Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study.

Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Our findings show schizophrenia-related cortical thinning is spatially associated with functional and structural hubs, suggesting that highly interconnected regions are more vulnerable to morphological alterations. Predominantly temporo-paralimbic and frontal regions emerged as epicenters with connectivity profiles linked to schizophrenia's alteration patterns. Findings were robust across sites, disease stages, and related to individual symptoms. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, suggestive of a pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters at both the level of the group and the individual. Subtle variations of epicenters across disease stages suggest interacting pathological processes, while associations with patient-specific symptoms support additional inter-individual variability of hub vulnerability and epicenters in schizophrenia. Our work outlines potential pathways to better understand macroscale structural alterations, and inter- individual variability in schizophrenia.

Cortical volume abnormalities in schizophrenia: Correlations with symptoms and cognitive impairment.

BACKGROUND: Schizophrenic symptoms are known to segregate into reality distortion, negative and disorganization syndromes, but the correlates of these syndromes with regional brain structural change are not well established. Cognitive impairment is a further clinical feature of schizophrenia, whose brain structural correlates are the subject of conflicting findings. METHODS: 165 patients with schizophrenia were rated for symptoms using the PANSS, and cognitive impairment was indexed by estimated premorbid-current IQ discrepancy. Cortical volume was measured using surface-based morphometry in the patients and in 50 healthy controls. Correlations between clinical and cognitive measures and cortical volume were examined using whole-brain FreeSurfer tools. RESULTS: No clusters of volume reduction were seen associated with reality distortion or disorganization. Negative symptom scores showed a significant inverse correlation with volume in a small cluster in the left medial orbitofrontal gyrus. Larger estimated premorbid-current IQ discrepancies were associated with clusters of reduced cortical volume in the left precentral gyrus and the left temporal lobe. The cluster of association with negative symptoms disappeared when estimated premorbid-current IQ discrepancy was controlled for. CONCLUSIONS: This study does not provide support for an association between brain structural abnormality and reality distortion or disorganization syndromes in schizophrenia. The cluster of volume reduction found in the left medial orbitofrontal cortex correlated with negative symptoms may have reflected the association between this class of symptoms and cognitive impairment. The study adds to existing findings of an association between cognitive impairment and brain structural changes in the disorder.

Brain Functional Correlates of Recall of Life Events in Medication-Naïve Adolescents with Borderline Personality Disorder.

INTRODUCTION: Recall of autobiographical events has been found to be impaired in borderline personality disorder (BPD), but few studies have examined if this impairment has brain functional correlates. This study evaluated brain functional alterations during autobiographical recall using medication-naive adolescent patients to avoid potential confounding effects of treatment. METHODS: Thirty-two adolescent female patients with BPD who were never-medicated and without psychiatric comorbidity and 33 matched healthy females underwent fMRI while they viewed individualized cue words that evoked autobiographical memories. Control conditions included viewing non-memory-evoking cues and a low-level baseline (cross-fixation). RESULTS: During autobiographical recall, in comparison to the low-level baseline, the BPD patients showed increased brain activity in regions including the posterior hippocampus, the lingual and calcarine cortex, and the precuneus compared to the healthy controls. The BPD patients also showed a failure to deactivate the right dorsolateral prefrontal cortex during autobiographical recall. No patient-control differences were found when memory-evoking words were compared to non-memory-evoking words. DISCUSSION/CONCLUSIONS: This study finds evidence of hippocampal/lingual/calcarine/precuneus hyperactivation to stimuli that evoke autobiographical memories in patients with BPD. As the changes were seen in never-treated patients without other comorbidities, they could be considered intrinsic to the disorder. Our study also adds to existing evidence for failure of deactivation in BPD, this time outside the default mode network.

Improved estimation of the risk of manic relapse by combining clinical and brain scan data.

INTRODUCTION: Estimating the risk of manic relapse could help the psychiatrist individually adjust the treatment to the risk. Some authors have attempted to estimate this risk from baseline clinical data. Still, no studies have assessed whether the estimation could improve by adding structural magnetic resonance imaging (MRI) data. We aimed to evaluate it. MATERIAL AND METHODS: We followed a cohort of 78 patients with a manic episode without mixed symptoms (bipolar type I or schizoaffective disorder) at 2-4-6-9-12-15-18 months and up to 10 years. Within a cross-validation scheme, we created and evaluated a Cox lasso model to estimate the risk of manic relapse using both clinical and MRI data. RESULTS: The model successfully estimated the risk of manic relapse (Cox regression of the time to relapse as a function of the estimated risk: hazard ratio (HR)=2.35, p=0.027; area under the curve (AUC)=0.65, expected calibration error (ECE)<0.2). The most relevant variables included in the model were the diagnosis of schizoaffective disorder, poor impulse control, unusual thought content, and cerebellum volume decrease. The estimations were poorer when we used clinical or MRI data separately. CONCLUSION: Combining clinical and MRI data may improve the risk of manic relapse estimation after a manic episode. We provide a website that estimates the risk according to the model to facilitate replication by independent groups before translation to clinical settings.

Human-specific evolutionary markers linked to foetal neurodevelopment modulate brain surface area in schizophrenia.

Schizophrenia may represent a trade-off in the evolution of human-specific ontogenetic mechanisms that guide neurodevelopment. Human Accelerated Regions (HARs) are evolutionary markers functioning as neurodevelopmental transcription enhancers that have been associated with brain configuration, neural information processing, and schizophrenia risk. Here, we have investigated the influence of HARs' polygenic load on neuroanatomical measures through a case-control approach (128 patients with schizophrenia and 115 controls). To this end, we have calculated the global schizophrenia Polygenic Risk Score (Global PRSSZ) and that specific to HARs (HARs PRSSZ). We have also estimated the polygenic burden restricted to the HARs linked to transcriptional regulatory elements active in the foetal brain (FB-HARs PRSSZ) and the adult brain (AB-HARs PRSSZ). We have explored the main effects of the PRSs and the PRSs x diagnosis interactions on brain regional cortical thickness (CT) and surface area (SA). The results indicate that a higher FB-HARs PRSSZ is associated with patients' lower SA in the lateral orbitofrontal cortex, the superior temporal cortex, the pars triangularis and the paracentral lobule. While noHARs-derived PRSs show an effect on the risk, our neuroanatomical findings suggest that the human-specific transcriptional regulation during the prenatal period underlies SA variability, highlighting the role of these evolutionary markers in the schizophrenia genomic architecture.

Two neurostructural subtypes: results of machine learning on brain images from 4,291 individuals with schizophrenia.

Machine learning can be used to define subtypes of psychiatric conditions based on shared clinical and biological foundations, presenting a crucial step toward establishing biologically based subtypes of mental disorders. With the goal of identifying subtypes of disease progression in schizophrenia, here we analyzed cross-sectional brain structural magnetic resonance imaging (MRI) data from 4,291 individuals with schizophrenia (1,709 females, age=32.5 years±11.9) and 7,078 healthy controls (3,461 females, age=33.0 years±12.7) pooled across 41 international cohorts from the ENIGMA Schizophrenia Working Group, non-ENIGMA cohorts and public datasets. Using a machine learning approach known as Subtype and Stage Inference (SuStaIn), we implemented a brain imaging-driven classification that identifies two distinct neurostructural subgroups by mapping the spatial and temporal trajectory of gray matter (GM) loss in schizophrenia. Subgroup 1 (n=2,622) was characterized by an early cortical-predominant loss (ECL) with enlarged striatum, whereas subgroup 2 (n=1,600) displayed an early subcortical-predominant loss (ESL) in the hippocampus, amygdala, thalamus, brain stem and striatum. These reconstructed trajectories suggest that the GM volume reduction originates in the Broca's area/adjacent fronto-insular cortex for ECL and in the hippocampus/adjacent medial temporal structures for ESL. With longer disease duration, the ECL subtype exhibited a gradual worsening of negative symptoms and depression/anxiety, and less of a decline in positive symptoms. We confirmed the reproducibility of these imaging-based subtypes across various sample sites, independent of macroeconomic and ethnic factors that differed across these geographic locations, which include Europe, North America and East Asia. These findings underscore the presence of distinct pathobiological foundations underlying schizophrenia. This new imaging-based taxonomy holds the potential to identify a more homogeneous sub-population of individuals with shared neurobiological attributes, thereby suggesting the viability of redefining existing disorder constructs based on biological factors.

Cortical morphology in patients with the deficit and non-deficit syndrome of schizophrenia: a worldwide meta- and mega-analyses.

Converging evidence suggests that schizophrenia (SZ) with primary, enduring negative symptoms (i.e., Deficit SZ (DSZ)) represents a distinct entity within the SZ spectrum while the neurobiological underpinnings remain undetermined. In the largest dataset of DSZ and Non-Deficit (NDSZ), we conducted a meta-analysis of data from 1560 individuals (168 DSZ, 373 NDSZ, 1019 Healthy Controls (HC)) and a mega-analysis of a subsampled data from 944 individuals (115 DSZ, 254 NDSZ, 575 HC) collected across 9 worldwide research centers of the ENIGMA SZ Working Group (8 in the mega-analysis), to clarify whether they differ in terms of cortical morphology. In the meta-analysis, sites computed effect sizes for differences in cortical thickness and surface area between SZ and control groups using a harmonized pipeline. In the mega-analysis, cortical values of individuals with schizophrenia and control participants were analyzed across sites using mixed-model ANCOVAs. The meta-analysis of cortical thickness showed a converging pattern of widespread thinner cortex in fronto-parietal regions of the left hemisphere in both DSZ and NDSZ, when compared to HC. However, DSZ have more pronounced thickness abnormalities than NDSZ, mostly involving the right fronto-parietal cortices. As for surface area, NDSZ showed differences in fronto-parietal-temporo-occipital cortices as compared to HC, and in temporo-occipital cortices as compared to DSZ. Although DSZ and NDSZ show widespread overlapping regions of thinner cortex as compared to HC, cortical thinning seems to better typify DSZ, being more extensive and bilateral, while surface area alterations are more evident in NDSZ. Our findings demonstrate for the first time that DSZ and NDSZ are characterized by different neuroimaging phenotypes, supporting a nosological distinction between DSZ and NDSZ and point toward the separate disease hypothesis.

Concurrent validity and reliability of suicide risk assessment instruments: A meta-analysis of 20 instruments across 27 international cohorts.

OBJECTIVE: A major limitation of current suicide research is the lack of power to identify robust correlates of suicidal thoughts or behavior. Variation in suicide risk assessment instruments used across cohorts may represent a limitation to pooling data in international consortia. METHOD: Here, we examine this issue through two approaches: (a) an extensive literature search on the reliability and concurrent validity of the most commonly used instruments and (b) by pooling data (N ∼ 6,000 participants) from cohorts from the Enhancing NeuroImaging Genetics Through Meta-Analysis (ENIGMA) Major Depressive Disorder and ENIGMA-Suicidal Thoughts and Behaviour working groups, to assess the concurrent validity of instruments currently used for assessing suicidal thoughts or behavior. RESULTS: We observed moderate-to-high correlations between measures, consistent with the wide range (κ range: 0.15-0.97; r range: 0.21-0.94) reported in the literature. Two common multi-item instruments, the Columbia Suicide Severity Rating Scale and the Beck Scale for Suicidal Ideation were highly correlated with each other (r = 0.83). Sensitivity analyses identified sources of heterogeneity such as the time frame of the instrument and whether it relies on self-report or a clinical interview. Finally, construct-specific analyses suggest that suicide ideation items from common psychiatric questionnaires are most concordant with the suicide ideation construct of multi-item instruments. CONCLUSIONS: Our findings suggest that multi-item instruments provide valuable information on different aspects of suicidal thoughts or behavior but share a modest core factor with single suicidal ideation items. Retrospective, multisite collaborations including distinct instruments should be feasible provided they harmonize across instruments or focus on specific constructs of suicidality. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Do the negative symptoms of schizophrenia reflect reduced responsiveness to reward? Examination using a reward prediction error (RPE) task.

BACKGROUND: A leading theory of the negative symptoms of schizophrenia is that they reflect reduced responsiveness to rewarding stimuli. This proposal has been linked to abnormal (reduced) dopamine function in the disorder, because phasic release of dopamine is known to code for reward prediction error (RPE). Nevertheless, few functional imaging studies have examined if patients with negative symptoms show reduced RPE-associated activations. METHODS: Matched groups of DSM-5 schizophrenia patients with high negative symptom scores (HNS, N = 27) or absent negative symptoms (ANS, N = 27) and healthy controls (HC, N = 30) underwent fMRI scanning while they performed a probabilistic monetary reward task designed to generate a measure of RPE. RESULTS: In the HC, whole-brain analysis revealed that RPE was positively associated with activation in the ventral striatum, the putamen, and areas of the lateral prefrontal cortex and orbitofrontal cortex, among other regions. Group comparison revealed no activation differences between the healthy controls and the ANS patients. However, compared to the ANS patients, the HNS patients showed regions of significantly reduced activation in the left ventrolateral and dorsolateral prefrontal cortex, and in the right lingual and fusiform gyrus. HNS and ANS patients showed no activation differences in ventral striatal or midbrain regions-of-interest (ROIs), but the HNS patients showed reduced activation in a left orbitofrontal cortex ROI. CONCLUSIONS: The findings do not suggest that a generalized reduction of RPE signalling underlies negative symptoms. Instead, they point to a more circumscribed dysfunction in the lateral frontal and possibly the orbitofrontal cortex.

Brain functional abnormality in drug treated and drug naïve adolescents with borderline personality disorder: Evidence for default mode network dysfunction.

BACKGROUND: Patients with borderline personality disorder (BPD) have been found to show functional brain abnormality, including in the medial frontal cortex and other areas of the default mode network (DMN). The current study aimed to examine activations and de-activations in drug treated and medication-free female adolescents with the disorder. METHODS: 39 DSM-5 adolescent female patients with BPD without psychiatric comorbidity and 31 matched healthy female adolescents underwent fMRI during the performance of 1-back and 2-back versions of the n-back working memory task. Linear models were used to obtain maps of within-group activations and de-activations and areas of differences between the groups. RESULTS: On corrected whole-brain analysis, the BPD patients showed failure to de-activate a region of the medial frontal cortex in the 2-back > 1-back comparison. The 30 never-medicated patients additionally showed a failure to de-activate the right hippocampus in the 2-back versus baseline contrast. CONCLUSIONS: Evidence of DMN dysfunction was observed in adolescent patients with BPD. Because the relevant medial frontal and hippocampal changes were seen in unmedicated young patients without comorbidity, they might be considered intrinsic to the disorder.

Bridging Big Data: Procedures for Combining Non-equivalent Cognitive Measures from the ENIGMA Consortium.

Investigators in neuroscience have turned to Big Data to address replication and reliability issues by increasing sample sizes, statistical power, and representativeness of data. These efforts unveil new questions about integrating data arising from distinct sources and instruments. We focus on the most frequently assessed cognitive domain - memory testing - and demonstrate a process for reliable data harmonization across three common measures. We aggregated global raw data from 53 studies totaling N = 10,505 individuals. A mega-analysis was conducted using empirical bayes harmonization to remove site effects, followed by linear models adjusting for common covariates. A continuous item response theory (IRT) model estimated each individual's latent verbal learning ability while accounting for item difficulties. Harmonization significantly reduced inter-site variance while preserving covariate effects, and our conversion tool is freely available online. This demonstrates that large-scale data sharing and harmonization initiatives can address reproducibility and integration challenges across the behavioral sciences.

Neural correlates of referential/persecutory delusions in schizophrenia: examination using fMRI and a virtual reality underground travel paradigm.

BACKGROUND: The brain functional correlates of delusions have been relatively little studied. However, a virtual reality paradigm simulating travel on the London Underground has been found to evoke referential ideation in both healthy subjects and patients with schizophrenia, making brain activations in response to such experiences potentially identifiable. METHOD: Ninety patients with schizophrenia/schizoaffective disorder and 28 healthy controls underwent functional magnetic resonance imaging while they viewed virtual reality versions of full and empty Barcelona Metro carriages. RESULTS: Compared to the empty condition, viewing the full carriage was associated with activations in the visual cortex, the cuneus and precuneus/posterior cingulate cortex, the inferior parietal cortex, the angular gyrus and parts of the middle and superior temporal cortex including the temporoparietal junction bilaterally. There were no significant differences in activation between groups. Nor were there activations associated with referentiality or presence of delusions generally in the patient group. However, patients with persecutory delusions showed a cluster of reduced activation compared to those without delusions in a region in the right temporal/occipital cortex. CONCLUSIONS: Performance of the metro task is associated with a widespread pattern of activations, which does not distinguish schizophrenic patients and controls, or show an association with referentiality or delusions in general. However, the finding of a cluster of reduced activation close to the right temporoparietal junction in patients with persecutory delusions specifically is of potential interest, as this region is believed to play a role in social cognition.

Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium.

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.55 years (95% CI: 2.91, 4.19; I2 = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen's d = 0.48). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.

Brain correlates of impaired goal management in bipolar mania.

BACKGROUND: Although executive impairment has been reported in mania, its brain functional correlates have been relatively little studied. This study examined goal management, believed to be more closely related to executive impairment in daily life than other executive tasks, using a novel functional magnetic resonance imaging (fMRI) paradigm in patients in this illness phase. METHODS: Twenty-one currently manic patients with bipolar disorder and 30 matched healthy controls were scanned while performing the Computerized Multiple Elements Test (CMET). This requires participants to sequentially play four simple games, with transition between games being made either voluntarily (executive condition) or automatically (control condition). RESULTS: CMET performance was impaired in the manic patients compared to the healthy controls. Manic patients failed to increase activation in the lateral frontal, cingulate and inferior parietal cortex when the executive demands of the task increased, while this increase was observed in the healthy controls. Activity in these regions was associated with task performance. CONCLUSIONS: Manic patients show evidence of impaired goal management, which is associated with a pattern of reduced medial and lateral frontal and parietal activity.

Brain correlates of speech perception in schizophrenia patients with and without auditory hallucinations.

The experience of auditory verbal hallucinations (AVH, "hearing voices") in schizophrenia has been found to be associated with reduced auditory cortex activation during perception of real auditory stimuli like tones and speech. We re-examined this finding using 46 patients with schizophrenia (23 with frequent AVH and 23 hallucination-free), who underwent fMRI scanning while they heard words, sentences and reversed speech. Twenty-five matched healthy controls were also examined. Perception of words, sentences and reversed speech all elicited activation of the bilateral superior temporal cortex, the inferior and lateral prefrontal cortex, the inferior parietal cortex and the supplementary motor area in the patients and the healthy controls. During the sentence and reversed speech conditions, the schizophrenia patients as a group showed reduced activation in the left primary auditory cortex (Heschl's gyrus) relative to the healthy controls. No differences were found between the patients with and without hallucinations in any condition. This study therefore fails to support previous findings that experience of AVH attenuates speech-perception-related brain activations in the auditory cortex. At the same time, it suggests that schizophrenia patients, regardless of presence of AVH, show reduced activation in the primary auditory cortex during speech perception, a finding which could reflect an early information processing deficit in the disorder.

Evolución de primeros episodios psicóticos: relación entre neuroimagen funcional, clínica y neuropsicología / Evolution of first psychotic episodes: relationship between functional, clinical neuroimaging and neuropsychology

Una de las principales líneas de investigación en desarrollo sobre los primeros episodios psicóticos se centra en el estudio de biomarcadores con el objetivo de dar respuesta a cuestiones como la gran heterogeneidad clínica o el riesgo de recaídas. Sin embargo, los estudios de neuroimagen muestran resultados contradictorios y los estudios longitudinales son escasos. Por ello se ha realizado un seguimiento de entre 8 y 10 años a una cohorte de 30 pacientes con un primer episodio psicótico y un grupo equivalente de controles sanos, tanto a nivel de neuroimagen estructural como funcional durante la realización de una tarea de memoria de trabajo, la N-Back. En la evaluación inicial los PEP mostraron una reducción del volumen global y un fallo en desactivación en zonas frontales durante la realización de la N-Back, que fue más significativo en pacientes con un posterior diagnóstico de esquizofrenia. En la evaluación de seguimiento los resultados muestran un fallo en desactivación en el grupo de pacientes que se extiende a regiones parietales posteriores. Estas regiones forman la llamada red neuronal por defecto, una serie de regiones que se activan en reposo, pero que se desactivan durante la realización de tareas con una alta demanda cognitiva. Estos resultados apuntan a una disfunción progresiva de la red neural por defecto en primeros episodios, subyacentes a la progresión del trastorno, y proporcionan una mejor comprensión de la evolución de los factores fisiopatológicos que afectan a los PEP (AU)

A major developing area on first psychotic episodes (FEP) research focuses on the study of biomarkers with the aim of answering questions such as the great clinical heterogeneity or the risk of relapse. However, neuroimaging studies show contradictory results and longitudinal studies are scarce. Therefore, a cohort of 30 patients with a first psychotic episode and an equivalent group of healthy controls were followed up for 8 to 10 years, both at the structural and functional neuroimaging level during the performance of a working memory task, the N-Back. At baseline, the FEP group showed a reduced global volume and a failure to deactivate frontal areas during the N-Back task. This failure was more pronounced in patients with a later diagnosis of schizophrenia. At the follow-up assessment the results show a failure of deactivation in the patient group that extends to posterior parietal regions. These regions form the so-called default mode network, a series of regions that are activated at rest, but deactivated during the performance of cognitively demanding tasks. These results point to a progressive dysfunction of the default mode network in first episodes psychosis underlying the progression of the disorder and provide a better understanding of the evolution of pathophysiological factors affecting FEP (AU)

A functional neuroimaging association study on the interplay between two schizophrenia genome-wide associated genes (CACNA1C and ZNF804A).

The CACNA1C and the ZNF804A genes are among the most relevant schizophrenia GWAS findings. Recent evidence shows that the interaction of these genes with the schizophrenia diagnosis modulates brain functional response to a verbal fluency task. To better understand how these genes might influence the risk for schizophrenia, we aimed to study the interplay between CACNA1C and ZNF804A on working memory brain functional correlates. The analyses included functional and behavioural N-back task data (obtained from an fMRI protocol) and CACNA1C-rs1006737 and ZNF804A-rs1344706 genotypes for 78 healthy subjects and 78 patients with schizophrenia (matched for age, sex and premorbid IQ). We tested the effects of the epistasis between these genes as well as of the three-way interaction (CACNA1C × ZNAF804A × diagnosis) on working memory-associated activity (N-back: 2-back vs 1-back). We detected a significant CACNA1C × ZNAF804A interaction on working memory functional response in regions comprising the ventral caudate medially and within the left hemisphere, the superior and inferior orbitofrontal gyrus, the superior temporal pole and the ventral-anterior insula. The individuals with the GWAS-identified risk genotypes (CACNA1C-AA/AG and ZNF804A-AA) displayed a reduced working memory modulation response. This genotypic combination was also associated with opposite brain activity patterns between patients and controls. While further research will help to comprehend the neurobiological mechanisms of this interaction, our data highlight the role of the epistasis between CACNA1C and ZNF804A in the functional mechanisms underlying the pathophysiology of schizophrenia.

Negative schizophrenic symptoms as prefrontal cortex dysfunction: Examination using a task measuring goal neglect.

BACKGROUND: The negative symptoms of schizophrenia have been proposed to reflect prefrontal cortex dysfunction. However, this proposal has not been consistently supported in functional imaging studies, which have also used executive tasks that may not capture key aspects of negative symptoms such as lack of volition. METHOD: Twenty-four DSM-5 schizophrenic patients with high negative symptoms (HNS), 25 with absent negative symptoms (ANS) and 30 healthy controls underwent fMRI during performance of the Computerized Multiple Elements Test (CMET), a task designed to measure poor organization of goal directed behaviour or 'goal neglect'. Negative symptoms were rated using the PANSS and the Clinical Assessment Interview for Negative Symptoms (CAINS). RESULTS: On whole brain analysis, the ANS patients showed no significant clusters of reduced activation compared to the healthy controls. In contrast, the HNS patients showed hypoactivation compared to the healthy controls in the left anterior frontal cortex, the right dorsolateral prefrontal cortex (DLPFC), the anterior insula bilaterally and the bilateral inferior parietal cortex. When compared to the ANS patients, the HNS patients showed reduced activation in the left anterior frontal cortex, the left DLPFC and the left inferior parietal cortex. After controlling for disorganization scores, differences remained in clusters in the left anterior frontal cortex and the bilateral inferior parietal cortex. CONCLUSIONS: This study provides evidence that reduced prefrontal activation, perhaps especially in the left anterior frontal cortex, is a brain functional correlate of negative symptoms in schizophrenia. The simultaneous finding of reduced inferior parietal cortex activation was unexpected, but could reflect this region's involvement in cognitive control, particularly the 'regulative' component of this.

The role of educational attainment and brain morphology in major depressive disorder: Findings from the ENIGMA major depressive disorder consortium.

Brain structural abnormalities and low educational attainment are consistently associated with major depressive disorder (MDD), yet there has been little research investigating the complex interaction of these factors. Brain structural alterations may represent a vulnerability or differential susceptibility marker, and in the context of low educational attainment, predict MDD. We tested this moderation model in a large multisite sample of 1958 adults with MDD and 2921 controls (aged 18 to 86) from the ENIGMA MDD working group. Using generalized linear mixed models and within-sample split-half replication, we tested whether brain structure interacted with educational attainment to predict MDD status. Analyses revealed that cortical thickness in a number of occipital, parietal, and frontal regions significantly interacted with education to predict MDD. For the majority of regions, models suggested a differential susceptibility effect, whereby thicker cortex was more likely to predict MDD in individuals with low educational attainment, but less likely to predict MDD in individuals with high educational attainment. Findings suggest that greater thickness of brain regions subserving visuomotor and social-cognitive functions confers susceptibility to MDD, dependent on level of educational attainment. Longitudinal work, however, is ultimately needed to establish whether cortical thickness represents a preexisting susceptibility marker. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Regularized Functional Connectivity in Schizophrenia.

Regularization may be used as an alternative to dimensionality reduction when the number of variables in a model is much larger than the number of available observations. In a recent study from our group regularized regression was employed to quantify brain functional connectivity in a sample of healthy controls using a brain parcellation and resting state fMRI images. Here regularization is applied to evaluate resting state connectivity abnormalities at the voxel level in a sample of patients with schizophrenia. Specifically, ridge regression is implemented with different degrees of regularization. Results are compared to those delivered by the weighted global brain connectivity method (GBC), which is based on averaged bivariate correlations and from the non-redundant connectivity method (NRC), a dimensionality reduction approach that applies supervised principal component regressions. Ridge regression is able to detect a larger set of abnormally connected regions than both GBC and NRC methods, including schizophrenia related connectivity reductions in fronto-medial, somatosensory and occipital structures. Due to its multivariate nature, the proposed method is much more sensitive to group abnormalities than the GBC, but it also outperforms the NRC, which is multivariate too. Voxel based regularized regression is a simple and sensitive alternative for quantifying brain functional connectivity.