981-52 Six-minute Walk Compared to Peak and Low-level Aerobic Capacity in 302 Patients with Heart Failure

Distances walked spontaneously during 6 min may reflect peak exerc capacity, the ability to sustain 6 min of low exercise without anaerobic metabolism, and non-metabolic factors such as stride. To determine how well 6-min walks in 302 heart failure patients reflected aerobic capacity at peak exercise (pkVO2) and/or R (VCO2/VO2) after 6min of low-level exercise similar to walking, 6-min walks were measured within 48 hrs of bicycle exercise with gas exchange during 6min 20-watt riding and then during incremental exercise.Although 6 min walk correlated with extremes of pkVO2, it varied widely (r=0.25) when pkVO2 was 10–20ml/kg/min (generally Class II-III). Although 6 min 20W ride required VO2 9 ±2ml/kg/min, similar to 3 METS estimated for walking, 6-min 20W R did not correlate well inversely with 6 min walk distance except at very short and long walks.In moderate heart failure, 6 min walk reflects factors other than aerobic capacity at peak or during 6 min of sustained low-level exercise

Offspring At High And Low Risk For Depression And Anxiety: Mechanisms Of Psychiatric Disorder

Objectives: To examine the effect of parental psychiatric diagnosis on the risk of psychiatric disorder in their offspring and to determine mediators and independent predictors of psychiatric disorder in offspring. Method: The sample consisted of 145 offspring (between the ages of 6 and 24 years, who were directly interviewed) of probands with earlyonset (before age 30 years) major depressive disorder (MDD) without panic, panic disorder with and without major depression, and a normal, never psychiatrically ill control group who were part of a large study conducted to determine the relationship between panic disorder and major depression. Results: The risk for offspring MDD was increased by proband recurrent early-onset MDD and coparent alcohol abuse. Chaotic family environment was the only independent predictor of dysthymia. The risk for offspring “any anxiety” disorder was increased by proband recurrent early-onset MDD and coparent impaired functioning. The association between MDD in proband and “panic spectrum” disorder in offspring was accounted for by chaotic family environment. Conclusion: Recurrent parental MDD has consistently been shown to be a strong risk factor for offspring MDD. Family environment plays an important role in low-level anxiety symptoms and dysthymia. Clinicians treating adults should be alert to risk factors for their offspring and to appropriate targets for early intervention. J. Am. Acad. Child Adolesc. Psychiatry, 1995, 34, 6:786-797. Key Words: depression, anxiety, environment, family

Sex-specific Neural Activity When Resolving Cognitive Interference In Individuals With Or Without Prior Internalizing Disorders

The processing of cognitive interference is a self-regulatory capacity that is impaired in persons with internalizing disorders. This investigation was to assess sex differences in the neural correlates of cognitive interference in individuals with and without an illness history of an internalizing disorder. We compared functional magnetic resonance imaging blood-oxygenation-level-dependent responses in both males (n ¼63) and females (n ¼80) with and without this illness history during performance of the Simon task. Females deactivated superior frontal gyrus, inferior parietal lobe, and posterior cingulate cortex to a greater extent than males. Females with a prior history of internalizing disorder also deactivated these regions more compared to males with that history, and they additionally demonstrated greater activation of right inferior frontal gyrus. These group differences were represented in a significant sex-by-illness interaction in these regions. These deactivated regions compose a task-negative or default mode network, whereas the inferior frontal gyrus usually activates when performing an attention-demanding task and is a key component of a task-positive network. Our findings suggest that a prior history of internalizing disorders disproportionately influences functioning of the default mode network and is associated with an accompanying activation of the task-positive network in females during the resolution of cognitive interference

Nineteen novel NPHS1 mutations in a worldwide cohort of patients with congenital nephrotic syndrome (CNS)

Background. Recessive mutations in the NPHS1 gene encoding nephrin account for ∼40% of infants with congenital nephrotic syndrome (CNS). CNS is defined as steroid-resistant nephrotic syndrome (SRNS) within the first 90 days of life. Currently, more than 119 different mutations of NPHS1 have been published affecting most exons. Methods. We here performed mutational analysis of NPHS1 in a worldwide cohort of 67 children from 62 different families with CNS. Results. We found bi-allelic mutations in 36 of the 62 families (58%) confirming in a worldwide cohort that about one-half of CNS is caused by NPHS1 mutations. In 26 families, mutations were homozygous, and in 10, they were compound heterozygous. In an additional nine patients from eight families, only one heterozygous mutation was detected. We detected 37 different mutations. Nineteen of the 37 were novel mutations (∼51.4%), including 11 missense mutations, 4 splice-site mutations, 3 nonsense mutations and 1 small deletion. In an additional patient with later manifestation, we discovered two further novel mutations, including the first one affecting a glycosylation site of nephrin. Conclusions. Our data hereby expand the spectrum of known mutations by 17.6%. Surprisingly, out of the two siblings with the homozygous novel mutation L587R in NPHS1, only one developed nephrotic syndrome before the age of 90 days, while the other one did not manifest until the age of 2 years. Both siblings also unexpectedly experienced an episode of partial remission upon steroid treatmen

Temporal Stability Of Posterior EEG Alpha Over Twelve Years

Objective: We previously identified posterior EEG alpha as a potential biomarker for antidepressant treatment response. To meet the definition of a trait biomarker or endophenotype, it should be independent of the course of depression. Accordingly, this report evaluated the temporal stability of posterior EEG alpha at rest. Methods: Resting EEG was recorded from 70 participants (29 male; 46 adults), during testing sessions separated by 12 ± 1.1 years. EEG alpha was identified, separated and quantified using reference-free methods that combine current source density (CSD) with principal components analysis (PCA). Measures of overall (eyes closed-plus-open) and net (eyes closed-minus-open) posterior alpha amplitude and asymmetry were compared across testing sessions. Results: Overall alpha was stable for the full sample (Spearman-Brown [rSB] = .834, Pearson’s r = .718), and showed excellent reliability for adults (rSB = .918; r = 0.848). Net alpha showed acceptable reliability for adults (rSB = .750; r = .600). Hemispheric asymmetries (right-minus-left hemisphere) of posterior overall alpha showed significant correlations, but revealed acceptable reliability only for adults (rSB = .728; r = .573). Findings were highly comparable between 29 male and 41 female participants. Conclusions: Overall posterior EEG alpha amplitude is reliable over long time intervals in adults. Significance: The temporal stability of posterior EEG alpha oscillations at rest over long time intervals is indicative of an individual trait. Ó 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved

Offspring Of Depressed Parents: 30 Years Later

Objective: While the increased risk of psychopathology in the biological offspring of depressed parents has been widely replicated, the long-term outcome through their full age of risk is less known. The authors present a 30-year follow-up of biological offspring (mean age=47 years) of depressed (high-risk) and nondepressed (low-risk) parents. Method: One hundred forty-seven offspring of moderately to severely depressed or nondepressed parents selected from the same community were followed for up to 30 years. Diagnostic assessments were conducted blind to parents’ clinical status. Final diagnoses were made by a blinded M.D. or Ph.D. evaluator. Results: The risk for major depression was approximately three times as high in the high-risk offspring. The period of highest risk for first onset was between ages 15 and 25 in both groups. Prepubertal onsets were uncommon, but high-risk offspring had over 10-fold increased risk. The early onset of major depression seen in the offspring of depressed parents was not offset by later first onsets in the low-risk group as they matured. The increased rates of major depression in the high-risk group were largely accounted for by the early onsets, but later recurrences in the high-risk group were significantly increased. The high-risk offspring continue to have overall poorer functioning and receive more treatment for emotional problems. There was increased mortality in the high-risk group (5.5% compared with 2.5%) due to unnatural causes, with a nearly 8-year difference in the mean age at death (38.8 years compared with 46.5 years). Conclusions: The offspring of depressed parents remain at high risk for depression, morbidity, and mortality that persists into their middle years. While adolescence is the major period of onset for major depression in both risk groups, it is the offspring with family history who go on to have recurrences and a poor outcome as they mature. In the era of personalized medicine, until a more biologically based understanding of individual risk is found, a simple family history assessment of major depression as part of clinical care can be a predictor of individuals at long-term risk

Neuronal Generator Patterns At Scalp Elicited By Lateralized Aversive Pictures Reveal Consecutive Stages Of Motivated Attention

Event-related potential (ERP) studies have provided evidence for an allocation of attentional resources to enhance perceptual processing of motivationally salient stimuli. Emotional modulation affects several consecutive components associated with stages of affective-cognitive processing, beginning as early as 100–200 ms after stimulus onset. In agreement with the notion that the right parietotemporal region is critically involved during the perception of arousing affective stimuli, some ERP studies have reported asymmetric emotional ERP effects. However, it is difficult to separate emotional from non-emotional effects because differences in stimulus content unrelated to affective salience or task demands may also be associated with lateralized function or promote cognitive processing. Other concerns pertain to the operational definition and statistical independence of ERP component measures, their dependence on an EEG reference, and spatial smearing due to volume conduction, all of which impede the identification of distinct scalp activation patterns associated with affective processing. Building on prior research using a visual half-field paradigm with highly controlled emotional stimuli (pictures of cosmetic surgery patients showing disordered [negative] or healed [neutral] facial areas before or after treatment), 72channel ERPs recorded from 152 individuals (ages 13–68 years; 81 female) were transformed into reference-free current source density (CSD) waveforms and submitted to temporal principal components analysis (PCA) to identify their underlying neuronal generator patterns. Using both nonparametric randomization tests and repeated measures ANOVA, robust effects of emotional content were found over parietooccipital regions for CSD factors corresponding to N2 sink (212 ms peak latency), P3 source (385 ms) and a late centroparietal source (630 ms), all indicative of greater positivity for negative than neutral stimuli. For the N2 sink, emotional effects were right-lateralized and modulated by hemifield, with larger amplitude and asymmetry for left hemifield (right hemisphere) presentations. For all three factors, more positive amplitudes at parietooccipital sites were associated with increased ratings of negative valence and greater arousal. Distributed inverse solutions of the CSDPCA-based emotional effects implicated a sequence of maximal activations in right occipitotemporal cortex, bilateral posterior cingulate cortex, and bilateral inferior temporal cortex. These findings are consistent with hierarchical activations of the ventral visual pathway reflecting subsequent processing stages in response to motivationally salient stimuli

Motivated Attention And Family Risk For Depression: Neuronal Generator Patterns At Scalp Elicited By Lateralized Aversive Pictures Reveal Blunted Emotional Responsivity

Behavioral and electrophysiologic evidence suggests that major depression (MDD) involves right parietotemporal dysfunction, a region activated by arousing affective stimuli. Building on prior event-related potential (ERP) findings (Kayser et al. 2016 NeuroImage 142:337–350), this study examined whether these abnormalities also characterize individuals at clinical high risk for MDD. We systematically explored the impact of family risk status and personal history of depression and anxiety on three distinct stages of emotional processing comprising the late positive potential (LPP). ERPs (72 channels) were recorded from 74 high and 53 low risk individuals (age 13–59 years, 58 male) during a visual half-field paradigm using highly-controlled pictures of cosmetic surgery patients showing disordered (negative) or healed (neutral) facial areas before or after treatment. Reference-free current source density (CSD) transformations of ERP waveforms were quantified by temporal principal components analysis (tPCA). Component scores of prominent CSD-tPCA factors sensitive to emotional content were analyzed via permutation tests and repeated measures ANOVA for mixed factorial designs with unstructured covariance matrix, including gender, age and clinical covariates. Factor-based distributed inverse solutions provided descriptive estimates of emotional brain activations at group level corresponding to hierarchical activations along ventral visual processing stream. Risk status affected emotional responsivity (increased positivity to negative-than-neutral stimuli) overlapping early N2 sink (peak latency 212 ms), P3 source (385 ms), and a late centroparietal source (630 ms). High risk individuals had reduced right-greater-thanleft emotional lateralization involving occipitotemporal cortex (N2 sink) and bilaterally reduced emotional effects involving posterior cingulate (P3 source) and inferior temporal cortex (630 ms) when compared to those at low risk. While the early emotional effects were enhanced for left hemifield (right hemisphere) presentations, hemifield modulations did not differ between risk groups, suggesting top-down rather than bottom-up effects of risk. Groups did not differ in their stimulus valence or arousal ratings. Similar effects were seen for individuals with a lifetime history of depression or anxiety disorder in comparison to those without. However, there was no evidence that risk status and history of MDD or anxiety disorder interacted in their impact on emotional responsivity, suggesting largely independent attenuation of attentional resource allocation to enhance perceptual processing of motivationally salient stimuli. These findings further suggest that a deficit in motivated attention preceding conscious awareness may be a marker of risk for depression

Adult Outcomes Of Childhood Disruptive Disorders In Offspring Of Depressed And Healthy Parents

Background: Longitudinal studies of children with disruptive disorders (DDs) have shown high rates of antisocial personality disorder (ASPD) and substance use in adulthood, but few have examined the contribution of parental disorders. We examine child-/adulthood outcomes of DDs in offspring, whose biological parents did not have a history of ASPD, bipolar disorder, or substance use disorders. Method: Offspring (N = 267) of parents with or without major depression (MDD), but no ASPD or bipolar disorders were followed longitudinally over 33 years, and associations between DDs and psychiatric and functional outcomes were tested. Results: Eighty-nine (33%) offspring had a DD. Those with, compared to without DDs, had higher rates of MDD (adjusted odds ratio, AOR = 3.42, p < 0.0001), bipolar disorder (AOR = 3.10, p = 0.03), and substance use disorders (AOR = 5.69, p < 0.0001) by age 18, as well as poorer school performance and global functioning. DDs continued to predict MDD and substance use outcomes in adulthood, even after accounting for presence of the corresponding disorder in childhood (MDD: hazards ratio, HR = 3.25, p < 0.0001; SUD, HR = 2.52, p < 0.0001). Associations were similar among the offspring of parents with and without major depression. DDs did not predict adulthood ASPD in either group. Limitations: Associations are largely accounted for by conduct disorder (CD), as there were few offspring with ADHD, and oppositional defiant disorder (ODD) was not diagnosed at the time this study began. Conclusion: If there is no familial risk for ASPD, bipolar disorder or substance use, childhood DDs do not lead to ASPD in adulthood; however, the children still have poorer prognosis into midlife. Early treatment of children with DD, particularly CD, while carefully considering familial risk for these disorders, may help mitigate later adversity

A systematic approach to mapping recessive disease genes in individuals from outbred populations

The identification of recessive disease-causing genes by homozygosity mapping is often restricted by lack of suitable consanguineous families. To overcome these limitations, we apply homozygosity mapping to single affected individuals from outbred populations. In 72 individuals of 54 kindred ascertained worldwide with known homozygous mutations in 13 different recessive disease genes, we performed total genome homozygosity mapping using 250,000 SNP arrays. Likelihood ratio Z-scores (ZLR) were plotted across the genome to detect ZLR peaks that reflect segments of homozygosity by descent, which may harbor the mutated gene. In 93% of cases, the causative gene was positioned within a consistent ZLR peak of homozygosity. The number of peaks reflected the degree of inbreeding. We demonstrate that disease-causing homozygous mutations can be detected in single cases from outbred populations within a single ZLR peak of homozygosity as short as 2 Mb, containing an average of only 16 candidate genes. As many specialty clinics have access to cohorts of individuals from outbred populations, and as our approach will result in smaller genetic candidate regions, the new strategy of homozygosity mapping in single outbred individuals will strongly accelerate the discovery of novel recessive disease genes