Abstract Elucidating the neurobiological basis of neurodevelopmental and psychiatric conditions (NDPCs) remains challenging because brain alterations vary within diagnoses and overlap across them. Whether diverse alterations follow a systematic organization that may reflect shared vulnerabilities remains unknown. Here, we assembled 10,135 individuals with schizophrenia, autism, bipolar, obsessive-compulsive, generalized anxiety, and major depressive disorders, and 11,998 reference participants across six continents through the ENIGMA consortium. Using normative modeling, we quantified individual deviations in cortical thickness, surface area, and subcortical volumes relative to lifespan reference trajectories (5 to 80 years). We show that structural deviations converged along cortical axes reflecting connectome organization, maturation, and cytoarchitectonic diversity. These axes mirrored typical population variation, but their expression differed across diagnoses and partly scaled with symptom severity. Even rare and highly individualized extreme deviations followed this organization, concentrating in densely connected regions. Finally, brain structural deviations overlapped substantially across diagnoses, while differences between them increased toward the association cortex. Together, we provide large-scale evidence that structural deviations across NDPCs are systematically constrained by the brain’s intrinsic architecture. This shared organization provides a framework for reconciling individual variability with transdiagnostic similarities and motivates an integrative, systems-level understanding of mental health.

BACKGROUND:Specific cognitive difficulties are common in major depressive disorder, impacting functioning and quality of life. Yet, the timing of their emergence and longitudinal course remains poorly understood. This study aimed to characterise longitudinal cognitive functioning following recent onset depression and its association with changes in depressive symptoms. METHODS:Longitudinal data from the PRONIA (Personalised Prognostic Tools for Early Psychosis Management) cohort recruited from ten European sites were used to evaluate trajectory differences between Healthy Controls (HC) and individuals experiencing recent onset depression (ROD). Linear mixed effect models were used with group-by-time interaction term for trajectory differences between baseline and nine-month follow-up, and the associations between changes in depression symptoms and cognitive functioning among ROD. RESULTS:The sample comprised 420 participants (ROD, N = 151; HC, N = 269) aged 15-40 years (M = 25.4, SD = 6.1; 55% female). Two distinct group-level cognitive trajectories were observed. First, a similar trajectory (i.e., no difference) to HC in visual memory, attention span, verbal learning and memory, visuospatial working memory, emotion recognition, and processing speed. A stable deficit trajectory was observed in mental flexibility, auditory verbal working memory, phonetic and semantic verbal fluency among the ROD group. Analysis within ROD group suggested that these outcomes were unrelated to reductions in depressive symptoms. Changes in visual memory, visuospatial working memory, sustained attention, and processing speed were associated with changes in depressive symptoms, despite being unrelated to baseline variations in depressive symptoms, possibly suggesting a sensitivity to state effects of illness, regardless of baseline severity. CONCLUSIONS:Specific cognitive difficulties are already evident at the first depressive episode and may endure in the short-medium term, irrespective of depressive course. Tailored treatment addressing cognition should be provided early to promote cognitive health and functional recovery.

Resumo Esta primeira parte da revisão apresenta quase 60 anos de experiência de nosso laboratório na padronização de testes autonômicos cardiovasculares em indivíduos saudáveis. A ampla gama de testes inclui bloqueio farmacológico dos sistemas simpático e parassimpático, avaliação da sensibilidade barorreflexa por meio de episódios transitórios de hipertensão e hipotensão, manobra de Valsalva, teste de inclinação ortostática, exercícios isométricos e dinâmicos, imersão facial em água fria, arritmia sinusal respiratória, análise da variabilidade da frequência cardíaca no domínio da frequência e exames de imagem com 123I-metaiodobenzilguanidina. A função autonômica foi avaliada com base nas respostas aos testes em condições basais em indivíduos saudáveis. A análise também aborda adaptações fisiológicas ao treinamento de resistência e ao envelhecimento, fornecendo uma estrutura de referência para a identificação de disfunções autonômicas envolvendo componentes parassimpáticos e adrenérgicos em pacientes com diversas condições fisiopatológicas, conforme discutido na segunda parte desta revisão.

Resumo Por meio da comparação das respostas de voluntários normais, a avaliação da função autonômica em condições clínicas anormais se focou na detecção de disautonomia envolvendo os sistemas parassimpático e adrenérgico em pacientes com cardiopatia chagásica, pós-cirurgia cardíaca, insuficiência cardíaca crônica, prolapso da valva mitral e hipertireoidismo. Em particular, o comprometimento autonômico observado em pacientes com doença de Chagas envolveu predominantemente o controle parassimpático da frequência cardíaca ao nível do nó sinusal e a inervação adrenérgica ao nível ventricular do miocárdio. Os distúrbios autonômicos observados em pacientes com cardiomiopatia chagásica só recentemente foram explorados em termos de sua relevância prognóstica, e suas potenciais implicações clínicas para fins terapêuticos ainda precisam ser investigadas. Ao longo das últimas quase sete décadas, nosso laboratório acumulou expertise significativa utilizando diversos testes descritos acima para avaliar o controle autonômico da frequência cardíaca, agora com foco em diversas condições clínicas fisiopatológicas. O efeito do treinamento físico de resistência e do envelhecimento foi focado principalmente em estudos com voluntários normais, cujas respostas basais serviram como controles a serem comparados durante testes empregados em indivíduos com algumas condições clínicas mórbidas. De longe, a fisiopatologia da cardiopatia chagásica envolvendo o sistema nervoso autônomo foi o assunto mais predominantemente estudado em nosso laboratório, desde os primeiros estudos na década de 1960 até os estudos tardios recentemente publicados em periódicos internacionais (Figura Central). Outras condições patológicas focadas em nossos estudos foram prolapso da valva mitral, insuficiência cardíaca, pós-cirurgia cardíaca e hipertireoidismo.

Substance use disorders (SUD) are chronic conditions with devastating effects on brain health, functioning, and survival. In this study, we compared brain morphometry of 2,782 individuals with SUD to 1,951 controls and assessed the topographic overlap of these differences with brain connectivity and receptor architecture. Across SUD, we identified a morphometric signature involving frontal, parietal, temporal and limbic systems that overlapped with cortical hub regions and harbored cortical and subcortical disease epicenters. Findings were highly consistent across six substances and numerous robustness and generalizability analyses. Transdiagnostic comparisons showed high spatial overlap of SUD epicenters with those of schizophrenia and bipolar disorder, suggesting shared network-constrained cortical differences. Finally, multivariate mapping revealed that SUD brain differences aligned with two neurotransmitter axes contrasting cannabinoid-opioid and dopaminergic systems. These findings indicate that addiction-related brain differences are shaped by connectome and neurotransmitter architecture, positioning brain network and neurochemical organization as key principles of SUD-related brain alterations.

The Clinical High Risk (CHR) state for psychosis is consistently associated with widespread cortical thinning. However, the underlying mechanisms driving this neuroanatomical phenotype remain poorly understood. Here, we integrated the ENIGMA CHR Working Group's large pooled dataset (N = 1782 CHR, N = 1333 healthy controls) with an open-source PET molecular atlas to identify, for the first time, potential neurochemical drivers of cortical thinning associated with psychosis risk, transition, and its core symptoms. Using multilinear model analysis, we show that local chemoarchitecture significantly explains CT differences associated with CHR case-control status, the severity of negative symptoms, and future psychosis transition after excluding medication confounds. PET-based maps of dopamine, GABA, glutamate, serotonin, and norepinephrine consistently emerged as the strongest predictors of lower CT in CHR and psychosis transition (total dominance range: 62-69% and 58-87%, respectively), with contributions of monoamine systems being especially sensitive to medication exposure (8-23% change in dominance range). Negative symptom-associated cortical thinning was best explained by PET-based maps of dopamine, histamine, serotonin and opioid systems (total dominance range: 60-81%), with contributions of histamine being sensitive to medication exposure (9-19% change in dominance range). Combined, these results uniquely identify specific neurochemical systems - particularly monoaminergic, glutamatergic, and GABAergic pathways - as key molecular mechanisms associated with cortical thinning in people at high risk of developing psychosis.

Abstract Background Psychosis has been conceptualised as a continuum extending from healthy individuals with psychotic-like experiences to clinical populations with schizophrenia. It is unclear which biological mechanisms found in chronic schizophrenia extend across the psychosis continuum to healthy individuals with high positive schizotypy (HS). In this study, we used computational modeling to test whether changes in effective connectivity and excitation/inhibition (E/I) balance reported in schizophrenia are also found in HS. Methods A total of 2425 individuals from the general population were screened for HS. A subset (N=141) was invited for in-depth phenotyping. Resting-state functional magnetic resonance imaging (rsfMRI) and proton magnetic resonance spectroscopy ( 1 H-MRS) were recorded in n=69 HS individuals and n=72 group-matched controls with low schizotypy (LS). We used dynamic causal modeling to estimate effective connectivity between bilateral primary auditory cortex (A1), superior temporal gyrus (STG), and inferior frontal gyrus (IFG). Results Bilateral backward connectivity from IFG to STG was significantly reduced in HS compared to LS. Widespread cortical disinhibition in the auditory cortex-IFG network correlated with more severe positive schizotypy scores and impulsive nonconformity. Reduced excitability in the same network was correlated with stronger cognitive disorganisation. Conclusions Our results favour a psychosis-continuum hypothesis, suggesting that reduced top-down drive from frontal cortex and compensatory allostatic upregulation of cortical excitability, as observed in chronic schizophrenia, also extend to groups with sub-clinical psychotic symptoms. Frontal cortex dysfunction may serve as a biologically interpretable biomarker of psychosis risk and a target for preventative interventions.

The clinical and biological heterogeneity of major depressive disorder (MDD) may reflect the aggregation of different conditions with distinct pathologies under a single diagnostic label. Neuroanatomical heterogeneity in MDD was examined using a harmonized, age- and sex-matched sample from the ENIGMA MDD consortium (N = 5146; age range: 9-82 years; 64% female). Analyses of global neurostrucutral variability revealed greater cortical thickness heterogeneity in MDD compared with healthy controls (Cohen's d = -0.26). Regionally, increased variability in cortical thickness was most prominent in the cingulate (+6.1 to +6.6% more variation in MDD) and insular (+5.8%) cortices, as well as in the frontal (+5.7 to +6.8%) and temporal (+6.1 to +6.8%) lobes. Heterogeneity in cortical thickness was more pronounced among patients using antidepressant medication (Cohen's d = -0.39). Patient-specific analyses further showed that individuals with markedly increased cortical thickness variability (<5th percentile relative to the normative range) exhibited greater depressive symptom severity than those within the normative range (5th-95th percentile; Cohen's d = 0.19-0.36). Overall, the results indicate that neuroanatomical heterogeneity in MDD is primarily expressed in cortical thickness, offering refined insights into the neurobiological complexity of structural alterations associated with depression. These findings could guide future stratification efforts examining whether regionally confined changes in cortical thickness within areas of pronounced variability reflect clinically meaningful patient subgroups.

Exergame-based training is emerging as the most effective exercise modality for improving cognition, yet its neural correlates remain largely unexplored. This study explored gray matter (GM) and white matter (WM) changes following the addition of ‘Brain-IT’ training to usual care in mild neurocognitive disorder (mNCD) and their associations with cognitive performance changes. We included 41 participants with mNCD, randomized to either the intervention (‘Brain-IT’ training + usual care) or the control (usual care only) group. ‘Brain-IT’ is a holistic, individually tailored “exercise as medicine” program for secondary mNCD prevention delivered through serious exergames. T1-weighted and diffusion tensor imaging data were analyzed via standard neuroimaging analysis pipelines (FreeSurfer, tract-based spatial statistics) to assess GM/WM volumes in predefined regions of interest and WM integrity at the voxel-to-voxel level. Intervention-related changes were explored via analyses of covariance, focusing on effect size estimates. One-sided bivariate correlation analyses explored associations between changes in brain structure and cognitive performance. Complete datasets from 30 study participants (72.0 ± 8.6 years; 27 https://clinicaltrials.gov/ct2/show/NCT05387057 .

This first part of the review presents nearly 60 years of experience from our laboratory in standardizing cardiovascular autonomic tests in healthy individuals. The wide range of tests includes pharmacological blockade of both the sympathetic and parasympathetic divisions, baroreflex sensitivity assessment through transient hypertension and hypotension, the Valsalva maneuver, head-up tilt testing, isometric and dynamic exercise, facial immersion in cold water, respiratory sinus arrhythmia, heart rate variability analysis in the frequency domain, and imaging with 123I-metaiodobenzylguanidine. Autonomic function was evaluated based on test responses under baseline conditions in healthy individuals. The analysis also covers physiological adaptations to endurance training and aging, providing a reference framework for identifying autonomic dysfunction involving both parasympathetic and adrenergic components in patients with various pathophysiological conditions, as discussed in the second part of this review.

RATIONALE:Ketamine and psilocybin have demonstrated therapeutic potential for mental disorders, including major depressive disorder, yet they engage distinct mechanisms of action. Ketamine, a dissociative hallucinogen, acts by blocking N-methyl-D-aspartate receptors (NMDAR), whereas psilocybin primarily targets serotonin receptors. These divergent mechanisms are reflected in their electrophysiological biomarkers. OBJECTIVES:This study aimed to investigate the divergent effects of ketamine and psilocybin on different elements of the EEG frequency spectrum, focusing on aperiodic components as an indicator of excitation-inhibition balance in the neural circuitry. METHODS:We re-analyzed a previously acquired EEG dataset from healthy volunteers using a placebo-controlled within-subject crossover design (Schmidt et al., Neuropsychopharmacology 37(4):865-875 2012). Participants received either placebo or S-ketamine (N=19) and placebo or psilocybin (N=16) during an auditory roving paradigm. Spectral parameters including periodic and aperiodic were extracted and partial least squares analysis was employed. RESULTS:Ketamine significantly altered the offset and slope of the EEG spectrum, suggesting a disruption in excitatory-inhibitory balance. While both drugs commonly reduced alpha power in similar regions, beta band activity was decreased exclusively under ketamine. CONCLUSIONS:These findings highlight ketamine's unique effects on aperiodic EEG components, reinforcing its role as a neurochemical model of prodromal psychosis. Psilocybin's effects appear distinct, emphasizing its targeted influence on oscillatory activity.

Background:The hippocampus plays a critical role in psychosis, with reduced volume observed across the psychosis continuum. These structural changes are associated with cognitive deficits, symptom severity, and increased risk of psychosis progression. Elevated hippocampal perfusion and glutamate/GABA (gamma-aminobutyric acid) imbalance further suggest metabolic dysregulation as a key mechanism. Gut microbiota composition can influence hippocampal metabolism, but their interplay remains to be explored. Methods:In this cross-sectional study, we recruited 142 healthy participants from the general population, yielding 69 individuals with high schizotypy (HS) and 72 individuals with low schizotypy. All underwent clinical and cognitive testing, multimodal neuroimaging, and gut microbiota analysis via 16S ribosomal RNA gene sequencing. Hippocampal subfield volumes (structural magnetic resonance imaging), perfusion (arterial spin labeling) and glutamate/GABA levels (proton magnetic resonance spectroscopy), and microbial taxa (abundance, diversity, enterotypes) were assessed. Results:Group comparisons of cognition, multimodal neuroimaging, and gut microbiome composition did not reveal significant differences after correction for multiple comparisons. Within the HS group, glutamate (r = 0.38, p = .003) and GABA (r = -0.36, p = .003) ratios were linked to social withdrawal. Across the entire sample, left hippocampal subfield volumes and glutamate/GABA levels differed significantly between predominant gut microbial enterotypes. Conclusions:Our results suggest a potential relationship between aberrant gut microbial composition and hippocampal alterations in people with positive schizotypy from the general population. Our findings inform future large-scale research that further explores specific mechanisms of gut microbiome-hippocampus interactions in psychosis and the potential of tailored microbial interventions targeting hippocampal-mediated symptoms.

Ketamine and psilocybin show potential as therapies for various mental illnesses, including major depressive disorder. However, further investigation into their neural mechanisms is required to understand their effects on the brain. By combining computational modelling with electroencephalography (EEG), we examine the effects of ketamine and psilocybin on hierarchical sensory pwPE learning in the context of the auditory mismatch negativity, an event-related potential consistently shown to be reduced under psychotomimetic interventions. We employed a Bayesian framework and re-analyzed a previously acquired EEG dataset (Schmidt et al., 2012) by modelling single-trial EEG data using the Hierarchical Gaussian Filter. Using a placebo-controlled within-subject crossover design, healthy subjects were administered either S-ketamine or psilocybin during an auditory roving paradigm of pure sinusoidal tones. Our findings elucidate distinct neural impacts of ketamine and psilocybin on sensory learning: ketamine led to a larger reduction in the effect of sensory precision compared to placebo from 207 to 316 ms peaking at 277 ms in the frontal central channels, while psilocybin showed no significant effect. Both drugs reduced the expression of belief precision between 160 to 184 ms, peaking at 172 ms. For higher-level volatility pwPEs, ketamine reduced the expression at 312 ms while psilocybin had a null effect. For perception of elementary imagery, ketamine had a greater effect than psilocybin on sensory and volatility precision, while psilocybin had a greater effect on volatility pwPEs. Our findings suggest hallucinogens have distinct effects on sensory learning that could inform tailored therapies for major depression. ### Competing Interest Statement The authors have declared no competing interest. Schweizerischer Nationalfonds zur FM-CM-6rderung der Wissenschaftlichen Forschung (Swiss National Science Foundation) - P1BSP3-200054 [Hauke], P1BSP3-200054 Schweizerischer Nationalfonds zur FM-CM-6rderung der Wissenschaftlichen Forschung (Swiss National Science Foundation), PZ00P3-167952 Centre for Addiction and Mental Health and Mental Health, CAMH Discovery Fund Swiss Neuromatrix Foundation - Stiftung fM-CM-<r Bewusstseinsforschung

IntroductionChronic Chagas cardiomyopathy (CCC) is associated with a high incidence of cardiovascular events. Global longitudinal strain (GLS) is useful in predicting adverse cardiovascular outcomes in several cardiomyopathies. However, its prognostic value in CCC is not well established.MethodsThis study was a retrospective echocardiography analysis with prospective follow-up of CCC subjects. GLS was defined as the average of three apical peak longitudinal strain measurements of the LV using vendor-independent software. GLS groups were defined according to tertiles: (1) GLS ≤ -18.4%, (2) GLS > -18.4% and <-13.8%, and (3) GLS ≥ -13.8%. The primary outcome was a composite of death, hospitalization, sustained ventricular tachycardia (SVT), new heart failure, any systemic embolism, hospitalization, reverted cardiac arrest and cardiac heart transplantation.ResultsGLS was obtained in 77 subjects, 50.6% were males and the mean age was 56 ± 15 years. There were 6.49% losses of follow-up and the mean LVEF was 51 ± 14%. After a follow-up period of 35 ± 19 months (2.9 y), 33 subjects reached the composite outcome. Death and hospitalization were the most frequent outcomes (n = 9), followed by new heart failure (n = 6), embolism (n = 6), and SVT (n = 3). The GLS ≥ -13.8% was associated with a worse prognosis when compared with the other tertile GLS groups (log rank-p-value = 0.001 for both comparisons). On the multivariate Cox proportional hazard model, adjusting for age, gender, and LVEF, GLS was an independent predictor of outcomes with an HR of 1.20 (CI = 1.05-1.38;p = 0.008).ConclusionLeft ventricle GLS is an independent predictor of cardiovascular outcomes in patients with CCC. GLS may be an important tool for Chagas disease risk stratification, independent of LVEF.

BACKGROUND:Complementary diagnostic examinations have replaced the importance of Physical Examination (PE) in Clinical Decision-making (CDM). 1. Medical clinical practice has lost confidence in Physical Examination (PE) compared to complementary diagnostic examinations (CE). More importance has been deposited on Echocardiography (ECHO) in cardiac valvular dysfunction scenarios. No studies have measured the impact of cardiac PE in Clinical Decision-making (CDM). 2. Discrepancies between PE findings and ECHO reports are common and may impact CDM in different forms. 3. PE has proven essential to enhancing diagnosis confidence and grading of dysfunction in cardiac valvular dysfunctions. ECHO still plays a significant importance in CDM, even when discordant from physical examination. 4. The number of solicitations of an invasive test such as Cardiac Catheterization (CATE) is influenced by PE. The number of orderings was higher when volunteers did not perform a PE. OBJECTIVE:To evaluate the impact of cardiovascular PE in scenarios of cardiac valvular diseases. METHODS:An interventional study with volunteers' patients having or not having the opportunity to perform PE in scenarios of valvopathies. The PE was simulated in a high-fidelity cardiopulmonary simulator. Volunteers received questions about CDM before and after receiving an ECHO Concordant or ECHO Discordant report. Cohen´s kappa coefficient and square contingency tables compared diagnostic accuracy. ANOVA tests compared the number of requested tests; the significance level was set as p < 0.05. RESULTS:Sixty volunteers performed 239 clinical observations in 4 valvular dysfunctions. The diagnostic accuracy of valvular dysfunction was good (kappa = 0.935, p < 0.001). After receiving ECHO reports, the accuracy was worse without PE (p = 0.0047). The confidence level in diagnosis was 28.18% higher when PE was performed (p < 0.01). However, after receiving ECHO reports, diagnostic confidence levels were only 4% higher in the group with PE (p = 0.03). There were significantly more CATE requests when PE was not performed (p = 0.0326). The indication of valvular intervention was not related to having or not having the opportunity to perform PE (79 with PE vs 78 without PE, p = 0.0607), but was influenced by ECHO Concordant vs ECHO Discordant reports (p < 0.001). CONCLUSIONS:Performing PE enhanced diagnosis confidence in valvulopathy scenarios and correct dysfunction grading. Treatment decisions were more based on ECHO reports than on PE when they were discordant, and requests for CATE increased when volunteers had no chance to perform PE.

Brain network architecture is anticipated to influence future grey matter loss in individuals at Clinical High Risk (CHR) for psychosis. However, existing studies on grey matter structural network properties in CHR are scarce and constrained by small sample sizes. Here, we examined network topology differences comparing a) CHR versus healthy controls (HC); b) CHR who transitioned to psychosis (CHR-T) versus those who did not (CHR-NT); and c) different subsyndromes. We included structural scans from 1842 CHR individuals and 1417 HC individuals from 31 sites within the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium. At the global level, CHR individuals exhibited lower structural covariance (q < 0.001; Cohen’s d = 0.164) and less optimal structural network configuration than HC (lower global efficiency and clustering coefficient, d = 0.100,0.087, qs <= 0.027). Though no global difference between CHR-T and CHR-NT, network distinctiveness of the frontal and temporal surface area networks was higher in CHR-T than CHR-NT (d = 0.223,0.237) and HC (d = 0.208,0.219) (qs < 0.001). Network distinctiveness of the frontal cortical thickness network was lower in CHR-T (d = 0.218, q < 0.001) than CHR-NT and HC (d = 0.165, q < 0.001). Importantly, higher network distinctiveness was associated with worse positive symptoms in CHR-NT (frontal surface area, q = 0.008, R2 = 0.013) and at trend with worse negative symptoms in CHR-T (frontal thickness, q = 0.063, R2 = 0.049). Further, the brief intermittent psychotic syndrome subgroup showed more severe network alterations. Together, brain structural networks inform symptoms and the risk of transition to psychosis in CHR individuals.