MATRICS Consensus Cognitive Battery Research Articles

Glucose metabolism, hippocampal subfields and cognition in first-episode and never-treated schizophrenia

BackgroundPrevious studies have indicated that glucose metabolism and altered hippocampal structure and function play a pivotal role in cognitive deficits in schizophrenia (SZ). This study was designed to explore the inter-relationship between glucose metabolism, hippocampal subfield volume, and cognitive function in the antipsychotics-naive first episode (ANFE) SZ patients. MethodsWe chose the fasting insulin, glucose, and insulin resistance (HOMA-IR) index as biomarkers of glucose metabolism. Cognitive function was assessed by the MATRICS Consensus Cognitive Battery (MCCB). The hippocampal subfield volume, glucose metabolism biomarkers, and cognitive function were evaluated in 43 ANFE SZ and 29 healthy controls (HCs). ResultsCompared with HCs, SZ patients had higher fasting blood glucose and insulin levels and HOMA-IR (all p < 0.05). Correlation analysis revealed that category fluency performance was positively associated with fasting glucose level. Fasting insulin or HOMA-IR was positively associated with the hippocampal subfield volume in patients (all p<0.05). Moreover, the spatial span index score was associated with the volume of the right presubiculum, subiculum, and right hippocampal tail. In addition, multiple regression analysis found that the interaction effects of insulin × right fimbria or insulin × left fimbria were independent predictors of the MCCB total score. ConclusionsOur findings suggest that abnormal glucose metabolism and cognitive decline occur in the early stage of SZ. The interaction between abnormal glucose metabolism and hippocampal subfields was associated with cognitive functions in SZ.

Impact of cognitive performance and negative symptoms on psychosocial functioning in Czech schizophrenia patients

Schizophrenia has a profound influence on the real-life functioning of patients. There are several factors inherent to the disease course affecting the level of psychosocial functioning. Our study focused on the impact of cognitive deficit and severity of negative symptoms (i.e., the experiential domain (avolition, asociality, and anhedonia) and the expressive domain (blunted affect and alogia)) to explore psychosocial functioning in schizophrenia. Schizophrenia patients (n = 211) were tested for the presence of cognitive impairment using the NIMH-MATRICS: Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Cattery (MCCB; MATRICS Consensus Cognitive Battery) and the extent of negative symptoms using the PANSS (PANSS; Positive and Negative Syndrome Scale—selected items). The level of psychosocial functioning was measured with the Personal and Social Performance Scale (PSP). The path analysis using three regression models was used to analyse variables influencing psychosocial functioning (PSP). One of these models analyzed influence of cognitive functioning (MCCB) and negative schizophrenia symptoms (PANSS selected items reflecting expressive and experiential deficits) as predictors and NART/CRT and disease length as confounders. R2 was 0.54. The direct effect of the MCCB (β = 0.09) on the PSP was suppressed by the strong effect of the negative symptoms (β = −0.64). The presence of cognitive deficits and negative symptoms in our sample of schizophrenia patients significantly influences the level of their psychosocial functioning, a key factor in remission and recovery.

Anomalous self-experiences and neurocognitive functioning in adolescents at risk for psychosis: Still no significant associations found between these two vulnerability markers

BackgroundAnomalous self-experiences (ASEs) and neurocognitive impairments are considered essential domains of vulnerability for developing psychotic disorders. However, little research exists of possible associations between ASEs and neurocognitive functions in individuals at-risk for psychosis. The interconnections between ASEs and neurocognitive impairments should therefore be clarified as much as possible, especially in young individuals at risk. No previous studies have investigated these two fundamental domains in non-help-seeking adolescents at risk for developing psychosis. MethodsThis study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa). Adolescents (N = 48, 94% females, mean age = 15.3) were invited to participate after completing a 14-year-old survey distributed by MoBA. At-risk adolescents were selected based on the 0.4% highest scores on 19 items assessing both psychotic-like experiences and ASEs. Five specifically selected and formulated items measuring ASEs were computed to an ASEs total score. Neurocognitive functioning was assessed using the MATRICS Consensus Cognitive Battery. ResultsRegression analyses revealed no significant relationships between ASEs and any neurocognitive domain. ConclusionsWe did not find any significant associations between ASEs and neurocognitive functions in non-help-seeking adolescents at risk for psychotic disorders, which is in line with reports from other types of cohorts. Thus, ASEs and neurocognitive functions may be understood as two relatively separate domains that co-exist in at-risk states. These results underline the need for a wider scope when making predictions about future trajectories, e.g. the development of psychotic disorders. Including both ASEs and neurocognitive functioning in at-risk populations may increase the specificity of vulnerability criteria in this population and enhance our understanding of early psychosis psychopathology.

Longitudinal Investigation of Auditory Dynamic Range Deficits in Early Psychosis and its Relationship to Negative Symptoms.

Despite accounting for significant disease morbidity in schizophrenia, the neuropathological basis of negative symptoms remains poorly understood and options for treatment limited. Our recent study identified robust associations between diminished auditory cortex (AC) dynamic range and social functioning impairments and negative symptoms in first episode psychosis (FESz). The current investigation examined the progression of these relationships 4-8 months from baseline testing. Twenty-six FESz and 38 healthy controls (HC) were tested at baseline and follow-up. Magnetoencephalography (MEG) was recorded during binaural presentation of tones (75, 80, and 85 dB). Assessments included the MATRICS cognitive consensus battery (MCCB) and Global Functioning: Role and Social scales (GFR/GFS) and the Positive and Negative Syndrome Scale. Overall, FESz exhibited a blunted response to increasing tone intensity relative to HC. While this deficit did not change over time at the group level, recovery of right hemisphere AC dynamic range (85-75 dB response) among FESz individuals was associated with reductions in negative symptoms (ρ = -0.50). Diminished dynamic range was also associated with impaired GFS (ρ = 0.65), GFR (ρ = 0.51), and MCCB (ρ = 0.49) at baseline and increased negative symptoms at baseline (ρ = -0.53) and follow-up (ρ = -0.51). Despite persistent dynamic range impairment in FESz as a group, individual recovery of this AC response property was associated with significant reduction in negative symptoms. Identification of a functional neural deficit that tracts progression of negative symptoms during a critical period for disease modification is essential to the management of these devastating and historically treatment refractory symptoms.

Establishment of diagnostic model for schizophrenia based on neurotrophic factor and other biomarkers

Objective: To construct a diagnostic model of schizophrenia (SCZ) based on biomarkers such as serum neurotrophic factor. Methods: Patients of schizophrenia (SCZ group) and healthy controls (HC group) who were admitted to the First Affiliated Hospital of Zhengzhou University from January 2017 to December 2019 were prospectively selected. In the SCZ group, the mental symptoms were assessed by the positive and negative symptom scale (PANSS), cognitive function was assessed by the MATRICS consensus cognitive battery (MCCB), brain-derived neurotrophic factor (BDNF), glial cell derived neurotrophic factor (GDNF), fasting glucose (FGB) and fasting insulin (FINS) levels were detected, and insulin resistance (HOMA-IR) was calculated. The same methods were used to evaluate cognitive function, measure BDNF, GDNF, FGB and FINS levels, and calculate HOMA-IR in HC group. The indexes with statistically significant differences between the two groups were selected to be included in the model. The diagnostic model was constructed by machine learning and verified by cross-validation method, the receiver operating curve (ROC) was plotted, and the area under the curve (AUC), sensitivity and specificity were calculated. Results: (1) A total of 142 patients (70 males and 72 females) with schizophrenia were finally included, and aged (25±4) years. Meanwhile, 140 healthy controls (72 males and 68 females) were also enrolled, and aged (26±4) years. In SCZ group, scores in all areas of cognitive function were lower than those in HC group (all P<0.001), the levels of serum BDNF and GDNF [(6.7±1.8) ng/ml and (405±93) pg/ml] were also lower than those in HC group [(12.3±3.2) ng/ml and (574±139) pg/ml] (both P<0.001), but the levels of FINS and HOMA-IR [(8.4±0.8) μU/ml and 1.7±0.3] were higher than those in HC group [(6.7±0.9) μU/ml and 1.4±0.3] (both P<0.001). (2) Correlation analysis showed that the level of serum BDNF had a negative correlation with negative symptom scores and total scores (r=-0.31, P<0.001; r=-0.17, P=0.040), but had a positive correlation with attention/alertness (CPT-IP) T scores, working memory (WSM-Ⅲ) T scores and visual learning (BVMT) T scores in SCZ group (r=0.39, 0.37 and 0.29, all P<0.001). The level of serum GDNF also had a positive correlation with CPT-IP T scores, WSM-Ⅲ T scores and BVMT T scores (r=0.32, P<0.001; r=0.23, P=0.007; r=0.40, P<0.001). The values of HOMA-IR had a positive correlation with social cognition (MSCEIT) T scores in SCZ group (r=0.18, P=0.033). (3) AUC of the early diagnosis model constructed by combining BDNF, GDNF and HOMA-IR was 0.890 (95%CI: 0.832-0.940), the accuracy was 0.89, the sensitivity and specificity was 0.94 and 0.82, respectively. Conclusion: The final diagnostic model based on biomarkers of serum neurotrophic factor has good diagnostic efficiency for SCZ, but large-scale independent sample verification is still needed.

Biochemical metabolism in the anterior cingulate cortex and cognitive function in major depressive disorder with or without insomnia syndrome

BackgroundMajor depressive disorder (MDD) and insomnia have been linked to deficiencies in cognitive performance. However, the underlying mechanism of cognitive impairment in MDD patients with insomnia symptoms (IS) remains unclear. This study aimed to explore the effects of IS in patients with MDD by comparing cognitive function indices among those with IS, those without insomnia symptoms (NIS), and healthy controls (HCs). In addition, we assessed whether the dysfunction of central nervous system (CNS) is one of the important pathophysiologic mechanisms of IS in patients with MDD by comparing the biochemical metabolism ratios in the anterior cingulate cortex (ACC). MethodFifty-five MDD with IS, 39 MDD without IS, and 47 demographically matched HCs underwent the MATRICS Consensus Cognitive Battery (MCCB) assessment and proton magnetic resonance spectroscopy (1H-MRS). MCCB cognitive scores and biochemical metabolism in ACC were assessed and compared between groups. ResultsCompared to the HCs group, IS and NIS groups scored significantly lower in seven MCCB cognitive domains (speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning problem solving and social cognition). IS group showed a lower speed of processing and lower Cho/Cr ratio in the left ACC vs. NIS group and HCs. Also, in IS group, the Cho/Cr ratio in the left ACC was positively correlated with the composite T-score. ConclusionPatients with comorbidity of MDD with IS may exhibit more common MCCB cognitive impairments than those without IS, particularly speed of processing. Also, dysfunction of ACC may underlie the neural substrate of cognitive impairment in MDD with IS.

Abnormalities of Regional Brain Activity in Patients With Schizophrenia: A Longitudinal Resting-State fMRI Study.

Evidence from functional and structural research suggests that abnormal brain activity plays an important role in the pathophysiology of schizophrenia (SZ). However, limited studies have focused on post-treatment changes, and current conclusions are inconsistent. We recruited 104 SZ patients to have resting-state functional magnetic resonance imaging scans at baseline and 8 weeks of treatment with second-generation antipsychotics, along with baseline scanning of 86 healthy controls (HCs) for comparison purposes. Individual regional homogeneity (ReHo), amplitude of low-frequency fluctuations (ALFF), and degree centrality values were calculated to evaluate the functional activity. The Positive and Negative Syndrome Scale (PANSS) and MATRICS Consensus Cognitive Battery were applied to measure psychiatric symptoms and cognitive impairment in SZ patients. Compared with HCs at baseline, SZ patients had higher ALFF and ReHo values in the bilateral inferior temporal gyrus, inferior frontal gyrus, and lower ALFF and ReHo values in fusiform gyrus and precuneus. Following 8 weeks of treatment, ReHo was increased in right medial region of the superior frontal gyrus (SFGmed) and decreased in the left middle occipital gyrus and the left postcentral gyrus. Meanwhile, ReHo of the right SFGmed was increased after treatment in the response group (the reduction rate of PANSS ≥50%). Enhanced ALFF in the dorsolateral of SFG correlated with improvement in depressive factor score. These findings provide novel evidence for the abnormal functional activity hypothesis of SZ, suggesting that abnormality of right SFGmed can be used as a biomarker of treatment response in SZ.

Mismatch negativity predicts initial auditory-based targeted cognitive training performance in a heterogeneous population across psychiatric disorders

Auditory-based targeted cognitive training (ATCT) programs are emerging pro-cognitive therapeutic interventions which aim to improve auditory processing to attenuate cognitive impairment in a “bottom up” manner. Biomarkers of early auditory information processing (EAIP) like mismatch negativity (MMN) and P3a have been used successfully to predict gains from a full 40 h course of ATCT in schizophrenia (SZ). Here we investigated the ability of EAIP biomarkers to predict ATCT performance in a group of subjects (n = 26) across SZ, MDD, PTSD and GAD diagnoses. Cognition was assessed via the MATRICS Consensus Cognitive Battery (MCCB) and MMN/P3a were collected prior to completing 1 h of “Sound Sweeps,” a representative ATCT exercise. Baseline and final performance over the first two levels of cognitive training served as the primary dependent variables. Groups had similar MMN, but the SZ group had attenuated P3a. MMN and MCCB cognitive domain t-scores, but not P3a, were strongly correlated with most ATCT performance measures, and explained up to 61% of variance in ATCT performance. Diagnosis was not a significant predictor for ATCT performance. These data suggest that MMN can predict ATCT performance in heterogeneous neuropsychiatric populations and should be considered in ATCT studies across diagnostically diverse cohorts.

Oxidative stress impairs cognitive function by affecting hippocampal fimbria volume in drug-naïve, first-episode schizophrenia.

The aim of the present study was to explore influencing factors of cognitive impairments and their interrelationships in drug-naïve, first-episode schizophrenia (SCZ). Patients with drug naïve, first episode SCZ and healthy controls (HCs) were enrolled. Cognitive function was assessed by the MATRICS Consensus Cognitive Battery (MCCB). Serum levels of oxidative stress indices, including folate, superoxide dismutase (SOD), uric acid (UA) and homocysteine (Hcy), were determined after an overnight fast. Hippocampal subfield volumes were measured using FreeSurfer. Mediation models were conducted using the SPSS PROCESS v3.4 macro. A false discovery rate (FDR) correction was applied for multiple comparisons. Sixty-seven patients with SCZ and 65 HCs were enrolled in our study. The patient group had significantly lower serum levels of folate and SOD and higher serum levels of HCY compared with the HCs (all p < 0.05). The patient group had a significantly smaller volume of the whole hippocampus than the HC group (p < 0.05). We also found significant volume differences between the two groups in the following subfields: CA1, molecular layer, GC-ML-DG and fimbria (all p < 0.05, uncorrected). The partial correlation analysis controlling for age and sex showed that the fimbria volume in the patient group was significantly positively associated with NAB scores (r = 0.382, pFDR = 0.024); serum levels of SOD in the patient group showed a significantly positive correlation with fimbria volume (r = 0.360, pFDR = 0.036). Mediation analyses controlling for age and sex showed that the serum levels of SOD in patients with SCZ had significant indirect effects on the NAB scores which were mediated by the fimbria volume [indirect effect = 0.0565, 95% CI from the bootstrap test excluding zero (0.0066 to 0.0891)]. Oxidative stress, a reduction in hippocampal subfield volumes and cognitive impairments occur in early SCZ. Oxidative stress impairs cognitive function by affecting hippocampal subfield volumes.

Psychotic symptoms and neurocognition among patients with major depressive disorder: A chained mediation model of depressive symptoms and socio-occupational functioning

BackgroundDepressive symptom and psychotic symptom have been identified as risk factors for impaired socio-occupational functioning in patients with major depressive disorder (MDD), while neurocognitive functioning is considered to be a potential protective factor against socio-occupational functioning. Nevertheless, little is known about the complex relationship among these factors in patients with MDD. The purpose of this research was to explore whether the relationship between depressive symptom severity and social-occupational functioning is mediated by neurocognitive functioning and psychotic symptom severity in MDD patients. MethodsA total of 659 eligible MDD patients included male and female, and their depressive symptoms and psychotic symptoms at baseline were assessed by the 17-item Hamilton Depression Scale (HAMD-17) and The Brief Psychiatric Rating Scale (BPRS) respectively. Cognitive domains were assessed by the MATRICS Consensus Cognitive Battery (MCCB), and subjective and objective functioning were measured by the Global Assessment of Functioning (GAF). LimitationThe analysis is cross-sectional, which limits causal inference. Result(1) The correlation between depressive symptoms and thought disturbance was positive (r = 0.125, p = 0.001), whereas the correlations with visual learning and memory (r = −0.146, p < 0.001) and socio-occupational functioning (r = −0.175, p < 0.001) were negative. (2) Depressive symptoms mainly affect the socio-occupational functioning of MDD patients via three indirect effects: the single mediating effect of psychotic symptoms and neurocognitive functioning, and the chain mediating effect of psychotic symptoms and neurocognitive functioning. ConclusionsThe results suggest that the relationship between depressive symptom severity and socio-occupational functioning in MDD patients is partially mediated by psychotic symptom severity and neurocognitive functioning.

Combining Iclepertin (BI 425809) With Computerized Cognitive Training in Patients With Schizophrenia: Baseline Data From an Ongoing Phase II Trial

AbstractIntroductionThere are currently no approved pharmacotherapies to treat cognitive impairment associated with schizophrenia (CIAS). Iclepertin (BI 425809) is a novel glycine transporter-1 inhibitor under development for treatment of CIAS. A previous study demonstrated pro-cognitive effects of iclepertin in patients with schizophrenia; however, concurrent cognitive stimulation could in theory enhance any pro-cognitive pharmacological effects on neuroplasticity. We present preliminary demographics and baseline data from a trial exploring the efficacy of iclepertin together with at-home computerized cognitive training (CCT).MethodsThis is an ongoing Phase II, double-blind, placebo-controlled, parallel-group trial in patients with schizophrenia on stable antipsychotic therapy across ~58 centers in 6 countries. Patients aged 18–50 years, compliant with CCT during the run-in period (completing ≥2 hours/week for 2 weeks), were randomized (1:1) to receive once-daily iclepertin 10 mg or placebo together with CCT for 12 weeks. Thereafter, minimum compliance for at-home CCT is 1 hour/week, with a target of ~30 hours across 3–5 sessions totaling 2.5 hours/week. Patients have been stratified to balance potential effects of age (18–40; 41–50 years). Primary endpoint is change from baseline (CfB) in neurocognitive composite T-score of the MATRICS Consensus Cognitive Battery (MCCB) at Week 12. Secondary endpoints include CfB in the Schizophrenia Cognition Rating Scale (SCoRS) total score, MCCB overall composite T-score, and Positive and Negative Syndrome Scale (PANSS) total scores. Novel exploratory endpoints include the Virtual Reality Functional Capacity Assessment Tool to assess daily functioning and the Balloon Effort Task to assess motivation in cognitive performance.ResultsOf the planned sample of 200 randomized patients, the overall treated population currently includes 183: 67% (n=122) are male; mean (standard deviation [SD]) age and time since first diagnosis are 38.2 (7.9) years and 13.5 (8.5) years. Overall, 49% (n=89) are White and 43% (n=79) are Black or African American; 80% (n=147) are from North America, 15% (n=28) from Europe, and 4% (n=8) from Australia/New Zealand. Mean (SD) baseline MCCB neurocognitive composite and overall T-scores (n=178) are 33.7 (11.9) and 32.5 (12.6). Mean (SD) baseline SCoRS total score (n=167) is 35.2 (8.7). Mean (SD) baseline PANSS total and negative symptom scale scores (n=183) are 64.7 (14.6) and 17.3 (5.4). Median (Q1, Q3) CCT compliance over the on-treatment period for patients who have completed or discontinued early is 2.00 (1.21, 2.51) hours/week.ConclusionThis trial is, to our knowledge, the largest of its kind combining daily pharmacotherapy for CIAS with at-home CCT. It will indicate whether iclepertin together with concurrent cognitive stimulation provides enhanced cognitive benefit, and whether any improvements in neurocognition can translate into improved measures of daily functioning in patients.FundingBoehringer Ingelheim International GmbH (NCT03859973/1346-0038)

Efficacy and Safety of Iclepertin (BI 425809) in Patients With Schizophrenia: CONNEX, A Phase III Randomized Controlled Trial Program

AbstractIntroductionCognitive impairment is a major determinant of poor functional outcome in schizophrenia and there are currently no available pharmacotherapies. Deficits in glutamatergic signaling play a key role in the neuropathology of cognitive symptoms. Iclepertin (BI 425809), an inhibitor of glycine transporter-1, enhances glutamatergic signaling by increasing synaptic levels of the N-methyl-D-aspartate receptor co-agonist, glycine. A 12-week, Phase II trial (NCT02832037) in 509 patients with schizophrenia demonstrated that iclepertin was well tolerated and significantly improved cognition. The Phase III CONNEX program aims to confirm the efficacy, safety, and tolerability of iclepertin in improving cognition and functioning in a larger cohort of patients.MethodsCONNEX consists of three replicate randomized, double-blind, placebo-controlled parallel-group trials in patients with schizophrenia (NCT04846868, NCT04846881, NCT04860830) currently stable on antipsychotic treatment. Each trial aims to recruit ~586 patients, 18–50 years old, treated with 1–2 antipsychotic medications (≥12 weeks on current drug; ≥35 days on current dose prior to treatment), who have functional impairment in day-to-day activities, and interact ≥1 hour per week with a designated study partner. Patients with cognitive impairment due to developmental, neurological, or other disorders, or receiving cognitive remediation therapy within 12 weeks prior to screening, will be excluded. Patients will be recruited from multiple centers across 32 countries in Asia, North and South America, and Europe, and randomized 1:1 to receive either oral iclepertin 10 mg (n=293), or placebo (n=293) once daily over 26 weeks. The primary efficacy endpoint is change from baseline (CfB) in the MATRICS Consensus Cognitive Battery overall composite T-score. Key secondary efficacy endpoints are CfB in Schizophrenia Cognition Rating Scale total score and CfB in the adjusted total time in the Virtual Reality Functional Capacity Assessment Tool. Long-term safety and tolerability data will be collected in an open-label safety extension study (CONNEX-X).ResultsThe studies are currently recruiting (first patients enrolled Aug–Sept 2021), with completion expected in Q2 2024. Here we present an overview of the current study status, including any information relating to screening failures, and the experience of collecting these data as part of a large multi-country, multi-center study.ConclusionTo date, most large, industry-sponsored studies testing various compounds to address cognitive function have failed to show proof-of-clinical concept. Demonstration of efficacy of iclepertin in improving cognition in this Phase III program would provide important insight into the role of glutamate in cognitive symptoms that may also have relevance for other cognitive disorders. Iclepertin may represent the first efficacious medication for cognitive impairment associated with schizophrenia.FundingBoehringer Ingelheim International GmbH (1346-0011, NCT04846868; 1346-0012, NCT04846881; 1346-0013, NCT04860830)

374 Identification of Psychosis Risk Biomarkers in 22q11DS for future translational studies

OBJECTIVES/GOALS: 22q.11 deletion syndrome (22q11DS) is a genomic syndrome that elevates risk for psychosis &gt;20-fold. We used a battery of cognitive and psychophysiological psychosis-risk biomarkers in 22q11DS patients and healthy subjects in order to identify biomarkers of psychosis in 22q11DS that could be used as translational targets in intervention studies. METHODS/STUDY POPULATION: We recruited 15 22q11DS individuals (Mean age=30, M/F=9/6) and 19 healthy controls (HCs; Mean age=34, M/F=5/14). Each individual completed the MATRICS Consensus Cognitive Battery (MCCB), the Wechsler Abbreviated Scale of Intelligence, Second edition (WASI-II) Verbal IQ subtests, and the computerized Wisconsin Card Sorting Task (WCST). To examine auditory EEG responses, each participant completed the 'Double-Deviant' target detection paradigm, which presents a pseudorandom sequence of frequent standard tones and infrequent deviant tones. Mismatch negativity (MMN) metrics were generated from this assessment. Welch's t-tests were completed for neurocognitive variables. One-Way ANOVAs were completed to examine EEG results, with sex entered as a separate factor and age entered as a covariate. RESULTS/ANTICIPATED RESULTS: Significant group differences were found in 8 of the 9 neurocognitive measurements (FDR-adjusted p's&lt; 0.02, average Cohen's d=1.62, average observed power= 0.91) indicating widespread cognitive deficits in 22q11DS subjects across multiple domains. The Double-Deviant MMN ERP response was significantly smaller in absolute magnitude in the 22q11DS group (FDR-adjusted p=0.048, Cohen’s d= -0.864, observed power= 0.58). The MMN ERPs for the frequency and duration deviants were not significantly different (FDR-adjusted p's&gt; 0.33). No group by sex interactions were observed in any of the measures. Neurocognitive variables were associated with psychosis positive, negative, general, and disorganized symptom scales. DISCUSSION/SIGNIFICANCE: Our results identify potential psychosis-risk biomarkers in 22q11DS. If replicated, these biomarkers could provide important translational targets for future clinical trials for individuals with 22q11DS and other individuals at-risk for psychosis syndromes.

Shared and distinct structural brain alterations and cognitive features in drug-naïve schizophrenia and bipolar disorder.

Our study aimed to examine the shared and distinct structural brain alterations, including cortical thickness(CT) and local gyrification index(LGI), and cognitive impairments between the early course stage of drug-naïve schizophrenia(SZ) and bipolar disorder(BD) patients when compared to healthy controls(HCs), and to further explore the correlation between altered brain structure and cognitive impairments. We included 72 SZ patients, 35 BD patients and 43 HCs. The cognitive function was assessed using the MATRICS Consensus Cognitive Battery. Cerebral cortex analyses were performed with FreeSurfer. Furthermore, any structural aberrations related to cognition impairments were examined. Cognitive impairments existed in SZ and BD patients and were much more severe and widespread in SZ patients, compared to HCs. There were no significant differences in LGI among three groups. Compared to HCs, SZ had thicker cortex in left pars triangularis, and BD showed thinner CT in left postcentral gyrus. In addition, BD showed thinner cortex in left pars triangularis, left pars opercularis, left insula and right fusiform gyrus compared to SZ. Moreover, our results indicated that CT in many brain areas were significantly correlated with cognitive function in HCs, but only CT of left pars triangularis was correlated with impaired social cognition found in SZ. The findings suggest that changes of CT in the left pars triangularis and left postcentral gyrus may be potential pathophysiological mechanisms of the cognition impairments in SZ and BD, respectively, and the divergent CT of partly brain areas in BD vs. SZ may help distinguish them in early phases.

A Bayesian Network Approach to Social and Nonsocial Cognition in Schizophrenia: Are Some Domains More Fundamental than Others?

Social and nonsocial cognition are defined as distinct yet related constructs. However, the relative independence of individual variables-and whether specific tasks directly depend on performance in other tasks-is still unclear. The current study aimed to answer this question by using a Bayesian network approach to explore directional dependencies among social and nonsocial cognitive domains. The study sample comprised 173 participants with schizophrenia (71.7% male; 28.3% female). Participants completed 5 social cognitive tasks and the MATRICS Consensus Cognitive Battery. We estimated Bayesian networks using directed acyclic graph structures to examine directional dependencies among the variables. After accounting for negative symptoms and demographic variables, including age and sex, all nonsocial cognitive variables depended on processing speed. More specifically, attention, verbal memory, and reasoning and problem solving solely depended on processing speed, while a causal chain emerged between processing speed and visual memory (processing speed → attention → working memory → visual memory). Social processing variables within social cognition, including emotion in biological motion and empathic accuracy, depended on facial affect identification. These results suggest that processing speed and facial affect identification are fundamental domains of nonsocial and social cognition, respectively. We outline how these findings could potentially help guide specific interventions that aim to improve social and nonsocial cognition in people with schizophrenia.

Time discrimination in psychosis: findings from a neuroimaging study

IntroductionPrevious functional neuroimaging studies have demonstrated a brain network responsible of time discrimination (TD) processes, which may play a significant mediating role in other cognitive processes, such as change detection and cognitive control. The study of TD and its dysfunction in psychosis has become a matter of growing interest. We hypothesize that the impairment of the TD network is involved both in the mechanisms of psychosis and in the cognitive deficit presented by patients.Objectives1.To delimit the brain regions involved in TD.2.To examine the dysfunction in TD brain network in patients diagnosed with psychosis.3.To sudy the integrity of brain white matter pathways in psychosis.4.To verify whether the neuroimaging findings and TD test performance predict the neurocognitive profile of the patients.MethodsParticipants included 20 patients with psychosis (PSY group) and 13 healthy controls (HC group). PSY group participants met remission criteria for 6 months prior to the study. Participants were interviewed for sociodemographic information and clinical assessments. They underwent a detailed cognitive assesment using the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB). Neuroimaging study was performed on a 3 Tesla MRI scanner. We designed an experimental task including a test tool to assess TD and Oddbal detection (OD) paradigms with a cognitive control component. The task was conducted under functional magentic resonance imaging (fMRI). We used the general linear model analysis of the individual data of the fMRI images and the random effects model for group inference. Group differences in DTI were tested using tract-based spatial statistics (TBSS).ResultsWe find statistically significant differences (fMRI) in the activity related to TD (in HC), with greater activity in frontal cortical regions, the insular cortex and the cerebellum. In the PSY group, differences in the functionality and activation pattern of brain networks responsible for TD are observed, although voxel clustering does not reach the cluster significance limit when compared to HC. Compared to the HC, the PSY group has a significant deficit of fractional anisotropy (DTI) in the whole brain and in 21 specific brain regions. The PSY group has significantly lower scores in six of the seven cognitive domains than the control group, as well as in the overall composite. We correlated FA values in the groups of interest with MCCB scores.Image:Image 2:Image 3:ConclusionsWe have defined the TD network, its relationship with other brain networks and cognitive processes of more complexity. The inclusion of participants with stable psychosis allowed us to analyze de TD disfunction in the PSY group. We compared the integrity of TD related brain pathways and correlated the findings with various clinical characteristics and the cognitive impairment present in psychotic patients.Disclosure of InterestNone Declared

Relationship between CAINS negative symptoms and cognition, psychosocial functioning and quality of life in patients with a first psychotic episode of schizophrenia

IntroductionNegative symptoms has been classically associated with cognition, psychosocial functioning and quality of life in patients with schizophrenia. But negative symptoms are not a unitary construct, encompassing two different factors: diminished expression, and motivation and pleasure. Few works have studied the relationship between these two different negative symptoms factors and cognition (neuro and social cognition), psychosocial functioning and quality of life, jointly, in patients with a first psychotic episode of schizophrenia.ObjectivesThe objective of the present work was to study, in a sample of patients with a first psychotic episode of schizophrenia, the relationship between the negative symptoms (diminished expression and motivation and pleasure) and neurocognition, social cognition, functioning and quality of life.MethodsThe study was carried out with 82 outpatients with a first psychotic episode of schizophrenia from two Spanish hospitals (“12 de Octubre” University Hospital, Madrid and “Virgen de la Luz” Hospital, Cuenca). The patients were assessed with the Clinical Assessment Interview for Negative Symptoms (CAINS) for evaluating diminished expression (EXP) and motivation and pleasure (MAP) symptoms, the MATRICS Consensus Cognitive Battery (MCCB) for evaluating neurocognition and social cognition, the Social and Occupational Functioning Assessment Scale (SOFAS), and the Quality of Life Scale (QLS).ResultsA negative correlation was found between neurocognition and the two negative symptoms subscales: CAINS-EXP (r=-0.458, p&lt;0.001) and CAINS-MAP (r=-0.374, p&lt;0.001); but with social cognition only CAINS-EXP was correlated (r=-0.236, p=0.033). Also, it was found a high negative correlation between SOFAS scores and CAINS-MAP (r=-0.717, p&lt;0.001); and a medium negative correlation with CAINS-EXP (r=-0.394, p&lt;0.001). Finally, QLS score was high correlated with both CAINS subscales: CAINS-EXP (r=-0.681, p&lt;0.001) and CAINS-MAP (r=-0.770, p&lt;0.001).ConclusionsThis study found a relationship between negative symptoms and neurocognition, social cognition, functioning and quality of life in a sample of patients with a first psychotic episode of schizophrenia. But the two different negative symptom factors, diminished expression, and motivation and pleasure, are associated differently with psychosocial functioning, but especially with social cognition where the relationship was only found with diminished expression symptoms.Disclosure of InterestNone Declared

Efficacy and auditory biomarker analysis of fronto-temporal transcranial direct current stimulation (tDCS) in targeting cognitive impairment associated with recent-onset schizophrenia: study protocol for a multicenter randomized double-blind sham-controlled trial

BackgroundIn parallel to the traditional symptomatology, deficits in cognition (memory, attention, reasoning, social functioning) contribute significantly to disability and suffering in individuals with schizophrenia. Cognitive deficits have been closely linked to alterations in early auditory processes (EAP) that occur in auditory cortical areas. Preliminary evidence indicates that cognitive deficits in schizophrenia can be improved with a reliable and safe non-invasive brain stimulation technique called tDCS (transcranial direct current stimulation). However, a significant proportion of patients derive no cognitive benefits after tDCS treatment. Furthermore, the neurobiological mechanisms of cognitive changes after tDCS have been poorly explored in trials and are thus still unclear.MethodThe study is designed as a randomized, double-blind, 2-arm parallel-group, sham-controlled, multicenter trial. Sixty participants with recent-onset schizophrenia and cognitive impairment will be randomly allocated to receive either active (n=30) or sham (n=30) tDCS (20-min, 2-mA, 10 sessions during 5 consecutive weekdays). The anode will be placed over the left dorsolateral prefrontal cortex and the cathode over the left auditory cortex. Cognition, tolerance, symptoms, general outcome and EAP (measured with EEG and multimodal MRI) will be assessed prior to tDCS (baseline), after the 10 sessions, and at 1- and 3-month follow-up. The primary outcome will be the number of responders, defined as participants demonstrating a cognitive improvement ≥Z=0.5 from baseline on the MATRICS Consensus Cognitive Battery total score at 1-month follow-up. Additionally, we will measure how differences in EAP modulate individual cognitive benefits from active tDCS and whether there are changes in EAP measures in responders after active tDCS.DiscussionBesides proposing a new fronto-temporal tDCS protocol by targeting the auditory cortical areas, we aim to conduct a randomized controlled trial (RCT) with follow-up assessments up to 3 months. In addition, this study will allow identifying and assessing the value of a wide range of neurobiological EAP measures for predicting and explaining cognitive deficit improvement after tDCS. The results of this trial will constitute a step toward the use of tDCS as a therapeutic tool for the treatment of cognitive impairment in recent-onset schizophrenia.Trial registrationClinicalTrials.gov NCT05440955. Prospectively registered on July 1st, 2022.

Association of serum homocysteine levels with intestinal flora and cognitive function in schizophrenia

Some studies have indicated that elevated homocysteine (Hcy) levels and intestinal flora may be involved in schizophrenia (SZ) cognition pathophysiology. This study was the first to investigate the association among Hcy, intestinal flora and schizophrenia cognition. Here, 140 individuals were divided into two groups: SZ patients (N = 68) and healthy controls (HCs, N = 72). Participant data on serum Hcy levels, intestinal flora and cognitive function evaluation using the MATRICS Consensus Cognitive Battery (MCCB) were collected. Clinical symptoms of patients were evaluated using the Positive and Negative Syndrome Scale. Serum Hcy levels and the incidence of hyperhomocysteinaemia were considerably increased in SZ patients compared with HCs. Hcy levels were significantly negatively associated with verbal learning index scores (r = −0.425, p < 0.001) but positively associated with Eubacterium (r = 0.32, p = 0.007), Lactobacillus (r = 0.32, p = 0.008), Corynebacterium (r = 0.26, p = 0.035), Mogibacterium (r = 0.31, p = 0.01), and Bulleidia (r = 0.31, p = 0.01) in SZ patients. Our findings suggest that serum Hcy levels are associated with cognitive function and intestinal flora in SZ patients. However, the mechanism of the interaction between Hcy and intestinal flora and its effects on cognitive function in SZ patients requires further investigation.

Differences in cognitive functions of atypical and non-atypical depression based on propensity score matching

BackgroundClinical and etiological heterogeneity have hindered our understanding of depression, thus driving the studies of major depressive disorder (MDD) subtypes. Atypical depression (AD) is a subtype of MDD with atypical features. Cognitive impairment is one of the factors that contribute to the suffering of patients with MDD. Therefore, this study investigated the characteristics and differences in cognitive functioning of AD and non-atypical depression (non-AD) using the MATRICS Consensus Cognitive Battery (MCCB). MethodsA total of 101 patients with AD and 252 patients with non-AD were assessed with the MCCB and clinical scales. Propensity score matching (PSM) was used to balance confounders between groups. After PSM, between-group differences were compared for cognitive and clinical variables. In addition, multiple linear regression analyses were performed to explore the effects of cognitive and clinical variables on the quality of life. ResultsThe AD group scored significantly lower in attention/vigilance and social cognition in all cognitive domains than the non-AD group. Attention/vigilance and social cognition were significant positive predictors of quality of life, whereas atypical symptoms and depressive severity were significant negative predictors. ConclusionsThis study suggests significant differences in cognitive functions between the AD and non-AD subtypes. Atypical symptoms and impaired cognition have a negative impact on patients' quality of life. Attention/vigilance and social cognition are worse in AD than non-AD, which the atypical features of patients with AD may explain. The pathological mechanisms and treatment strategies of AD should be further explored in the future to promote individualized treatment strategies.