Bright light therapy and early morning attention, mathematical performance, electroencephalography and brain connectivity in adolescents with morning sleepiness.

Adolescents typically sleep too little and feel drowsy during morning classes. We assessed whether morning use of an LED bright light device could increase alertness in school students. Twenty-six (8M/18F) healthy, unmedicated participants, ages 13-18 years, (mean 17.1±1.4) were recruited following screenings to exclude psychopathology. Baseline assessments were made of actigraph-assessed sleep, attention, math solving ability, electroencephalography and structural and functional MRI (N = 10-11, pre-post). Participants nonrandomly received 3-4 weeks of bright light therapy (BLT) for 30 minutes each morning and used blue light blocking glasses for 2 hours before bedtime. BLT devices were modified to surreptitiously record degree of use so that the hypothesis tested was whether there was a significant relationship between degree of use and outcome. They were used 57±18% (range 23%-90%) of recommended time. There was a significant association between degree of use and: (1) increased beta spectral power in frontal EEG leads (primary measure); (2) greater post-test improvement in math performance and reduction in errors of omission on attention test; (3) reduced day-to-day variability in bed times, sleep onset, and sleep duration during school days; (4) increased dentate gyrus volume and (5) enhanced frontal connectivity with temporal, occipital and cerebellar regions during Go/No-Go task performance. BLT was associated with improvement in sleep cycle consistency, arousal, attention and functional connectivity, but not sleep onset or duration (primary measures). Although this was an open study, it suggests that use of bright morning light and blue light blocking glasses before bed may benefit adolescents experiencing daytime sleepiness. Clinical trial registration: Clinicaltrials.gov ID-NCT05383690.

Open assessment of the therapeutic and rate-dependent effects of brain balance center® and interactive metronome® exercises on children with attention deficit hyperactivity disorder.

The aim of this open study was to delineate domains of benefit and effect size measures to design an appropriately powered randomized control trial to assess the efficacy of Brain Balance@ exercises and Interactive Metronome@ training (BB/IM) on ADHD symptoms in children. Participants underwent an extensive 15-week, 5 time per week, at-home training program. Results were assessed in 16 youths with ADHD (14M/2F, 10.8±1.7 years) who completed the program and compared to 8 typically developing controls (4M/F4, 11.0±1.8 years). BB/IM was associated with a significant reduction of 8.3 and 8.2 points on the Conner's Parent Rating Scale - Revised and the ADHD Rating Scale - IV. BB/IM was not associated with improvement on the Quotient ADHD System but with rate-dependent effects on hyperactivity and attention that were similar to previously reported effects of low dose methylphenidate. Both therapeutic and rate-dependent effects were observed on the Tower of London. The study provides information that could be used to design a randomized control trial, which is required for proof of efficacy. A key limitation is that 59% of the 39 enrolled participants with ADHD dropped out of the study and a new study should include multiple ratings during the course of treatment.

Sex and sensitive period differences in potential effects of maltreatment on axial versus radial diffusivity in the corpus callosum.

Corpus callosum (CC) abnormalities have been observed in several psychiatric disorders. Maltreatment has also been associated with marked differences in CC anatomy and microstructure, though rarely controlled for in psychiatric neuroimaging studies. The aim of this study was to identify type and timing of maltreatment associated with alterations in CC microstructure and to ascertain if they differ by sex. T1 and diffusion-weighted MRIs were obtained from 345 (135 M/210 F) healthy 18-25-year-olds. The Maltreatment and Abuse Chronology of Exposure scale provided retrospective data on exposure to ten types of maltreatment across each year of childhood. AI predictive analytics were used to identify the most significant type and time risk factors. The most striking maltreatment-associated alterations in males were in axial diffusivity and were most specifically associated with exposure to emotional abuse or neglect during segment-specific sensitive periods. In contrast, maltreatment was associated with marked alteration in radial diffusivity and fractional anisotropy in females and was most specifically associated with early physical neglect during one common sensitive period involving all segments except the splenium. Overall sex differences, controlling for maltreatment, brain size, and sociodemographic factors were limited to the genu with greater fractional anisotropy in males and radial diffusivity in females. These findings suggest that maltreatment may target myelinization in females and axonal development in males and that these sex differences need to be taken into account in studies seeking to delineate the contribution of CC abnormalities and interhemispheric communication to psychiatric disorders.

Susceptibility or Resilience to Maltreatment Can Be Explained by Specific Differences in Brain Network Architecture.

BACKGROUND: Childhood maltreatment is a major risk factor for psychopathology. However, some maltreated individuals appear remarkably resilient to the psychiatric effects while manifesting the same array of brain abnormalities as maltreated individuals with psychopathology. Hence, a critical aim is to identify compensatory brain alterations that enable resilient individuals to maintain mental well-being despite alterations in stress-susceptible regions. METHODS: Network models were constructed from diffusion tensor imaging and tractography in physically healthy unmedicated 18- to 25-year-old participants (N = 342, n = 192 maltreated) to develop network-based explanatory models. RESULTS: First, we determined that susceptible and resilient individuals had the same alterations in global fiber stream network architecture using two different definitions of resilience: 1) no lifetime history of Axis I or II disorders, and 2) no clinically significant symptoms of anxiety, depression, anger-hostility, or somatization. Second, we confirmed an a priori hypothesis that right amygdala nodal efficiency was lower in asymptomatic resilient than in susceptible participants or control subjects. Third, we identified eight other nodes with reduced nodal efficiency in resilient individuals and showed that nodal efficiency moderated the relationship between maltreatment and psychopathology. Fourth, we found that models based on global network architecture and nodal efficiency could delineate group membership (control, susceptible, resilient) with 75%, 82%, and 80% cross-validated accuracy. CONCLUSIONS: Together these findings suggest that sparse fiber networks with increased small-worldness following maltreatment render individuals vulnerable to psychopathology if abnormalities occur in specific nodes, but that decreased ability of certain nodes to propagate information throughout the network mitigates the effects and leads to resilience.

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

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.

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

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.

Actigraph measures discriminate pediatric bipolar disorder from attention-deficit/hyperactivity disorder and typically developing controls.

BACKGROUND: Distinguishing pediatric bipolar disorder (BD) from attention-deficit hyperactivity disorder (ADHD) can be challenging. Hyperactivity is a core feature of both disorders, but severely disturbed sleep and circadian dysregulation are more characteristic of BD, at least in adults. We tested the hypothesis that objective measures of activity, sleep, and circadian rhythms would help differentiate pediatric subjects with BD from ADHD and typically developing controls. METHODS: Unmedicated youths (N = 155, 97 males, age 5-18) were diagnosed using DSM-IV criteria with Kiddie-SADS PL/E. BD youths (n = 48) were compared to typically developing controls (n = 42) and children with ADHD (n = 44) or ADHD plus comorbid depressive disorders (n = 21). Three-to-five days of minute-to-minute belt-worn actigraph data (Ambulatory Monitoring Inc.), collected during the school week, were processed to yield 28 metrics per subject, and assessed for group differences with analysis of covariance. Cross-validated machine learning algorithms were used to determine the predictive accuracy of a four-parameter model, with measures reflecting sleep, hyperactivity, and circadian dysregulation, plus Indic's bipolar vulnerability index (VI). RESULTS: There were prominent group differences in several activity measures, notably mean 5 lowest hours of activity, skewness of diurnal activity, relative circadian amplitude, and VI. A predictive support vector machine model discriminated bipolar from non-bipolar with mean accuracy of 83.1 ± 5.4%, ROC area of 0.781 ± 0.071, kappa of 0.587 ± 0.136, specificity of 91.7 ± 5.3%, and sensitivity of 64.4 ± 13.6%. CONCLUSIONS: Objective measures of sleep, circadian rhythmicity, and hyperactivity were abnormal in BD. Wearable sensor technology may provide bio-behavioral markers that can help differentiate children with BD from ADHD and healthy controls.

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: t 9 = 16.39, p < 10(-7); females t 9 = 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.

Hurtful words: association of exposure to peer verbal abuse with elevated psychiatric symptom scores and corpus callosum abnormalities.

OBJECTIVE: Previous studies have shown that exposure to parental verbal abuse in childhood is associated with higher rates of adult psychopathology and alterations in brain structure. In this study the authors sought to examine the symptomatic and neuroanatomic effects, in young adulthood, of exposure to peer verbal abuse during childhood. METHOD: A total of 848 young adults (ages 18-25 years) with no history of exposure to domestic violence, sexual abuse, or parental physical abuse rated their childhood exposure to parental and peer verbal abuse and completed a self-report packet that included the Kellner Symptom Questionnaire, the Limbic Symptom Checklist-33, and the Dissociative Experiences Scale. Diffusion tensor images were collected for a subset of 63 young adults with no history of abuse or exposure to parental verbal abuse selected for varying degrees of exposure to peer verbal abuse. Images were analyzed using tract-based spatial statistics. RESULTS: Analysis of covariance revealed dose-dependent effects of peer verbal abuse on anxiety, depression, anger-hostility, dissociation, "limbic irritability," and drug use. Peer and parental verbal abuse were essentially equivalent in effect size on these ratings. Path analysis indicated that peer verbal abuse during the middle school years had the most significant effect on symptom scores. Degree of exposure to peer verbal abuse correlated with increased mean and radial diffusivity and decreased fractional anisotropy in the corpus callosum and the corona radiata. CONCLUSIONS: These findings parallel results of previous reports of psychopathology associated with childhood exposure to parental verbal abuse and support the hypothesis that exposure to peer verbal abuse is an aversive stimulus associated with greater symptom ratings and meaningful alterations in brain structure.

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.

Methylphenidate blood levels and therapeutic response in children with attention-deficit hyperactivity disorder: I. Effects of different dosing regimens.

BACKGROUND AND PURPOSE: Methylphenidate (MPH) is a drug of choice for treating attention-deficit/hyperactivity disorder (ADHD), although its use has been complicated by its short duration of action. The development of ideal long-acting preparations requires detailed understanding of the pharmacokinetic and pharmacodynamic consequences of complex dosing regimens. The purpose of this study was to ascertain if administration paradigms that produce stable or rising MPH levels alter the rate with which MPH is absorbed, and to determine how effectively long-acting administration paradigms compare with thrice daily administration of immediate-release MPH. METHOD: Forty-eight boys diagnosed with ADHD (mean age 10.6 +/- 1.1 year) participated in this double-blind, parallel group study to evaluate the pharmacokinetics and efficacy and of 1 mg/kg/day MPH administered in five different paradigms and placebo. Objective measures of activity and attention (McLean Motion Attention Test; M-MAT) and plasma measures of d- and l-MPH were obtained hourly during the course of a 12-hour laboratory session. RESULTS: The rate of absorption and elimination of d-MPH was dependent on the pattern of administration, particularly on the initial bolus concentration. This suggests that d-MPH may act on the gastrointestinal system to slow absorption of additional d-MPH. There were significant differences among regimens on time course and degree of therapeutic response. Pulsatile administration produced greater improvement than escalating levels.

Sticks, stones, and hurtful words: relative effects of various forms of childhood maltreatment.

OBJECTIVE: Childhood maltreatment is an important psychiatric risk factor. Research has focused primarily on the effects of physical abuse, sexual abuse, or witnessing domestic violence. Parental verbal aggression has received little attention as a specific form of abuse. This study was designed to delineate the impact of parental verbal aggression, witnessing domestic violence, physical abuse, and sexual abuse, by themselves and in combination, on psychiatric symptoms. METHOD: Symptoms and exposure ratings were collected from 554 subjects 18-22 years of age (68% female) who responded to advertisements. The Verbal Abuse Questionnaire was used to assess exposure to parental verbal aggression. Outcome measures included dissociation and symptoms of "limbic irritability," depression, anxiety, and anger-hostility. Comparisons were made by using effect sizes. RESULTS: Verbal aggression was associated with moderate to large effects, comparable to those associated with witnessing domestic violence or nonfamilial sexual abuse and larger than those associated with familial physical abuse. Exposure to multiple forms of maltreatment had an effect size that was often greater than the component sum. Combined exposure to verbal abuse and witnessing domestic violence had a greater negative effect on some measures than exposure to familial sexual abuse. CONCLUSIONS: Parental verbal aggression was a potent form of maltreatment. Exposure to multiple forms of abuse was associated with very large effect sizes. Most maltreated children had been exposed to multiple types of abuse, and the number of different types is a critically important factor.

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.