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1.
J Abnorm Psychol ; 130(7): 775-784, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34780231

RESUMO

It has been proposed that agency disorders found in schizophrenia rely on aberrant processing of prediction error. Overreactivity to nonpertinent prediction errors may lead to the attribution of one's own actions to an external source. When applied to perception, this could explain hallucinations. However, experiments in motor control or perception have mainly suggested deficient prediction errors. Using a novel approach based on the manipulation of temporal delays, 23 patients with schizophrenia, 18 patients with bipolar disorder, and 22 healthy participants performed a pointing task with a haptic device that provided haptic feedback without or with delays, which were processed consciously (65 ms) or unconsciously (15 ms). The processing of prediction errors was measured via the adaptation of the hand trajectory, that is, the deceleration in anticipation of the surface, and its modulation as a function of recent history (stable or unstable sensory feedback). Agency was evaluated by measuring the participants' feeling of controlling the device. Only patients with schizophrenia reported a decrease in the feeling of control following subliminally delayed haptic feedback and adapted deceleration durations following subliminally delayed haptic feedback. This effect was correlated with positive symptoms. The overreactivity to subliminal delays was present only when delays occurred repeatedly in an unpredictable way, that is, with a volatile distribution. The results suggest that small temporal uncertainties that should be held as negligible, trigger an aberrant overreactivity which could account for hallucinations and alterations of the patients' conscious feeling of control. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Assuntos
Controle Interno-Externo , Esquizofrenia , Psicologia do Esquizofrênico , Emoções , Retroalimentação Sensorial/fisiologia , Alucinações , Humanos , Esquizofrenia/fisiopatologia
3.
Sci Rep ; 11(1): 17852, 2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34497330

RESUMO

The brain at rest generates cycles of electrical activity that have been shown to be abnormal in people with schizophrenia. The alpha rhythm (~ 10 Hz) is the dominant resting state electrical cycle and each person has a propensity toward a particular frequency of oscillation for this rhythm. This individual alpha peak frequency (IAPF) is hypothesized to be central to visual perceptual processes and may have downstream influences on cognitive functions such as attention, working memory, or problem solving. In the current study we sought to determine whether IAPF was slower in schizophrenia, and whether lower IAPF predicted deficits in visual perception and cognition that are often observed in schizophrenia. Eyes-closed resting state EEG activity, visual attention, and global cognitive functioning were assessed in individuals with schizophrenia (N = 104) and a group of healthy controls (N = 101). Compared to controls, the schizophrenia group showed slower IAPF and was associated with poorer discrimination of visual targets and nontargets on a computerized attention task, as well as impaired global cognition measured using neuropsychological tests across groups. Notably, disruptions in visual attention fully mediated the relationship between IAPF and global cognition across groups. The current findings demonstrate that slower alpha oscillatory cycling accounts for global cognitive deficits in schizophrenia by way of impairments in perceptual discrimination measured during a visual attention task.


Assuntos
Ritmo alfa/fisiologia , Encéfalo/fisiopatologia , Cognição/fisiologia , Esquizofrenia/fisiopatologia , Percepção Visual/fisiologia , Adolescente , Adulto , Atenção/fisiologia , Eletroencefalografia , Feminino , Humanos , Masculino , Memória de Curto Prazo/fisiologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Psicologia do Esquizofrênico , Adulto Jovem
4.
Int J Mol Sci ; 22(18)2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34576238

RESUMO

Despite the growing importance of the cerebellum as a region highly vulnerable to accumulating molecular errors in schizophrenia, limited information is available regarding altered molecular networks with potential therapeutic targets. To identify altered networks, we conducted one-shot liquid chromatography-tandem mass spectrometry in postmortem cerebellar cortex in schizophrenia and healthy individuals followed by bioinformatic analysis (PXD024937 identifier in ProteomeXchange repository). A total of 108 up-regulated proteins were enriched in stress-related proteins, half of which were also enriched in axonal cytoskeletal organization and vesicle-mediated transport. A total of 142 down-regulated proteins showed an enrichment in proteins involved in mitochondrial disease, most of which were also enriched in energy-related biological functions. Network analysis identified a mixed module of mainly axonal-related pathways for up-regulated proteins with a high number of interactions for stress-related proteins. Energy metabolism and neutrophil degranulation modules were found for down-regulated proteins. Further, two double-hit postnatal stress murine models based on maternal deprivation combined with social isolation or chronic restraint stress were used to investigate the most robust candidates of generated networks. CLASP1 from the axonal module in the model of maternal deprivation was combined with social isolation, while YWHAZ was not altered in either model. METTL7A from the degranulation pathway was reduced in both models and was identified as altered also in previous gene expression studies, while NDUFB9 from the energy network was reduced only in the model of maternal deprivation combined with social isolation. This work provides altered stress- and mitochondrial disease-related proteins involved in energy, immune and axonal networks in the cerebellum in schizophrenia as possible novel targets for therapeutic interventions and suggests that METTL7A is a possible relevant altered stress-related protein in this context.


Assuntos
Cerebelo/metabolismo , Vias Neurais , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia , Regulação para Cima , Proteínas 14-3-3/metabolismo , Animais , Axônios/metabolismo , Encéfalo/metabolismo , Proteínas de Transporte/metabolismo , Biologia Computacional , Citoesqueleto/metabolismo , Modelos Animais de Doenças , Redes Reguladoras de Genes , Humanos , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , NADH Desidrogenase/metabolismo , Neutrófilos/metabolismo , Proteômica/métodos , Ratos , Ratos Wistar
5.
Clin Neurophysiol ; 132(11): 2739-2750, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34571367

RESUMO

OBJECTIVES: The study investigated the role of top-down versus bottom-up connectivity, during the processing of predictive information, in three different psychiatric disorders. METHODS: Electroencephalography (EEG) was recorded during the performance of a task, which evaluates the ability to use predictive information in order to facilitate predictable versus random target detection. We evaluated EEG event-related directed connectivity, in patients with schizophrenia (SZ), major depressive disorder (MDD), and autism spectrum disorder (ASD), compared with healthy age-matched controls. Directed connectivity was evaluated using phase transfer entropy. RESULTS: We showed that top-down frontal-parietal connectivity was weaker in SZ (theta and beta bands) and ASD (alpha band) compared to control subjects, during the processing of stimuli consisting of the predictive sequence. In SZ patients, top-down connectivity was also attenuated, during the processing of predictive targets in the beta frequency band. In contrast, compared with controls, MDD patients displayed an increased top-down flow of information, during the processing of predicted targets (alpha band). CONCLUSIONS: The findings suggest that top-down frontal-parietal connectivity is altered differentially across three major psychiatric disorders, specifically during the processing of predictive stimuli. SIGNIFICANCE: Altered top-down connectivity may contribute to the specific prediction deficits observed in each of the patient populations.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Encéfalo/fisiopatologia , Transtorno Depressivo Maior/fisiopatologia , Rede Nervosa/fisiopatologia , Esquizofrenia/fisiopatologia , Adulto , Transtorno do Espectro Autista/diagnóstico , Transtorno Depressivo Maior/diagnóstico , Eletroencefalografia/métodos , Feminino , Previsões , Humanos , Masculino , Pessoa de Meia-Idade , Estimulação Luminosa/métodos , Desempenho Psicomotor/fisiologia , Esquizofrenia/diagnóstico , Adulto Jovem
6.
Nat Rev Neurosci ; 22(11): 657-673, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34545240

RESUMO

Almost 60 years have passed since the initial discovery by Hubel and Wiesel that changes in neuronal activity can elicit developmental rewiring of the central nervous system (CNS). Over this period, we have gained a more comprehensive picture of how both spontaneous neural activity and sensory experience-induced changes in neuronal activity guide CNS circuit development. Here we review activity-dependent synaptic pruning in the mammalian CNS, which we define as the removal of a subset of synapses, while others are maintained, in response to changes in neural activity in the developing nervous system. We discuss the mounting evidence that immune and cell-death molecules are important mechanistic links by which changes in neural activity guide the pruning of specific synapses, emphasizing the role of glial cells in this process. Finally, we discuss how these developmental pruning programmes may go awry in neurodevelopmental disorders of the human CNS, focusing on autism spectrum disorder and schizophrenia. Together, our aim is to give an overview of how the field of activity-dependent pruning research has evolved, led to exciting new questions and guided the identification of new, therapeutically relevant mechanisms that result in aberrant circuit development in neurodevelopmental disorders.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Sistema Nervoso Central/fisiologia , Imunidade Celular/fisiologia , Plasticidade Neuronal/fisiologia , Esquizofrenia/fisiopatologia , Fatores Etários , Animais , Transtorno do Espectro Autista/imunologia , Sistema Nervoso Central/citologia , Humanos , Transtornos do Neurodesenvolvimento/imunologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Esquizofrenia/imunologia
7.
Psychiatriki ; 32(3): 219-223, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34390554

RESUMO

People with mental illness are known to have poorer physical health outcomes. Among them, patients with schizophrenia spectrum disorders are disproportionately burdened. A number of recent studies have highlighted that patients with schizophrenia are particularly at risk from COVID-19. The aim of this systematic review is to clarify whether patients with schizophrenia spectrum disorders are at greater risk for poor COVID-19 outcomes. We conducted a systematic review of the literature following the PRISMA guidelines, using PubMed, PsycINFO (via Ovid) and Scopus as databases, to identify all studies which investigated infection and/or mortality rate from SARS-CoV-2 in patients with schizophrenia spectrum disorders. Following a formal screening process, seven studies met our inclusion criteria. The results of these seven studies were reported using odds ratios or adjusted odds ratios. The collective results indicated a moderate, but statistically significant effect for higher infection rates, and a strong statistically significant effect for higher mortality rates in patients with schizophrenia. Our findings indicate that people with schizophrenia have a high risk of being infected by the new coronavirus and have a significantly higher mortality rate than the general population. There are contradictory findings concerning other outcomes, including the frequency of intensive care unit admissions for this group. Collectively, these results indicate that people with schizophrenia spectrum disorders may be more vulnerable to being infected and more likely to die due to COVID-19, and yet their access to Intensive Care Units does not seem to be higher. We conclude that patients with schizophrenia constitute a vulnerable group for COVID-19 related infection and mortality, consequently there is a necessity for this vulnerable group of people to have better access to healthcare, including priority in nationwide COVID-19 vaccination programs and expedited intensive care treatment. Our conclusion adds to the ongoing debate arguing for equitable access to healthcare for people with schizophrenia spectrum disorders.


Assuntos
COVID-19 , Esquizofrenia , Populações Vulneráveis , COVID-19/mortalidade , COVID-19/prevenção & controle , COVID-19/psicologia , COVID-19/terapia , Causalidade , Disparidades em Assistência à Saúde , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Mortalidade , SARS-CoV-2 , Esquizofrenia/epidemiologia , Esquizofrenia/fisiopatologia , Populações Vulneráveis/psicologia , Populações Vulneráveis/estatística & dados numéricos
8.
Int J Mol Sci ; 22(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34445065

RESUMO

Postmortem studies reveal that the brain pH in schizophrenia patients is lower than normal. The exact cause of this low pH is unclear, but increased lactate levels due to abnormal energy metabolism appear to be involved. Schizophrenia patients display distinct changes in mitochondria number, morphology, and function, and such changes promote anaerobic glycolysis, elevating lactate levels. pH can affect neuronal activity as H+ binds to numerous proteins in the nervous system and alters the structure and function of the bound proteins. There is growing evidence of pH change associated with cognition, emotion, and psychotic behaviors. Brain has delicate pH regulatory mechanisms to maintain normal pH in neurons/glia and extracellular fluid, and a change in these mechanisms can affect, or be affected by, neuronal activities associated with schizophrenia. In this review, we discuss the current understanding of the cause and effect of decreased brain pH in schizophrenia based on postmortem human brains, animal models, and cellular studies. The topic includes the factors causing decreased brain pH in schizophrenia, mitochondria dysfunction leading to altered energy metabolism, and pH effects on the pathophysiology of schizophrenia. We also review the acid/base transporters regulating pH in the nervous system and discuss the potential contribution of the major transporters, sodium hydrogen exchangers (NHEs), and sodium-coupled bicarbonate transporters (NCBTs), to schizophrenia.


Assuntos
Encéfalo/patologia , Esquizofrenia/patologia , Animais , Encéfalo/fisiopatologia , Química Encefálica , Humanos , Concentração de Íons de Hidrogênio , Esquizofrenia/fisiopatologia
9.
Int J Mol Sci ; 22(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34445411

RESUMO

BACKGROUND: The present study investigated the role of proteins from the bromodomain and extra-terminal (BET) family in schizophrenia-like abnormalities in a neurodevelopmental model of schizophrenia induced by prenatal methylazoxymethanol (MAM) administration (MAM-E17). METHODS: An inhibitor of BET proteins, JQ1, was administered during adolescence on postnatal days (P) 23-P29, and behavioural responses (sensorimotor gating, recognition memory) and prefrontal cortical (mPFC) function (long-term potentiation (LTP), molecular and proteomic analyses) studies were performed in adult males and females. RESULTS: Deficits in sensorimotor gating and recognition memory were observed only in MAM-treated males. However, adolescent JQ1 treatment affected animals of both sexes in the control but not MAM-treated groups and reduced behavioural responses in both sexes. An electrophysiological study showed LTP impairments only in male MAM-treated animals, and JQ1 did not affect LTP in the mPFC. In contrast, MAM did not affect activity-dependent gene expression, but JQ1 altered gene expression in both sexes. A proteomic study revealed alterations in MAM-treated groups mainly in males, while JQ1 affected both sexes. CONCLUSIONS: MAM-induced schizophrenia-like abnormalities were observed only in males, while adolescent JQ1 treatment affected memory recognition and altered the molecular and proteomic landscape in the mPFC of both sexes. Thus, transient adolescent inhibition of the BET family might prompt permanent alterations in the mPFC.


Assuntos
Azepinas/administração & dosagem , Acetato de Metilazoximetanol/análogos & derivados , Córtex Pré-Frontal/crescimento & desenvolvimento , Esquizofrenia/fisiopatologia , Triazóis/administração & dosagem , Adolescente , Desenvolvimento do Adolescente/efeitos dos fármacos , Animais , Azepinas/farmacologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Humanos , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Acetato de Metilazoximetanol/toxicidade , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Proteômica , Ratos , Reconhecimento Psicológico/efeitos dos fármacos , Esquizofrenia/induzido quimicamente , Esquizofrenia/metabolismo , Caracteres Sexuais , Triazóis/farmacologia
10.
Expert Opin Investig Drugs ; 30(8): 877-891, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34213981

RESUMO

INTRODUCTION: Schizophrenia is a neuropsychiatric disorder that affects approximately 1% of individuals worldwide. There are no available medications to treat cognitive impairment in this patient population currently. Preclinical evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve cognitive function. There is a need to evaluate how GLP-1 RAs alter specific domains of cognition and whether they will be of therapeutic benefit in individuals with schizophrenia. AREAS COVERED: This paper summarizes the effects of GLP-1 RAs on metabolic processes in the brain and how these mechanisms relate to improved cognitive function. We provide an overview of preclinical studies that demonstrate GLP-1 RAs improve cognition and comment on their potential therapeutic benefit in individuals with schizophrenia. EXPERT OPINION: To understand the benefits of GLP-1 RAs in individuals with schizophrenia, further preclinical research with rodent models relevant to schizophrenia symptomology are needed. Moreover, preclinical studies must focus on using a wider range of behavioral assays to understand whether important aspects of cognition such as executive function, attention, and goal-directed behavior are improved using GLP-1 RAs. Further research into the specific mechanisms of how GLP-1 RAs affect cognitive function and their interactions with antipsychotic medication commonly prescribed is necessary.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Esquizofrenia/tratamento farmacológico , Animais , Disfunção Cognitiva/etiologia , Modelos Animais de Doenças , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Roedores , Esquizofrenia/fisiopatologia
11.
Schizophr Bull ; 47(6): 1518-1523, 2021 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-34259874

RESUMO

COVID-19 has led to a great deal of general suffering and an increased prevalence of psychiatric illness worldwide. Within the area of psychosis-risk syndromes, a highly heterogeneous clinical population, the picture is quite nuanced as the social restrictions resulting from the pandemic have reduced stress for some and increased it for others. Further, a number of pandemic-related societal and cultural changes have obfuscated the diagnostic and treatment landscape in this area as well. In this opinion article, we describe several prototypical cases, representative of presentations seen in our clinical high-risk (CHR) research programs. The cases highlight considerable clinical variability and, in addition, speak to the current complexities faced by diagnosticians and treatment providers. In addition to discussing these issues, this piece introduces potential solutions highlighting the promise of incorporating data-driven strategies to identify more homogenous CHR subtypes and employ precision medicine.


Assuntos
COVID-19 , Transtornos Psicóticos , Esquizofrenia , Adolescente , Adulto , Feminino , Humanos , Masculino , Sintomas Prodrômicos , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/fisiopatologia , Transtornos Psicóticos/terapia , Risco , Esquizofrenia/diagnóstico , Esquizofrenia/fisiopatologia , Esquizofrenia/terapia
12.
PLoS One ; 16(7): e0254695, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34270620

RESUMO

OBJECTIVE: Cognitive impairments are a frequent and difficult to treat symptom in patients with schizophrenia and the strongest predictor for a successful reintegration in occupational and everyday life. Recent research suggests transcranial direct current stimulation (tDCS) to enhance cognition in this patient group. However, the question regarding its acute effectiveness on executive functions remains largely unanswered. Here, we examined in a randomized, double blind, sham-controlled repeated-measures design the impact of tDCS on performance in several executive functions in patients with schizophrenia, schizoaffective disorder or acute transient psychotic disorder. METHODS: Patients (N = 48) were tested twice using standardized, well-constructed and clinically validated neuropsychological tests assessing verbal working memory, response inhibition, mental flexibility and problem solving. In session 1 they solely underwent the neuropsychological assessment, whereas in session 2 they additionally received 2 mA of anodal tDCS stimulation over the left dorsolateral prefrontal cortex (DLPFC), cathode right supraorbital ridge, or sham stimulation for 20 minutes. RESULTS: Patients of both groups were not able to correctly discriminate the type of stimulation received confirming the success of the blinding procedure. However, analyzing the whole sample the change in performance from session 1 to session 2 was the same in the verum as in the sham condition (all p >.5). Moreover, a subsequent exploratory analysis showed that performance in the response inhibition task was worse for patients that engaged in the task within 20 minutes after the end of the verum stimulation. CONCLUSION: Hence, 2 mA of anodal tDCS applied over the left DLPFC did not acutely enhance executive functions in patients with schizophrenia or related disorders but impaired performance in the response inhibition task shortly after. Future studies should continue to seek for effective stimulation configurations for this patient group. CLINICAL TRIAL REGISTRATION: The study is registered in the "Deutsches Register Klinischer Studien DRKS", German Clinical Trial Register and has been allocated the following number: DRKS00022126.


Assuntos
Função Executiva/fisiologia , Córtex Pré-Frontal/fisiopatologia , Esquizofrenia/terapia , Estimulação Transcraniana por Corrente Contínua/métodos , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Estudos Prospectivos , Esquizofrenia/diagnóstico , Esquizofrenia/fisiopatologia , Estimulação Transcraniana por Corrente Contínua/instrumentação , Resultado do Tratamento , Adulto Jovem
13.
J Neurosci ; 41(32): 6954-6965, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34253630

RESUMO

Episodic memory requires information to be stored and recalled in sequential order, and these processes are disrupted in schizophrenia. Hippocampal phase precession and theta sequences are thought to provide a biological mechanism for sequential ordering of experience at timescales suitable for plasticity. These phenomena have not previously been examined in any models of schizophrenia risk. Here, we examine these phenomena in a maternal immune activation (MIA) rodent model. We show that while individual pyramidal cells in the CA1 region continue to precess normally in MIA animals, the starting phase of precession as an animal enters a new place field is considerably more variable in MIA animals than in controls. A critical consequence of this change is a disorganization of the ordered representation of experience via theta sequences. These results provide the first evidence of a biological-level mechanism that, if it occurs in schizophrenia, may explain aspects of disorganized sequential processing that contribute to the cognitive symptoms of the disorder.SIGNIFICANCE STATEMENT Hippocampal phase precession and theta sequences have been proposed as biophysical mechanisms by which the sequential structure of cognition might be ordered. Disturbances of sequential processing have frequently been observed in schizophrenia. Here, we show for the first time that phase precession and theta sequences are disrupted in a maternal immune activation (MIA) model of schizophrenia risk. This is a result of greater variability in the starting phase of precession, indicating that the mechanisms that coordinate precession at the assembly level are disrupted. We propose that this disturbance in phase precession underlies some of the disorganized cognitive symptoms that occur in schizophrenia. These findings could have important preclinical significance for the identification and treatment of schizophrenia risk factors.


Assuntos
Hipocampo/fisiopatologia , Memória Episódica , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Esquizofrenia/fisiopatologia , Animais , Modelos Animais de Doenças , Feminino , Inflamação/induzido quimicamente , Indutores de Interferon/toxicidade , Masculino , Exposição Materna/efeitos adversos , Poli I-C/toxicidade , Gravidez , Ratos Sprague-Dawley , Esquizofrenia/etiologia
14.
Aging (Albany NY) ; 13(12): 16353-16366, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34135129

RESUMO

ApoE gene polymorphism may be involved in the change in blood lipid profile and cognitive impairment of the general population. However, few studies explored the effects of ApoE gene polymorphism on blood lipid levels and cognition in schizophrenia. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was employed to evaluate the cognition and the SNPStats was used to investigate the association of ApoE rs429358 with schizophrenia. The models of analysis of covariance and multivariate analysis were conducted to investigate the effect of ApoE rs429358 on cognition in schizophrenia. Altogether, 637 patients with schizophrenia and 467 healthy controls were recruited in this study. The findings in the case group found that both the ApoA1 and ApoB levels were predictors for RBANS total score (p < 0.001 vs. p = 0.011), immediate memory (p < 0.001 vs. p = 0.019), language (p < 0.001 vs. p = 0.013), attention (p < 0.001 vs. p < 0.001), except ApoA1 level only was a predictor for visuospatial/constructional (p = 0.014) and delayed memory (p < 0.001). When the association was examined in different ApoE rs429358 genotype subgroups, the association between ApoA1 level and RBANS scores (except for the language score) or between ApoB level and RBANS scores (except for the attention score) was regulated by ApoE rs429358. Our results suggest that patients with schizophrenia have broad cognitive impairment compared with healthy controls. For patients with schizophrenia, both ApoA1 and ApoB levels were positively associated with cognition. There was a significant association between ApoA1 or ApoB levels and cognition in schizophrenia, which was regulated by the ApoE rs429358.


Assuntos
Apolipoproteína A-I/sangue , Apolipoproteína B-100/sangue , Apolipoproteínas E/genética , Disfunção Cognitiva/sangue , Estudos de Associação Genética , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/sangue , Esquizofrenia/genética , Adulto , Estudos de Casos e Controles , Doença Crônica , Cognição , Disfunção Cognitiva/fisiopatologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/fisiopatologia
15.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073710

RESUMO

Cortical circuit dysfunction is thought to be an underlying mechanism of schizophrenia (SZ) pathophysiology with normalization of aberrant circuit activity proposed as a biomarker for antipsychotic efficacy. Cannabidiol (CBD) shows potential as an adjunctive antipsychotic therapy; however, potential sex effects in these drug interactions remain unknown. In the present study, we sought to elucidate sex effects of CBD coadministration with the atypical antipsychotic iloperidone (ILO) on the activity of primary cortical neuron cultures derived from the rat methylazoxymethanol acetate (MAM) model used for the study of SZ. Spontaneous network activity measurements were obtained using a multielectrode array at baseline and following administration of CBD or ILO alone, or combined. At baseline, MAM male neurons displayed increased bursting activity whereas MAM female neurons exhibited no difference in bursting activity compared to sex-matched controls. CBD administered alone showed a rapid but transient increase in neuronal activity in the MAM networks, an effect more pronounced in females. Furthermore, ILO had an additive effect on CBD-induced elevations in activity in the MAM male neurons. In the MAM female neurons, CBD or ILO administration resulted in time-dependent elevations in neuronal activity, but the short-term CBD-induced increases in activity were lost when CBD and ILO were combined. Our findings indicate that CBD induces rapid increases in cortical neuronal activity, with sex-specific drug interactions upon ILO coadministration. This suggests that sex should be a consideration when implementing adjunct therapy for treatment of SZ.


Assuntos
Canabidiol/farmacologia , Isoxazóis/farmacologia , Neurônios/efeitos dos fármacos , Piperidinas/farmacologia , Esquizofrenia/tratamento farmacológico , Animais , Animais Recém-Nascidos , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Canabidiol/uso terapêutico , Técnicas de Cultura de Células , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Modelos Animais de Doenças , Feminino , Isoxazóis/uso terapêutico , Masculino , Neurônios/fisiologia , Piperidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Esquizofrenia/fisiopatologia , Caracteres Sexuais
16.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069523

RESUMO

Cognitive dysfunction is one of the core symptoms in schizophrenia, and it is predictive of functional outcomes and therefore useful for treatment targets. Rather than improving cognitive deficits, currently available antipsychotics mainly focus on positive symptoms, targeting dopaminergic/serotoninergic neurons and receptors in the brain. Apart from investigating the neural mechanisms underlying schizophrenia, emerging evidence indicates the importance of glial cells in brain structure development and their involvement in cognitive functions. Although the etiopathology of astrocytes in schizophrenia remains unclear, accumulated evidence reveals that alterations in gene expression and astrocyte products have been reported in schizophrenic patients. To further investigate the role of astrocytes in schizophrenia, we highlighted recent progress in the investigation of the effect of astrocytes on abnormalities in glutamate transmission and impairments in the blood-brain barrier. Recent advances in animal models and behavioral methods were introduced to examine schizophrenia-related cognitive deficits and negative symptoms. We also highlighted several experimental tools that further elucidate the role of astrocytes. Instead of focusing on schizophrenia as a neuron-specific disorder, an additional astrocytic perspective provides novel and promising insight into its causal mechanisms and treatment. The involvement of astrocytes in the pathogenesis of schizophrenia and other brain disorders is worth further investigation.


Assuntos
Astrócitos/fisiologia , Disfunção Cognitiva/fisiopatologia , Esquizofrenia/fisiopatologia , Animais , Astrócitos/metabolismo , Encéfalo/metabolismo , Cognição , Transtornos Cognitivos/metabolismo , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Ácido Glutâmico/metabolismo , Humanos , Neuroglia/metabolismo , Neurônios/metabolismo , Esquizofrenia/metabolismo
17.
Nat Commun ; 12(1): 3478, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108456

RESUMO

Dynamical brain state transitions are critical for flexible working memory but the network mechanisms are incompletely understood. Here, we show that working memory performance entails brain-wide switching between activity states using a combination of functional magnetic resonance imaging in healthy controls and individuals with schizophrenia, pharmacological fMRI, genetic analyses and network control theory. The stability of states relates to dopamine D1 receptor gene expression while state transitions are influenced by D2 receptor expression and pharmacological modulation. Individuals with schizophrenia show altered network control properties, including a more diverse energy landscape and decreased stability of working memory representations. Our results demonstrate the relevance of dopamine signaling for the steering of whole-brain network dynamics during working memory and link these processes to schizophrenia pathophysiology.


Assuntos
Encéfalo/fisiologia , Memória de Curto Prazo/fisiologia , Rede Nervosa/fisiologia , Esquizofrenia/fisiopatologia , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2/farmacologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Pessoa de Meia-Idade , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/efeitos dos fármacos , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiologia , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/genética , Esquizofrenia/metabolismo , Adulto Jovem
18.
Neuroimage ; 238: 118245, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34111515

RESUMO

Developing sensitive and reliable methods to distinguish normal and abnormal brain states is a key neuroscientific challenge. Topological Data Analysis, despite its relative novelty, already generated many promising applications, including in neuroscience. We conjecture its prominent tool of persistent homology may benefit from going beyond analysing structural and functional connectivity to effective connectivity graphs capturing the direct causal interactions or information flows. Therefore, we assess the potential of persistent homology to directed brain network analysis by testing its discriminatory power in two distinctive examples of disease-related brain connectivity alterations: epilepsy and schizophrenia. We estimate connectivity from functional magnetic resonance imaging and electrophysiology data, employ Persistent Homology and quantify its ability to distinguish healthy from diseased brain states by applying a support vector machine to features quantifying persistent homology structure. We show how this novel approach compares to classification using standard undirected approaches and original connectivity matrices. In the schizophrenia classification, topological data analysis generally performs close to random, while classifications from raw connectivity perform substantially better; potentially due to topographical, rather than topological, specificity of the differences. In the easier task of seizure discrimination from scalp electroencephalography data, classification based on persistent homology features generally reached comparable performance to using raw connectivity, albeit with typically smaller accuracies obtained for the directed (effective) connectivity compared to the undirected (functional) connectivity. Specific applications for topological data analysis may open when direct comparison of connectivity matrices is unsuitable - such as for intracranial electrophysiology with individual number and location of measurements. While standard homology performed overall better than directed homology, this could be due to notorious technical problems of accurate effective connectivity estimation.


Assuntos
Encéfalo/diagnóstico por imagem , Conectoma , Epilepsia/diagnóstico por imagem , Modelos Neurológicos , Rede Nervosa/diagnóstico por imagem , Esquizofrenia/diagnóstico por imagem , Convulsões/diagnóstico por imagem , Encéfalo/fisiopatologia , Mapeamento Encefálico , Eletroencefalografia , Epilepsia/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Rede Nervosa/fisiopatologia , Esquizofrenia/fisiopatologia , Convulsões/fisiopatologia
19.
Cells ; 10(5)2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067760

RESUMO

Schizophrenia is a common debilitating disease characterized by continuous or relapsing episodes of psychosis. Although the molecular mechanisms underlying this psychiatric illness remain incompletely understood, a growing body of clinical, pharmacological, and genetic evidence suggests that G protein-coupled receptors (GPCRs) play a critical role in disease development, progression, and treatment. This pivotal role is further highlighted by the fact that GPCRs are the most common targets for antipsychotic drugs. The GPCRs activation evokes slow synaptic transmission through several downstream pathways, many of them engaging intracellular Ca2+ mobilization. Dysfunctions of the neurotransmitter systems involving the action of GPCRs in the frontal and limbic-related regions are likely to underly the complex picture that includes the whole spectrum of positive and negative schizophrenia symptoms. Therefore, the progress in our understanding of GPCRs function in the control of brain cognitive functions is expected to open new avenues for selective drug development. In this paper, we review and synthesize the recent data regarding the contribution of neurotransmitter-GPCRs signaling to schizophrenia symptomology.


Assuntos
Encéfalo/metabolismo , Sinalização do Cálcio , Receptores de Quimiocinas/metabolismo , Receptores de Neurotransmissores/metabolismo , Esquizofrenia/metabolismo , Psicologia do Esquizofrênico , Transmissão Sináptica , Animais , Antipsicóticos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Sinalização do Cálcio/efeitos dos fármacos , Humanos , Neurotransmissores/uso terapêutico , Receptores de Quimiocinas/antagonistas & inibidores , Receptores de Neurotransmissores/antagonistas & inibidores , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia , Transmissão Sináptica/efeitos dos fármacos
20.
J Manag Care Spec Pharm ; 27(7): 904-914, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34185557

RESUMO

BACKGROUND: Patients with schizophrenia struggle with disease relapses and uncontrolled symptoms, which can either result in or be a result of non-adherence to antipsychotics (APs). The economic burden of such patients is hypothesized to be substantial. OBJECTIVE: To evaluate the economic burden of recently relapsed schizophrenia or of uncontrolled symptoms of schizophrenia with non-adherence to APs in Medicaid beneficiaries. METHODS: Adults with ≥ 2 schizophrenia diagnoses and controls without schizophrenia were identified in Medicaid data (1997Q1-2018Q1) from Iowa, Kansas, Mississippi, Missouri, New Jersey, and Wisconsin. The index date was the last observed schizophrenia diagnosis (cohort with schizophrenia) or the last service claim (control cohort) with ≥ 12 months of continuous Medicaid enrollment before and after it. Cohorts were matched 1:1 using propensity scores. After matching, two subgroups were identified among adults with schizophrenia: (1) patients with schizophrenia and a recent relapse (≥ 1 schizophrenia-related inpatient or emergency department claim ≤ 60 days before or on the index date) and (2) patients with uncontrolled symptoms of schizophrenia (≥ 2 schizophrenia-related hospitalizations) and non-adherence to APs (proportion of days covered < 80%) in the 12-month pre-index period. Previously matched controls were then subset to patients in each subgroup and their matched pairs without schizophrenia, thus maintaining the 1:1 matching ratio. Healthcare resource utilization (HRU) and costs ($2018 USD) in the 12-month post-index (observation) period were compared between matched pairs using adjusted regression models. RESULTS: Among 158,763 patients with schizophrenia, 18,771 (11.8%) had a recent relapse (mean age 50.5 years; 48.6% female, 51.4% male) and 13,697 (8.6%) were not adherent to APs and had uncontrolled symptoms of schizophrenia (mean age 47.1 years; 48.0% female, 52.0% male). During the observation period, patients with recently relapsed schizophrenia and those non-adherent to APs with uncontrolled symptoms of schizophrenia had significantly higher HRU relative to their controls without schizophrenia. Patients with recently relapsed schizophrenia had mean total healthcare costs $21,862 higher relative to their controls ($37,424 vs $15,563), driven by $8,486 higher mean long-term care costs (all P < 0.001). Patients non-adherent to APs with uncontrolled symptoms of schizophrenia had adjusted mean total healthcare costs $20,787 higher relative to their controls ($38,337 vs $15,241), driven by $8,019 higher adjusted mean inpatient costs (all P < 0.001). Additional total healthcare costs incurred by patients with recently relapsed schizophrenia and those of patients non-adherent to APs with uncontrolled symptoms of schizophrenia exceeded by 55.2% and 47.6%, respectively, incremental total healthcare costs incurred by all patients with schizophrenia ($14,087). CONCLUSIONS: Patients with recently relapsed schizophrenia and those non-adherent to AP therapy with uncontrolled symptoms of schizophrenia incurred higher HRU and costs relative to patients without schizophrenia. Additional healthcare costs of these subgroups of patients with schizophrenia appeared higher than in the overall population with schizophrenia. DISCLOSURES: This study was supported by Janssen Scientific Affairs, LLC. The sponsor was involved in the study design, data collection, data analysis, manuscript preparation, and publication decisions. Pilon, Lafeuille, Zhdanava, Côté-Sergent, Rossi, and Lefebvre are employees of Analysis Group, Inc., a consulting company that has provided paid consulting services to Janssen Scientific Affairs, LLC, which funded the development and conduct of this study and manuscript. Patel, Joshi, and Lin are employees of Janssen Scientific Affairs, LLC and stockholders of Johnson & Johnson. Part of the material in this manuscript has been presented at the US Psych Congress, October 3-6, 2019, San Diego, CA, and at the Virtual ISPOR Meeting, May 18-20, 2020.


Assuntos
Antipsicóticos/uso terapêutico , Medicaid , Adesão à Medicação , Esquizofrenia/tratamento farmacológico , Esquizofrenia/economia , Adolescente , Adulto , Idoso , Efeitos Psicossociais da Doença , Feminino , Humanos , Revisão da Utilização de Seguros , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Recidiva , Estudos Retrospectivos , Esquizofrenia/fisiopatologia , Estados Unidos , Adulto Jovem
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