Letter Reversals, Default Mode, and Childhood ADHD.

Objective: To investigate the relationship of static reversals, handedness and gender to reaction time variability (RTV) in a sequentional sample of 1,109 children referred to a child psychiatry clinic for investigation of possible ADHD. Method: A DSM-III ADHD diagnosis and ADHD severity ratings (mild, moderate, and severe) by the present investigator was recorded. The age at which the children were still manifesting static reversals as reported by their mother, and right, left, or both-handedness as reported by the mother and observed by the investigator, were noted. Results: The age that letter reversals were still manifested was significantly associated with RTV for male and female children. Conclusions: The findings may represent an early manifestation of a failure of suppression of visually symmetrical information and/or a failure of default mode suppression.

White matter hyperintensities in young individuals with bipolar disorder or at high genetic risk.

BACKGROUND: Increased white matter hyperintensities (WMHs) is one of the most consistent imaging findings amongst participants with bipolar disorder (BD). This study investigated WMHs in a young population at high genetic risk for bipolar disorder (HR). METHODS: MRI scans were conducted at baseline in HR individuals (n = 131), patients with BD (n = 47) and controls (CON) (n = 108). Most of the HR (n = 77) and CON (n = 74) group completed scans after two years. Scans were examined for the presence of WMHs. RESULTS: There were significantly more periventricular WMHs in the BD compared to the CON group at baseline (p = .04). Although the prevalence of periventricular WMHs was intermediate in the HR group, there were no significant differences between the HR and CON or BD participants. Deep WMHs did not differ significantly between the groups. Over time, there was a significant increase in the prevalence of periventricular WMHs in both the HR and CON groups (p = .02). LIMITATIONS: The use of a visual rating scale to examine WMHs is subjective. As the gradings were collapsed into 'present' or 'absent', we could not ascertain whether the severity of hyperintensities worsened over time. CONCLUSIONS: Periventricular WMHs are more prevalent in young individuals with BD than controls. As these are not more prevalent in HR individuals, it is possible that these are either secondary to the development of bipolar disorder, its treatment, or resulting changes in lifestyle. In a novel finding, there were similar increases in the prevalence of WMHs in controls and HR youth over the 2-year period.

Continuous performance task in ADHD: Is reaction time variability a key measure?

OBJECTIVE: To compare the use of the Continuous Performance Task (CPT) reaction time variability (intraindividual variability or standard deviation of reaction time), as a measure of vigilance in attention-deficit hyperactivity disorder (ADHD), and stimulant medication response, utilizing a simple CPT X-task vs an A-X-task. METHOD: Comparative analyses of two separate X-task vs A-X-task data sets, and subgroup analyses of performance on and off medication were conducted. RESULTS: The CPT X-task reaction time variability had a direct relationship to ADHD clinician severity ratings, unlike the CPT A-X-task. Variability in X-task performance was reduced by medication compared with the children's unmedicated performance, but this effect did not reach significance. When the coefficient of variation was applied, severity measures and medication response were significant for the X-task, but not for the A-X-task. CONCLUSION: The CPT-X-task is a useful clinical screening test for ADHD and medication response. In particular, reaction time variability is related to default mode interference. The A-X-task is less useful in this regard.

Standardised assessment of functioning in ADHD: consensus on the ICF Core Sets for ADHD.

Attention-deficit/hyperactivity disorder (ADHD) is associated with significant impairments in social, educational, and occupational functioning, as well as specific strengths. Currently, there is no internationally accepted standard to assess the functioning of individuals with ADHD. WHO's International Classification of Functioning, Disability and Health-child and youth version (ICF) can serve as a conceptual basis for such a standard. The objective of this study is to develop a comprehensive, a common brief, and three age-appropriate brief ICF Core Sets for ADHD. Using a standardised methodology, four international preparatory studies generated 132 second-level ICF candidate categories that served as the basis for developing ADHD Core Sets. Using these categories and following an iterative consensus process, 20 ADHD experts from nine professional disciplines and representing all six WHO regions selected the most relevant categories to constitute the ADHD Core Sets. The consensus process resulted in 72 second-level ICF categories forming the comprehensive ICF Core Set-these represented 8 body functions, 35 activities and participation, and 29 environmental categories. A Common Brief Core Set that included 38 categories was also defined. Age-specific brief Core Sets included a 47 category preschool version for 0-5 years old, a 55 category school-age version for 6-16 years old, and a 52 category version for older adolescents and adults 17 years old and above. The ICF Core Sets for ADHD mark a milestone toward an internationally standardised functional assessment of ADHD across the lifespan, and across educational, administrative, clinical, and research settings.

Clinical predictors of conversion to bipolar disorder in a prospective longitudinal familial high-risk sample: focus on depressive features.

BACKGROUND: Identifying clinical features that predict conversion to bipolar disorder (BD) in those at high familial risk (HR) would assist in identifying a more focused population for early intervention. METHOD: In total 287 participants aged 12-30 (163 HR with a first-degree relative with BD and 124 controls (CONs)) were followed annually for a median of 5 years. We used the baseline presence of DSM-IV depressive, anxiety, behavioural and substance use disorders, as well as a constellation of specific depressive symptoms (as identified by the Probabilistic Approach to Bipolar Depression) to predict the subsequent development of hypo/manic episodes. RESULTS: At baseline, HR participants were significantly more likely to report ⩾4 Probabilistic features (40.4%) when depressed than CONs (6.7%; p < .05). Nineteen HR subjects later developed either threshold (n = 8; 4.9%) or subthreshold (n = 11; 6.7%) hypo/mania. The presence of ⩾4 Probabilistic features was associated with a seven-fold increase in the risk of 'conversion' to threshold BD (hazard ratio = 6.9, p < .05) above and beyond the fourteen-fold increase in risk related to major depressive episodes (MDEs) per se (hazard ratio = 13.9, p < .05). Individual depressive features predicting conversion were psychomotor retardation and ⩾5 MDEs. Behavioural disorders only predicted conversion to subthreshold BD (hazard ratio = 5.23, p < .01), while anxiety and substance disorders did not predict either threshold or subthreshold hypo/mania. CONCLUSIONS: This study suggests that specific depressive characteristics substantially increase the risk of young people at familial risk of BD going on to develop future hypo/manic episodes and may identify a more targeted HR population for the development of early intervention programs.

Deformability- and size-based microcapsule sorting.

Biomedical applications often require to sort cells according to their physical properties, such as size, density or deformability. In recent years, microfluidics has provided a variety of tools to sort micro-objects. We present here a simple microfluidic device consisting of a channel containing a semi-cylindrical obstacle against which capsules are squeezed by the flow, followed by a diverging chamber where streamlines separate. We demonstrate that this basic system is capable of sorting elastic microcapsules according to their size at low flow strength, and according to the stiffness of their membrane at high flow strength. Contrary to most existing sorting devices, we show that the present one is very sensitive and capable of discriminating between capsules with differences in membrane elasticity of order unity.

First-Dose Methylphenidate-Induced Changes in Brain Functional Connectivity Are Correlated With 3-Month Attention-Deficit/Hyperactivity Disorder Symptom Response.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) symptoms are most commonly treated with stimulant medication such as methylphenidate (MPH); however, approximately 25% of patients show little or no symptomatic response. We examined the extent to which initial changes in brain functional connectivity (FC) associated with the first MPH dose in boys newly diagnosed with ADHD predict MPH-associated changes in ADHD inattentiveness and hyperactivity symptoms at 3 months. METHODS: Brain FC was estimated using steady-state visual evoked potential partial coherence before and 90 minutes after the administration of the first MPH dose to 40 stimulant drug-naïve boys newly diagnosed with ADHD while they performed the AX version of the continuous performance task. The change in parent-rated inattention and hyperactivity scores over the first 3 months of MPH medication was correlated with the initial 90-minute MPH-mediated FC changes. RESULTS: Hyperactivity improvements at 3 months were associated with first-dose MPH-mediated FC reductions restricted to frontal-prefrontal sites following the appearance of the "A" and at frontal and right temporal sites during the appearance of the "X." Corresponding 3-month inattention score improvement was associated with initial MPH-mediated FC reductions restricted to occipitoparietal sites following the appearance of the "A." CONCLUSIONS: These findings are discussed in the context of MPH effects on the default mode network and the possible role of the default mode network in MPH-mediated improvements in inattention and hyperactivity symptom scores.

Influence of chemically modified alginate esters on the preparation of microparticles by transacylation with protein in W/O emulsions.

Microencapsulation using the transacylation reaction in a W/O emulsion is based on the creation of amide bonds between the protein's amine functions and the ester groups of a polysaccharide in the aqueous phase after alkalization. Commercial propylene glycol alginate (PGA) has been the only modified polysaccharide involved in the process up to now. In the present work, we describe the effect of substituting the commercial PGA by other chemically modified alginates in the formation of microparticles. Alkyl and hydroxyalkyl alginate esters, were synthesized and tested in the encapsulation process with human serum albumin (HSA). It was found that the hydroxyalkyl alginates were suitable polysaccharide substitutes for PGA in the transacylation reaction, whereas the alkyl alginates did not lead to microparticle formation in the same process. Hydroxyalkyl alginates with high esterification degree (DE) (>50) led to microparticles when involved in the preparation procedure. However with lower DE (<30), no microparticles could be obtained from 2% ester solution concentrations. This difference in reactivity was explained by the formation of hydrophobic microdomains with the alkyl esters that hindered the transacylation reaction, as opposed to hydroxyalkyl esters that bore hydrophilic ester groups.

Functional Dysconnection of the Inferior Frontal Gyrus in Young People With Bipolar Disorder or at Genetic High Risk.

BACKGROUND: Bipolar disorder (BD) is characterized by a dysregulation of affect and impaired integration of emotion with cognition. These traits are also expressed in probands at high genetic risk of BD. The inferior frontal gyrus (IFG) is a key cortical hub in the circuits of emotion and cognitive control, and it has been frequently associated with BD. Here, we studied resting-state functional connectivity of the left IFG in participants with BD and in those at increased genetic risk. METHODS: Using resting-state functional magnetic resonance imaging we compared 49 young BD participants, 71 individuals with at least one first-degree relative with BD (at-risk), and 80 control subjects. We performed between-group analyses of the functional connectivity of the left IFG and used graph theory to study its local functional network topology. We also used machine learning to study classification based solely on the functional connectivity of the IFG. RESULTS: In BD, the left IFG was functionally dysconnected from a network of regions, including bilateral insulae, ventrolateral prefrontal gyri, superior temporal gyri, and the putamen (p < .001). A small network incorporating neighboring insular regions and the anterior cingulate cortex showed weaker functional connectivity in at-risk than control participants (p < .006). These constellations of regions overlapped with frontolimbic regions that a machine learning classifier selected as predicting group membership with an accuracy significantly greater than chance. CONCLUSIONS: Functional dysconnectivity of the IFG from regions involved in emotional regulation may represent a trait abnormality for BD and could potentially aid clinical diagnosis.

Disruptive mood dysregulation disorder, severe mood dysregulation and chronic irritability in youth at high familial risk of bipolar disorder.

OBJECTIVE: Disruptive mood dysregulation disorder is a newly proposed childhood disorder included in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition to describe children ⩽18 years of age with chronic irritability/temper outbursts. This study aimed to examine the prevalence of disruptive mood dysregulation disorder, severe mood dysregulation and chronic irritability in an Australian study of young people at increased familial risk of developing bipolar disorder ('HR' group) and controls ('CON' group). METHODS: A total of 242 12- to 30-year-old HR or CON subjects were administered the severe mood dysregulation module. Of these, 42 were aged ⩽18 years at the time of assessment, with 29 subjects in the HR group and 13 in the CON group. RESULTS: No subjects ⩽18 years - in either group - fulfilled current or lifetime criteria for disruptive mood dysregulation disorder or severe mood dysregulation, the precursor to disruptive mood dysregulation disorder. Similarly, no subjects in either group endorsed the severe mood dysregulation/disruptive mood dysregulation disorder criteria for irritable mood or marked excessive reactivity. One HR participant endorsed three severe mood dysregulation criteria (distractibility, physical restlessness and intrusiveness), while none of the comparison subjects endorsed any criteria. Exploratory studies of the broader 12- to 30-year-old sample similarly found no subjects with severe mood dysregulation/disruptive mood dysregulation disorder in either the HR or CON group and no increased rates of chronic irritability, although significantly more HR subjects reported at least one severe mood dysregulation/disruptive mood dysregulation disorder criterion (likelihood ratio = 6.17; p = 0.013); most of the reported criteria were severe mood dysregulation 'chronic hyper-arousal' symptoms. CONCLUSION: This study comprises one of the few non-US reports on the prevalence of disruptive mood dysregulation disorder and severe mood dysregulation and is the first non-US study of the prevalence of these conditions in a high-risk bipolar disorder sample. The failure to replicate the finding of higher rates of disruptive mood dysregulation disorder and chronic irritability in high-risk offspring suggests that these are not robust precursors of bipolar disorder.

Dopaminergic modulation of default mode network brain functional connectivity in attention deficit hyperactivity disorder.

INTRODUCTION: Recent evidence suggests that attention deficit hyperactivity disorder (ADHD) is associated with a range of brain functional connectivity abnormalities, with one of the most prominent being reduced inhibition of the default mode network (DMN) while performing a cognitive task. In this study, we examine the effects of a methylphenidate dose on brain functional connectivity in boys diagnosed with ADHD while they performed a cognitive task. METHOD: Brain functional connectivity was estimated using steady-state visual evoked potential partial coherence before and 90 min after the administration of a methylphenidate dose to 42 stimulant drug-naïve boys newly diagnosed with ADHD while they performed the A-X version of the continuous performance task (CPT A-X). RESULTS: Methylphenidate robustly reversed the transient functional connectivity increase in the A-X interval seen premedication to a postmedication decrease during this interval. In addition, methylphenidate-induced reductions in individual reaction time were correlated with corresponding reductions in functional connectivity. CONCLUSION: These findings suggest that methylphenidate suppresses the increased functional connectivity observed in ADHD and that such suppression is associated with improved performance. Our findings support the suggestion that the increased functional connectivity we have observed in ADHD is associated with abnormal DMN activity. In addition, we comment on the significance of specific frequency channels mediating top-down communication within the cortex and the extent to which our findings are selectively sensitive to top-down intracortical communication.

Brain functional connectivity abnormalities in attention-deficit hyperactivity disorder.

INTRODUCTION: Recent evidence suggests that attention-deficit hyperactivity disorder (ADHD) is associated with brain functional connectivity (FC) abnormalities. METHODS: In this study, we use steady-state visually evoked potential event-related partial coherence as a measure of brain FC to examine functional connectivity differences between a typically developing (TD) group of 25 boys and an age/IQ-matched group of 42 drug naive boys newly diagnosed with ADHD (ADHD group). Functional connectivity was estimated while both groups performed a low-demand reference task and the A-X version of the continuous performance task (CPT A-X). RESULTS: While the TD and ADHD groups exhibited similar prefrontal FC increases prior to the appearance of the target in the reference task, these groups demonstrated significant FC differences in the interval preceding the appearance of the target in the CPT A-X task. Specifically, the ADHD group exhibited robust prefrontal and parieto-frontal FC increases that were not apparent in the TD group. CONCLUSION: The FC differences observed in the ADHD group are discussed in the context of inadequate suppression of cortical networks that may interfere with task performance.

Selective Stimulation of Cardiac Lymphangiogenesis Reduces Myocardial Edema and Fibrosis Leading to Improved Cardiac Function Following Myocardial Infarction.

BACKGROUND: The lymphatic system regulates interstitial tissue fluid balance, and lymphatic malfunction causes edema. The heart has an extensive lymphatic network displaying a dynamic range of lymph flow in physiology. Myocardial edema occurs in many cardiovascular diseases, eg, myocardial infarction (MI) and chronic heart failure, suggesting that cardiac lymphatic transport may be insufficient in pathology. Here, we investigate in rats the impact of MI and subsequent chronic heart failure on the cardiac lymphatic network. Further, we evaluate for the first time the functional effects of selective therapeutic stimulation of cardiac lymphangiogenesis post-MI. METHODS AND RESULTS: We investigated cardiac lymphatic structure and function in rats with MI induced by either temporary occlusion (n=160) or permanent ligation (n=100) of the left coronary artery. Although MI induced robust, intramyocardial capillary lymphangiogenesis, adverse remodeling of epicardial precollector and collector lymphatics occurred, leading to reduced cardiac lymphatic transport capacity. Consequently, myocardial edema persisted for several months post-MI, extending from the infarct to noninfarcted myocardium. Intramyocardial-targeted delivery of the vascular endothelial growth factor receptor 3-selective designer protein VEGF-CC152S, using albumin-alginate microparticles, accelerated cardiac lymphangiogenesis in a dose-dependent manner and limited precollector remodeling post-MI. As a result, myocardial fluid balance was improved, and cardiac inflammation, fibrosis, and dysfunction were attenuated. CONCLUSIONS: We show that, despite the endogenous cardiac lymphangiogenic response post-MI, the remodeling and dysfunction of collecting ducts contribute to the development of chronic myocardial edema and inflammation-aggravating cardiac fibrosis and dysfunction. Moreover, our data reveal that therapeutic lymphangiogenesis may be a promising new approach for the treatment of cardiovascular diseases.

Towards an ICF core set for ADHD: a worldwide expert survey on ability and disability.

This is the second in a series of four empirical studies designed to develop International Classification of Functioning, Disability and Health (ICF and Children and Youth version, ICF-CY) core sets for attention deficit hyperactivity disorder (ADHD). The objective of this stage was to gather the opinions from international experts on which ability and disability concepts were considered relevant to functioning in ADHD. An email-based survey was carried out amongst international experts in ADHD. Relevant functional ability and disability concepts were extracted from their responses and linked to the ICF/-CY categories by two independent researchers using a standardised linking procedure. 174 experts from 11 different disciplines and 45 different countries completed the survey. Meaningful concepts identified in their responses were linked to 185 ICF/-CY categories. Of these, 83 categories were identified by at least 5 % of the experts and considered the most relevant to ADHD: 30 of these were related to Body functions (most identified: attention functions, 85 %), 30 to Activities and Participation (most identified: school education, 52 %), 20 to Environmental factors (most identified: support from immediate family, 61 %), and 3 to Body structures (most identified: structure of brain, 83 %). Experts also provided their views on particular abilities related to ADHD, naming characteristics such as high-energy levels, flexibility and resiliency. Gender differences in the expression of ADHD identified by experts pertained mainly to females showing more internalising (e.g. anxiety, low self-esteem) and less externalising behaviours (e.g. hyperactivity), leading to a risk of late- and under-diagnosis in females. Results indicate that the impact of ADHD extends beyond the core symptom domains, into all areas of life and across the lifespan. The current study in combination with three additional preparatory studies (comprehensive scoping review, focus groups, clinical study) will provide the scientific basis to define the ADHD ICF/-CY core sets for multi-purpose use in basic and applied research and every day clinical practice.