Advances in the understanding of the pathophysiology of schizophrenia and bipolar disorder through induced pluripotent stem cell models.

The pathophysiology of schizophrenia and bipolar disorder involves a complex interaction between genetic and environmental factors that begins in the early stages of neurodevelopment. Recent advancements in the field of induced pluripotent stem cells (iPSCs) offer a promising tool for understanding the neurobiological alterations involved in these disorders and, potentially, for developing new treatment options. In this review, we summarize the results of iPSC-based research on schizophrenia and bipolar disorder, showing disturbances in neurodevelopmental processes, imbalance in glutamatergic-GABAergic transmission and neuromorphological alterations. The limitations of the reviewed literature are also highlighted, particularly the methodological heterogeneity of the studies, the limited number of studies developing iPSC models of both diseases simultaneously, and the lack of in-depth clinical characterization of the included samples. Further studies are needed to advance knowledge on the common and disease-specific pathophysiological features of schizophrenia and bipolar disorder and to promote the development of new treatment options.

Cognitive impairment after recovery from COVID-19: Frequency, profile, and relationships with clinical and laboratory indices.

Cognitive impairment (CI) is regarded as a remarkable burden in COVID-19 survivors. Its prevalence and profile, and relationships with the disease clinical and laboratory indices, remain unclear. The present study investigated, in a large sample of patients recovered from COVID-19, the frequency of CI with both a face-to-face screening tool and comprehensive test battery (MCCB). The study also evaluated the profile of CI and its relationships with COVID-19 clinical and laboratory indices and with psychopathological features. Out of 1344 subjects assessed for eligibility, 736 completed the screening phase 11 months after the COVID-19 infection; 402 participated in the baseline phase and completed an in depth cognitive, clinical and laboratory assessment about one month later. More than one third of the screened subjects presented a CI (COG+); it was associated to age, education, male gender, COVID-19 severity, and presence of anosmia, dyspnea at rest and exertional dyspnea during the acute phase. COG+ subjects showed a higher severity of depression, anxiety and post-traumatic distress, and worse global functioning, than subjects without CI. The MCCB showed that 45% of the subjects had a CI involving attention, working memory, verbal learning, visual learning, and reasoning and problem solving. Finally, neurocognitive functioning was inversely correlated with LDH blood levels, a potential biomarker of disease severity. According to our findings, cognitive functioning should be routinely and periodically assessed in COVID-19 patients, especially in older subjects, who experienced more severe COVID-19 symptoms. In case of persisting dysfunctions cognitive training programs should be considered as treatment strategies.

Correlations between Negative Symptoms and Cognitive Deficits in Individuals at First Psychotic Episode or at High Risk of Psychosis: A Systematic Review.

The present review aims to identify correlations between negative symptoms (NS) and deficits in neurocognition and social cognition in subjects with first-episode psychosis (FEP) and at-high-risk populations (HR). A systematic search of the literature published between 1 January 2005 and 31 December 2022 was conducted on PubMed, Scopus, and PsycInfo. Out of the 4599 records identified, a total of 32 studies met our inclusion/exclusion criteria. Data on a total of 3086 FEP and 1732 HR were collected. The available evidence shows that NS correlate with executive functioning and theory of mind deficits in FEP subjects, and with deficits in the processing speed, attention and vigilance, and working memory in HR subjects. Visual learning and memory do not correlate with NS in either FEP or HR subjects. More inconsistent findings were retrieved in relation to other cognitive domains in both samples. The available evidence is limited by sample and methodological heterogeneity across studies and was rated as poor or average quality for the majority of included studies in both FEP and CHR populations. Further research based on shared definitions of first-episode psychosis and at-risk states, as well as on more recent conceptualizations of negative symptoms and cognitive impairment, is highly needed.

The structure stability of negative symptoms: longitudinal network analysis of the Brief Negative Symptom Scale in people with schizophrenia.

BACKGROUND: The structure of negative symptoms of schizophrenia is still a matter of controversy. Although a two-dimensional model (comprising the expressive deficit dimension and the motivation and pleasure dimension) has gained a large consensus, it has been questioned by recent investigations. AIMS: To investigate the latent structure of negative symptoms and its stability over time in people with schizophrenia using network analysis. METHOD: Negative symptoms were assessed in 612 people with schizophrenia using the Brief Negative Symptom Scale (BNSS) at baseline and at 4-year follow-up. A network invariance analysis was conducted to investigate changes in the network structure and strength of connections between the two time points. RESULTS: The network analysis carried out at baseline and follow-up, supported by community detection analysis, indicated that the BNSS's items aggregate to form four or five distinct domains (avolition/asociality, anhedonia, blunted affect and alogia). The network invariance test indicated that the network structure remained unchanged over time (network invariance test score 0.13; P = 0.169), although its overall strength decreased (6.28 at baseline, 5.79 at follow-up; global strength invariance test score 0.48; P = 0.016). CONCLUSIONS: The results lend support to a four- or five-factor model of negative symptoms and indicate overall stability over time. These data have implications for the study of pathophysiological mechanisms and the development of targeted treatments for negative symptoms.

A multivariate approach to investigate the associations of electrophysiological indices with schizophrenia clinical and functional outcome.

BACKGROUND: Different electrophysiological (EEG) indices have been investigated as possible biomarkers of schizophrenia. However, these indices have a very limited use in clinical practice, as their associations with clinical and functional outcomes remain unclear. This study aimed to investigate the associations of multiple EEG markers with clinical variables and functional outcomes in subjects with schizophrenia (SCZs). METHODS: Resting-state EEGs (frequency bands and microstates) and auditory event-related potentials (MMN-P3a and N100-P3b) were recorded in 113 SCZs and 57 healthy controls (HCs) at baseline. Illness- and functioning-related variables were assessed both at baseline and at 4-year follow-up in 61 SCZs. We generated a machine-learning classifier for each EEG parameter (frequency bands, microstates, N100-P300 task, and MMN-P3a task) to identify potential markers discriminating SCZs from HCs, and a global classifier. Associations of the classifiers' decision scores with illness- and functioning-related variables at baseline and follow-up were then investigated. RESULTS: The global classifier discriminated SCZs from HCs with an accuracy of 75.4% and its decision scores significantly correlated with negative symptoms, depression, neurocognition, and real-life functioning at 4-year follow-up. CONCLUSIONS: These results suggest that a combination of multiple EEG alterations is associated with poor functional outcomes and its clinical and cognitive determinants in SCZs. These findings need replication, possibly looking at different illness stages in order to implement EEG as a possible tool for the prediction of poor functional outcome.

Resting-State Brain Activity Dysfunctions in Schizophrenia and Their Associations with Negative Symptom Domains: An fMRI Study.

The aim of the present study was to examine the neurobiological correlates of the two negative symptom domains of schizophrenia, the Motivational Deficit domain (including avolition, anhedonia, and asociality) and the Expressive Deficit domain (including blunted affect and alogia), focusing on brain areas that are most commonly found to be associated with negative symptoms in previous literature. Resting-state (rs) fMRI data were analyzed in 62 subjects affected by schizophrenia (SZs) and 46 healthy controls (HCs). The SZs, compared to the HCs, showed higher rs brain activity in the right inferior parietal lobule and the right temporoparietal junction, and lower rs brain activity in the right dorsolateral prefrontal cortex, the bilateral anterior dorsal cingulate cortex, and the ventral and dorsal caudate. Furthermore, in the SZs, the rs brain activity in the left orbitofrontal cortex correlated with negative symptoms (r = -0.436, p = 0.006), in particular with the Motivational Deficit domain (r = -0.424, p = 0.002), even after controlling for confounding factors. The left ventral caudate correlated with negative symptoms (r = -0.407, p = 0.003), especially with the Expressive Deficit domain (r = -0.401, p = 0.003); however, these results seemed to be affected by confounding factors. In line with the literature, our results demonstrated that the two negative symptom domains might be underpinned by different neurobiological mechanisms.

Cognitive Impairment after Post-Acute COVID-19 Infection: A Systematic Review of the Literature.

The present study aims to provide a critical overview of the literature on the relationships between post-acute COVID-19 infection and cognitive impairment, highlighting the limitations and confounding factors. A systematic search of articles published from 1 January 2020 to 1 July 2022 was performed in PubMed/Medline. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Only studies using validated instruments for the assessment of cognitive impairment were included. Out of 5515 screened records, 72 studies met the inclusion criteria. The available evidence revealed the presence of impairment in executive functions, speed of processing, attention and memory in subjects recovered from COVID-19. However, several limitations of the literature reviewed should be highlighted: most studies were performed on small samples, not stratified by severity of disease and age, used as a cross-sectional or a short-term longitudinal design and provided a limited assessment of the different cognitive domains. Few studies investigated the neurobiological correlates of cognitive deficits in individuals recovered from COVID-19. Further studies with an adequate methodological design are needed for an in-depth characterization of cognitive impairment in individuals recovered from COVID-19.

Unveiling the Associations between EEG Indices and Cognitive Deficits in Schizophrenia-Spectrum Disorders: A Systematic Review.

Cognitive dysfunctions represent a core feature of schizophrenia-spectrum disorders due to their presence throughout different illness stages and their impact on functioning. Abnormalities in electrophysiology (EEG) measures are highly related to these impairments, but the use of EEG indices in clinical practice is still limited. A systematic review of articles using Pubmed, Scopus and PsychINFO was undertaken in November 2021 to provide an overview of the relationships between EEG indices and cognitive impairment in schizophrenia-spectrum disorders. Out of 2433 screened records, 135 studies were included in a qualitative review. Although the results were heterogeneous, some significant correlations were identified. In particular, abnormalities in alpha, theta and gamma activity, as well as in MMN and P300, were associated with impairments in cognitive domains such as attention, working memory, visual and verbal learning and executive functioning during at-risk mental states, early and chronic stages of schizophrenia-spectrum disorders. The review suggests that machine learning approaches together with a careful selection of validated EEG and cognitive indices and characterization of clinical phenotypes might contribute to increase the use of EEG-based measures in clinical settings.

The Cognitive Assessment Interview (CAI): Association with neuropsychological scores and real-life functioning in a large sample of Italian subjects with schizophrenia.

INTRODUCTION: The Cognitive Assessment Interview (CAI) is an interview-based scale developed to measure cognitive impairment and its impact on functioning in subjects with schizophrenia (SCZ). Previous studies demonstrated good psychometric properties of the CAI. However, only relatively small samples of SCZ were investigated. This study aimed to determine in a large sample of SCZ (N = 580) the relationships of the Italian Version of the CAI with measures of cognitive performance and functional capacity and real-life functioning, using state-of-the-art instruments. METHODS: Intraclass correlation coefficients (ICCs) and Cronbach's alpha were calculated to examine the CAI's inter-rater reliability and internal consistency. Pearson's correlation coefficients were used to evaluate relationships between CAI global and domain composite scores with neurocognition, social cognition, functional capacity, and functioning. RESULTS: The inter-rater reliability and internal consistency were good to excellent. The CAI global composite score showed a strong correlation with the MATRICS Consensus Cognitive Battery (MCCB) composite score (r = -0.50) and moderate/strong associations with measures of functional capacity (-0.46 < r < -0.52) and real-life functioning (-0.30 < r < -0.51). Finally, CAI composite social cognition score correlated moderately with the Facial Emotion Identification Test (r = -0.31) and two subscales of the Awareness of Social Inference Test (-0.32 < r < -0.34). CONCLUSIONS: The study suggests that CAI is a valid co-primary measure for clinical trials and a suitable instrument to screen impairment in neurocognitive and social cognitive domains and its impact on functioning in SCZ in everyday clinical practice.

Investigating the Relationships of P3b with Negative Symptoms and Neurocognition in Subjects with Chronic Schizophrenia.

Neurocognitive deficits and negative symptoms (NS) have a pivotal role in subjects with schizophrenia (SCZ) due to their impact on patients' functioning in everyday life and their influence on goal-directed behavior and decision-making. P3b is considered an optimal electrophysiological candidate biomarker of neurocognitive impairment for its association with the allocation of attentional resources to task-relevant stimuli, an important factor for efficient decision-making, as well as for motivation-related processes. Furthermore, associations between P3b deficits and NS have been reported. The current research aims to fill the lack of studies investigating, in the same subjects, the associations of P3b with multiple cognitive domains and the expressive and motivation-related domains of NS, evaluated with state-of-the-art instruments. One hundred and fourteen SCZ and 63 healthy controls (HCs) were included in the study. P3b amplitude was significantly reduced and P3b latency prolonged in SCZ as compared to HCs. In SCZ, a positive correlation was found between P3b latency and age and between P3b amplitude and the Attention-vigilance domain, while no significant correlations were found between P3b and the two NS domains. Our results indicate that the effortful allocation of attention to task-relevant stimuli, an important component of decision-making, is compromised in SCZ, independently of motivation deficits or other NS.

Mismatch Negativity and P3a Impairment through Different Phases of Schizophrenia and Their Association with Real-Life Functioning.

Impairment in functioning since the onset of psychosis and further deterioration over time is a key aspect of subjects with schizophrenia (SCZ). Mismatch negativity (MMN) and P3a, indices of early attention processing that are often impaired in schizophrenia, might represent optimal electrophysiological candidate biomarkers of illness progression and poor outcome. However, contrasting findings are reported about the relationships between MMN-P3a and functioning. The study aimed to investigate in SCZ the influence of illness duration on MMN-P3a and the relationship of MMN-P3a with functioning. Pitch (p) and duration (d) MMN-P3a were investigated in 117 SCZ and 61 healthy controls (HCs). SCZ were divided into four illness duration groups: ≤ 5, 6 to 13, 14 to 18, and 19 to 32 years. p-MMN and d-MMN amplitude was reduced in SCZ compared to HCs, independently from illness duration, psychopathology, and neurocognitive deficits. p-MMN reduction was associated with lower "Work skills". The p-P3a amplitude was reduced in the SCZ group with longest illness duration compared to HCs. No relationship between P3a and functioning was found. Our results suggested that MMN amplitude reduction might represent a biomarker of poor functioning in SCZ.

EEG-Based Measures in At-Risk Mental State and Early Stages of Schizophrenia: A Systematic Review.

Introduction: Electrophysiological (EEG) abnormalities in subjects with schizophrenia have been largely reported. In the last decades, research has shifted to the identification of electrophysiological alterations in the prodromal and early phases of the disorder, focusing on the prediction of clinical and functional outcome. The identification of neuronal aberrations in subjects with a first episode of psychosis (FEP) and in those at ultra high-risk (UHR) or clinical high-risk (CHR) to develop a psychosis is crucial to implement adequate interventions, reduce the rate of transition to psychosis, as well as the risk of irreversible functioning impairment. The aim of the review is to provide an up-to-date synthesis of the electrophysiological findings in the at-risk mental state and early stages of schizophrenia. Methods: A systematic review of English articles using Pubmed, Scopus, and PsychINFO was undertaken in July 2020. Additional studies were identified by hand-search. Electrophysiological studies that included at least one group of FEP or subjects at risk to develop psychosis, compared to healthy controls (HCs), were considered. The heterogeneity of the studies prevented a quantitative synthesis. Results: Out of 319 records screened, 133 studies were included in a final qualitative synthesis. Included studies were mainly carried out using frequency analysis, microstates and event-related potentials. The most common findings included an increase in delta and gamma power, an impairment in sensory gating assessed through P50 and N100 and a reduction of Mismatch Negativity and P300 amplitude in at-risk mental state and early stages of schizophrenia. Progressive changes in some of these electrophysiological measures were associated with transition to psychosis and disease course. Heterogeneous data have been reported for indices evaluating synchrony, connectivity, and evoked-responses in different frequency bands. Conclusions: Multiple EEG-indices were altered during at-risk mental state and early stages of schizophrenia, supporting the hypothesis that cerebral network dysfunctions appear already before the onset of the disorder. Some of these alterations demonstrated association with transition to psychosis or poor functional outcome. However, heterogeneity in subjects' inclusion criteria, clinical measures and electrophysiological methods prevents drawing solid conclusions. Large prospective studies are needed to consolidate findings concerning electrophysiological markers of clinical and functional outcome.

Investigating the Relationship between White Matter Connectivity and Motivational Circuits in Subjects with Deficit Schizophrenia: A Diffusion Tensor Imaging (DTI) Study.

Deficit schizophrenia is a subtype of schizophrenia presenting primary and enduring negative symptoms (NS). Although one of the most updated hypotheses indicates a relationship between NS and impaired motivation, only a few studies have investigated abnormalities of motivational circuits in subjects with deficit schizophrenia (DS). Our aim was to investigate structural connectivity within motivational circuits in DS. We analyzed diffusion tensor imaging (DTI) data from 46 subjects with schizophrenia (SCZ) and 35 healthy controls (HCs). SCZ were classified as DS (n = 9) and non-deficit (NDS) (n = 37) using the Schedule for Deficit Syndrome. The connectivity index (CI) and the Fractional Anisotropy (FA) of the connections between selected brain areas involved in motivational circuits were examined. DS, as compared with NDS and HCs, showed increased CI between the right amygdala and dorsal anterior insular cortex and increased FA of the pathway connecting the left nucleus accumbens with the posterior insular cortex. Our results support previous evidence of distinct neurobiological alterations underlying different clinical subtypes of schizophrenia. DS, as compared with NDS and HCs, may present an altered pruning process (consistent with the hyperconnectivity) in cerebral regions involved in updating the stimulus value to guide goal-directed behavior.

Tracing Links Between Early Auditory Information Processing and Negative Symptoms in Schizophrenia: An ERP Study.

Background: Negative symptoms represent a heterogeneous dimension with a strong impact on functioning of subjects with schizophrenia (SCZ). Five constructs are included in this dimension: anhedonia, asociality, avolition, blunted affect, and alogia. Factor analyses revealed that these symptoms cluster in two domains: experiential domain (avolition, asociality, and anhedonia) and the expressive deficit (alogia and blunted affect), that might be linked to different neurobiological alterations. Few studies investigated associations between N100, an electrophysiological index of early sensory processing, and negative symptoms, reporting controversial results. However, none of these studies investigated electrophysiological correlates of the two negative symptom domains. Objectives: The aim of our study was to evaluate, within the multicenter study of the Italian Network for Research on Psychoses, the relationships between N100 and negative symptom domains in SCZ. Methods: Auditory N100 was analyzed in 114 chronic stabilized SCZ and 63 healthy controls (HCs). Negative symptoms were assessed with the Brief Negative Symptom Scale (BNSS). Repeated measures ANOVA and correlation analyses were performed to evaluate differences between SCZ and HCs and association of N100 features with negative symptoms. Results: Our findings demonstrated a significant N100 amplitude reduction in SCZ compared with HCs. In SCZ, N100 amplitude for standard stimuli was associated with negative symptoms, in particular with the expressive deficit domain. Within the expressive deficit, blunted affect and alogia had the same pattern of correlation with N100. Conclusion: Our findings revealed an association between expressive deficit and N100, suggesting that these negative symptoms might be related to deficits in early auditory processing in SCZ.

Special Report on the Impact of the COVID-19 Pandemic on Clinical EEG and Research and Consensus Recommendations for the Safe Use of EEG.

INTRODUCTION: The global COVID-19 pandemic has affected the economy, daily life, and mental/physical health. The latter includes the use of electroencephalography (EEG) in clinical practice and research. We report a survey of the impact of COVID-19 on the use of clinical EEG in practice and research in several countries, and the recommendations of an international panel of experts for the safe application of EEG during and after this pandemic. METHODS: Fifteen clinicians from 8 different countries and 25 researchers from 13 different countries reported the impact of COVID-19 on their EEG activities, the procedures implemented in response to the COVID-19 pandemic, and precautions planned or already implemented during the reopening of EEG activities. RESULTS: Of the 15 clinical centers responding, 11 reported a total stoppage of all EEG activities, while 4 reduced the number of tests per day. In research settings, all 25 laboratories reported a complete stoppage of activity, with 7 laboratories reopening to some extent since initial closure. In both settings, recommended precautions for restarting or continuing EEG recording included strict hygienic rules, social distance, and assessment for infection symptoms among staff and patients/participants. CONCLUSIONS: The COVID-19 pandemic interfered with the use of EEG recordings in clinical practice and even more in clinical research. We suggest updated best practices to allow safe EEG recordings in both research and clinical settings. The continued use of EEG is important in those with psychiatric diseases, particularly in times of social alarm such as the COVID-19 pandemic.

Die "Präzisionspsychiatrie" muss Teil der "personalisierten Psychiatrie" werden.

'Precision medicine' is defined as 'an emerging approach for treatment and prevention that takes into account each person's variability in genes, environment, and lifestyle'. Sometimes the term 'personalized medicine' is also used, either as a synonym or in a broader sense. In psychiatry, the term 'personalized' applies to different levels of health-care provision, such as the service organization and the choice of treatment plans based on the characterization of the individual patient. This approach is already feasible but, currently, it is often hampered by the shortage of human and financial resources. Recently, the terminology of 'precision medicine' has been extended to psychiatry: the term 'precision psychiatry' refers to the full exploitation of recent scientific and technological advances to achieve a close match between individual biosignature and prevention / treatment strategies. This article provides an overview of recent advances in neuroimaging, multi-omics and computational neuroscience, which have contributed to foster our understanding of the neurobiology of major mental disorders, and led to the implementation of a precision medicine-oriented approach in psychiatry.We argue that, while 'precision psychiatry' represents an important step to further advance the effectiveness of the 'personalized psychiatry', the distinction between the two terms is important to avoid dangerous neglect of the current potential of personalized care in psychiatry and to underscore the need for disseminating good existing practices aimed at organizing mental health services and providing care according to person's psychopathological characteristics, illness trajectory, needs, environment and preferences.In conclusion, 'precision psychiatry' will contribute to advance 'personalized psychiatry', but for the time being keeping the distinction between the two terms will contribute to fully exploit the current potential of personalized care.