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Williams syndrome (WS) is associated with atypical social communication and cognition reminiscent of the behaviours observed in autism. Nonetheless, WS also differs significantly from autism, such as regarding social motivation, which is typically enhanced in WS and reduced in autism. This study sought to examine the conditions' transdiagnostic similarities and differences for autistic symptoms and social functioning, and their developmental trajectories, by comparing individuals with WS (n = 24) and those diagnosed with idiopathic autism (n = 24) and attention deficit hyperactivity disorder (ADHD; n = 24), aged 9 to 53 years, on measures of autism, social functioning, IQ and cooccurring psychiatric conditions. Although only 12.5% in the WS group met the criteria for an autism diagnosis, a majority exhibited distinct difficulties within social communication, social cognition, repetitive behaviours, and atypical sensory reactivity resembling autism. Conversely, elevated social motivation and a high number of social initiatives accompany these characteristics. No group differences in the developmental trajectories of autism symptoms were found. Our results demonstrate that autistic behaviours are more frequent in individuals with WS, than in individuals with idiopathic ADHD, and emphasize the need for clinical management of these behaviours.
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Trastorno Autístico , Síndrome de Williams , Humanos , Síndrome de Williams/diagnóstico , Síndrome de Williams/fisiopatología , Adolescente , Masculino , Femenino , Niño , Trastorno Autístico/psicología , Trastorno Autístico/diagnóstico , Adulto , Adulto Joven , Persona de Mediana Edad , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Conducta SocialRESUMEN
INTRODUCTION: Autism is a common neurodevelopmental condition with a complex genetic aetiology that includes contributions from monogenic and polygenic factors. Many autistic people have unmet healthcare needs that could be served by genomics-informed research and clinical trials. The primary aim of the European Autism GEnomics Registry (EAGER) is to establish a registry of participants with a diagnosis of autism or an associated rare genetic condition who have undergone whole-genome sequencing. The registry can facilitate recruitment for future clinical trials and research studies, based on genetic, clinical and phenotypic profiles, as well as participant preferences. The secondary aim of EAGER is to investigate the association between mental and physical health characteristics and participants' genetic profiles. METHODS AND ANALYSIS: EAGER is a European multisite cohort study and registry and is part of the AIMS-2-TRIALS consortium. EAGER was developed with input from the AIMS-2-TRIALS Autism Representatives and representatives from the rare genetic conditions community. 1500 participants with a diagnosis of autism or an associated rare genetic condition will be recruited at 13 sites across 8 countries. Participants will be given a blood or saliva sample for whole-genome sequencing and answer a series of online questionnaires. Participants may also consent to the study to access pre-existing clinical data. Participants will be added to the EAGER registry and data will be shared externally through established AIMS-2-TRIALS mechanisms. ETHICS AND DISSEMINATION: To date, EAGER has received full ethical approval for 11 out of the 13 sites in the UK (REC 23/SC/0022), Germany (S-375/2023), Portugal (CE-085/2023), Spain (HCB/2023/0038, PIC-164-22), Sweden (Dnr 2023-06737-01), Ireland (230907) and Italy (CET_62/2023, CEL-IRCCS OASI/24-01-2024/EM01, EM 2024-13/1032 EAGER). Findings will be disseminated via scientific publications and conferences but also beyond to participants and the wider community (eg, the AIMS-2-TRIALS website, stakeholder meetings, newsletters).
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Trastorno Autístico , Genómica , Sistema de Registros , Secuenciación Completa del Genoma , Niño , Humanos , Masculino , Trastorno Autístico/genética , Estudios de Cohortes , Europa (Continente) , Estudios Multicéntricos como Asunto , Proyectos de InvestigaciónRESUMEN
Importance: Cognitive impairment contributes significantly to clinical outcome and level of function in individuals with psychotic disorders. These impairments are present already at psychosis onset at a group level; however, the question of heterogeneity in cognitive function among patients has not been systematically investigated. Objective: To provide an updated quantification of cognitive impairment at psychosis onset before patients receive potentially confounding antipsychotic treatment, and to investigate variability in cognitive function compared with healthy controls. Data Sources: In this systematic review and meta-analysis, PubMed articles were searched up to September 15, 2022. Study Selection: Original studies reporting data on cognitive function in antipsychotic drug-naive patients with first-episode psychosis (FEP) were included. Data Extraction and Synthesis: Data were independently extracted by 2 researchers. Cognitive tasks were clustered according to 6 domains of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery and the domain of executive function. Random-effects model meta-analyses of mean differences and coefficient of variation ratios (CVRs) were performed, as well as meta-regressions, assessment of study quality, and publication bias. Main Outcomes and Measures: The main outcome measure was Hedges g for mean differences in cognition and CVR for within-group variability. Results: Fifty studies were included in the analysis with a total of 2625 individuals with FEP (mean [SD] age, 25.2 [3.6] years, 60% male; 40% female) and 2917 healthy controls (mean [SD] age, 26.0 [4.6]; 55% male; 45% female). In all cognitive domains, the FEP group displayed significant impairment compared with controls (speed of processing: Hedges g = -1.16; 95% CI, -1.35 to -0.98; verbal learning: Hedges g = -1.08; 95% CI, -1.28 to -0.88; visual learning: Hedges g = -1.05; 95% CI, -1.27 to -0.82; working memory: Hedges g = -1.04; 95% CI, -1.35 to -0.73; attention: Hedges g = -1.03; 95% CI, -1.24 to -0.82; reasoning/problem solving: Hedges g = -0.90; 95% CI, -1.12 to -0.68; executive function: Hedges g = -0.88; 95% CI, -1.07 to -0.69). Individuals with FEP also exhibited a larger variability across all domains (CVR range, 1.34-1.92). Conclusions and Relevance: Results of this systematic review and meta-analysis identified cognitive impairment in FEP before the initiation of antipsychotic treatment, with large effect sizes. The high variability within the FEP group suggests the need to identify those individuals with more severe cognitive problems who risk worse outcomes and could benefit the most from cognitive remediation.
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Disfunción Cognitiva , Trastornos Psicóticos , Humanos , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/fisiopatología , Trastornos Psicóticos/psicología , Disfunción Cognitiva/etiología , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/tratamiento farmacológico , Función Ejecutiva/fisiología , Cognición , Antipsicóticos/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/fisiopatología , Esquizofrenia/complicacionesRESUMEN
BACKGROUND AND AIMS: Whereas striatal dopamine D2 receptor (D2R) availability has shown to be altered in individuals with alcohol use disorder (AUD) and in healthy individuals with a family history of AUD, the role of D2R in the development of AUD is unknown. In this positron emission tomography (PET) study, we measured whether D2R availability is associated with subsequent alcohol use and alcohol-related factors, at a follow-up 8 to 16 years post-PET scan, in social drinkers. DESIGN: Longitudinal study investigating the association between PET data and later self-report measures in healthy individuals. SETTING: Academic research imaging centre in Stockholm, Sweden. PARTICIPANTS: There were 71 individuals (68 of whom had evaluable PET data, 5 females, 42.0 years mean age) from a series of previous PET studies. MEASUREMENTS: One PET examination with the D2R antagonist radioligand [11 C]raclopride at baseline and self-report measures assessing alcohol use, drug use, impulsivity, reward sensitivity and family history of alcohol or substance use disorder at follow-up. FINDINGS: We found no evidence for an association between D2R availability and later alcohol use (B = -0.019, B 95% CI = -0.043 to -0.006, P = 0.147) nor for the majority of the alcohol-related factors (B 95% CI = -0.034 to 0.004, P = 0.273-0.288). A negative association with a small effect size was found between D2R availability and later impulsivity (B = -0.017, B 95% CI = -0.034 to -0.001, P = 0.046). CONCLUSIONS: Low striatal dopamine D2 receptor availability may not be a strong predictor in the development of alcohol use disorder.
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Consumo de Bebidas Alcohólicas , Alcoholismo , Cuerpo Estriado , Receptores de Dopamina D2 , Femenino , Humanos , Consumo de Bebidas Alcohólicas/genética , Consumo de Bebidas Alcohólicas/metabolismo , Alcoholismo/diagnóstico por imagen , Alcoholismo/genética , Alcoholismo/metabolismo , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Etanol , Estudios Longitudinales , Tomografía de Emisión de Positrones/métodos , Racloprida/farmacología , Receptores de Dopamina D2/genética , Receptores de Dopamina D3/metabolismo , Masculino , Adulto , Antagonistas de los Receptores de Dopamina D2/farmacología , Estudios de SeguimientoRESUMEN
BACKGROUND: The serotonin system has been implicated in several psychiatric disorders. All major psychiatric disorders are associated with cognitive impairment, but treatment improving cognitive deficits is lacking, partly due to limited understanding of the neurobiology of cognitive functioning. Several markers for the serotonin system have been associated with cognitive functions. Our research group previously has reported a positive correlation between serotonin (5-HT1B) receptor availability in the dorsal brainstem and visuospatial memory in a pilot study of healthy individuals. Here, we aim to replicate our previous finding in a larger group of healthy volunteers as well as to investigate putative associations between 5-HT1B receptor availability and other cognitive domains. METHODS: Forty-three healthy individuals were examined with positron emission tomography using the 5-HT1B receptor radioligand [11C]AZ10419369 and a visuospatial memory test to replicate our previous finding as well as tests of verbal fluency, cognitive flexibility, reaction time, and planning ability to explore other domains potentially associated with the serotonin system. RESULTS: Replication analysis revealed no statistically significant association between 5-HT1B receptor availability in the dorsal brainstem and visuospatial memory performance. Exploratory analyses showed age-adjusted correlations between 5-HT1B receptor availability in whole brain gray matter and specific brain regions, and number of commission errors, reaction time, and planning ability. CONCLUSIONS: Higher 5-HT1B receptor availability was associated with more false-positive responses and faster reaction time but lower performance in planning and problem-solving. These results corroborate previous research supporting an important role of the serotonin system in impulsive behavior and planning ability.
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Receptor de Serotonina 5-HT1B , Serotonina , Humanos , Radioisótopos de Carbono , Proyectos Piloto , Morfolinas , Encéfalo/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , CogniciónRESUMEN
Introduction: Social dysfunction is a key feature of psychotic disorders such as schizophrenia linked to disability. Less is known about social functioning in the early stages of the disorder and if there is an association to psychotic symptoms. Aims: Investigate if antipsychotic drug-naïve or briefly medicated individuals with first-episode psychosis (FEP), have impaired facial affect recognition (FAR) compared to control participants and if psychotic symptoms are associated with the FAR ability. Method: Individuals with FEP (n = 67) and control participants (n = 51) performed a computer-aided FAR task on basic emotions. Psychotic symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). Group performances were compared using age and gender as covariates. The associations between FAR and performance on the subscales of PANSS were analyzed. Results: Compared to control participants, individuals with FEP were impaired in general FAR (Beta = -2.04 [95 % conf: -3.75/-1.62], p < 0.001) and FAR of negative emotions (Beta = -1.74 [95 % conf: -3.08/-1.22], p < 0.001), driven by difficulties in recognition of anger and disgust. In both groups, there was a pattern of mistaking negative emotions for other negative emotions. There were no significant group differences in FAR of happiness. No significant associations between FAR and psychotic symptoms were observed. Discussion: The results indicate that FAR, an underlying mechanism of social functioning is impaired early in the course of psychotic disorders. Current findings do not support the hypothesis that misinterpretation of facial expressions in individuals with FEP underlies or contributes to symptoms of psychosis.
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BACKGROUND: Autism spectrum disorder (ASD) in adulthood is associated with severe impairments in functioning and poor health, while ASD is also affecting close relations. Accessible first-line interventions addressing the complex clinical needs and care coordination are lacking. METHODS: This study investigated the feasibility and preliminary effects of a new psychoeducational intervention (Prisma) developed for intellectually able adults with ASD and their close relations in an outpatient setting. The manualized Prisma intervention consist of four weekly group sessions guided by trained group leaders and providing information about autism, support, and services. Feasibility was examined through treatment completion rate and group-level comparisons between intervention completers and non-completers (Student's t-test, Fisher's exact test, and Pearson's chi-squared test). Perceived treatment credibility was investigated by within-group comparisons of participant's self-ratings from pre-intervention to post-intervention, as well as by group leaders' ratings using an adjusted questionnaire. Treatment satisfaction was examined quantitatively regarding the session evaluations (Student's t-tests), as well as by a qualitative thematic analysis of participants' feedback. Preliminary efficacy was studied using paired t-tests (pre- and post-intervention). RESULTS: Completion rate was 77% (n = 71 of the 92 adults with ASD) and 73% (n = 69 of the 94 close relations), respectively. Participants considered Prisma to be an acceptable intervention indicated by increases in treatment credibility and expectations from pre- to post-intervention. The group leaders reported treatment credibility in the same range as the participants. Both autistic adults and their close relations reported good treatment satisfaction for each session, while the qualitative thematic analysis indicated that Prisma could be improved by enhancing active participation. This participant feedback will be used to further improve the intervention for an upcoming RCT. Preliminary analyses of effects showed promising results with an increase in knowledge of ASD and some indications for improvements in relationship quality, mental health, quality of life, acceptance of diagnosis and burden of care. CONCLUSIONS: Overall, results indicate that the Prisma is a feasible and acceptable first-line intervention in outpatient services. Randomized controlled trials are needed to further corroborate the evidence base of this novel intervention. TRIAL REGISTRATION: Clinicaltrials.org NCT0446097, retrospectively registered July 8th 2020.
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Trastorno del Espectro Autista , Trastorno Autístico , Adulto , Humanos , Trastorno del Espectro Autista/terapia , Trastorno Autístico/terapia , Estudios de Factibilidad , Calidad de VidaRESUMEN
Decreased 5-HT1A receptor binding has been associated with Alzheimer's disease (AD) and interpreted as a consequence of neuron loss. The purpose of the present study was to compare [11 C]WAY100635 binding to the 5-HT1A receptor in the hippocampus, entorhinal cortex, amygdala and pericalcarine cortex in mild AD patients and elderly controls. AD patients (n = 7) and elderly control subjects (n = 8) were examined with positron emission tomography (PET) and [11 C]WAY100635. PET data acquisition was performed with an ECAT EXACT HR system. Wavelet-aided parametric images of nondisplaceable binding potential (BPND ) were generated using Logan's graphical analysis with cerebellum as the reference region. Correction for partial volume effects was performed with the Müller-Gärtner method. Regions of interest (ROIs) were applied to the individual parametric images, and the regional BPND was calculated as the average parametric voxel value within each ROI. In addition to comparisons between subject groups, correlations between BPND values and scores on the Mini-Mental State Examination, Disability Assessment for Dementia (DAD), and Neuropsychiatric Inventory were expressed by Pearson correlation coefficients. Mean regional BPND was lower in AD patients than in control subjects, and the difference was statistically significant for the hippocampus, entorhinal cortex, and amygdala. A statistically significant correlation was obtained between hippocampal BPND values and DAD scores. The results of the present study corroborate and extend previous findings of decreased 5-HT1A binding in AD and strengthen the support for 5-HT1A receptor PET as a tool for the assessment of neurodegenerative changes in mild AD.
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Enfermedad de Alzheimer , Anciano , Enfermedad de Alzheimer/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Corteza Entorrinal/metabolismo , Humanos , Tomografía de Emisión de Positrones/métodos , Receptor de Serotonina 5-HT1A/metabolismo , Serotonina/metabolismoRESUMEN
Impairments in social interaction and communication, in combination with restricted, repetitive behaviors and interests, define the neurodevelopmental diagnosis of autism spectrum disorder (ASD). The biological underpinnings of ASD are not well known, but the hypothesis of serotonin (5-HT) involvement in the neurodevelopment of ASD is one of the longest standing. Reuptake through the 5-HT transporter (5-HTT) is the main pathway decreasing extracellular 5-HT in the brain and a marker for the 5-HT system, but in vivo investigations of the 5-HTT and the 5-HT system in ASD are scarce and so far inconclusive. To quantify possible alterations in the 5-HT system in ASD, we used positron emission tomography and the radioligand [11C]MADAM to measure 5-HTT availability in the brain of 15 adults with ASD and 15 controls. Moreover, we examined correlations between regional 5-HTT availability and behavioral phenotype assessments regarding ASD core symptoms. In the ASD group, we found significantly lower 5-HTT availability in total gray matter, brainstem, and 9 of 18 examined subregions of gray matter. In addition, several correlations between regional 5-HTT availability and social cognitive test performance were found. The results confirm the hypothesis that 5-HTT availability is lower in the brain of adult individuals with ASD, and are consistent with the theory of 5-HT involvement in ASD neurodevelopment. The findings endorse the central role of 5-HT in the physiology of ASD, and confirm the need for a continued investigation of the 5-HT system in order to disentangle the biology of ASD.
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Trastorno del Espectro Autista , Trastorno Autístico , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Adulto , Trastorno del Espectro Autista/diagnóstico por imagen , Trastorno Autístico/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Humanos , Tomografía de Emisión de Positrones , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismoRESUMEN
The dopamine D1 receptor (D1R) is thought to play a role in psychosis and schizophrenia, however positron emission tomography studies comparing patients and controls have been inconsistent. To circumvent some of the limitations of clinical studies, such as antipsychotic exposure, an alternative approach is to examine subclinical psychotic symptoms within the general population, i.e. psychosis proneness traits. In this study, we investigated whether D1R availability is associated with delusional ideation in healthy controls, in four experiments, using [11C]SCH23390 PET (n = 76) and psychometric questionnaires (n = 217). We performed exploratory analyses, direct self-replication, and confirmatory analyses using Bayesian statistical modelling. Collectively, we found strong evidence that there is little to no linear association between delusional ideation and D1R. If hypothesised changes in D1R in drug-naive psychosis patients can be confirmed, our results suggest that they may either occur at disease onset, or that they are associated with specific aspects of psychosis other than delusional ideation.
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Trastornos Psicóticos , Receptores de Dopamina D1 , Esquizofrenia , Teorema de Bayes , Deluciones/diagnóstico por imagen , Humanos , Trastornos Psicóticos/diagnóstico por imagen , Trastornos Psicóticos/metabolismoRESUMEN
The schizophrenia and bipolar twin study in Sweden (STAR) is a large nation-wide cohort of monozygotic (MZ) and dizygotic (DZ) same-sex twins with schizophrenia or bipolar disorder and healthy control pairs, extensively characterized with brain imaging, neuropsychological tests, biomarkers, genetic testing, psychiatric symptoms and personality traits. The purpose is to investigate genetic and environmental mechanisms that give rise to schizophrenia and bipolar disorder as well as the intermediate phenotypes. This article describes the design, recruitment, data collection, measures, collected twins' characteristics, diagnostic procedures as well as ongoing and planned analyses. Identification of biomarkers, genetic and epigenetic variation and the development of specific and common endophenotypes for schizophrenia and bipolar disorder are potential gains from this cohort.
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Trastorno Bipolar , Endofenotipos , Interacción Gen-Ambiente , Sistema de Registros , Esquizofrenia , Adulto , Anciano , Biomarcadores , Trastorno Bipolar/diagnóstico por imagen , Trastorno Bipolar/etiología , Trastorno Bipolar/genética , Trastorno Bipolar/fisiopatología , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos de Investigación , Esquizofrenia/diagnóstico por imagen , Esquizofrenia/etiología , Esquizofrenia/genética , Esquizofrenia/fisiopatología , Suecia , Adulto JovenRESUMEN
High levels of trait impulsivity are considered a risk factor for substance abuse and drug addiction. We recently found that non-planning trait impulsivity was negatively correlated with post-commissural putamen volumes in men, but not women, using the Karolinska Scales of Personality (KSP). Here, we attempted to replicate this finding in an independent sample using an updated version of the KSP: the Swedish Universities Scales of Personality (SSP). Data from 88 healthy male participants (Mean Age: 28.16±3.34), who provided structural T1-weighted magnetic resonance images (MRIs) and self-reported SSP impulsivity scores, were analyzed. Striatal sub-region volumes were acquired using the Multiple Automatically Generated Templates (MAGeT-Brain) algorithm. Contrary to our previous findings trait impulsivity measured using SSP was not a significant predictor of post-commissural putamen volumes (ß = .14, df = 84, p = .94). A replication Bayes Factors analysis strongly supported this null result. Consistent with our previous findings, secondary exploratory analyses found no relationship between ventral striatum volumes and SSP trait impulsivity (ß = -.05, df = 84, p = .28). An exploratory analysis of the other striatal compartments showed that there were no significant associations with trait impulsivity. While we could not replicate our previous findings in the current sample, we believe this work will aide future studies aimed at establishing meaningful brain biomarkers for addiction vulnerability in healthy humans.
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Conducta Adictiva/fisiopatología , Conducta Impulsiva/fisiología , Personalidad/fisiología , Trastornos Relacionados con Sustancias/fisiopatología , Adulto , Algoritmos , Teorema de Bayes , Conducta Adictiva/diagnóstico por imagen , Conducta Adictiva/psicología , Humanos , Imagen por Resonancia Magnética , Masculino , Putamen/diagnóstico por imagen , Putamen/fisiología , Trastornos Relacionados con Sustancias/diagnóstico por imagen , Trastornos Relacionados con Sustancias/psicología , Suecia , Estriado Ventral/diagnóstico por imagen , Estriado Ventral/fisiopatologíaRESUMEN
OBJECTIVE: A putative relationship between markers for the serotonin system and the personality scale self-transcendence (ST) and its subscale spiritual acceptance (SA) has been demonstrated in a previous PET study of 5-HT1A receptor binding in healthy control subjects. The results could however not be replicated in a subsequent PET study at an independent centre. In this study, we performed a replication of our original study in a larger sample using Bayesian hypothesis testing to evaluate relative evidence both for and against this hypothesis. METHODS: Regional 5-HT1A receptor binding potential (BPND) was examined in 50 healthy male subjects using PET with the radioligand [11C]WAY100635. 5-HT1Aavailability was calculated using the simplified reference tissue model (SRTM) yielding regional BPND. ST and SA were measured using the Temperament and Character Inventory (TCI) questionnaire. Correlations between ST/SA scores and 5-HT1ABPND in frontal cortex, hippocampus and raphe nuclei were examined by calculation of default correlation Bayes factors (BFs) and replication BFs. RESULTS: There were no significant correlations between 5-HT1A receptor binding and ST/SA scores. Rather, five of six replication BFs provided moderate to strong evidence for no association between 5-HT1A availability and ST/SA, while the remaining BF provided only weak evidence. CONCLUSION: We could not replicate our previous findings of an association between 5-HT1A availability and the personality trait ST/SA. Rather, the Bayesian analysis provided evidence for a lack of correlation. Further research should focus on whether other components of the serotonin system may be related to ST or SA. This study also illustrates how Bayesian hypothesis testing allows for greater flexibility and more informative conclusions than traditional p-values, suggesting that this approach may be advantageous for analysis of molecular imaging data.
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Preliminary studies have suggested that γ-aminobutyric acid type A (GABAA) receptors, and potentially the GABAA α5 subtype, are deficient in autism spectrum disorder (ASD). However, prior studies have been confounded by the effects of medications, and these studies did not compare findings across different species. We measured both total GABAA and GABAA α5 receptor availability in two positron emission tomography imaging studies. We used the tracer [11C]flumazenil in 15 adults with ASD and in 15 control individuals without ASD and the tracer [11C]Ro15-4513 in 12 adults with ASD and in 16 control individuals without ASD. All participants were free of medications. We also performed autoradiography, using the same tracers, in three mouse models of ASD: the Cntnap2 knockout mouse, the Shank3 knockout mouse, and mice carrying a 16p11.2 deletion. We found no differences in GABAA receptor or GABAA α5 subunit availability in any brain region of adults with ASD compared to those without ASD. There were no differences in GABAA receptor or GABAA α5 subunit availability in any of the three mouse models. However, adults with ASD did display altered performance on a GABA-sensitive perceptual task. Our data suggest that GABAA receptor availability may be normal in adults with ASD, although GABA signaling may be functionally impaired.
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Trastorno del Espectro Autista/metabolismo , Receptores de GABA-A/metabolismo , Adulto , Animales , Trastorno del Espectro Autista/diagnóstico por imagen , Trastorno del Espectro Autista/patología , Azidas/farmacología , Conducta , Benzodiazepinas/farmacología , Radioisótopos de Carbono , Estudios de Casos y Controles , Modelos Animales de Enfermedad , Femenino , Flumazenil/farmacología , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/metabolismo , Sustancia Gris/patología , Humanos , Masculino , Ratones , Percepción de Movimiento/efectos de los fármacos , Tomografía de Emisión de Positrones , Subunidades de Proteína/metabolismo , Análisis y Desempeño de TareasRESUMEN
Positron emission tomography has, for 30 years, been used in numerous case-control studies searching for hypothesized differences in the density of neuroreceptor or transporter proteins in psychiatric disorders such as schizophrenia and depression. In most cases, the results have not been conclusive. One reason could be the sizeable interindividual variability in biochemical markers, which in twin studies have shown to emanate from both environmental and genetic factors, leading to low statistical power for the detection of group effects. On the other hand, the same interindividual variability has served as an opportunity for correlative studies on the biological underpinning of behaviour. Using this approach, a series of studies has linked markers for the dopamine and serotonin system to personality traits associated with psychiatric conditions. Based on increasing evidence for the view that many psychopathological states represent extremes of a continuum rather than distinct categories, this research strategy may lead to new biological insights about the vulnerability to and pathophysiology of major psychiatric disorders.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'.
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Depresión/fisiopatología , Dopamina/metabolismo , Trastornos de la Personalidad/fisiopatología , Esquizofrenia/fisiopatología , Células Receptoras Sensoriales/metabolismo , Serotonina/metabolismo , Adulto , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Encéfalo/fisiopatología , Mapeo Encefálico , Estudios de Casos y Controles , Depresión/diagnóstico por imagen , Depresión/metabolismo , Femenino , Humanos , Individualidad , Masculino , Neurotransmisores/metabolismo , Trastornos de la Personalidad/diagnóstico por imagen , Trastornos de la Personalidad/metabolismo , Tomografía de Emisión de Positrones , Esquizofrenia/diagnóstico por imagen , Esquizofrenia/metabolismoRESUMEN
OBJECTIVE: Surgery launches a systemic inflammatory reaction that reaches the brain and associates with immune activation and cognitive decline. Although preclinical studies have in part described this systemic-to-brain signaling pathway, we lack information on how these changes appear in humans. This study examines the short- and long-term impact of abdominal surgery on the human brain immune system by positron emission tomography (PET) in relation to blood immune reactivity, plasma inflammatory biomarkers, and cognitive function. METHODS: Eight males undergoing prostatectomy under general anesthesia were included. Prior to surgery (baseline), at postoperative days 3 to 4, and after 3 months, patients were examined using [11 C]PBR28 brain PET imaging to assess brain immune cell activation. Concurrently, systemic inflammatory biomarkers, ex vivo blood tests on immunoreactivity to lipopolysaccharide (LPS) stimulation, and cognitive function were assessed. RESULTS: Patients showed a global downregulation of gray matter [11 C]PBR28 binding of 26 ± 26% (mean ± standard deviation) at 3 to 4 days postoperatively compared to baseline (p = 0.023), recovering or even increasing after 3 months. LPS-induced release of the proinflammatory marker tumor necrosis factor-α in blood displayed a reduction (41 ± 39%) on the 3rd to 4th postoperative day, corresponding to changes in [11 C]PBR28 distribution volume. Change in Stroop Color-Word Test performance between postoperative days 3 to 4 and 3 months correlated to change in [11 C]PBR28 binding (p = 0.027). INTERPRETATION: This study translates preclinical data on changes in the brain immune system after surgery to humans, and suggests an interplay between the human brain and the inflammatory response of the peripheral innate immune system. These findings may be related to postsurgical impairments of cognitive function. Ann Neurol 2017;81:572-582.
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Encéfalo/inmunología , Disfunción Cognitiva/etiología , Sustancia Gris/inmunología , Tomografía de Emisión de Positrones/métodos , Prostatectomía/efectos adversos , Abdomen/cirugía , Anciano , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Encéfalo/fisiopatología , Disfunción Cognitiva/fisiopatología , Regulación hacia Abajo , Estudios de Seguimiento , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/metabolismo , Sustancia Gris/fisiopatología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: We performed a whole-genome expression study to clarify the nature of the biological processes mediating between inherited genetic variations and cognitive dysfunction in schizophrenia. METHOD: Gene expression was assayed from peripheral blood mononuclear cells using Illumina Human WG6 v3.0 chips in twins discordant for schizophrenia or bipolar disorder and control twins. After quality control, expression levels of 18,559 genes were screened for association with the California Verbal Learning Test (CVLT) performance, and any memory-related probes were then evaluated for variation by diagnostic status in the discovery sample (N = 190), and in an independent replication sample (N = 73). Heritability of gene expression using the twin design was also assessed. RESULTS: After Bonferroni correction (p < 2.69 × 10-6), CVLT performance was significantly related to expression levels for 76 genes, 43 of which were differentially expressed in schizophrenia patients, with comparable effect sizes in the same direction in the replication sample. For 41 of these 43 transcripts, expression levels were heritable. Nearly all identified genes contain common or de novo mutations associated with schizophrenia in prior studies. CONCLUSION: Genes increasing risk for schizophrenia appear to do so in part via effects on signaling cascades influencing memory. The genes implicated in these processes are enriched for those related to RNA processing and DNA replication and include genes influencing G-protein coupled signal transduction, cytokine signaling, and oligodendrocyte function.
Asunto(s)
Trastornos del Conocimiento/genética , Cognición , Endofenotipos , Esquizofrenia/genética , Psicología del Esquizofrénico , Adulto , Anciano , Trastorno Bipolar/genética , Trastorno Bipolar/psicología , Trastornos del Conocimiento/psicología , Femenino , Finlandia , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Leucocitos Mononucleares , Masculino , Memoria , Análisis por Micromatrices , Persona de Mediana Edad , ARN/análisis , Sistema de Registros , Suecia , Gemelos/genética , Gemelos/psicologíaRESUMEN
Motor response inhibition is mediated by neural circuits involving dopaminergic transmission; however, the relative contributions of dopaminergic signaling via D1- and D2-type receptors are unclear. Although evidence supports dissociable contributions of D1- and D2-type receptors to response inhibition in rats and associations of D2-type receptors to response inhibition in humans, the relationship between D1-type receptors and response inhibition has not been evaluated in humans. Here, we tested whether individual differences in striatal D1- and D2-type receptors are related to response inhibition in human subjects, possibly in opposing ways. Thirty-one volunteers participated. Response inhibition was indexed by stop-signal reaction time on the stop-signal task and commission errors on the continuous performance task, and tested for association with striatal D1- and D2-type receptor availability [binding potential referred to nondisplaceable uptake (BPND)], measured using positron emission tomography with [(11)C]NNC-112 and [(18)F]fallypride, respectively. Stop-signal reaction time was negatively correlated with D1- and D2-type BPND in whole striatum, with significant relationships involving the dorsal striatum, but not the ventral striatum, and no significant correlations involving the continuous performance task. The results indicate that dopamine D1- and D2-type receptors are associated with response inhibition, and identify the dorsal striatum as an important locus of dopaminergic control in stopping. Moreover, the similar contribution of both receptor subtypes suggests the importance of a relative balance between phasic and tonic dopaminergic activity subserved by D1- and D2-type receptors, respectively, in support of response inhibition. The results also suggest that the stop-signal task and the continuous performance task use different neurochemical mechanisms subserving motor response inhibition.
Asunto(s)
Cuerpo Estriado/fisiología , Inhibición Psicológica , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Adulto , Benzamidas/farmacocinética , Benzazepinas/farmacocinética , Benzofuranos/farmacocinética , Conducta de Elección , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/efectos de los fármacos , Femenino , Fluorodesoxiglucosa F18/farmacocinética , Humanos , Imagenología Tridimensional , Imagen por Resonancia Magnética , Masculino , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones , Análisis de Regresión , Adulto JovenRESUMEN
The mammalian circadian clock underlies both diurnal and seasonal changes in physiology, and its function is thought to be disturbed in both seasonal and non-seasonal depression. In humans, molecular imaging studies have reported seasonal changes in the serotonin system. Despite the role of the circadian clock in generating seasonal physiological changes, however, diurnal variation of serotonin receptors and transporters has never been directly studied in humans. We used positron emission tomography to examine diurnal and seasonal changes in the serotonin 5-HT1A receptor and serotonin transporter in two large cohorts of healthy male subjects, employing a cross-sectional design. In 56 subjects measured with [(11)C]WAY-100635, we observed diurnal increases in the availability of 5-HT1A receptors in the cortex. In 40 subjects measured with [(11)C]MADAM, a decrease in 5-HTT was observed in the midbrain across the day. We also found seasonal changes in the 5-HT1A receptor in serotonin projection regions, with higher availability on days with a longer duration of daylight. Our observation that serotonin receptor and transporter levels may change across the day in humans is corroborated by experimental research in rodents. These findings have important implications for understanding the relationship between the circadian and serotonin systems in both the healthy brain and in affective disorders, as well as for the design of future molecular imaging studies.