Deficits In Schizophrenia Research Articles

Elevations in the Mitochondrial Matrix Protein Cyclophilin D Correlate With Reduced Parvalbumin Expression in the Prefrontal Cortex of Patients With Schizophrenia.

Cognitive deficits in schizophrenia are linked to dysfunctions of the dorsolateral prefrontal cortex (DLPFC), including alterations in parvalbumin (PV)-expressing interneurons (PVIs). Redox dysregulation and oxidative stress may represent convergence points in the pathology of schizophrenia, causing dysfunction of GABAergic interneurons and loss of PV. Here, we show that the mitochondrial matrix protein cyclophilin D (CypD), a critical initiator of the mitochondrial permeability transition pore (mPTP) and modulator of the intracellular redox state, is altered in PVIs in schizophrenia. Western blotting was used to measure CypD protein levels in postmortem DLPFC specimens of schizophrenic patients (n = 27) and matched comparison subjects with no known history of psychiatric or neurological disorders (n = 26). In a subset of this cohort, multilabel immunofluorescent confocal microscopy with unbiased stereological sampling methods were used to quantify (1) numbers of PVI across the cortical mantle (20 unaffected comparison, 14 schizophrenia) and (2) PV and CypD protein levels from PVIs in the cortical layers 2-4 (23 unaffected comparison, 18 schizophrenia). In schizophrenic patients, the overall number of PVIs in the DLPFC was not significantly altered, but in individual PVIs of layers 2-4 PV protein levels decreased along a superficial-to-deep gradient when compared to unaffected comparison subjects. These laminar-specific PVI alterations were reciprocally linked to significant CypD elevations both in PVIs and total DLPFC gray matter. Our findings support previously reported PVI anomalies in schizophrenia and suggest that CypD-mediated mPTP formation could be a potential contributor to PVI dysfunction in schizophrenia.

Polygenic risk for major depression, attention deficit hyperactivity disorder, neuroticism, and schizophrenia are correlated with experience of intimate partner violence

Research has suggested that mental illness may be a risk factor for, as well as a sequela of, experiencing intimate partner violence (IPV). The association between IPV and mental illness may also be due in part to gene-environment correlations. Using polygenic risk scores for six psychiatric disorders - attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BPD), major depressive disorder (MDD), neuroticism, and schizophrenia—and a combined measure of overall genetic risk for mental illness, we tested whether women’s genetic risk for mental illness was associated with the experience of three types of intimate partner violence. In this cohort of women of European ancestry (N = 11,095), participants in the highest quintile of genetic risk for ADHD (OR range: 1.38–1.49), MDD (OR range: 1.28–1.43), neuroticism (OR range: (1.18–1.25), schizophrenia (OR range: 1.30–1.34), and overall genetic risk (OR range: 1.30–1.41) were at higher risk for experiencing more severe emotional and physical abuse, and, except schizophrenia, more severe sexual abuse, as well as more types of abuse and chronic abuse. In addition, participants in the highest quintile of genetic risk for neuroticism (OR = 1.43 95% CI: 1.18, 1.72), schizophrenia (OR = 1.33 95% CI: 1.10, 1.62), and the overall genetic risk (OR = 1.40 95% CI: 1.15, 1.71) were at higher risk for experiencing intimate partner intimidation and control. Participants in the highest quintile of genetic risk for ADHD, ASD, MDD, schizophrenia, and overall genetic risk, compared to the lowest quintile, were at increased risk for experiencing harassment from a partner (OR range: 1.22–1.92). No associations were found between genetic risk for BPD with IPV. A better understanding of the salience of the multiple possible pathways linking genetic risk for mental illness with risk for IPV may aid in preventing IPV victimization or re-victimization.

Functional Connectivity of Language-Related Cerebellar Regions Is Reduced in Schizophrenia Patients.

Schizophrenia (SZ) is a widespread psychiatric disorder that is traditionally characterized by positive and negative symptoms. However, recent focus has shifted to cognitive deficits as a crucial aspect. The cerebellum, conventionally tied to motor coordination, is now recognized as pivotal in the pathophysiology of SZ cognitive impairments. Proposed disruptions in the cortico-cerebellar-thalamic-cortico circuit contribute to these deficits. Despite evidence of cerebellar abnormalities, within-cerebellum functional connectivity is often overlooked. This study explores spontaneous functional interactions within the cerebellum and their link to cognitive deficits in SZ. Using a multi-domain task battery (MDTB) parcellation, fMRI data from SZ patients and healthy controls were analyzed. Significant differences in cerebellar connectivity emerged, particularly in regions related to attention, language, and memory processing. Correlations between connectivity values and SZ symptomatology were identified. A post hoc analysis, considering the patients' hallucination vulnerability, revealed distinct connectivity patterns. Non-hallucinating and low-hallucinating SZ patients exhibited higher cerebellar connectivity than high-hallucinating patients, especially in language and motor control regions. These findings suggest a gradient of cerebellar connectivity alterations corresponding to hallucination vulnerability in SZ patients. This study offers novel insights into cerebellar impairments in SZ, highlighting the role of within-cerebellum connectivity in cognitive deficits. The observed connectivity patterns in language-related regions contribute to understanding language development and auditory verbal hallucinations in SZ.

Trajectories and predictors of response to social cognition training in people with schizophrenia: A proof-of-concept machine learning study

BackgroundSocial cognition training (SCT) can improve social cognition deficits in schizophrenia. However, little is known about patterns of response to SCT or individual characteristics that predict response. Methods76 adults with schizophrenia randomized to receive 8–12 weeks of remotely-delivered SCT were included in this analysis. Social cognition was measured with a composite of six assessments. Latent class growth analyses identified trajectories of social cognitive response to SCT. Random forest and logistic regression models were trained to predict membership in the trajectory group that showed improvement from baseline measures including symptoms, functioning, motivation, and cognition. ResultsFive trajectory groups were identified: Group 1 (29 %) began with slightly above average social cognition, and this ability significantly improved with SCT. Group 2 (9 %) had baseline social cognition approximately one standard deviation above the sample mean and did not improve with training. Groups 3 (18 %) and 4 (36 %) began with average to slightly below-average social cognition and showed non-significant trends toward improvement. Group 5 (8 %) began with social cognition approximately one standard deviation below the sample mean, and experienced significant deterioration in social cognition. The random forest model had the best performance, predicting Group 1 membership with an area under the curve of 0.73 (SD 0.24; 95 % CI [0.51–0.87]). ConclusionsFindings suggest that there are distinct patterns of response to SCT in schizophrenia and that those with slightly above average social cognition at baseline may be most likely to experience gains. Results may inform future research seeking to individualize SCT treatment for schizophrenia.

A Narrative Review Exploring Attention Deficit/Hyperactivity Disorder in Patients with Early Psychosis.

While both Attention deficit hyperactivity disorder (ADHD) and schizophrenia are considered to have neurodevelopmental origins with associated impairments in executive functioning, there is a paucity of clinical guidelines pertaining specifically to this comorbidity. We sought to summarize the existing literature on ADHD in early psychosis patients, focusing on issues that would be most relevant to clinical practice. For this narrative review, we completed a search on PubMed and PsycINFO with 22 papers meeting criteria for review. Overall, it appears that a diagnosis of ADHD in childhood increases the risk of the subsequent development of a primary psychotic disorder. This risk may be modified by higher rates of substance use and could be related to shared premorbid risk factors for both conditions, such as obstetrical complications. Stimulant use has been associated with the onset of psychotic symptoms in some individuals, but it is unclear whether certain subgroups are more susceptible. Despite the fact that these two conditions co-occur relatively frequently, there is currently a lack of objective diagnostic tests for ADHD specific to populations with primary psychotic disorders, and a paucity of evidence on whether stimulants are effective for ADHD symptoms in this sub-group. Future research is warranted to investigate whether stimulant treatment confers any additional risks for symptom exacerbation in individuals with primary psychotic disorders taking antipsychotic maintenance treatment.

Polygenic effects on brain functional endophenotype for deficit and non-deficit schizophrenia

Deficit schizophrenia (DS) is a subtype of schizophrenia (SCZ). The polygenic effects on the neuroimaging alterations in DS still remain unknown. This study aims to calculate the polygenic risk scores for schizophrenia (PRS-SCZ) in DS, and further explores the potential associations with functional features of brain. PRS-SCZ was calculated according to the Whole Exome sequencing and Genome-wide association studies (GWAS). Resting-state fMRI, as well as biochemical features and neurocognitive data were obtained from 33 DS, 47 NDS and 41 HCs, and association studies of genetic risk with neuroimaging were performed in this sample. The analyses of amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo) and functional connectivity (FC) were performed to detect the functional alterations between DS and NDS. In addition, correlation analysis was used to investigate the relationships between functional features (ALFF, ReHo, FC) and PRS-SCZ. The PRS-SCZ of DS was significantly lower than that in NDS and HC. Compared to NDS, there was a significant increase in the ALFF of left inferior temporal gyrus (ITG.L) and left inferior frontal gyrus (IFG.L) and a significant decrease in the ALFF of right precuneus (PCUN.R) and ReHo of right middle frontal gyrus (MFG.R) in DS. FCs were widely changed between DS and NDS, mainly concentrated in default mode network, including ITG, PCUN and angular gyrus (ANG). Correlation analysis revealed that the ALFF of left ITG, the ReHo of right middle frontal gyrus, the FC value between insula and ANG, left ITG and right corpus callosum, left ITG and right PCUN, as well as the scores of Trail Making Test-B, were associated with PRS-SCZ in DS. The present study demonstrated the differential polygenic effects on functional changes of brain in DS and NDS, providing a potential neuroimaging-genetic perspective for the pathogenesis of schizophrenia.

Cannabidiol, cognition and schizophrenia: a narrative review

Schizophrenia is a serious mental disorder affecting about 1% of the population. It is characterised by multiple symptoms which are mostly responsive to treatment with antipsychotic medications. Cognitive impairment is regarded as a core feature of illness which is mostly poorly responsive to treatment with the current antipsychotic medications. Improving cognitive function is an important treatment goal as it is associated with better outcomes in employment and quality of life. Adjunctive pharmacological treatments have been examined to improve measures of cognition but with limited success. Cannabidiol (CBD), has shown promise in preclinical models of cognitive deficits of schizophrenia. On the other hand, limited studies in small groups of patients with schizophrenia have shown no significant clinical benefits for cognitive function as an adjunct to ongoing treatment with antipsychotics. A single trial, in which CBD as a standalone treatment was compared to the antipsychotic medication amisulpride, showed significant changes in cognitive measures for both agents, with no statistically significant difference between them. It might therefore be concluded that the preclinical findings have failed to translate to the clinic. However, the preclinical findings themselves are based on a circumscribed set of studies in multiple cognitive models and have used varying doses and routes of drug administration. The same general methodological issues are present in the suite of clinical studies. Issues such as patient heterogeneity in terms of illness duration, formulation and dose of CBD employed, and length of cannabinoid treatment might militate positive findings. The limited clinical database available makes the benefits (or lack thereof) of CBD for the cognitive effects of schizophrenia uncertain. Continued research in much larger patient populations than have so far been investigated as well as a consideration of dose ranging studies are required to fully assess the potential risks against the benefits of CBD treatment for cognitive deficits in schizophrenia.

A prefrontal network model operating near steady and oscillatory states links spike desynchronization and synaptic deficits in schizophrenia.

Schizophrenia results in part from a failure of prefrontal networks but we lack full understanding of how disruptions at a synaptic level cause failures at the network level. This is a crucial gap in our understanding because it prevents us from discovering how genetic mutations and environmental risks that alter synaptic function cause prefrontal network to fail in schizophrenia. To address that question, we developed a recurrent spiking network model of prefrontal local circuits that can explain the link between NMDAR synaptic and 0-lag spike synchrony deficits we recently observed in a pharmacological monkey model of prefrontal network failure in schizophrenia. We analyze how the balance between AMPA and NMDA components of recurrent excitation and GABA inhibition in the network influence oscillatory spike synchrony to inform the biological data. We show that reducing recurrent NMDAR synaptic currents prevents the network from shifting from a steady to oscillatory state in response to extrinsic inputs such as might occur during behavior. These findings strongly parallel dynamic modulation of 0-lag spike synchrony we observed between neurons in monkey prefrontal cortex during behavior, as well as the suppression of this 0-lag spiking by administration of NMDAR antagonists. As such, our cortical network model provides a plausible mechanism explaining the link between NMDAR synaptic and 0-lag spike synchrony deficits observed in a pharmacological monkey model of prefrontal network failure in schizophrenia.

Social cognition and social motivation in schizophrenia and bipolar disorder: are impairments linked to the disorder or to being socially isolated?

People with schizophrenia on average are more socially isolated, lonelier, have more social cognitive impairment, and are less socially motivated than healthy individuals. People with bipolar disorder also have social isolation, though typically less than that seen in schizophrenia. We aimed to disentangle whether the social cognitive and social motivation impairments observed in schizophrenia are a specific feature of the clinical condition v. social isolation generally. We compared four groups (clinically stable patients with schizophrenia or bipolar disorder, individuals drawn from the community with self-described social isolation, and a socially connected community control group) on loneliness, social cognition, and approach and avoidance social motivation. Individuals with schizophrenia (n = 72) showed intermediate levels of social isolation, loneliness, and social approach motivation between the isolated (n = 96) and connected control (n = 55) groups. However, they showed significant deficits in social cognition compared to both community groups. Individuals with bipolar disorder (n = 48) were intermediate between isolated and control groups for loneliness and social approach. They did not show deficits on social cognition tasks. Both clinical groups had higher social avoidance than both community groups. The results suggest that social cognitive deficits in schizophrenia, and high social avoidance motivation in both schizophrenia and bipolar disorder, are distinct features of the clinical conditions and not byproducts of social isolation. In contrast, differences between clinical and control groups on levels of loneliness and social approach motivation were congruent with the groups' degree of social isolation.

Imaging the Vesicular Acetylcholine Transporter in Schizophrenia: A Positron Emission Tomography Study Using [18F]-VAT

BackgroundDespite longstanding interest in the central cholinergic system in schizophrenia (SCZ), cholinergic imaging studies with patients have been limited to receptors. Here, we conducted a proof-of-concept positron emission tomography study using [18F]-VAT, a new radiotracer that targets the vesicular acetylcholine transporter as a proxy measure of acetylcholine transmission capacity, in patients with SCZ and explored relationships of vesicular acetylcholine transporter with clinical symptoms and cognition. MethodsA total of 18 adult patients with SCZ or schizoaffective disorder (the SCZ group) and 14 healthy control participants underwent a positron emission tomography scan with [18F]-VAT. Distribution volume (VT) for [18F]-VAT was derived for each region of interest, and group differences in VT were assessed with 2-sample t tests. Functional significance was explored through correlations between VT and scores on the Positive and Negative Syndrome Scale and a computerized neurocognitive battery (PennCNB). ResultsNo group differences in [18F]-VAT VT were observed. However, within the SCZ group, psychosis symptom severity was positively associated with VT in multiple regions of interest, with the strongest effects in the hippocampus, thalamus, midbrain, cerebellum, and cortex. In addition, in the SCZ group, working memory performance was negatively associated with VT in the substantia innominata and several cortical regions of interest including the dorsolateral prefrontal cortex. ConclusionsIn this initial study, the severity of 2 important features of SCZ—psychosis and working memory deficit—was strongly associated with [18F]-VAT VT in several cortical and subcortical regions. These correlations provide preliminary evidence of cholinergic activity involvement in SCZ and, if replicated in larger samples, could lead to a more complete mechanistic understanding of psychosis and cognitive deficits in SCZ and the development of therapeutic targets.

Lower-level oculomotor deficits in schizophrenia during multi-line reading: Evidence from return-sweeps.

Reading fluency deficits in schizophrenia (Sz) have been attributed to dysfunction in both lower-level, oculomotor processing and higher-level, lexical processing, according to the two-hit deficit model. Given that prior work examining reading deficits in individuals with Sz has primarily focused on single-line and single-word reading tasks, eye movements that are unique to passage reading, such as return-sweep saccades, have not yet been examined in Sz. Return-sweep saccades are large eye movements that are made when readers move from the end of one line to the beginning of the next line during natural passage reading. Examining return-sweeps provides an opportunity to examine lower-level, oculomotor deficits during reading under circumstances when upcoming higher-level, lexical information is not available for visual processing because visual acuity constraints do not permit detailed lexical processing of line-initial words when return-sweeps are programmed. To examine the source of reading deficits in Sz, we analysed an existing data set in which participants read multi-line passages with manipulations to line spacing. Readers with Sz made significantly more return-sweep targeting errors followed by corrective saccades compared with healthy controls. Both groups showed similar effects of line spacing on return-sweep targeting accuracy, suggesting similar sensitivities to visual crowding during reading. Furthermore, the patterns of fixation durations in readers with Sz corroborate prior work indicating reduced parafoveal processing of upcoming words. Together, these findings suggest that lower-level visual and oculomotor dysfunction contribute to reading deficits in Sz, providing support for the two-hit deficit model.

An event-related potential study of prepotent motor activity and response inhibition deficits in schizophrenia.

Response inhibition deficits in schizophrenia (SZ) are accompanied by reduced neural activities using event-related potential (ERP) measurements. However, it remains unclear whether the reduction in inhibition-related ERPs in SZ is contingent upon prepotent motor tendencies. This study aimed to examine the relationship between ERP markers of prepotent motor activity (lateralised readiness potential, LRP) and response inhibition (P3) by collecting behavioural and EEG data from healthy control (HC) subjects and SZ patients during a modified Go/No-Go task. A trial-averaged analysis revealed that SZ patients made more commission errors in No-Go trials compared with HC subjects, although there was no significant difference in the inhibition-related P3 effect (i.e. larger P3 amplitudes in No-Go compared with Go trials) between the two groups. Subsequently, No-Go trials were sorted and median-split into bins of stronger and weaker motor tendencies. Both HC and SZ participants made more commission errors when faced with stronger motor tendencies. The LRP-sorted P3 data indicated that HC subjects exhibited larger P3 effects in response to stronger motor tendencies, whereas this trial-by-trial association between P3 and motor tendencies was absent in SZ patients. Furthermore, SZ patients displayed diminished P3 effects in No-Go trials with stronger motor tendencies but not in trials with weaker motor tendencies, relative to HC subjects. Taken together, these findings suggest that SZ patients are unable to dynamically adjust inhibition-related neural activities in response to changing inhibitory control demands and emphasise the importance of considering prepotent motor activity when investigating the neural mechanisms underlying response inhibition deficits in SZ.

Immune dysregulation is associated with symptom dimensions and cognitive deficits in schizophrenia: accessible evidence from complete blood count

BackgroundSchizophrenia (SCZ) is a psychotic disorder with an unknown pathogenesis accompanied by varying degrees of cognitive deficits. Recent studies have shown that immune dysregulation plays an important role in developing symptoms and cognitive deficits in SCZ. This study aimed to determine the complete blood count (CBC), including white blood cells, neutrophils, monocytes, lymphocytes, platelets, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and monocyte-lymphocyte ratio (MLR), in patients with SCZ and explore their correlations with SCZ symptom dimensions and cognitive function.MethodsSeventy-four patients with SCZ and 57 age- and sex-matched healthy controls with available demographic and clinical information were recruited for this study. Blood samples were collected, and symptom dimensions and cognitive function were evaluated using the Positive and Negative Syndrome Scale (PANSS) and MATRICS Consensus Cognitive Battery (MCCB) separately.ResultsOur results demonstrate that SCZ patients showed higher monocyte counts, PLR, MLR, and worse performance in the total MCCB than healthy controls. Neutrophil and lymphocyte counts and NLR were positively related to symptom severity and negatively related to depressive symptoms. White blood cell (WBC) count, monocyte count, and MLR were positively correlated with cognitive performance in patients with SCZ.ConclusionIn summary, this study suggests that cognitive deficits and symptom severity in patients were associated with dysregulation of immunity. Moreover, we found that WBC could be used as a marker for symptom severity and cognitive deficits in SCZ and that neutrophils are more closely related to the former and monocytes to the latter. We hope that clinicians will pay more attention to dysregulated immunity in patients with SCZ in the future.

Multisensory integration deficits in Schizophrenia and Autism evidenced in behaviour but not event related potentials

The process of integrating information from different sensory channels, known as multisensory integration (MSI) was assessed in two disorders, Autism Spectrum Disorder (ASD) and Schizophrenia (SCZ). 32 healthy controls (HC), 35 SCZ patients, and 23 ASD patients performed an audiovisual (AV) synchronous target detection task while reaction time (RT) and scalp recorded electrophysiological (EEG) activity were measured. MSI in the AV condition resulted in faster and less variable RTs compared to the unimodal conditions. Using our novel bootstrap method, MSI gain was observed in 78 % of HC, 26 % of ASD, and 48 % of SCZ patients. At the neural level, MSI in the AV condition resulted in larger amplitude of sensory evoked responses and cognitive P3 response compared to the corresponding unimodal conditions. These neural effects of MSI were not related to the behavioural MSI gain identified at the individual level and could not explain the deficits in behavioural MSI of patient groups. In conclusion, a robust MSI gain deficit in RT was observed in both patient groups that was not reflected in early perceptual and cognitive electro-cortical responses, suggesting that behavioural MSI deficits in ASD and SCZ may arise at late processing stages such as response selection.

ЭМПИРИЧЕСКАЯ ТЕОРИЯ ФОРМИРОВАНИЯ ЭМОЦИОНАЛЬНОГО И ВОЛЕВОГО ДЕФИЦИТА ПРИ ШИЗОФРЕНИИ С ПРЕОБЛАДАНИЕМ НЕГАТИВНЫХ РАССТРОЙСТВ, ПОЛУЧЕННАЯ НА ОСНОВЕ АНАЛИЗА СВЯЗИ КЛИНИЧЕСКИХ И ГЕНЕТИЧЕСКИХ ДАННЫХ С ПРИМЕНЕНИЕМ ДСМ-МЕТОДА АВТОМАТИЗИРОВАННОЙ ПОДДЕРЖКИ ИССЛЕДОВАНИЙ

The study attempted to test experts' assumptions about the difference in the genetic mechanisms of the formation of emotional and volitional deficits in schizophrenia with predominance of negative disorders. The aim of the study is to create empirical theory of these two phenomena using an approach based on JSM-method for automated research support (JSM-method ARS). Polymorphisms of four genes associated with schizophrenia (BDNF, 5HTR2A, HTTLPR, ZNF804A) and clinical data presented as PANSS score were used as empirical data. The use of generalized JSM-method ARS, which generates ternary relationships “cause-blocker-effect”, allows us considering in detail the interaction of specific gene variants for emotional and volitional deficits in negative schizophrenia. The result of the study is confirmation of the experts' hypothesis about the difference in the mechanisms of these clinical manifestations. This conclusion was based on a comparison of knowledge fragments for two phenomena. The utilized approach can be extrapolated to a larger number of genes. We suggest that the use of the generalized JSM-method ARS is a promising approach to studying gene interactions in schizophrenia.

Giftedness and atypical sexual differentiation: enhanced perceptual functioning through estrogen deficiency instead of androgen excess.

Syndromic autism spectrum conditions (ASC), such as Klinefelter syndrome, also manifest hypogonadism. Compared to the popular Extreme Male Brain theory, the Enhanced Perceptual Functioning model explains the connection between ASC, savant traits, and giftedness more seamlessly, and their co-emergence with atypical sexual differentiation. Overexcitability of primary sensory inputs generates a relative enhancement of local to global processing of stimuli, hindering the abstraction of communication signals, in contrast to the extraordinary local information processing skills in some individuals. Weaker inhibitory function through gamma-aminobutyric acid type A (GABAA) receptors and the atypicality of synapse formation lead to this difference, and the formation of unique neural circuits that process external information. Additionally, deficiency in monitoring inner sensory information leads to alexithymia (inability to distinguish one's own emotions), which can be caused by hypoactivity of estrogen and oxytocin in the interoceptive neural circuits, comprising the anterior insular and cingulate gyri. These areas are also part of the Salience Network, which switches between the Central Executive Network for external tasks and the Default Mode Network for self-referential mind wandering. Exploring the possibility that estrogen deficiency since early development interrupts GABA shift, causing sensory processing atypicality, it helps to evaluate the co-occurrence of ASC with attention deficit hyperactivity disorder, dyslexia, and schizophrenia based on phenotypic and physiological bases. It also provides clues for understanding the common underpinnings of these neurodevelopmental disorders and gifted populations.

A comparison for thyroid functions and clinical features in deficit and non-deficit schizophrenia

A comparison for thyroid functions and clinical features in deficit and non-deficit schizophrenia

Activity of Protein Kinase A in the Frontal Cortex in Schizophrenia.

Schizophrenia is a serious cognitive disorder characterized by disruptions in neurotransmission, a process requiring the coordination of multiple kinase-mediated signaling events. Evidence suggests that the observed deficits in schizophrenia may be due to imbalances in kinase activity that propagate through an intracellular signaling network. Specifically, 3'-5'-cyclic adenosine monophosphate (cAMP)-associated signaling pathways are coupled to the activation of neurotransmitter receptors and modulate cellular functions through the activation of protein kinase A (PKA), an enzyme whose function is altered in the frontal cortex in schizophrenia. In this study, we measured the activity of PKA in human postmortem anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) tissue from schizophrenia and age- and sex-matched control subjects. No significant differences in PKA activity were observed in male and female individuals in either brain region; however, correlation analyses indicated that PKA activity in the ACC may be influenced by tissue pH in all subjects and by age and tissue pH in females. Our data provide novel insights into the function of PKA in the ACC and DLPFC in schizophrenia.

Abnormal interhemispheric functional cooperation in schizophrenia follows the neurotransmitter profiles.

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. 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. 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. 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.

Activation of prefrontal parvalbumin interneurons ameliorates working memory deficit even under clinically comparable antipsychotic treatment in a mouse model of schizophrenia

One of the critical unmet medical needs in schizophrenia is the treatment for cognitive deficits. However, the neural circuit mechanisms of them remain unresolved. Previous studies utilizing animal models of schizophrenia did not consider the fact that patients with schizophrenia generally cannot discontinue antipsychotic medication due to the high risk of relapse. Here, we used multi-dimensional approaches, including histological analysis of the prelimbic cortex (PL), LC-MS/MS-based in vivo dopamine D2 receptor occupancy analysis for antipsychotics, in vivo calcium imaging, and behavioral analyses of mice using chemogenetics to investigate neural mechanisms and potential therapeutic strategies for working memory deficit in a chronic phencyclidine (PCP) mouse model of schizophrenia. Chronic PCP administration led to alterations in excitatory and inhibitory synapses, specifically in dendritic spines of pyramidal neurons, vesicular glutamate transporter 1 (VGLUT1) positive terminals, and parvalbumin (PV) positive GABAergic interneurons located in layer 2–3 of the PL. Continuous administration of olanzapine, which achieved a sustained therapeutic window of dopamine D2 receptor occupancy (60–80%) in the striatum, did not ameliorate these synaptic abnormalities and working memory deficit in the chronic PCP-treated mice. We demonstrated that chemogenetic activation of PV neurons in the PL, as confirmed by in vivo calcium imaging, ameliorated working memory deficit in this model even under clinically comparable olanzapine treatment which by itself inhibited only PCP-induced psychomotor hyperactivity. Our study suggests that targeting prefrontal PV neurons could be a promising therapeutic intervention for cognitive deficits in schizophrenia in combination with antipsychotic medication.