Isabelle Massat

Working Memory-Related Functional Brain Patterns in Never Medicated Children with ADHD

Attention Deficit/Hyperactivity Disorder (ADHD) is a pervasive neurodevelopmental disorder characterized by 3 clusters of age-inappropriate cardinal symptoms: inattention, hyperactivity and impulsivity. These clinical/behavioural symptoms are assumed to result from disturbances within brain systems supporting executive functions including working memory (WM), which refers to the ability to transiently store and flexibly manipulate task-relevant information. Ongoing or past medications, co-morbidity and differences in task performance are potential, independent confounds in assessing the integrity of cerebral patterns in ADHD. In the present study, we recorded WM-related cerebral activity during a memory updating N-back task using functional Magnetic Resonance Imaging (fMRI) in control children and never medicated, prepubescent children with ADHD but without comorbid symptoms. Despite similar updating performance than controls, children with ADHD exhibited decreased, below baseline WM-related activation levels in a widespread cortico-subcortical network encompassing bilateral occipital and inferior parietal areas, caudate nucleus, cerebellum and functionally connected brainstem nuclei. Distinctive functional connectivity patterns were also found in the ADHD in these regions, with a tighter coupling in the updating than in the control condition with a distributed WM-related cerebral network. Especially, cerebellum showed tighter coupling with activity in an area compatible with the brainstem red nucleus. These results in children with clinical core symptoms of ADHD but without comorbid affections and never treated with medication yield evidence for a core functional neuroanatomical network subtending WM-related processes in ADHD, which may participate to the pathophysiology and expression of clinical symptoms.

Executive and attentional contributions to Theory of Mind deficit in attention deficit/hyperactivity disorder (ADHD)

Attention deficit/hyperactivity disorder (ADHD) in children has been associated with attentional and executive problems, but also with socioemotional difficulties possibly associated with deficits in Theory of Mind (ToM). Socioemotional problems in ADHD are associated with more negative prognoses, notably interpersonal, educational problems, and an increased risk of developing other psychiatric disorders that emphasize the need to clarify the nature of their ToM deficits. In this study, we hypothesized that ToM dysfunction in children with ADHD is largely attributable to their attentional and/or executive deficits. Thirty-one children with ADHD (8–12 years, IQ > 85) and 31 typically developing (TD) children were assessed using executive functions (inhibition, planning, and flexibility) and attentional tasks, as well as two advanced ToM tasks (Reading the Mind in the Eyes and Faux Pas) involving different levels of executive control. Children with ADHD performed more poorly than TD children in attentional, executive function, and ToM tasks. Linear regression analyses conducted in the ADHD group indicated that inhibition scores predicted performance on the “Faux Pas” task the best, while attention scores were the best for predicting performance on the Reading the Mind in the Eyes task. When controlled for inhibition and attentional variables, ToM performance in children with ADHD was actually similar to TD children. Contrarily, controlling for ToM scores did not normalize performance for inhibition and attentional tasks in children with ADHD. This unidirectional relationship suggests that deficits in the EF and attentional domains are responsible for ToM deficits in ADHD, which therefore may contribute to their socioemotional difficulties.

Evaluation of the role of MAPK1 and CREB1 polymorphisms on treatment resistance, response and remission in mood disorder patients

Treatment resistant depression (TRD) is a significant clinical and public health problem. Among others, neuroplasticity and inflammatory pathways seem to play a crucial role in the pathomechanisms of antidepressant efficacy. The primary aim of this study was to investigate whether a set of single nucleotide polymorphisms (SNPs) within two genes implicated in neuroplasticity and inflammatory processes (the mitogen activated protein kinase 1, MAPK1 (rs3810608, rs6928, rs13515 and rs8136867), and the cyclic AMP responsive element binding protein 1, CREB1 (rs889895, rs6740584, rs2551922 and rs2254137)) was associated with antidepressant treatment resistance (according to two different definitions), in 285 Major Depressive Disorder (MDD) patients. As secondary aims, we investigated the genetic modulation of the same SNPs on response, remission and other clinical features both in MDD patients and in a larger sample including 82 Bipolar Disorder (BD) patients as well. All patients were screened in the context of a European multicenter project. No association between both the investigated genes and treatment resistance and response was found in MDD patients. However, considering remission, higher rates of CREB1 rs889895 GG genotype were reported in MDD patients. Moreover, MAPK1 rs8136867 AG genotype was found to be associated with remission in the whole sample (MDD and BD). Present results suggest that some genetic polymorphisms in both CREB1 and MAPK1 could be associated with treatment remission. Although further research is needed to draw more definitive conclusions, such results are intriguing since suggest a potential role of two genes implicated in neuroplasticity and inflammatory processes in symptom remission after antidepressant treatment.

Genetics of schizophrenia: A consensus paper of the WFSBP task force on genetics

Abstract Objectives: Schizophrenia is a severe psychiatric disease affecting about 1% of the general population. The relative contribution of genetic factors has been estimated to be up to 80%. The mode of inheritance is complex, non-Mendelian, and in most cases involving the combined action of large numbers of genes. Methods: This review summarises recent efforts to identify genetic variants associated with schizophrenia detected, e.g., through genome-wide association studies, studies on copy-number variants or next-generation sequencing. Results: A large, new body of evidence on genetics of schizophrenia has accumulated over recent years. Many new robustly associated genetic loci have been detected. Furthermore, there is consensus that at least a dozen microdeletions and microduplications contribute to the disease. Genetic overlap between schizophrenia, other psychiatric disorders, and neurodevelopmental syndromes raised new questions regarding the current classification of psychiatric and neurodevelopmental diseases. Conclusions: Future studies will address especially the functional characterisation of genetic variants. This will hopefully open the doors to our understanding of the pathophysiology of schizophrenia and other related diseases. Complementary, integrated systems biology approaches to genomics, transcriptomics, proteomics and metabolomics may also play crucial roles in enabling a precision medicine approach to the treatment of individual patients.

Grey matter volumes in treatment naïve vs. chronically treated children with attention deficit / hyperactivity disorder: a combined approach

Psychostimulants are the first-line treatment in attention deficit/hyperactivity disorder (ADHD), but their effects on brain development remain poorly understood. In particular, previous structural magnetic resonance imaging (sMRI) studies only investigated treatment effects on grey matter (GM) volumes in selected regions of interest (ROIs). In this study, voxel-based morphometry (VBM) was used to assess medication-related GM volume differences across the entire brain. Automated tracing measurements of selected ROIs were also obtained. Three groups (77 participants aged 7-to-13 year old) underwent MRI scans and were compared: never-medicated children with ADHD (n=33), medicated (methylphenidate) children with ADHD (n=20) and typically developing children (TD; n=24). Optimised VBM was used to investigate regional GM volumes, controlling for age and gender. Automated tracing procedures were also used to assess the average volume of the caudate nucleus, the amygdala and the nucleus accumbens. When compared to both medicated children with ADHD and TD children, never-medicated children with ADHD exhibited decreased GM volume in the insula and in the middle temporal gyrus. When compared to TD children, medicated children with ADHD had decreased GM volume in the middle frontal gyrus and in the precentral gyrus. Finally, ROI analyses revealed a significant association between duration of treatment and GM volume of the left nucleus accumbens in medicated children with ADHD. In conclusion, this study documents potential methylphenidate-related GM volume normalization and deviation in previously unexplored brain structures, and reports a positive association between treatment history and GM volume in the nucleus accumbens, a key region for reward-processing.

Grey matter volume differences associated with gender in children with attention-deficit/hyperactivity disorder: A voxel-based morphometry study

Highlights • We studied gender effect on grey matter volumes in children with ADHD.• A gender-by-diagnosis interaction was found in the ventral Anterior Cingulate Gyrus.• This finding may underlie emotion dysregulation symptoms in ADHD.• Contribute to differences in symptoms profiles between boys and girls with ADHD.

Structural correlates of COMT Val158Met polymorphism in childhood ADHD: a voxel-based morphometry study.

Abstract Objectives. The Val158-allele of the catechol-O-methyltransferase (COMT) Val158Met (rs4680) functional polymorphism has been identified as a risk factor for antisocial behaviour in attention-deficit/hyperactivity disorder (ADHD). Here, we used voxel-based morphometry to investigate the effects of Val158Met polymorphism on grey matter (GM) volumes in a sample of 7–13-year-old children. Methods. MRI and genotype data were obtained for 38 children with combined-type ADHD and 24 typically developing (TD) children. Four regions of interest were identified: striatum, cerebellum, temporal lobe and inferior frontal gyrus (IFG). Results. When compared to TD children, those with ADHD had a significant decrease of GM volume in the IFG. Volume in this region was negatively correlated with ratings of hyperactivity/impulsivity symptoms. Furthermore, the smaller GM volume in the IFG was attributed to the presence of the Met158-allele, as only children with ADHD carrying a Met158-allele exhibited such decrease in the IFG. Children with ADHD homozygotes for the Val158-allele presented increased GM volume in the caudate nucleus when compared with TD children. Conclusions. This study provides the first evidence of a modulation of ADHD-related GM volume alterations by Val158Met in two key regions, possibly mediating the relationship between Val158Met polymorphism and antisocial behaviour in children with ADHD.

Behavioral and neurophysiological study of attentional and inhibitory processes in ADHD-combined and control children

This study compares behavioral and electrophysiological (P300) responses recorded in a cued continuous performance task (CPT-AX) performed by children with attention deficit hyperactivity disorder-combined subtype (ADHD-com) and age-matched healthy controls. P300 cognitive-evoked potentials and behavioral data were recorded in eight children with ADHD (without comorbidity) and nine control children aged 8–12xa0years while performing a CPT-AX task. Such task enables to examine several kinds of false alarms and three different kinds of P300 responses: the “Cue P300”, the “Go P300” and the “NoGo P300”, respectively, associated with preparatory processing/attentional orienting, motor/response execution and motor/response inhibition. Whereas hit rates were about 95xa0% in each group, ADHD children made significantly more false alarm responses (inattention- and inhibition-related) than control children. ADHD children had a marginally smaller Cue P300 than the control children. Behavioral and electrophysiological findings both highlighted inhibition and attention deficits in ADHD-com children in the CPT-AX task. A rarely studied kind of false alarm, the “Other” FA, seems to be a sensitive FA to take into account, even if its interpretation remains unclear.

Hyperactivity in motor response inhibition networks in unmedicated children with attention deficit hyperactivity disorder.

Abstract Objectives: Hypo/reduced activity in motor response inhibition (RI) cerebral networks was recently proposed as a promising specific neurobiological marker of attention deficit-hyperactivity disorder (ADHD). Before adopting such a pattern as a key diagnosis tool, we aim to replicate in an independent study the mechanisms underlying reduced RI-related activity in ADHD, after controlling for potentially confounding effects. Methods: In this fMRI study, we investigated the neural networks mediating successful and failed motor RI in children with ADHD and typically developing children (TDC) using the stop-signal task (SST) paradigm. Results: In contrast to hypofrontality predictions, children with ADHD exhibit increased neural activity during successful response inhibition in an RI-related brain network encompassing the indirect and/or hyperdirect pathways between the basal ganglia and cortex. Voxel-based morphometry analyses have further evidenced reduced grey matter volume in the left caudate in children with ADHD, which paralleled higher functional responses. Finally, connectivity analyses disclosed tighter coupling between a set of cortical regions and the right caudate as well as the right IFG, networks involved in successful RI. Conclusions: Hypo/reduced activity in RI cerebral networks in children with ADHD cannot at this time be considered as a systematic biomarker for ADHD.

Attentional control of emotional interference in children with ADHD and typically developing children: An emotional N-back study

Emotional interference control refers to the ability to remain focused on goal-oriented processes when confronted with disrupting but irrelevant emotional stimuli, a process that may be impaired in children and adults with attention deficit/hyperactivity disorder (ADHD). However, emotional interference levels are known to be associated with trait anxiety, and patients with ADHD often display elevated levels of trait anxiety, such as these may have confounded previous findings of decreased emotional interference control in this population. In the present study, male and female 8-13 years old (mean =11.0 years) children with ADHD (n=33) and typically developing (TD) children (n=24) performed a visual emotional working memory (n-back) task with 2 memory loads and three different background pictures (neutral/positive/negative), and trait anxiety measures were obtained. Children with ADHD performed less well, and displayed increased emotional interference in the presence of aversive distractors when compared with TD children. Contrary to our expectations, trait anxiety did not mediate the association between diagnostic group membership and the degree of emotional interference control; however, co-morbid ODD was associated with decreased levels of emotional interference in ADHD. Future research should aim at characterizing the mechanisms subtending decreased emotional interference control in the ADHD population.