Glutamate imbalance in key structure of the default mode network in adults with attention-deficit/hyperactivity disorder.

The default mode network (DMN) is atypically active in patients with ADHD, likely contributing to the inattention patterns observed in patients with the disorder. Nonetheless, magnetic resonance spectroscopy (MRS) studies have rarely targeted the posterior cingulate cortex, a key DMN region, and little is known about the biochemical setting within this network in patients with ADHD. We aimed to assess the differences in metabolite profiles of the posterior cingulate cortex-a key region of the DMN-between patients with ADHD and controls. Five brain metabolites-glutamate, inositol, N-acetyl aspartate, choline, and creatine-were measured through MRS in the posterior cingulate cortex of patients and controls in a 3.0 T scanner. Between-group comparison of neurometabolite concentrations in PCC was performed using multivariate analysis of covariance. A total of 88 patients and 44 controls were included in the analysis. Patients with ADHD showed lower levels of glutamate in the posterior cingulate cortex compared to controls (p = 0.003). Lower concentrations of glutamate in the posterior cingulate cortex suggest that a glutamatergic imbalance within the posterior cingulate cortex might play a role in the pathogenesis of ADHD. Further understanding of the causes and consequences of such glutamate decrease might help explain how some glutamate-related drug effects impact on ADHD symptomatology.

Refining patterns of MEF2C effects in white matter microstructure and psychiatric features.

Several GWAS reported Myocyte Enhancer Factor 2 C (MEF2C) gene associations with white matter microstructure and psychiatric disorders, and MEF2C involvement in pathways related to neuronal development suggests a common biological factor underlying these phenotypes. We aim to refine the MEF2C effects in the brain relying on an integrated analysis of white matter and psychiatric phenotypes in an extensively characterized sample. This study included 870 Brazilian adults (47% from an attention-deficit/hyperactivity disorder outpatient clinic) assessed through standardized psychiatric interviews, 139 of which underwent a magnetic resonance imaging scan. We evaluated variants in the MEF2C region using two approaches: 1) a gene-wide analysis, which uses the sum of polymorphism effects, and 2) SNP analyses, restricted to the independent variants within the gene. The outcomes included psychiatric phenotypes and fractional anisotropy for brain images. Results: The gene-wide analyses pointed to a nominal association between MEF2C and the Temporal Portion of the Superior Longitudinal Fasciculus (SLFTEMP). The SNP analysis identified four independent variants significantly associated with SLFTEMP and one (rs4218438) with Substance Use Disorder. Our findings showing specific associations of MEF2C variants with temporal-frontal circuitry components may help to elucidate how the MEF2C gene underlies a broad range of psychiatric phenotypes since these regions are relevant to executive and cognitive functions.

Emerging findings of glutamate-glutamine imbalance in the medial prefrontal cortex in attention deficit/hyperactivity disorder: systematic review and meta-analysis of spectroscopy studies.

One of the main challenges in investigating the neurobiology of ADHD is our limited capacity to study its neurochemistry in vivo. Magnetic resonance spectroscopy (MRS) estimates metabolite concentrations within the brain, but approaches and findings have been heterogeneous. To assess differences in brain metabolites between patients with ADHD and healthy controls, we searched 12 databases screening for MRS studies. Studies were divided into 'children and adolescents' and 'adults' and meta-analyses were performed for each brain region with more than five studies. The quality of studies was assessed by the Newcastle-Ottawa Scale. Thirty-three studies met our eligibility criteria, including 874 patients with ADHD. Primary analyses revealed that the right medial frontal area of children with ADHD presented higher concentrations of a composite of glutamate and glutamine (p = 0.02, SMD = 0.53). Glutamate might be implicated in pruning and neurodegenerative processes as an excitotoxin, while glutamine excess might signal a glutamate depletion that could hinder neurotrophic activity. Both neuro metabolites could be implicated in the differential cortical thinning observed in patients with ADHD across all ages. Notably, more homogeneous designs and reporting guidelines are the key factors to determine how suitable MRS is for research and, perhaps, for clinical psychiatry. Results of this meta-analysis provided an overall map of the brain regions evaluated so far, addressed the role of glutamatergic metabolites in the pathophysiology of ADHD, and pointed to new perspectives for consistent use of the tool in the field.

The course of attention-deficit/hyperactivity disorder through midlife.

The course of ADHD from childhood up to young adulthood has been characterized in several studies. However, little is known about the course of symptoms into middle age and beyond. This study aims to evaluate predictors of ADHD trajectories in midlife based on three assessments. The follow-up sample comprised 323 adults with ADHD, evaluated at baseline and seven and thirteen years later, from the average ages of 34 up to 47 years old. ADHD status at reassessments was used to characterize trajectories. Demographics, ADHD features, comorbidities, and polygenic scores for ADHD and genetically correlated psychiatric disorders were evaluated to predict ADHD trajectories. Study retention rate was 67% at T2 (n = 216) and 62% at T3 (n = 199). Data from patients evaluated three times showed that 68.8% coursed stable, 25.5% unstable, and 5.7% remission trajectory of ADHD. Women, individuals with more severe syndromes, higher frequency of comorbidities at reassessments, and genetic liability to depression present a higher probability of a stable trajectory. Our findings shed light on midlife ADHD trajectories and their gender, genomic and clinical correlates.

Long-term stability of the cortical volumetric profile and the functional human connectome throughout childhood and adolescence.

There is compelling evidence showing that between-subject variability in several functional and structural brain features is sufficient for unique identification in adults. However, individuation of brain functional connectomes depends on the stabilization of neurodevelopmental processes during childhood and adolescence. Here, we aimed to (1) evaluate the intra-subject functional connectome stability over time for the whole brain and for large scale functional networks and (2) determine the long-term identification accuracy or 'fingerprinting' for the cortical volumetric profile and the functional connectome. For these purposes, we analysed a longitudinal cohort of 239 children and adolescents scanned in two sessions with an interval of approximately 3 years (age range 6-15 years at baseline and 9-18 years at follow-up). Corroborating previous results using short between-scan intervals in children and adolescents, we observed a moderate identification accuracy (38%) for the whole functional profile. In contrast, identification accuracy using cortical volumetric profile was 95%. Among the large-scale networks, the default-mode (26.8%), the frontoparietal (23.4%) and the dorsal-attention (27.6%) networks were the most discriminative. Our results provide further evidence for a protracted development of specific individual structural and functional connectivity profiles.

The current status of psychiatric education in Brazil.

The aim of this review is to present a brief historical perspective, the current status of psychiatric education in Brazil, discuss its role in Latin America, and its challenges ahead. The history of psychiatry in Brazil is intertwined with the history of medical assistance in Brazil. Psychiatric education in Brazil started in the asylum-centric era during the second half of the 19th century and evolved to occupy university teaching-hospital in the 20th century. The medical residency in psychiatry has shown considerable growth since its implementation 70 years ago. Undoubtedly, it currently occupies a prominent place in Brazilian medicine. However, there is a need to create and expand it in the less developed regions of the country. Brazilian psychiatric journals also have a leading position in developing evidence-based psychiatry in Latin America.

Associations between children's family environment, spontaneous brain oscillations, and emotional and behavioral problems.

The family environment in childhood has a strong effect on mental health outcomes throughout life. This effect is thought to depend at least in part on modifications of neurodevelopment trajectories. In this exploratory study, we sought to investigate whether a feasible resting-state fMRI metric of local spontaneous oscillatory neural activity, the fractional amplitude of low-frequency fluctuations (fALFF), is associated with the levels of children's family coherence and conflict. Moreover, we sought to further explore whether spontaneous activity in the brain areas influenced by family environment would also be associated with a mental health outcome, namely the incidence of behavioral and emotional problems. Resting-state fMRI data from 655 children and adolescents (6-15 years old) were examined. The quality of the family environment was found to be positively correlated with fALFF in the left temporal pole and negatively correlated with fALFF in the right orbitofrontal cortex. Remarkably, increased fALFF in the temporal pole was associated with a lower incidence of behavioral and emotional problems, whereas increased fALFF in the orbitofrontal cortex was correlated with a higher incidence.

Default mode network maturation and psychopathology in children and adolescents.

BACKGROUND: The human default mode (DMN) is involved in a wide array of mental disorders. Current knowledge suggests that mental health disorders may reflect deviant trajectories of brain maturation. METHOD: We studied 654 children using functional magnetic resonance imaging (fMRI) scans under a resting-state protocol. A machine-learning method was used to obtain age predictions of children based on the average coefficient of fractional amplitude of low frequency fluctuations (fALFFs) of the DMN, a measure of spontaneous local activity. The chronological ages of the children and fALFF measures from regions of this network, the response and predictor variables were considered respectively in a Gaussian Process Regression. Subsequently, we computed a network maturation status index for each subject (actual age minus predicted). We then evaluated the association between this maturation index and psychopathology scores on the Child Behavior Checklist (CBCL). RESULTS: Our hypothesis was that the maturation status of the DMN would be negatively associated with psychopathology. Consistent with previous studies, fALFF significantly predicted the age of participants (p < .001). Furthermore, as expected, we found an association between the DMN maturation status (precocious vs. delayed) and general psychopathology scores (p = .011). CONCLUSIONS: Our findings suggest that child psychopathology seems to be associated with delayed maturation of the DMN. This delay in the neurodevelopmental trajectory may offer interesting insights into the pathophysiology of mental health disorders.

Does collateral retrospective information about childhood attention-deficit/hyperactivity disorder symptoms assist in the diagnosis of attention-deficit/hyperactivity disorder in adults? Findings from a large clinical sample.

OBJECTIVES: In accordance with consolidated clinical practice, Diagnostic and Statistical Manual of Mental Disorders, 5th edition suggests a key role of collateral information in the evaluation of retrospective childhood attention-deficit/hyperactivity disorder symptoms in adults despite poor evidence supporting its use. This study aims to assess the incremental value of collateral information on the presence of childhood attention-deficit/hyperactivity disorder symptoms when evaluating adults with attention-deficit/hyperactivity disorder. METHODS: Adult patients with attention-deficit/hyperactivity disorder (n = 449) and non-attention-deficit/hyperactivity disorder subjects (n = 143) underwent an extensive clinical assessment based on Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria. For patients, retrospective collateral information regarding childhood attention-deficit/hyperactivity disorder was obtained and used to sort them into two groups: agreement (n = 277) and disagreement (n = 172) between self- and collateral reports. We compared demographic, clinical and response to treatment profiles among groups to test the relevance of collateral information on the specific issue of childhood attention-deficit/hyperactivity disorder symptoms. RESULTS: Both attention-deficit/hyperactivity disorder groups had higher rates of several comorbidities (oppositional defiant, conduct, substance use and bipolar disorders; all p < 0.001) and impairments than controls. Disagreement between self- and collateral reports on childhood attention-deficit/hyperactivity disorder symptoms occurred in 38% of patients. Overall, attention-deficit/hyperactivity disorder disagreement and agreement groups had similar profiles in response to treatment and comorbidity, and the few differences detected in impairment measures were of small magnitude (Eta(2) < 0.05). CONCLUSION: Although collateral report has an important role for diagnosing attention-deficit/hyperactivity disorder in children, it has no incremental value in the evaluation of childhood attention-deficit/hyperactivity disorder symptoms in adults with a self-reported history of attention-deficit/hyperactivity disorder assessed in clinical settings.

Decreased centrality of subcortical regions during the transition to adolescence: a functional connectivity study.

Investigations of brain maturation processes are a key step to understand the cognitive and emotional changes of adolescence. Although structural imaging findings have delineated clear brain developmental trajectories for typically developing individuals, less is known about the functional changes of this sensitive development period. Developmental changes, such as abstract thought, complex reasoning, and emotional and inhibitory control, have been associated with more prominent cortical control. The aim of this study is to assess brain networks connectivity changes in a large sample of 7- to 15-year-old subjects, testing the hypothesis that cortical regions will present an increasing relevance in commanding the global network. Functional magnetic resonance imaging (fMRI) data were collected in a sample of 447 typically developing children from a Brazilian community sample who were submitted to a resting state acquisition protocol. The fMRI data were used to build a functional weighted graph from which eigenvector centrality (EVC) was extracted. For each brain region (a node of the graph), the age-dependent effect on EVC was statistically tested and the developmental trajectories were estimated using polynomial functions. Our findings show that angular gyrus become more central during this maturation period, while the caudate; cerebellar tonsils, pyramis, thalamus; fusiform, parahippocampal and inferior semilunar lobe become less central. In conclusion, we report a novel finding of an increasing centrality of the angular gyrus during the transition to adolescence, with a decreasing centrality of many subcortical and cerebellar regions.

Temporal stability of network centrality in control and default mode networks: Specific associations with externalizing psychopathology in children and adolescents.

Abnormal connectivity patterns have frequently been reported as involved in pathological mental states. However, most studies focus on "static," stationary patterns of connectivity, which may miss crucial biological information. Recent methodological advances have allowed the investigation of dynamic functional connectivity patterns that describe non-stationary properties of brain networks. Here, we introduce a novel graphical measure of dynamic connectivity, called time-varying eigenvector centrality (tv-EVC). In a sample 655 children and adolescents (7-15 years old) from the Brazilian "High Risk Cohort Study for Psychiatric Disorders" who were imaged using resting-state fMRI, we used this measure to investigate age effects in the temporal in control and default-mode networks (CN/DMN). Using support vector regression, we propose a network maturation index based on the temporal stability of tv-EVC. Moreover, we investigated whether the network maturation is associated with the overall presence of behavioral and emotional problems with the Child Behavior Checklist. As hypothesized, we found that the tv-EVC at each node of CN/DMN become more stable with increasing age (P < 0.001 for all nodes). In addition, the maturity index for this particular network is indeed associated with general psychopathology in children assessed by the total score of Child Behavior Checklist (P = 0.027). Moreover, immaturity of the network was mainly correlated with externalizing behavior dimensions. Taken together, these results suggest that changes in functional network dynamics during neurodevelopment may provide unique insights regarding pathophysiology.

Exploring Neuroimaging Association Scores in adulthood ADHD and middle-age trajectories.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder associated with brain differences in children, but not in adults. A combined evaluation of the regional brain differences could improve statistical power and, consequently, allow the detection of possible effects in adults. Thus, our aim is to verify whether Neuroimaging Association Scores (NAS) are associated with adulthood ADHD and clinical trajectories of the disorder in midlife. Clinical and neuroimaging data were collected for 121 subjects with ADHD (mean age: 47.1 ± 10.5; 43% male) and 82 controls (mean age: 38.2 ± 9.0; 54.9% male). Cases were assessed seven and thirteen years after baseline diagnosis, and their clinical trajectories were classified as stable if they fulfilled ADHD diagnosis in all assessments or unstable if they presented remission and recurrence of symptoms. Neuroimaging data were acquired in the last clinical assessment (thirteen years after baseline) and NAS were calculated as a weighted sum of the associations previously reported by meta-analyses for three types of structural brain modalities: cortical thickness, cortical surface area, and subcortical volume. The NAS for cortical surface area was higher in cases compared to controls. No association was found for NAS and number of symptoms of ADHD or clinical trajectories. The fact that differences were restricted to ADHD diagnostic status suggests a susceptibility effect that is not extended to subtle aspects of the disorder. Our results also suggest that evaluating overall effects may have advantages especially when applied to adult ADHD samples.

Associations between Family Functioning and Maternal Behavior on Default Mode Network Connectivity in School-Age Children.

Background: Most early children's experiences will occur in a family context; therefore, the quality of this environment is critical for development outcomes. Not many studies have assessed the correlations between brain functional connectivity (FC) in important areas such as the default mode network (DMN) and the quality of parent-child relationships in school-age children and early adolescence. The quality of family relationships and maternal behavior have been suggested to modulate DMN FC once they act as external regulators of children's affect and behavior. Objective: We aimed to test the associations between the quality of family environment/maternal behavior and FC within the DMN of school-age children. Method: Resting-state, functional magnetic resonance imaging data, were collected from 615 children (6-12 age range) enrolled in the Brazilian High-Risk Cohort (HRC) study. We assessed DMN intra-connectivity between the medial prefrontal cortex (mPFC), posterior cingulate cortex (PCC), and inferior parietal lobule (IPL-bilateral) regions. The family functioning was assessed by levels of family cohesiveness and conflict and by maternal behavior styles such as maternal responsiveness, maternal stimulus to the child's autonomy, and maternal overprotection. The family environment was assessed with the Family Environment Scale (FES), and maternal behavior was assessed by the mother's self-report. Results: We found that the quality of the family environment was correlated with intra-DMN FC. The more conflicting the family environment was, the greater the FC between the mPFC-left IPL (lIPL), while a more cohesive family functioning was negatively correlated with FC between the PCC-lIPL. On the other hand, when moderated by a positive maternal behavior, cohesive family functioning was associated with increased FC in both regions of the DMN (mPFC-lIPL and PCC-lIPL). Conclusions: Our results highlight that the quality of the family environment might be associated with differences in the intrinsic DMN FC.

ADRA2A polymorphisms and ADHD in adults: possible mediating effect of personality.

Several studies have tested for the association between polymorphisms in the ADRA2A gene and childhood ADHD. A meta-analysis of these results, however, has pointed towards a significant heterogeneity, raising the need for explanatory studies. As the effect of other relevant clinical characteristics could be a possible source, we studied three polymorphisms in the ADRA2A gene (-1291 C>G-MspI or rs1800544; -262 G>A-HhaI or rs1800544; 1780 C>T-DraI or rs553668) in 403 adult patients with ADHD assessed in relation to comorbidity and personality characteristics, as well as in 232 controls. The diagnosis followed DSM-IV criteria, and personality dimensions were evaluated with the Temperament and Character Inventory (TCI). There were no significant differences in allele and genotype frequencies between cases and controls. Patients carrying the G allele of rs1800544 presented lower scores in harm avoidance, and carriers of the T allele of rs553668 had more novelty seeking and less harm avoidance and persistence. Additionally, the haplotype carrying the G-G-T alleles (rs1800544-rs1800545-rs553668) was associated with lower scores in harm avoidance and persistence, and higher scores in novelty seeking compared to other haplotypes. These findings suggest that the conflicting findings obtained in association studies between ADRA2A polymorphisms and ADHD might be related to temperament profiles, and support additional studies addressing these effects in larger samples.

Methylphenidate Alters Functional Connectivity of Default Mode Network in Drug-Naive Male Adults With ADHD.

Objective: This study evaluated the hypothesis that methylphenidate immediate release (MPH-IR) treatment would improve Default Mode Network (DMN) within-connectivity. Method: Resting-state functional connectivity of the main nodes of DMN was evaluated in a highly homogeneous sample of 18 drug-naive male adult participants with ADHD. Results: Comparing resting-state functional connectivity functional magnetic resonance imaging (R-fMRI) scans before and after MPH treatment focusing exclusively on within-DMN connectivity, we evidenced the strengthening of functional connectivity between two nodes of the DMN: posterior cingulate cortex (PCC) and left lateral parietal cortex (LLP). Conclusion: Our results contribute to the further understanding on how MPH affects functional connectivity within DMN of male adults with ADHD and corroborate the hypothesis of ADHD being a delayed neurodevelopmental disorder.

Reduced fronto-striatal volume in attention-deficit/hyperactivity disorder in two cohorts across the lifespan.

Attention-Deficit/Hyperactivity Disorder (ADHD) has been associated with altered brain anatomy in neuroimaging studies. However, small and heterogeneous study samples, and the use of region-of-interest and tissue-specific analyses have limited the consistency and replicability of these effects. We used a data-driven multivariate approach to investigate neuroanatomical features associated with ADHD in two independent cohorts: the Dutch NeuroIMAGE cohort (n = 890, 17.2 years) and the Brazilian IMpACT cohort (n = 180, 44.2 years). Using independent component analysis of whole-brain morphometry images, 375 neuroanatomical components were assessed for association with ADHD. In both discovery (corrected-p = 0.0085) and replication (p = 0.032) cohorts, ADHD was associated with reduced volume in frontal lobes, striatum, and their interconnecting white-matter. Current results provide further evidence for the role of the fronto-striatal circuit in ADHD in children, and for the first time show its relevance to ADHD in adults. The fact that the cohorts are from different continents and comprise different age ranges highlights the robustness of the findings.

Association Between Fractional Amplitude of Low-Frequency Spontaneous Fluctuation and Degree Centrality in Children and Adolescents.

The fractional amplitude of low-frequency fluctuations (fALFFs) of the BOLD signal have been successfully applied as exploratory tools in neuroimaging. This metric has been useful in mapping brain functional changes in many clinical populations. However, little is known about the neurophysiological correlates of fALFF. This study aimed at demonstrating that fALFF is related to local network centrality during childhood and adolescence. The establishment of this relationship is fundamental to provide a more meaningful explanation to previous clinical and neurodevelopmental studies based on fALFF. Our findings show a correlation of ∼0.5 between these two metrics at a group level, which is a finding replicated in four large independent samples. However, when considering the across-subject and intra-subject correlations between the two metrics, the correlation is much lower, probably due to the low signal-to-noise ratio. Moreover, we found that regions with high fALFF and degree centrality overlapped modestly, particularly the posterior cingulate/precuneus and lateral parietal cortices.

Association between abnormal brain functional connectivity in children and psychopathology: A study based on graph theory and machine learning.

OBJECTIVES: One of the major challenges facing psychiatry is how to incorporate biological measures in the classification of mental health disorders. Many of these disorders affect brain development and its connectivity. In this study, we propose a novel method for assessing brain networks based on the combination of a graph theory measure (eigenvector centrality) and a one-class support vector machine (OC-SVM). METHODS: We applied this approach to resting-state fMRI data from 622 children and adolescents. Eigenvector centrality (EVC) of nodes from positive- and negative-task networks were extracted from each subject and used as input to an OC-SVM to label individual brain networks as typical or atypical. We hypothesised that classification of these subjects regarding the pattern of brain connectivity would predict the level of psychopathology. RESULTS: Subjects with atypical brain network organisation had higher levels of psychopathology (p < 0.001). There was a greater EVC in the typical group at the bilateral posterior cingulate and bilateral posterior temporal cortices; and significant decreases in EVC at left temporal pole. CONCLUSIONS: The combination of graph theory methods and an OC-SVM is a promising method to characterise neurodevelopment, and may be useful to understand the deviations leading to mental disorders.

Effects of the brain-derived neurotropic factor variant Val66Met on cortical structure in late childhood and early adolescence.

BACKGROUND: The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265) has been associated with several neuropsychiatric disorders and regional structural brain changes in adults, but little is known about Val66Met's effect on brain morphology during typical or atypical neurodevelopment. Windows of vulnerability to psychopathology may be associated with the different alleles of the Val66Met polymorphism during childhood and adolescence. METHODOLOGY: We investigated the effect of Val66Met on cortical thickness in MRI scans of 718 children and adolescents (6-12 years old) with typical development, and in those meeting DSM criteria for a psychiatric disorder. RESULTS: Val66Met had a significant effect on cortical thickness. Considering the typically developing group, Met-carriers presented thicker parietal and occipital lobes and prefrontal cortices compared to Val homozygotes. Met-carriers with psychiatric disorders presented thicker medial and lateral temporal cortices than Val homozygotes. Furthermore, a significant genotype × psychiatric diagnosis interaction was found: Met-carriers with a psychiatric diagnosis presented thinner bilateral prefrontal cortices than Val homozygotes. CONCLUSION: This study provides evidence that Val66Met is associated with cortical maturation in children and adolescents with and without psychiatric disorders.

Age-effects in white matter using associated diffusion tensor imaging and magnetization transfer ratio during late childhood and early adolescence.

In the last decade, several studies have described the typical brain white matter maturation in children and adolescents. Diffusion tensor imaging (DTI) is the most frequent MRI technique used to investigate the structural changes across development. However, few previous studies have used the magnetization transfer ratio (MTR), which gives a closer measure of myelin content. Here, we employed both techniques for the same sample of 176 typically developing children from 7 to 14years of age. We investigated the associations between DTI parameters and MTR measure, to assess the myelination in the brain in development. Secondly, we investigated age-effects on DTI parameters (fractional anisotropy, axial, radial and mean diffusivities) and MTR. No significant correlations between MTR and DTI parameters were observed. In addition, a significant age-effect was detected for DTI data but was not visible for MTR data. Thereby, changes in white matter at this age might be primarily correlated with microstructural changes.