Publications by authors named "Moji Aghajani"

24 Publications

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Contributing factors to advanced brain aging in depression and anxiety disorders.

Transl Psychiatry 2021 07 21;11(1):402. Epub 2021 Jul 21.

Department of Psychiatry, Amsterdam University Medical Centers, Vrije Universiteit and GGZ inGeest, Amsterdam Neuroscience, Amsterdam, The Netherlands.

Depression and anxiety are common and often comorbid mental health disorders that represent risk factors for aging-related conditions. Brain aging has shown to be more advanced in patients with major depressive disorder (MDD). Here, we extend prior work by investigating multivariate brain aging in patients with MDD, anxiety disorders, or both, and examine which factors contribute to older-appearing brains. Adults aged 18-57 years from the Netherlands Study of Depression and Anxiety underwent structural MRI. A pretrained brain-age prediction model based on >2000 samples from the ENIGMA consortium was applied to obtain brain-predicted age differences (brain PAD, predicted brain age minus chronological age) in 65 controls and 220 patients with current MDD and/or anxiety. Brain-PAD estimates were associated with clinical, somatic, lifestyle, and biological factors. After correcting for antidepressant use, brain PAD was significantly higher in MDD (+2.78 years, Cohen's d = 0.25, 95% CI -0.10-0.60) and anxiety patients (+2.91 years, Cohen's d = 0.27, 95% CI -0.08-0.61), compared with controls. There were no significant associations with lifestyle or biological stress systems. A multivariable model indicated unique contributions of higher severity of somatic depression symptoms (b = 4.21 years per unit increase on average sum score) and antidepressant use (-2.53 years) to brain PAD. Advanced brain aging in patients with MDD and anxiety was most strongly associated with somatic depressive symptomatology. We also present clinically relevant evidence for a potential neuroprotective antidepressant effect on the brain-PAD metric that requires follow-up in future research.
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http://dx.doi.org/10.1038/s41398-021-01524-2DOI Listing
July 2021

Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years.

Hum Brain Mapp 2021 Feb 17. Epub 2021 Feb 17.

Laboratory of Psychiatric Neuroimaging, Departamento e Instituto de Psiquiatria, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.
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http://dx.doi.org/10.1002/hbm.25364DOI Listing
February 2021

Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3-90 years.

Hum Brain Mapp 2021 Feb 11. Epub 2021 Feb 11.

Department of Psychology, Center for Brain Science, Harvard University, Cambridge, Massachusetts, USA.

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.
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http://dx.doi.org/10.1002/hbm.25320DOI Listing
February 2021

Greater male than female variability in regional brain structure across the lifespan.

Hum Brain Mapp 2020 Oct 12. Epub 2020 Oct 12.

FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain.

For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders.
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http://dx.doi.org/10.1002/hbm.25204DOI Listing
October 2020

Neural processing of socioemotional content in conduct-disordered juvenile offenders with limited prosocial emotions.

Prog Neuropsychopharmacol Biol Psychiatry 2021 03 29;105:110045. Epub 2020 Jul 29.

Leiden University Medical Center, Dept. of Child and Adolescent Psychiatry, Curium, the Netherlands; Leiden Institute for Brain and Cognition, the Netherlands; Örebro University, Dept. of Behavioral, Social, and Legal Sciences, Sweden; Ghent University, Dept. Special Needs Education, Belgium.

Background: Reflecting evidence on Callous-Unemotional (CU) traits (e.g., lack of empathy and guilt, shallow affect), the DSM-5 added a categorical CU-based specifier for Conduct Disorder (CD), labeled 'with Limited Prosocial Emotions' (LPE). Theory and prior work suggest that CD youths with and without LPE will likely differ in neural processing of negative socioemotional content. This proposition, however, is mainly derived from studies employing related, yet distinct, operationalizations of CU traits (e.g., dimensional measure/median split/top quartile), thus precluding direct examination of LPE-specific neurocognitive deficits.

Methods: Employing a DSM-5 informed LPE proxy, neural processing of recognizing and resonating negative socioemotional content (angry and fearful faces) was therefore examined here among CD offenders with LPE (CD/LPE+; N = 19), relative to CD offenders without LPE (CD/LPE-; N = 31) and healthy controls (HC; N = 31).

Results: Relative to HC and CD/LPE- youths and according to a linearly increasing trend (CD/LPE- < HC < CD/LPE+), CD/LPE+ youths exhibited hyperactivity within dorsolateral, dorsomedial, and ventromedial prefrontal regions during both emotion recognition and resonance. During emotion resonance, CD/LPE+ youths additionally showed increased activity within the posterior cingulate and precuneal cortices in comparison to HC and CD/LPE- youths, which again followed a linearly increasing trend (CD/LPE- < HC < CD/LPE+). These effects moreover seemed specific to the LPE specifier, when compared to a commonly employed method for CU-based grouping in CD (i.e., median split on CU scores).

Conclusions: These data cautiously suggest that CD/LPE+ youths may exhibit an over-reliance on cortical neurocognitive systems when explicitly processing negative socioemotional information, which could have adverse downstream effects on relevant socioemotional functions. The findings thus seem to provide novel, yet preliminary, clues on the neurocognitive profile of CD/LPE+, and additionally highlight the potential scientific utility of the LPE specifier.
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http://dx.doi.org/10.1016/j.pnpbp.2020.110045DOI Listing
March 2021

ENIGMA-anxiety working group: Rationale for and organization of large-scale neuroimaging studies of anxiety disorders.

Hum Brain Mapp 2020 Jul 3. Epub 2020 Jul 3.

Department of Psychiatry & Mental Health, University of Cape Town, Cape Town, South Africa.

Anxiety disorders are highly prevalent and disabling but seem particularly tractable to investigation with translational neuroscience methodologies. Neuroimaging has informed our understanding of the neurobiology of anxiety disorders, but research has been limited by small sample sizes and low statistical power, as well as heterogenous imaging methodology. The ENIGMA-Anxiety Working Group has brought together researchers from around the world, in a harmonized and coordinated effort to address these challenges and generate more robust and reproducible findings. This paper elaborates on the concepts and methods informing the work of the working group to date, and describes the initial approach of the four subgroups studying generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobia. At present, the ENIGMA-Anxiety database contains information about more than 100 unique samples, from 16 countries and 59 institutes. Future directions include examining additional imaging modalities, integrating imaging and genetic data, and collaborating with other ENIGMA working groups. The ENIGMA consortium creates synergy at the intersection of global mental health and clinical neuroscience, and the ENIGMA-Anxiety Working Group extends the promise of this approach to neuroimaging research on anxiety disorders.
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http://dx.doi.org/10.1002/hbm.25100DOI Listing
July 2020

Mega-analysis methods in ENIGMA: The experience of the generalized anxiety disorder working group.

Hum Brain Mapp 2020 Jun 29. Epub 2020 Jun 29.

Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA.

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA-Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega-analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between-country transfer of subject-level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega-analyses.
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http://dx.doi.org/10.1002/hbm.25096DOI Listing
June 2020

Brain aging in major depressive disorder: results from the ENIGMA major depressive disorder working group.

Mol Psychiatry 2020 May 18. Epub 2020 May 18.

Department of Psychiatry, University of Münster, Münster, Germany.

Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted "brain age" and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen's d = 0.14, 95% CI: 0.08-0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates.
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http://dx.doi.org/10.1038/s41380-020-0754-0DOI Listing
May 2020

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries.

Transl Psychiatry 2020 03 20;10(1):100. Epub 2020 Mar 20.

Department of Psychiatry & Behavioral Sciences, Stanford University, Stanford, CA, USA.

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.
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http://dx.doi.org/10.1038/s41398-020-0705-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083923PMC
March 2020

The neuroscience of sadness: A multidisciplinary synthesis and collaborative review.

Neurosci Biobehav Rev 2020 04 27;111:199-228. Epub 2020 Jan 27.

Department of Psychology, Swansea University, United Kingdom; Department of Psychiatry, University of Sao Paulo, Brazil; Discipline of Psychiatry, and School of Psychology, University of Sydney, Sydney, Australia. Electronic address:

Sadness is typically characterized by raised inner eyebrows, lowered corners of the mouth, reduced walking speed, and slumped posture. Ancient subcortical circuitry provides a neuroanatomical foundation, extending from dorsal periaqueductal grey to subgenual anterior cingulate, the latter of which is now a treatment target in disorders of sadness. Electrophysiological studies further emphasize a role for reduced left relative to right frontal asymmetry in sadness, underpinning interest in the transcranial stimulation of left dorsolateral prefrontal cortex as an antidepressant target. Neuroimaging studies - including meta-analyses - indicate that sadness is associated with reduced cortical activation, which may contribute to reduced parasympathetic inhibitory control over medullary cardioacceleratory circuits. Reduced cardiac control may - in part - contribute to epidemiological reports of reduced life expectancy in affective disorders, effects equivalent to heavy smoking. We suggest that the field may be moving toward a theoretical consensus, in which different models relating to basic emotion theory and psychological constructionism may be considered as complementary, working at different levels of the phylogenetic hierarchy.
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http://dx.doi.org/10.1016/j.neubiorev.2020.01.006DOI Listing
April 2020

Default Mode Network Connectivity and Social Dysfunction in Major Depressive Disorder.

Sci Rep 2020 01 13;10(1):194. Epub 2020 Jan 13.

Department of Psychiatry, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands.

Though social functioning is often hampered in Major Depressive Disorder (MDD), we lack a complete and integrated understanding of the underlying neurobiology. Connectional disturbances in the brain's Default Mode Network (DMN) might be an associated factor, as they could relate to suboptimal social processing. DMN connectional integrity, however, has not been explicitly studied in relation to social dysfunctioning in MDD patients. Applying Independent Component Analysis and Dual Regression on resting-state fMRI data, we explored DMN intrinsic functional connectivity in relation to social dysfunctioning (i.e. composite of loneliness, social disability, small social network) among 74 MDD patients (66.2% female, Mean age = 36.9, SD = 11.9). Categorical analyses examined whether DMN connectivity differs between high and low social dysfunctioning MDD groups, dimensional analyses studied linear associations between social dysfunction and DMN connectivity across MDD patients. Threshold-free cluster enhancement (TFCE) with family-wise error (FWE) correction was used for statistical thresholding and multiple comparisons correction (P < 0.05). The analyses cautiously linked greater social dysfunctioning among MDD patients to diminished DMN connectivity, specifically within the rostromedial prefrontal cortex and posterior superior frontal gyrus. These preliminary findings pinpoint DMN connectional alterations as potentially germane to social dysfunction in MDD, and may as such improve our understanding of the underlying neurobiology.
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http://dx.doi.org/10.1038/s41598-019-57033-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957534PMC
January 2020

White matter architecture in major depression with anxious distress symptoms.

Prog Neuropsychopharmacol Biol Psychiatry 2019 08 31;94:109664. Epub 2019 May 31.

Amsterdam UMC, Location VUMC, Dept. of Psychiatry & Amsterdam Neuroscience, the Netherlands; GGZ InGeest Specialized Mental Health Care, the Netherlands. Electronic address:

Background: Comorbid anxious distress is common in Major Depressive Disorder (MDD), and associated with significantly worse clinical course and treatment response. While DSM-5 recently introduced the Anxious Distress (AD) specifier as a potentially useful symptom-based subtyping scheme for MDD, its neurobiological underpinnings remain unclear. The current study hence uniquely probed whether MDD with co-occurring AD (MDD/AD+) relates to distinct perturbations in frontolimbic white matter (WM) pathways tentatively theorized in MDD/AD+ pathophysiology.

Methods: Tract-based spatial statistics (TBSS) was therefore used to analyze diffusion tensor imaging data on WM microstructure, in MDD/AD+ patients (N = 20) relative to MDD patients without AD (MDD/AD-; N = 29) and healthy controls (HC; N = 39). Using TBSS, we probed fractional anisotropy and axial/radial/mean diffusivity as proxies for WM integrity. Categorical (between-groups) and dimensional (within-patients) analyses subsequently assessed how Anxious Distress in MDD impacts frontolimbic WM connectivity. Receiver-Operating Characteristics additionally assessed classification capabilities of between-groups WM effects.

Results: Compared to MDD/AD- and HC participants, MDD/AD+ patients exhibited diminished integrity within the anterior thalamic radiation (ATR). Higher AD specifier scores within MDD patients additionally related to diminished integrity of the uncinate fasciculus and cingulum pathways. These effects were not confounded by key clinical (e.g., comorbid anxiety disorder) and sociodemographic (e.g., age/sex) factors, with altered ATR integrity moreover successfully classifying MDD/AD+ patients from MDD/AD- and HC participants (90% sensitivity | 73% specificity | 77% accuracy).

Conclusions: These findings collectively link MDD/AD+ to distinct WM anomalies in frontolimbic tracts important to adaptive emotional functioning, and may as such provide relevant, yet preliminary, clues on MDD/AD+ pathophysiology.
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http://dx.doi.org/10.1016/j.pnpbp.2019.109664DOI Listing
August 2019

Social brain, social dysfunction and social withdrawal.

Neurosci Biobehav Rev 2019 02 20;97:10-33. Epub 2018 Sep 20.

Department of Biomedical and NeuroMotor Sciences, University of Bologna, Italy.

The human social brain is complex. Current knowledge fails to define the neurobiological processes underlying social behaviour involving the (patho-) physiological mechanisms that link system-level phenomena to the multiple hierarchies of brain function. Unfortunately, such a high complexity may also be associated with a high susceptibility to several pathogenic interventions. Consistently, social deficits sometimes represent the first signs of a number of neuropsychiatric disorders including schizophrenia (SCZ), Alzheimer's disease (AD) and major depressive disorder (MDD) which leads to a progressive social dysfunction. In the present review we summarize present knowledge linking neurobiological substrates sustaining social functioning, social dysfunction and social withdrawal in major psychiatric disorders. Interestingly, AD, SCZ, and MDD affect the social brain in similar ways. Thus, social dysfunction and its most evident clinical expression (i.e., social withdrawal) may represent an innovative transdiagnostic domain, with the potential of being an independent entity in terms of biological roots, with the perspective of targeted interventions.
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http://dx.doi.org/10.1016/j.neubiorev.2018.09.012DOI Listing
February 2019

Epigenetic Aging in Major Depressive Disorder.

Am J Psychiatry 2018 08 16;175(8):774-782. Epub 2018 Apr 16.

From the Department of Psychiatry, VU University Medical Center, Amsterdam Neuroscience, GGZ inGeest, the Amsterdam Public Health Research Institute, Amsterdam; the Center for Biomarker Research and Precision Medicine, School of Pharmacy, Virginia Commonwealth University, Richmond; the Molecular Psychiatry Laboratory, Florey Department of Neuroscience and Mental Health, Melbourne, Australia; and the Centre for Mental Health, Faculty of Health, Arts, and Design, Swinburne University, Hawthorne, Australia.

Objective: Major depressive disorder is associated with an increased risk of mortality and aging-related diseases. The authors examined whether major depression is associated with higher epigenetic aging in blood as measured by DNA methylation (DNAm) patterns, whether clinical characteristics of major depression have a further impact on these patterns, and whether the findings replicate in brain tissue.

Method: DNAm age was estimated using all methylation sites in blood of 811 depressed patients and 319 control subjects with no lifetime psychiatric disorders and low depressive symptoms from the Netherlands Study of Depression and Anxiety. The residuals of the DNAm age estimates regressed on chronological age were calculated to indicate epigenetic aging. Major depression diagnosis and clinical characteristics were assessed with questionnaires and psychiatric interviews. Analyses were adjusted for sociodemographic characteristics, lifestyle, and health status. Postmortem brain samples of 74 depressed patients and 64 control subjects were used for replication. Pathway enrichment analysis was conducted using ConsensusPathDB to gain insight into the biological processes underlying epigenetic aging in blood and brain.

Results: Significantly higher epigenetic aging was observed in patients with major depression compared with control subjects (Cohen's d=0.18), with a significant dose effect with increasing symptom severity in the overall sample. In the depression group, epigenetic aging was positively and significantly associated with childhood trauma score. The case-control difference was replicated in an independent data set of postmortem brain samples. The top significantly enriched Gene Ontology terms included neuronal processes.

Conclusions: As compared with control subjects, patients with major depression exhibited higher epigenetic aging in blood and brain tissue, suggesting that they are biologically older than their corresponding chronological age. This effect was even more profound in the presence of childhood trauma.
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http://dx.doi.org/10.1176/appi.ajp.2018.17060595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6094380PMC
August 2018

Interactions Between Oxytocin Receptor Gene Methylation and Callous-Unemotional Traits Impact Socioaffective Brain Systems in Conduct-Disordered Offenders.

Biol Psychiatry Cogn Neurosci Neuroimaging 2018 04 10;3(4):379-391. Epub 2018 Jan 10.

Department of Pschiatry, Curium, Leiden University Medical Center, Leiden, the Netherlands; Leiden Institute for Brain and Cognition, Leiden, the Netherlands.

Background: The developmental trajectory of psychopathy seemingly begins early in life and includes the presence of callous-unemotional (CU) traits (e.g., perturbed socioaffective reactivity and empathy, callousness) in youths with conduct disorder (CD). Whereas oxytocin receptor gene methylation (OXTR) and its downstream neuromodulatory effects are deemed relevant to CU traits, nothing is known of how OXTR interacts with CU traits to impact socioaffective brain systems in youngsters with CD.

Methods: Hence, we uniquely probed OXTR × CU trait interactions on corticolimbic activity and amygdala subregional connections during recognition and resonance of distressing socioaffective stimuli (angry and fearful faces), in juvenile offenders with CD (n = 39) versus matched healthy control youths (n = 27).

Results: Relative to healthy control youths, elevated OXTR and CU levels in youths with CD essentially interacted to predict frontoparietal hyperactivity and amygdalo-frontoparietal disconnection during task performance. Specifically, increasing OXTR and CU levels in youths with CD interactively predicted midcingulate hyperactivity during both emotion conditions, with insular, temporoparietal, and precuneal hyperactivity additionally emerging during emotion recognition. Interactions between high OXTR and CU levels in youths with CD additionally predicted centromedial amygdala decoupling from ventromedial/orbitofrontal regions during emotion recognition, along with basolateral amygdala decoupling from precuneal and temporoparietal cortices during emotion resonance.

Conclusions: These results uniquely suggest that interactions between OXTR and CU traits in youths with CD may affect brain systems critical to decoding and integrating socioaffective information. Developmental models of CU traits and psychopathy could thus possibly advance by further examining OXTR epigenetic effects, which may hold promise for indicated prevention and personalized treatment by targeting oxytocinergic function.
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http://dx.doi.org/10.1016/j.bpsc.2017.12.010DOI Listing
April 2018

Increased hippocampal-prefrontal functional connectivity in insomnia.

Neurobiol Learn Mem 2019 04 12;160:144-150. Epub 2018 Feb 12.

Department of Sleep and Cognition, Netherlands Institute for Neuroscience, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands; Department of Psychiatry, VU Medical Center, Oldenaller 1, 1081 HJ Amsterdam, The Netherlands; Department of Integrative Neurophysiology, Neuroscience Campus, VU University and Medical Center, de Boelelaan, 1081 HV Amsterdam, The Netherlands.

Insomnia Disorder (ID) is the second-most common mental disorder and has a far-reaching impact on daytime functioning. A meta-analysis indicates that, of all cognitive domains, declarative memory involving the hippocampus is most affected in insomnia. Hippocampal functioning has consistently been shown to be sensitive to experimental sleep deprivation. Insomnia however differs from sleep deprivation in many aspects, and findings on hippocampal structure and function have been equivocal. The present study used both structural and resting-state functional Magnetic Resonance Imaging in a larger sample than previously reported to evaluate hippocampal volume and functional connectivity in ID. Included were 65 ID patients (mean age = 48.3 y ± 14.0, 17 males) and 65 good sleepers (mean age = 44.1 y ± 15.2, 23 males). Insomnia severity was assessed with the Insomnia Severity Index (ISI), subjective sleep with the Consensus Sleep Diary (CSD) and objective sleep by two nights of polysomnography (PSG). Seed-based analysis showed a significantly stronger connectivity of the bilateral hippocampus with the left middle frontal gyrus in ID than in controls (p = .035, cluster based correction for multiple comparisons). Further analyses across all participants moreover showed that individual differences in the strength of this connectivity were associated with insomnia severity (ISI, r = 0.371, p = 9.3e-5) and with subjective sleep quality (CSD sleep efficiency, r = -0.307, p = .009) (all p FDR-corrected). Hippocampal volume did not differ between ID and controls. The findings indicate more severe insomnia and worse sleep quality in people with a stronger functional connectivity between the bilateral hippocampus and the left middle frontal gyrus, part of a circuit that characteristically activates with maladaptive rumination and deactivates with sleep.
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http://dx.doi.org/10.1016/j.nlm.2018.02.006DOI Listing
April 2019

Differential Fairness Decisions and Brain Responses After Expressed Emotions of Others in Boys with Autism Spectrum Disorders.

J Autism Dev Disord 2017 08;47(8):2390-2400

Department of Child and Adolescent Psychiatry, Curium - Leiden University Medical Center, Postbus 15, 2300 AA, Leiden, The Netherlands.

Little is known about how emotions expressed by others influence social decisions and associated brain responses in autism spectrum disorders (ASD). We investigated the neural mechanisms underlying fairness decisions in response to explicitly expressed emotions of others in boys with ASD and typically developing (TD) boys. Participants with ASD adjusted their allocation behavior in response to the emotions but reacted less unfair than TD controls in response to happiness. We also found reduced brain responses in the precental gyrus in the ASD versus TD group when receiving happy versus angry reactions and autistic traits were positively associated with activity in the postcentral gyrus. These results provide indications for a role of precentral and postcentral gyrus in social-affective difficulties in ASD.
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http://dx.doi.org/10.1007/s10803-017-3159-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509841PMC
August 2017

Disorganized Amygdala Networks in Conduct-Disordered Juvenile Offenders With Callous-Unemotional Traits.

Biol Psychiatry 2017 08 27;82(4):283-293. Epub 2016 May 27.

Department of Child and Adolescent Psychiatry, Curium-Leiden University Medical Center, Leiden; Leiden Institute for Brain and Cognition, Leiden.

Background: The developmental trajectory of psychopathy seemingly begins early in life and includes the presence of callous-unemotional (CU) traits (e.g., deficient emotional reactivity, callousness) in conduct-disordered (CD) youth. Though subregion-specific anomalies in amygdala function have been suggested in CU pathophysiology among antisocial populations, system-level studies of CU traits have typically examined the amygdala as a unitary structure. Hence, nothing is yet known of how amygdala subregional network function may contribute to callous-unemotionality in severely antisocial people.

Methods: We addressed this important issue by uniquely examining the intrinsic functional connectivity of basolateral amygdala (BLA) and centromedial amygdala (CMA) networks across three matched groups of juveniles: CD offenders with CU traits (CD/CU+; n = 25), CD offenders without CU traits (CD/CU-; n = 25), and healthy control subjects (n = 24). We additionally examined whether perturbed amygdala subregional connectivity coincides with altered volume and shape of the amygdaloid complex.

Results: Relative to CD/CU- and healthy control youths, CD/CU+ youths showed abnormally increased BLA connectivity with a cluster that included both dorsal and ventral portions of the anterior cingulate and medial prefrontal cortices, along with posterior cingulate, sensory associative, and striatal regions. In contrast, compared with CD/CU- and healthy control youths, CD/CU+ youths showed diminished CMA connectivity with ventromedial/orbitofrontal regions. Critically, these connectivity changes coincided with local hypotrophy of BLA and CMA subregions (without being statistically correlated) and were associated to more severe CU symptoms.

Conclusions: These findings provide unique insights into a putative mechanism for perturbed attention-emotion interactions, which could bias salience processing and associative learning in youth with CD/CU+.
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http://dx.doi.org/10.1016/j.biopsych.2016.05.017DOI Listing
August 2017

Dissociable relations between amygdala subregional networks and psychopathy trait dimensions in conduct-disordered juvenile offenders.

Hum Brain Mapp 2016 11;37(11):4017-4033

Department of Child and Adolescent Psychiatry, Curium, Leiden University Medical Center, Leiden, the Netherlands.

Psychopathy is a serious psychiatric phenomenon characterized by a pathological constellation of affective (e.g., callous, unemotional), interpersonal (e.g., manipulative, egocentric), and behavioral (e.g., impulsive, irresponsible) personality traits. Though amygdala subregional defects are suggested in psychopathy, the functionality and connectivity of different amygdala subnuclei is typically disregarded in neurocircuit-level analyses of psychopathic personality. Hence, little is known of how amygdala subregional networks may contribute to psychopathy and its underlying trait assemblies in severely antisocial people. We addressed this important issue by uniquely examining the intrinsic functional connectivity of basolateral (BLA) and centromedial (CMA) amygdala networks in relation to affective, interpersonal, and behavioral traits of psychopathy, in conduct-disordered juveniles with a history of serious delinquency (N = 50, mean age = 16.83 ± 1.32). As predicted, amygdalar connectivity profiles exhibited dissociable relations with different traits of psychopathy. Interpersonal psychopathic traits not only related to increased connectivity of BLA and CMA with a corticostriatal network formation accommodating reward processing, but also predicted stronger CMA connectivity with a network of cortical midline structures supporting sociocognitive processes. In contrast, affective psychopathic traits related to diminished CMA connectivity with a frontolimbic network serving salience processing and affective responding. Finally, behavioral psychopathic traits related to heightened BLA connectivity with a frontoparietal cluster implicated in regulatory executive functioning. We suggest that these trait-specific shifts in amygdalar connectivity could be particularly relevant to the psychopathic phenotype, as they may fuel a self-centered, emotionally cold, and behaviorally disinhibited profile. Hum Brain Mapp 37:4017-4033, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/hbm.23292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5129576PMC
November 2016

Fairness decisions in response to emotions: a functional MRI study among criminal justice-involved boys with conduct disorder.

Soc Cogn Affect Neurosci 2016 Apr 29;11(4):674-82. Epub 2016 Feb 29.

Department of Child and Adolescent Psychiatry, Curium-Leiden University Medical Center, Leiden, The Netherlands, Leiden Institute for Brain and Cognition (LIBC), Leiden, The Netherlands.

Research suggests that individuals with conduct disorder (CD) are marked by social impairments, such as difficulties in processing the affective reactions of others. Little is known, though, about how they make decisions during social interactions in response to emotional expressions of others. In this study, we therefore investigated the neural mechanisms underlying fairness decisions in response to communicated emotions of others in aggressive, criminal justice-involved boys with CD (N = 32) compared with typically developing (TD) boys (N = 33), aged 15-19 years. Participants received written emotional responses (angry, disappointed or happy) from peers in response to a previous offer and then had to make fairness decisions in a version of the Dictator Game. Behavioral results showed that CD boys did not make differential fairness decisions in response to the emotions, whereas the TD boys did show a differentiation and also responded more unfair to happy reactions than the CD boys. Neuroimaging results revealed that when receiving happy vs disappointed and angry reactions, the CD boys showed less activation than the TD boys in the temporoparietal junction and supramarginal gyrus, regions involved in perspective taking and attention. These results suggest that boys with CD have difficulties with processing explicit emotional cues from others on behavioral and neural levels.
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http://dx.doi.org/10.1093/scan/nsv150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814796PMC
April 2016

Abnormal functional architecture of amygdala-centered networks in adolescent posttraumatic stress disorder.

Hum Brain Mapp 2016 Mar 6;37(3):1120-35. Epub 2016 Jan 6.

Department of Child and Adolescent Psychiatry, Leiden University Medical Center, Curium, Leiden, the Netherlands.

Posttraumatic stress disorder (PTSD) is a prevalent, debilitating, and difficult to treat psychiatric disorder. Very little is known of how PTSD affects neuroplasticity in the developing adolescent brain. Whereas multiple lines of research implicate amygdala-centered network dysfunction in the pathophysiology of adult PTSD, no study has yet examined the functional architecture of amygdala subregional networks in adolescent PTSD. Using intrinsic functional connectivity analysis, we investigated functional connectivity of the basolateral (BLA) and centromedial (CMA) amygdala in 19 sexually abused adolescents with PTSD relative to 23 matched controls. Additionally, we examined whether altered amygdala subregional connectivity coincides with abnormal grey matter volume of the amygdaloid complex. Our analysis revealed abnormal amygdalar connectivity and morphology in adolescent PTSD patients. More specifically, PTSD patients showed diminished right BLA connectivity with a cluster including dorsal and ventral portions of the anterior cingulate and medial prefrontal cortices (p < 0.05, corrected). In contrast, PTSD patients showed increased left CMA connectivity with a cluster including the orbitofrontal and subcallosal cortices (p < 0.05, corrected). Critically, these connectivity changes coincided with diminished grey matter volume within BLA and CMA subnuclei (p < 0.05, corrected), with CMA connectivity shifts additionally relating to more severe symptoms of PTSD. These findings provide unique insights into how perturbations in major amygdalar circuits could hamper fear regulation and drive excessive acquisition and expression of fear in PTSD. As such, they represent an important step toward characterizing the neurocircuitry of adolescent PTSD, thereby informing the development of reliable biomarkers and potential therapeutic targets.
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http://dx.doi.org/10.1002/hbm.23093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867491PMC
March 2016

Different brain responses during empathy in autism spectrum disorders versus conduct disorder and callous-unemotional traits.

J Child Psychol Psychiatry 2016 06 17;57(6):737-47. Epub 2015 Dec 17.

Department of Child and Adolescent Psychiatry, Curium - Leiden University Medical Center, Leiden, The Netherlands.

Background: Deficits in empathy are reported in autism spectrum disorders (ASD) and also underlie antisocial behavior of individuals with conduct disorder and callous-unemotional traits (CD/CU+). Many studies suggest that individuals with ASD are typically impaired in cognitive aspects of empathy, and individuals with CD/CU+ typically in affective aspects. In the current study, we compared the neural correlates of cognitive and affective aspects of empathy between youth with ASD and youth with CD/CU+.

Methods: Functional magnetic resonance imaging (fMRI) was used to assess boys with ASD (N = 23), boys with CD/CU+ (N = 23), and typically developing (TD) boys (N = 33), aged 15-19 years. Angry and fearful faces were presented and participants were asked to either infer the emotional state from the face (other-task; emotion recognition) or to judge their own emotional response to the face (self-task; emotional resonance).

Results: During emotion recognition, boys with ASD showed reduced responses compared to the other groups in the ventromedial prefrontal cortex (vmPFC). During emotional resonance, the CD/CU+ and ASD groups showed reduced amygdala responses compared to the TD controls, boys with ASD showed reduced responses in bilateral hippocampus, and the CD/CU+ boys showed reduced responses in the inferior frontal gyrus (IFG) and anterior insula (AI).

Conclusion: Results suggest differential abnormal brain responses associated with specific aspects of empathic functioning in ASD and CD/CU+. Decreased amygdala responses in ASD and CD/CU+ might point to impaired emotion processing in both disorders, whereas reduced vmPFC responses suggest problems in processing cognitive aspects of empathy in ASD. Reduced IFG/AI responses, finally, suggest decreased emotional resonance in CD/CU+.
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http://dx.doi.org/10.1111/jcpp.12498DOI Listing
June 2016

Neuroticism and extraversion are associated with amygdala resting-state functional connectivity.

Cogn Affect Behav Neurosci 2014 Jun;14(2):836-48

Leiden Institute for Brain and Cognition (LIBC), Leiden, The Netherlands.

The personality traits neuroticism and extraversion are differentially related to socioemotional functioning and susceptibility to affective disorders. However, the neurobiology underlying this differential relationship is still poorly understood. This discrepancy could perhaps best be studied by adopting a brain connectivity approach. Whereas the amygdala has repeatedly been linked to neuroticism and extraversion, no study has yet focused on the intrinsic functional architecture of amygdala-centered networks in relation to both traits. To this end, seed-based correlation analysis was employed to reveal amygdala resting-state functional connectivity (RSFC) and its associations with neuroticism and extraversion in 50 healthy participants. Higher neuroticism scores were associated with increased amygdala RSFC with the precuneus, and decreased amygdala RSFC with the temporal poles, insula, and superior temporal gyrus (p < .05, cluster corrected). Conversely, higher extraversion scores were associated with increased amygdala RSFC with the putamen, temporal pole, insula, and several regions of the occipital cortex (p < .05, cluster corrected). The shifts in amygdala RSFC associated with neuroticism may relate to the less-adaptive perception and processing of self-relevant and socioemotional information that is frequently seen in neurotic individuals, whereas the amygdala RSFC pattern associated with extraversion may relate to the heightened reward sensitivity and enhanced socioemotional functioning in extraverts. We hypothesize that the variability in amygdala RSFC observed in the present study could potentially link neuroticism and extraversion to the neurobiology underlying increased susceptibility or resilience to affective disorders.
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http://dx.doi.org/10.3758/s13415-013-0224-0DOI Listing
June 2014

Diffusion tensor imaging in anxiety disorders.

Curr Psychiatry Rep 2012 Jun;14(3):197-202

Leiden University Medical Center, The Netherlands.

Diffusion tensor imaging (DTI) can be used to examine the structural integrity of regional white matter and to map white matter tracts. DTI studies have been performed in several psychiatric disorders, especially in those for which a developmental or a neuropsychiatric component was postulated. Thus far, the use of DTI has been very limited in panic disorder, social anxiety disorder, and generalized anxiety disorder, and somewhat more extensive in post-traumatic stress disorder and obsessive-compulsive disorder. In most anxiety disorders, the results of DTI studies are in line with other structural and functional MRI findings and can be interpreted within the frameworks of existing models for the neurocircuitry of the various disorders. DTI findings could further enrich neurobiological models for anxiety disorders, although replication is often warranted, and studies in pediatric populations are lagging behind remarkably.
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http://dx.doi.org/10.1007/s11920-012-0273-zDOI Listing
June 2012
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