Hyperactivity persists in male and female adults with ADHD and remains a highly discriminative feature of the disorder: a case-control study

Background: Symptoms of hyperactivity are believed to fade with age leaving ADHD adults mostly inattentive and impulsive. Our aim was to test this assertion using objective measures of hyperactivity, impulsivity and inattention. Method Participants were 40 subjects with ADHD (23M/17F; 35±10 yrs) and 60 healthy adults (28M/32F; 29±9 yrs) blindly assessed using Wender-Reimherr interview ratings, Structured Clinical Interview for DSM-IV Disorders and DSM-IV criteria. Infrared motion capture systems tracked head and leg movements during performance of a No-4’s cognitive control task. Subjects also completed the Conners’ CPT-II. Results: ADHD and controls differed significantly in activity and attention. Effect sizes for activity measures (d’ = 0.7–1.6) were, on average, two-fold larger than differences in attention or impulsivity, correlated more strongly with executive function ratings and were more discriminatory (ROC area = 0.83 for activity composite, 0.65 for No-4’s distraction composite, 0.63 for Conners’ CPT-II confidence index, 0.96 for the combined activity and attention diagnostic index). This finding was true for subjects with the predominantly inattentive subtype as well as subjects with combined or predominantly hyperactive/impulsive subtype. Males and females with ADHD were equally active. The superior accuracy of activity measures was confirmed using Random Forest and predictive modeling techniques. Conclusions: Objectively measured hyperactivity persists in adults with ADHD and is a more discriminative feature of the disorder than computerized measures of inattention or impulsivity. This finding supports the hypothesis that a deficient ability to sit still remains a defining feature of the disorder in adults when it is measured objectively

Bioenergetic Measurements in Children with Bipolar Disorder: A Pilot 31^{31}P Magnetic Resonance Spectroscopy Study

Background: Research exploring Bipolar Disorder (BD) phenotypes and mitochondrial dysfunction, particularly in younger subjects, has been insufficient to date. Previous studies have found abnormal cerebral pH levels in adults with BD, which may be directly linked to abnormal mitochondrial activity. To date no such studies have been reported in children with BD. Methods: Phosphorus Magnetic Resonance Spectroscopy ($^{31}$P MRS) was used to determine pH, phopshocreatine (PCr) and inorganic phosphate (Pi) levels in 8 subjects with BD and 8 healthy comparison subjects (HCS) ages 11 to 20 years old. Results: There was no significant difference in pH between the patients and HCS. However, frontal pH values for patients with BD increased with age, contrary to studies of HCS and the pH values in the frontal lobe correlated negatively with the YMRS values. Global Pi was significantly lower in subjects with BD compared with HCS. There were no significant differences in PCr between the groups. Global PCr-to-Pi ratio (PCr/Pi) was significantly higher in subjects with BD compared with HCS. Conclusions: The change in Pi levels for the patients with BD coupled with the no difference in PCr levels, suggest an altered mitochondrial phosphorylation. However, our findings require further investigation of the underlying mechanisms with the notion that a mitochondrial dysfunction may manifest itself differently in children than that in adults. Limitations: Further investigations with larger patient populations are necessary to draw further conclusions

Childhood Maltreatment, Depression, and Suicidal Ideation: Critical Importance of Parental and Peer Emotional Abuse during Developmental Sensitive Periods in Males and Females

Background: The adverse childhood experience (ACE) study found that risk for depression increased as a function of number of types of childhood maltreatment, and interpret this as a result of cumulative stress. An alternative hypothesis is that risk depends on type and timing of maltreatment. This will also present as a linear increase, since exposure to more types of abuse increases likelihood of experiencing a critical type of abuse at a critical age. Methods: 560 (223M/337F) young adults (18–25 years) were recruited from the community without regard to diagnosis and balanced to have equal exposure to 0–4 plus types of maltreatment. The Maltreatment and Abuse Chronology of Exposure Scale assessed severity of exposure to 10 types of maltreatment across each year of childhood. Major depressive disorder (MDD) and current symptoms were evaluated by SCID, interview, and self-report. Predictive analytics assessed importance of exposure at each age and evaluated whether exposure at one or two ages was a more important predictor than number, severity, or duration of maltreatment across childhood. Results: The most important predictors of lifetime history of MDD were non-verbal emotional abuse in males and peer emotional abuse (EA) in females at 14 years of age, and these were more important predictors across models than number of types of maltreatment (males: t9 = 16.39, p < 10-7; females t9 = 5.78, p < 10-4). Suicidal ideation was predicted, in part, by NVEA and peer EA at age 14, but most importantly by parental verbal abuse at age 5 in males and sexual abuse at age 18 in females. Conclusion: This study provides evidence for sensitive exposure periods when maltreatment maximally impacts risk for depression, and provides an alternative interpretation of the ACE study results. These findings fit with emerging neuroimaging evidence for regional sensitivity periods. The presence of sensitive exposure periods has important implications for prevention, preemption, and treatment of MDD

Resting state brain dynamics: Associations with childhood sexual abuse and major depressive disorder

Early life stress (ELS) and major depressive disorder (MDD) share neural network abnormalities. However, it is unclear how ELS and MDD may separately and/or jointly relate to brain networks, and whether neural differences exist between depressed individuals with vs without ELS. Moreover, prior work evaluated static versus dynamic network properties, a critical gap considering brain networks show changes in coordinated activity over time. Seventy-one unmedicated females with and without childhood sexual abuse (CSA) histories and/or MDD completed a resting state scan and a stress task in which cortisol and affective ratings were collected. Recurring functional network co-activation patterns (CAPs) were examined and time in CAP (number of times each CAP is expressed) and transition frequencies (transitioning between different CAPs) were computed. The effects of MDD and CSA on CAP metrics were examined and CAP metrics were correlated with depression and stress-related variables. Results showed that MDD, but not CSA, related to CAP metrics. Specifically, individuals with MDD (N = 35) relative to HCs (N = 36), spent more time in a posterior default mode (DMN)-frontoparietal network (FPN) CAP and transitioned more frequently between posterior DMN-FPN and prototypical DMN CAPs. Across groups, more time spent in a posterior DMN-FPN CAP and greater DMN-FPN and prototypical DMN CAP transition frequencies were linked to higher rumination. Imbalances between the DMN and the FPN appear central to MDD and might contribute to MDD-related cognitive dysfunction, including rumination. Unexpectedly, CSA did not modulate such dysfunctions, a finding that needs to be replicated by future studies with larger sample sizes. &nbsp;</p

New Clathrin-Based Nanoplatforms for Magnetic Resonance Imaging

Background: Magnetic Resonance Imaging (MRI) has high spatial resolution, but low sensitivity for visualization of molecular targets in the central nervous system (CNS). Our goal was to develop a new MRI method with the potential for non-invasive molecular brain imaging. We herein introduce new bio-nanotechnology approaches for designing CNS contrast media based on the ubiquitous clathrin cell protein. Methodology/Principal Findings: The first approach utilizes three-legged clathrin triskelia modified to carry 81 gadolinium chelates. The second approach uses clathrin cages self-assembled from triskelia and designed to carry 432 gadolinium chelates. Clathrin triskelia and cages were characterized by size, structure, protein concentration, and chelate and gadolinium contents. Relaxivity was evaluated at 0.47 T. A series of studies were conducted to ascertain whether fluorescent-tagged clathrin nanoplatforms could cross the blood brain barriers (BBB) unaided following intranasal, intravenous, and intraperitoneal routes of administration. Clathrin nanoparticles can be constituted as triskelia (18.5 nm in size), and as cages assembled from them (55 nm). The mean chelate: clathrin heavy chain molar ratio was 27.0464.8: 1 fo

Witnessing Violence Toward Siblings: An Understudied but Potent Form of Early Adversity

Research on the consequences of witnessing domestic violence has focused on inter-adult violence and most specifically on violence toward mothers. The potential consequences of witnessing violence to siblings have been almost entirely overlooked. Based on clinical experience we sought to test the hypothesis that witnessing violence toward siblings would be as consequential as witnessing violence toward mothers. The community sample consisted of unmedicated, right-handed, young adults who had siblings (n = 1,412; 62.7% female; 21.8±2.1 years of age). History of witnessing threats or assaults to mothers, fathers and siblings, exposure to parental and sibling verbal abuse and physical abuse, sexual abuse and sociodemographic factors were assessed by self-report. Symptoms of depression, anxiety, somatization, anger-hostility, dissociation and ‘limbic irritability’ were assessed by rating scales. Data were analyzed by multiple regression, with techniques to gauge relative importance; logistic regression to assess adjusted odds ratios for clinically-significant ratings; and random forest regression using conditional trees. Subjects reported witnessing violence to siblings slightly more often than witnessing violence to mothers (22% vs 21%), which overlapped by 51–54%. Witnessing violence toward siblings was associated with significant effects on all ratings. Witnessing violence toward mother was not associated with significant effects on any scale in these models. Measures of the relative importance of witnessing violence to siblings were many fold greater than measures of importance for witnessing violence towards mothers or fathers. Mediation and structural equation models showed that effects of witnessing violence toward mothers or fathers were predominantly indirect and mediated by changes in maternal behavior. The effects of witnessing violence toward siblings were more direct. These findings suggest that greater attention be given to the effects of witnessing aggression toward siblings in studies of domestic violence, abuse and early adversity

Новa нанотехнологијa на бази клатрина за пренос великих протеинских молекула у централни нервни систем

Antibodies (Abs) have great promise for detection and treatment of central nervous system (CNS) disorders. However, the blood-brain barrier (BBB) is a major impediment to effective delivery. Only 0.1% of plasma Abs enter the CNS naturally via diffusion through a compromised BBB or via BBB saturation and CNS concentrations may still be insufficient for therapeutic efficacy. Moreover, Abs may take days to diffuse only a few millimeters and intracellular targets are not easily accessible to Abs. Thus, new, efficient, and noninvasive strategies are required for transporting large molecules like Abs into the CNS and inside targeted cells. Here we tested the hypothesis that clathrin, a coat protein naturally used to transport molecules across biological barriers and within cells, could serve as a nanoplatform for high-efficiency delivery of antibodies and imaging agents to the CNS. Clathrin triskelia (17.7 nm in size) were modified to carry 81 gadolinium chelates or 25 fluorescent tags. Nanoplatforms were characterized by size, structure, protein concentration, chelate and gadolinium contents and nanoparticle relaxivity was evaluated at 0.47 T. Clathrin triskelia exhibited ionic relaxivity of 16 mM-1s-1, and molecular relaxivity of 1166 mM-1s-1. A series of studies were conducted to ascertain whether fluorescent-tagged clathrin nanoplatforms could cross the blood brain barrier. Clathrin nanoplatforms were able to cross or bypass the BBB without enhancements following intraperitoneal and intranasal administration in rats. To demonstrate specific targeting clathrin triskelia were modified with dopamine-3- receptor-antibody (D3R-Ab), as there are no small-molecule ligands that bind exclusively to D3 receptors. One molecule of D3R-Ab was attached per clathrin triskelion and antibody remained intact and immunoreactive after the nanoparticle preparation. Low doses (64 μg/ kg) of nanoparticles (42.3±14.8 nm) were delivered intranasally in rats. Three hours later intact D3R-Ab-triskelia nanoparticles were found in D3R-brain regions inside neurons, with the highest concentration detected in islands of Calleja /ventral pallidum (2753 ng/g or 17.2% ID/g) and nucleus accumbens (1028 ng/g). High nanoprobe concentrations (1062 ng/g) were also found in hippocampal cells that have high concentrations of D3- receptors in the cytoplasm, but low expression of D3-receptors on the cell membrane. Low concentrations were detected in the cerebellum (84 ng/g.) Nanoprobes were not detected in regions lacking D3 receptors. D3R-Abs delivered without clathrin intranasally did not enter the brain..

Witnessing Violence Toward Siblings: An Understudied but Potent Form of Early Adversity

Research on the consequences of witnessing domestic violence has focused on inter-adult violence and most specifically on violence toward mothers. The potential consequences of witnessing violence to siblings have been almost entirely overlooked. Based on clinical experience we sought to test the hypothesis that witnessing violence toward siblings would be as consequential as witnessing violence toward mothers. The community sample consisted of unmedicated, righthanded, young adults who had siblings (n = 1,412; 62.7 % female; 21.862.1 years of age). History of witnessing threats or assaults to mothers, fathers and siblings, exposure to parental and sibling verbal abuse and physical abuse, sexual abuse and sociodemographic factors were assessed by self-report. Symptoms of depression, anxiety, somatization, anger-hostility, dissociation and ‘limbic irritability ’ were assessed by rating scales. Data were analyzed by multiple regression, with techniques to gauge relative importance; logistic regression to assess adjusted odds ratios for clinically-significant ratings; and random forest regression using conditional trees. Subjects reported witnessing violence to siblings slightly more often than witnessing violence to mothers (22 % vs 21%), which overlapped by 51–54%. Witnessing violence toward siblings was associated with significant effects on all ratings. Witnessing violence toward mother was not associated with significant effects on any scale in these models. Measures of the relative importance of witnessing violence to siblings were many fold greater than measures of importance for witnessing violence towards mothers or fathers. Mediation and structural equatio

Beta weights and comparative ratios indicating the role of maternal verbal aggression in mediating the association between symptom ratings and witnessing threats or assaults to mothers.

<p>*p<0.05,</p><p>**p<0.01,</p>¥<p>p<0.001,</p>§<p>p<0.0001,</p>†<p>p<10⁻¹⁰.</p><p>DV – Dependent Variable, IV – Independent Variable, M – Mediator, SOS – Shared over simple effects index.</p

Regression coefficients and 95% confidence intervals for the association between exposure to multiple forms of maltreatment and socioeconomic factors on psychiatric symptom ratings.

<p>*p<0.05,</p><p>**p<0.01,</p>¥<p>p<0.001,</p>§<p>p<0.0001,</p>†<p>p<10⁻¹⁵.</p><p>— Covariates were excluded from the final model if their degree of association with the dependent variable was weak (p>0.2).</p