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Ingrid Agartz

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15 papers
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15

AIIM Journal 2026 Journal Article

An explainable three dimensional framework to uncover learning patterns: A unified look in variable sulci recognition

  • Michail Mamalakis
  • Héloïse de Vareilles
  • Atheer Al-Manea
  • Samantha C. Mitchell
  • Ingrid Agartz
  • Lynn Egeland Mørch-Johnsen
  • Jane Garrison
  • Jon Simons

The significant features identified in a representative subset of the dataset during the learning process of an artificial intelligence model are referred to as a 'global' explanation. Three-dimensional (3D) global explanations are crucial in neuroimaging, where a complex representational space demands more than basic two-dimensional interpretations. However, current studies in the literature often lack the accuracy, comprehensibility, and 3D global explanations needed in neuroimaging and beyond. To address this gap, we developed an explainable artificial intelligence (XAI) 3D-Framework capable of providing accurate, low-complexity global explanations. We evaluated the framework using various 3D deep learning models trained on a well-annotated cohort of 596 structural MRIs. The binary classification task focused on detecting the presence or absence of the paracingulate sulcus (PCS), a highly variable brain structure associated with psychosis. Our framework integrates statistical features (Shape) and XAI methods (GradCam and SHAP) with dimensionality reduction, ensuring that explanations reflect both model learning and cohort-specific variability. By combining Shape, GradCam, and SHAP, our framework reduces inter-method variability, enhancing the faithfulness and reliability of global explanations. These robust explanations facilitated the identification of critical sub-regions, including the posterior temporal and internal parietal regions, as well as the cingulate region and thalamus, suggesting potential genetic or developmental influences. For the first time, this XAI 3D-Framework leverages global explanations to uncover the broader developmental context of specific cortical features. This approach advances the fields of deep learning and neuroscience by offering insights into normative brain development and atypical trajectories linked to mental illness, paving the way for more reliable and interpretable AI applications in neuroimaging.

YNICL Journal 2022 Journal Article

Aberrant default mode connectivity in adolescents with early-onset psychosis: A resting state fMRI study

  • Eva Hilland
  • Cecilie Johannessen
  • Rune Jonassen
  • Dag Alnæs
  • Kjetil N. Jørgensen
  • Claudia Barth
  • Dimitrios Andreou
  • Stener Nerland

Abnormal default mode network (DMN) connectivity has been found in schizophrenia and other psychotic disorders. However, there are limited studies on early onset psychosis (EOP), and their results show lack of agreement. Here, we investigated within-network DMN connectivity in EOP compared to healthy controls (HC), and its relationship to clinical characteristics. A sample of 68 adolescent patients with EOP (mean age 16.53 ± 1.12 [SD] years, females 66%) and 95 HC (mean age 16.24 ± 1.50 [SD], females 60%) from two Scandinavian cohorts underwent resting state functional magnetic resonance imaging (rsfMRI). A group independent component analysis (ICA) was performed to identify the DMN across all participants. Dual regression was used to estimate spatial maps reflecting each participant's DMN network, which were compared between EOP and HC using voxel-wise general linear models and permutation-based analyses. Subgroup analyses were performed within the patient group, to explore associations between diagnostic subcategories and current use of psychotropic medication in relation to connectivity strength. The analysis revealed significantly reduced DMN connectivity in EOP compared to HC in the posterior cingulate cortex, precuneus, fusiform cortex, putamen, pallidum, amygdala, and insula. The subgroup analysis in the EOP group showed strongest deviations for affective psychosis, followed by other psychotic disorders and schizophrenia. There was no association between DMN connectivity strength and the current use of psychotropic medication. In conclusion, the findings demonstrate weaker DMN connectivity in adolescent patients with EOP compared to healthy peers, and differential effects across diagnostic subcategories, which may inform our understanding of underlying disease mechanisms in EOP.

YNIMG Journal 2022 Journal Article

Deep neural networks learn general and clinically relevant representations of the ageing brain

  • Esten H. Leonardsen
  • Han Peng
  • Tobias Kaufmann
  • Ingrid Agartz
  • Ole A. Andreassen
  • Elisabeth Gulowsen Celius
  • Thomas Espeseth
  • Hanne F. Harbo

The discrepancy between chronological age and the apparent age of the brain based on neuroimaging data — the brain age delta — has emerged as a reliable marker of brain health. With an increasing wealth of data, approaches to tackle heterogeneity in data acquisition are vital. To this end, we compiled raw structural magnetic resonance images into one of the largest and most diverse datasets assembled (n=53542), and trained convolutional neural networks (CNNs) to predict age. We achieved state-of-the-art performance on unseen data from unknown scanners (n=2553), and showed that higher brain age delta is associated with diabetes, alcohol intake and smoking. Using transfer learning, the intermediate representations learned by our model complemented and partly outperformed brain age delta in predicting common brain disorders. Our work shows we can achieve generalizable and biologically plausible brain age predictions using CNNs trained on heterogeneous datasets, and transfer them to clinical use cases.

YNICL Journal 2022 Journal Article

The age of violence: Mapping brain age in psychosis and psychopathy

  • Natalia Tesli
  • Christina Bell
  • Gabriela Hjell
  • Thomas Fischer-Vieler
  • Ivan I Maximov
  • Genevieve Richard
  • Martin Tesli
  • Ingrid Melle

Young chronological age is one of the strongest predictors for antisocial behaviour in the general population and for violent offending in individuals with psychotic disorders. An individual's age can be predicted with high accuracy using neuroimaging and machine-learning. The deviation between predicted and chronological age, i.e., brain age gap (BAG) has been suggested to reflect brain health, likely relating partly to neurodevelopmental and aging-related processes and specific disease mechanisms. Higher BAG has been demonstrated in patients with psychotic disorders. However, little is known about the brain-age in violent offenders with psychosis and the possible associations with psychopathy traits. We estimated brain-age in 782 male individuals using T1-weighted MRI scans. Three machine learning models (random forest, extreme gradient boosting with and without hyper parameter tuning) were first trained and tested on healthy controls (HC, n = 586). The obtained BAGs were compared between HC and age matched violent offenders with psychosis (PSY-V, n = 38), violent offenders without psychosis (NPV, n = 20) and non-violent psychosis patients (PSY-NV, n = 138). We ran additional comparisons between BAG of PSY-V and PSY-NV and associations with Positive and Negative Syndrome Scale (PANSS) total score as a measure of psychosis symptoms. Psychopathy traits in the violence groups were assessed with Psychopathy Checklist-revised (PCL-R) and investigated for associations with BAG. We found significantly higher BAG in PSY-V compared with HC (4.9 years, Cohen'sd = 0.87) and in PSY-NV compared with HC (2.7 years, d = 0.41). Total PCL-R scores were negatively associated with BAG in the violence groups (d = 1.17, p < 0.05). Additionally, there was a positive association between psychosis symptoms and BAG in the psychosis groups (d = 1.12, p < 0.05). While the significant BAG differences related to psychosis and not violence suggest larger BAG for psychosis, the negative associations between BAG and psychopathy suggest a complex interplay with psychopathy traits. This proof-of-concept application of brain age prediction in severe mental disorders with a history of violence and psychopathy traits should be tested and replicated in larger samples.

YNIMG Journal 2021 Journal Article

Multisite reproducibility and test-retest reliability of the T1w/T2w-ratio: A comparison of processing methods

  • Stener Nerland
  • Kjetil N. Jørgensen
  • Wibeke Nordhøy
  • Ivan I. Maximov
  • Robin A.B. Bugge
  • Lars T. Westlye
  • Ole A. Andreassen
  • Oliver M. Geier

BACKGROUND: The ratio of T1-weighted (T1w) and T2-weighted (T2w) magnetic resonance imaging (MRI) images is often used as a proxy measure of cortical myelin. However, the T1w/T2w-ratio is based on signal intensities that are inherently non-quantitative and known to be affected by extrinsic factors. To account for this a variety of processing methods have been proposed, but a systematic evaluation of their efficacy is lacking. Given the dependence of the T1w/T2w-ratio on scanner hardware and T1w and T2w protocols, it is important to ensure that processing pipelines perform well also across different sites. METHODS: We assessed a variety of processing methods for computing cortical T1w/T2w-ratio maps, including correction methods for nonlinear field inhomogeneities, local outliers, and partial volume effects as well as intensity normalisation. These were implemented in 33 processing pipelines which were applied to four test-retest datasets, with a total of 170 pairs of T1w and T2w images acquired on four different MRI scanners. We assessed processing pipelines across datasets in terms of their reproducibility of expected regional distributions of cortical myelin, lateral intensity biases, and test-retest reliability regionally and across the cortex. Regional distributions were compared both qualitatively with histology and quantitatively with two reference datasets, YA-BC and YA-B1+, from the Human Connectome Project. RESULTS: Reproducibility of raw T1w/T2w-ratio distributions was overall high with the exception of one dataset. For this dataset, Spearman rank correlations increased from 0.27 to 0.70 after N3 bias correction relative to the YA-BC reference and from -0.04 to 0.66 after N4ITK bias correction relative to the YA-B1+ reference. Partial volume and outlier corrections had only marginal effects on the reproducibility of T1w/T2w-ratio maps and test-retest reliability. Before intensity normalisation, we found large coefficients of variation (CVs) and low intraclass correlation coefficients (ICCs), with total whole-cortex CV of 10.13% and whole-cortex ICC of 0.58 for the raw T1w/T2w-ratio. Intensity normalisation with WhiteStripe, RAVEL, and Z-Score improved total whole-cortex CVs to 5.91%, 5.68%, and 5.19% respectively, whereas Z-Score and Least Squares improved whole-cortex ICCs to 0.96 and 0.97 respectively. CONCLUSIONS: In the presence of large intensity nonuniformities, bias field correction is necessary to achieve acceptable correspondence with known distributions of cortical myelin, but it can be detrimental in datasets with less intensity inhomogeneity. Intensity normalisation can improve test-retest reliability and inter-subject comparability. However, both bias field correction and intensity normalisation methods vary greatly in their efficacy and may affect the interpretation of results. The choice of T1w/T2w-ratio processing method must therefore be informed by both scanner and acquisition protocol as well as the given study objective. Our results highlight limitations of the T1w/T2w-ratio, but also suggest concrete ways to enhance its usefulness in future studies.

YNICL Journal 2020 Journal Article

Distinct structural brain circuits indicate mood and apathy profiles in bipolar disorder

  • Wenhao Jiang
  • Ole A. Andreassen
  • Ingrid Agartz
  • Trine V. Lagerberg
  • Lars T. Westlye
  • Vince D. Calhoun
  • Jessica A. Turner

Bipolar disorder (BD) is a severe manic-depressive illness. Patients with BD have been shown to have gray matter (GM) deficits in prefrontal, frontal, parietal, and temporal regions; however, the relationship between structural effects and clinical profiles has proved elusive when considered on a region by region or voxel by voxel basis. In this study, we applied parallel independent component analysis (pICA) to structural neuroimaging measures and the positive and negative syndrome scale (PANSS) in 110 patients (mean age 34.9 ± 11.65) with bipolar disorder, to examine networks of brain regions that relate to symptom profiles. The pICA revealed two distinct symptom profiles and associated GM concentration alteration circuits. The first PANSS pICA profile mainly involved anxiety, depression and guilty feelings, reflecting mood symptoms. Reduced GM concentration in right temporal regions predicted worse mood symptoms in this profile. The second PANSS pICA profile generally covered blunted affect, emotional withdrawal, passive/apathetic social withdrawal, depression and active social avoidance, exhibiting a withdrawal or apathy dominating component. Lower GM concentration in bilateral parietal and frontal regions showed worse symptom severity in this profile. In summary, a pICA decomposition suggested BD patients showed distinct mood and apathy profiles differing from the original PANSS subscales, relating to distinct brain structural networks.

YNICL Journal 2017 Journal Article

Distinct multivariate brain morphological patterns and their added predictive value with cognitive and polygenic risk scores in mental disorders

  • Nhat Trung Doan
  • Tobias Kaufmann
  • Francesco Bettella
  • Kjetil Nordbø Jørgensen
  • Christine Lycke Brandt
  • Torgeir Moberget
  • Dag Alnæs
  • Gwenaëlle Douaud

The brain underpinnings of schizophrenia and bipolar disorders are multidimensional, reflecting complex pathological processes and causal pathways, requiring multivariate techniques to disentangle. Furthermore, little is known about the complementary clinical value of brain structural phenotypes when combined with data on cognitive performance and genetic risk. Using data-driven fusion of cortical thickness, surface area, and gray matter density maps (GMD), we found six biologically meaningful patterns showing strong group effects, including four statistically independent multimodal patterns reflecting co-occurring alterations in thickness and GMD in patients, over and above two other independent patterns of widespread thickness and area reduction. Case-control classification using cognitive scores alone revealed high accuracy, and adding imaging features or polygenic risk scores increased performance, suggesting their complementary predictive value with cognitive scores being the most sensitive features. Multivariate pattern analyses reveal distinct patterns of brain morphology in mental disorders, provide insights on the relative importance between brain structure, cognitive and polygenetic risk score in classification of patients, and demonstrate the importance of multivariate approaches in studying the pathophysiological substrate of these complex disorders.

YNIMG Journal 2017 Journal Article

Distinguishing early and late brain aging from the Alzheimer's disease spectrum: consistent morphological patterns across independent samples

  • Nhat Trung Doan
  • Andreas Engvig
  • Krystal Zaske
  • Karin Persson
  • Martina Jonette Lund
  • Tobias Kaufmann
  • Aldo Cordova-Palomera
  • Dag Alnæs

Alzheimer's disease (AD) is a debilitating age-related neurodegenerative disorder. Accurate identification of individuals at risk is complicated as AD shares cognitive and brain features with aging. We applied linked independent component analysis (LICA) on three complementary measures of gray matter structure: cortical thickness, area and gray matter density of 137 AD, 78 mild (MCI) and 38 subjective cognitive impairment patients, and 355 healthy adults aged 18–78 years to identify dissociable multivariate morphological patterns sensitive to age and diagnosis. Using the lasso classifier, we performed group classification and prediction of cognition and age at different age ranges to assess the sensitivity and diagnostic accuracy of the LICA patterns in relation to AD, as well as early and late healthy aging. Three components showed high sensitivity to the diagnosis and cognitive status of AD, with different relationships with age: one reflected an anterior-posterior gradient in thickness and gray matter density and was uniquely related to diagnosis, whereas the other two, reflecting widespread cortical thickness and medial temporal lobe volume, respectively, also correlated significantly with age. Repeating the LICA decomposition and between-subject analysis on ADNI data, including 186 AD, 395 MCI and 220 age-matched healthy controls, revealed largely consistent brain patterns and clinical associations across samples. Classification results showed that multivariate LICA-derived brain characteristics could be used to predict AD and age with high accuracy (area under ROC curve up to 0. 93 for classification of AD from controls). Comparison between classifiers based on feature ranking and feature selection suggests both common and unique feature sets implicated in AD and aging, and provides evidence of distinct age-related differences in early compared to late aging.

YNIMG Journal 2017 Journal Article

Task modulations and clinical manifestations in the brain functional connectome in 1615 fMRI datasets

  • Tobias Kaufmann
  • Dag Alnæs
  • Christine Lycke Brandt
  • Nhat Trung Doan
  • Karolina Kauppi
  • Francesco Bettella
  • Trine V. Lagerberg
  • Akiah O. Berg

Objective An abundance of experimental studies have motivated a range of models concerning the cognitive underpinnings of severe mental disorders, yet the conception that cognitive and brain dysfunction is confined to specific cognitive domains and contexts has limited ecological validity. Schizophrenia and bipolar spectrum disorders have been conceptualized as disorders of brain connectivity; yet little is known about the pervasiveness across cognitive tasks. Methods To address this outstanding issue of context specificity, we estimated functional network connectivity from fMRI data obtained during five cognitive tasks (0-back, 2-back, go/no-go, recognition of positive faces, negative faces) in 90 patients with schizophrenia spectrum, 97 patients with bipolar spectrum disorder, and 136 healthy controls, including 1615 fMRI datasets in total. We tested for main effects of task and group, and their interactions, and used machine learning to classify task labels and predict cognitive domain scores from brain connectivity. Results Connectivity profiles were positively correlated across tasks, supporting the existence of a core functional connectivity backbone common to all tasks. However, 76. 2% of all network links also showed significant task-related alterations, robust on the single subject level as evidenced by high machine-learning performance when classifying task labels. Independent of such task-specific modulations, 9. 5% of all network links showed significant group effects, particularly including sensory (sensorimotor, visual, auditory) and cognitive (frontoparietal, default-mode, dorsal attention) networks. A lack of group by task interactions revealed that the pathophysiological sensitivity remained across tasks. Such pervasiveness across tasks was further supported by significant predictions of cognitive domain scores from the connectivity backbone obtained across tasks. Conclusions The high accuracies obtained when classifying cognitive tasks support that brain connectivity indices provide sensitive and specific measures of cognitive states. Importantly, we provide evidence that brain network dysfunction in severe mental disorders is not confined to specific cognitive tasks and show that the connectivity backbone common to all tasks is predictive of cognitive domain traits. Such pervasiveness across tasks may support a generalization of pathophysiological models from different domains, thereby reducing their complexity and increasing their ecological validity. Future research incorporating a wider range of cognitive tasks, involving other sensory modalities (auditory, somatosensory, motor) and requirements (learning, perceptual inference, decision making, etc.), is needed to assess if under certain circumstances, context dependent aberrations may evolve. Our results provide further evidence from a large sample that fMRI based functional network connectivity can be used to reveal both, state and trait effects in the connectome.

YNICL Journal 2015 Journal Article

Assessing brain structural associations with working memory related brain patterns in schizophrenia and healthy controls using linked independent component analysis

  • Christine Lycke Brandt
  • Nhat Trung Doan
  • Siren Tønnesen
  • Ingrid Agartz
  • Kenneth Hugdahl
  • Ingrid Melle
  • Ole A. Andreassen
  • Lars T. Westlye

Schizophrenia (SZ) is a psychotic disorder with significant cognitive dysfunction. Abnormal brain activation during cognitive processing has been reported, both in task-positive and task-negative networks. Further, structural cortical and subcortical brain abnormalities have been documented, but little is known about how task-related brain activation is associated with brain anatomy in SZ compared to healthy controls (HC). Utilizing linked independent component analysis (LICA), a data-driven multimodal analysis approach, we investigated structure-function associations in a large sample of SZ (n = 96) and HC (n = 142). We tested for associations between task-positive (fronto-parietal) and task-negative (default-mode) brain networks derived from fMRI activation during an n-back working memory task, and brain structural measures of surface area, cortical thickness, and gray matter volume, and to what extent these associations differed in SZ compared to HC. A significant association (p < .05, corrected for multiple comparisons) was found between a component reflecting the task-positive fronto-parietal network and another component reflecting cortical thickness in fronto-temporal brain regions in SZ, indicating increased activation with increased thickness. Other structure-function associations across, between and within groups were generally moderate and significant at a nominal p-level only, with more numerous and stronger associations in SZ compared to HC. These results indicate a complex pattern of moderate associations between brain activation during cognitive processing and brain morphometry, and extend previous findings of fronto-temporal brain abnormalities in SZ by suggesting a coupling between cortical thickness of these brain regions and working memory-related brain activation.

YNIMG Journal 2013 Journal Article

Pathway analysis of genetic markers associated with a functional MRI faces paradigm implicates polymorphisms in calcium responsive pathways

  • Morten Mattingsdal
  • Andrew Anand Brown
  • Srdjan Djurovic
  • Ida Elken Sønderby
  • Andres Server
  • Ingrid Melle
  • Ingrid Agartz
  • Eivind Hovig

Several lines of evidence suggest that common polygenic variation influences brain function in humans. Combining high-density genetic markers with brain imaging techniques is constricted by the practicalities of collecting sufficiently large brain imaging samples. Pathway analysis promises to leverage knowledge on function of genes to detect recurring signals of moderate effect. We adapt this approach, exploiting the deep information collected on brain function by fMRI methods, to identify molecular pathways containing genetic variants which influence brain activation during a commonly applied experiment based on a face matching task (n =246) which was developed to study neural processing of faces displaying negative emotions. Genetic markers moderately associated (p <10−4) with whole brain activation phenotypes constructed by applying principal components to contrast maps, were tested for pathway enrichment using permutation based methods. The most significant pathways are related to post NMDA receptor activation events, driven by genetic variants in calcium/calmodulin-dependent protein kinase II (CAMK2G, CAMK2D) and a calcium-regulated nucleotide exchange factor (RASGRF2) in which all are activated by intracellular calcium/calmodulin. The most significant effect of the combined polygenic model were localized to the left inferior frontal gyrus (p =1. 03×10−9), a region primarily involved in semantic processing but also involved in processing negative emotions. These findings suggest that pathway analysis of GWAS results derived from principal component analysis of fMRI data is a promising method, to our knowledge, not previously described.

YNIMG Journal 2009 Journal Article

Increased sensitivity to effects of normal aging and Alzheimer's disease on cortical thickness by adjustment for local variability in gray/white contrast: A multi-sample MRI study

  • Lars T. Westlye
  • Kristine B. Walhovd
  • Anders M. Dale
  • Thomas Espeseth
  • Ivar Reinvang
  • Naftali Raz
  • Ingrid Agartz
  • Douglas N. Greve

MRI-based estimates of cerebral morphometric properties, e. g. cortical thickness, are pivotal to studies of normal and pathological brain changes. These measures are based on automated or manual segmentation procedures, which utilize the tissue contrast between gray and white matter on T1-weighted MR images. Tissue contrast is unlikely to remain a constant property across groups of different age and health. An important question is therefore how the sensitivity of cortical thickness estimates is influenced by variability in WM/GM contrast. The effect of adjusting for variability in WM/GM contrast on age sensitivity of cortical thickness was tested in 1189 healthy subjects from six different samples, enabling evaluation of consistency of effects within and between sites and scanners. Further, the influence of Alzheimer's disease (AD) diagnosis on cortical thickness with and without correction for contrast was tested in an additional sample of 96 patients. In healthy controls, regional increases in the sensitivity of the cortical thickness measure to age were found after correcting for contrast. Across samples, the strongest effects were observed in frontal, lateral temporal and parietal areas. Controlling for contrast variability also increased the cortical thickness estimates' sensitivity to AD, thus replicating the finding in an independent clinical sample. The results showed increased sensitivity of cortical estimates to AD in areas earlier reported to be compromised in AD, including medial temporal, inferior and superior parietal regions. In sum, the findings indicate that adjusting for contrast can increase the sensitivity of MR morphometry to variables of interest.

YNIMG Journal 2009 Journal Article

Local and covariate-modulated false discovery rates applied in neuroimaging

  • Glenn Lawyer
  • Egil Ferkingstad
  • Ragnar Nesvåg
  • Katarina Varnäs
  • Ingrid Agartz

False discovery rate (FDR) control has become a standard technique in neuroimaging. Recent work has shown that a finer grained estimate of the FDR is obtained by estimating, at a specific value of the test statistic, the scaled ratio of the null density to the observed density of the test statistic. The method can be extended by allowing an external covariate, also measured on the points where the hypothesis was tested, to modulate estimation of this local FDR. The current work, in addition to demonstrating these methods by re-analyzing results from two previously published investigations of cortical thickness, presents a method to test if the covariate modulation differs significantly from chance. The first study compared schizophrenia patients to healthy controls and the second compared genotypes of the −633 T/A polymorphism of the gene coding the brain derived neurotrophic factor (BDNF) protein in a subset of the subjects from the case/control study. Local FDR estimates increased findings over FDR in both studies. Using p-values from the case/control study to modulate local FDR estimation in the BDNF study further increased findings. The relationship between case/control related and BDNF related cortical thickness variation was found to be highly significant, providing support for this gene's involvement in the etiology of the disease. The increased statistical precision from more accurate models of the distribution of the test statistic demonstrates the potential of these methods for neuroimaging and suggests the possibility to test novel hypothesis.

v2026.09.13