Biology subjects

Pozzi, E.

Publications and source records attributed to Pozzi, E..

5 recordsLinked to original sources

bioRxiv2025

Image-Based Meta- and Mega-Analysis (IBMMA): A Unified Framework for Large-Scale, Multi-Site, Neuroimaging Data Analysis

The increasing scale and complexity of neuroimaging datasets aggregated from multiple study sites present substantial analytic challenges, as existing statistical analysis tools struggle to handle missing voxel-data, suffer from limited computational speed and inefficient memory allocation, and are restricted in the types of statistical designs they are able to model. We introduce Image-Based Meta- & Mega-Analysis (IBMMA), a novel software package implemented in R and Python that provides a unified framework for analyzing diverse neuroimaging features, efficiently handles large-scale datasets through parallel processing, offers flexible statistical modeling options, and properly manages missing voxel-data commonly encountered in multi-site studies. IBMMA produced stronger effect sizes and revealed findings in brain regions that traditional software overlooked due to missing voxel-data resulting in gaps in brain coverage. IBMMA has the potential to accelerate discoveries in neuroscience and enhance the clinical utility of neuroimaging findings.

neuroscience↗

bioRxiv2025

Dissecting heterogeneity in cortical thickness abnormalities in major depressive disorder: a large-scale ENIGMA MDD normative modelling study

ImportanceMajor depressive disorder (MDD) is highly heterogeneous, with marked individual differences in clinical presentation and neurobiology, which may obscure identification of structural brain abnormalities in MDD. To explore this, we used normative modeling to index regional patterns of variability in cortical thickness (CT) across individual patients. ObjectiveTo use normative modeling in a large dataset from the ENIGMA MDD consortium to obtain individualised CT deviations from the norm (relative to age, sex and site) and examine the relationship between these deviations and clinical characteristics. Design, setting, and participantsA normative model adjusting for age, sex and site effects was trained on 35 CT measures from FreeSurfer parcellation of 3,181 healthy controls (HC) from 34 sites (40 scanners). Individualised z-score deviations from this norm for each CT measure were calculated for a test set of 2,119 HC and 3,645 individuals with MDD. For each individual, each CT z-score was classified as being within the normal range (95% of individuals) or within the extreme range (2.5% of individuals with the thinnest or thickest cortices). Main outcome measuresZ-score deviations of CT measures of MDD individuals as estimated from a normative model based on HC. ResultsZ-score distributions of CT measures were largely overlapping between MDD and HC (minimum 92%, range 92-98%), with overall thinner cortices in MDD. 34.5% of MDD individuals, and 30% of HC individuals, showed an extreme deviation in at least one region, and these deviations were widely distributed across the brain. There was high heterogeneity in the spatial location of CT deviations across individuals with MDD: a maximum of 12% of individuals with MDD showed an extreme deviation in the same location. Extreme negative CT deviations were associated with having an earlier onset of depression and more severe depressive symptoms in the MDD group, and with higher BMI across MDD and HC groups. Extreme positive deviations were associated with being remitted, of not taking antidepressants and less severe symptoms. Conclusions and relevanceOur study illustrates a large heterogeneity in the spatial location of CT abnormalities across patients with MDD and confirms a substantial overlap of CT measures with HC. We also demonstrate that individualised extreme deviations can identify protective factors and individuals with a more severe clinical picture. Key points QuestionCan z-scores derived from normative modelling shed light on the heterogeneous group-level findings of cortical thickness abnormalities in major depression and what characterises individuals at the extreme ends of cortical thickness abnormalities? FindingWe confirmed a large overlap in z-score distributions between depressed individuals and healthy controls and a heterogeneous spatial distribution of extreme z-deviations across brain regions across individual patients. Lower z-scores for cortical thickness were related to more severe clinical characteristics. MeaningOur findings confirm the heterogeneity in individual variation in the location and extent of CT abnormalities across patients with MDD and stress the importance of individualised predictions when examining cortical thickness abnormalities.

neuroscience↗

bioRxiv2021

ENIGMA HALFpipe: Interactive, reproducible, and efficient analysis for resting-state and task-based fMRI data

The reproducibility crisis in neuroimaging has led to an increased demand for standardized data processing workflows. Within the ENIGMA consortium, we developed HALFpipe (Harmonized AnaLysis of Functional MRI pipeline), an open-source, containerized, user-friendly tool that facilitates reproducible analysis of task-based and resting-state fMRI data through uniform application of preprocessing, quality assessment, single-subject feature extraction, and group-level statistics. It provides state-of-the-art preprocessing using fMRIPrep without the requirement for input data in Brain Imaging Data Structure (BIDS) format. HALFpipe extends the functionality of fMRIPrep with additional preprocessing steps, which include spatial smoothing, grand mean scaling, temporal filtering, and confound regression. HALFpipe generates an interactive quality assessment (QA) webpage to assess the quality of key preprocessing outputs and raw data in general. HALFpipe features myriad post-processing functions at the individual subject level, including calculation of task-based activation, seed-based connectivity, network-template (or dual) regression, atlas-based functional connectivity matrices, regional homogeneity (ReHo), and fractional amplitude of low frequency fluctuations (fALFF), offering support to evaluate a combinatorial number of features or preprocessing settings in one run. Finally, flexible factorial models can be defined for mixed-effects regression analysis at the group level, including multiple comparison correction. Here, we introduce the theoretical framework in which HALFpipe was developed, and present an overview of the main functions of the pipeline. HALFpipe offers the scientific community a major advance toward addressing the reproducibility crisis in neuroimaging, providing a workflow that encompasses preprocessing, post-processing, and QA of fMRI data, while broadening core principles of data analysis for producing reproducible results. Instructions and code can be found at https://github.com/HALFpipe/HALFpipe.

neuroscience↗

bioRxiv2019

Subcortical Shape Alterations in Major Depressive Disorder: Findings from the ENIGMA Major Depressive Disorder Working Group

Alterations in regional subcortical brain volumes have been widely investigated as part of the efforts of an international consortium, ENIGMA, to determine reliable structural brain signatures for Major Depressive Disorder (MDD). Given that subcortical structures are comprised of distinct subfields, we sought to build significantly from prior work to precisely map localized MDD-related differences in subcortical regions using shape analysis. In this meta-analysis of subcortical shape from the ENIGMA-MDD working group, we compared 1,781 patients with MDD and 2,953 healthy controls (CTL) on individual measures of shape metrics (thickness and surface area) on the surface of seven bilateral subcortical structures: nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus. Harmonized data processing and statistical analyses were conducted locally at each site, and findings were aggregated by meta-analysis. Relative to CTL, patients with MDD had lower surface area in the subiculum of the hippocampus, the basolateral amygdala, and the nucleus accumbens shell. Relative to CTL, patients with adolescent-onset MDD ([≤] 21 years) had lower thickness and surface area of the subiculum of the hippocampus and the basolateral amygdala. Relative to first-episode MDD, recurrent MDD patients had lower thickness and surface area in the CA1 of the hippocampus and the basolateral amygdala. Our results suggest that previously reported MDD-associated volumetric differences may be localized to specific subfields of these structures that have been shown to be sensitive to the effects of stress, with important implications for mapping treatments to patients based on specific neural targets and key clinical features.

neuroscience↗

bioRxiv2018

Mice harboring a SCA28 patient mutation in AFG3L2 develop late-onset ataxia associated with enhanced mitochondrial proteotoxicity.

Spinocerebellar ataxia 28 is an autosomal dominant neurodegenerative disorder caused by missense mutations affecting the proteolytic domain of AFG3L2, a major component of the mitochondrial m-AAA protease. However, little is known of the underlying pathogenetic mechanisms or how to treat patients with SCA28. Currently available Afg3l2 mutant mice harbour deletions that lead to severe, early-onset neurological phenotypes that do not faithfully reproduce the late-onset and slowly progressing SCA28 phenotype. Here we describe production and detailed analysis of a new knock-in murine model harbouring an Afg3l2 allele carrying the p.Met665Arg patient-derived mutation. Heterozygous mutant mice developed normally but signs of ataxia were detectable by beam test at 18 months. Cerebellar pathology was negative; electrophysiological analysis showed increased spontaneous firing in Purkinje cells from heterozygous mutants with respect to wild-type controls, although not statistically significant. As homozygous mutants died perinatally with evidence of cardiac atrophy, for each genotype we generated mouse embryonic fibroblasts (MEFs) to investigate mitochondrial function. MEFs from mutant mice showed altered mitochondrial bioenergetics, with decreased basal oxygen consumption rate, ATP synthesis and mitochondrial membrane potential. Mitochondrial network formation and morphology was also altered, in line with greatly reduced expression of Opa1 fusogenic protein L-isoforms. The mitochondrial alterations observed in MEFs were also detected in cerebella of 18-month-old heterozygous mutants, suggesting they may be a hallmark of disease. Pharmacological inhibition of de novo mitochondrial protein translation with chloramphenicol caused reversal of mitochondrial morphology in homozygous mutant MEFs, supporting the relevance of mitochondrial proteotoxicity for SCA28 pathogenesis and therapy development.

genetics↗