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Cognitive impairments are core features in individuals across the psychosis continuum and predict functional outcomes. Nevertheless, substantial variability in cognitive functioning within diagnostic groups, along with considerable overlap with healthy controls, hampers the translation of research findings into personalized treatment planning. Aligned with precision medicine, we employed a data driven machine learning method, self-organizing maps, to conduct transdiagnostic clustering based on cognitive functions in a sample comprising 228 healthy controls, 200 individuals at ultra-high risk for psychosis, and 98 antipsychotic-naïve patients with first-episode psychosis. The self-organizing maps revealed six clinically distinct cognitive profiles that significantly predicted baseline functional level and changes in functional level after one year. Cognitive flexibility in particular, as well as specific executive functions emerged as cardinal in differentiating the profiles. The application of self-organizing maps appears to be a promising approach to inform clinical decision-making based on individualized cognitive profiles, including patient allocation to different interventions. Moreover, this method has the potential to enable cross-diagnostic stratification in research trials, utilizing data-driven subgrouping informed by categories from underlying dimensions of cognition rather than from clinical diagnoses. Finally, the method enables cross-diagnostic profiling across other data modalities, such as brain networks or metabolic subtypes., Competing Interests: Declaration of competing interest Dr. Ebdrup is part of the Advisory Board of Eli Lilly Denmark A/S, Janssen-Cilag, Lundbeck Pharma A/S, and Takeda Pharmaceutical Company Ltd; and has received lecture fees from Bristol-Myers Squibb, Otsuka Pharma Scandinavia AB, Eli Lilly Company, and Lundbeck Pharma A/S. Dr. Bojesen received lecture fees from Lundbeck Pharma A/S. The rest of the authors have no conflicts to disclose., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Patients with schizophrenia exhibit structural and functional dysconnectivity but the relationship to the well-documented cognitive impairments is less clear. This study investigates associations between structural and functional connectivity and executive functions in antipsychotic-naïve patients experiencing schizophrenia. Sixty-four patients with schizophrenia and 95 matched controls underwent cognitive testing, diffusion weighted imaging and resting state functional magnetic resonance imaging. In the primary analyses, groupwise interactions between structural connectivity as measured by fixel-based analyses and executive functions were investigated using multivariate linear regression analyses. For significant structural connections, secondary analyses examined whether functional connectivity and associations with executive functions also differed for the two groups. In group comparisons, patients exhibited cognitive impairments across all executive functions compared to controls (p < 0.001), but no group difference were observed in the fixel-based measures. Primary analyses revealed a groupwise interaction between planning abilities and fixel-based measures in the left anterior thalamic radiation (p = 0.004), as well as interactions between cognitive flexibility and fixel-based measures in the isthmus of corpus callosum and cingulum (p = 0.049). Secondary analyses revealed increased functional connectivity between grey matter regions connected by the left anterior thalamic radiation (left thalamus with pars opercularis p = 0.018, and pars orbitalis p = 0.003) in patients compared to controls. Moreover, a groupwise interaction was observed between cognitive flexibility and functional connectivity between contralateral regions connected by the isthmus (precuneus p = 0.028, postcentral p = 0.012), all p-values corrected for multiple comparisons. We conclude that structural and functional connectivity appear to associate with executive functions differently in antipsychotic-naïve patients with schizophrenia compared to controls., (© 2024. The Author(s).)

Background: Facial expressions are a core aspect of non-verbal communication. Reduced emotional expressiveness of the face is a common negative symptom of schizophrenia, however, quantifying negative symptoms can be clinically challenging and involves a considerable element of rater subjectivity. We used computer vision to investigate if (i) automated assessment of facial expressions captures negative as well as positive and general symptom domains, and (ii) if automated assessments are associated with treatment response in initially antipsychotic-naïve patients with first-episode psychosis., Method: We included 46 patients (mean age 25.4 (6.1); 65.2% males). Psychopathology was assessed at baseline and after 6 weeks of monotherapy with amisulpride using the Positive and Negative Syndrome Scale (PANSS). Baseline interview videos were recorded. Seventeen facial action units (AUs), that is, activation of muscles, from the Facial Action Coding System were extracted using OpenFace 2.0. A correlation matrix was calculated for each patient. Facial expressions were identified using spectral clustering at group-level. Associations between facial expressions and psychopathology were investigated using multiple linear regression., Results: Three clusters of facial expressions were identified related to different locations of the face. Cluster 1 was associated with positive and general symptoms at baseline, Cluster 2 was associated with all symptom domains, showing the strongest association with the negative domain, and Cluster 3 was only associated with general symptoms. Cluster 1 was significantly associated with the clinically rated improvement in positive and general symptoms after treatment, and Cluster 2 was significantly associated with clinical improvement in all domains., Conclusion: Using automated computer vision of facial expressions during PANSS interviews did not only capture negative symptoms but also combinations of the three overall domains of psychopathology. Moreover, automated assessments of facial expressions at baseline were associated with initial antipsychotic treatment response. The findings underscore the clinical relevance of facial expressions and motivate further investigations of computer vision in clinical psychiatry., (© 2024 The Author(s). Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Background: Anorexia nervosa (AN) is a potentially fatal psychiatric condition, associated with structural brain changes such as gray matter volume loss. The pathophysiological mechanisms for these changes are not yet fully understood. Iron is a crucial element in the development and function of the brain. Considering the systemic alterations in iron homeostasis in AN, we hypothesized that brain iron would be altered as a possible factor associated with structural brain changes in AN., Methods: In this study, we used quantitative susceptibility mapping (QSM) magnetic resonance imaging to investigate brain iron in current AN (c-AN) and weight-restored AN compared with healthy individuals. Whole-brain voxel wise comparison was used to probe areas with possible group differences. Further, the thalamus, caudate nucleus, putamen, nucleus accumbens, hippocampus, and amygdala were selected as the regions of interest (ROIs) for ROI-based comparison of mean QSM values., Results: Whole-brain voxel-wise and ROI-based comparison of QSM did not reveal any differences between groups. Exploratory analyses revealed a correlation between higher regional QSM (higher iron) and lower body mass index, higher illness severity, longer illness duration, and younger age at onset in the c-AN group., Conclusions: This study did not find evidence of altered brain iron in AN compared to healthy individuals. However, the correlations between clinical variables and QSM suggest a link between brain iron and weight status or biological processes in AN, which warrants further investigation., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background and Purpose: While brain iron dysregulation has been observed in several neurodegenerative disorders, its association with the progressive neurodegeneration in Niemann-Pick type C is unknown. Systemic iron abnormalities have been reported in patients with Niemann-Pick type C and in animal models of Niemann-Pick type C. In this study, we examined brain iron using quantitative susceptibility mapping MR imaging in individuals with Niemann-Pick type C compared with healthy controls., Materials and Methods: A cohort of 10 patients with adolescent- and adult-onset Niemann-Pick type C and 14 age- and sex-matched healthy controls underwent 7T brain MR imaging with T1 and quantitative susceptibility mapping acquisitions. A probing whole-brain voxelwise comparison of quantitative susceptibility mapping between groups was conducted. Mean quantitative susceptibility mapping in the ROIs (thalamus, hippocampus, putamen, caudate nucleus, and globus pallidus) was further compared. The correlations between regional volume, quantitative susceptibility mapping values, and clinical features, which included disease severity on the Iturriaga scale, cognitive function, and the Social and Occupational Functioning Assessment Scale, were explored as secondary analyses., Results: We observed lower volume in the thalamus and voxel clusters of higher quantitative susceptibility mapping in the pulvinar nuclei bilaterally in patients with Niemann-Pick type C compared with the control group. In patients with Niemann-Pick type C, higher quantitative susceptibility mapping in the pulvinar nucleus clusters correlated with lower volume of the thalamus on both sides. Moreover, higher quantitative susceptibility mapping in the right pulvinar cluster was associated with greater disease severity., Conclusions: Our findings suggest iron deposition in the pulvinar nucleus in Niemann-Pick type C disease, which is associated with thalamic atrophy and disease severity. This preliminary evidence supports the link between iron and neurodegeneration in Niemann-Pick type C, in line with existing literature on other neurodegenerative disorders., (© 2023 by American Journal of Neuroradiology.)

Brain iron is central to dopaminergic neurotransmission, a key component in schizophrenia pathology. Iron can also generate oxidative stress, which is one proposed mechanism for gray matter volume reduction in schizophrenia. The role of brain iron in schizophrenia and its potential link to oxidative stress has not been previously examined. In this study, we used 7-Tesla MRI quantitative susceptibility mapping (QSM), magnetic resonance spectroscopy (MRS), and structural T 1 imaging in 12 individuals with chronic schizophrenia and 14 healthy age-matched controls. In schizophrenia, there were higher QSM values in bilateral putamen and higher concentrations of phosphocreatine and lactate in caudal anterior cingulate cortex (caCC). Network-based correlation analysis of QSM across corticostriatal pathways as well as the correlation between QSM, MRS, and volume, showed distinct patterns between groups. This study introduces increased iron in the putamen in schizophrenia in addition to network-wide disturbances of iron and metabolic status., (© 2022. The Author(s).)

Episodic memory ability relies on hippocampal-prefrontal connectivity. However, few studies have examined relationships between memory performance and white matter (WM) microstructure in hippocampal-prefrontal pathways in schizophrenia-spectrum disorder (SSDs). Here, we investigated these relationships in individuals with first-episode psychosis (FEP) and chronic schizophrenia-spectrum disorders (SSDs) using tractography analysis designed to interrogate the microstructure of WM tracts in the hippocampal-prefrontal pathway. Measures of WM microstructure (fractional anisotropy [FA], radial diffusivity [RD], and axial diffusivity [AD]) were obtained for 47 individuals with chronic SSDs, 28 FEP individuals, 52 older healthy controls, and 27 younger healthy controls. Tractography analysis was performed between the hippocampus and three targets involved in hippocampal-prefrontal connectivity (thalamus, amygdala, nucleus accumbens). Measures of WM microstructure were then examined in relation to episodic memory performance separately across each group. Both those with FEP and chronic SSDs demonstrated impaired episodic memory performance. However, abnormal WM microstructure was only observed in individuals with chronic SSDs. Abnormal WM microstructure in the hippocampal-thalamic pathway in the right hemisphere was associated with poorer memory performance in individuals with chronic SSDs. These findings suggest that disruptions in WM microstructure in the hippocampal-prefrontal pathway may contribute to memory impairments in individuals with chronic SSDs but not FEP., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Population-centric frameworks of biomarker identification for psychiatric disorders focus primarily on comparing averages between groups and assume that diagnostic groups are (1) mutually-exclusive, and (2) homogeneous. There is a paucity of individual-centric approaches capable of identifying individual-specific 'fingerprints' across multiple domains. To address this, we propose a novel framework, combining a range of biopsychosocial markers, including brain structure, cognition, and clinical markers, into higher-level 'fingerprints', capable of capturing intra-illness heterogeneity and inter-illness overlap. A multivariate framework was implemented to identify individualised patterns of brain structure, cognition and clinical markers based on affinity to other participants in the database. First, individual-level affinity scores defined each participant's "neighbourhood" across each measure based on variable-specific hop sizes. Next, diagnostic verification and classification algorithms were implemented based on multivariate affinity score profiles. To perform affinity-based classification, data were divided into training and test samples, and 5-fold nested cross-validation was performed on the training data. Affinity-based classification was compared to weighted K-nearest neighbours (KNN) classification. The framework was applied to the Australian Schizophrenia Research Bank (ASRB) dataset, which included data from individuals with chronic and treatment resistant schizophrenia and healthy controls. Individualised affinity scores provided a 'fingerprint' of brain structure, cognition, and clinical markers, which described the affinity of an individual to the representative groups in the dataset. Diagnostic verification capability was moderate to high depending on the choice of multivariate affinity metric. Affinity score-based classification achieved a high degree of accuracy in the training, nested cross-validation and prediction steps, and outperformed KNN classification in the training and test datasets. Affinity scores demonstrate utility in two keys ways: (1) Early and accurate diagnosis of neuropsychiatric disorders, whereby an individual can be grouped within a diagnostic category/ies that best matches their fingerprint, and (2) identification of biopsychosocial factors that most strongly characterise individuals/disorders, and which may be most amenable to intervention., (© 2022. The Author(s).)

Background: Antipsychotic drugs are primarily efficacious in treating positive symptoms by blocking the dopamine D2 receptor, but they fail to substantially improve negative symptoms and cognitive deficits. The limited efficacy may be attributed to the fact that the pathophysiology of psychosis involves multiple neurotransmitter systems. In patients with chronic schizophrenia, memantine, a non-competitive glutamatergic NMDA receptor antagonist, shows promise for ameliorating negative symptoms and improving cognition. Yet, it is unknown how memantine modulates glutamate levels, and memantine has not been investigated in patients with first-episode psychosis., Aims: This investigator-initiated double-blinded randomized controlled trial is designed to (1) test the clinical effects on negative symptoms of add-on memantine to antipsychotic medication, and (2) neurobiologically characterize the responders to add-on memantine., Materials and Equipment: Antipsychotic-naïve patients with first-episode psychosis will be randomized to 12 weeks treatment with [amisulpride + memantine] or [amisulpride + placebo]. We aim for a minimum of 18 patients in each treatment arm to complete the trial. Brain mapping will be performed before and after 12 weeks focusing on glutamate and neuromelanin in predefined regions. Regional glutamate levels will be probed with proton magnetic resonance spectroscopy (MRS), while neuromelanin signal will be mapped with neuromelanin-sensitive magnetic resonance imaging (MRI). We will also perform structural and diffusion weighted, whole-brain MRI. MRS and MRI will be performed at an ultra-high field strength (7 Tesla). Alongside, participants undergo clinical and neuropsychological assessments. Twenty matched healthy controls will undergo similar baseline- and 12-week examinations, but without receiving treatment., Outcome Measures: The primary endpoint is negative symptom severity. Secondary outcomes comprise: (i) clinical endpoints related to cognition, psychotic symptoms, side effects, and (ii) neurobiological endpoints related to regional glutamate- and neuromelanin levels, and structural brain changes., Anticipated Results: We hypothesize that add-on memantine to amisulpride will be superior to amisulpride monotherapy in reducing negative symptoms, and that this effect will correlate with thalamic glutamate levels. Moreover, we anticipate that add-on memantine will restore regional white matter integrity and improve cognitive functioning., Perspectives: By combining two licensed, off-patent drugs, AMEND aims to optimize treatment of psychosis while investigating the memantine response. Alongside, AMEND will provide neurobiological insights to effects of dual receptor modulation, which may enable future stratification of patients with first-episode psychosis before initial antipsychotic treatment., Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT04789915]., Competing Interests: BE was part of the Advisory Board of Eli Lilly Denmark A/S, Janssen-Cilag, Lundbeck Pharma A/S, and Takeda Pharmaceutical Company Ltd; and has received lecture fees from Bristol-Myers Squibb, Boehringer Ingelheim, Otsuka Pharma Scandinavia AB, Eli Lilly Company, and Lundbeck Pharma A/S. HS has received honoraria as speaker from Sanofi Genzyme, Denmark and Novartis, Denmark, as consultant from Sanofi Genzyme, Denmark, and Lundbeck AS, Denmark, and as editor-in-chief (Neuroimage Clinical) and senior editor (NeuroImage) from Elsevier Publishers, Amsterdam, The Netherlands. He has received royalties as book editor from Springer Publishers, Stuttgart, Germany and from Gyldendal Publishers, Copenhagen, Denmark. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sandström, Baltzersen, Marsman, Lemvigh, Boer, Bojesen, Nielsen, Lundell, Sulaiman, Sørensen, Fagerlund, Lahti, Syeda, Pantelis, Petersen, Glenthøj, Siebner and Ebdrup.)

Background: Brain structural alterations and cognitive dysfunction are independent predictors for poor clinical outcome in schizophrenia, and the associations between these domains remains unclear. We employed a novel, multiblock partial least squares correlation (MB-PLS-C) technique and investigated multivariate cortico-cognitive patterns in patients with treatment-resistant schizophrenia (TRS) and matched healthy controls (HC)., Method: Forty-one TRS patients (age 38.5 ± 9.1, 30 males (M)), and 45 HC (age 40.2 ± 10.6, 29 M) underwent 3T structural MRI. Volumes of 68 brain regions and seven variables from CANTAB covering memory and executive domains were included. Univariate group differences were assessed, followed by the MB-PLS-C analyses to identify group-specific multivariate patterns of cortico-cognitive coupling. Supplementary three-group analyses, which included 23 non-affected first-degree relatives (NAR), were also conducted., Results: Univariate tests demonstrated that TRS patients showed impairments in all seven cognitive tasks and volume reductions in 12 cortical regions following Bonferroni correction. The MB-PLS-C analyses revealed two significant latent variables (LVs) explaining > 90% of the sum-of-squares variance. LV1 explained 78.86% of the sum-of-squares variance, describing a shared, widespread structure-cognitive pattern relevant to both TRS patients and HCs. In contrast, LV2 (13.47% of sum-of-squares variance explained) appeared specific to TRS and comprised a differential cortico-cognitive pattern including frontal and temporal lobes as well as paired associates learning (PAL) and intra-extra dimensional set shifting (IED). Three-group analyses also identified two significant LVs, with NARs more closely resembling healthy controls than TRS patients., Conclusions: MB-PLS-C analyses identified multivariate brain structural-cognitive patterns in the latent space that may provide a TRS signature., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Between adolescence and adulthood, the brain critically undergoes maturation and refinement of synaptic and neural circuits that shape cognitive processing. Adolescence also represents a vulnerable period for the onset of symptoms in neurodevelopmental psychiatric disorders. Despite the wide use of rodent models to unravel neurobiological mechanisms underlying neurodevelopmental disorders, there is a surprising paucity of rigorous studies focusing on normal cognitive-developmental trajectories in such models. Here, we sought to behaviorally capture maturational changes in cognitive trajectories during adolescence and into adulthood in male and female mice using distinct behavioral paradigms. C57 BL/6J mice (4.5, 6, and 12 weeks of age) were assessed on three behavioral paradigms: drug-induced locomotor hyperactivity, prepulse inhibition, and a novel validated version of a visuospatial paired-associate learning touchscreen task. We show that the normal maturational trajectories of behavioral performance on these paradigms are dissociable. Responses in drug-induced locomotor hyperactivity and prepulse inhibition both displayed a 'U-shaped' developmental trajectory; lower during mid-adolescence relative to early adolescence and adulthood. In contrast, visuospatial learning and memory, memory retention, and response times indicative of motivational processing progressively improved with age. Our study offers a framework to investigate how insults at different developmental stages might perturb normal trajectories in cognitive development. We provide a brain maturational approach to understand resilience factors of brain plasticity in the face of adversity and to examine pharmacological and non-pharmacological interventions directed at ameliorating or rescuing perturbed trajectories in neurodevelopmental and neuropsychiatric disorders., (© 2021. The Author(s).)

As the global health crisis unfolded, many academic conferences moved online in 2020. This move has been hailed as a positive step towards inclusivity in its attenuation of economic, physical, and legal barriers and effectively enabled many individuals from groups that have traditionally been underrepresented to join and participate. A number of studies have outlined how moving online made it possible to gather a more global community and has increased opportunities for individuals with various constraints, e.g., caregiving responsibilities. Yet, the mere existence of online conferences is no guarantee that everyone can attend and participate meaningfully. In fact, many elements of an online conference are still significant barriers to truly diverse participation: the tools used can be inaccessible for some individuals; the scheduling choices can favour some geographical locations; the set-up of the conference can provide more visibility to well-established researchers and reduce opportunities for early-career researchers. While acknowledging the benefits of an online setting, especially for individuals who have traditionally been underrepresented or excluded, we recognize that fostering social justice requires inclusivity to actively be centered in every aspect of online conference design. Here, we draw from the literature and from our own experiences to identify practices that purposefully encourage a diverse community to attend, participate in, and lead online conferences. Reflecting on how to design more inclusive online events is especially important as multiple scientific organizations have announced that they will continue offering an online version of their event when in-person conferences can resume., (© The Author(s) 2021. Published by Oxford University Press on behalf of GigaScience. 2021.)

Although COVID-19 is predominantly a respiratory disease, it is known to affect multiple organ systems. In this article, we highlight the impact of SARS-CoV-2 (the coronavirus causing COVID-19) on the central nervous system as there is an urgent need to understand the longitudinal impacts of COVID-19 on brain function, behaviour and cognition. Furthermore, we address the possibility of intergenerational impacts of COVID-19 on the brain, potentially via both maternal and paternal routes. Evidence from preclinical models of earlier coronaviruses has shown direct viral infiltration across the blood-brain barrier and indirect secondary effects due to other organ pathology and inflammation. In the most severely ill patients with pneumonia requiring intensive care, there appears to be additional severe inflammatory response and associated thrombophilia with widespread organ damage, including the brain. Maternal viral (and other) infections during pregnancy can affect the offspring, with greater incidence of neurodevelopmental disorders, such as autism, schizophrenia and epilepsy. Available reports suggest possible vertical transmission of SARS-CoV-2, although longitudinal cohort studies of such offspring are needed. The impact of paternal infection on the offspring and intergenerational effects should also be considered. Research targeted at mechanistic insights into all aspects of pathogenesis, including neurological, neuropsychiatric and haematological systems alongside pulmonary pathology, will be critical in informing future therapeutic approaches. With these future challenges in mind, we highlight the importance of national and international collaborative efforts to gather the required clinical and preclinical data to effectively address the possible long-term sequelae of this global pandemic, particularly with respect to the brain and mental health.

Hippocampal atrophy is increasingly described in many neurodegenerative syndromes in humans, including stroke and vascular cognitive impairment. However, the progression of brain volume changes after stroke in rodent models is poorly characterized. We aimed to monitor hippocampal atrophy occurring in mice up to 48-weeks post-stroke. Male C57BL/6J mice were subjected to an intraluminal filament-induced middle cerebral artery occlusion (MCAO). At baseline, 3-days, and 1-, 4-, 12-, 24-, 36- and 48-weeks post-surgery, we measured sensorimotor behavior and hippocampal volumes from T 2 -weighted MRI scans. Hippocampal volume-both ipsilateral and contralateral-increased over the life-span of sham-operated mice. In MCAO-subjected mice, different trajectories of ipsilateral hippocampal volume change were observed dependent on whether the hippocampus contained direct infarction, with a decrease in directly infarcted tissue and an increase in non-infarcted tissue. To further investigate these volume changes, neuronal and glial cell densities were assessed in histological brain sections from the subset of MCAO mice lacking hippocampal infarction. Our findings demonstrate previously uncharacterized changes in hippocampal volume and potentially brain parenchymal cell density up to 48-weeks in both sham- and MCAO-operated mice.

Purpose: Quantitative susceptibility mapping (QSM) is a novel MR technique that allows mapping of tissue susceptibility values from MR phase images. QSM is an ill-conditioned inverse problem, and although several methods have been proposed in the field, in the presence of a wide range of susceptibility sources, streaking artifacts appear around high susceptibility regions and contaminate the whole QSM map. QSMART is a post-processing pipeline that uses two-stage parallel inversion to reduce the streaking artifacts and remove banding artifact at the cortical surface and around the vasculature., Method: Tissue and vein susceptibility values were separately estimated by generating a mask of vasculature driven from the magnitude data using a Frangi filter. Spatially dependent filtering was used for the background field removal step and the two susceptibility estimates were combined in the final QSM map. QSMART was compared to RESHARP/iLSQR and V-SHARP/iLSQR inversion in a numerical phantom, 7T in vivo single and multiple-orientation scans, 9.4T ex vivo mouse data, and 4.7T in vivo rat brain with induced focal ischemia., Results: Spatially dependent filtering showed better suppression of phase artifacts near cortex compared to RESHARP and V-SHARP, while preserving voxels located within regions of interest without brain edge erosion. QSMART showed successful reduction of streaking artifacts as well as improved contrast between different brain tissues compared to the QSM maps obtained by RESHARP/iLSQR and V-SHARP/iLSQR., Conclusion: QSMART can reduce QSM artifacts to enable more robust estimation of susceptibility values in vivo and ex vivo., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)