Aberrant microstructure of the uncinate fasciculus (UNC), a white matter (WM) tract implicated in emotion regulation, has been hypothesized as a neurobiological mechanism of depression. However, ...studies testing this hypothesis have yielded inconsistent results. The present meta-analysis consolidates evidence from 44 studies comparing fractional anisotropy (FA) and radial diffusivity (RD), two metrics characterizing WM microstructure, of the UNC in individuals with depression (n = 5016) to healthy individuals (n = 18 425). We conduct meta-regressions to identify demographic and clinical characteristics that contribute to cross-study heterogeneity in UNC findings. UNC FA was reduced in individuals with depression compared to healthy individuals. UNC RD was comparable between individuals with depression and healthy individuals. Comorbid anxiety explained inter-study heterogeneity in UNC findings. Depression is associated with perturbations in UNC microstructure, specifically with respect to UNC FA and not UNC RD. The association between depression and UNC microstructure appears to be moderated by anxiety. Future work should unravel the cellular mechanisms contributing to aberrant UNC microstructure in depression; clarify the relationship between UNC microstructure, depression, and anxiety; and link UNC microstructure to psychological processes, such as emotion regulation.
The origins of youth psychopathology are best studied by integrating clinical and developmental science, an approach known as developmental psychopathology.
This relatively young scientific ...discipline views youth psychopathology as the result of the dynamic interplay of neurobiological, psychological, and environmental risk and protective factors that transcend traditional diagnostic categories. Etiological questions within this framework include whether clinically relevant phenotypes, such as perturbed emotion regulation cross-sectionally linked to atypical brain morphometry, drive deviations from normative neurodevelopmental trajectories or should be viewed as the consequence of atypical brain maturation. The answer to such questions will have important treatment implications but necessitates the skillful integration of different levels of analysis across time. So, studies employing such an approach are rare.
Attention bias modification training (ABMT) and cognitive behavioral therapy (CBT) likely target different aspects of aberrant threat responses in anxiety disorders and may be combined to maximize ...therapeutic benefit. However, studies investigating the effect of ABMT in the context of CBT have yielded mixed results. Here, we propose an enhanced ABMT to target the attentional bias towards threat, in addition to classic CBT for anxiety disorders in youth. This enhanced ABMT integrates the modified dot-probe task used in previous studies, where a target is always presented at the previous location of the neutral and not the simultaneously presented threatening stimulus, with a visual search, where the targets are always presented distally of threatening distractors. These two training elements (modified dot-probe and visual search) are embedded in an engaging game to foster motivation and adherence. Our goal is to determine the efficacy of the enhanced ABMT in the context of CBT. Further, we aim to replicate two previous findings: (a) aberrant amygdala connectivity being the neurobiological correlate of the attentional bias towards threat at baseline; and (b) amygdala connectivity being a mediator of the ABMT effect. We will also explore moderators of treatment response (age, sex, depressive symptoms and irritability) on a behavioral and neuronal level.
One hundred and twenty youth (8-17 years old) with a primary anxiety disorder diagnosis all receive CBT and are randomized to nine weeks of either active or control ABMT and symptom improvement will be compared between the two study arms. We will also recruit 60 healthy comparison youth, who along with eligible anxious youth, will be assessed with the dot-probe task during fMRI (anxious youth: before and after training; healthy volunteers: second measurement twelve weeks after initial assessment).
The present study will contribute to the literature by (1) potentially replicating that aberrant amygdala connectivity mediates the attentional bias towards threat in anxious youth; (2) determining the efficacy of enhanced ABMT; and (3) advancing our understanding of the mechanisms underlying ABMT.
Clinicaltrials.gov: NCT03283930 Trial registration date: September 14th 2017. The trial registration took place retrospectively. Data acquisition started February 1st 2017.
Excessive expression of fear responses in anticipation of threat occurs in anxiety, but understanding of underlying pathophysiological mechanisms is limited. Animal research indicates that ...threat-anticipatory defensive responses are dynamically organized by threat imminence and rely on conserved circuitry. Insight from basic neuroscience research in animals on threat imminence could guide mechanistic research in humans mapping abnormal function in this circuitry to aberrant defensive responses in pathological anxiety.
50 pediatric anxiety patients and healthy-comparisons (33 females) completed an instructed threat-anticipation task whereby cues signaled delivery of painful (threat) or non-painful (safety) thermal stimulation. Temporal changes in skin-conductance indexed anxiety effects on anticipatory responding as function of threat imminence. Multivariate network analyses of resting-state functional connectivity data from a subsample were used to identify intrinsic-function correlates of anticipatory-response dynamics, within a specific, distributed network derived from translational research on defensive responding.
By considering threat imminence, analyses revealed specific anxiety effects. Importantly, pathological anxiety was associated with excessive deployment of anticipatory physiological response as threat, but not safety, outcomes became more imminent. Magnitude of increase in threat-anticipatory physiological responses corresponded with magnitude of intrinsic connectivity within a cortical-subcortical circuit. Moreover, more severe anxiety was associated with stronger associations between anticipatory physiological responding and connectivity that ventromedial prefrontal cortex showed with hippocampus and basolateral amygdala, regions implicated in animal models of anxiety.
These findings link basic and clinical research, highlighting variations in intrinsic function in conserved defensive circuitry as a potential pathophysiological mechanism in anxiety.
•We translate animal insight on fear dynamics into human research on anxiety.•Patients and controls completed threat anticipation task and resting-state scan.•We observed aberrant threat-anticipatory physiological response dynamics in anxiety.•Aberrant dynamics in anxiety linked to cortical-subcortical intrinsic function.•Findings link basic, clinical research; highlight potential pathophysiological mechanism.
•Uses region-of-interest approach to examine properties of uncinate fasciculus.•Patients with bipolar disorder show lower uncinate fasciculus fractional anisotropy.•First-degree relatives do not show ...lower uncinate fasciculus fractional anisotropy.•Remains inconclusive whether aberrancies in uncinate fasciculus are an endophenotype.
Bipolar disorder (BD) is a severe mental disorder, characterized by prominent mood swings and emotion regulation (ER) deficits. The uncinate fasciculus (UF), a white matter tract connecting the amygdala and the ventral prefrontal cortex, has been implicated in ER. Aberrancies in UF microstructure may be an endophenotype associated with increased risk for BD. However, studies in individuals with BD and their first-degree relatives (REL) have yielded inconsistent findings. This meta-analysis takes a region-of-interest approach to consolidate the available evidence and elucidate the role of the UF in the risk-architecture of BD.
Using web-based search engines, we identified diffusion tensor imaging (DTI) studies focusing on the left and right UF and conducted meta-analyses comparing fractional anisotropy (FA) and radial diffusivity (RD) between BD or REL and healthy control participants (HC).
We included 32 studies (nBD=1186, nREL=289, nHC=2315). Compared to HC, individuals with BD showed lower FA in the right (WMD=-0.31, p<0.0001) and left UF (WMD=−0.21, p = 0.010), and higher RD in the right UF (WMD=0.32, p = 0.009). We found no significant differences between REL and HC. In the right but not left UF, REL showed higher FA than BD (p = 0.043).
Our findings support aberrant UF microstructure, potentially related to alterations in myelination, as a mechanism, but not as an endophenotype of BD. However, given the limited power in the REL subsample, the latter finding must be considered preliminary. Studies examining the role of the UF in individuals at familial risk for BD are warranted.
To date, it is still a matter of debate, whether valence or valence and arousal interactively foster implicit approach and avoidance tendencies, and which neural circuitries underlie these effects. ...To address these questions, we investigated the effects of valence and arousal on implicit approach/avoidance tendencies during fMRI in healthy volunteers (N=46). The implicit approach of positive social scenes was associated with shorter response preparation times and increased activation of the lingual, parahippocampal and fusiform gyri. Valence and arousal did not influence reaction times interactively, but we observed increased activation of prefrontal, motor, temporal, middle cingulate and parietal cortex during the approach of positive highly arousing and negative mildly arousing pictures, and the avoidance of positively mildly arousing and negative highly arousing pictures. These findings confirm the facilitation of implicit approach by positive scenes and advance our understanding regarding the neurobiological correlates of implicit approach-/avoidance biases.
•Approach-/ avoidance biases are thought to be relevant for different psychopathologies such as anxiety or addiction.•We investigated, which characteristics of a situation (valence, arousal) determine approach-/ avoidance biases using fMRI.•Independent of arousal, positive valence fostered faster implicit approach behavior.•Individual differences in the behavioral activation system also determine the approach of positive scenes.•During the implicit approach of positive scenes, we observed greater activity in brain regions relevant for face processing and motor responses.
The Affective Reactivity Index (ARI) is widely used to assess young people's irritability symptoms, but youth and caregivers often diverge in their assessments. Such informant discrepancy might be ...rooted in poor psychometric properties, the differential conceptualization of irritability across informants, or reflect sociodemographic and clinical characteristics. We use an out-of-sample replication approach and leverage longitudinal data, available for a subset of the participants, to test these hypotheses.
Across two independent samples (NCohort-1 = 765, 8–21 years; NCohort-2 = 1910, 6–21 years), we investigate the reliability and measurement invariance of the ARI, examine sociodemographic and clinical predictors of discrepant reporting and probe the utility of a bifactor model for cross-informant integration.
Despite good internal consistency and 6-week-retest-reliability of parent (Cohort-1: α = 0.92, ICC = 0.85; Cohort-2: α = 0.93) and youth forms (Cohort-1: α = 0.88, ICC = 0.78; Cohort-2: α = 0.82), we confirm substantial informant discrepancy in ARI ratings (3 points on a scale from 0 to 12), which is stable over six weeks (ICC = 0.53). Measurement invariance across informants was weak, indicating that parents and youth may interpret ARI items differently. Irritability severity and diagnostic status predicted informant-discrepancy, albeit in opposing directions: higher severity was linked to relative, higher irritability-ratings by youth (Cohort-1: β = −0.06, p < .001; Cohort-2: β = −0.06, p < .001), while diagnoses of Disruptive Mood Dysregulation Disorder (Cohort-1: β = 0.44, p < .001; Cohort-2: β = 0.84, p < .001) and Oppositional Defiant Disorder (Cohort-1: β = 0.41, p < .001; Cohort-2: β = 0.42, p < .001) predicted relative higher irritability-ratings by caregivers. In both datasets, a bifactor model parsing informant-specific from shared irritability-related variance fit the data well (CFI = 0.99, RMSEA = 0.05; N2: CFI = 0.99; RMSEA = 0.04).
Parent and youth ARI reports and their discrepancy are reliable and reflect different interpretations of the scale items; hence they should not be averaged. This finding also suggests that irritability is not a unitary construct. Future work should investigate and model how different aspects of irritability might differ in their impact on the responses of specific informants.
•Parents and youth disagree substantially in their assessment of irritability.•Discrepancies between parent and youth ratings are stable and depend on irritability severity and diagnostic status.•Parent-youth discrepancies in irritability ratings reflect different conceptualizations of irritability.•Parent- and youth-reports of irritability should not be averaged for clinical or research purposes.
Irritability, inattention, and hyperactivity, which are common presentations of childhood psychopathology, have been associated with perturbed white matter microstructure. However, similar tracts ...have been implicated across these phenotypes; such non-specificity could be rooted in their high co-occurrence. To address this problem, we use a bifactor approach parsing unique and shared components of irritability, inattention, and hyperactivity, which we then relate to white matter microstructure.
We developed a bifactor model based on the Conners Comprehensive Behavioral Rating Scale in a sample of youth with no psychiatric diagnosis or a primary diagnosis of attention-deficit/hyperactivity disorder or disruptive mood dysregulation disorder (n = 521). We applied the model to an independent yet sociodemographically and clinically comparable sample (n = 152), in which we tested associations between latent variables and fractional anisotropy (FA).
The bifactor model fit well (comparative fit index = 0.99; root mean square error of approximation = 0.07). The shared factor was positively associated with an independent measure of impulsivity (ρS = 0.88, pFDR < .001) and negatively related to whole-brain FA (r = −0.20), as well as FA of the corticospinal tract (all pFWE < .05). FA increased with age and deviation from this curve, indicating that altered white matter maturation was associated with the hyperactivity-specific factor (r = −0.16, pFWE < .05). Inattention-specific and irritability-specific factors were not linked to FA.
Perturbed white matter microstructure may represent a shared neurobiological mechanism of irritability, inattention, and hyperactivity related to heightened impulsivity. Furthermore, hyperactivity might be uniquely associated with a delay in white matter maturation.
Objectives
Bipolar disorder (BD) and familial risk for BD have been associated with aberrant white matter (WM) microstructure in the corpus callosum and fronto‐limbic pathways. These abnormalities ...might constitute trait or state marker and have been suggested to result from aberrant maturation and to relate to difficulties in emotion regulation.
Methods
To determine whether WM alterations represent a trait, disease or resilience marker, we compared youth at risk for BD (n = 36 first‐degree relatives, REL) to youth with BD (n = 36) and healthy volunteers (n = 36, HV) using diffusion tensor imaging.
Results
Individuals with BD and REL did not differ from each other in WM microstructure and, compared to HV, showed similar aberrations in the superior corona radiata (SCR)/corticospinal tract (CST) and the body of the corpus callosum. WM microstructure of the anterior CC showed reduced age‐related in‐creases in BD compared to REL and HV. Further, individuals with BD and REL showed in‐creased difficulties in emotion regulation, which were associated with the microstructure of the anterior thalamic radiation.
Discussion
Alterations in the SCR/CST and the body of the corpus callosum appear to represent a trait marker of BD, whereas changes in other WM tracts seem to be a disease state marker. Our findings also support the role of aberrant developmental trajectories of WM microstructure in the risk architecture of BD, although longitudinal studies are needed to confirm this association. Finally, our findings show the relevance of WM microstructure for difficulties in emotion regulation—a core characteristic of BD.
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