Normative modelling of molecular-based functional circuits captures clinical heterogeneity transdiagnostically in psychiatric patients.

Advanced methods such as REACT have allowed the integration of fMRI with the brain's receptor landscape, providing novel insights transcending the multiscale organisation of the brain. Similarly, normative modelling has allowed translational neuroscience to move beyond group-average differences and characterise deviations from health at an individual level. Here, we bring these methods together for the first time. We used REACT to create functional networks enriched with the main modulatory, inhibitory, and excitatory neurotransmitter systems and generated normative models of these networks to capture functional connectivity deviations in patients with schizophrenia, bipolar disorder (BPD), and ADHD. Substantial overlap was seen in symptomatology and deviations from normality across groups, but these could be mapped into a common space linking constellations of symptoms through to underlying neurobiology transdiagnostically. This work provides impetus for developing novel biomarkers that characterise molecular- and systems-level dysfunction at the individual level, facilitating the transition towards mechanistically targeted treatments.

Building diagnostic neuroimaging biomarkers for psychiatric disorders using reverse inference approaches: A viable route?

The advent of structural magnetic resonance imaging (sMRI) at the end of the 20th century opened the way toward a deeper understanding of the neurophysiology of psychiatric disorders, substantiating regional structural abnormalities underlying this group of clinical conditions. However, despite abundant and flourishing scientific research, sMRI methodologies are not currently integrated into daily diagnostic practice. One reason behind this failed translation may be the prevailing approach to logical reasoning in neuroimaging: The forward inference via frequentist-based statistics. This reasoning prevents clinicians from obtaining information about the selectivity of results, which are therefore of limited use regarding the definition of biomarkers and refinement of diagnostic processes. Recently, another type of inferential approach has started to emerge in the neuroimaging field: The reverse inference via Bayesian statistics. Here, we introduce the key concepts of this approach, with a particular emphasis on the clinical sMRI environment. We survey recent findings showing significant potential for clinical translation. Clinical opportunities and challenges for developing reverse inference-based neural markers for psychiatry are also discussed. We propose that a systematic sharing of imaging data across the human brain mapping community is an essential first step toward a paradigmatic clinical shift. We conclude that a defined synergy between forward-based and reverse-based sMRI research can illuminate current discussions on diagnostic brain markers, offering clarity on key issues and fostering new tailored diagnostic avenues.

Modeling brain sex in the limbic system as phenotype for female-prevalent mental disorders.

BACKGROUND: Sex differences exist in the prevalence and clinical manifestation of several mental disorders, suggesting that sex-specific brain phenotypes may play key roles. Previous research used machine learning models to classify sex from imaging data of the whole brain and studied the association of class probabilities with mental health, potentially overlooking regional specific characteristics. METHODS: We here investigated if a regionally constrained model of brain volumetric imaging data may provide estimates that are more sensitive to mental health than whole brain-based estimates. Given its known role in emotional processing and mood disorders, we focused on the limbic system. Using two different cohorts of healthy subjects, the Human Connectome Project and the Queensland Twin IMaging, we investigated sex differences and heritability of brain volumes of limbic structures compared to non-limbic structures, and subsequently applied regionally constrained machine learning models trained solely on limbic or non-limbic features. To investigate the biological underpinnings of such models, we assessed the heritability of the obtained sex class probability estimates, and we investigated the association with major depression diagnosis in an independent clinical sample. All analyses were performed both with and without controlling for estimated total intracranial volume (eTIV). RESULTS: Limbic structures show greater sex differences and are more heritable compared to non-limbic structures in both analyses, with and without eTIV control. Consequently, machine learning models performed well at classifying sex based solely on limbic structures and achieved performance as high as those on non-limbic or whole brain data, despite the much smaller number of features in the limbic system. The resulting class probabilities were heritable, suggesting potentially meaningful underlying biological information. Applied to an independent population with major depressive disorder, we found that depression is associated with male-female class probabilities, with largest effects obtained using the limbic model. This association was significant for models not controlling for eTIV whereas in those controlling for eTIV the associations did not pass significance correction. CONCLUSIONS: Overall, our results highlight the potential utility of regionally constrained models of brain sex to better understand the link between sex differences in the brain and mental disorders.

Psychiatric disorders have different prevalence between sexes, with women being twice as likely to develop depression and anxiety across the lifespan. Previous studies have investigated sex differences in brain structure that might contribute to this prevalence but have mostly focused on a single-structure level, potentially overlooking the interplay between brain regions. Sex differences in structures responsible for emotional regulation (limbic system), affected in many psychiatric disorders, have been previously reported. Here, we apply a machine learning model to obtain an estimate of brain sex for each participant based on the volumes of multiple brain regions. Particularly, we compared the estimates obtained with a model based solely on limbic structures with those obtained with a non-limbic model (entire brain except limbic structures) and a whole brain model. To investigate the genetic determinants of the models, we assessed the heritability of the estimates between identical twins and fraternal twins. The estimates of all our models were heritable, suggesting a genetic component contributing to brain sex. Finally, to investigate the association with mental health, we compared brain sex estimates in healthy subjects and in a depressed population. We found an association between depression and brain sex in females for the limbic model, but not for the non-limbic model. No effect was found in males. Overall, our results highlight the potential utility of machine learning models of brain sex based on relevant structures to better understand the link between sex differences in the brain and mental disorders.

[Neuroimaging-based study of scalp acupuncture targets for common psychiatric diseases].

Scalp acupuncture is a unique acupuncture method, developed based on the cerebral cortex localization. Neuroimaging technology enables the combination of contemporary brain science findings with the studies of scalp stimulation sites. In this study, based on the neuroimaging literature retrieved from Neurosynth platform, the scalp stimulation targets of common psychiatric diseases are developed, which provides the stimulation target protocol of scalp acupuncture for anxiety, bipolar disorder, major depressive disorder and post-traumatic stress disorder. The paper introduces the functions of the brain areas that are involved in each target and closely related to the diseases, and lists the therapeutic methods of common acupuncture and scalp acupuncture for each disease so as to provide the references for clinical practice. These targets can be used not only for the stimulation of scalp acupuncture, but also for the different neuromodulation techniques to treat related diseases.

BPI-GNN: Interpretable brain network-based psychiatric diagnosis and subtyping.

Converging evidence increasingly suggests that psychiatric disorders, such as major depressive disorder (MDD) and autism spectrum disorder (ASD), are not unitary diseases, but rather heterogeneous syndromes that involve diverse, co-occurring symptoms and divergent responses to treatment. This clinical heterogeneity has hindered the progress of precision diagnosis and treatment effectiveness in psychiatric disorders. In this study, we propose BPI-GNN, a new interpretable graph neural network (GNN) framework for analyzing functional magnetic resonance images (fMRI), by leveraging the famed prototype learning. In addition, we introduce a novel generation process of prototype subgraph to discover essential edges of distinct prototypes and employ total correlation (TC) to ensure the independence of distinct prototype subgraph patterns. BPI-GNN can effectively discriminate psychiatric patients and healthy controls (HC), and identify biological meaningful subtypes of psychiatric disorders. We evaluate the performance of BPI-GNN against 11 popular brain network classification methods on three psychiatric datasets and observe that our BPI-GNN always achieves the highest diagnosis accuracy. More importantly, we examine differences in clinical symptom profiles and gene expression profiles among identified subtypes and observe that our identified brain-based subtypes have the clinical relevance. It also discovers the subtype biomarkers that align with current neuro-scientific knowledge.

The power of many brains: Catalyzing neuropsychiatric discovery through open neuroimaging data and large-scale collaboration.

Recent advances in open neuroimaging data are enhancing our comprehension of neuropsychiatric disorders. By pooling images from various cohorts, statistical power has increased, enabling the detection of subtle abnormalities and robust associations, and fostering new research methods. Global collaborations in imaging have furthered our knowledge of the neurobiological foundations of brain disorders and aided in imaging-based prediction for more targeted treatment. Large-scale magnetic resonance imaging initiatives are driving innovation in analytics and supporting generalizable psychiatric studies. We also emphasize the significant role of big data in understanding neural mechanisms and in the early identification and precise treatment of neuropsychiatric disorders. However, challenges such as data harmonization across different sites, privacy protection, and effective data sharing must be addressed. With proper governance and open science practices, we conclude with a projection of how large-scale imaging resources and collaborations could revolutionize diagnosis, treatment selection, and outcome prediction, contributing to optimal brain health.

Arterial spin labelling magnetic resonance imaging and perfusion patterns in neurocognitive and other mental disorders: a systematic review.

We reviewed 33 original research studies assessing brain perfusion, using consensus guidelines from a "white paper" issued by the International Society for Magnetic Resonance in Medicine Perfusion Study Group and the European Cooperation in Science and Technology Action BM1103 ("Arterial Spin Labelling Initiative in Dementia"; https://www.cost.eu/actions/BM1103/ ). The studies were published between 2011 and 2023 and included participants with subjective cognitive decline plus; neurocognitive disorders, including mild cognitive impairment (MCI), Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD), dementia with Lewy bodies (DLB) and vascular cognitive impairment (VCI); as well as schizophrenia spectrum disorders, bipolar and major depressive disorders, autism spectrum disorder, attention-deficit/hyperactivity disorder, panic disorder and alcohol use disorder. Hypoperfusion associated with cognitive impairment was the major finding across the spectrum of cognitive decline. Regional hyperperfusion also was reported in MCI, AD, frontotemporal dementia phenocopy syndrome and VCI. Hypoperfused structures found to aid in diagnosing AD included the precunei and adjacent posterior cingulate cortices. Hypoperfused structures found to better diagnose patients with FTLD were the anterior cingulate cortices and frontal regions. Hypoperfusion in patients with DLB was found to relatively spare the temporal lobes, even after correction for partial volume effects. Hyperperfusion in the temporal cortices and hypoperfusion in the prefrontal and anterior cingulate cortices were found in patients with schizophrenia, most of whom were on medication and at the chronic stage of illness. Infratentorial structures were found to be abnormally perfused in patients with bipolar or major depressive disorders. Brain perfusion abnormalities were helpful in diagnosing most neurocognitive disorders. Abnormalities reported in VCI and the remaining mental disorders were heterogeneous and not generalisable.

Brain Imaging in Routine Psychiatric Practice.

Technologies in the 21st century provide increasingly detailed and accurate maps of brain structure and function. So why don't psychiatrists order brain imaging on all our patients? Here we briefly review major neuroimaging methods and some of their findings in psychiatry. As clinicians and neuroimaging researchers, we are eager to bring brain imaging into daily clinical practice. However, to be clinically useful, any test in medicine must demonstrate adequate test statistics, and show proven benefits that outweigh its risks and costs. In 2024, beyond certain limited circumstances, we have no imaging tests that can meet those standards to provide diagnosis or guide treatment. This cold fact explains why for most psychiatric patients, neuroimaging is not currently recommended by professional organizations or the National Institute of Mental Health.

Neuromelanin-sensitive magnetic resonance imaging in the study of mental disorder: A systematic review.

Dopamine and norepinephrine are implicated in the pathophysiology of mental disorders, but non-invasive study of their neuronal function remains challenging. Recent research suggests that neuromelanin-sensitive magnetic resonance imaging (NM-MRI) techniques may overcome this limitation by enabling the non-invasive imaging of the substantia nigra (SN)/ ventral tegmental area (VTA) dopaminergic and locus coeruleus (LC) noradrenergic systems. A review of 19 studies that met the criteria for NM-MRI application in mental disorders found that despite the use of heterogeneous sequence parameters and metrics, nearly all studies reported differences in contrast ratio (CNR) of LC or SN/VTA between patients with mental disorders and healthy controls. These findings suggest that NM-MRI is a valuable tool in psychiatry, but the differences in sequence parameters across studies hinder comparability, and a standardized analysis pipeline is needed to improve the reliability of results. Further research using standardized methods is needed to better understand the role of dopamine and norepinephrine in mental disorders.

Elevating the field for applying neuroimaging to individual patients in psychiatry.

Although neuroimaging has been widely applied in psychiatry, much of the exuberance in decades past has been tempered by failed replications and a lack of definitive evidence to support the utility of imaging to inform clinical decisions. There are multiple promising ways forward to demonstrate the relevance of neuroimaging for psychiatry at the individual patient level. Ultra-high field magnetic resonance imaging is developing as a sensitive measure of neurometabolic processes of particular relevance that holds promise as a new way to characterize patient abnormalities as well as variability in response to treatment. Neuroimaging may also be particularly suited to the science of brain stimulation interventions in psychiatry given that imaging can both inform brain targeting as well as measure changes in brain circuit communication as a function of how effectively interventions improve symptoms. We argue that a greater focus on individual patient imaging data will pave the way to stronger relevance to clinical care in psychiatry. We also stress the importance of using imaging in symptom-relevant experimental manipulations and how relevance will be best demonstrated by pairing imaging with differential treatment prediction and outcome measurement. The priorities for using brain imaging to inform psychiatry may be shifting, which compels the field to solidify clinical relevance for individual patients over exploratory associations and biomarkers that ultimately fail to replicate.

Anhedonia in adolescents at transdiagnostic familial risk for severe mental illness: Clustering by symptoms and mechanisms of association with behavior.

BACKGROUND: Anhedonia is a transdiagnostic symptom of severe mental illness (SMI) and emerges during adolescence. Possible subphenotypes and neural mechanisms of anhedonia in adolescents at risk for SMI are understudied. METHODS: Adolescents at familial risk for SMI (N = 81) completed anhedonia (e.g., consummatory, anticipatory, social), demographic, and clinical measures and one year prior, a subsample (N = 46) completed fMRI scanning during a monetary reward task. Profiles were identified using k-means clustering of anhedonia type and differences in demographics, suicidal ideation, impulsivity, and emotional processes were examined. Moderation analyses were conducted to investigate whether levels of brain activation of reward regions moderated the relationships between anhedonia type and behaviors. RESULTS: Two-clusters emerged: a high anhedonia profile (high-anhedonia), characterized by high levels of all types of anhedonia, (N = 32) and a low anhedonia profile (low-anhedonia), characterized by low levels of anhedonia types (N = 49). Adolescents in the high-anhedonia profile reported more suicidal ideation and negative affect, and less positive affect and desire for emotional closeness than low-anhedonia profile. Furthermore, more suicidal ideation, less positive affect, and less desire for emotional closeness differentiated the familial high-risk, high-anhedonia profile adolescents from the familial high-risk, low-anhedonia profile adolescents. Across anhedonia profiles, moderation analyses revealed that adolescents with high dmPFC neural activation in response to reward had positive relationships between social, anticipatory, and consummatory anhedonia and suicidal ideation. LIMITATIONS: Small subsample with fMRI data. CONCLUSION: Profiles of anhedonia emerge transdiagnostically and vary on clinical features. Anhedonia severity and activation in frontostriatal reward areas have value for clinically important outcomes such as suicidal ideation.

Visual cortex repetitive transcranial magnetic stimulation (rTMS) reversing neurodevelopmental impairments in adolescents with major psychiatric disorders (MPDs): A cross-species translational study.

AIMS: Neurodevelopmental impairments are closely linked to the basis of adolescent major psychiatric disorders (MPDs). The visual cortex can regulate neuroplasticity throughout the brain during critical periods of neurodevelopment, which may provide a promising target for neuromodulation therapy. This cross-species translational study examined the effects of visual cortex repetitive transcranial magnetic stimulation (rTMS) on neurodevelopmental impairments in MPDs. METHODS: Visual cortex rTMS was performed in both adolescent methylazoxymethanol acetate (MAM) rats and patients with MPDs. Functional magnetic resonance imaging (fMRI) and brain tissue proteomic data in rats and fMRI and clinical symptom data in patients were analyzed. RESULTS: The regional homogeneity (ReHo) analysis of fMRI data revealed an increase in the frontal cortex and a decrease in the posterior cortex in the MAM rats, representing the abnormal neurodevelopmental pattern in MPDs. In regard to the effects of rTMS, similar neuroimaging changes, particularly reduced frontal ReHo, were found both in MAM rats and adolescent patients, suggesting that rTMS may reverse the abnormal neurodevelopmental pattern. Proteomic analysis revealed that rTMS modulated frontal synapse-associated proteins, which may be the underpinnings of rTMS efficacy. Furthermore, a positive relationship was observed between frontal ReHo and clinical symptoms after rTMS in patients. CONCLUSION: Visual cortex rTMS was proven to be an effective treatment for adolescent MPDs, and the underlying neural and molecular mechanisms were uncovered. Our study provides translational evidence for therapeutics targeting the neurodevelopmental factor in MPDs.

Risk of data leakage in estimating the diagnostic performance of a deep-learning-based computer-aided system for psychiatric disorders.

Deep-learning approaches with data augmentation have been widely used when developing neuroimaging-based computer-aided diagnosis (CAD) systems. To prevent the inflated diagnostic performance caused by data leakage, a correct cross-validation (CV) method should be employed, but this has been still overlooked in recent deep-learning-based CAD studies. The goal of this study was to investigate the impact of correct and incorrect CV methods on the diagnostic performance of deep-learning-based CAD systems after data augmentation. To this end, resting-state electroencephalogram (EEG) data recorded from post-traumatic stress disorder patients and healthy controls were augmented using a cropping method with different window sizes, respectively. Four different CV approaches were used to estimate the diagnostic performance of the CAD system, i.e., subject-wise CV (sCV), overlapped sCV (oSCV), trial-wise CV (tCV), and overlapped tCV (otCV). Diagnostic performances were evaluated using two deep-learning models based on convolutional neural network. Data augmentation can increase the performance with all CVs, but inflated diagnostic performances were observed when using incorrect CVs (tCV and otCV) due to data leakage. Therefore, the correct CV (sCV and osCV) should be used to develop a deep-learning-based CAD system. We expect that our investigation can provide deep-insight for researchers who plan to develop neuroimaging-based CAD systems for psychiatric disorders using deep-learning algorithms with data augmentation.

Common and disorder-specific cortical thickness alterations in internalizing, externalizing and thought disorders during early adolescence: an Adolescent Brain and Cognitive Development study.

BACKGROUND: A growing body of neuroimaging studies has reported common neural abnormalities among mental disorders in adults. However, it is unclear whether the distinct disorder-specific mechanisms operate during adolescence despite the overlap among disorders. METHODS: We studied a large cohort of more than 11 000 preadolescent (age 9-10 yr) children from the Adolescent Brain and Cognitive Development cohort. We adopted a regrouping approach to compare cortical thickness (CT) alterations and longitudinal changes between healthy controls (n = 4041) and externalizing (n = 1182), internalizing (n = 1959) and thought disorder (n = 347) groups. Genome-wide association study (GWAS) was performed on regional CT across 4468 unrelated European youth. RESULTS: Youth with externalizing or internalizing disorders exhibited increased regional CT compared with controls. Externalizing (p = 8 × 10-4, Cohen d = 0.10) and internalizing disorders (p = 2 × 10-3, Cohen d = 0.08) shared thicker CT in the left pars opercularis. The somatosensory and the primary auditory cortex were uniquely affected in externalizing disorders, whereas the primary motor cortex and higher-order visual association areas were uniquely affected in internalizing disorders. Only youth with externalizing disorders showed decelerated cortical thinning from age 10-12 years. The GWAS found 59 genome-wide significant associated genetic variants across these regions. Cortical thickness in common regions was associated with glutamatergic neurons, while internalizing-specific regional CT was associated with astrocytes, oligodendrocyte progenitor cells and GABAergic neurons. LIMITATIONS: The sample size of the GWAS was relatively small. CONCLUSION: Our study provides strong evidence for the presence of specificity in CT, developmental trajectories and underlying genetic underpinnings among externalizing and internalizing disorders during early adolescence. Our results support the neurobiological validity of the regrouping approach that could supplement the use of a dimensional approach in future clinical practice.

Cross-attractor modeling of resting-state functional connectivity in psychiatric disorders.

Resting-state functional connectivity (RSFC) is altered across various psychiatric disorders. Brain network modeling (BNM) has the potential to reveal the neurobiological underpinnings of such abnormalities by dynamically modeling the structure-function relationship and examining biologically relevant parameters after fitting the models with real data. Although innovative BNM approaches have been developed, two main issues need to be further addressed. First, previous BNM approaches are primarily limited to simulating noise-driven dynamics near a chosen attractor (or a stable brain state). An alternative approach is to examine multi(or cross)-attractor dynamics, which can be used to better capture non-stationarity and switching between states in the resting brain. Second, previous BNM work is limited to characterizing one disorder at a time. Given the large degree of co-morbidity across psychiatric disorders, comparing BNMs across disorders might provide a novel avenue to generate insights regarding the dynamical features that are common across (vs. specific to) disorders. Here, we address these issues by (1) examining the layout of the attractor repertoire over the entire multi-attractor landscape using a recently developed cross-attractor BNM approach; and (2) characterizing and comparing multiple disorders (schizophrenia, bipolar, and ADHD) with healthy controls using an openly available and moderately large multimodal dataset from the UCLA Consortium for Neuropsychiatric Phenomics. Both global and local differences were observed across disorders. Specifically, the global coupling between regions was significantly decreased in schizophrenia patients relative to healthy controls. At the same time, the ratio between local excitation and inhibition was significantly higher in the schizophrenia group than the ADHD group. In line with these results, the schizophrenia group had the lowest switching costs (energy gaps) across groups for several networks including the default mode network. Paired comparison also showed that schizophrenia patients had significantly lower energy gaps than healthy controls for the somatomotor and visual networks. Overall, this study provides preliminary evidence supporting transdiagnostic multi-attractor BNM approaches to better understand psychiatric disorders' pathophysiology.

Source Free Semi-Supervised Transfer Learning for Diagnosis of Mental Disorders on fMRI Scans.

The high prevalence of mental disorders gradually poses a huge pressure on the public healthcare services. Deep learning-based computer-aided diagnosis (CAD) has emerged to relieve the tension in healthcare institutions by detecting abnormal neuroimaging-derived phenotypes. However, training deep learning models relies on sufficient annotated datasets, which can be costly and laborious. Semi-supervised learning (SSL) and transfer learning (TL) can mitigate this challenge by leveraging unlabeled data within the same institution and advantageous information from source domain, respectively. This work is the first attempt to propose an effective semi-supervised transfer learning (SSTL) framework dubbed S3TL for CAD of mental disorders on fMRI data. Within S3TL, a secure cross-domain feature alignment method is developed to generate target-related source model in SSL. Subsequently, we propose an enhanced dual-stage pseudo-labeling approach to assign pseudo-labels for unlabeled samples in target domain. Finally, an advantageous knowledge transfer method is conducted to improve the generalization capability of the target model. Comprehensive experimental results demonstrate that S3TL achieves competitive accuracies of 69.14%, 69.65%, and 72.62% on ABIDE-I, ABIDE-II, and ADHD-200 datasets, respectively. Furthermore, the simulation experiments also demonstrate the application potential of S3TL through model interpretation analysis and federated learning extension.

Specificity of associations between parental psychopathology and offspring brain structure.

Multiple forms of parental psychopathology have been associated with differences in subcortical brain volume. However, few studies have considered the role of comorbidity. Here, we examine if alterations in child subcortical brain structure are specific to parental depression, anxiety, mania, or alcohol/substance use parental psychopathology, common across these disorders, or altered by a history of multiple disorders. We examined 6581 children aged 9 to 10 years old from the ABCD study with no history of mental disorders. We found several significant interactions such that the effects of a parental history of depression, anxiety, and substance use problems on amygdala and striatal volumes were moderated by comorbid parental history of another disorder. Interactions tended to suggest smaller volumes in the presence of a comorbid disorder. However, effect sizes were small, and no associations remained significant after correcting for multiple comparisons. Results suggest that associations between familial risk for psychopathology and offspring brain structure in 9-10-year-olds are modest, and relationships that do exist tend to implicate the amygdala and striatal regions and are moderated by a comorbid parental psychopathology history. Several methodological factors, including controlling for intracranial volume and other forms of parental psychopathology and excluding child psychopathology, likely contribute to inconsistencies in the literature.

Precision Neuroimaging for Localization-Related Psychiatry.

This Viewpoint describes how precision functional mapping may be helpful for associating neuroanatomical regions with specific psychiatric disorders.