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Studies in adults have linked stress-related activation of the immune system to the manifestation of psychiatric conditions. Using a translational design, this study aimed to examine the impact of social stress on immune activity in adolescents and on neuronal activity in a preclinical mouse model. Participants were 31 adolescents (ages 12–19), including 25 with mood and anxiety symptoms. Whole-blood samples were collected before and after the Trier Social Stress Test (TSST), a stress-inducing public speaking task, then cultured for 6 hours in the presence and absence of the inflammatory endotoxin lipopolysaccharide (LPS). Effects of TSST and LPS on 41 immune biomarkers were examined using repeated-measures analysis of variance. Separately, juvenile (8-week-old) male mice were non-stressed or exposed to reminder social defeat then intraperitoneally injected with saline or LPS ( n  = 6/group). Brains were perfused and collected for immunohistochemistry and confocal microscopy at 0, 1, 6, and 24 hours post-injection. The activity was determined by the density of cFos-positive neurons in the paraventricular hypothalamus, paraventricular thalamus, and basolateral amygdala, regions known to show sustained activation to immunological challenge. Analyses in the adolescent study indicated a strong effect of LPS but no effects of TSST or TSST×LPS interaction on immune biomarkers. Similarly, reminder social defeat did not induce sustained neuronal activity changes comparable to LPS immunological challenge in juvenile mice. Our convergent findings across species suggest that the acute immune response to stress documented in adults is not present in youth. Thus, aging and chronicity effects may play an important role in the inflammatory response to acute psychosocial stress.

Adolescence is a period of rapid brain development when psychiatric symptoms often first emerge. Studying adolescents may therefore facilitate the identification of neural alterations early in the course of psychiatric conditions. Here, we sought to utilize new, high-quality brain parcellations and data-driven graph theory approaches to characterize associations between resting-state networks and the severity of depression, anxiety, and anhedonia symptoms—salient features across psychiatric conditions. As reward circuitry matures considerably during adolescence, we examined both Whole Brain and three task-derived reward networks. Subjects were 87 psychotropic-medication-free adolescents (age = 12–20) with diverse psychiatric conditions (n = 68) and healthy controls (n = 19). All completed diagnostic interviews, dimensional clinical assessments, and 3T resting-state fMRI (10 min/2.3 mm/TR = 1 s). Following high-quality Human Connectome Project-style preprocessing, multimodal surface matching (MSMAll) alignment, and parcellation via the Cole-Anticevic Brain-wide Network Partition, weighted graph theoretical metrics (Strength Centrality = CStr; Eigenvector Centrality = CEig; Local Efficiency = ELoc) were estimated within each network. Associations with symptom severity and clinical status were assessed non-parametrically (two-tailed pFWE < 0.05). Across subjects, depression scores correlated with ventral striatum CStr within the Reward Attainment network, while anticipatory anhedonia correlated with CStr and ELoc in the subgenual anterior cingulate, dorsal anterior cingulate, orbitofrontal cortex, caudate, and ventral striatum across multiple networks. Group differences and associations with anxiety were not detected. Using detailed functional and clinical measures, we found that adolescent depression and anhedonia involve increased influence and communication efficiency in prefrontal and limbic reward areas. Resting-state network properties thus reflect positive valence system anomalies related to discrete reward sub-systems and processing phases early in the course of illness.

The habenula (Hb) inhibits dopaminergic reward signaling in response to negative outcomes and has been linked to numerous functional domains relevant to mental health, including reward prediction, motivation, and aversion processing. Despite its important neuroscientific and clinical implications, however, the human Hb remains poorly understood due to its small size and the associated technical hurdles to in vivo functional magnetic resonance imaging (fMRI) investigation. Using high-resolution 3 T fMRI data from 68 healthy young adults acquired through the Human Connectome Project, we developed a rigorous approach for mapping the whole-brain resting-state functional connectivity of the human Hb. Our study combined an optimized strategy for defining subject-level connectivity seeds to maximize Hb blood-oxygen-level-dependent (BOLD) signal sensitivity with high-quality surface-based alignment for robust functional localization and cortical sensitivity. We identified significant positive Hb connectivity with: (i) conserved brainstem targets, including the dopaminergic ventral tegmental area, serotonergic raphe nuclei, and periaqueductal gray; (ii) subcortical structures related to reward and motor function, including the nucleus accumbens, dorsal striatum, pallidum, thalamus, and cerebellum; and (iii) cortical areas associated with the Salience Network and early sensory processing, including the dorsal anterior cingulate, anterior insula, and primary visual and auditory cortices. Hb connectivity was strongly biased towards task-positive brain regions, with weak or negative connectivity observed throughout the task-negative Default Mode Network. Our study provides a detailed characterization of Hb resting-state functional connectivity in healthy young adults, demonstrating both the feasibility and clinical potential of studying the human Hb using high-resolution 3 T fMRI. [Display omitted]

The habenula consists of a pair of small epithalamic nuclei located adjacent to the dorsomedial thalamus. Despite increasing interest in imaging the habenula due to its critical role in mediating subcortical reward circuitry, in vivo neuroimaging research targeting the human habenula has been limited by its small size and low anatomical contrast. In this work, we have developed an objective semi-automated habenula segmentation scheme consisting of histogram-based thresholding, region growing, geometric constraints, and partial volume estimation steps. This segmentation scheme was designed around in vivo 3T myelin-sensitive images, generated by taking the ratio of high-resolution T1w over T2w images. Due to the high myelin content of the habenula, the contrast-to-noise ratio with the thalamus in the in vivo 3T myelin-sensitive images was significantly higher than the T1w or T2w images alone. In addition, in vivo 7T myelin-sensitive images (T1w over T2*w ratio images) and ex vivo proton density-weighted images, along with histological evidence from the literature, strongly corroborated the in vivo 3T habenula myelin contrast used in the proposed segmentation scheme. The proposed segmentation scheme represents a step toward a scalable approach for objective segmentation of the habenula suitable for both morphological evaluation and habenula seed region selection in functional and diffusion MRI applications. [Display omitted] •Objective semi-automated habenula (Hb) segmentation using in vivo 3T anatomical MRI.•Multi-step segmentation to overcome small size, low, and individually variable CNR.•Higher Hb-thalamus CNR in 3T myelin map than T1w or T2w image alone.•3T Hb myelin contrast was corroborated by in vivo 7T and ex vivo MRI, and histology.

Background In recent years, diffusion tensor imaging (DTI) studies have detected subtle microstructural abnormalities of white matter (WM) in obsessive–compulsive disorder (OCD). However, findings have been inconsistent, and it is unclear whether WM abnormalities are related to cognitive processes. The aim of this study was to explore the relationship of WM alterations with cognitive variables in OCD in order to investigate the structural correlates of behaviorally relevant features of the disorder. Methods We compared DTI‐derived fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) measures between OCD patients (n = 16) and healthy controls (n = 18) using a whole‐brain tract‐based spatial statistics (TBSS) approach. We also explored the correlations of WM alterations with clinical and cognitive variables. Results Patients with OCD demonstrated increases in MD in the bilateral posterior corona radiata; left anterior corona radiata; bilateral superior longitudinal fasciculus; genu, body, and splenium of the corpus callosum; and left posterior limb of the internal capsule. An increase in RD values was also found in some of the same tracts (right posterior corona radiata, right superior longitudinal fasciculus, left anterior corona radiata, and corpus callosum). Furthermore, increased MD value in the internal capsule was correlated with the percentage of errors made during a target detection task, which was greater in the OCD group overall. Conclusions These findings indicate that OCD patients show greater diffusivity in several white‐matter regions. The correlation between cognitive performance and diffusivity in the internal capsule suggests that microstructural WM alternations may have functional consequences for the disorder. Patients with obsessive–compulsive disorder demonstrated increases in mean diffusivity in the bilateral posterior corona radiata, left anterior corona radiata, and left posterior limb of the internal capsule. Increased mean diffusivity value in the internal capsule was correlated with a specific disturbance in cognitive performance following negative internal thoughts, which was greater in the obsessive–compulsive group overall. This relationship suggests that alterations in white‐matter microstructure may be linked to obsessive–compulsive‐related behaviors.

No diagnostic biomarkers are available for obsessive-compulsive disorder (OCD). Here, we aimed to identify magnetic resonance imaging (MRI) biomarkers for OCD, using 46 data sets with 2304 OCD patients and 2068 healthy controls from the ENIGMA consortium. We performed machine learning analysis of regional measures of cortical thickness, surface area and subcortical volume and tested classification performance using cross-validation. Classification performance for OCD vs. controls using the complete sample with different classifiers and cross-validation strategies was poor. When models were validated on data from other sites, model performance did not exceed chance-level. In contrast, fair classification performance was achieved when patients were grouped according to their medication status. These results indicate that medication use is associated with substantial differences in brain anatomy that are widely distributed, and indicate that clinical heterogeneity contributes to the poor performance of structural MRI as a disease marker.

While inflammation has been implicated in depression, little is known of immune-inhibitory agents for individuals with depression. This study sought to assess whether β2-agonist clenbuterol (CBL) would attenuate increased cytokine secretion in adolescents with mood and anxiety symptoms following ex vivo exposure of whole blood to lipopolysaccharide (LPS). Our focus on adolescents aimed to target a critical developmental period when psychiatric conditions often emerge and prior to chronicity effects. Participants (15.25 ± 2.16 years old, 59% female) were 97 psychotropic-medication free adolescents with mood and anxiety symptoms and 33 healthy controls. All had comprehensive evaluations and dimensional assessments of psychiatric symptoms. Fasting whole-blood samples were collected and stimulated with LPS in the presence and absence of CBL for 6 hours and analyzed for 41 cytokines. Comparison analyses used Bonferroni-corrected nonparametric tests. Exploratory factor analysis reduced 41 cytokines into 5 cytokine factors in each experimental condition, and their relationships with psychiatric symptoms were examined. Levels of nine cytokines were significantly reduced by CBL treatment compared to LPS alone. A cytokine factor in the LPS+CBL condition significantly correlated with anticipatory (rho = −0.39, p = 7.4 × 10-5) and consummatory anhedonia (rho = −0.36, p = 3.3 × 10-4), which remained significant when controlling for depression. This study supports the possible inhibitory effect of CBL on immune activation. Using a data-driven method, distinctive relationships between CBL-affected cytokines and dimensional anhedonia were reported, further elucidating the role of β2-agonism in adolescent affective symptomatology. Competing Interest Statement The authors have declared no competing interest. Footnotes * Author list updated; Minor edits to Abstract, Introduction, Methods, and Results; Discussion was revised to be more succinct; Figure 1 in previous version was moved to Supplementary Materials; Supplementary Materials were updated.

Reward system dysfunction is thought to underlie many core features of depression, addiction, and other mental illnesses. Over the past decade, research has increasingly identified the habenula (Hb) as a critical hub in reward regulation. Neurons of the lateral Hb inhibit dopaminergic reward signaling in response to reward prediction errors, negative outcomes, and aversive stimuli across a wide range of species, while stimulation or ablation of the Hb respectively induce depressive or impulsive phenotypes. Despite its important neuroscientific and clinical implications, however, the human Hb remains poorly understood due to its small size, which makes it technically challenging to study in vivo using functional magnetic resonance imaging (fMRI). This dissertation focuses on high-resolution fMRI approaches to study the human Hb and its possible role in mental illness. I first overview the major features of the reward system and evidence linking the Hb, reward dysregulation, psychiatric symptomatology. Using 3T resting-state fMRI data from the Human Connectome Project (HCP), I then perform the first high-resolution whole-brain study of human Hb functional connectivity, reporting highly significant connectivity with the dopaminergic ventral tegmental area (VTA), motor system, and Salience Network, as well as potential Hb connectivity alterations related to subclinical depression. This is followed by an intensive investigation of strategies to maximize Hb fMRI sensitivity and generate detailed, neuroanatomically accurate maps of whole-brain Hb connectivity in healthy young adults from the HCP. I next replicate these Hb connectivity patterns in an independent sample of healthy and mentally ill adolescents, and further find intriguing evidence of elevated Hb connectivity with the Default Mode Network in clinical subjects which appears to be driven by anxiety levels. Finally, I describe related efforts to measure subject-level Hb responses to thermal pain using 7T task fMRI and to improve VTA segmentation using 3T anatomical MRI. The work described in this dissertation thus establishes a feasible, reproducible approach for studying the human Hb using high-resolution fMRI; provides a detailed characterization of healthy human Hb connectivity patterns; and suggests associations between altered Hb connectivity and psychiatric symptoms.

Objective: Adolescence is a period of rapid brain development when symptoms of mood, anxiety, and other disorders often first emerge, suggesting disruptions in maturing reward circuitry may play a role in mental illness onset. Here, we characterized associations between resting-state network properties and psychiatric symptomatology in medication-free adolescents with a wide range of symptom severity. Methods: Adolescents (age 12-20) with mood and/or anxiety symptoms (n=68) and healthy controls (n=19) completed diagnostic interviews, depression/anhedonia/anxiety questionnaires, and 3T resting-state fMRI (10min/2.3mm/TR=1s). Data were preprocessed (HCP Pipelines), aligned (MSMAll), and parcellated into 750 nodes encompassing the entire cortex/subcortex (Cole-Anticevic Brain-wide Network Partition). Weighted graph theoretical metrics (Strength Centrality=CStr; Eigenvector Centrality=CEig; Local Efficiency=ELoc) were estimated within Whole Brain and task-derived Reward Anticipation/Attainment/Prediction Error networks. Associations with clinical status and symptoms were assessed non-parametrically (two-tailed pFWE<0.05). Results: Relative to controls, clinical adolescents had increased ventral striatum CEig within the Reward Attainment network. Across subjects, depression correlated with subgenual cingulate CStr and ELoc, anhedonia correlated with ventromedial prefrontal CStr and lateral amygdala ELoc, and anxiety negatively correlated with parietal operculum CEig and medial amygdala ELoc within the Whole Brain network. Conclusions: Using a data-driven analysis approach, high-quality parcellation, and clinically diverse adolescent cohort, we found that symptoms within positive and negative valence system constructs differentially associated with resting-state network abnormalities: depression and anhedonia, as well as clinical status, involved greater influence and communication efficiency in prefrontal and limbic reward areas, whereas anxiety was linked to reduced influence/efficiency in amygdala and cortical regions involved in stimulus monitoring. Footnotes * https://balsa.wustl.edu/study/show/x278x

Atmospheric warming is increasing surface melting across the Antarctic Peninsula, with unknown impacts upon glacier dynamics at the ice-bed interface. Using high-resolution satellite-derived ice velocity data, optical satellite imagery and regional climate modelling, we show that drainage of surface meltwater to the bed of outlet glaciers on the Antarctic Peninsula occurs and triggers rapid ice flow accelerations (up to 100% greater than the annual mean). This provides a mechanism for this sector of the Antarctic Ice Sheet to respond rapidly to atmospheric warming. We infer that delivery of water to the bed transiently increases basal water pressure, enhancing basal motion, but efficient evacuation subsequently reduces water pressure causing ice deceleration. Currently, melt events are sporadic, so efficient subglacial drainage cannot be maintained, resulting in multiple short-lived (<6 day) ice flow perturbations. Future increases in meltwater could induce a shift to a glacier dynamic regime characterised by seasonal-scale hydrologically-driven ice flow variations. Surface meltwater is known to influence the dynamics of some glaciers and the Greenland ice sheet. Here, the authors have identified the first examples of the drainage of surface meltwater to the bed of outlet glaciers on the Antarctic Peninsula that trigger large and rapid accelerations of ice flow.