Predicting depression risk in early adolescence via multimodal brain imaging.

Depression is an incapacitating psychiatric disorder with increased risk through adolescence. Among other factors, children with family history of depression have significantly higher risk of developing depression. Early identification of pre-adolescent children who are at risk of depression is crucial for early intervention and prevention. In this study, we used a large longitudinal sample from the Adolescent Brain Cognitive Development (ABCD) Study (2658 participants after imaging quality control, between 9-10 years at baseline), we applied advanced machine learning methods to predict depression risk at the two-year follow-up from the baseline assessment, using a set of comprehensive multimodal neuroimaging features derived from structural MRI, diffusion tensor imaging, and task and rest functional MRI. Prediction performance underwent a rigorous cross-validation method of leave-one-site-out. Our results demonstrate that all brain features had prediction scores significantly better than expected by chance, with brain features from rest-fMRI showing the best classification performance in the high-risk group of participants with parental history of depression (N = 625). Specifically, rest-fMRI features, which came from functional connectomes, showed significantly better classification performance than other brain features. This finding highlights the key role of the interacting elements of the connectome in capturing more individual variability in psychopathology compared to measures of single brain regions. Our study contributes to the effort of identifying biological risks of depression in early adolescence in population-based samples.

Family environment modulates linkage of transdiagnostic psychiatric phenotypes and dissociable brain features in the developing brain.

BACKGROUND: Family environment has long been known for shaping brain function and psychiatric phenotypes, especially in childhood and adolescence. Accumulating neuroimaging evidence suggests that across different psychiatric disorders, common phenotypes might share common neural bases, indicating latent brain-behavior relationships beyond diagnostic categories. However, the influence of family environment on the brain-behavior relationship from a transdiagnostic perspective remains unknown. METHOD: We included a community-based sample of 699 subjects (5-22 yrs.) and applied partial least squares regression analysis to determine latent brain-behavior relationships from the whole brain functional connectivity and comprehensive phenotypic measures. Comparisons were conducted between diagnostic and non-diagnostic groups to help interpret the latent brain-behavior relationships. A moderation model was introduced to examine the potential moderating role of family factors in the estimated brain-behavior association. RESULTS: Four significant latent brain-behavior pairs reflecting relationship of dissociable brain network and general behavioral problems, cognitive and language skills, externalizing problems, and social dysfunction, respectively, were identified. The group comparisons exhibited interpretable variations across different diagnostic groups. Warmth family environment was found to moderate the brain-behavior relationship of core symptoms in internalizing disorders. However, in neurodevelopmental disorders, family factors were not found to moderate the brain-behavior relationship of core symptoms, but were found to affect brain-behavior relationship in other domains. CONCLUSION: Our findings leveraged the transdiagnostic analysis investigating the moderating effects of the family factors on brain-behavior association, emphasizing the different role family factors take in developmental period across distinct diagnostic groups.

The developmental trajectory of 1H-MRS brain metabolites from childhood to adulthood.

Human brain development is ongoing throughout childhood, with for example, myelination of nerve fibers and refinement of synaptic connections continuing until early adulthood. 1H-Magnetic Resonance Spectroscopy (1H-MRS) can be used to quantify the concentrations of endogenous metabolites (e.g. glutamate and γ -aminobutyric acid (GABA)) in the human brain in vivo and so can provide valuable, tractable insight into the biochemical processes that support postnatal neurodevelopment. This can feasibly provide new insight into and aid the management of neurodevelopmental disorders by providing chemical markers of atypical development. This study aims to characterize the normative developmental trajectory of various brain metabolites, as measured by 1H-MRS from a midline posterior parietal voxel. We find significant non-linear trajectories for GABA+ (GABA plus macromolecules), Glx (glutamate + glutamine), total choline (tCho) and total creatine (tCr) concentrations. Glx and GABA+ concentrations steeply decrease across childhood, with more stable trajectories across early adulthood. tCr and tCho concentrations increase from childhood to early adulthood. Total N-acetyl aspartate (tNAA) and Myo-Inositol (mI) concentrations are relatively stable across development. Trajectories likely reflect fundamental neurodevelopmental processes (including local circuit refinement) which occur from childhood to early adulthood and can be associated with cognitive development; we find GABA+ concentrations significantly positively correlate with recognition memory scores.

From vision to memory: How scene-sensitive regions support episodic memory formation during child development.

Previous brain imaging studies have identified three brain regions that selectively respond to visual scenes, the parahippocampal place area (PPA), the occipital place area (OPA), and the retrosplenial cortex (RSC). There is growing evidence that these visual scene-sensitive regions process different types of scene information and may have different developmental timelines in supporting scene perception. How these scene-sensitive regions support memory functions during child development is largely unknown. We investigated PPA, OPA and RSC activations associated with episodic memory formation in childhood (5-7 years of age) and young adulthood, using a subsequent scene memory paradigm and a functional localizer for scenes. PPA, OPA, and RSC subsequent memory activation and functional connectivity differed between children and adults. Subsequent memory effects were found in activations of all three scene regions in adults. In children, however, robust subsequent memory effects were only found in the PPA. Functional connectivity during successful encoding was significant among the three regions in adults, but not in children. PPA subsequently memory activations and PPA-RSC subsequent memory functional connectivity correlated with accuracy in adults, but not children. These age-related differences add new evidence linking protracted development of the scene-sensitive regions to the protracted development of episodic memory.

PREDICTING DEPRESSION RISK IN EARLY ADOLESCENCE VIA MULTIMODAL BRAIN IMAGING.

Depression is an incapacitating psychiatric disorder with high prevalence in adolescent populations that is influenced by many risk factors, including family history of depression. The ability to predict who may develop depression before adolescence, when rates of depression increase markedly, is important for early intervention and prevention. Using a large longitudinal sample from the Adolescent Brain Cognitive Development (ABCD) Study (2658 participants after imaging quality control, between 9-10 years at baseline), we applied machine learning methods on a set of comprehensive multimodal neuroimaging features to predict depression risk at the two-year follow-up from the baseline visit. Features include derivatives from structural MRI, diffusion tensor imaging, and task and rest functional MRI. A rigorous cross-validation method of leave-one-site-out was used. Additionally, we tested the prediction models in a high-risk group of participants with parental history of depression (N=625). The results showed all brain features had prediction scores significantly better than expected by chance. When predicting depression onset in the high-risk group, brain features from resting-state functional connectomes showed the best classification performance, outperforming other brain features based on structural MRI and task-based fMRI. Results demonstrate that the functional connectivity of the brain can predict the risk of depression in early adolescence better than other univariate neuroimaging derivatives, highlighting the key role of the interacting elements of the connectome capturing more individual variability in psychopathology compared to measures of single brain regions.

Family History of Depression and Neural Reward Sensitivity: Findings From the Adolescent Brain Cognitive Development Study.

BACKGROUND: Previous studies have found that offspring of depressed parents exhibit reduced striatal reward response to anticipating and receiving rewards, suggesting that this may constitute a neurobiological risk marker for depression. The present study aimed to assess whether maternal and paternal depression history have independent effects on offspring reward processing and whether greater family history density of depression is associated with increased blunting of striatal reward responses. METHODS: Data from the baseline visit of the ABCD (Adolescent Brain Cognitive Development) Study were used. After exclusion criteria, 7233 9- and 10-year-old children (49% female) were included in analyses. Neural responses to reward anticipation and receipt in the monetary incentive delay task were examined in 6 striatal regions of interest. Using mixed-effects models, we evaluated the effect of maternal or paternal depression history on striatal reward response. We also evaluated the effect of family history density on reward response. RESULTS: Across all 6 striatal regions of interest, neither maternal nor paternal depression significantly predicted blunted response to reward anticipation or feedback. Contrary to hypotheses, paternal depression history was associated with increased response in the left caudate during anticipation, and maternal depression history was associated with increased response in the left putamen during feedback. Family history density was not associated with striatal reward response. CONCLUSIONS: Our findings suggest that family history of depression is not strongly associated with blunted striatal reward response in 9- and 10-year-old children. Factors contributing to heterogeneity across studies need to be examined in future research to reconcile these results with past findings.

Interhemispheric functional brain connectivity predicts new language learning success in adults.

Investigating interhemispheric interactions between homologous cortical regions during language processing is of interest. Despite prevalent left hemisphere lateralization of language, the right hemisphere also plays an important role and interhemispheric connectivity is influenced by language experience and is implicated in second language (L2) acquisition. Regions involved in language processing have differential connectivity to other cortical regions and to each other, and play specific roles in language. We examined the interhemispheric interactions of subregions of the inferior frontal gyrus (areas 44 and 45), the adjacent area 9/46v in the middle frontal gyrus, the superior temporal gyrus (STG), and the posterior inferior parietal lobule (pIPL) in relation to distinct and specific aspects of L2 learning success. The results indicated that the connectivity between left and right areas 44 and 9/46v predicted improvement in sentence repetition, connectivity between left and right area 45 and mid-STG predicted improvement in auditory comprehension, and connectivity between left and right pIPL predicted improvement in reading speed. We show interhemispheric interactions in the specific context of facilitating performance in adult L2 acquisition that follow an anterior to posterior gradient in the brain, and are consistent with the respective roles of these regions in language processing.

Development of the neural correlates of recollection.

Recollection of past events has been associated with the core recollection network comprising the posterior medial temporal lobe and parietal regions, as well as the medial prefrontal cortex (mPFC). The development of the brain basis for recollection is understudied. In a sample of adults (n = 22; 18-25 years) and children (n = 23; 9-13 years), the present study aimed to address this knowledge gap using a cued recall paradigm, known to elicit recollection experience. Successful recall was associated with activations in regions of the core recollection network and frontoparietal network. Adults exhibited greater successful recall activations compared with children in the precuneus and right angular gyrus. In contrast, similar levels of successful recall activations were observed in both age groups in the mPFC. Group differences were also seen in the hippocampus and lateral frontal regions. These findings suggest that the engagement of the mPFC in episodic retrieval may be relatively early maturing, whereas the contribution to episodic retrieval of more posterior regions such as the precuneus and angular gyrus undergoes more protracted maturation.

Development of self-referential effect on memory recollection.

Information learned in relation to oneself is typically better remembered, termed the self-reference effect (SRE). This study aimed to elucidate the developmental trajectory of the SRE in recollection and source memory from mid-childhood to young adulthood. In 2018-2019 in Baltimore, Maryland, 136 seven- to thirty-year-olds (77 female; approximately 80% White, 15% Asian American, 5% Black) viewed objects on one of two backgrounds and answered a self-referential or semantic question for each. A recognition test probed memory for objects and source details (inherent: question type; peripheral: background image). SRE increased with age for detailed recollection (r = .189), but not familiarity, and extended to inherent source memory. This suggests that self-referencing promotes richer memory in children and develops into young adulthood.

Correction: Self-referential encoding of source information in recollection memory.

[This corrects the article DOI: 10.1371/journal.pone.0248044.].

Frontoparietal Anatomical Connectivity Predicts Second Language Learning Success.

There is considerable individual variability in second language (L2) learning abilities in adulthood. The inferior parietal lobule, important in L2 learning success, is anatomically connected to language areas in the frontal lobe via the superior longitudinal fasciculus (SLF). The second and third branches of the SLF (SLF II and III) have not been examined separately in the context of language, yet they are known to have dissociable frontoparietal connections. Studying these pathways and their functional contributions to L2 learning is thus of great interest. Using diffusion MRI tractography, we investigated individuals undergoing language training to explore brain structural predictors of L2 learning success. We dissected SLF II and III using gold-standard anatomical definitions and related prelearning white matter integrity to language improvements corresponding with hypothesized tract functions. SLF II properties predicted improvement in lexical retrieval, while SLF III properties predicted improvement in articulation rate. Finer grained separation of these pathways enables better understanding of their distinct roles in language, which is essential for studying how anatomical connectivity relates to L2 learning abilities.

Self-referential encoding of source information in recollection memory.

Information that is encoded in relation to the self has been shown to be better remembered, yet reports have disagreed on whether the memory benefit from self-referential encoding extends to source memory (the context in which information was learned). In this study, we investigated the self-referential effect on source memory in recollection and familiarity-based memory. Using a Remember/Know paradigm, we compared source memory accuracy under self-referential encoding and semantic encoding. Two types of source information were included, a "peripheral" source which was not inherent to the encoding activity, and a source information about the encoding context. We observed the facilitation in item memory from self-referential encoding compared to semantic encoding in recollection but not in familiarity-based memory. The self-referential benefit to source accuracy was observed in recollection memory, with source memory for the encoding context being stronger in the self-referential condition. No significant self-referential effect was observed with regards to peripheral source information (information not required for the participant to focus on), suggesting not all source information benefit from self-referential encoding. Self-referential encoding also resulted in a higher ratio of "Remember/Know" responses rate than semantically encoded items, denoting stronger recollection. These results suggest self-referential encoding creates a richer, more detailed memory trace which can be recollected later on.

Cingulum-Callosal white-matter microstructure associated with emotional dysregulation in children: A diffusion tensor imaging study.

Emotional dysregulation symptoms in youth frequently predispose individuals to increased risk for mood disorders and other mental health difficulties. These symptoms are also known as a behavioral risk marker in predicting pediatric mood disorders. The underlying neural mechanism of emotional dysregulation, however, remains unclear. This study used the diffusion tensor imaging (DTI) technique to identify anatomically specific variation in white-matter microstructure that is associated with pediatric emotional dysregulation severity. Thirty-two children (mean age 9.53 years) with varying levels of emotional dysregulation symptoms were recruited by the Massachusetts General Hospital and underwent the DTI scans at Massachusetts Institute of Technology. Emotional dysregulation severity was measured by the empirically-derived Child Behavior Checklist Emotional Dysregulation Profile that includes the Attention, Aggression, and Anxiety/Depression subscales. Whole-brain voxel-wise regression tests revealed significantly increased radial diffusivity (RD) and decreased fractional anisotropy (FA) in the cingulum-callosal regions linked to greater emotional dysregulation in the children. The results suggest that microstructural differences in cingulum-callosal white-matter pathways may manifest as a neurodevelopmental vulnerability for pediatric mood disorders as implicated in the clinical phenotype of pediatric emotional dysregulation. These findings may offer clinically and biologically relevant neural targets for early identification and prevention efforts for pediatric mood disorders.

Association of Intrinsic Brain Architecture With Changes in Attentional and Mood Symptoms During Development.

Importance: Understanding the neurodevelopmental trajectory of psychiatric symptoms is important for improving early identification, intervention, and prevention of mental disorders. Objective: To test whether the strength of the coupling of activation between specific brain regions, as measured by resting-state functional magnetic resonance imaging (fMRI), predicted individual children's developmental trajectories in terms of attentional problems characteristic of attention-deficit/hyperactivity disorder and internalizing problems characteristics of major depressive disorder (MDD). Design, Setting, and Participants: A community cohort of 94 children was recruited from Vanderbilt University between 2010 and 2013. They were followed up longitudinally for 4 years and the data were analyzed from 2016 to 2019. Based on preregistered hypotheses and an analytic plan, we examined whether specific brain connectivity patterns would be associated with longitudinal changes in scores on the Child Behavior Checklist (CBCL), a parental-report assessment used to screen for emotional, behavioral, and social problems and to predict psychiatric illnesses. Main Outcomes and Measures: We used the strength of resting-state fMRI connectivity at age 7 years to predict subsequent changes in CBCL measures 4 years later and investigated the mechanisms of change by associating brain connectivity changes with changes in the CBCL. Results: We analyzed data from a longitudinal brain development study involving children assessed at age 7 years (n = 94; 41 girls [43.6%]) and 11 years (n = 54; 32 girls [59.3%]). As predicted, less positive coupling at age 7 years between the medial prefrontal cortex and dorsolateral prefrontal cortex (DLPFC) was associated with a decrease in attentional symptoms by age 11 years (t49 = 2.38; P = .01; ß = 0.32). By contrast, a less positive coupling between a region implicated in mood, the subgenual anterior cingulate cortex (sgACC), and DLPFC at age 7 years was associated with an increase in internalizing (eg, anxiety/depression) behaviors by age 11 years (t49 = -2.4; P = .01; ß = -0.30). Logistic regression analyses revealed that sgACC-DLPFC connectivity was a more accurate predictor than baseline CBCL measures for progression to a subclinical score on internalization (t50 = -2.61; P = .01; ß = -0.29). We then replicated and extended the sgACC-DLPFC result in an independent sample of children with (n = 25) or without (n = 18) familial risk for MDD. Conclusions and Relevance: These resting-state fMRI metrics are promising biomarkers for the early identification of children at risk of developing MDD or attention-deficit/hyperactivity disorder.

Language learning experience and mastering the challenges of perceiving speech in noise.

Given the ubiquity of noisy environments and increasing globalization, the necessity to perceive speech in noise in a non-native language is common and necessary for successful communication. In the current investigation, bilingual individuals who learned their non-native language at different ages underwent magnetic resonance imaging while listening to sentences in both of their languages, in quiet and in noise. Sentence context was varied such that the final word could be of high or low predictability. Results show that early non-native language learning is associated with superior ability to benefit from contextual information behaviourally, and a pattern of neural recruitment in the left inferior frontal gyrus that suggests easier processing when perceiving non-native speech in noise. These findings have implications for our understanding of speech processing in non-optimal listening conditions and shed light on how individuals navigate every day complex communicative environments, in a native and non-native language.

Brain functional organization and structure in patients with arteriovenous malformations.

PURPOSE: Developmental in nature, brain arteriovenous malformations (AVM) have the potential to affect whole brain organization. Here we investigated the impact of AVM on functional and structural brain organization using resting-state functional MRI (rsfMRI) and cortical thickness measures. METHODS: We investigated brain functional organization and structure using rsfMRI in conjunction with cortical thickness analyses in 23 patients with cerebral arteriovenous malformations (AVMs) and 20 healthy control subjects. RESULTS: Healthy controls showed the expected anti-correlation between activity in the default mode network (DMN) and frontal areas that are part of the attentional control network. By contrast, patients demonstrated a disruption of this anti-correlation. Disruptions to this anti-correlation were even observed in a subgroup of patients with lesions remote from the main nodes of the DMN and were unrelated to differences in perfusion. Functional connectivity differences were accompanied by reduced cortical thickness in frontal attentional areas in patients compared to the controls. CONCLUSIONS: These results contribute to the discussion that AVMs affect whole brain networks and not simply the area surrounding the lesion.

Intrinsic Functional Brain Connectivity Predicts Onset of Major Depression Disorder in Adolescence: A Pilot Study.

Children with familial risk for major depressive disorder (MDD) have elevated risk for developing depression as adolescents. Here, we investigated longitudinally whether resting-state functional connectivity (RSFC) could predict the onset of MDD. In this pilot study, we followed a group of never-depressed children with familial risk for MDD and a group of age-matched controls without familial risk who had undergone an MRI study at 8-14 years of age. Participants were reassessed 3-4 years later with diagnostic interviews. We first investigated group differences in RSFC from regions in the emotion regulation, cognitive control, and default mode networks in the children who later developed MDD (converted), the children who did not develop MDD (nonconverted), and the control group. We then built a prediction model based on baseline RSFC that was independent of the group differences to classify the individuals who later developed MDD. Compared with the nonconverted group, the converted group exhibited hypoconnectivity between subgenual anterior cingulate cortex (sgACC) and inferior parietal lobule (IPL) and between left and right dorsolateral prefrontal cortices. The nonconverted group exhibited higher sgACC-IPL connectivity than did both the converted and control groups, suggesting a possible resilience factor to MDD. Classification between converted and nonconverted individuals based on baseline RSFC yielded high predictive accuracy with high sensitivity and specificity that was superior to classification based on baseline clinical rating scales. Intrinsic brain connectivity measured in healthy children with familial risk for depression has the potential to predict MDD onset, and it can be a useful neuromarker in early identification of children for preventive treatment.

Neural markers of depression risk predict the onset of depression.

Although research highlights neural correlates of Major Depressive Disorder (MDD), it is unclear whether these correlates reflect the state of depression or a pre-existing risk factor. The current study examined whether baseline differences in brain activations, resting-state connectivity, and brain structural differences between non-symptomatic children at high- and low-risk for MDD based on familial depression prospectively predict the onset of a depressive episode or increases in depressive symptomatology. We re-assessed 44 participants (28 high-risk; 16 low-risk) who had undergone neuroimaging in a previous study 3-4 years earlier (Mean age at follow-up = 14.3 years, SD = 1.9 years; 45% females; 70% Caucasian). We investigated whether baseline brain imaging data (including an emotional face match task fMRI, resting-state fMRI and structural MRI) that differentiated the risk groups also predicted the onset of depression. Resting-state functional connectivity abnormalities in the default mode and cognitive control network that differentiated high-risk from low-risk youth at baseline predicted the onset of MDD during adolescence, after taking risk status into account. Increased functional activation to both happy and fearful faces was associated with greater decreases in self-reported depression symptoms at follow-up. This preliminary evidence could be used to identify youth at-risk for depression and inform early intervention strategies.

Lewis-Base-Catalyzed [1 + 2 + 2] Annulation Reaction of Morita-Baylis-Hillman Carbonates with Unsaturated Pyrazolones: Construction of All-Stereogenic Carbon Cyclopentane-Fused Dispiropyrazolones.

The first Lewis-base-catalyzed unexpected [1 + 2 + 2] annulation reaction between Morita-Baylis-Hillman carbonates and unsaturated pyrazolones was developed. The multicyclic cyclopentane-fused dispiropyrazolone constructions containing five contiguous stereogenic centers, including two spiro quaternary centers, were prepared with excellent yields (81-98%) and moderate to good diastereoselectivities (1:1 to 13:1). Further transformation and gram-scale operations were also achieved efficiently.

Bilingual experience and resting-state brain connectivity: Impacts of L2 age of acquisition and social diversity of language use on control networks.

We investigated the independent contributions of second language (L2) age of acquisition (AoA) and social diversity of language use on intrinsic brain organization using seed-based resting-state functional connectivity among highly proficient French-English bilinguals. There were two key findings. First, earlier L2 AoA related to greater interhemispheric functional connectivity between homologous frontal brain regions, and to decreased reliance on proactive executive control in an AX-Continuous Performance Task completed outside the scanner. Second, greater diversity in social language use in daily life related to greater connectivity between the anterior cingulate cortex and the putamen bilaterally, and to increased reliance on proactive control in the same task. These findings suggest that early vs. late L2 AoA links to a specialized neural framework for processing two languages that may engage a specific type of executive control (e.g., reactive control). In contrast, higher vs. lower degrees of diversity in social language use link to a broadly distributed set of brain networks implicated in proactive control and context monitoring.