Assessing the utility of a novel cortical marker of delay discounting (C-DD) in two independent samples of early adolescents: Links with externalizing pathology.

Delay discounting is a well-established risk factor for risky behaviors and the development of externalizing spectrum disorders. Building upon recent work that developed a novel cortical marker of delay discounting (C-DD) in adult samples, the objective of this study was to test whether the C-DD relates to delay discounting and subsequently externalizing pathology in adolescent samples. The current study used two samples: 9992 early adolescents participating in the ABCD study (Mage = 9.93 years old, 48.7% female), and 56 early adolescents recruited from the community (Mage = 12.27 years old, 55.4% female). Cortical thickness was estimated using the FreeSurfer standard pipeline, and the cortical marker of delay discounting (C-DD) was calculated based on procedures outlined by the initial validation study. All data are cross-sectional in nature. As expected, C-DD was positively related to delay discounting in the ABCD sample, even after accounting for age, biological sex, collection site and data quality indicators. Moreover, results showed that C-DD was discriminately associated with externalizing, but not internalizing, symptoms in both samples of young adolescents. Findings replicate those found in adult samples, suggestive that C-DD may be a useful neuroanatomical marker of youth delay discounting. Replication of findings in other samples will be needed to determine whether C-DD has translational relevance to understanding externalizing psychopathology in adolescent samples.

Negative emotion differentiation and white matter microstructure.

BACKGROUND: Deficits in the differentiation of negative emotions - the ability to specifically identify one's negative emotions - are associated with poorer mental health outcomes. However, the processes that lead to individual differences in negative emotion differentiation are not well understood, hampering our understanding of why this process is related to poor mental health outcomes. Given that disruptions in some affective processes are associated with white matter microstructure, identifying the circuitry associated with different affective processes can inform our understanding of how disturbances in these networks may lead to psychopathology. Thus, examination of how white matter microstructure relates to individual differences in negative emotion differentiation (NED) may provide insights into (i) its component processes and (ii) its relationship to brain structure. METHOD: The relationship between white matter microstructure and NED was examined. RESULTS: NED was related to white matter microstructure in right anterior thalamic radiation and inferior fronto-occipital fasciculus and left peri-genual cingulum. LIMITATIONS: Although participants self-reported psychiatric diagnoses and previous psychological treatment, psychopathology was not directly targeted, and thus, the extent to which microstructure related to NED could be examined in relation to maladaptive outcomes is limited. CONCLUSIONS: Results indicate that NED is related to white matter microstructure and suggest that pathways subserving processes that facilitate memory, semantics, and affective experience are important for NED. Our findings provide insights into the mechanisms by which individual differences in NED arise, suggesting intervention targets that may disrupt the relationship between poor differentiation and psychopathology.

Mapping brain mechanical property maturation from childhood to adulthood.

Magnetic resonance elastography (MRE) is a phase contrast MRI technique which uses external palpation to create maps of brain mechanical properties noninvasively and in vivo. These mechanical properties are sensitive to tissue microstructure and reflect tissue integrity. MRE has been used extensively to study aging and neurodegeneration, and to assess individual cognitive differences in adults, but little is known about mechanical properties of the pediatric brain. Here we use high-resolution MRE imaging in participants of ages ranging from childhood to adulthood to understand brain mechanical properties across brain maturation. We find that brain mechanical properties differ considerably between childhood and adulthood, and that neuroanatomical subregions have differing maturational trajectories. Overall, we observe lower brain stiffness and greater brain damping ratio with increasing age from 5 to 35 years. Gray and white matter change differently during maturation, with larger changes occurring in gray matter for both stiffness and damping ratio. We also found that subregions of cortical and subcortical gray matter change differently, with the caudate and thalamus changing the most with age in both stiffness and damping ratio, while cortical subregions have different relationships with age, even between neighboring regions. Understanding how brain mechanical properties mature using high-resolution MRE will allow for a deeper understanding of the neural substrates supporting brain function at this age and can inform future studies of atypical maturation.

The structural brain network topology of episodic memory.

Episodic memory is supported by a distributed network of brain regions, and this complex network of regions does not operate in isolation. To date, neuroscience research in this area has typically focused on the activation levels in specific regions or pairwise connectivity between such regions. However, research has yet to investigate how the complex interactions of structural brain networks influence episodic memory abilities. We applied graph theory methods to diffusion-based anatomical networks in order to examine the structural architecture of the medial temporal lobe needed to support effective episodic memory functioning. We examined the relationship between performance on tests of verbal and non-verbal episodic memory with node strength, which indexes how well connected a brain region is in the network. Findings mapped onto the Posterior Medial memory system, subserved by the parahippocampal cortex and overlapped with findings of previous studies of episodic memory employing different methodologies. This expands our current understanding by providing independent evidence for the importance of identified regions and suggesting the particular manner in which these regions support episodic memory.

Affect Regulation-Related Emergent Brain Network Properties Differentiate Depressed Bipolar Disorder From Major Depression and Track Risk for Bipolar Disorder.

BACKGROUND: Individuals with or at risk for bipolar disorder (BD) often present initially for the treatment of depressive symptoms. Unfortunately, pharmacological treatments for major depressive disorder (MDD) can be iatrogenic, precipitating mania that may not have otherwise occurred. Current diagnostic procedures rely solely on self-reported/observable symptoms, and thus alternative data sources, such as brain network properties, are needed to supplement current self-report/observation-based indices of risk for mania. METHODS: Brain connectivity during affect maintenance/regulation was examined in a large (N = 249), medication-free sample of currently depressed patients with BD (n = 50) and MDD (n = 116) and healthy control subjects (n = 83). BD risk was categorized in a subset of patients with MDD. We used graph theory to identify emergent network properties that differentiated between patients with BD and MDD and between patients with MDD at high and low risk for BD. RESULTS: BD and MDD differed in the extent to which the rostral anterior cingulate cortex was embedded in the local network, amount of influence the hippocampus exerted over global network communication, and clarity of orbitofrontal cortex communication. Patients with MDD at high risk for BD showed a pattern of local network clustering around the right amygdala that was similar to the pattern observed in healthy control subjects, whereas patients with MDD at low risk for BD deviated from this pattern. CONCLUSIONS: BD and MDD differed in emergent network mechanisms subserving affect regulation, and amygdala properties tracked BD risk in patients with MDD. If replicated, our findings may be combined with other markers to assess the presence of BD and/or BD risk in individuals presenting with depressive symptoms to prevent the use of iatrogenic treatments.

Identifying brain regions supporting amygdalar functionality: Application of a novel graph theory technique.

Effective amygdalar functionality depends on the concerted activity of a complex network of regions. Thus, the role of the amygdala cannot be fully understood without identifying the set of brain structures that allow the processes performed by the amygdala to emerge. However, this identification has yet to occur, hampering our ability to understand both normative and pathological processes that rely on the amygdala. We developed and applied novel graph theory methods to diffusion-based anatomical networks in a large sample (n = 1,052, 54.28% female, mean age=28.75) to identify nodes that critically support amygdalar interactions with the larger brain network. We examined three graph properties, each indexing a different emergent aspect of amygdalar network communication: current-flow betweenness centrality (amygdalar influence on information flowing between other pairs of nodes), node communicability (clarity of communication between the amygdala and other nodes), and subgraph centrality (amygdalar influence over local network processing). Findings demonstrate that each of these aspects of amygdalar communication is associated with separable sets of regions and, in some cases, these sets map onto previously identified sub-circuits. For example, betweenness and communicability were each associated with different sub-circuits that have been identified in previous work as supporting distinct aspects of memory-guided behavior. Other regions identified span basic (e.g., visual cortex) to higher-order (e.g., insula) sensory processing and executive functions (e.g., dorsolateral prefrontal cortex). Present findings expand our current understanding of amygdalar function by showing that there is no single 'amygdala network', but rather multiple networks, each supporting different modes of amygdalar interaction with the larger brain network. Additionally, our novel method allowed for the identification of how such regions support the amygdala, which has not been previously explored.

Differential spatial patterns of structural connectivity of amygdala nuclei with orbitofrontal cortex.

The orbitofrontal cortex (OFC)-amygdala circuit is critical to goal-directed behavior, learning, and valuation. However, our understanding of the OFC-amygdala connections that support these emergent processes is hampered by our reliance on the primate literature and insufficient knowledge regarding the connectivity patterns between regions of OFC and amygdala nuclei, each of which is differentially involved in these processes in humans. Thus, we examined structural connectivity between different OFC regions and four amygdala nuclei in healthy adults (n = 1,053) using diffusion-based anatomical networks and probabilistic tractography in four conceptually distinct ways. First, we identified the OFC regions that connect with each nucleus. Second, we identified the OFC regions that were more likely to connect with a given nucleus than the others. Finally, we developed probabilistic and rank-order maps of OFC (one for each nucleus) based upon the likelihood of each OFC voxel exhibiting preferential connectivity with each nucleus and the relative density of connectivity between each OFC voxel and each nucleus, respectively. The first analyses revealed that the connections of each nucleus spanned all of OFC, reflecting widespread overall amygdala linkage with OFC. Analysis of preferential connectivity and probabilistic and rank-order maps of OFC converged to reveal differential patterns of connectivity between OFC and each nucleus. Present findings illustrate the importance of accounting for spatial specificity when examining links between OFC and amygdala. This fine-grained examination of OFC-amygdala connectivity can be applied to understand how such connectivity patterns support a range of emergent functions including affective and motivational processes.

Anxiety in transition: Neuroendocrine mechanisms supporting the development of anxiety pathology in adolescence and young adulthood.

Adolescence marks a key developmental window during which emotion dysregulation increases, along with risk for the onset of anxiety and other affect-related pathologies. Although emotion dysregulation and related pathologies normatively decline during the transition into adulthood, this does not occur for a sizable minority of individuals. Finally, sex differences in anxiety emerge during adolescence, with females developing a 2-fold increase in risk relative to males. Unfortunately, a neurobiological model of the mechanisms that cause these changes during adolescence has yet to be proposed. In the present work, we first provide brief reviews of relevant literature. Next, we outline a dual-mechanism model focused on (i) the influence of pubertal testosterone on key emotion-regulation circuitry (i.e., orbitofrontal cortex-amygdala coupling) and (ii) myelination of the fiber bundles connecting such circuitry (i.e., uncinate fasciculus). The proposed model offers a set of specific, testable hypotheses that will hopefully spur much needed cross-disciplinary research.

Lithium monotherapy associated longitudinal effects on resting state brain networks in clinical treatment of bipolar disorder.

OBJECTIVES: Lithium is one of the most effective and specific treatments for bipolar disorder (BP), but the neural mechanisms by which lithium impacts symptoms remain unclear. Past research has been limited by a reliance on cross-sectional designs, which does not allow for identification of within-person changes due to lithium and has not examined communication between brain regions (ie, networks). In the present study, we prospectively investigated the lithium monotherapy associated effects in vivo on the brain connectome in medication-free BP patients. In particular, we examined the within-person impact of lithium treatment on connectome indices previously linked to mania and depression in bipolar disorder. METHODS: Thirty-nine medication-free subjects - 26 BP (13 (hypo)manic and 13 depressed) and 13 closely matched healthy controls (HC) - were included. fMRI data were obtained at 3 timepoints: baseline, after 2 weeks, and after 8 weeks (total of 117 scans: 78 BP and 39 HC scans). BP subjects were clinically treated with lithium for 8 weeks while HC were scanned at the same time points but not treated. Graph theory metrics and repeated measures GLM were used to analyze lithium treatment associated effects. RESULTS: Consistent with hypotheses, lithium treatment was associated with a normalizing effect on mania-related connectome indices. Furthermore, shifts in both mania- and depression-related connectome indices were proportional to symptom change. Finally, lithium treatment-associated impact on amygdala function differed depending on baseline mood. CONCLUSIONS: Present findings provide deeper insight into the therapeutic neural mechanisms associated with lithium treatment.