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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.

Decreased 5-HT

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.

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.

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 group intervention (Prisma) developed for intellectually able adults with ASD and their close relations in an outpatient setting. Results: Completion rate was 77% (n=71) of the 92 adults with ASD and 73% (n=69) of the 94 close relations. Participants considered Prisma to be an acceptable intervention and their feedback will be used to further improve the Prisma for an upcoming RCT. Preliminary analyses of effects showed promising results with an increase in knowledge of ASD. Conclusions: Overall, results indicate that the Prisma is a feasible first-line intervention in a stepped-care process in outpatient services. Trial registration: Clinicaltrials.org (NCT04460976).

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.

The neurotransmitter serotonin has been widely implicated in the pathophysiology of major depressive disorder (MDD). In animal studies and human neuroimaging studies, involvement of the serotonin receptor 1B (5-HT1BR) in MDD and memory performance has been reported. However, the role of the 5-HT1BR in cognitive functions affected in MDD remains to be clarified. Ten patients with MDD diagnosis were examined with positron emission tomography (PET) and a battery of cognitive tests before and after Internet-based Cognitive Behavioral Therapy (ICBT). The results were compared to ten matched control subjects in order to investigate putative changes in 5-HT1BR availability and cognitive performance. Patients treated with ICBT showed statistically significant improvement relative to baseline in Verbal fluency, both letter and category production. Significant correlations were found between improvement in letter production and changes in 5-HT1BR availability in ventral striatum, between category production and amygdala, as well as between the improvement in Trailmaking test B and change in 5-HT1BR binding in dorsal brainstem, in amygdala and in hippocampus. The results suggest an association between 5-HT1BR binding and improvement in cognitive functioning. Replications in larger-scale studies are required to confirm these findings.

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 [11C]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 [11C]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 [11C]PBR28 distribution volume. Change in Stroop Color-Word Test performance between postoperative days 3 to 4 and 3 months correlated to change in [11C]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

Schizophrenia Schizophrenia is a highly heritable, genetically complex, and heterogeneous psychiatric syndrome. Twin and family studies estimate 80–85% of variance in disease liability can be accounted for by genetic factors (Cannon, Kaprio, Lonnqvist, Huttunen, & Koskenvuo, 1998). Thus, substantial efforts have been dedicated towards uncovering genetic loci increasing risk for schizophrenia. Though many methodologies have been employed including genome-wide surveys of common genetic polymorphisms (Purcell et al., 2009; Ripke et al., 2013; Schizophrenia Working Group of the Psychiatric Genomics, 2014), exome sequencing investigating rare variants (Fromer et al., 2014; Purcell et al., 2014), gene expression analyses (Gardiner et al., 2013; Guillozet-Bongaarts et al., 2014; Gulsuner et al., 2013), and integration of multiple methods (Hertzberg, Katsel, Roussos, Haroutunian, & Domany, 2015; Luo et al., 2015; van Eijk et al., 2014), nearly all gene-finding efforts in schizophrenia to date have employed diagnostic level classification as the phenotype of interest. However, there is substantial evidence that risk-increasing genes confer risk via impacting intermediate levels of impairment, such as cognitive dysfunction, suggesting that these may also be useful phenotypic targets in gene discovery studies (Cannon & Keller, 2006; Greenwood, Light, Swerdlow, Radant, & Braff, 2012; Lencz et al., 2014; Tan, Callicott, & Weinberger, 2008; Toulopoulou et al., 2007). Compared to the diagnosis of schizophrenia, which could imply dysfunction across a host of brain systems and signaling pathways, a given endophenotype provides a more constrained framework within which to interpret the functional-biological relevance of statistically identified genes (Heck et al., 2014; Ibrahim-Verbaas et al., 2015; Lencz et al., 2014). One of the most reliable endophenotypes in schizophrenia – and most profound areas of cognitive impairment – is verbal memory (Cannon et al., 2000; Greenwood et al., 2013; Schaefer, Giangrande, Weinberger, & Dickinson, 2013; van Erp et al., 2008). The California Verbal Learning Test (CVLT), a list-learning exercise, is a robust measure of memory impairment in schizophrenia (Haut, in prep; Stone et al., 2011; van Erp et al., 2008), is heritable (Carmelli, Swan, DeCarli, & Reed, 2002; Greenwood et al., 2007; Kremen et al., 2014; Panizzon et al., 2011), and shows intermediate levels of affection among relatives of patients with schizophrenia in twin and family studies (Greenwood et al., 2013; van Erp et al., 2008), supporting its role as a candidate endophenotype in genetic studies. Initial molecular genetic investigations of endophenotypes for schizophrenia have provided evidence that genes associated with putative cognitive endophenotypes at least partially overlap with those associated with schizophrenia (Heck et al., 2014; Lencz et al., 2014). However, so far this approach has been used largely to demonstrate the broad, shared genetic etiology between these phenotypes, rather than to identify specific genetic loci impinging on both, which is critical for elucidating the functional-physiologic significance of the underlying genetic associations. Furthermore, all of these studies have assayed common polymorphisms. Over 90% of common polymorphisms previously related to psychiatric illness are located in regulatory regions of DNA, rather than in coding regions where mutations more directly affect protein structure, suggesting that many of these loci may exert their effects via regulation of gene expression (Kim et al., 2014; Maurano et al., 2012). Thus, examining gene expression in relation to a cognitive endophenotype for schizophrenia may yield insights into genotypic effects on disease status and help to elucidate mechanisms by which cognitive dysfunction manifests in this disease. In the current study, we used a discordant twin design to identify genes differentially expressed in relation to verbal memory performance, a cognitive endophenotype for schizophrenia. Gene expression was assayed from peripheral blood mononuclear cells (PBMCs) – the most feasible way to assess expression levels in living patients. Gene expression in PBMCs is broadly heritable and correlates with central nervous system expression patterns (Cheung et al., 2003). While it is likely that some genes influencing memory performance will not be schizophrenia-related, given the endophenotypic pattern of the CVLT, which suggests shared genetic etiology between memory and schizophrenia, we expected some proportion of these memory-related genes to show differential expression by diagnostic status (Glahn et al., 2007; Greenwood et al., 2007; van Erp et al., 2008). This subset would represent a selection of genes potentially involved in those systems underlying memory impairment in schizophrenia. A twin design further allowed us to test the heritability of expression for each of these genes, dissociating potentially etiologically relevant genetic alterations from disease-related secondary effects.

Swedish healthcare quality registries are tools for the evaluation and improvement of clinical services and population-based research. There are presently 11 national quality registries that focus on psychiatric disorders; but none cover all neurodevelopmental disorders (NDDs) as defined by the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Health care professionals have called for more user-friendly; time-saving; and clinically informative registers. To fill this gap, the NEUROPSYK Quality Register was established in 2014 by the Center of Neurodevelopmental Disorders at Karolinska Institutet. Initially, this was a clinical register of child and adolescent psychiatry for the Stockholm County Council. The main objectives of NEUROPSYK are to improve the assessment of and interventions used for individuals with NDDs by doing the following: 1) supporting adequate follow-up related to the implementation of existing regional and national guidelines for assessment and treatment; 2) providing clinical decision-making aids; and 3) conducting large-scale clinical epidemiological research. The registry incorporates all legal requirements for quality registries in Sweden. NEUROPSYK includes patients of all ages diagnosed with NDDs per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. These diagnoses include autism spectrum disorder, attention-deficit/hyperactivity disorder, intellectual disabilities, communication disorders, specific learning disorders, and motor disorders. Medication and behavioral interventions are recorded and patient outcomes over time are measured with the economical and user-friendly Clinical Global Impression tool, the Global Assessment of Functioning instrument, and patient-reported health-related quality of life. NEUROPSYK minimizes administrative work for health care professionals because it is integrated with structured digital patient records, thereby increasing the likelihood of high coverage and data quality. NEUROPSYK combines several strengths to exemplify a new generation of quality research registers for use in psychiatry and other areas of health care. Read more about NEUROPSYK: http://ki.se/en/kind/neuropsyk-quality-registry-for-neurodevelopmental-disorders

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 (beta = .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 (beta = -.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.

The dopamine D1 receptor (D1R) is thought to play a role in psychosis and schizophrenia, however the exact nature of this involvement is not clear. Positron emission tomography studies comparing D1R between patients and control subjects have produced inconsistent results. An important confounding factor in most clinical studies is previous exposure to antipsychotic treatment, which is thought to influence the density of D1R. To circumvent some of the limitations of clinical studies, an alternative approach for studying the relationship between D1R and psychosis is to examine individuals at increased risk for psychotic disorders, or variation in subclinical psychotic symptoms such as delusional ideation within the general population, referred to as psychosis proneness traits. In this study, we investigated whether D1R availability is associated with delusional ideation in healthy controls using data from 76 individuals measured with PET using [11C]SCH23390 and 217 individuals who completed delusional ideation questionnaires, belonging to three different study cohorts. We first performed exploratory, hypothesis-generating, analyses by creating and evaluating a new measure of delusional ideation (n=132 and n=27), which was then found to show a negative association with D1R availability (n=24). Next, we performed confirmatory analyses using Bayesian statistical modelling, in which we first attempted to replicate this result (n=20), and then evaluated the association of Peters Delusion Inventory scores with D1R availability in two independent cohorts (n=41 and 20). Collectively, we found strong evidence that there is little to no linear association between delusional ideation and D1R availability in healthy controls. If differences in D1R can be confirmed in drug-naive schizophrenia patients compared to controls, further studies are needed to ascertain whether these changes occur at the onset of psychotic symptoms or if they are associated with specific behavioural or genetic aspects of psychosis proneness other than delusional ideation.

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.

The dopamine (DA) and serotonin (5-HT) neurotransmission systems are of fundamental importance for normal brain function and serve as targets for treatment of major neuropsychiatric disorders. Despite central interest for these neurotransmission systems in psychiatry research, little is known about the regulation of receptor and transporter density levels. This lack of knowledge obscures interpretation of differences in protein availability reported in psychiatric patients. In this study, we used positron emission tomography (PET) in a twin design to estimate the relative contribution of genetic and environmental factors, respectively, on dopaminergic and serotonergic markers in the living human brain. Eleven monozygotic and 10 dizygotic healthy male twin pairs were examined with PET and [(11)C]raclopride binding to the D2- and D3-dopamine receptor and [(11)C]WAY100635 binding to the serotonin 5-HT1A receptor. Heritability, shared environmental effects and individual-specific non-shared effects were estimated for regional D2/3 and 5-HT1A receptor availability in projection areas. We found a major contribution of genetic factors (0.67) on individual variability in striatal D2/3 receptor binding and a major contribution of environmental factors (pairwise shared and unique individual; 0.70-0.75) on neocortical 5-HT1A receptor binding. Our findings indicate that individual variation in neuroreceptor availability in the adult brain is the end point of a nature-nurture interplay, and call for increased efforts to identify not only the genetic but also the environmental factors that influence neurotransmission in health and disease.

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.

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'.

Preliminary studies have suggested that γ-aminobutyric acid type A (GABA

Imaging the 18-kDa translocator protein (TSPO) is considered a potential tool for in vivo evaluation of microglial activation and neuroinflammation in the early stages of Alzheimer's disease (AD). ((R)-1-(2-chlorophenyl)-N-[(11)C]-methyl-N-(1-methylpropyl)-3-isoquinoline caboxamide ([(11)C]-(R)-PK11195) has been widely used for PET imaging of TSPO and, despite its low specific-to-nondisplaceable binding ratio, increased TSPO binding has been shown in AD patients. The high-affinity radioligand N-(5-fluoro-2-phenoxyphenyl)-N-(2-[(18)F]fluoroethyl-5-methoxybenzyl)acetamide ([(18)F]FEDAA1106) has been developed as a potential in vivo imaging tool for better quantification of TSPO binding. The aim of this study was to quantify in vivo binding of [(18)F]FEDAA1106 to TSPO in control subjects and AD patients.Seven controls (five men, two women, age 68±3 years, MMSE score 29±1) and nine AD patients (six men, three women, age 69±4 years, MMSE score 25±3) were studied with [(18)F]FEDAA1106. PET measurements were performed on an ECAT EXACT HR system (Siemens Medical Solutions) in two 60-min dynamic PET sessions with a 30-min interval between sessions. Arterial blood radioactivity was measured using an automated blood sampling system for the first 5 min and using manually drawn samples thereafter. Quantification was performed using both kinetic analysis based on a two-tissue compartment model and Logan graphical analysis. Outcome measures were total distribution volume (V T) and binding potential (BP(ND)=k3/k4). An estimate of nondisplaceable distribution volume was obtained with the Logan graphical analysis using the first 15 min of PET measurements (V(ND 1-15 min)). Binding potential (BP(ND)) was also calculated as: V(T)/V(ND 1-15 min) - 1.No statistically significant differences in V(T), k3/k4 or BP(ND) were observed between controls and AD patients.This study suggests that TSPO imaging with [(18)F]FEDAA1106 does not enable the detection of microglial activation in AD.

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.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 [Patients showed a global downregulation of gray matter [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.

Animal studies and pharmacological studies in man have suggested that the serotonin 5-HT(1A) receptor may serve as a biomarker for cognitive functioning and a target for treatment of cognitive impairment. Consistent findings in man have nonetheless hitherto remained sparse. Positron emission tomography (PET) imaging of the 5-HT(1A) receptor in patients with Alzheimer's disease, schizophrenia and depression implicate an alteration in 5-HT(1A) receptor binding compared to control subjects, but it is yet unknown whether these alterations are related to the cognitive impairment associated with these disorders. Pharmacological challenge studies using 5-HT(1A) agonism and antagonism to manipulate the serotonin system support involvement of the 5-HT(1A) receptor in human cognition, mainly in verbal memory functioning. However, the effect varies across studies and it remains unclear if the 5-HT(1A) receptor serves as a validated target for treatment of cognitive deficits. This lack of confirmation of experimental preclinical data, calls for increased efforts in translational research. Molecular imaging techniques such as PET, holds the potential to facilitate translational neuroscience by confirming observations from animal models in man, and aid development of validated animal models of use for advancement of pharmacological treatment. Furthermore, in combination with molecular genetics, molecular imaging may suggest novel strategies for prevention and intervention, based on an understanding of the molecular mechanisms involved in disease pathogenesis of major neuropsychiatric disorder and associated cognitive impairment.

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 [11C]NNC-112 and [18F]fallypride, respectively. Stop-signal reaction time was negatively correlated with D1- and D2-type BPNDin 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.

The serotonin system has long been of interest in biological models of human personality. The purpose of this positron emission tomography (PET) study was to search for relationships between serotonin 5-HT(1A) receptor density and personality traits.Fifteen normal male subjects, ages 20-45 years, were examined with PET and the radioligand [(11)C]WAY100635. Personality traits were assessed with the Swedish version of the Temperament and Character Inventory self-report questionnaire. Binding potential, an index for the density of available 5-HT(1A) receptors, was calculated for the dorsal raphe nuclei, the hippocampal formation, and the neocortex. For each region, correlation coefficients between 5-HT(1A) receptor binding potential and Temperament and Character Inventory personality dimensions were calculated and analyzed in two-tailed tests for significance.The authors found that the binding potential correlated inversely with scores for self-transcendence, a personality trait covering religious behavior and attitudes. No correlations were found for any of the other six Temperament and Character Inventory dimensions. The self-transcendence dimension consists of three distinct subscales, and further analysis showed that the subscale for spiritual acceptance correlated significantly with binding potential but not with the other two subscales.This finding in normal male subjects indicated that the serotonin system may serve as a biological basis for spiritual experiences. The authors speculated that the several-fold variability in 5-HT(1A) receptor density may explain why people vary greatly in spiritual zeal.

Based on evidence linking creativity and bipolar disorder, a model has been proposed whereby factors influencing liability to bipolar disorder confer certain traits with positive effects on reproductive fitness. The authors tested this model by examining key traits known to be associated with evolutionary fitness, namely, temperament and neurocognition, in individuals carrying liability for bipolar disorder. Schizophrenia probands and their co-twins were included as psychiatric controls.Twin pairs discordant for bipolar disorder and schizophrenia and control pairs were identified through the Swedish Twin Registry. The authors administered a neuropsychological test battery and temperament questionnaires to samples of bipolar probands, bipolar co-twins, schizophrenia probands, schizophrenia co-twins, and controls. Multivariate mixed-model analyses of variance were conducted to compare groups on temperament and neurocognitive scores.Bipolar co-twins showed elevated scores on a "positivity" temperament scale compared with controls and bipolar probands, while bipolar probands scored higher on a "negativity" scale compared with their co-twins and controls, who did not differ. Additionally, bipolar co-twins showed superior performance compared with controls on tests of verbal learning and fluency, while bipolar probands showed performance decrements across all neurocognitive domains. In contrast, schizophrenia co-twins showed attenuated impairments in positivity and overall neurocognitive functioning relative to their ill proband counterparts.These findings suggest that supra-normal levels of sociability and verbal functioning may be associated with liability for bipolar disorder. These effects were specific to liability for bipolar disorder and did not apply to schizophrenia. Such benefits may provide a partial explanation for the persistence of bipolar illness in the population.

Sex hormones and the serotonergic system interact in the regulation of mood, learning, memory and sexual behaviour. However, the mechanisms have not been fully explored. The serotonin transporter protein (5-HTT) regulates synaptic concentrations of serotonin and is a primary target for selective serotonin reuptake inhibitors. The aim of this study was to explore how estrogen treatment alone or in combination with testosterone affects 5-HTT binding potentials measured by positron emission tomography (PET) in specific brain regions of postmenopausal women. Ten healthy surgically postmenopausal women (years since oophorectomy 7.5 ± 4.0, mean ± SD) underwent PET examinations at baseline, after three months of estrogen treatment (transdermal estradiol 100 μg/24 hours) and after another three months of combined estrogen and testosterone (testosterone undecanoate 40 mg daily) treatment using the radioligand [(11)C] MADAM developed for examination of the serotonin transporter. The 5-HTT binding potentials decreased significantly in several cortical regions, as well as in limbic and striatal regions after both estrogen treatment alone and combined estrogen/testosterone treatment in comparison to baseline. The observed decrease in 5-HTT could either be due to direct effects on serotonin transporter expression or be the result of indirect adaptation to estrogen and /or testosterone effects on synaptic serotonin levels. Although the mechanism still needs further exploration, the study supports the view that gonadal hormones play a role in serotonin regulated mood disorders.

Dysfunctional interpersonal behavior is thought to underlie a wide spectrum of psychiatric disorders; however, the neurobiological underpinnings of these behavioral disturbances are poorly understood. Previous molecular imaging studies have shown associations between striatal dopamine (DA) D2-receptor binding and interpersonal traits, such as social conformity. The objective of this study was to explore, for the first time, the role of DA D1-receptors (D1-Rs) in human interpersonal behavior. Twenty-three healthy subjects were examined using positron emission tomography and the radioligand [(11)C]SCH23390, yielding D1-R binding potential values. Striatal D1-R binding was related to personality scales selected to specifically assess one dimension of interpersonal behavior, namely a combination of affiliation and dominance (i.e., the Social Desirability, Verbal Trait Aggression and Physical Trait Aggression scales from Swedish Universities Scales of Personality). An exploratory analysis was also performed for extrastriatal brain regions. D1-R binding potential values in the limbic striatum (r = .52; p = .015), associative striatum (r = .55; p = .009), and sensorimotor striatum (r = .67; p = .001) were positively related to Social Desirability scores. D1-R binding potential in the limbic striatum (r = -.51; p = .019) was negatively associated with Physical Trait Aggression scores. For extrastriatal regions, Social Desirability scores showed positive correlations in the amygdala (r = .60; p = .006) and medial frontal cortex (r = .60; p = .004). This study provides further support for the role of DA function in the expression of disaffiliative and dominant traits. Specifically, D1-R availability may serve as a marker for interpersonal behavior in humans. Associations were demonstrated for the same dimension of interpersonal behavior as for D2-R, but in the opposite direction, suggesting that the two receptor subtypes are involved in the same behavioral processes, but with different functional roles.

The human serotonin transporter (5-HTT) gene is one of the most extensively studied in psychiatry. A functional polymorphism in the promoter region of the 5-HTT gene (5-HTTLPR) has been associated with several psychiatric disorders as well as anxiety-related personality traits. In search of a mechanistic understanding of the functional implications of 5-HTTLPR, the influence of this polymorphism on regional 5-HT1A receptor density has previously been examined in two positron emission tomography (PET) studies in humans, yielding, however, contradictory results. In the present study, 54 control subjects were examined with [11C]WAY 100635 PET and a battery of cognitive tests. Regional binding potential (BP) of [11C]WAY 100635 to 5-HT1A receptor was calculated for the dorsal raphe nuclei, the hippocampus, the anterior cingulate, the insula, the temporal cortex and the frontal cortex. The influence of 5-HTTLPR genotype on regional 5-HT1A BP and cognitive performance was investigated. No differences in 5-HT1A receptor density between carriers and non-carriers of the S allele were found. Thus, we could not replicate any of the previously reported associations between 5-HTTLPR and 5-HT1A density. There was, however, a highly significant association between 5-HTTLPR genotype and performance in Wisconsin Card Sorting Test; carriers of the S allele had a superior performance compared to the LL carriers. These observations suggest that functional implications of the 5-HTTLPR polymorphism are not likely to be mediated by differences in 5-HT1A expression levels and that other biomarkers must be considered for future investigations at phenotype level.

Several lines of evidence suggest inter-dependency between the serotonin transporter (5-HTT) and the 5HT1A receptor, two recognised targets for the treatment of anxiety and depression.to examine the correlation of regional expression levels for these two serotonergic markers in the human brain in vivo.Twelve male control subjects were examined with PET twice on the same day, using the radioligands [11C]WAY 100635 and [11C]MADAM for quantification of the 5-HT1A receptor and the 5-HTT, respectively. The binding potential (BP) was calculated for raphe nuclei, hippocampus and frontal cortex.In all regions, the BP for both [11C]WAY 100635 (raphe nuclei 1.85-4.71, hippocampus 2.52-6.17, frontal cortex 2.03-3.79) and [11C]MADAM (2.70-7.65, 0.47-1.76, 0.18-0.51) varied several fold between subjects. In the raphe nuclei, where the two markers are situated on the same neurons, the ratio of [11C]WAY 100635 binding to [11C]MADAM BP binding varied considerably (0.43-1.05). There was a positive correlation between the two markers in the raphe nuclei (rxy=0.68, p0.05) and in the hippocampus (rxy=0.97, p0.001) but not in the frontal cortex (rxy=-0.25, p=0.44).The results support a correlation between density levels of the 5-HT1A-receptor and the 5-HTT in the raphe nuclei and hippocampus but not in the frontal cortex. A suggested clinical implication is that the inter-individual variability in 5-HT1A-receptor and 5-HTT densities, as well as the ratio of these, is of particular interest in relation to individual responses to selective serotonin reuptake inhibitor treatment.

Animal studies and studies of human aging have suggested that the serotonin 5-HT1A receptor may serve as a biomarker for cognitive functioning and a target for pharmacological treatment of cognitive deficits. The purpose of this positron emission tomography (PET) study was to search for relationships between interindividual variability in serotonin 5-HT1A receptor binding potential (BP) and cognitive functioning. Twenty-four male control subjects, age 20–55 years, were examined with [11C]WAY100635 PET and a battery of cognitive tests. 5-HT1A receptor binding potential were calculated for the raphe nuclei, the hippocampus and the neocortex. Correlation coefficients between BP and cognitive performance were obtained for each region. There was a severalfold of variability in 5-HT1A BP between individuals. We found no significant correlation between regional [11C]WAY100635 binding and cognitive performance. The results do not provide support for involvement of the 5-HT1A receptor in cognitive functioning in man and question the predictive validity of some currently used animal models in translational neuroscience.

The aim was to test the dopamine hypothesis of schizophrenia in a further analysis of D 2 -like dopamine binding using the radioligand [ 11 C]raclopride and high resolution 3-dimensional (3D) PET. Eighteen drug-naive patients with schizophrenia and seventeen control subjects were examined. The D 2 binding potential (BP) in the putamen, the caudate and the thalamus was calculated using the simplified reference tissue model. The volume of regions of interest was controlled for by MRI. Symptoms were rated with the Positive and Negative Syndrome Scale for Schizophrenia (PANSS). No significant group differences were found for D 2 BP in the putamen or in the caudate and there was no significant hemispheric difference for any region. In the right thalamus the D 2 BP was significantly lower in patients as compared to control subjects, whereas a numerical difference did not reach statistical significance for the left thalamus. There was no significant correlation between D 2 BP and total PANSS score in any region. There was a highly significant age effect in the caudate and in the putamen, but not in the thalamus. In this relatively large PET study of exclusively drug-naive schizophrenic patients, a lower D 2 BP in the right thalamus was found in the patient group. This finding is in agreement with two previous studies in Sweden and in Japan using the high-affinity radioligand [ 11 C]FLB 457 and provide further support for a role of dopamine in the thalamus related to the pathophysiology of schizophrenia.