Reward-Related Neural Circuitry in Depressed and Anxious Adolescents: A Human Connectome Project.

OBJECTIVE: Although depression and anxiety often have distinct etiologies, they frequently co-occur in adolescence. Recent initiatives have underscored the importance of developing new ways of classifying mental illness based on underlying neural dimensions that cut across traditional diagnostic boundaries. Accordingly, the aim of the study was to clarify reward-related neural circuitry that may characterize depressed-anxious youth. METHOD: The Boston Adolescent Neuroimaging of Depression and Anxiety Human Connectome Project tested group differences regarding subcortical volume and nucleus accumbens activation during an incentive processing task among 14- to 17-year-old adolescents presenting with a primary depressive and/or anxiety disorder (n = 129) or no lifetime history of mental disorders (n = 64). In addition, multimodal modeling examined predictors of depression and anxiety symptom change over a 6-month follow-up period. RESULTS: Our findings highlighted considerable convergence. Relative to healthy youth, depressed-anxious adolescents exhibited reduced nucleus accumbens volume and activation following reward receipt. These findings remained when removing all medicated participants (∼59% of depressed-anxious youth). Subgroup analyses comparing anxious-only, depressed-anxious, and healthy youth also were largely consistent. Multimodal modeling showed that only structural alterations predicted depressive symptoms over time. CONCLUSION: Multimodal findings highlight alterations within nucleus accumbens structure and function that characterize depressed-anxious adolescents. In the current hypothesis-driven analyses, however, only reduced nucleus accumbens volume predicted depressive symptoms over time. An important next step will be to clarify why structural alterations have an impact on reward-related processes and associated symptoms.

Quantification of volumetric morphometry and optical property in the cortex of human cerebellum at micrometer resolution.

The surface of the human cerebellar cortex is much more tightly folded than the cerebral cortex. Volumetric analysis of cerebellar morphometry in magnetic resonance imaging studies suffers from insufficient resolution, and therefore has had limited impact on disease assessment. Automatic serial polarization-sensitive optical coherence tomography (as-PSOCT) is an emerging technique that offers the advantages of microscopic resolution and volumetric reconstruction of large-scale samples. In this study, we reconstructed multiple cubic centimeters of ex vivo human cerebellum tissue using as-PSOCT. The morphometric and optical properties of the cerebellar cortex across five subjects were quantified. While the molecular and granular layers exhibited similar mean thickness in the five subjects, the thickness varied greatly in the granular layer within subjects. Layer-specific optical property remained homogenous within individual subjects but showed higher cross-subject variability than layer thickness. High-resolution volumetric morphometry and optical property maps of human cerebellar cortex revealed by as-PSOCT have great potential to advance our understanding of cerebellar function and diseases.

Altered connectivity of the default mode network in cognitively stable adults with Down syndrome: "Accelerated aging" or a prelude to Alzheimer's disease?

INTRODUCTION: Most individuals with Down syndrome (DS) have the neuropathological changes of Alzheimer's disease (AD) by age 40 and will have developed dementia by age 60. Alterations of the intrinsic connectivity of the default mode network (DMN) are associated with AD in the neurotypical population. In this study, we sought to determine whether, and how, connectivity between the hubs of the DMN were altered in cognitively stable adults with DS who did not have evidence of either mild cognitive impairment or AD. METHODS: Resting state functional MRI scans were collected from 26 healthy adults with DS and 26 healthy age-matched non-DS controls. Nodes comprising the DMN were generated as ROI's (regions of interest) and inter-nodal correlations estimated. RESULTS: Analysis of intra-network connectivity of the DMN revealed anterior-posterior DMN dissociation and hyper- and hypo-connectivity, suggesting "accelerated aging" in DS. DISCUSSION: Disruption of the DMN may serve as a prelude for AD in DS.

Functional Alterations in Cerebellar Functional Connectivity in Anxiety Disorders.

Adolescents with anxiety disorders exhibit excessive emotional and somatic arousal. Neuroimaging studies have shown abnormal cerebral cortical activation and connectivity in this patient population. The specific role of cerebellar output circuitry, specifically the dentate nuclei (DN), in adolescent anxiety disorders remains largely unexplored. Resting-state functional connectivity analyses have parcellated the DN, the major output nuclei of the cerebellum, into three functional territories (FTs) that include default-mode, salience-motor, and visual networks. The objective of this study was to understand whether FTs of the DN are implicated in adolescent anxiety disorders. Forty-one adolescents (mean age 15.19 ± 0.82, 26 females) with one or more anxiety disorders and 55 age- and gender-matched healthy controls completed resting-state fMRI scans and a self-report survey on anxiety symptoms. Seed-to-voxel functional connectivity analyses were performed using the FTs from DN parcellation. Brain connectivity metrics were then correlated with State-Trait Anxiety Inventory (STAI) measures within each group. Adolescents with an anxiety disorder showed significant hyperconnectivity between salience-motor DN FT and cerebral cortical salience-motor regions compared to controls. Salience-motor FT connectivity with cerebral cortical sensorimotor regions was significantly correlated with STAI-trait scores in HC (R2 = 0.41). Here, we report DN functional connectivity differences in adolescents diagnosed with anxiety, as well as in HC with variable degrees of anxiety traits. These observations highlight the relevance of DN as a potential clinical and sub-clinical marker of anxiety.

Image acquisition and quality assurance in the Boston Adolescent Neuroimaging of Depression and Anxiety study.

The Connectomes Related to Human Diseases (CRHD) initiative was developed with the Human Connectome Project (HCP) to provide high-resolution, open-access, multi-modal MRI data to better understand the neural correlates of human disease. Here, we present an introduction to a CRHD project, the Boston Adolescent Neuroimaging of Depression and Anxiety (BANDA) study, which is collecting multimodal neuroimaging, clinical, and neuropsychological data from 225 adolescents (ages 14-17), 150 of whom are expected to have a diagnosis of depression and/or anxiety. Our transdiagnostic recruitment approach samples the full spectrum of depressed/anxious symptoms and their comorbidity, consistent with NIMH Research Domain Criteria (RDoC). We focused on an age range that is critical for brain development and for the onset of mental illness. This project sought to harmonize imaging sequences, hardware, and functional tasks with other HCP studies, although some changes were made to canonical HCP methods to accommodate our study population and questions. We present a thorough overview of our imaging sequences, hardware, and scanning protocol. We detail similarities and differences between this study and other HCP studies. We evaluate structural-, diffusion-, and functional-image-quality measures that may be influenced by clinical factors (e.g., disorder, symptomatology). Signal-to-noise and motion estimates from the first 140 adolescents suggest minimal influence of clinical factors on image quality. We anticipate enrollment of an additional 85 participants, most of whom are expected to have a diagnosis of anxiety and/or depression. Clinical and neuropsychological data from the first 140 participants are currently freely available through the National Institute of Mental Health Data Archive (NDA).

Registration-free analysis of diffusion MRI tractography data across subjects through the human lifespan.

Diffusion MRI tractography produces massive sets of streamlines that need to be clustered into anatomically meaningful white-matter bundles. Conventional clustering techniques group streamlines based on their proximity in Euclidean space. We have developed AnatomiCuts, an unsupervised method for clustering tractography streamlines based on their neighboring anatomical structures, rather than their coordinates in Euclidean space. In this work, we show that the anatomical similarity metric used in AnatomiCuts can be extended to find corresponding clusters across subjects and across hemispheres, without inter-subject or inter-hemispheric registration. Our proposed approach enables group-wise tract cluster analysis, as well as studies of hemispheric asymmetry. We evaluate our approach on data from the pilot MGH-Harvard-USC Lifespan Human Connectome project, showing improved correspondence in tract clusters across 184 subjects aged 8-90. Our method shows up to 38% improvement in the overlap of corresponding clusters when comparing subjects with large age differences. The techniques presented here do not require registration to a template and can thus be applied to populations with large inter-subject variability, e.g., due to brain development, aging, or neurological disorders.

AnatomiCuts: Hierarchical clustering of tractography streamlines based on anatomical similarity.

Diffusion MRI tractography produces massive sets of streamlines that contain a wealth of information on brain connections. The size of these datasets creates a need for automated clustering methods to group the streamlines into meaningful bundles. Conventional clustering techniques group streamlines based on their spatial coordinates. Neuroanatomists, however, define white-matter bundles based on the anatomical structures that they go through or next to, rather than their spatial coordinates. Thus we propose a similarity measure for clustering streamlines based on their position relative to cortical and subcortical brain regions. We incorporate this measure into a hierarchical clustering algorithm and compare it to a measure that relies on Euclidean distance, using data from the Human Connectome Project. We show that the anatomical similarity measure leads to a 20% improvement in the overlap of clusters with manually labeled tracts. Importantly, this is achieved without introducing any prior information from a tract atlas into the clustering algorithm, therefore without imposing the existence of any named tracts.

Joint T1 and brain fiber log-demons registration using currents to model geometry.

We present an extension of the diffeomorphic Geometric Demons algorithm which combines the iconic registration with geometric constraints. Our algorithm works in the log-domain space, so that one can efficiently compute the deformation field of the geometry. We represent the shape of objects of interest in the space of currents which is sensitive to both location and geometric structure of objects. Currents provides a distance between geometric structures that can be defined without specifying explicit point-to-point correspondences. We demonstrate this framework by registering simultaneously T1 images and 65 fiber bundles consistently extracted in 12 subjects and compare it against non-linear T1, tensor, and multi-modal T1 + Fractional Anisotropy (FA) registration algorithms. Results show the superiority of the Log-domain Geometric Demons over their purely iconic counterparts.