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Background. Despite behavioural signs of flattened affect, patients affected by schizophrenia show enhanced sensitivity to negative stimuli. The current literature concerning neural circuitry for emotions supports dysregulations of cortico-limbic networks, but gives contrasting results. Adverse childhood experiences (ACEs) could persistently influence emotional regulation and neural correlates of response to emotional stimuli in healthy humans. This study evaluated the effect of ACEs and chronic undifferentiated schizophrenia on neural responses to emotional stimuli (negative facial expression). Method. Brain blood-oxygen-level-dependent functional magnetic resonance imaging neural responses to a face-matching paradigm, and regional grey matter (GM) volumes were studied at 3.0 T in the amygdala, hippocampus, anterior cingulated cortex (ACC) and prefrontal cortex (PFC). The severity of ACEs was assessed. Participants included 20 consecutively admitted in-patients affected by chronic undifferentiated schizophrenia, and 20 unrelated healthy volunteers from the general population. Results. Patients reported higher ACEs than controls. Worse ACEs proportionally led to decreasing responses in the amygdala and hippocampus, and to increasing responses in the PFC and ACC in all participants. Patients showed higher activations in the amygdala and hippocampus, and lower activations in the PFC and ACC. Higher ACEs were associated with higher GM volumes in the PFC and ACC, and schizophrenia was associated with GM reduction in all studied regions. Conclusions. Structural and functional brain correlates of emotional reactivity are influenced by both current chronic undifferentiated schizophrenia and the severity of past ACEs. "Background. Despite behavioural signs of flattened affect, patients affected by schizophrenia show enhanced sensitivity to negative stimuli. The current literature concerning neural circuitry for emotions supports dysregulations of cortico-limbic networks, but gives contrasting results. Adverse childhood experiences (ACEs) could persistently influence emotional regulation and neural correlates of response to emotional stimuli in healthy humans. This study evaluated the effect of ACEs and chronic undifferentiated schizophrenia on neural responses to emotional stimuli (negative facial expression). Method. Brain blood-oxygen-level-dependent functional magnetic resonance imaging neural responses to a face-matching paradigm, and regional grey matter (GM) volumes were studied at 3.0 T in the amygdala, hippocampus, anterior cingulated cortex (ACC) and prefrontal cortex (PFC). The severity of ACEs was assessed. Participants included 20 consecutively admitted in-patients affected by chronic undifferentiated schizophrenia, and 20 unrelated healthy volunteers from the general population. Results. Patients reported higher ACEs than controls. Worse ACEs proportionally led to decreasing responses in the amygdala and hippocampus, and to increasing responses in the PFC and ACC in all participants. Patients showed higher activations in the amygdala and hippocampus, and lower activations in the PFC and ACC. Higher ACEs were associated with higher GM volumes in the PFC and ACC, and schizophrenia was associated with GM reduction in all studied regions. Conclusions. Structural and functional brain correlates of emotional reactivity are influenced by both current chronic undifferentiated schizophrenia and the severity of past ACEs."

Impairments in social cognition are critical predictors of social functioning in patients with schizophrenia. Emotion processing (EP) and theory of mind (ToM) are hypothesized to influence real-world behavior more directly than basic cognition and represent important targets of intervention. The use of video scenes depicting human interactions could constitute an appropriate tool to enhance understanding of the characters' behavior and stimulate inferences on mental states. The aim of our pilot study was to evaluate longitudinally, with a controlled trial, the feasibility and the efficacy of a single-paradigm emotion recognition and ToM training designed for outpatients affected by schizophrenia, with the goal to create an ecological treatment, overcoming artificial laboratory biases, by the use of specific videotaped material. Fifty-two outpatients were randomly assigned to an EP and ToM video-based training (n=27) or to a standard social cognitive rehabilitation treatment (n=24). They were assessed before and after 12 weeks of intervention and compared to a time-matched control group (n=24). Our results show a statistically significant improvement in ToM abilities, confirming the hypothesis of the enhancing potential of social cognitive interventions, but no changes with respect to EP; despite the need for a deeper examination, these data support further development of this treatment approach.

One of the major challenges in the study of language in schizophrenia is to identify specific levels of the linguistic structure that might be selectively impaired. While historically a main semantic deficit has been widely claimed, results are mixed, with also evidence of syntactic impairment. This might be due to heterogeneity in materials and paradigms across studies, which often do not allow to tap into single linguistic components. Moreover, the interaction between linguistic and neurocognitive deficits is still unclear. In this study, we concentrated on syntactic and semantic knowledge. We employed an anomaly detection task including short and long sentences with either syntactic errors violating the principles of Universal Grammar, or a novel form of semantic errors, resulting from a contradiction in the computation of the whole sentence meaning. Fifty-eight patients with diagnosis of schizophrenia were compared to 30 healthy subjects. Results showed that, in patients, only the ability to identify syntactic anomaly, both in short and long sentences, was impaired. This result cannot be explained by working memory abilities or psychopathological features. These findings suggest the presence of an impairment of syntactic knowledge in schizophrenia, at least partially independent of the cognitive and psychopathological profile. On the contrary, we cannot conclude that there is a semantic impairment, at least in terms of compositional semantics abilities. (C) 2015 Elsevier Ltd. All rights reserved.

BackgroundA Metacognitive Training for Schizophrenia patients (MCT) was developed to target the cognitive biases that characterize the illness. Results suggest positive MCT effects encompassing several aspects of psychopathology and subjective well-being. There are still open questions concerning the effect on different cognitive biases and the interplay between them and both psychopathology and neurocognition. Specifically, the bias against disconfirmatory evidence (BADE) has never been tested in previous trials on MCT. In this study we evaluated the feasibility of MCT combined with a cognitive remediation therapy (CACR) in schizophrenia and its effect on BADE. Moreover, we investigated the relationships between BADE and both neuropsychology and psychopathology, taking into account mutual influences on the degree of improvement.MethodsFifty-seven schizophrenia outpatients were randomly assigned to CACR + control group or MCT+CACR and assessed at baseline and after treatment for psychopathology, neurocognition and BADE.ResultsAfter MCT+CACR patients showed significantly greater improvements on BADE. Although BADE baseline performances correlated with several cognitive domains, no association was found between BADE improvement and neurocognitive nor psychopathological measures.ConclusionsThis study enlightened for the first time the efficacy of MCT+CACR on BADE in schizophrenia, suggesting the importance to develop a more specific intervention tailored on individual needs of patients.

Objective Bipolar disorder (BD) is associated with a higher risk of suicide and with worse early life stress. A serotonin (5-hydroxytryptamine; 5-HT) transporter-linked polymorphic region (5-HTTLPR) has been shown to influence the relationship between stress and the risk of attempting suicide in the general population, but has not been investigated in BD. Methods We studied 136 inpatients (93 females, 43 males) with a major depressive episode in the course of BD. Early and recent stressful life events were scored on the Social Readjustment Rating Scale (SRRS). Regional gray matter (GM) volumes were analyzed, acquiring T1-weighted images on a 3.0 Tesla scanner. Results Homozygote l/l patients attempted suicide in a higher proportion than *s carriers. A separate-slopes logistic regression showed a significant effect of 5-HTTLPR on the relationship between stress, depression, and suicide among *s carriers, but not among l/l homozygotes, early stress associated with worse probability of attempting suicide and with earlier age at onset of BD. Exposure to early stress correlated with GM volumes in the right prefrontal cortex (Brodmann area 46) – again, in *s carriers only. Conclusions 5-HTTLPR modulated the relationship between early life stress and the core features of bipolar illness. 5-HTTLPR*s carriers showed a higher sensitivity to the effects of stress; when exposed to low levels of early stress, they were protected against suicide in respect to l/l, but higher levels of stress progressively increased their risk of suicide and reduced the age at onset of illness.

BACKGROUND: One third of patients with bipolar disorder attempt suicide. Depression in bipolar disorder is associated with drug resistance. The efficacy of antidepressants on suicidality has been questioned. Total sleep deprivation and light therapy prompt a rapid and stable antidepressant response in bipolar disorder. METHOD: We studied 143 consecutively admitted inpatients (December 2006-August 2012) with a major depressive episode in the course of bipolar disorder (DSM-IV criteria). Among the 141 study completers, 23% had a positive history of attempted suicide and 83% had a positive history of drug resistance. During 1 week, patients were administered 3 consecutive total sleep deprivation cycles (each composed of a period of 36 hours awake followed by recovery sleep) combined with bright light therapy in the morning for 2 weeks. At admission, patients who had been taking lithium continued it, and those who had not been taking lithium started it. Severity of depression was rated according to the Hamilton Depression Rating Scale (HDRS) (primary outcome measure) and Beck Depression Inventory (BDI). RESULTS: Two patients switched polarity. Among the 141 who completed the treatment, 70% achieved a 50% reduction in HDRS score in 1 week, which persisted 1 month after in 55%. The amelioration involved an immediate and persistent decrease in suicide scores soon after the first total sleep deprivation cycle (F3,411 = 42.78, P < .00001). A positive history of suicide attempts was associated with worse early life stress and with worse suicide scores at baseline, but it did not influence response. Patients with current suicidal thinking or planning responded equally well (F3,42 = 20.70, P < .000001). Remarkably, however, nonresponders achieved a benefit, with significantly decreased final scores also including suicidality ratings (F3,120 = 6.55, P = .0004). Self-ratings showed the same pattern of change. Previous history of drug resistance did not hamper response. During the following month, 78 of 99 responders continued to stay well and were discharged from the hospital on lithium therapy alone. CONCLUSIONS: The combination of total sleep deprivation, light therapy, and lithium is able to rapidly decrease depressive suicidality and prompt antidepressant response in drug-resistant major depression in the course of bipolar disorder.

"Cognitive impairment has been recognized since the earliest descriptions of schizophrenia as a core feature of the illness and different programmes have been developed to remediate these deficits. In all likelihood it is important for compliance and adherence to treatment that not only the patients but also their relatives be aware of the patients; cognitive deficits. Sixty-two patients with a diagnosis of schizophrenia and, for each one of them, one family member and an informant from the medical staff, were recruited and administered the Schizophrenia Cognition Rating Scale (SCoRS) ratings. Patients were tested for cognitive deficits with a neuropsychological battery and their performance was compared to the ratings of cognitive functioning provided by the patient himself, his family member and the informant. Results show no significant association between cognitive performance and SCoRS ratings in patients; only for executive functions the patient's performance was found to be predictive of the respective judgment on the SCoRS that was given by the relative. This is the first study to investigate awareness of the patients' cognitive deficits, both in the patients themselves and in their first degree relatives, through a direct comparison between subjective clinical ratings and objective measures of cognitive performances. When both patients and relatives are unaware of the patients' cognitive deficits, this could affect adherence to remediation treatment and need to be specifically addressed in future rehabilitation strategies." Cognitive impairment has been recognized since the earliest descriptions of schizophrenia as a core feature of the illness and different programmes have been developed to remediate these deficits. In all likelihood it is important for compliance and adherence to treatment that not only the patients but also their relatives be aware of the patients cognitive deficits. 62 patients with a diagnosis of schizophrenia and, for each one of them, one family member and an informant from the medical staff, were recruited and administered the Schizophrenia Cognition Rating Scale. Patients were tested for cognitive deficits with a neuropsychological battery and their performance was compared to the ratings of patients cognitive functioning provided by the patient himself, his family member and the informant. Results show no significant association between cognitive performance and SCoRS ratings in patients; only for executive functions the patient's performance was found to be predictive of the respective judgment at SCoRS given by the relative. This is the first study to investigate awareness of the patients cognitive deficits, both in the patients itself and in first degree relatives, through a direct comparison between subjective clinical ratings and objective measures of cognitive performances. Both patients and relatives are unaware of the patients' cognitive deficits, this could affect adherence to remediation treatment and need to be specifically addressed from future rehabilitation strategies.

Previous studies documented a bias against disconfirmatory evidence (BADE) in patients affected by schizophrenia spectrum disorders, with some discrepant findings on its relationship with delusions. In order to further investigate the patterns of evidence integration in schizophrenia and delusion, we recruited 40 deluded and non-deluded patients with schizophrenia and 40 healthy control subjects. Participants were administered the BADE test, which consisted of 30 delusion-neutral scenarios, each one progressively described by three subsequent disambiguating statements and providing four types of interpretation to rate for plausibility; at every additional evidence presentation, participants were asked to adjust their ratings. In contrast to previous works, patients displayed both a BADE and a bias against confirmatory evidence (BACE) relative to healthy subjects, as they reduced plausibility ratings on incorrect interpretations and increased plausibility ratings on correct interpretation significantly less over trial progress. Moreover, BACE and BADE measures showed to discriminate differentially control from schizophrenia participants and delusional from non-delusional patients.

Background: Patients affected by schizophrenia show deficits in social cognition, with abnormal performance on tasks targeting theory of mind (ToM) and empathy (Emp). Brain imaging studies suggested that ToM and Emp depend on the activation of brain networks mainly localized at the superior temporal lobe and temporo-parietal junction. Methods: Participants included 24 schizophrenia patients and 20 control subjects. We used brain blood oxygen level dependent fMRI to study the neural responses to tasks targeting ToM and Emp. We then studied voxel-based morphometry of grey matter in areas where diagnosis influenced functional activation to both tasks. Outcomes were analyzed in the context of the general linear model, with global grey matter volume as nuisance covariate for structural MRI. Results: Patients showed worse performance on both tasks. We found significant effects of diagnosis on neural responses to the tasks in a wide cluster in right posterior superior temporal lobe (encompassing BA 22-42), in smaller clusters in left temporo-parietal junction and temporal pole (13A 38 and 39), and in a white matter region adjacent to medial prefrontal cortex (BA 10). A pattern of double dissociation of the effects of diagnosis and task on neural responses emerged. Among these areas, grey matter volume was found to be reduced in right superior temporal lobe regions of patients. Conclusions: Functional and structural abnormalities were observed in areas affected by the schizophrenic process early in the illness course, and known to be crucial for social cognition, suggesting a biological basis for social cognition deficits in schizophrenia. (C) 2009 Elsevier B.V. All rights reserved. Background: Patients affected by schizophrenia show deficits in social cognition, with abnormal performance on tasks targeting theory of mind (ToM) and empathy (Emp). Brain imaging studies suggested that ToM and Emp depend on the activation of brain networks mainly localized at the superior temporal lobe and temporo-parietal junction. Methods: Participants included 24 schizophrenia patients and 20 control subjects. We used brain blood oxygen level dependent fMRI to study the neural responses to tasks targeting ToM and Emp. We then studied voxel-based morphometry of grey matter in areas where diagnosis influenced functional activation to both tasks. Outcomes were analyzed in the context of the general linear model, with global grey matter volume as nuisance covariate for structural MRI. Results: Patients showed worse performance on both tasks. We found significant effects of diagnosis on neural responses to the tasks in a wide cluster in right posterior superior temporal lobe (encompassing BA 22-42), in smaller clusters in left temporo-parietal junction and temporal pole (13A 38 and 39), and in a white matter region adjacent to medial prefrontal cortex (BA 10). A pattern of double dissociation of the effects of diagnosis and task on neural responses emerged. Among these areas, grey matter volume was found to be reduced in right superior temporal lobe regions of patients. Conclusions: Functional and structural abnormalities were observed in areas affected by the schizophrenic process early in the illness course, and known to be crucial for social cognition, suggesting a biological basis for social cognition deficits in schizophrenia. (C) 2009 Elsevier B.V. All rights reserved.

Theory of Mind, the ability to understand the potential mental states and intentions of others, represents a relevant aspect of social cognition, with high impact on the capacity to interact within the social world. This very human ability has been one of the focuses of neuroscience research in the past decades and data from neuroimaging studies allowed to identify a Theory of Mind network and to formulate a neurobiological model. Concurrent neuropsychiatric studies showed that Theory of Mind is differently impaired in several conditions, among these, in schizophrenia, a disease characterized by functional and social disability. This paper addresses the issue of neurofunctional correlates of Theory of Mind deficits in schizophrenia, reviewing functional imaging studies of the past ten years comparing schizophrenia patients to healthy controls. Several differences in hemodynamic response between patients and controls were observed in the areas known to be critically involved in social cognition, such as the medial prefrontal cortex, temporal cortex surrounding superior temporal sulcus and temporo-parietal junction and cingulate cortex. Results are promising, however they are still heterogeneous. The reported variability could depend on factors related to the construct of Theory of Mind itself, technical aspects and psychopathological/physiopathological mechanisms and needs to be further addressed by future studies.

Il suicidio è un problema di salute pubblica sottostimato, così come è un lutto almeno parzialmente prevenibile: ogni contributo alla conoscenza dei fattori di rischio ad esso associati possono aiutare lo sviluppo di interventi terapeutici efficaci rivolti a fasce vulnerabili della popolazione. Più del 90% delle persone che si suicidano, o provano a farlo, hanno una malattia psichiatrica diagnosticabile e circa il 60% di tutte le morti per suicidio si verificano nel contesto di un disturbo dell’umore, soprattutto di tipo bipolare. Il suicidio ha oltretutto alta familiarità: la suicidalità è ereditabile, indipendentemente dalla diagnosi associata. Lo stress è un fattore di rischio sia prossimale che distale. Gli eventi di vita stressanti sono fattori precipitanti che possono innescare i comportamenti suicidari e gli stress infantili possono produrre modificazioni epigenetiche nell’espressione genica che, a loro volta, aumentano ulteriormente il rischio di suicidio, sensibilizzando allo stress. Lo stress, sia acuto che cronico, può modificare la funzione serotoninergica e avere effetti durevoli sul substrato neurale dei processi cognitivi e affettivi. Inoltre, alcune varianti genetiche coinvolte nella trasmissione serotoninergica (e in particolare il gene che codifica per il trasportatore della serotonina) interagiscono con gli stress infantili nel conferire vulnerabilità per i disturbi dell’umore e la suicidalità. Lo stress influenza anche i ritmi stagionali e circadiani dei cicli biologici, e le alterazioni del sistema circadiano possono contribuire all’eziopatologia del comportamento suicidario e dei disturbi affettivi. I geni dell’orologio circadiano interagiscono strettamente con l’attività ritmica dei sistemi di neurotrasmissione del cervello, così che i fattori di rischio ambientali e genetici per il suicidio sono modulati dall’azione congiunta del sistema di risposta allo stress e di quello circadiano. Date: 1) la relazione tra i meccanismi circadiani e la regolazione serotoninergica dell’umore, entrambi compromessi nei disturbi affettivi, 2) l’interazione tra questi sistemi e il sistema di risposta allo stress e 3) il crescente riscontro del ruolo causale dell’interazione geni-ambiente stressante nella genesi del suicidio, abbiamo modellato uno studio G x G x E (5-HTTLPR x CLOCK 3111T/C x ELS) sul suicidio nel Disturbo Bipolare. Il risultato principale della ricerca è l’associazione significativa dell’interazione ipotizzata col fenotipo comportamentale del tentato suicidio nel Disturbo Bipolare: il sostrato genetico fornito dalla combinazione dei due polimorfismi indagati modula la relazione tra l’esposizione allo stress nell’infanzia e la probabilità di commettere un suicidio. Nei soggetti omozigoti sia per l’allele corto del polimorfismo serotoninergico 5-HTTLPR, sia per l’allele T del genotipo CLOCK 3111T/C (l/l-T/T) la suicidalità non è legata al carico di stress infantili; tra i C carriers, gli s carriers sono il sottogruppo in cui questa relazione raggiunge la massima significatività (significatività comunque presente anche nel gruppo l/l-c carriers, seppur minore). Nel complesso, l’interazione G x G x E sembra seguire un andamento continuo e addittivo , in cui l’associazione stress-suicidio ha il suo massimo nei pazienti l/l-T/T e il suo minimo negli s carriers-C carriers, con le due restanti combinazioni di varianti in posizione intermedia. Sebbene lontana dall’essere esaustiva, questa ricerca ha fornito risultati coerenti con la letteratura precedente ed arricchisce la nostra comprensione del complesso fenotipo che rappresenta il comportamento suicidario nei pazienti affetti da Disturbo Bipolare. Suicide is an underestimated public health problem, as well as a grief at least partially preventable: every increment in the knowledge about associated risk factors can suggest the implementation of effective interventions in vulnerable populations. Over 90% of suicide victims or attempters have a diagnosable psychiatric illness and about 60% of all suicides occur in the context of a Mood Disorder, with Bipolar Disorder carrying the higher risk. Suicide is also familial: suicide completion and attempt are heritable, independently of the associated diagnosis. Stress is both a distal and a proximal suicide risk factor. Stressful life events are recognized precipitating factors that can trigger suicidality in predisposed subjects and early life stress (ELS) can produce epigenetic modification in gene expression, which in turn further increase the risk for suicide by heightening sensitivity to stress. Both acute and chronic stress has an impact on serotonergic function and can have enduring effects on the neural substrates of affect and cognition. Moreover, some genetic variants involved in the serotonin (5-HT) pathway (in particular in the gene coding for the serotonin transporter) interact with ELS in conferring higher probability of Mood Disorder and suicidal behaviour. Stress influences the seasonal and circadian rhythms of biological cycles, too, and the disruption of the circadian timing system can contribute to the etiopathology of suicide behaviour and Mood Disorders. The circadian clock genes closely interact with the rhythmic activity of brain neurotransmission system, so that the individual genetic and environmental risk factors for suicide are modulated by the combined action of the stress-response and circadian systems. Given 1) the relationship between the circadian machinery and the serotonergic mood-regulating network, both disrupted in Mood Disorder 2) the interactions between these systems and the stress-response system and 3) the increasing evidence of the causal role of the interaction between genetic factors and environmental stressors in the phenotype of suicidal behaviour, we modelled a G x G x E study (5-HTTLPR x CLOCK rs1801260 x ELS) on suicide in Bipolar Disorder. The main finding of the present research is the significant association of the modelled G x G x E interaction with the behavioural phenotype of suicide attempt in BD: the relationship between early life stress and the probability to commit suicide is modulated by the action of the genetic background conferred by the 5-HTTLPR and rs1801260 combination of variants. In individuals who are homozygotes for both the 5-HTTLPR l alleles and the 3111T genotype (l/l-T/T group), suicidality is not related to the amount of childhood stress; among rs1801260 C carriers, the 5-HTTLPR s carriers are the subgroup in which this relationship showed the highest significance but suicidality is associated to ELS in l/l-C carriers also, even if to a lesser extent. Overall, the G x G x E interaction seems to follow a continuous and addictive trend, so that the pattern of the stress-suicide association has its maximum in l/l-T/T group and its minimum in s carriers-C carriers, with the other two combination of variants occupying the intermediate values. Even if far from being exhaustive, these results are coherent with previous literature and enrich our understanding of the complex phenotype of suicidal behaviour in patients affected with Bipolar Disorder.