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

Association of Hippocampal Glutamate Levels With Adverse Outcomes in Individuals at Clinical High Risk for Psychosis

Importance: Preclinical and human data suggest that hippocampal dysfunction plays a critical role in the onset of psychosis. Neural hyperactivity in the hippocampus is thought to drive an increase in subcortical dopamine function through glutamatergic projections to the striatum. Objective: To examine the association between hippocampal glutamate levels in individuals at clinical high risk for psychosis and their subsequent clinical outcomes. Design, Setting, and Participants: This cross-sectional study of 86 individuals at clinical high risk for psychosis and 30 healthy control individuals, with a mean follow-up of 18.5 months, was conducted between November 1, 2011, and November 1, 2017, at early detection services in London and Cambridge, United Kingdom. Main Outcomes and Measures: Concentrations of glutamate and other metabolites were measured in the left hippocampus using 3-T proton magnetic resonance spectroscopy at the first clinical presentation. At follow-up, clinical outcomes were assessed in terms of transition or nontransition to psychosis using the Comprehensive Assessment of the At-Risk Mental State criteria and the level of overall functioning using the Global Assessment of Function scale. Results: Of 116 total participants, 86 were at clinical high risk for psychosis (50 [58%] male; mean [SD] age, 22.4 [3.5] years) and 30 were healthy controls (14 [47%] male; mean [SD] age, 24.7 [3.8] years). At follow-up, 12 clinical high-risk individuals developed a first episode of psychosis whereas 74 clinical high-risk individuals did not; 19 clinical high-risk individuals showed good overall functioning (Global Assessment of Function ≥65), whereas 38 clinical high-risk individuals had a poor functional outcome (Global Assessment of Function <65). Compared with clinical high-risk individuals who did not become psychotic, clinical high-risk individuals who developed psychosis showed higher hippocampal glutamate levels (mean [SD], 8.33 [1.48] vs 9.16 [1.28] glutamate levels; P = .048). The clinical high-risk individuals who developed psychosis also had higher myo-inositol levels (mean [SD], 7.60 [1.23] vs 6.24 [1.36] myo-inositol levels; P = .002) and higher creatine levels (mean [SD], 8.18 [0.74] vs 7.32 [1.09] creatine levels; P = .01) compared with clinical high-risk individuals who did not become psychotic, and higher myo-inositol levels compared with healthy controls (mean [SD], 7.60 [1.23] vs 6.19 [1.51] myo-inositol levels; P = .005). Higher hippocampal glutamate levels in clinical high-risk individuals were also associated with a poor functional outcome (mean [SD], 8.83 [1.43] vs 7.76 [1.40] glutamate levels; P = .02). In the logistic regression analyses, hippocampal glutamate levels were significantly associated with clinical outcome in terms of transition and nontransition to psychosis (β = 0.48; odds ratio = 1.61; 95% CI, 1.00-2.59; P = .05) and overall functioning (β = 0.53; odds ratio = 1.71; 95% CI, 1.10-2.66; P = .02). Conclusions and Relevance: The findings indicate that adverse clinical outcomes in individuals at clinical high risk for psychosis may be associated with an increase in baseline hippocampal glutamate levels, as well as an increase in myo-inositol and creatine levels. This conclusion suggests that these measures could contribute to the stratification of clinical high-risk individuals according to future clinical outcomes

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

Integrated metastate functional connectivity networks predict change in symptom severity in clinical high risk for psychosis

The ability to identify biomarkers of psychosis risk is essential in defining effective preventive measures to potentially circumvent the transition to psychosis. Using samples of people at clinical high risk for psychosis (CHR) and Healthy controls (HC) who were administered a task fMRI paradigm, we used a framework for labelling time windows of fMRI scans as ‘integrated’ FC networks to provide a granular representation of functional connectivity (FC). Periods of integration were defined using the ‘cartographic profile’ of time windows and k‐means clustering, and sub‐network discovery was carried out using Network Based Statistics (NBS). There were no network differences between CHR and HC groups. Within the CHR group, using integrated FC networks, we identified a sub‐network negatively associated with longitudinal changes in the severity of psychotic symptoms. This sub‐network comprised brain areas implicated in bottom‐up sensory processing and in integration with motor control, suggesting it may be related to the demands of the fMRI task. These data suggest that extracting integrated FC networks may be useful in the investigation of biomarkers of psychosis risk

Afrikaans as Standaard Gemiddelde Europees:Wanneer ‘n lid uit sy taalarea beweeg

A recent trend in the study of Standard Average European is the extraterritorial perspective of examining the extent to which non-European languages have converged with this Sprachbund as a result of contact with one or more of its members. The present article complements this line of research in that it investigates the extent to which a European language has diverged from Standard Average European after leaving the linguistic area. The focus is on Dutch, a nuclear member of the Sprachbund, and Afrikaans, its colonial offshoot. The two languages are compared with respect to twelve of the most distinctive linguistic features of Standard Average European. Afrikaans is found to share ten of them with Dutch, including anticausative prominence and formally distinguished intensifiers and reflexives, and could therefore still be considered a core member of the Sprachbund, despite deviations in the expression of negative pronouns and the grammaticality of external possessor constructions. This relatively low degree of divergence may be attributed to the continuity from Settler Dutch to at least the variety of Afrikaans on which the standard language is based and to the important role that Dutch continued to play in the history of Afrikaans

Involvement of the endocannabinoid system in reward processing in the human brain

Rationale Disturbed reward processing in humans has been associated with a number of disorders, such as depression, addiction, and attention-deficit hyperactivity disorder. The endocannabinoid (eCB) system has been implicated in reward processing in animals, but in humans, the relation between eCB functioning and reward is less clear. Objectives The current study uses functional magnetic resonance imaging (fMRI) to investigate the role of the eCB system in reward processing in humans by examining the effect of the eCB agonist Δ9-tetrahydrocannabinol (THC) on reward-related brain activity. Methods Eleven healthy males participated in a randomized placebo-controlled pharmacological fMRI study with administration of THC to challenge the eCB system. We compared anticipatory and feedback-related brain activity after placebo and THC, using a monetary incentive delay task. In this task, subjects are notified before each trial whether a correct response is rewarded (“reward trial”) or not (“neutral trial”). Results Subjects showed faster reaction times during reward trials compared to neutral trials, and this effect was not altered by THC. THC induced a widespread attenuation of the brain response to feedback in reward trials but not in neutral trials. Anticipatory brain activity was not affected. Conclusions These results suggest a role for the eCB system in the appreciation of rewards. The involvement of the eCB system in feedback processing may be relevant for disorders in which appreciation of natural rewards may be affected such as addiction

The governance of justice and internal security in Scotland: Between the Scottish independence referendum and British decisions on the EU

This article examines how the governance of justice and internal security in Scotland could be affected by the outcome of the Scottish independence referendum in September 2014. The article argues that it is currently impossible to equate a specific result in the referendum with a given outcome for the governance of justice and internal security in Scotland. This is because of the complexities of the current arrangements in that policy area and the existence of several changes that presently affect them and are outside the control of the government and of the people of Scotland. This article also identifies an important paradox. In the policy domain of justice and internal security, a ‘no’ vote could, in a specific set of circumstances, actually lead to more changes than a victory of the ‘yes’ camp

Reversible Disruption of Pre-Pulse Inhibition in Hypomorphic-Inducible and Reversible CB1-/- Mice

Although several genes are implicated in the pathogenesis of schizophrenia, in animal models for such a severe mental illness only some aspects of the pathology can be represented (endophenotypes). Genetically modified mice are currently being used to obtain or characterize such endophenotypes. Since its cloning and characterization CB1 receptor has increasingly become of significant physiological, pharmacological and clinical interest. Recently, its involvement in schizophrenia has been reported. Among the different approaches employed, gene targeting permits to study the multiple roles of the endocannabinoid system using knockout (-/-) mice represent a powerful model but with some limitations due to compensation. To overcome such a limitation, we have generated an inducible and reversible tet-off dependent tissue-specific CB1-/- mice where the CB1R is re-expressed exclusively in the forebrain at a hypomorphic level due to a mutation (IRh-CB1-/-) only in absence of doxycycline (Dox). In such mice, under Dox+ or vehicle, as well as in wild-type (WT) and CB1-/-, two endophenotypes motor activity (increased in animal models of schizophrenia) and pre-pulse inhibition (PPI) of startle reflex (disrupted in schizophrenia) were analyzed. Both CB1-/- and IRh-CB1-/- showed increased motor activity when compared to WT animals. The PPI response, unaltered in WT and CB1-/- animals, was on the contrary highly and significantly disrupted only in Dox+ IRh-CB1-/- mice. Such a response was easily reverted after either withdrawal from Dox or haloperidol treatment. This is the first Inducible and Reversible CB1-/- mice model to be described in the literature. It is noteworthy that the PPI disruption is not present either in classical full CB1-/- mice or following acute administration of rimonabant. Such a hypomorphic model may provide a new tool for additional in vivo and in vitro studies of the physiological and pathological roles of cannabinoid system in schizophrenia and in other psychiatric disorders