroundSchizophrenia is a severe brain disorder with profound deficits in prefrontal cortical cognitive functioning. These cognitive deficits form a core feature in schizophrenia for which treatment has been proven to be clinically challenging. One of the key neurotransmitters involved in cognitive functioning is noradrenaline. Previous research has demonstrated disrupted noradrenergic activity in schizophrenia while several studies report improvements in prefrontal cognitive functioning by a selective α2-agonist. Clonidine is such a selective α2A-agonist and previous research in our lab has demonstrated that a (range of) single dosage(s) of clonidine normalize(s) sensory gating in chronically ill, yet stably medicated patients with schizophrenia. Currently, we investigated if clonidine also normalizes Mismatch Negativity (MMN) deficits in this same group of patients. This is important, since reports have shown that MMN amplitude is associated with negative symptoms and cognitive functioning in schizophrenia.MethodsIn a pseudo-randomized, double-blind, placebo-controlled experiment twenty chronically ill, yet stably medicated, male patients with schizophrenia were tested with the MMN paradigm from the Copenhagen Psychophysiological Test-Battery (CPTB) on 5 different occasions, each separated by a week. Four hours prior to testing patients were randomized administered either a placebo (non psycho-active compound) or a single dose of 25, 50, 75 or 150 μg of clonidine (Catapresan) on top of their usual medication on each occasion, in such a way that each patient received every dose once. Patients were matched on age and gender with 20 healthy controls (HC), who did not receive any treatment. The MMN paradigm consisted of 1800 stimuli with 4 types of stimuli: 1 standard (1000 Hz, 50 ms) presented 82% of the time and 3 types of deviants, based on either frequency (FreqMMN: 1200 Hz, 50 ms), duration (DurMMN: 1000 Hz, 100 ms) or their combination (FreqDurMMN: 1200 Hz, 100 ms) each with a probability of 6%. All stimuli had an intensity of 75dB and were presented with an interstimulus interval randomized between 300 and 500 ms. Subjects were requested to ignore all stimuli and were therefore watching a (muted) nature documentary.ResultsIn the placebo condition, patients had significantly reduced DurMMN and FreqDurMMN amplitude compared to HC, whereas FreqMMN did not show significant group differences. Furthermore, all doses of clonidine normalized FreqDurMMN amplitude in such a way that it was not significantly different anymore from the HC, while DurMMN only normalized with the highest dose (150ug).DiscussionOur results indicate disrupted MMN amplitude in chronically ill patients with schizophrenia in spite of the fact that they were stable on their medical treatment. In addition, our data provide evidence that a single dose of clonidine is able to normalize MMN amplitude in these patients. Furthermore, patients could not distinguish between the placebo and the treatment conditions or reported any side effects of these low doses of clonidine. Together with our previous reports indicating normalized sensory and sensorimotor gating in these patients following administration of clonidine, our results could be of potential high clinical relevance in the treatment of schizophrenia. Future studies should therefore focus on longer trial periods to investigate if clonidine, besides normalizing MMN amplitude and sensory(motor) gating, can also ameliorate negative symptoms and cognitive functioning in schizophrenia.

T140. RESTING STATE NETWORKS ALTERATION IN SCHIZOPHRENIA

BackgroundWhile functional MRI and PET studies have shown altered task-related brain activity in schizophrenia, recent studies suggest that such differences might also be found in the resting state (RS). Here we used ICA based analysis to investigate RS fMRI data to compare connectivity of 11 well known networks (Auditory, Cerebellum, DMN, Exectutive Control, Fronto-parietal 1, Fronto-parietal 2, Salience, Sensorimotor, Visual1, Visual2, Visual3 network) between patients with schizophrenia and healthy controls suggesting deficits in related neuropsychological functions.MethodsWe obtained RS fMRI series (3T, 3x3x3mm resolution, 45 slices, TR 2.55s, 210 volumes) in 25 schizophrenia patients (mean age 30a±7.3), on stable antipsychotic medication and 25 matched healthy controls (30.3a±8.6). Subjects were asked to lie in the scanner keeping eyes closed with no further specific instructions. Data were pre-processed; we applied FSL MELODIC (pICA) yielding IC, we used FIX to auto-classify ICA components which represent artifacts and an automated routine to select for each subject the component matching the anatomical definition of resting state networks. SPM12 was used for second level analysis, we used two sample t-test to compare networks functional connectivity between groups. We then analysed the power spectrum density (PSD) for the extracted networks, estimating the power of the signal at different frequencies.ResultsOur method reliably identified all networks in every control and patients. We found significant differences in the anatomical pattern of areas. Patients showed decreased functional connectivity in comparison to healthy controls in portions of Cerebellum, DMN, Executive Control, Fronto-parietal1 and sensorimotor networks; in addition patients showed increased functional connectivity in comparison to healthy controls in portions of DMN network. Finally, PSD was found altered in patients with Schizophrenia when compared to healthy controls in Fronto-parietal1, Sensorimotor, visual1and visual2 networks.DiscussionWell known resting state networks were reliable identified from RS fMRI in Schizophrenia patients. The differences in anatomical distribution point to possible alterations in functional connectivity in Schizophrenia, which suggests disruption in Cerebellum, DMN, Executive control, Fronto-parietal and sensorimotor activity. The comparison of the PSD suggests changes in Fronto-parietal1, Sensorimotor and in addition visual1, visual2 networks.

Alterations in resting-state gamma activity in patients with schizophrenia: a high-density EEG study.

Alterations of EEG gamma activity in schizophrenia have been reported during sensory and cognitive tasks, but it remains unclear whether changes are present in resting state. Our aim was to examine whether changes occur in resting state, and to delineate those brain regions where gamma activity is altered. Furthermore, we wanted to identify the associations between changes in gamma activity and psychopathological characteristics. We studied gamma activity (30-48Hz) in 60 patients with schizophrenia and 76 healthy controls. EEGs were acquired in resting state with closed eyes using a high-density, 256-channel EEG-system. The two groups were compared in absolute power measures in the gamma frequency range. Compared to controls, in patients with schizophrenia the absolute power was significantly elevated (false discovery rate corrected p < 0.05). The alterations clustered into fronto-central and posterior brain regions, and were positively associated with the severity of psychopathology, measured by the PANSS. Changes in gamma activity can lead to disturbed coordination of large-scale brain networks. Thus, the increased gamma activity in certain brain regions that we found may result in disturbances in temporal coordination of task-free/resting-state networks in schizophrenia. Positive association of increased gamma power with psychopathology suggests that altered gamma activity provides a contribution to symptom presentation.

The impact of cognitive remediation on cerebral activity in schizophrenia: Systematic review of the literature.

Contextcognitive remediation involves either intensive training of impaired functions or implementing strategies to compensate for these impairments. In cases of schizophrenia, both methods have demonstrated benefits in terms of behavior and cerebral activity. However, despite the major differences between these two approaches, their impact has not yet been compared.MethodWe searched the PsychInfo, Pubmed, and ScienceDirect databases using the key words “cognitive remediation,” “schizophrenia,” “cerebral activity,” and “magnetic resonance imaging,” in order to select studies investigating the effects of cognitive remediation on patients with schizophrenia. The studies selected had to present their approach in detail and measure its impact in terms of both cerebral activity and cognitive function, both before and after therapy. We divided the studies into two groups, those using the strategy method and those using the training method.ResultsEight studies were included in the review, four for the strategy method (88 patients, 44 of whom underwent remediation) and 4 for the training method (87 patients, 43 of whom underwent remediation). The analysis of the results of this study indicates that the training method is capable of activating more the targeted brain areas than the strategy method. However, the latter appears to encourage more extensive activation of the cerebral networks.DiscussionThe studies used for this review vary widely in terms of the imaging methods and protocol. However, differences were found between the two methods and lead us to suggest that further studies, with proper bias control, should be conducted to systematically compare the two approaches.

Effects of four atypical antipsychotics on autonomic nervous system activity in schizophrenia

Effects of four atypical antipsychotics on autonomic nervous system activity in schizophrenia

Chapter 25 - Mapping pathologic circuitry in schizophrenia

Schizophrenia is a complex disorder lacking an effective treatment option for the pervasive and debilitating cognitive impairments experienced by patients. Working memory is a core cognitive function impaired in schizophrenia that depends upon activation of distributed neural network, including the circuitry of the dorsolateral prefrontal cortex (DLPFC). Accordingly, individuals diagnosed with schizophrenia show reduced DLPFC activation while performing working-memory tasks. This lower DLPFC activation appears to be an integral part of the disease pathophysiology, and not simply a reflection of poor performance. Thus, the cellular and circuitry alterations that underlie lower DLPFC neuronal activity in schizophrenia must be determined in order to identify appropriate therapeutic targets. Studies using human postmortem brain tissue provide a robust way to investigate and characterize these cellular and circuitry alterations at multiple levels of resolution, and such studies provide essential information that cannot be obtained either through in vivo studies in humans or through experimental animal models. Studies examining neuronal morphology, protein expression and localization, and transcript levels indicate that a microcircuit composed of excitatory pyramidal cells and inhibitory interneurons containing the calcium-binding protein parvalbumin is altered in the DLPFC of subjects with schizophrenia and likely contributes to DLPFC dysfunction.

CaMKIIα expression in a mouse model of NMDAR hypofunction schizophrenia: Putative roles for IGF-1R and TLR4

Schizophrenia (SCZ) is a neuropsychiatric disorder that is linked to social behavioral deficits and other negative symptoms associated with hippocampal synaptic dysfunction. Synaptic mechanism of schizophrenia is characterized by loss of hippocampal N-Methyl-d-Aspartate Receptor (NMDAR) activity (NMDAR hypofunction) and dendritic spines. Previous studies show that genetic deletion of hippocampal synaptic regulatory calcium-calmodulin dependent kinase II alpha (CaMKIIα) cause synaptic and behavioral defects associated with schizophrenia in mice. Although CaMKIIα is involved in modulation of NMDAR activity, it is equally linked to inflammatory and neurotropin signaling in neurons. Based on these propositions, we speculate that non-neurotransmitter upstream receptors associated with neurotropic and inflammatory signaling activities of CaMKIIα may alter its synaptic function. Besides, how these receptors (i.e. inflammatory and neurotropic receptors) alter CaMKIIα function (phosphorylation) relative to hippocampal NMDAR activity in schizophrenia is poorly understood. Here, we examined the relationship between toll-like receptor (TLR4; inflammatory), insulin-like growth factor receptor 1 (IGF-1R; neurotropic) and CaMKIIα expression in the hippocampus of behaviorally deficient schizophrenic mice after we induced schizophrenia through NMDAR inhibition.Schizophrenia was induced in WT (C57BL/6) mice through intraperitoneal administration of 30mg/Kg ketamine (NMDAR antagonist) for 5days (WT/SCZ). Five days after the last ketamine treatment, wild type schizophrenic mice show deficiencies in sociability and social novelty behavior. Furthermore, there was a significant decrease in hippocampal CaMKIIα (p<0.001) and IGF-1R (p<0.001) expression when assessed through immunoblotting and confocal immunofluorescence microscopy. Additionally, WT schizophrenic mice show an increased percentage of phosphorylated CaMKIIα in addition to upregulated TLR4 signaling (TLR4, NF-κB, and MAPK/ErK) in the hippocampus. To ascertain the functional link between TLR4, IGF-1R and CaMKIIα relative to NMDAR hypofunction in schizophrenia, we created hippocampal-specific TLR4 knockdown mouse using AAV-driven Cre-lox technique (TLR4 KD). Subsequently, we inhibited NMDAR function in TLR4 KD mice in an attempt to induce schizophrenia (TLR4 KD SCZ). Interestingly, IGF-1R and CaMKIIα expressions were preserved in the TLR4 KD hippocampus after attenuation of NMDAR function. Furthermore, TLR4 KD SCZ mice showed no prominent defects in sociability and social novelty behavior when compared with the control (WT).Our results show that a sustained IGF-1R expression may preserve the synaptic activity of CaMKIIα while TLR4 signaling ablates hippocampal CaMKIIα expression in NMDAR hypofunction schizophrenia. Together, we infer that IGF-1R depletion and increased TLR4 signaling are non-neurotransmitter pro-schizophrenic cues that can reduce synaptic CaMKIIα activity in a pharmacologic mouse model of schizophrenia.

Linked functional network abnormalities during intrinsic and extrinsic activity in schizophrenia as revealed by a data-fusion approach.

Abnormalities in functional brain networks in schizophrenia have been studied by examining intrinsic and extrinsic brain activity under various experimental paradigms. However, the identified patterns of abnormal functional connectivity (FC) vary depending on the adopted paradigms. Thus, it is unclear whether and how these patterns are inter-related. In order to assess relationships between abnormal patterns of FC during intrinsic activity and those during extrinsic activity, we adopted a data-fusion approach and applied partial least square (PLS) analyses to FC datasets from 25 patients with chronic schizophrenia and 25 age- and sex-matched normal controls. For the input to the PLS analyses, we generated a pair of FC maps during the resting state (REST) and the auditory deviance response (ADR) from each participant using the common seed region in the left middle temporal gyrus, which is a focus of activity associated with auditory verbal hallucinations (AVHs). PLS correlation (PLS-C) analysis revealed that patients with schizophrenia have significantly lower loadings of a component containing positive FCs in default-mode network regions during REST and a component containing positive FCs in the auditory and attention-related networks during ADR. Specifically, loadings of the REST component were significantly correlated with the severities of positive symptoms and AVH in patients with schizophrenia. The co-occurrence of such altered FC patterns during REST and ADR was replicated using PLS regression, wherein FC patterns during REST are modeled to predict patterns during ADR. These findings provide an integrative understanding of altered FCs during intrinsic and extrinsic activity underlying core schizophrenia symptoms.

PET imaging of putative microglial activation in individuals at ultra-high risk for psychosis, recently diagnosed and chronically ill with schizophrenia

We examined putative microglial activation as a function of illness course in schizophrenia. Microglial activity was quantified using [11C](R)-(1-[2-chrorophynyl]-N-methyl-N-[1-methylpropyl]-3 isoquinoline carboxamide (11C-(R)-PK11195) positron emission tomography (PET) in: (i) 10 individuals at ultra-high risk (UHR) of psychosis; (ii) 18 patients recently diagnosed with schizophrenia; (iii) 15 patients chronically ill with schizophrenia; and, (iv) 27 age-matched healthy controls. Regional-binding potential (BPND) was calculated using the simplified reference-tissue model with four alternative reference inputs. The UHR, recent-onset and chronic patient groups were compared to age-matched healthy control groups to examine between-group BPND differences in 6 regions: dorsal frontal, orbital frontal, anterior cingulate, medial temporal, thalamus and insula. Correlation analysis tested for BPND associations with gray matter volume, peripheral cytokines and clinical variables. The null hypothesis of equality in BPND between patients (UHR, recent-onset and chronic) and respective healthy control groups (younger and older) was not rejected for any group comparison or region. Across all subjects, BPND was positively correlated to age in the thalamus (r=0.43, P=0.008, false discovery rate). No correlations with regional gray matter, peripheral cytokine levels or clinical symptoms were detected. We therefore found no evidence of microglial activation in groups of individuals at high risk, recently diagnosed or chronically ill with schizophrenia. While the possibility of 11C-(R)-PK11195-binding differences in certain patient subgroups remains, the patient cohorts in our study, who also displayed normal peripheral cytokine profiles, do not substantiate the assumption of microglial activation in schizophrenia as a regular and defining feature, as measured by 11C-(R)-PK11195 BPND.

The complement system: a gateway to gene-environment interactions in schizophrenia pathogenesis.

The pathogenesis of schizophrenia is considered to be multi-factorial, with likely gene-environment interactions (GEI). Genetic and environmental risk factors are being identified with increasing frequency, yet their very number vastly increases the scope of possible GEI, making it difficult to identify them with certainty. Accumulating evidence suggests a dysregulated complement pathway among the pathogenic processes of schizophrenia. The complement pathway mediates innate and acquired immunity, and its activation drives the removal of damaged cells, autoantigens and environmentally-derived antigens. Abnormalities in complement functions occur in many infectious and auto-immune disorders that have been linked to schizophrenia. Many older reports indicate altered serum complement activity in schizophrenia, though the data are inconclusive. Compellingly, recent genome-wide association studies suggest repeat polymorphisms incorporating the complement 4A (C4A) and 4B (C4B) genes as risk factors for schizophrenia. The C4A/C4B genetic associations have re-ignited interest not only in inflammation-related models for schizophrenia pathogenesis, but also in neurodevelopmental theories, because rodent models indicate a role for complement proteins in synaptic pruning and neurodevelopment. Thus, the complement system could be used as one of the ‘staging posts’ for a variety of focused studies of schizophrenia pathogenesis. They include GEI studies of the C4A/C4B repeat polymorphisms in relation to inflammation-related or infectious processes, animal model studies and tests of hypotheses linked to auto-immune diseases that can co-segregate with schizophrenia. If they can be replicated, such studies would vastly improve our understanding of pathogenic processes in schizophrenia through GEI analyses and open new avenues for therapy.