Cynthia E. McGreenery

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.

Novel Strategy for the Analysis of CPT Data Provides New Insight into the Effects of Methylphenidate on Attentional States in Children with ADHD

Continuous performance tasks (CPTs) provide a method for studying some components of attention, but do not take into account that attention fluctuates from moment to moment. To address this issue, CPT performance was classified into one of four states (on-task, impulsive, distracted, or randomly responding) every 30 seconds, based on commission and omission error rates. We evaluated this method on 60 boys (10.6 +/- 1.1 years) with attention-deficit hyperactivity disorder (ADHD)-Combined subtype, tested before and after a dose of methylphenidate (MPH, 0.4 mg/kg), and 8 unmedicated healthy control boys (11.3 +/- 2.0 years of age). Healthy controls were on-task during 82.4% of the 30-second epochs, and made an average of 5.4 attention shifts. In contrast, children with ADHD were only on-task during 42.6% of the epochs (p = 0.0006), and they made an average of 12.8 attention shifts (p = 0.00004). These state measures provided more robust indicators of the difference between children with ADHD and controls than did traditional CPT measures of error rates, latency, and variability. The new state measures were also more significantly affected by MPH. MPH produced a 77% increase in the percent of time children with ADHD spent on-task (p < 10(12)). Conversely, MPH reduced time spent in the distracted, impulsive, and random response states by 79%, 44.5%, and 69.2%, respectively (all p values < 0.0002). Unlike errors of omission and commission, which are highly correlated (r = 0.722, n = 60, p < 10(-11)), the percent of epochs spent in impulsive, distracted, and random response states were uncorrelated, and loaded onto discrete independent factors on principal component analysis. The level of activity during the CPT correlated with the degree of distraction, but not with the degree of impulsivity. Children with ADHD could be subtyped according to the nature of their attention performance problems, and these subtypes differed in levels of hyperactivity and degrees of response to MPH.

Utility of Objective Measures of Activity and Attention in the Assessment of Therapeutic Response to Stimulants in Children with Attention-Deficit/Hyperactivity Disorder

BACKGROUND AND PURPOSE Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent disorder that can respond dramatically to medication, if dose is appropriately titrated. Studies suggest that computer measures of attention cannot be used for titration as they show improvement on doses too low to produce clinical benefits. We assessed whether measures of motor activity and attention using the McLean Motion Attention Test (M-MAT) could identify doses associated with optimal clinical response. METHODS Eleven boys (9.6 +/- 1.8 years), receiving treatment with methylphenidate, and meeting DSM-IV criteria for ADHD, participated in this triple-blind (parent, child, rater), within-subject, efficacy study. Subjects received 1 week each of placebo, low (0.4 mg/kg), medium (0.8 mg/kg), and high (1.5 mg/kg) daily doses of methylphenidate. Parents rated response using an index of clinical global improvement. RESULTS In 9/11 subjects, the dose that produced the best improvement on M-MAT measures was also the dose that produced the best clinical outcome (p < 10(5)). Parents rated response to this dose significantly better than response to previously prescribed treatment. Objective measures of primarily activity and secondarily attention responded to treatment in a manner concordant with clinical ratings, suggesting that these measures have ecological validity, and the potential to facilitate medication management and titration.

Circadian rest-activity disturbances in children with seasonal affective disorder.

OBJECTIVE Seasonal affective disorder (SAD) affects from 1.7% to 5.5% of children. Previous studies found that nonseasonally depressed children had a blunted circadian rhythm, while adults with SAD had a delayed and poorly entrained rhythm. The purpose of this study was to determine whether pediatric SAD more closely resembles nonseasonal pediatric depression or adult SAD. METHOD Twelve normal, healthy volunteers (11.6 +/- 3.7 years; 6 female, 6 male) and 14 unmedicated children with SAD (11.0 +/- 3.3 years; 9 female, 5 male) meeting Rosenthal/NIMH criteria for SAD and Schedule for Affective Disorders and Schizophrenia for School-Age Children-Epidemiologic version criteria for major depression had their levels of activity recorded for 72 hours (weekdays) using belt-worn actigraphs. RESULTS The SAD group had blunted circadian amplitudes that were 10% lower than normal (p = .004). They were more poorly modeled by the standard cosinor equation (p = .001), and a circadian rhythm accounted for 39% less of the variability in their activity profile (p = .007). The amplitude of the 12-hour harmonic rhythm was markedly increased. There were no differences between SAD and control children in the timing of the circadian rhythm and degree of entrainment. CONCLUSIONS Children with SAD displayed dysregulated circadian activity rhythms comparable with those reported in nonseasonally depressed children, yet different from those observed in adults.

Differential effects of childhood neglect and abuse during sensitive exposure periods on male and female hippocampus

ABSTRACT The hippocampus is a highly stress susceptible structure and hippocampal abnormalities have been reported in a host of psychiatric disorders including major depression and post‐traumatic stress disorder (PTSD). The hippocampus appears to be particularly susceptible to early life stress with a graded reduction in volume based on number of types (multiplicity) or severity of maltreatment. We assessed whether the most important predictors of adult hippocampal volume were multiplicity, severity or duration of exposure or timing of maltreatment during developmental sensitive periods. 3T MRIs were collected on 336 unmedicated, right‐handed subjects (132M/204F, 18–25 years). Exposure to broad categories of abuse and neglect during each year of childhood were assessed using the Maltreatment and Abuse Chronology of Exposure scale and evaluated using artificial intelligence and predictive analytics. Male hippocampal volume was predicted by neglect, but not abuse, up through 7 years of age. Female hippocampal volume was predicted by abuse, but not neglect, at 10, 11, 15 and 16 years. Exposure at peak age had greater predictive importance than multiplicity, severity or duration. There were also marked gender differences in subfields and portions (head, body or tail) affected by exposure. History and symptoms of major depression, PTSD or anxiety disorders were not predictive of hippocampal volume once maltreatment was accounted for. Neglect appears to foster inadequate hippocampal development in males while abuse appears to produce a stress‐related deficit in females. Studies assessing hippocampal volume in psychiatric disorders need to control for the gender‐specific effects of abuse and neglect. HighlightsHippocampal volume in males was predicted by neglect during first seven years.Hippocampal volume in females was predicted by abuse, particular at ages 10 and 11.Neglect at peak age correlated most strongly with volume of the CA1 in males.Abuse at peak age correlated most strongly with volume of CA3 in females.Abuse had greater effects on shape of female hippocampal head and tail than body.

Childhood maltreatment is associated with alteration in global network fiber-tract architecture independent of history of depression and anxiety

Abstract Childhood maltreatment is a major risk factor for psychopathology. It is also associated with alterations in the network architecture of the brain, which we hypothesized may play a significant role in the development of psychopathology. In this study, we analyzed the global network architecture of physically healthy unmedicated 18–25 year old subjects (n=262) using diffusion tensor imaging (DTI) MRI and tractography. Anatomical networks were constructed from fiber streams interconnecting 90 cortical or subcortical regions for subjects with no‐to‐low (n=122) versus moderate‐to‐high (n=140) exposure to maltreatment. Graph theory analysis revealed lower degree, strength, global efficiency, and maximum Laplacian spectra, higher pathlength, small‐worldness and Laplacian skewness, and less deviation from artificial networks in subjects with moderate‐to‐high exposure to maltreatment. On balance, local clustering was similar in both groups, but the different clusters were more strongly interconnected in the no‐to‐low exposure group. History of major depression, anxiety and attention deficit hyperactivity disorder did not have a significant impact on global network measures over and above the effect of maltreatment. Maltreatment is an important factor that needs to be taken into account in studies examining the relationship between network differences and psychopathology. HighlightsChildhood maltreatment was associated with global network architecture abnormalitiesAbnormalities included increased small‐worldness and decreased degree and efficiencyMood, anxiety and ADHD didn’t account for network differences related to maltreatmentFiber stream numbers were reduced bilaterally especially frontal to basal ganglia