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Gray matter volumes of the left and right striatum in the MDD patients and the healthy comparison subjects . Horizontal lines indicate means. Ordinate indicates volume (cm 3 ) adjusted for total brain volume, age, sex, and IQ. a Significant difference between groups (F (1, 47) 5.9, p 0.02). MDD Major depressive disorder; IQ intelligence quotient.
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The striatum, including the putamen and caudate, plays an important role in executive and emotional processing and may be involved in the pathophysiology of mood disorders. Few studies have examined structural abnormalities of the striatum in pediatric major depressive disorder (MDD) patients. We report striatal volume abnormalities in medication-n...
Citations
... The striatum is crucial for executive and emotional processing, making it a potential target for pathological changes in psychiatric disorders [44,45]. A smaller caudate nucleus volume has been reported in early-onset mental disorders [46,47], drug-naïve first episode MDD [48], and adolescents at high risk for mental disorders [49]. However, due to the lack of longitudinal experimental design, the exact period of abnormal striatum development in early-onset patients with mental disorders remains unknown. ...
Early-onset mental disorders are associated with disrupted neurodevelopmental processes during adolescence. The methylazoxymethanol acetate (MAM) animal model, in which disruption in neurodevelopmental processes is induced, mimics the abnormal neurodevelopment associated with early-onset mental disorders from an etiological perspective. We conducted longitudinal structural magnetic resonance imaging (MRI) scans during childhood, adolescence, and adulthood in MAM rats to identify specific brain regions and critical windows for intervention. Then, the effect of repetitive transcranial magnetic stimulation (rTMS) intervention on the target brain region during the critical window was investigated. In addition, the efficacy of this intervention paradigm was tested in a group of adolescent patients with early-onset mental disorders (diagnosed with major depressive disorder or bipolar disorder) to evaluate its clinical translational potential. The results demonstrated that, compared to the control group, the MAM rats exhibited significantly lower striatal volume from childhood to adulthood (all P <0.001). In contrast, the volume of the hippocampus did not show significant differences during childhood (P >0.05) but was significantly lower than the control group from adolescence to adulthood (both P <0.001). Subsequently, rTMS was applied to the occipital cortex, which is anatomically connected to the hippocampus, in the MAM models during adolescence. The MAM-rTMS group showed a significant increase in hippocampal volume compared to the MAM-sham group (P <0.01), while the volume of the striatum remained unchanged (P >0.05). In the clinical trial, adolescents with early-onset mental disorders showed a significant increase in hippocampal volume after rTMS treatment compared to baseline (P <0.01), and these volumetric changes were associated with improvement in depressive symptoms (r = − 0.524, P = 0.018). These findings highlight the potential of targeting aberrant hippocampal development during adolescence as a viable intervention for early-onset mental disorders with neurodevelopmental etiology as well as the promise of rTMS as a therapeutic approach for mitigating aberrant neurodevelopmental processes and alleviating clinical symptoms.
... Eighteen studies were identified which included 19 comparisons between 611 adolescents with MDD (mean age: 15.1 y; female: 62 %) and 570 healthy controls (mean age: 14.8 y; female: 62 %). Six studies of these were whole-brain VBM studies (Shad et al., 2012;Pannekoek et al., 2014;Hagan et al., 2015;Wehry et al., 2015;Redlich et al., 2018;Straub et al., 2019), and twelve were ROI studies (Nolan et al., 2002, MacMillan et al., 2003, Rosso et al., 2005, MacMaster et al., 2006, Caetano et al., 2007, Chen et al., 2008, MacMaster et al., 2008a, 2008b, Matsuo et al., 2008, MacMaster et al., 2014, Henje Blom et al., 2015, Tannous et al., 2018, Kim et al., 2019. Of these 611 individuals with MDD, 164 (27 %) were medication-naïve, 66 (11 %) had taken antidepressants; for the remaining 246 (40 %) the medication situation was not specified. ...
Background:
Gray matter volume (GMV) alterations in several emotion-related brain areas are implicated in mood disorders, but findings have been inconsistent in adolescents with major depressive disorder (MDD) or bipolar disorder (BD).
Methods:
We conducted a comprehensive meta-analysis of 35 region-of-interest (ROI) and 18 whole-brain voxel-based morphometry (VBM) MRI studies in adolescent MDD and adolescent BD, and indirectly compared the results in the two groups. The effects of age, sex, and other demographic and clinical scale scores were explored using meta-regression analysis.
Results:
In the ROI meta-analysis, right putamen volume was decreased in adolescents with MDD, while bilateral amygdala volume was decreased in adolescents with BD compared to healthy controls (HC). In the whole-brain VBM meta-analysis, GMV was increased in right middle frontal gyrus and decreased in left caudate in adolescents with MDD compared to HC, while in adolescents with BD, GMV was increased in left superior frontal gyrus and decreased in limbic regions compared with HC. MDD vs BD comparison revealed volume alteration in the prefrontal-limbic system.
Limitation:
Different clinical features limit the comparability of the samples, and small sample size and insufficient clinical details precluded subgroup analysis or meta-regression analyses of these variables.
Conclusions:
Distinct patterns of GMV alterations in adolescent MDD and adolescent BD could help to differentiate these two populations and provide potential diagnostic biomarkers.
... In addition to the a priori ROIs, the caudate nucleus was newly implicated in the context of AMD exposure. Whereas the caudate is not the most consistently implicated subcortical brain region in the neurobiology of depression, meta-analyses of adult depressed patients (Arnone et al., 2012;Bora et al., 2012) and two studies in depressed adolescents (Matsuo et al., 2008;Shad et al., 2012) have identified smaller caudate volumes. The caudate nucleus is an important region in the brain reward network and is thought to play a role in anhedonic depressive symptoms (Enneking et al., 2019). ...
Background
Several studies have reported enlarged amygdala and smaller hippocampus volumes in children and adolescents exposed to maternal depression. It is unclear whether similar volumetric differences are detectable in the infants’ first weeks of life, following exposure in utero. We investigated subcortical volumes in 2-to-6 week old infants exposed to antenatal maternal depression (AMD) from a South African birth cohort.
Methods
AMD was measured with the Beck Depression Inventory 2nd edition (BDI-II) at 28-32 weeks gestation. T2-weighted structural images were acquired during natural sleep on a 3T Siemens Allegra scanner. Subcortical regions were segmented based on the University of North Carolina neonatal brain atlas. Volumetric estimates were compared between AMD-exposed (BDI-II⩾20) and unexposed (BDI-II<14) infants, adjusted for age, sex and total intracranial volume using analysis of covariance.
Results
Larger volumes were observed in AMD-exposed (N=49) compared to unexposed infants (N=75) for the right amygdala (1.93% difference, p=0.039) and bilateral caudate nucleus (left: 5.79% difference, p=0.001; right: 6.09% difference, p<0.001). A significant AMD-by-sex interaction was found for the hippocampus (left: F(1,118)=4.80, p=0.030; right: F(1,118)=5.16, p=0.025), reflecting greater volume in AMD-exposed females (left: 5.09% difference, p=0.001, right: 3.54% difference, p=0.010), but not males.
Conclusions
Volumetric differences in subcortical regions can be detected in AMD-exposed infants soon after birth, suggesting structural changes may occur in utero. Female infants might exhibit volumetric changes that are not observed in male infants. The potential mechanisms underlying these early volumetric differences, and their significance for long-term child mental health, require further investigation.
... In contrast to the QSM results, there were no associations between brain volume and behavior. This differs from the research on mental health and brain structure in unexposed participants that has found associations between caudate volume, putamen development, amygdala, hippocampus, and thalamus abnormalities and internalizing and externalizing disorders [14][15][16][17][18][19][20][21][22]. Only one study of children with PAE found a trend-level association between caudate volume and internalizing symptoms [54]. ...
Prenatal alcohol exposure (PAE) negatively affects brain development and increases the risk of poor mental health. We investigated if brain volumes or magnetic susceptibility, an indirect measure of brain iron, were associated with internalizing or externalizing symptoms in youth with and without PAE. T1-weighted and quantitative susceptibility mapping (QSM) MRI scans were collected for 19 PAE and 40 unexposed participants aged 7.5–15 years. Magnetic susceptibility and volume of basal ganglia and limbic structures were extracted using FreeSurfer. Internalizing and Externalizing Problems were assessed using the Behavioural Assessment System for Children (BASC-2-PRS). Susceptibility in the nucleus accumbens was negatively associated with Internalizing Problems, while amygdala susceptibility was positively associated with Internalizing Problems across groups. PAE moderated the relationship between thalamus susceptibility and internalizing symptoms as well as the relationship between putamen susceptibility and externalizing symptoms. Brain volume was not related to internalizing or externalizing symptoms. These findings highlight that brain iron is related to internalizing and externalizing symptoms differently in some brain regions for youth with and without PAE. Atypical iron levels (high or low) may indicate mental health issues across individuals, and iron in the thalamus may be particularly important for behavior in individuals with PAE.
... Similarly, externalizing disorders such as attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder are 10 and 13 time more common than in the general population [13]. Unexposed youth and adults with internalizing (depression and anxiety) and externalizing (ADHD) disorders tend to show volumetric abnormalities of limbic and basal ganglia structures [14][15][16][17][18][19][20][21][22]. Youth with PAE have similar volumetric abnormalities [23][24][25]; however, little research has investigated the neural underpinnings between brain and internalizing or externalizing symptoms in individuals with PAE. ...
... In contrast to the QSM results, there were no associations between brain volume and behaviour. This differs from research on mental health and brain structure in unexposed participants that has found associations between caudate volume, putamen development, amygdala, hippocampus, and thalamus abnormalities and internalizing and externalizing disorders [14][15][16][17][18][19][20][21][22]. Only one study on children with PAE found a trend-level association between caudate volume and internalizing symptoms [52]. ...
Prenatal alcohol exposure (PAE) negatively affects brain development and increases the risk of poor mental health. We investigated if brain susceptibility, measuring iron, or volume were associated with internalizing or externalizing symptoms in youth with and without PAE. T1-weighted and quantitative susceptibility mapping (QSM) MRI scans were collected for 19 PAE and 40 unexposed participants aged 7.5-15 years. Magnetic susceptibility and volume of basal ganglia and limbic structures were extracted using FreeSurfer. Internalizing and externalizing problems were assessed using the Behavioural Assessment System for Children (BASC-2-PRS). Susceptibility in the nucleus accumbens was negatively associated with internalizing problems, while amygdala susceptibility was positively associated with internalizing problems across groups. In the PAE group, thalamus susceptibility was negatively associated with internalizing problems, and putamen susceptibility was positively associated with externalizing problems. Brain volume was not related to internalizing or externalizing symptoms. These findings highlight that brain iron is related to internalizing and externalizing symptoms differently in some brain regions for youth with and without PAE. Atypical iron levels (high or low) may indicate mental health problems across individuals, and iron in the thalamus and putamen may be particularly important for behaviour in individuals with PAE.
... affectivity and the anhedonic, irritable mood state that cuts across the internalizing and externalizing spectra (see Beauchaine & Constantino, 2017;Beauchaine, Klein, Knapton, & Zisner, 2019;Beauchaine & Tackett, 2020;Laakso et al., 2003). Smaller striatal volumes are also observed in both internalizing and externalizing disorders (e.g., Matsuo et al., 2008;Wallace et al., 2014). ...
... In addition to the Internalizing × Externalizing interactions for the ACC, an expected main effect was observed linking smaller NAcc volumes to externalizing behavior for boys, consistent with previous research (Wallace et al., 2014). Unexpectedly, however, no other main effects were significant for either the striatum or amygdala, despite well-replicated negative associations for both sexes between (a) striatal volumes and externalizing (e.g., Wallace et al., 2014), (b) striatal volumes and internalizing (e.g., Matsuo et al., 2008), and (c) amygdala volumes and internalizing (e.g., Rosso et al., 2005). Two differences between this study and previous work may account, at least in part, for observed null findings. ...
Despite nonoverlapping diagnostic criteria, internalizing and externalizing disorders show substantial comorbidity. This comorbidity is attributable, at least in part, to transdiagnostic neuroaffective mechanisms. Both unipolar depression and externalizing disorders are characterized by structural and functional compromises in the striatum and its projections to the anterior cingulate cortex (ACC) and other frontal regions. Smaller volumes and dampened reward responding in these regions are associated with anhedonia and irritability – mood states that cut across the internalizing and externalizing spectra. In contrast, smaller amygdala volumes and dampened amygdala function differentiate externalizing disorders from internalizing disorders. Little is known, however, about associations between internalizing–externalizing comorbidity and brain volumes in these regions, or whether such patterns differ by sex. Using a transdiagnostic, research domain criteria (RDoC)-informed approach, we evaluate associations between heterotypic (Internalizing × Externalizing) symptom interactions and striatal, amygdalar, and ACC volumes among participants in the Adolescent Brain Cognitive Development study ( N = 6,971, mean age 9.9 years, 51.6% female). Heterotypic symptoms were associated with ACC volumes for both sexes, over and above the main effects of internalizing and externalizing alone. However, heterotypic comorbidity was associated with larger ACC volumes for girls, but with smaller ACC volumes for boys. These findings suggest a need for further studies and transdiagnostic assessment by sex.
... Post hoc effect sizes between profiles were small (d = 0.04 to .13) and are similar to those previously reported in case-control studies of youth psychopathology in other samples (e.g. depression, Matsuo et al. (2008) and ADHD, Hoogman et al. (2017)). The effect sizes are also similar to those previously found between individual regions and dimensional psychopathology in the ABCD sample, before controlling for ICV (Durham et al., 2021). ...
Brain structure is often studied as a marker of youth psychopathology by examining associations between volume or thickness of individual regions and specific diagnoses. However, these univariate approaches do not address whether the effect of a particular region may depend on the structure of other regions. Here, we identified subgroups of individuals with distinct profiles of brain structure and examined how these profiles were associated with concurrent and future youth psychopathology. We used latent profile analysis to identify distinct neuroanatomical profiles of subcortical region volume and orbitofrontal cortical thickness in the ABCD study (N = 9376, mean age = 9.91, SD = 0.62). We identified a five-profile solution consisting of a reduced subcortical volume profile, a reduced orbitofrontal thickness profile, a reduced limbic and elevated striatal volume profile, an elevated orbitofrontal thickness and reduced striatal volume profile, and an elevated orbitofrontal thickness and subcortical volume profile. While controlling for age, sex, and intracranial volume, profiles exhibited differences in concurrent psychopathology measured dimensionally and categorically and in psychopathology at 1-year follow-up measured dimensionally. Results show that profiles of brain structure have incremental validity for associations with youth psychopathology beyond intracranial volume.
... First, there is accumulating evidence for their key role in higher cognitive and emotional processes crucial to successful development (Arnsten & Rubia, 2012;Radoman, Phan, & Gorka, 2019). Second, evidence from studies including depressed child and adolescent samples have documented alterations in both the function and structure of these regions (Bessette, Nave, Caprihan, & Stevens, 2014;Matsuo et al., 2008). Such findings in older samples raise the possibility that alterations in subcortical and midbrain regions at earlier time-points may be indicative of a depression-related risk factor. ...
Background: Maternal depression in pregnancy increases the risk for adverse neurodevelopmental outcomes in the offspring. The reason for this is unknown, however, one plausible mechanism may include the impact of maternal antenatal depression on infant brain. Nevertheless, relatively few studies have examined the brain anatomy of infants born to clinically diagnosed mothers.
Methods: A legacy magnetic resonance imaging (MRI) dataset was used to compare regional brain volumes in 3-to-6-month-old infants born to women with a clinically confirmed diagnosis of major depressive disorder (MDD) during pregnancy (n = 31) and a reference sample of infants born to women without a current or past psychiatric diagnosis (n = 33). A method designed for analysis of low-resolution scans enabled examination of subcortical and midbrain regions previously found to be sensitive to the parent-child environment.
Results: Compared with infants of non-depressed mothers, infants exposed to maternal antenatal depression had significantly larger subcortical grey matter volumes and smaller midbrain volumes. There was no association between gestational medication exposure and the infant regional brain volumes examined in our sample.
Limitations: Our scanning approach did not allow for an examination of fine-grained structural differences, and without repeated measures of brain volume, it is unknown whether the direction of reported associations are dependent on developmental stage.
Conclusions: Maternal antenatal depression is associated with an alteration in infant brain anatomy in early postnatal life; and that this is not accounted for by medication exposure. However, our study cannot address whether anatomical differences impact on future outcomes of the offspring.
... First, there is accumulating evidence for their key role in higher cognitive and emotional processes crucial to successful development (Arnsten and Rubia, 2012;Radoman et al., 2019). Second, evidence from studies including depressed child and adolescent samples have documented alterations in both the function and structure of these regions (Bessette et al., 2014;Matsuo et al., 2008). Such findings in older samples raise the possibility that alterations in subcortical and midbrain regions at earlier time-points may be indicative of a depression-related risk factor. ...
... Among adolescents and adults, depression has been linked to structural differences in the amygdala, [30][31][32] hippocampus, [33][34][35][36][37][38][39][40] and striatum 36,[41][42][43][44][45][46] ; yet, these findings may be related to antidepressant medication use, 37,47 depression recurrence, 24 and episode duration. 48 A recent study, however, showed that children at high-risk for depression based on a parental history exhibited reduced nucleus accumbens and putamen volumes even prior to depression onset, suggesting that these differences may play a role in depression risk and onset. ...
Objective: Although depression and anxiety often have distinct etiologies, they frequently co-occur in adolescence. Recent initiatives have underscored the importance of developing new ways of classifying mental illness based on underlying neural dimensions that cuts across traditional diagnostic boundaries. Accordingly, the aim of the study was to clarify reward-related neural circuitry that may characterize depressed-anxious youth.
Method: The Boston Adolescent Neuroimaging of Depression and Anxiety Human Connectome Project tested group differences regarding subcortical volume and nucleus accumbens activation during an incentive processing task among 14-17-year-old adolescents presenting with a primary depressive and/or anxiety disorder (n=129) or no lifetime history of mental disorders (n=64). Additionally, multimodal modeling examined predictors of depression and anxiety symptom change over a 6-month follow-up period.
Results: Our findings highlighted considerable convergence. Relative to healthy youth, depressed-anxious adolescents exhibited reduced nucleus accumbens volume and activation following reward receipt. These findings remained when removing all medicated participants (~59% of depressed-anxious youth); subgroup analyses comparing anxious-only, depressed-anxious, and healthy youth also were largely consistent. Multimodal modeling showed that only structural alterations predicted depressive symptoms over time.
Conclusion: Multimodal findings highlight alterations within nucleus accumbens structure and function that characterize depressed-anxious adolescents. In the current hypothesis-driven analyses, only reduced nucleus accumbens volume, however, predicted depressive symptoms over time. An important next step will be to clarify why structural alterations impact reward-related processes and associated symptoms.
