Kailyn A.L. Bradley

The role of the kynurenine pathway in suicidality in adolescent major depressive disorder

The neuroimmunological kynurenine pathway (KP) has been implicated in major depressive disorder (MDD) in adults and adolescents, most recently in suicidality in adults. The KP is initiated by the enzyme indoleamine 2,3-dioxygenase (IDO), which degrades tryptophan (TRP) into kynurenine (KYN) en route to neurotoxins. Here, we examined the KP in 20 suicidal depressed adolescents-composed of past attempters and those who expressed active suicidal intent-30 non-suicidal depressed youth, and 22 healthy controls (HC). Plasma levels of TRP, KYN, 3-hydroxyanthranilic acid (3-HAA), and KYN/TRP (index of IDO) were assessed. Suicidal adolescents showed decreased TRP and elevated KYN/TRP compared to both non-suicidal depressed adolescents and HC. Findings became more significantly pronounced when excluding medicated participants, wherein there was also a significant positive correlation between KYN/TRP and suicidality. Finally, although depressed adolescents with a history of suicide attempt differed from acutely suicidal adolescents with respect to disease severity, anhedonia, and suicidality, the groups did not differ in KP measures. Our findings suggest a possible specific role of the KP in suicidality in depressed adolescents, while illustrating the clinical phenomenon that depressed adolescents with a history of suicide attempt are similar to acutely suicidal youth and are at increased risk for completion of suicide.

Language experience differentiates prefrontal and subcortical activation of the cognitive control network in novel word learning

The purpose of this study was to examine the cognitive control mechanisms in adult English speaking monolinguals compared to early sequential Spanish-English bilinguals during the initial stages of novel word learning. Functional magnetic resonance imaging during a lexico-semantic task after only 2h of exposure to novel German vocabulary flashcards showed that monolinguals activated a broader set of cortical control regions associated with higher-level cognitive processes, including the supplementary motor area (SMA), anterior cingulate (ACC), and dorsolateral prefrontal cortex (DLPFC), as well as the caudate, implicated in cognitive control of language. However, bilinguals recruited a more localized subcortical network that included the putamen, associated more with motor control of language. These results suggest that experience managing multiple languages may differentiate the learning strategy and subsequent neural mechanisms of cognitive control used by bilinguals compared to monolinguals in the early stages of novel word learning.

Neural correlates of self-perceptions in adolescents with major depressive disorder

Alteration in self-perception is a salient feature in major depression. Hyperactivity of anterior cortical midline regions has been implicated in this phenomenon in depressed adults. Here, we extend this work to depressed adolescents during a developmental time when neuronal circuitry underlying the sense of self matures by using task-based functional magnetic resonance imaging (fMRI) and connectivity analyses. Twenty-three depressed adolescents and 18 healthy controls (HC) viewed positive and negative trait words in a scanner and judged whether each word described them (‘self’ condition) or was a good trait to have (‘general’ condition). Self-perception scores were based on participants’ endorsements of positive and negative traits during the fMRI task. Depressed adolescents exhibited more negative self-perceptions than HC. Both groups activated cortical midline regions in response to self-judgments compared to general-judgments. However, depressed adolescents recruited the posterior cingulate cortex/precuneus more for positive self-judgments. Additionally, local connectivity of the dorsal medial prefrontal cortex was reduced during self-reflection in depressed adolescents. Our findings highlight differences in self-referential processing network function between depressed and healthy adolescents and support the need for further investigation of brain mechanisms associated with the self, as they may be paramount to understanding the etiology and development of major depressive disorder.

Increased ventricular cerebrospinal fluid lactate in depressed adolescents

BACKGROUND Mitochondrial dysfunction has been increasingly examined as a potential pathogenic event in psychiatric disorders, although its role early in the course of major depressive disorder (MDD) is unclear. Therefore, the purpose of this study was to investigate mitochondrial dysfunction in medication-free adolescents with MDD through in vivo measurements of neurometabolites using high-spatial resolution multislice/multivoxel proton magnetic resonance spectroscopy. METHODS Twenty-three adolescents with MDD and 29 healthy controls, ages 12-20, were scanned at 3T and concentrations of ventricular cerebrospinal fluid lactate, as well as N-acetyl-aspartate (NAA), total creatine (tCr), and total choline (tCho) in the bilateral caudate, putamen, and thalamus were reported. RESULTS Adolescents with MDD exhibited increased ventricular lactate compared to healthy controls [F(1,41)=6.98, P=0.01]. However, there were no group differences in the other neurometabolites. Dimensional analyses in the depressed group showed no relation between any of the neurometabolites and symptomatology, including anhedonia and fatigue. CONCLUSIONS Increased ventricular lactate in depressed adolescents suggests mitochondrial dysfunction may be present early in the course of MDD; however it is still not known whether the presence of mitochondrial dysfunction is a trait vulnerability of individuals predisposed to psychopathology or a state feature of the disorder. Therefore, there is a need for larger multimodal studies to clarify these chemical findings in the context of network function.

A pilot resting-state functional connectivity study of the kynurenine pathway in adolescents with depression and healthy controls

BACKGROUND The neuroimmunological kynurenine pathway (KP) has been hypothesized to play a role in depressive/anhedonic symptoms and related CNS disturbances. Indoleamine 2,3-dioxygenase (IDO) is the rate limiting enzyme which leads to neurotrophic [kynurenic acid (KA)] and neurotoxic [Quinolinic acid (QUIN)] branches. In this pilot, we sought to examine associations between blood KP neuro-toxic/trophic measures and anhedonia/depression associated networks in youth with major depression (MDD) and healthy controls (HC). METHODS Subjects were 14 psychotropic-medication free adolescents with MDD and 7 HC, ages 12-19 yo. All underwent resting-state functional magnetic resonance imagining (fMRI) scans. Voxel-wise maps were generated indicating correlation strengths among 4 bilateral seeds [(dorsal anterior cingulate cortex (dACC), perigenual ACC (pgACC), subgenual ACC (sgACC) and nucleus accumbens (NAc)] and remaining brain regions. FMRI analyses were family-wise error corrected. KP metabolites were measured using liquid chromatography-tandem mass spectrometry. RESULTS Connectivity between the right dACC and the right precuneus was positively correlated with KA levels. This same cluster demonstrated an inverse correlation with IDO activity. Exploratory analysis at a more liberal clustering threshold showed the KA/QUIN ratio was positively correlated with connectivity between the pgACC and the right medial prefrontal cortex. Lastly, connectivity between the pgACC and the left inferior temporal gyrus was positively correlated with QUIN levels. LIMITATIONS Findings are preliminary due to the small sample size. CONCLUSIONS This pilot study is the first report in depressed adolescents demonstrating associations between the KP and anhedonia/depression-associated brain networks. This pilot adds evidence to the putative role of the KP in MDD.

Bilingual Cortical Control of Between- and Within-Language Competition

The human capacity to master multiple languages is remarkable and leads to structural and functional changes in the brain. Understanding how the brain accommodates multiple languages simultaneously is crucial to developing a complete picture of our species’ linguistic capabilities. To examine the neural mechanisms involved in processing two languages, we looked at cortical activation in Spanish-English bilinguals in response to phonological competition either between two languages or within a language. Participants recognized spoken words in a visual world task while their brains were scanned using functional magnetic resonance imaging (fMRI). Results revealed that between-language competition recruited a larger network of frontal control and basal ganglia regions than within-language competition. Bilinguals also recruited more neural resources to manage between-language competition from the dominant language compared to competition from the less dominant language. Additionally, bilinguals’ activation of the basal ganglia was inversely correlated with their executive function ability, suggesting that bilinguals compensated for lower levels of cognitive control by recruiting a broader neural network to manage more difficult tasks. These results provide evidence for differences in neural responses to linguistic competition between versus within languages, and demonstrate the brain’s remarkable plasticity, where language experience can change neural processing.

Neural signatures of second language learning and control

&NA; Experience with multiple languages has unique effects on cortical structure and information processing. Differences in gray matter density and patterns of cortical activation are observed in lifelong bilinguals compared to monolinguals as a result of their experience managing interference across languages. Monolinguals who acquire a second language later in life begin to encounter the same type of linguistic interference as bilinguals, but with a different pre‐existing language architecture. The current study used functional magnetic resonance imaging to explore the beginning stages of second language acquisition and cross‐linguistic interference in monolingual adults. We found that after English monolinguals learned novel Spanish vocabulary, English and Spanish auditory words led to distinct patterns of cortical activation, with greater recruitment of posterior parietal regions in response to English words and of left hippocampus in response to Spanish words. In addition, cross‐linguistic interference from English influenced processing of newly‐learned Spanish words, decreasing hippocampus activity. Results suggest that monolinguals may rely on different memory systems to process a newly‐learned second language, and that the second language system is sensitive to native language interference. HighlightsPhonological memory and inhibitory control affect second language vocabulary learning.Distinct neural activation for native versus newly‐learned second language words.Cross‐linguistic interference alters hippocampus activation in the second language.

Neural correlates of RDoC reward constructs in adolescents with diverse psychiatric symptoms: A Reward Flanker Task pilot study

BACKGROUND There has been growing interest under the Research Domain Criteria initiative to investigate behavioral constructs and their underlying neural circuitry. Abnormalities in reward processes are salient across psychiatric conditions and may precede future psychopathology in youth. However, the neural circuitry underlying such deficits has not been well defined. Therefore, in this pilot, we studied youth with diverse psychiatric symptoms and examined the neural underpinnings of reward anticipation, attainment, and positive prediction error (PPE, unexpected reward gain). Clinically, we focused on anhedonia, known to reflect deficits in reward function. METHODS Twenty-two psychotropic medication-free youth, 16 with psychiatric symptoms, exhibiting a full range of anhedonia, were scanned during the Reward Flanker Task. Anhedonia severity was quantified using the Snaith-Hamilton Pleasure Scale. Functional magnetic resonance imaging analyses were false discovery rate corrected for multiple comparisons. RESULTS Anticipation activated a broad network, including the medial frontal cortex and ventral striatum, while attainment activated memory and emotion-related regions such as the hippocampus and parahippocampal gyrus, but not the ventral striatum. PPE activated a right-dominant fronto-temporo-parietal network. Anhedonia was only correlated with activation of the right angular gyrus during anticipation and the left precuneus during PPE at an uncorrected threshold. LIMITATIONS Findings are preliminary due to the small sample size. CONCLUSIONS This pilot characterized the neural circuitry underlying different aspects of reward processing in youth with diverse psychiatric symptoms. These results highlight the complexity of the neural circuitry underlying reward anticipation, attainment, and PPE. Furthermore, this study underscores the importance of RDoC research in youth.

Plasticity of Interhemispheric Temporal Lobe White Matter Pathways Due to Early Disruption of Corpus Callosum Development in Spina Bifida

Spina bifida myelomeningocele (SBM) is commonly associated with anomalous development of the corpus callosum (CC) because of congenital partial hypogenesis and hydrocephalus-related hypoplasia. It represents a model disorder to examine the effects of early disruption of CC neurodevelopment and the plasticity of interhemispheric white matter connections. Diffusion tensor imaging was acquired on 76 individuals with SBM and 27 typically developing individuals, aged 8-36 years. Probabilistic tractography was used to isolate the interhemispheric connections between the posterior superior temporal lobes, which typically traverse the posterior third of the CC. Early disruption of CC development resulted in restructuring of interhemispheric connections through alternate commissures, particularly the anterior commissure (AC). These rerouted fibers were present in people with SBM and both CC hypoplasia and hypogenesis. In addition, microstructural integrity was reduced in the interhemispheric temporal tract in people with SBM, indexed by lower fractional anisotropy, axial diffusivity, and higher radial diffusivity. Interhemispheric temporal tract volume was positively correlated with total volume of the CC, such that more severe underdevelopment of the CC was associated with fewer connections between the posterior temporal lobes. Therefore, both the macrostructure and microstructure of this interhemispheric tract were reduced, presumably as a result of more extensive CC malformation. The current findings suggest that early disruption in CC development reroutes interhemispheric temporal fibers through both the AC and more anterior sections of the CC in support of persistent hypotheses that the AC may serve a compensatory function in atypical CC development.

Elevated striatal γ-aminobutyric acid in youth with major depressive disorder

Background: Alterations in &ggr;‐aminobutyric acid (GABA) have been hypothesized to play a role in the pathogenesis of psychiatric illness. Our previous work has specifically linked anterior cingulate cortex (ACC) GABA deficits with anhedonia in youth with major depressive disorder (MDD). As anhedonia reflects alterations within the reward circuitry, we sought to extend this investigation and examine GABA levels in another key reward‐related region, the striatum, in the same adolescent population. Methods: Thirty‐six youth [20 with MDD and 16 healthy controls; (HC)], ages 12 to 21 years old, underwent J‐edited proton magnetic resonance spectroscopy (1H MRS) whereby GABA levels were measured in striatal and ACC voxels. GABA levels were compared between groups and between voxel positions and were examined in relation to clinical symptomatology, such as depression severity, anhedonia, anxiety, and suicidality. Results: Depressed youth had unexpectedly higher GABA levels in the striatum compared to HC. In both depressed and healthy youth, GABA levels were higher in the striatum than in the ACC, while the differences in depressed youth were greater. Moreover, in depressed youth, higher striatal GABA above the mean of HCs was correlated with lower ACC GABA below the mean of HCs. Striatal GABA was not correlated with clinical symptomatology in this small sample. Conclusions: Together, these findings suggest that higher striatal GABA levels may serve some compensatory function as a result of lower ACC GABA in depressed adolescents. It is also possible that, like lower ACC GABA, higher striatal GABA might simply be another pathological feature of adolescent depression. HighlightsHigher striatal GABA levels found in depressed youth compared to healthy controls.Striatal GABA higher than ACC GABA in both groups; greater difference in depression.Higher striatal GABA correlated with lower ACC GABA in depressed youth.No correlation between striatal GABA and clinical symptomatology