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Cognitive control enables us to translate our knowledge into actions, allowing us to flexibly adjust our behavior, according to environmental contexts, our internal goals, and future plans. Multimodal neuroimaging and neurostimulation techniques have proven essential for advancing our understanding of how cognitive control emerges from the coordination of distributed neuronal activities in the brain. In this review, we examine the literature on multimodal studies of cognitive control. We explore how these studies provide converging evidence for a novel, multiplexed model of cognitive control, in which neural oscillations support different levels of control processing along a functionally hierarchical organization of distinct frontoparietal networks.

The precuneus is a site of early amyloid-beta (Aß) accumulation. Previous cross-sectional studies reported increased precuneus fMRI activity in older adults with mild cognitive deficits or elevated Aß. However, longitudinal studies in early Alzheimer's disease (AD) are lacking and the relationship to the Apolipoprotein-E (APOE) genotype is unclear. Investigating the PREVENT-AD dataset, we assessed how baseline and longitudinal precuneus activity during successful memory retrieval relates to future Aß and tau burden and change in memory performance. We further studied the moderation by APOE4 genotype. We included 165 older adults (age, 62.8 ± 4.4 years; 113 female; 66 APOE4 carriers) who were cognitively normal at baseline with a family history of AD. All participants performed task-fMRI at baseline and underwent 18F-flortaucipir-PET and 18F-NAV4694-Aß-PET on average 5 years later. We found that higher baseline activity and greater longitudinal increase in precuneus activity were associated with higher Aß burden in APOE4 carriers but not noncarriers. We observed no effects of precuneus activity on tau burden. Finally, APOE4 noncarriers with low baseline precuneus activity exhibited better longitudinal performance in an independent memory test compared with (1) noncarriers with higher baseline activity and (2) APOE4 carriers. Our findings suggest that higher task-related precuneus activity duringmemory retrieval at baseline and over time are associated with greater Aß burden in cognitively normal APOE4 carriers. Our results further indicate that the absence of "hyperactivation" and the absence of the APOE4 allele is related with better future cognitive outcomes in cognitively normal older adults at risk for AD. [ABSTRACT FROM AUTHOR]

Glutathione (GSH) is a crucial antioxidant in the human brain. Although proton magnetic resonance spectroscopy using the Mescher-Garwood point-resolved spectroscopy sequence is highly recommended, limited literature has measured cortical GSH using this method in major psychiatric disorders. By combining magnetic resonance spectroscopy and resting-state functional magnetic resonance imaging, we quantified brain GSH and glutamate in the medial prefrontal cortex and precuneus and explored relationships between GSH levels and intrinsic neuronal activity as well as clinical symptoms among healthy control (HC) participants (n = 30), people with major depressive disorder (MDD) (n = 28), and people with obsessive-compulsive disorder (OCD) (n = 28). GSH concentrations were lower in the medial prefrontal cortex and precuneus in both the MDD and OCD groups than in the HC group. In the HC group, positive correlations were noted between GSH and glutamate levels and between GSH and fractional amplitude of low-frequency fluctuations in both regions. However, while these correlations were absent in both patient groups, there was a weak positive correlation between glutamate and fractional amplitude of low-frequency fluctuations. Moreover, GSH levels were negatively correlated with depressive and compulsive symptoms in MDD and OCD, respectively. These findings suggest that reduced GSH levels and an imbalance between GSH and glutamate could increase oxidative stress and alter neurotransmitter signaling, thereby leading to disruptions in GSH-related neurochemical-neuronal coupling and psychopathologies across MDD and OCD. Understanding these mechanisms could provide valuable insights into the processes that underlie these disorders and potentially become a springboard for future directions and advancing our knowledge of their neurobiological foundations. [ABSTRACT FROM AUTHOR]

Understanding the complex activation patterns of brain regions during motor tasks is crucial. Integrated functional magnetic resonance imaging (fMRI) and functional near-infrared spectroscopy (fNIRS) offers advanced insights into how brain activity fluctuates with motor activities. This study explores neuronal activation patterns in the cerebral cortex during active, passive, and imagined wrist movements using these functional imaging techniques. Data were collected from 10 right-handed volunteers performing a motor task using fMRI and fNIRS. fMRI utilized a 3T scanner and a 20-channel head coil, while fNIRS recorded data with a 48-channel device at 765 nm and 855 nm. Analysis focused on key motor and sensory cortices using NIRS-SPM and SPM12, applying a significance threshold of p < 0.05 and a minimum cluster size of 10 voxels for group analysis. Super-threshold voxels were identified with FWE thresholding in SPM12. For activation map extraction we focused on the primary motor cortex, primary somatosensory cortex, somatosensory association cortex, premotor cortex, and supplementary motor cortex. Both fMRI and fNIRS detected activation in the primary motor cortex (M1). The primary somatosensory cortex was found to influence movement direction coding, with smaller activation sizes for upward movements. Combining fNIRS with fMRI provided clearer differentiation of brain activation patterns for wrist movements in various directions and conditions (p < 0.05). This study highlights variations in left motor cortex activity across different movement states. fNIRS proved effective in detecting brain function and showed strong correlation with fMRI results, suggesting it as a viable alternative for those unable to undergo fMRI. [ABSTRACT FROM AUTHOR]

Despite advancements in brain-computer interface (BCI) research, effectively integrating electroencephalogram (EEG) and functional near-infrared spectroscopy (fNIRS) data remains a challenge due to the reliance on handcrafted features and limited channel selection. To address these issues, this study introduces the autoencoder-led multimodal fusion network (AMFN) for EEG–fNIRS classification. AMFN utilizes an autoencoder for automated feature extraction from EEG data and integrates these features with fNIRS data using advanced fusion techniques. This approach significantly enhances classification accuracy, surpassing traditional methods. Experimental results on motor imagery (MI) tasks demonstrate AMFN's superior performance, achieving an average intra-subject accuracy of 95.69% in left and right MI classification. This research paves the way for more intuitive and reliable BCI systems, with potential applications in robotic control, neurorehabilitation, and human-machine interaction. [ABSTRACT FROM AUTHOR]

Introduction: There is a growing interest in the effect of Long-COVID (LC) on cognition, and neuroimaging allows us to gain insight into the structural and functional changes underlying cognitive impairment in LC. We used multimodal neuroimaging data in combination with neuropsychological evaluations to study cognitive complaints in a cohort of LC patients with mild to moderate severity symptoms. Methods: We conducted a 3T brain magnetic resonance imaging (MRI) study with diffusion tensor imaging (DTI) and functional MRI (fMRI) sequences on 53 LC patients 1.8 years after acute COVID-19 onset. We administered neuropsychological tests to evaluate cognitive domains and examined correlations with Tract-Based Spatial Statistics (TBSS) and resting state. Results: We included 53 participants with LC (mean age, 48.23 years; 88.7% females). According to the Frascati criteria, more than half of the participants had deficits in the executive (59%) and attentional (55%) domains, while 40% had impairments in the memory domain. Only one participant (1.89%) showed problems in the visuospatial and visuoconstructive domain. We observed that increased radial diffusivity in different white matter tracts was negatively correlated with the memory domain. Our results showed that higher resting state activity in the fronto-parietal network was associated with lower memory performance. Moreover, we detected increased functional connectivity among the bilateral hippocampus, the right hippocampus and the left amygdala, and the right hippocampus and the left middle temporal gyrus. These connectivity patterns were inversely related to memory and did not survive false discovery rate (FDR) correction. Discussion: People with LC exhibit cognitive impairments linked to long-lasting changes in brain structure and function, which justify the cognitive alterations detected. [ABSTRACT FROM AUTHOR]

Atypical social impairments (i.e., impaired social cognition and social communication) are vital manifestations of autism spectrum disorder (ASD) patients, and the incidence rate of ASD is significantly higher in males than in females. Characterizing the atypical brain patterns underlying social deficits of ASD is significant for understanding the pathogenesis. However, there are no robust imaging biomarkers that are specific to ASD, which may be due to neurobiological complexity and limitations of single‐modality research. To describe the multimodal brain patterns related to social deficits in ASD, we highlighted the potential functional role of white matter (WM) and incorporated WM functional activity and gray matter structure into multimodal fusion. Gray matter volume (GMV) and fractional amplitude of low‐frequency fluctuations of WM (WM‐fALFF) were combined by fusion analysis model adopting the social behavior. Our results revealed multimodal spatial patterns associated with Social Responsiveness Scale multiple scores in ASD. Specifically, GMV exhibited a consistent brain pattern, in which salience network and limbic system were commonly identified associated with all multiple social impairments. More divergent brain patterns in WM‐fALFF were explored, suggesting that WM functional activity is more sensitive to ASD's complex social impairments. Moreover, brain regions related to social impairment may be potentially interconnected across modalities. Cross‐site validation established the repeatability of our results. Our research findings contribute to understanding the neural mechanisms underlying social disorders in ASD and affirm the feasibility of identifying biomarkers from functional activity in WM. [ABSTRACT FROM AUTHOR]

Schizophrenia is a complex and serious brain disorder. Neuroscientists have become increasingly interested in using magnetic resonance-based brain imaging-derived phenotypes (IDPs) to investigate the etiology of psychiatric disorders. IDPs capture valuable clinical advantages and hold biological significance in identifying brain abnormalities. In this review, we aim to discuss current and prospective approaches to identify potential biomarkers for schizophrenia using clinical multimodal neuroimaging and imaging genetics. We first described IDPs through their phenotypic classification and neuroimaging genomics. Secondly, we discussed the applications of multimodal neuroimaging by clinical evidence in observational studies and randomized controlled trials. Thirdly, considering the genetic evidence of IDPs, we discussed how can utilize neuroimaging data as an intermediate phenotype to make association inferences by polygenic risk scores and Mendelian randomization. Finally, we discussed machine learning as an optimum approach for validating biomarkers. Together, future research efforts focused on neuroimaging biomarkers aim to enhance our understanding of schizophrenia. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer’s disease (AD), the most prevalent age-related dementia, leads to significant cognitive decline. While genetic risk factors and neuroimaging biomarkers have been extensively studied, establishing a neuroimaging-based metric to assess AD risk has received less attention. This study introduces the Brain-wide Risk Score (BRS), a novel approach using multimodal neuroimaging data to assess the risk of mild cognitive impairment (MCI), a precursor to AD. Methods: Participants from the OASIS-3 cohort (N = 1,389) were categorized into control (CN) and MCI groups. Structural MRI (sMRI) data provided gray matter (GM) segmentation maps, while resting-state functional MRI (fMRI) data yielded functional network connectivity (FNC) matrices via spatially constrained independent component analysis. Similar imaging features were computed from the UK Biobank (N = 37,780). The BRS was calculated by comparing each participant’s neuroimaging features to the difference between average features of CN and MCI groups. Both GM and FNC features were used. The BRS effectively differentiated CN from MCI individuals within OASIS-3 and in an independent dataset from the ADNI cohort (N = 729), demonstrating its ability to identify MCI risk. Results: Unimodal analysis revealed that sMRI provided greater differentiation than fMRI, consistent with prior research. Using the multimodal BRS, we identified two distinct groups: one with high MCI risk (negative GM and FNC BRS) and another with low MCI risk (positive GM and FNC BRS). Additionally, 46 UK Biobank participants diagnosed with AD showed FNC and GM patterns similar to the high-risk groups. Conclusion: Validation using the ADNI dataset confirmed our results, highlighting the potential of FNC and sMRI-based BRS in early Alzheimer’s detection.

Background: Post-traumatic stress disorder (PTSD) is increasingly prevalent in individuals with adverse childhood experiences (ACE). However, the underlying neurobiology of ACE-related PTSD remains unclear.Objective: The present study investigated the brain connectivity in ACE-related PTSD using multimodal neuroimaging data.Methods: Using a total of 119 participants with ACE (70 with ACE-related PTSD and 49 ACE-exposed controls), this study acquired T1-weighted MRI, diffusion-weighted MRI, and resting-state fMRI data to examine structural and functional connectivity between groups. Joint connectivity matrix independent component analysis (Jcm-ICA) was employed to allow shared information from all modalities to be examined and assess structural and functional connectivity differences between groups.Results: Jcm-ICA revealed distinct connectivity alterations in key brain regions involved in cognitive control, self-referential processing, and social behaviour. Compared to controls, the PTSD group exhibited functional hyperconnectivity of the right medial prefrontal cortex (PFC) of the default mode network and right inferior temporal cortex, and functional hypoconnectivity in the lateral-PFC of the central executive network and structural hypoconnectivity in white matter pathways including the right orbitofrontal region (OFC) linked to social behaviour. Post-hoc analyses using the joint brain-based information revealed that the severity of ACE, the number of traumas, and PTSD symptoms later in life significantly predicted the effects of ACE-related PTSD on the brain. Notably, no direct association between brain connectivity alterations and PTSD symptoms or the number of traumas within the PTSD group was observed.Conclusion: This study offers novel insights into the neurobiology of ACE-related PTSD using multimodal data fusion. We identified alterations in key brain networks (DMN, CEN) and OFC, suggesting potential deficits in cognitive control and social behaviour alongside heightened emotional processing in individuals with PTSD. Furthermore, our findings highlight the combined influence of ACE exposure, number of traumas experienced, and PTSD severity on brain connectivity disruptions, potentially informing future interventions.

The intricate dynamics of brain aging, especially the neurodegenerative mechanisms driving accelerated (ABA) and resilient brain aging (RBA), are pivotal in neuroscience. Understanding the temporal dynamics of these phenotypes is crucial for identifying vulnerabilities to cognitive decline and neurodegenerative diseases. Currently, there is a lack of comprehensive understanding of the temporal dynamics and neuroimaging biomarkers linked to ABA and RBA. This study addressed this gap by utilizing a large-scale UK Biobank (UKB) cohort, with the aim to elucidate brain aging heterogeneity and establish the foundation for targeted interventions. Employing Lasso regression on multimodal neuroimaging data, structural MRI (sMRI), diffusion MRI (dMRI), and resting-state functional MRI (rsfMRI), we predicted the brain age and classified individuals into ABA and RBA cohorts. Our findings identified 1949 subjects (6.2%) as representative of the ABA subpopulation and 3203 subjects (10.1%) as representative of the RBA subpopulation. Additionally, the Discriminative Event-Based Model (DEBM) was applied to estimate the sequence of biomarker changes across aging trajectories. Our analysis unveiled distinct central ordering patterns between the ABA and RBA cohorts, with profound implications for understanding cognitive decline and vulnerability to neurodegenerative disorders. Specifically, the ABA cohort exhibited early degeneration in four functional networks and two cognitive domains, with cortical thinning initially observed in the right hemisphere, followed by the temporal lobe. In contrast, the RBA cohort demonstrated initial degeneration in the three functional networks, with cortical thinning predominantly in the left hemisphere and white matter microstructural degeneration occurring at more advanced stages. The detailed aging progression timeline constructed through our DEBM analysis positioned subjects according to their estimated stage of aging, offering a nuanced view of the aging brain's alterations. This study holds promise for the development of targeted interventions aimed at mitigating age-related cognitive decline. [ABSTRACT FROM AUTHOR]

Statistical analysis of multimodal imaging data is a challenging task, since the data involves high-dimensionality, strong spatial correlations and complex data structures. In this article, we propose rigorous statistical testing procedures for making inferences on the complex dependence of multimodal imaging data. Motivated by the analysis of multi-task fMRI data in the Human Connectome Project (HCP) study, we particularly address three hypothesis testing problems: (a) testing independence among imaging modalities over brain regions, (b) testing independence between brain regions within imaging modalities, and (c) testing independence between brain regions across different modalities. Considering a general form for all the three tests, we develop a global testing procedure and a multiple testing procedure controlling the false discovery rate. We study theoretical properties of the proposed tests and develop a computationally efficient distributed algorithm. The proposed methods and theory are general and relevant for many statistical problems of testing independence structure among the components of high-dimensional random vectors with arbitrary dependence structures. We also illustrate our proposed methods via extensive simulations and analysis of five task fMRI contrast maps in the HCP study. for this article are available online. [ABSTRACT FROM AUTHOR]

Obsessive-compulsive disorder (OCD) is a highly heterogeneous mental condition with a diverse symptom. Existing studies classified OCD on the basis of conventional phenomenology-based taxonomy ignoring the fact that the same subtype identified in accordance with clinical symptom may have different mechanisms and treatment responses. This research involved 50 medicine-free patients with OCD and 50 matched healthy controls (HCs). All the participants were subjected to structural and functional magnetic resonance imaging (MRI). Voxel-based morphometry (VBM) and amplitude of low frequency fluctuation (ALFF) were used to evaluate gray matter volume (GMV) and spontaneous neuronal activities at rest respectively. Similarity network fusion (SNF) was utilized to integrate GMVs and spontaneous neuronal activities, and heterogeneity by discriminant analysis was applied to characterise OCD subtypes. Two OCD subtypes were identified: Subtype 1 exhibited decreased GMVs (i.e., left inferior temporal gyrus, right supplementary motor area and right lingual gyrus) and increased ALFF value (i.e., right orbitofrontal cortex), whereas subtype 2 exhibited increased GMVs (i.e., left cuneus, right precentral gyrus, left postcentral gyrus and left hippocampus) and decreased ALFF value (i.e., right caudate nucleus). Furthermore, the altered GMVs was negatively correlated with abnormal ALFF values in both subtype 1 and 2. This study requires further validation via a larger, independent dataset and should consider the potential influences of psychotropic medication on OCD patients' brain activities. Results revealed two reproducible subtypes of OCD based on underlying multimodal neuroimaging and provided new perspectives on the classification of OCD. • Data-driven subtype analysis of OCD patients rather than previous symptom-based analysis • The multimodal fusion method fuses the magnetic resonance images of two modalities. • Semi-supervised machine learning approach for subtype analysis of obsessive-compulsive disorder [ABSTRACT FROM AUTHOR]

In recent years, Alzheimer's disease (AD) has been a serious threat to human health. Researchers and clinicians alike encounter a significant obstacle when trying to accurately identify and classify AD stages. Several studies have shown that multimodal neuroimaging input can assist in providing valuable insights into the structural and functional changes in the brain related to AD. Machine learning (ML) algorithms can accurately categorize AD phases by identifying patterns and linkages in multimodal neuroimaging data using powerful computational methods. This study aims to assess the contribution of ML methods to the accurate classification of the stages of AD using multimodal neuroimaging data. A systematic search is carried out in IEEE Xplore, Science Direct/Elsevier, ACM DigitalLibrary, and PubMed databases with forward snowballing performed on Google Scholar. The quantitative analysis used 47 studies. The explainable analysis was performed on the classification algorithm and fusion methods used in the selected studies. The pooled sensitivity and specificity, including diagnostic efficiency, were evaluated by conducting a meta-analysis based on a bivariate model with the hierarchical summary receiver operating characteristics (ROC) curve of multimodal neuroimaging data and ML methods in the classification of AD stages. Wilcoxon signed-rank test is further used to statistically compare the accuracy scores of the existing models. With a 95% confidence interval of 78.87–87.71%, the combined sensitivity for separating participants with mild cognitive impairment (MCI) from healthy control (NC) participants was 83.77%; for separating participants with AD from NC, it was 94.60% (90.76%, 96.89%); for separating participants with progressive MCI (pMCI) from stable MCI (sMCI), it was 80.41% (74.73%, 85.06%). With a 95% confidence interval (78.87%, 87.71%), the Pooled sensitivity for distinguishing mild cognitive impairment (MCI) from healthy control (NC) participants was 83.77%, with a 95% confidence interval (90.76%, 96.89%), the Pooled sensitivity for distinguishing AD from NC was 94.60%, likewise (MCI) from healthy control (NC) participants was 83.77% progressive MCI (pMCI) from stable MCI (sMCI) was 80.41% (74.73%, 85.06%), and early MCI (EMCI) from NC was 86.63% (82.43%, 89.95%). Pooled specificity for differentiating MCI from NC was 79.16% (70.97%, 87.71%), AD from NC was 93.49% (91.60%, 94.90%), pMCI from sMCI was 81.44% (76.32%, 85.66%), and EMCI from NC was 85.68% (81.62%, 88.96%). The Wilcoxon signed rank test showed a low P-value across all the classification tasks. Multimodal neuroimaging data with ML is a promising future in classifying the stages of AD but more research is required to increase the validity of its application in clinical practice. [ABSTRACT FROM AUTHOR]

The dorsomedial prefrontal cortex (dmPFC) plays a crucial role in social cognitive functions, including perspective-taking. Although perspective-taking has been linked to self-control, the mechanism by which the dmPFC might facilitate self-control remains unclear. Using the multimodal neuroimaging dataset from the Human Connectome Project (Study 1, N =978 adults), we established a reliable association between the dmPFC and self-control, as measured by discounting rate—the tendency to prefer smaller, immediate rewards over larger, delayed ones. Experiments (Study 2, N = 36 adults) involving high-definition transcranial direct current stimulation showed that anodal stimulation of the dmPFC reduces the discounting of delayed rewards and decreases the congruency effect in egocentric but not allocentric perspective in the visual perspective-taking tasks. These findings suggest that the dmPFC promotes self-control by inhibiting the egocentric perspective, offering new insights into the neural underpinnings of self-control and perspective-taking, and opening new avenues for interventions targeting disorders characterized by impaired self-regulation.

IntroductionThere is a growing interest in the effect of Long-COVID (LC) on cognition, and neuroimaging allows us to gain insight into the structural and functional changes underlying cognitive impairment in LC. We used multimodal neuroimaging data in combination with neuropsychological evaluations to study cognitive complaints in a cohort of LC patients with mild to moderate severity symptoms.MethodsWe conducted a 3T brain magnetic resonance imaging (MRI) study with diffusion tensor imaging (DTI) and functional MRI (fMRI) sequences on 53 LC patients 1.8 years after acute COVID-19 onset. We administered neuropsychological tests to evaluate cognitive domains and examined correlations with Tract-Based Spatial Statistics (TBSS) and resting state.ResultsWe included 53 participants with LC (mean age, 48.23 years; 88.7% females). According to the Frascati criteria, more than half of the participants had deficits in the executive (59%) and attentional (55%) domains, while 40% had impairments in the memory domain. Only one participant (1.89%) showed problems in the visuospatial and visuoconstructive domain. We observed that increased radial diffusivity in different white matter tracts was negatively correlated with the memory domain. Our results showed that higher resting state activity in the fronto-parietal network was associated with lower memory performance. Moreover, we detected increased functional connectivity among the bilateral hippocampus, the right hippocampus and the left amygdala, and the right hippocampus and the left middle temporal gyrus. These connectivity patterns were inversely related to memory and did not survive false discovery rate (FDR) correction.DiscussionPeople with LC exhibit cognitive impairments linked to long-lasting changes in brain structure and function, which justify the cognitive alterations detected.

Background: Stress and depression have a reciprocal relationship, but the neural underpinnings of this reciprocity are unclear. We investigated neuroimaging phenotypes that facilitate the reciprocity between stress and depressive symptoms. Methods: In total, 22 195 participants (52.0% females) from the population-based UK Biobank study completed two visits (initial visit: 2006–2010, age = 55.0 ± 7.5 [40–70] years; second visit: 2014–2019; age = 62.7 ± 7.5 [44–80] years). Structural equation modeling was used to examine the longitudinal relationship between self-report stressful life events (SLEs) and depressive symptoms. Cross-sectional data were used to examine the overlap between neuroimaging correlates of SLEs and depressive symptoms on the second visit among 138 multimodal imaging phenotypes. Results: Longitudinal data were consistent with significant bidirectional causal relationship between SLEs and depressive symptoms. In cross-sectional analyses, SLEs were significantly associated with lower bilateral nucleus accumbal volume and lower fractional anisotropy of the forceps major. Depressive symptoms were significantly associated with extensive white matter hyperintensities, thinner cortex, lower subcortical volume, and white matter microstructural deficits, mainly in corticostriatal-limbic structures. Lower bilateral nucleus accumbal volume were the only imaging phenotypes with overlapping effects of depressive symptoms and SLEs (B = −0.032 to −0.023, p = 0.006–0.034). Depressive symptoms and SLEs significantly partially mediated the effects of each other on left and right nucleus accumbens volume (proportion of effects mediated = 12.7–14.3%, p < 0.001− p = 0.008). For the left nucleus accumbens, post-hoc seed-based analysis showed lower resting-state functional connectivity with the left orbitofrontal cortex (cluster size = 83 voxels, p = 5.4 × 10−5) in participants with high v. no SLEs. Conclusions: The nucleus accumbens may play a key role in the reciprocity between stress and depressive symptoms. [ABSTRACT FROM AUTHOR]

Background: Obsessive–compulsive disorder (OCD) is a classic disorder on the compulsivity spectrum, with diverse comorbidities. In the current study, we sought to understand OCD from a dimensional perspective by identifying multimodal neuroimaging patterns correlated with multiple phenotypic characteristics within the striatum-based circuits known to be affected by OCD. Methods: Neuroimaging measurements of local functional and structural features and clinical information were collected from 110 subjects, including 51 patients with OCD and 59 healthy control subjects. Linked independent component analysis (LICA) and correlation analysis were applied to identify associations between local neuroimaging patterns across modalities (including gray matter volume, white matter integrity, and spontaneous functional activity) and clinical factors. Results: LICA identified eight multimodal neuroimaging patterns related to phenotypic variations, including three related to symptoms and diagnosis. One imaging pattern (IC9) that included both the amplitude of low-frequency fluctuation measure of spontaneous functional activity and white matter integrity measures correlated negatively with OCD diagnosis and diagnostic scales. Two imaging patterns (IC10 and IC27) correlated with compulsion symptoms: IC10 included primarily anatomical measures and IC27 included primarily functional measures. In addition, we identified imaging patterns associated with age, gender, and emotional expression across subjects. Conclusions: We established that data fusion techniques can identify local multimodal neuroimaging patterns associated with OCD phenotypes. The results inform our understanding of the neurobiological underpinnings of compulsive behaviors and OCD diagnosis. [ABSTRACT FROM AUTHOR]

Objective.The differential diagnosis of behavioral variant frontotemporal dementia (bvFTD) and Alzheimers disease (AD) remains challenging in underrepresented, underdiagnosed groups, including Latinos, as advanced biomarkers are rarely available. Recent guidelines for the study of dementia highlight the critical role of biomarkers. Thus, novel cost-effective complementary approaches are required in clinical settings.Approach. We developed a novel framework based on a gradient boosting machine learning classifier, tuned by Bayesian optimization, on a multi-feature multimodal approach (combining demographic, neuropsychological, magnetic resonance imaging (MRI), and electroencephalography/functional MRI connectivity data) to characterize neurodegeneration using site harmonization and sequential feature selection. We assessed 54 bvFTD and 76 AD patients and 152 healthy controls (HCs) from a Latin American consortium (ReDLat).Main results. The multimodal model yielded high area under the curve classification values (bvFTD patients vs HCs: 0.93 (±0.01); AD patients vs HCs: 0.95 (±0.01); bvFTD vs AD patients: 0.92 (±0.01)). The feature selection approach successfully filtered non-informative multimodal markers (from thousands to dozens).Results. Proved robust against multimodal heterogeneity, sociodemographic variability, and missing data.Significance. The model accurately identified dementia subtypes using measures readily available in underrepresented settings, with a similar performance than advanced biomarkers. This approach, if confirmed and replicated, may potentially complement clinical assessments in developing countries.

The integration of electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) can facilitate the advancement of brain-computer interfaces (BCIs). However, existing research in this domain has grappled with the challenge of the efficient selection of features, resulting in the underutilization of the temporal richness of EEG and the spatial specificity of fNIRS data.To effectively address this challenge, this study proposed a deep learning architecture called the multimodal DenseNet fusion (MDNF) model that was trained on two-dimensional (2D) EEG data images, leveraging advanced feature extraction techniques. The model transformed EEG data into 2D images using a short-time Fourier transform, applied transfer learning to extract discriminative features, and consequently integrated them with fNIRS-derived spectral entropy features. This approach aimed to bridge existing gaps in EEG-fNIRS-based BCI research by enhancing classification accuracy and versatility across various cognitive and motor imagery tasks.Experimental results on two public datasets demonstrated the superiority of our model over existing state-of-the-art methods.Thus, the high accuracy and precise feature utilization of the MDNF model demonstrates the potential in clinical applications for neurodiagnostics and rehabilitation, thereby paving the method for patient-specific therapeutic strategies.

The article discusses the use of multimodal neuroimaging to map the depressed brain under stress. It highlights the challenges of replicating brain-behavior associations in small cohorts and proposes new approaches to address this issue, such as using generative artificial intelligence models and conducting multimodal experimental studies. The article presents a specific study that examines the neural mechanisms and correlates of stress responses in individuals with major depressive disorder (MDD) and remitted MDD. The study finds disruptions in cortisol signaling, GABA levels, and large-scale brain network dynamics in individuals with MDD, providing insights into the maladaptive stress responses in depression. The article also discusses the potential implications of these findings for identifying biomarkers, developing interventions, and understanding sex differences in depression. [Extracted from the article]

This document is an editorial published in Frontiers in Neuroscience titled "Translational applications of neuroimaging." The editorial discusses the limited use of neuroimaging in clinical applications and highlights recent research efforts to bridge the gap between scientific insights and clinical solutions. The editorial features five original studies that explore the use of electroencephalography (EEG) as a tool for diagnosing and prognosing neurological and psychiatric disorders. Other topics covered include the use of neuroimaging for studying brain structure changes, the combination of different imaging techniques, and the potential of real-time interventions. The editorial concludes by identifying promising applications of neuroimaging in the management of various conditions such as chronic pain, epilepsy, stroke, and mental health disorders. [Extracted from the article]

BackgroundConcordance between cortical atrophy and cortical glucose hypometabolism within distributed brain networks was evaluated among cerebrospinal fluid (CSF) biomarker-defined amyloid/tau/neurodegeneration (A/T/N) groups.MethodWe computed correlations between cortical thickness and fluorodeoxyglucose metabolism within 12 functional brain networks. Differences among A/T/N groups (biomarker normal [BN], Alzheimer's disease [AD] continuum, suspected non-AD pathologic change [SNAP]) in network concordance and relationships to longitudinal change in cognition were assessed.ResultsNetwork-wise markers of concordance distinguish SNAP subjects from BN subjects within the posterior multimodal and language networks. AD-continuum subjects showed increased concordance in 9/12 networks assessed compared to BN subjects, as well as widespread atrophy and hypometabolism. Baseline network concordance was associated with longitudinal change in a composite memory variable in both SNAP and AD-continuum subjects.ConclusionsOur novel study investigates the interrelationships between atrophy and hypometabolism across brain networks in A/T/N groups, helping disentangle the structure-function relationships that contribute to both clinical outcomes and diagnostic uncertainty in AD.

Episodic memory performance declines with increasing age, and older adults typically show reduced activation of inferior temporo-parietal cortices in functional magnetic resonance imaging (fMRI) studies of episodic memory formation. Given the age-related cortical volume loss, it is conceivable that age-related reduction of memory-related fMRI activity may be partially attributable to reduced grey matter volume (GMV). We performed a voxel-wise multimodal neuroimaging analysis of fMRI correlates of successful memory encoding, using regional GMV as covariate. In a large cohort of healthy adults (106 young, 111 older), older adults showed reduced GMV across the entire neocortex and reduced encoding-related activation of inferior temporal and parieto-occipital cortices compared to young adults. Importantly, these reduced fMRI activations during successful encoding could in part be attributed to lower regional GMV. Our results highlight the importance of controlling for structural MRI differences in fMRI studies in older adults but also demonstrate that age-related differences in memory-related fMRI activity cannot be attributed to structural variability alone. [Display omitted] • Structural differences in distinct age groups may in part explain fMRI differences. • We included voxel-wise GMV into models of the fMRI subsequent memory effect. • Reduced encoding-related activations could in part be attributed to lower local GMV. • Care is advised when modelling fMRI effects for groups with structural differences. • Structural modalities may in part explain alleged differences in function. [ABSTRACT FROM AUTHOR]

Combining multimodal approaches with functional magnetic resonance imaging (fMRI) has catapulted the research on brain circuitries of non-human primates (NHPs) into a new era. However, many studies are constrained by a lack of appropriate RF coils. In this study, a single loop transmit and 16-channel receive array coil was constructed for brain imaging of macaques at 7 Tesla (7 T). The 16 receive channels were mounted on a 3D-printed helmet-shaped form closely fitting the macaque head, with fourteen openings arranged for multimodal devices around the cortical regions. Coil performance was evaluated by quantifying and comparing signal-to-noise ratio (SNR) maps, noise correlations, g-factor maps and flip-angle maps with a 28-channel commercial knee coil. The in vivo results suggested that the macaque coil has higher SNR in cortical regions and better acceleration ability in parallel imaging, which may benefit revealing mesoscale organizations in the brain. [ABSTRACT FROM AUTHOR]

Multimodal neuroimaging has gained traction in Alzheimer's Disease (AD) diagnosis by integrating information from multiple imaging modalities to enhance classification accuracy. However, effectively handling heterogeneous data sources and overcoming the challenges posed by multiscale transform methods remains a significant hurdle. This article proposes a novel approach to address these challenges. To harness the power of diverse neuroimaging data, we employ a strategy that leverages optimized convolution techniques. These optimizations include varying kernel sizes and the incorporation of instance normalization, both of which play crucial roles in feature extraction from magnetic resonance imaging (MRI) and positron emission tomography (PET) images. Specifically, varying kernel sizes allow us to adapt the receptive field to different image characteristics, enhancing the model's ability to capture relevant information. Furthermore, we employ transposed convolution, which increases spatial resolution of feature maps, and it is optimized with varying kernel sizes and instance normalization. This heightened resolution facilitates the alignment and integration of data from disparate MRI and PET data. The use of larger kernels and strides in transposed convolution expands the receptive field, enabling the model to capture essential cross-modal relationships. Instance normalization, applied to each modality during the fusion process, mitigates potential biases stemming from differences in intensity, contrast, or scale between modalities. This enhancement contributes to improved model performance by reducing complexity and ensuring robust fusion. The performance of the proposed fusion method is assessed on three distinct neuroimaging datasets, which include: Alzheimer's Disease Neuroimaging Initiative (ADNI), consisting of 50 participants each at various stages of AD for both MRI and PET (Cognitive Normal, AD, and Early Mild Cognitive); Open Access Series of Imaging Studies (OASIS), consisting of 50 participants each at various stages of AD for both MRI and PET (Cognitive Normal, Mild Dementia, Very Mild Dementia); and whole-brain atlas neuroimaging (AANLIB) (consisting of 50 participants each at various stages of AD for both MRI and PET (Cognitive Normal, AD). To evaluate the quality of the fused images generated via our method, we employ a comprehensive set of evaluation metrics, including Structural Similarity Index Measurement (SSIM), which assesses the structural similarity between two images; Peak Signal-to-Noise Ratio (PSNR), which measures how closely the generated image resembles the ground truth; Entropy (E), which assesses the amount of information preserved or lost during fusion; the Feature Similarity Indexing Method (FSIM), which assesses the structural and feature similarities between two images; and Edge-Based Similarity (EBS), which measures the similarity of edges between the fused and ground truth images. The obtained fused image is further evaluated using a Mobile Vision Transformer. In the classification of AD vs. Cognitive Normal, the model achieved an accuracy of 99.00%, specificity of 99.00%, and sensitivity of 98.44% on the AANLIB dataset. [ABSTRACT FROM AUTHOR]

Cognitive dysfunction is an important non-motor symptom in amyotrophic lateral sclerosis (ALS) that has a negative impact on survival and caregiver burden. It shows a wide spectrum ranging from subjective cognitive decline to frontotemporal dementia (FTD) and covers various cognitive domains, mainly executive/attention, language and verbal memory deficits. The frequency of cognitive impairment across the different ALS phenotypes ranges from 30% to 75%, with up to 45% fulfilling the criteria of FTD. Significant genetic, clinical, and pathological heterogeneity reflects deficits in various cognitive domains. Modern neuroimaging studies revealed frontotemporal degeneration and widespread involvement of limbic and white matter systems, with hypometabolism of the relevant areas. Morphological substrates are frontotemporal and hippocampal atrophy with synaptic loss, associated with TDP-43 and other co-pathologies, including tau deposition. Widespread functional disruptions of motor and extramotor networks, as well as of frontoparietal, frontostriatal and other connectivities, are markers for cognitive deficits in ALS. Cognitive reserve may moderate the effect of brain damage but is not protective against cognitive decline. The natural history of cognitive dysfunction in ALS and its relationship to FTD are not fully understood, although there is an overlap between the ALS variants and ALS-related frontotemporal syndromes, suggesting a differential vulnerability of motor and non-motor networks. An assessment of risks or the early detection of brain connectivity signatures before structural changes may be helpful in investigating the pathophysiological mechanisms of cognitive impairment in ALS, which might even serve as novel targets for effective disease-modifying therapies. [ABSTRACT FROM AUTHOR]

Multimodal data are now prevailing in scientific research. One of the central questions in multimodal integrative analysis is to understand how two data modalities associate and interact with each other given another modality or demographic variables. The problem can be formulated as studying the associations among three sets of random variables, a question that has received relatively less attention in the literature. In this article, we propose a novel generalized liquid association analysis method, which offers a new and unique angle to this important class of problems of studying three-way associations. We extend the notion of liquid association from the univariate setting to the sparse, multivariate, and high-dimensional setting. We establish a population dimension reduction model, transform the problem to sparse Tucker decomposition of a three-way tensor, and develop a higher-order orthogonal iteration algorithm for parameter estimation. We derive the nonasymptotic error bound and asymptotic consistency of the proposed estimator, while allowing the variable dimensions to be larger than and diverge with the sample size. We demonstrate the efficacy of the method through both simulations and a multimodal neuroimaging application for Alzheimer's disease research. for this article are available online. [ABSTRACT FROM AUTHOR]

• We examined the multimodal connectivity changes of the Papez circuit in Alzheimer's disease. • The ventral cingulum is critical for the early detection of Alzheimer's disease. • The functional connectivity between retrosplenial and parahippocampal cortices is affected early in the disease. Alzheimer's disease (AD) is a progressive neurodegenerative continuum with memory impairment. We aimed to examine the detailed functional (FC) and structural connectivity (SC) pattern of the Papez circuit, known as the memory circuit, along the AD. MRI data of 15 patients diagnosed with AD dementia (ADD), 15 patients with the amnestic mild cognitive impairment (MCI), and 15 patients with subjective cognitive impairment were analyzed. The FC analyses were performed between main nodes of the Papez circuit, and the SC was quantified as fractional anisotropy (FA) of the main white matter pathways of the Papez circuit. The FC between the retrosplenial (RSC) and parahippocampal cortices (PHC) was the earliest affected FC, while a manifest SC change in the ventral cingulum and fornix was observed in the later ADD stage. The RSC-PHC FC and the ventral cingulum FA efficiently predicted the memory performance of the non-demented participants. Our findings revealed the importance of the Papez circuit as target regions along the AD. The ventral cingulum connecting the RSC and PHC, a critical overlap area between the Papez circuit and the default mode network, seems to be a target region associated with the earliest objective memory findings in AD. [ABSTRACT FROM AUTHOR]

ObjectivesTemporal lobe epilepsy (TLE) is known to affect large-scale gray and white matter networks, and these network changes likely contribute to the verbal memory impairments observed in many patients. In this study, we investigate multimodal imaging patterns of brain alterations in TLE and evaluate the sensitivity of different imaging measures to verbal memory impairment.MethodsDiffusion tensor imaging (DTI), volumetric magnetic resonance imaging (vMRI), and resting-state functional MRI (rs-fMRI) were evaluated in 46 patients with TLE and 33 healthy controls to measure patterns of microstructural, structural, and functional alterations, respectively. These measurements were obtained within the white matter directly beneath neocortex (ie, superficial white matter [SWM]) for DTI and across neocortex for vMRI and rs-fMRI. The degree to which imaging alterations within left medial temporal lobe/posterior cingulate (LMT/PC) and left lateral temporal regions were associated with verbal memory performance was evaluated.ResultsPatients with left TLE and right TLE both demonstrated pronounced microstructural alterations (ie, decreased fractional anisotropy [FA] and increased mean diffusivity [MD]) spanning the entire frontal and temporolimbic SWM, which were highly lateralized to the ipsilateral hemisphere. Conversely, reductions in cortical thickness in vMRI and alterations in the magnitude of the rs-fMRI response were less pronounced and less lateralized than the microstructural changes. Both stepwise regression and mediation analyses further revealed that FA and MD within SWM in LMT/PC regions were the most robust predictors of verbal memory, and that these associations were independent of left hippocampal volume.SignificanceThese findings suggest that microstructural loss within the SWM is pronounced in patients with TLE, and injury to the SWM within the LMT/PC region plays a critical role in verbal memory impairment.

Here we describe a publicly available dataset titled “Simultaneous EEG and fMRI signals during sleep from humans” on the OpenNeuro platform. To investigate spontaneous brain activity across distinct brain states, electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) were simultaneously acquired from 33 healthy participants (age: 22.1±3.2 years; male/female: 17/16) during the resting state and sleep. The dataset consisted of two resting-state scanning sessions and several sleep sessions for each participant. In addition, sleep staging of the EEG data was performed by a Registered Polysomnographic Technologist and provided along with the EEG and fMRI data. This dataset provides an opportunity to examine spontaneous brain activity using multimodal neuroimaging signals.

The vascular mild cognitive impairment (VaMCI) is generally accepted as the premonition stage of vascular dementia (VaD). However, most studies are focused mainly on VaD as a diagnosis in patients, thus neglecting the VaMCI stage. VaMCI stage, though, is easily diagnosed by vascular injuries and represents a high-risk period for the future decline of patients' cognitive functions. The existing studies in China and abroad have found that magnetic resonance imaging technology can provide imaging markers related to the occurrence and development of VaMCI, which is an important tool for detecting the changes in microstructure and function of VaMCI patients. Nevertheless, most of the existing studies evaluate the information of a single modal image. Due to the different imaging principles, the data provided by a single modal image are limited. In contrast, multi-modal magnetic resonance imaging research can provide multiple comprehensive data such as tissue anatomy and function. Here, a narrative review of published articles on multimodality neuroimaging in VaMCI diagnosis was conducted, and the utilization of certain neuroimaging bio-markers in clinical applications was narrated. These markers include evaluation of vascular dysfunction before tissue damages and quantification of the extent of network connectivity disruption. We further provide recommendations for early detection, progress, prompt treatment response of VaMCI, as well as optimization of the personalized treatment plan. [ABSTRACT FROM AUTHOR]

Probiotics are suggested to improve depressive symptoms via the microbiota-gut-brain axis. We have recently shown a beneficial clinical effect of probiotic supplementation in patients with depression. Their underlying neural mechanisms remain unknown. A multimodal neuroimaging approach including diffusion tensor imaging, resting-state functional MRI, and arterial spin labeling was used to investigate the effects of a four-weeks probiotic supplementation on fronto-limbic brain structure, function, and perfusion and whether these effects were related to symptom changes. Thirty-two patients completed both imaging assessments (18 placebo and 14 probiotics group). Probiotics maintained mean diffusivity in the left uncinate fasciculus, stabilized it in the right uncinate fasciculus, and altered resting-state functional connectivity (rsFC) between limbic structures and the temporal pole to a cluster in the precuneus. Moreover, a cluster in the left superior parietal lobule showed altered rsFC to the subcallosal cortex, the left orbitofrontal cortex, and limbic structures after probiotics. In the probiotics group, structural and functional changes were partly related to decreases in depressive symptoms. This study has a rather small sample size. An additional follow-up MRI session would be interesting for seeing clearer changes in the relevant brain regions as clinical effects were strongest in the follow-up. Probiotic supplementation is suggested to prevent neuronal degeneration along the uncinate fasciculus and alter fronto-limbic rsFC, effects that are partly related to the improvement of depressive symptoms. Elucidating the neural mechanisms underlying probiotics' clinical effects on depression provide potential targets for the development of more precise probiotic treatments. • Probiotic add-on intervention improved depressive symptoms in patients. • However, underlying neural mechanisms still remain unknown. • Probiotics impact fronto-limbic structure and function. • These brain changes are partly associated with clinical improvements. [ABSTRACT FROM AUTHOR]

Introduction: Resting-state network (RSN) connectivity is a widely used measure of the brain’s functional organization in health and disease; however, little is known regarding the underlying neurophysiology of RSNs. The aim of the current study was to investigate associations between RSN connectivity and synaptic density assessed using the synaptic vesicle glycoprotein 2A radioligand 11C-UCBJ PET. Methods: Independent component analyses (ICA) were performed on restingstate fMRI and PET data from 34 healthy adult participants (16F, mean age: 46 ± 15 years) to identify a priori RSNs of interest (default-mode, right frontoparietal executive-control, salience, and sensorimotor networks) and select sources of 11C-UCB-J variability (medial prefrontal, striatal, and medial parietal). Pairwise correlations were performed to examine potential intermodal associations between the fractional amplitude of low-frequency fluctuations (fALFF) of RSNs and subject loadings of 11C-UCB-J source networks both locally and along known anatomical and functional pathways. Results: Greater medial prefrontal synaptic density was associated with greater fALFF of the anterior default-mode, posterior default-mode, and executive-control networks. Greater striatal synaptic density was associated with greater fALFF of the anterior default-mode and salience networks. Post-hoc mediation analyses exploring relationships between aging, synaptic density, and RSN activity revealed a significant indirect effect of greater age on fALFF of the anterior default-mode network mediated by the medial prefrontal 11C-UCB-J source. Discussion: RSN functional connectivity may be linked to synaptic architecture through multiple local and circuit-based associations. Findings regarding healthy aging, lower prefrontal synaptic density, and lower default-mode activity provide initial evidence of a neurophysiological link between RSN activity and local synaptic density, which may have relevance in neurodegenerative and psychiatric disorders. [ABSTRACT FROM AUTHOR]

• Deep learning architecture for neuroimaging reconstruction. • Efficient convolutional neural networks based on separable convolutions. • Multimodality learning and interpretability of latent embeddings. • Clustering individuals phenotypes with structural multimodal brain features. Recently, it has become progressively more evident that classic diagnostic labels are unable to accurately and reliably describe the complexity and variability of several clinical phenotypes. This is particularly true for a broad range of neuropsychiatric illnesses such as depression and anxiety disorders or behavioural phenotypes such as aggression and antisocial personality. Patient heterogeneity can be better described and conceptualized by grouping individuals into novel categories, which are based on empirically-derived sections of intersecting continua that span both across and beyond traditional categorical borders. In this context, neuroimaging data (i.e. the set of images which result from functional/metabolic (e.g. functional magnetic resonance imaging, functional near-infrared spectroscopy, or positron emission tomography) and structural (e.g. computed tomography, T1-, T2- PD- or diffusion weighted magnetic resonance imaging) carry a wealth of spatiotemporally resolved information about each patient's brain. However, they are usually heavily collapsed a priori through procedures which are not learned as part of model training, and consequently not optimized for the downstream prediction task. This is due to the fact that every individual participant usually comes with multiple whole-brain 3D imaging modalities often accompanied by a deep genotypic and phenotypic characterization, hence posing formidable computational challenges. In this paper we design and validate a deep learning architecture based on generative models rooted in a modular approach and separable convolutional blocks (which result in a 20-fold decrease in parameter utilization) in order to a) fuse multiple 3D neuroimaging modalities on a voxel-wise level, b) efficiently convert them into informative latent embeddings through heavy dimensionality reduction, c) maintain good generalizability and minimal information loss. As proof of concept, we test our architecture on the well characterized Human Connectome Project database (n = 974 healthy subjects), demonstrating that our latent embeddings can be clustered into easily separable subject strata which, in turn, map to different phenotypical information (including organic, neuropsychological, personality variables) which was not included in the embedding creation process. The ability to extract meaningful and separable phenotypic information from brain images alone can aid in creating multi-dimensional biomarkers able to chart spatio-temporal trajectories which may correspond to different pathophysiological mechanisms unidentifiable to traditional data analysis approaches. In turn, this may be of aid in predicting disease evolution as well as drug response, hence supporting mechanistic disease understanding and also empowering clinical trials. [Display omitted] [ABSTRACT FROM AUTHOR]

Multimodal data, where different types of data are collected from the same subjects, are fast emerging in a large variety of scientific applications. Factor analysis is commonly used in integrative analysis of multimodal data, and is particularly useful to overcome the curse of high dimensionality and high correlations. However, there is little work on statistical inference for factor analysis-based supervised modeling of multimodal data. In this article, we consider an integrative linear regression model that is built upon the latent factors extracted from multimodal data. We address three important questions: how to infer the significance of one data modality given the other modalities in the model; how to infer the significance of a combination of variables from one modality or across different modalities; and how to quantify the contribution, measured by the goodness of fit, of one data modality given the others. When answering each question, we explicitly characterize both the benefit and the extra cost of factor analysis. Those questions, to our knowledge, have not yet been addressed despite wide use of factor analysis in integrative multimodal analysis, and our proposal bridges an important gap. We study the empirical performance of our methods through simulations, and further illustrate with a multimodal neuroimaging analysis. [ABSTRACT FROM AUTHOR]

Introduction: Genetic mutation carriers of frontotemporal dementia can remain cognitively well despite neurodegeneration. A better understanding of brain structural, perfusion, and functional patterns in the pre-symptomatic stage could inform accurate staging and potential mechanisms., Methods: We included 207 pre-symptomatic genetic mutation carriers and 188 relatives without mutations. The gray matter volume, cerebral perfusion, and resting-state functional network maps were co-analyzed using linked independent component analysis (LICA). Multiple regression analysis was used to investigate the relationship of LICA components to genetic status and cognition., Results: Pre-symptomatic mutation carriers showed an age-related decrease in the left frontoparietal network integrity, while non-carriers did not. Executive functions of mutation carriers became dependent on the left frontoparietal network integrity in older age., Discussion: The frontoparietal network integrity of pre-symptomatic mutation carriers showed a distinctive relationship to age and cognition compared to non-carriers, suggesting a contribution of the network integrity to brain resilience., Highlights: A multimodal analysis of structure, perfusion, and functional networks. The frontoparietal network integrity decreases with age in pre-symptomatic carriers only. Executive functions of pre-symptomatic carriers dissociated from non-carriers., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Resting-state network (RSN) connectivity is a widely used measure of the brain’s functional organization in health and disease; however, little is known regarding the underlying neurophysiology of RSNs. The aim of the current study was to investigate associations between RSN connectivity and synaptic density assessed using the synaptic vesicle glycoprotein 2A radioligand 11C-UCB-J PET.Methods: Independent component analyses (ICA) were performed on resting-state fMRI and PET data from 34 healthy adult participants (16F, mean age: 46 ± 15 years) to identify a priori RSNs of interest (default-mode, right frontoparietal executive-control, salience, and sensorimotor networks) and select sources of 11C-UCB-J variability (medial prefrontal, striatal, and medial parietal). Pairwise correlations were performed to examine potential intermodal associations between the fractional amplitude of low-frequency fluctuations (fALFF) of RSNs and subject loadings of 11C-UCB-J source networks both locally and along known anatomical and functional pathways.Results: Greater medial prefrontal synaptic density was associated with greater fALFF of the anterior default-mode, posterior default-mode, and executive-control networks. Greater striatal synaptic density was associated with greater fALFF of the anterior default-mode and salience networks. Post-hoc mediation analyses exploring relationships between aging, synaptic density, and RSN activity revealed a significant indirect effect of greater age on fALFF of the anterior default-mode network mediated by the medial prefrontal 11C-UCB-J source.Discussion: RSN functional connectivity may be linked to synaptic architecture through multiple local and circuit-based associations. Findings regarding healthy aging, lower prefrontal synaptic density, and lower default-mode activity provide initial evidence of a neurophysiological link between RSN activity and local synaptic density, which may have relevance in neurodegenerative and psychiatric disorders.

Resting-state functional magnetic resonance imaging (rsfMRI) allows the study of functional brain connectivity based on spatially structured variations in neuronal activity. Proper evaluation of connectivity requires removal of non-neural contributions to the fMRI signal, in particular hemodynamic changes associated with autonomic variability. Regression analysis based on autonomic indicator signals has been used for this purpose, but may be inadequate if neuronal and autonomic activities covary. To investigate this potential co-variation, we performed rsfMRI experiments while concurrently acquiring electroencephalography (EEG) and autonomic indicator signals, including heart rate, respiratory depth, and peripheral vascular tone. We identified a recurrent and systematic spatiotemporal pattern of fMRI (named as fMRI cascade), which features brief signal reductions in salience and default-mode networks and the thalamus, followed by a biphasic global change with a sensory-motor dominance. This fMRI cascade, which was mostly observed during eyes-closed condition, was accompanied by large EEG and autonomic changes indicative of arousal modulations. Importantly, the removal of the fMRI cascade dynamics from rsfMRI diminished its correlations with various signals. These results suggest that the rsfMRI correlations with various physiological and neural signals are not independent but arise, at least partly, from the fMRI cascades and associated neural and physiological changes at arousal modulations.