Neural Circuitry of Novelty Salience Processing in Psychosis Risk: Association With Clinical Outcome

Psychosis has been proposed to develop from dysfunction in a hippocampal-striatal-midbrain circuit, leading to aberrant salience processing. Here, we used functional magnetic resonance imaging (fMRI) during novelty salience processing to investigate this model in people at clinical high risk (CHR) for psychosis according to their subsequent clinical outcomes. Seventy-six CHR participants as defined using the Comprehensive Assessment of At-Risk Mental States (CAARMS) and 31 healthy controls (HC) were studied while performing a novelty salience fMRI task that engaged an a priori hippocampal-striatal-midbrain circuit of interest. The CHR sample was then followed clinically for a mean of 59.7 months (~5 y), when clinical outcomes were assessed in terms of transition (CHR-T) or non-transition (CHR-NT) to psychosis (CAARMS criteria): during this period, 13 individuals (17%) developed a psychotic disorder (CHR-T) and 63 did not. Functional activation and effective connectivity within a hippocampal-striatal-midbrain circuit were compared between groups. In CHR individuals compared to HC, hippocampal response to novel stimuli was significantly attenuated (P = .041 family-wise error corrected). Dynamic Causal Modelling revealed that stimulus novelty modulated effective connectivity from the hippocampus to the striatum, and from the midbrain to the hippocampus, significantly more in CHR participants than in HC. Conversely, stimulus novelty modulated connectivity from the midbrain to the striatum significantly less in CHR participants than in HC, and less in CHR participants who subsequently developed psychosis than in CHR individuals who did not become psychotic. Our findings are consistent with preclinical evidence implicating hippocampal-striatal-midbrain circuit dysfunction in altered salience processing and the onset of psychosis

Microglial activity in people at ultra high risk of psychosis and in schizophrenia; an [11C]PBR28 PET brain imaging study

Objective: The purpose of this study was to determine whether microglial activity, measured using translocator-protein positron emission tomography (PET) imaging, is increased in unmedicated persons presenting with subclinical symptoms indicating that they are at ultra high risk of psychosis and to determine whether microglial activity is elevated in schizophrenia after controlling for a translocator-specific genetic polymorphism. Method: The authors used the second-generation radioligand [11C]PBR28 and PET to image microglial activity in the brains of participants at ultra high risk for psychosis. Participants were recruited from early intervention centers. The authors also imaged a cohort of patients with schizophrenia and matched healthy subjects for comparison. In total, 56 individuals completed the study. At screening, participants were genotyped to account for the rs6971 polymorphism in the gene encoding the 18Kd translocator protein. The main outcome measure was total gray matter [11C]PBR28 binding ratio, representing microglial activity. Results: [11C]PBR28 binding ratio in gray matter was elevated in ultra-high-risk participants compared with matched comparison subjects (Cohen’s d >1.2) and was positively correlated with symptom severity (r=0.730). Patients with schizophrenia also demonstrated elevated microglial activity relative to matched comparison subjects (Cohen’s d >1.7). Conclusions: Microglial activity is elevated in patients with schizophrenia and in persons with subclinical symptoms who are at ultra high risk of psychosis and is related to at-risk symptom severity. These findings suggest that neuroinflammation is linked to the risk of psychosis and related disorders, as well as the expression of subclinical symptoms

Reproducibility of the WHO histological criteria for the diagnosis of Philadelphia chromosome-negative myeloproliferative neoplasms.

This study, performed on behalf of the Italian Registry of Thrombocythaemias (Registro Italiano Trombocitemie), aimed to test the inter-observer reproducibility of the histological parameters proposed by the WHO classification for the diagnosis of the Philadelphia chromosome-negative myeloproliferative neoplasms. A series of 103 bone marrow biopsy samples of Philadelphia chromosome-negative myeloproliferative neoplasms consecutively collected in 2004 were classified according to the WHO criteria as follows: essential thrombocythaemia (n=34), primary myelofibrosis (n=44) and polycythaemia vera (n=25). Two independent groups of pathologists reviewed the bone marrow biopsies. The first group was asked to reach a collegial 'consensus' diagnosis. The second group reviewed individually all the cases to recognize the main morphological parameters indicated by the WHO classification and report their results in a database. They were subsequently instructed to individually build a 'personal' diagnosis of myeloproliferative neoplasms subtype just assembling the parameters collected in the database. Our results indicate that high levels of agreement ( 6570%) have been reached for about all of the morphological features. Moreover, among the 18 evaluated histological features, 11 resulted statistically more useful for the differential diagnosis among the different Philadelphia chromosome-negative myeloproliferative neoplasms. Finally, we found a high percentage of agreement (76%) between the 'personal' and 'consensus' diagnosis (Cohen's kappa statistic >0.40). In conclusion, our results support the use of the histological criteria proposed by the WHO classification for the Philadelphia chromosome-negative myeloproliferative neoplasms to ensure a more precise and early diagnosis for these patients

A Test of the Transdiagnostic Dopamine Hypothesis of Psychosis Using Positron Emission Tomographic Imaging in Bipolar Affective Disorder and Schizophrenia

Importance The dopamine hypothesis suggests that dopamine abnormalities underlie psychosis, irrespective of diagnosis, implicating dopamine dysregulation in bipolar affective disorder and schizophrenia, in line with the research domain criteria approach. However, this hypothesis has not been directly examined in individuals diagnosed with bipolar disorder with psychosis. Objectives To test whether dopamine synthesis capacity is elevated in bipolar disorder with psychosis and how this compares with schizophrenia and matched controls and to examine whether dopamine synthesis capacity is associated with psychotic symptom severity, irrespective of diagnostic class. Design, Setting, and Participants This cross-sectional case-control positron emission tomographic study was performed in the setting of first-episode psychosis services in an inner-city area (London, England). Sixty individuals participated in the study (22 with bipolar psychosis [18 antipsychotic naive or free], 16 with schizophrenia [14 antipsychotic naive or free], and 22 matched controls) and underwent fluorodihydroxyphenyl-l-alanine ([18F]-DOPA) positron emission tomography to examine dopamine synthesis capacity. Standardized clinical measures, including the Positive and Negative Syndrome Scale, Young Mania Rating Scale, and Global Assessment of Functioning, were administered. The study dates were March 2013 to November 2016. Main Outcomes and Measures Dopamine synthesis capacity (Kicer) and clinical measures (Positive and Negative Syndrome Scale, Young Mania Rating Scale, and Global Assessment of Functioning). Results The mean (SD) ages of participants were 23.6 (3.6) years in 22 individuals with bipolar psychosis (13 male), 26.3 (4.4) years in 16 individuals with schizophrenia (14 male), and 24.5 (4.5) years in controls (14 male). There was a significant group difference in striatal dopamine synthesis capacity (Kicer) (F2,57 = 6.80, P = .002). Kicer was significantly elevated in both the bipolar group (mean [SD], 13.18 [1.08] × 10−3 min−1; P = .002) and the schizophrenia group (mean [SD], 12.94 [0.79] × 10−3 min−1; P = .04) compared with controls (mean [SD], 12.16 [0.92] × 10−3 min−1). There was no significant difference in striatal Kicer between the bipolar and schizophrenia groups. Kicer was significantly positively correlated with positive psychotic symptom severity in the combined bipolar and schizophrenia sample experiencing a current psychotic episode, explaining 27% of the variance in symptom severity (n = 32, r = 0.52, P = .003). There was a significant positive association between Kicer and positive psychotic symptom severity in individuals with bipolar disorder experiencing a current psychotic episode (n = 16, r = 0.60, P = .01), which remained significant after adjusting for manic symptom severity. Conclusions and Relevance These findings are consistent with a transdiagnostic role for dopamine dysfunction in the pathoetiology of psychosis and suggest dopamine synthesis capacity as a potential novel drug target for bipolar disorder and schizophrenia

Basic self-disturbances related to reduced anterior cingulate volume in subjects at ultra-high risk for psychosis

Introduction: Alterations of the “pre-reflective” sense of first-person perspective (e.g., of the “basic self”) are characteristic features of schizophrenic spectrum disorders and are significantly present in the prodromal phase of psychosis and in subjects at ultra-high risk for psychosis (UHR). Studies in healthy controls suggest that neurobiological substrate of the basic self involves cortical midline structures, such as the anterior and posterior cingulate cortices. Neuroimaging studies have identified neuroanatomical cortical midline structure abnormalities in schizophrenic spectrum disorders. Objectives: i) To compare basic self-disturbances levels in UHR subjects and controls and ii) to assess the relationship between basic self-disturbances and alterations in cortical midline structures volume in UHR subjects. Methods: Thirty-one UHR subjects (27 antipsychotic-naïve) and 16 healthy controls were assessed using the 57-item semistructured Examination of Anomalous Self-Experiences (EASE) interview. All subjects were scanned using magnetic resonance imaging (MRI) at 3 T, and gray matter volume was measured in a priori defined regions of interest (ROIs) in the cortical midline structures. Results: EASE scores were much higher in UHR subjects than controls (p < 0.001). The UHR group had smaller anterior cingulate volume than controls (p = 0.037). There were no structural brain imaging alterations between UHR individuals with or without self-disturbances. Within the UHR sample, the subgroup with higher EASE scores had smaller anterior cingulate volumes than UHR subjects with lower EASE scores and controls (p = 0.018). In the total sample, anterior cingulate volume was inversely correlated with the EASE score (R = 0.52, p < 0.016). Conclusions: Basic self-disturbances in UHR subjects appear to be related to reductions in anterior cingulate volume

Tail biting in pigs: a multi-causal behavioural disorder

Grizenje repova poremećaj je ponašanja svinja, multikauzalne prirode, a smatra se da motivacija za grizenje proizlazi iz nemogućnosti izražavanja vrsti specifičnog ponašanja (rovanje ili žvakanje). Stoga, životinje preusmjeravaju svoje ponašanje na druge objekte koji su im na raspolaganju, kao što su primjerice uške ili repovi drugih životinja. Grizenje repova izrazito je raširena pojava u uzgoju svinja koja stvara velike ekonomske gubitke i utječe na dobrobit životinja. Ovaj poremećaj ponašanja svinja ima najmanje tri različita polazišta na osnovi kojih se dijeli na tri osnovna oblika. Prvi je oblik ‘dvofazno ili dvo-stupanjsko grizenje’, a kako mu i samo ime govori, sastoji se od dvije odvojene faze. U prvoj fazi svinja nježno drži rep druge u ustima bez da izazove bilo kakvo vidljivo oštećenje tkiva. Tada proces prelazi u drugu fazu, pri čemu ozljeda na repu i posljedično krvarenje privlači i druge životinje iz skupine te naglo dolazi da eskalacije poremećaja ponašanja. Drugi oblik naziva se ‘iznenadno-snažno grizenje’, i kod njega dolazi do naglog i snažnog napada jedne svinje na rep druge svinje. Kod ovog oblika poremećaja odmah dolazi do većih ozljeda, s mogućim djelomičnim ili potpunim gubitkom repa te se ovaj oblik grizenja vrlo često determinira kao kanibalizam. Treći se oblik ovog poremećaja u ponašanju naziva „opsesivno grizenje“. On podrazumijeva snažno i stalno grizenje repova od strane jedne ili nekoliko životinja u skupini. Životinje koje pokazuju ovaj oblik ponašanja stalno su u potrazi za žrtvom te iz tog razloga ovaj oblik grizenja rezultira vrlo brzo do većeg broja ozljeda. Kao mogući uzroci ovog poremećaja spominju se zdravstveno stanje, neodgovarajući uvjeti držanja i nedostatna, odnosno nepravilna hranidba, a kao ne manje važni čimbenici spominju se spol, stres, dosada i genetska predispozicija. Usporedba podataka iz različitih do sad provedenih istraživanja otežana je zbog neujednačene terminologije i različitih načina definiranja ovog poremećaja ponašanja. Ovaj pregledni rad predstavlja aktualni pregled literaturnih saznanja o grizenju repova u svinja, i razmatra različite čimbenike okoliša i uzgoja koji mogu utjecati na njegovo izražavanje i složenost.Tail biting is a multi-causal behavioural disorder in pigs. It is considered that the motivation behind it comes from the pig’s inability to express its species-specific behaviour, such as rooting or chewing. Therefore, animals redirect their behaviour onto other objects available to them, such as the ears or tails of other animals. Tail biting is a widespread phenomenon in breeding pigs, causing great economic losses and affecting the welfare of animals. This behavioural disorder has at least three different starting points, based on which it can be divided into three basic forms. The first is called ‘two-stage biting’, where in the first stage the pig gently holds the tail in the mouth and manipulates it without causing any visible tissue damage. This process proceeds to the second stage, where tail injury and consequent bleeding attracts other animals from the group, when the disorder suddenly escalates. The second form is called ‘sudden-strong biting’, and it is manifested as a sudden and strong attack of one pig against the tail of another. This form of the disorder results in immediate injuries, with possible partial or complete loss of the tail. This form of biting is often determined as cannibalism. The third form of this behavioural disorder is called ‘obsessive biting’. It implies strong and consistent biting of tails by one or several animals in the group. Animals that show this form of behaviour are constantly in search of a victim, and for this reason, this form of tail biting quickly results in a great number of injuries. Possible causes for the development of this disorder include a range of factors, such as health status, inadequate housing, boredom, gender, stress, genetics and insufficient or improper nutrition, as outlined in the literature. Comparison of data from different studies has been hampered by the lack of uniform terminology and the many different definitions of this disorder. This review presents the current findings on the tail-biting phenomena in pigs, and consider the various factors of the environment and husbandry that can affect its expression and complexity

Towards a Standard Psychometric Diagnostic Interview for Subjects at Ultra High Risk of Psychosis: CAARMS versus SIPS.

Background. Several psychometric instruments are available for the diagnostic interview of subjects at ultra high risk (UHR) of psychosis. Their diagnostic comparability is unknown. Methods. All referrals to the OASIS (London) or CAMEO (Cambridgeshire) UHR services from May 13 to Dec 14 were interviewed for a UHR state using both the CAARMS 12/2006 and the SIPS 5.0. Percent overall agreement, kappa, the McNemar-Bowker χ (2) test, equipercentile methods, and residual analyses were used to investigate diagnostic outcomes and symptoms severity or frequency. A conversion algorithm (CONVERT) was validated in an independent UHR sample from the Seoul Youth Clinic (Seoul). Results. There was overall substantial CAARMS-versus-SIPS agreement in the identification of UHR subjects (n = 212, percent overall agreement = 86%; kappa = 0.781, 95% CI from 0.684 to 0.878; McNemar-Bowker test = 0.069), with the exception of the brief limited intermittent psychotic symptoms (BLIPS) subgroup. Equipercentile-linking table linked symptoms severity and frequency across the CAARMS and SIPS. The conversion algorithm was validated in 93 UHR subjects, showing excellent diagnostic accuracy (CAARMS to SIPS: ROC area 0.929; SIPS to CAARMS: ROC area 0.903). Conclusions. This study provides initial comparability data between CAARMS and SIPS and will inform ongoing multicentre studies and clinical guidelines for the UHR psychometric diagnostic interview.Peer Reviewe

BCL3-rearrangements in B-cell lymphoid neoplasms occur in two breakpoint clusters associated with different diseases

The t(14;19)(q32;q13) often juxtaposes BCL3 with immunoglobulin heavy chain (IGH) resulting in overexpression of the gene. In contrast to other oncogenic translocations, BCL3 rearrangement (BCL3-R) has been associated with a broad spectrum of lymphoid neoplasms. Here we report an integrative whole-genome sequence, transcriptomic, and DNA methylation analysis of 13 lymphoid neoplasms with BCL3-R. The resolution of the breakpoints at single base-pair revealed that they occur in two clusters at 5' (n=9) and 3' (n=4) regions of BCL3 associated with two different biological and clinical entities. Both breakpoints were mediated by aberrant class switch recombination of the IGH locus. However, the 5' breakpoints (upstream) juxtaposed BCL3 next to an IGH enhancer leading to overexpression of the gene whereas the 3' breakpoints (downstream) positioned BCL3 outside the influence of the IGH and were not associated with its expression. Upstream BCL3-R tumors had unmutated IGHV, trisomy 12, and mutated genes frequently seen in chronic lymphocytic leukemia (CLL) but had an atypical CLL morphology, immunophenotype, DNA methylome, and expression profile that differ from conventional CLL. In contrast, downstream BCL3-R neoplasms were atypical splenic or nodal marginal zone lymphomas (MZL) with mutated IGHV, complex karyotypes and mutated genes typical of MZL. Two of the latter four tumors transformed to a large B-cell lymphoma. We designed a novel fluorescence in situ hybridization assay that recognizes the two different breakpoints and validated these findings in 17 independent tumors. Overall, upstream or downstream breakpoints of BCL3-R are mainly associated with two subtypes of lymphoid neoplasms with different (epi)genomic, expression, and clinicopathological features resembling atypical CLL and MZL, respectively