Faculty Bibliography
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414
Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3-90 years
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.
PMID: 33570244
ISSN: 1097-0193
CID: 4799802
Greater male than female variability in regional brain structure across the lifespan
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.
PMID: 33044802
ISSN: 1097-0193
CID: 4632482
Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder: The ENIGMA adventure
Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA-ADHD and ENIGMA-ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case-control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case-control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses.
PMID: 32420680
ISSN: 1097-0193
CID: 4446612
Resting-State fMRI to Identify the Brain Correlates of Treatment Response to Medications in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder: Lessons From the CUNMET Study
Neuroimaging research seeks to identify biomarkers to improve the diagnosis, prognosis, and treatment of attention-deficit/hyperactivity disorder (ADHD), although clinical translation of findings remains distant. Resting-state functional magnetic resonance imaging (R-fMRI) is increasingly being used to characterize functional connectivity in the brain. Despite mixed results to date and multiple methodological challenges, dominant hypotheses implicate hyperconnectivity across brain networks in patients with ADHD, which could be the target of pharmacological treatments. We describe the experience and results of the ClÃnica Universidad de Navarra (Spain) Metilfenidato (CUNMET) pilot study. CUNMET tested the feasibility of identifying R-fMRI markers of clinical response in children with ADHD undergoing naturalistical pharmacological treatments. We analyzed cross-sectional data from 56 patients with ADHD (18 treated with methylphenidate, 18 treated with lisdexamfetamine, and 20 treatment-naive patients). Standard preprocessing and statistical analyses with attention to control for head motion and correction for multiple comparisons were performed. The only results that survived correction were noted in contrasts of children who responded clinically to lisdexamfetamine after long-term treatment vs. treatment-naive patients. In these children, we observed stronger negative correlations (anticorrelations) across nodes in six brain networks, which is consistent with higher across-network functional segregation in patients treated with lisdexamfetamine, i.e., less inter-network interference than in treatment-naive patients. We also note the lessons learned, which could help those pursuing clinically relevant multidisciplinary research in ADHD en route to eventual personalized medicine. To advance reproducible open science, our report is accompanied with links providing access to our data and analytic scripts.
PMCID:8635006
PMID: 34867544
ISSN: 1664-0640
CID: 5110082
Predicting multiscan MRI outcomes in children with neurodevelopmental conditions following MRI simulator training
Pediatric brain imaging holds significant promise for understanding neurodevelopment. However, the requirement to remain still inside a noisy, enclosed scanner remains a challenge. Verbal or visual descriptions of the process, and/or practice in MRI simulators are the norm in preparing children. Yet, the factors predictive of successfully obtaining neuroimaging data remain unclear. We examined data from 250 children (6-12 years, 197 males) with autism and/or attention-deficit/hyperactivity disorder. Children completed systematic MRI simulator training aimed to habituate to the scanner environment and minimize head motion. An MRI session comprised multiple structural, resting-state, task and diffusion scans. Of the 201 children passing simulator training and attempting scanning, nearly all (94%) successfully completed the first structural scan in the sequence, and 88% also completed the following functional scan. The number of successful scans decreased as the sequence progressed. Multivariate analyses revealed that age was the strongest predictor of successful scans in the session, with younger children having lower success rates. After age, sensorimotor atypicalities contributed most to prediction. Results provide insights on factors to consider in designing pediatric brain imaging protocols.
PMCID:8517836
PMID: 34649041
ISSN: 1878-9307
CID: 5068032
Journal of the American Academy of Child and Adolescent Psychiatry. 2021:Conference:(68th):S168-S169.DOI: 10.1016/j.jaac.2021.09.105
6.32 Assessing the Effect of Youth Involvement in Adverse Event Reporting during a Clinical Trial of Cannabidiol for Youth WITH AUTISM SPECTRUM DISORDER with Complex Verbal Language [Meeting Abstract]
Objectives: Clinical trials in youth with autism spectrum disorder (ASD) have typically neglected the voices of the youth themselves. Besides raising ethical questions, this may also affect the quality of the data obtained. We examined differences in adverse event (AE) reporting between parents and parent-child dyads in an open trial of cannabidiol (CBD). We hypothesized that including youth with ASD in AE reporting would increase the number of total and related AEs independently of response.
Method(s): Twelve youth (ages 7-14 years) with ASD (verbally fluent, IQ >= 80) completed a 6-week, Phase 2 open trial of 98% CBD (Epidiolex [V], 100 mg/mL) at 3 or 6 mg/kg/day; target N = 30. An individualized target symptom domain was identified at baseline by clinician consensus from informant report, rating scales, and clinical observation. Responders were defined by Clinical Global Impression Scale-Improvement (CGI-I) <= 2 in their target symptom domain. AEs were assessed by phone with parents (weeks 1, 3, 5) and via the UKU (Udvalg for Kliniske Under-sogelser) Side Effects Rating Scale administered by clinicians to dyads (weeks 2, 4, 6). Clinician consensus determined the relatedness of AEs to treatment. Disease-related events (DREs) were considered adverse if the severity or frequency increased. In this interim analysis, we identified response to treatment and AEs, contrasted AE rates (parents vs dyads), and examined the relationship between treatment response and AE profile.
Result(s): All 12 initial participants completed the trial; 4 responded (33%). Clinical Global Impression Scale-Severity (CGI-S) improved significantly from pre- (M = 4.83; SD = 0.39) to posttreatment (M = 3.92; SD = 0.90) (t11 = 3.53; p < 0.004). The most frequent AEs were tiredness (n = 5) and increased emotionality (n = 3). Of 47 total AEs, all were mild and 39 were first reported by dyads. Of 14 related AEs, 9 were first reported by dyads. One DRE occurred: increased severity of restricted, repetitive behaviors. The number of AEs reported by dyads (M = 3.25; SD = 3.14) compared to parents alone (M = 0.67; SD = 0.89) was significantly higher (t11 = 2.18; p = 0.017). Responders and nonresponders did not differ significantly in the number of total or related AEs.
Conclusion(s): This interim analysis suggests that including the input of children with ASD in AE reporting captures a fuller profile of total and related AEs without compromising the study integrity or results. ASD, OLT, R
Copyright
Method(s): Twelve youth (ages 7-14 years) with ASD (verbally fluent, IQ >= 80) completed a 6-week, Phase 2 open trial of 98% CBD (Epidiolex [V], 100 mg/mL) at 3 or 6 mg/kg/day; target N = 30. An individualized target symptom domain was identified at baseline by clinician consensus from informant report, rating scales, and clinical observation. Responders were defined by Clinical Global Impression Scale-Improvement (CGI-I) <= 2 in their target symptom domain. AEs were assessed by phone with parents (weeks 1, 3, 5) and via the UKU (Udvalg for Kliniske Under-sogelser) Side Effects Rating Scale administered by clinicians to dyads (weeks 2, 4, 6). Clinician consensus determined the relatedness of AEs to treatment. Disease-related events (DREs) were considered adverse if the severity or frequency increased. In this interim analysis, we identified response to treatment and AEs, contrasted AE rates (parents vs dyads), and examined the relationship between treatment response and AE profile.
Result(s): All 12 initial participants completed the trial; 4 responded (33%). Clinical Global Impression Scale-Severity (CGI-S) improved significantly from pre- (M = 4.83; SD = 0.39) to posttreatment (M = 3.92; SD = 0.90) (t
Conclusion(s): This interim analysis suggests that including the input of children with ASD in AE reporting captures a fuller profile of total and related AEs without compromising the study integrity or results. ASD, OLT, R
Copyright
EMBASE:2014994967
ISSN: 1527-5418
CID: 5024292
A Biased Perspective on Brain Imaging of ADHD
PMID: 34383564
ISSN: 1535-7228
CID: 5010842
Disrupted intrinsic functional brain topology in patients with major depressive disorder
Aberrant topological organization of whole-brain networks has been inconsistently reported in studies of patients with major depressive disorder (MDD), reflecting limited sample sizes. To address this issue, we utilized a big data sample of MDD patients from the REST-meta-MDD Project, including 821 MDD patients and 765 normal controls (NCs) from 16 sites. Using the Dosenbach 160 node atlas, we examined whole-brain functional networks and extracted topological features (e.g., global and local efficiency, nodal efficiency, and degree) using graph theory-based methods. Linear mixed-effect models were used for group comparisons to control for site variability; robustness of results was confirmed (e.g., multiple topological parameters, different node definitions, and several head motion control strategies were applied). We found decreased global and local efficiency in patients with MDD compared to NCs. At the nodal level, patients with MDD were characterized by decreased nodal degrees in the somatomotor network (SMN), dorsal attention network (DAN) and visual network (VN) and decreased nodal efficiency in the default mode network (DMN), SMN, DAN, and VN. These topological differences were mostly driven by recurrent MDD patients, rather than first-episode drug naive (FEDN) patients with MDD. In this highly powered multisite study, we observed disrupted topological architecture of functional brain networks in MDD, suggesting both locally and globally decreased efficiency in brain networks.
PMID: 34385597
ISSN: 1476-5578
CID: 5006242
Journal of child psychology & psychiatry & allied disciplines. 2021:62(10):1202-1219.DOI: 10.1111/jcpp.13396
Analysis of structural brain asymmetries in attention-deficit/hyperactivity disorder in 39 datasets
OBJECTIVE:Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium. METHODS:We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries. RESULTS:There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen's d from -0.18 to 0.18) and would not survive study-wide correction for multiple testing. CONCLUSION/CONCLUSIONS:Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.
PMID: 33748971
ISSN: 1469-7610
CID: 4822272
Eight-week antidepressant treatment reduces functional connectivity in first-episode drug-naïve patients with major depressive disorder
Previous neuroimaging studies have revealed abnormal functional connectivity of brain networks in patients with major depressive disorder (MDD), but findings have been inconsistent. A recent big-data study found abnormal intrinsic functional connectivity within the default mode network in patients with recurrent MDD but not in first-episode drug-naïve patients with MDD. This study also provided evidence for reduced default mode network functional connectivity in medicated MDD patients, raising the question of whether previously observed abnormalities may be attributable to antidepressant effects. The present study (ClinicalTrials.gov identifier: NCT03294525) aimed to disentangle the effects of antidepressant treatment from the pathophysiology of MDD and test the medication normalization hypothesis. Forty-one first-episode drug-naïve MDD patients were administrated antidepressant medication (escitalopram or duloxetine) for 8 weeks, with resting-state functional connectivity compared between posttreatment and baseline. To assess the replicability of the big-data finding, we also conducted a cross-sectional comparison of resting-state functional connectivity between the MDD patients and 92 matched healthy controls. Both Network-Based Statistic analyses and large-scale network analyses revealed intrinsic functional connectivity decreases in extensive brain networks after treatment, indicating considerable antidepressant effects. Neither Network-Based Statistic analyses nor large-scale network analyses detected significant functional connectivity differences between treatment-naïve patients and healthy controls. In short, antidepressant effects are widespread across most brain networks and need to be accounted for when considering functional connectivity abnormalities in MDD.
PMID: 33638263
ISSN: 1097-0193
CID: 4802392
