Spindle chirp and other sleep oscillatory features in young children with autism.

OBJECTIVES: To determine whether spindle chirp and other sleep oscillatory features differ in young children with and without autism. METHODS: Automated processing software was used to re-assess an extant set of polysomnograms representing 121 children (91 with autism [ASD], 30 typically-developing [TD]), with an age range of 1.35-8.23 years. Spindle metrics, including chirp, and slow oscillation (SO) characteristics were compared between groups. SO and fast and slow spindle (FS, SS) interactions were also investigated. Secondary analyses were performed assessing behavioural data associations, as well as exploratory cohort comparisons to children with non-autism developmental delay (DD). RESULTS: Posterior FS and SS chirp was significantly more negative in ASD than TD. Both groups had comparable intra-spindle frequency range and variance. Frontal and central SO amplitude were decreased in ASD. In contrast to previous manual findings, no differences were detected in other spindle or SO metrics. The ASD group displayed a higher parietal coupling angle. No differences were observed in phase-frequency coupling. The DD group demonstrated lower FS chirp and higher coupling angle than TD. Parietal SS chirp was positively associated with full developmental quotient. CONCLUSIONS: For the first time spindle chirp was investigated in autism and was found to be significantly more negative than in TD in this large cohort of young children. This finding strengthens previous reports of spindle and SO abnormalities in ASD. Further investigation of spindle chirp in healthy and clinical populations across development will help elucidate the significance of this difference and better understand this novel metric.

Brain proton MR spectroscopy measurements in CLN3 disease.

BACKGROUND: CLN3 is an autosomal recessive lysosomal disorder with intracellular accumulation of ceroid-lipofuscins. CLN3 classically has onset around 4-6 years of age involving vision loss, followed by developmental regression and seizures. Symptoms are progressive and result in premature death. Because treatments are under development, here we explore magnetic resonance spectroscopy (MRS) measurements of metabolite levels in the brain as a potential objective outcome measures. METHODS: Individuals with genetically confirmed CLN3 were enrolled from October 2017-November 2021 in a prospective natural history study (NCT033007304). Baseline concentrations of brain metabolites measured by MRS were compared to concurrently collected dimensional assessment measures: Vineland-3 Adaptive Behavior Composite (ABC) score, verbal intelligence quotient (VIQ), and the Physical, Capability with actual vision, and Clinical global impression of change sub-domains of the Unified Batten Disease Rating Scale (UBDRS). RESULTS: 27 participants with typical CLN3 presentation (15F:12M; ages 6.0-20.7 years) completed MRS, ABC, and UBDRS; 20 (12F:8M; ages 6.5-20.7 years) also completed the VIQ assessment. N-acetyl aspartate [B(95% CI) = -0.61(-0.78;-0.45)] and glutamine/glutamate/GABA [B(95% CI) = -0.82(-1.04;-0.6)] in the parietal gray matter (PGM) decreased across the ages. The strongest correlations between MRS metabolite measurements and the clinical severity assessments were found with N-acetyl aspartate [VIQ (ρ = 0.58), Vineland-3 ABC (ρ = 0.59), UBDRS |ρ| range = (0.57;0.7)] and glutamine/glutamate/GABA [VIQ (ρ = 0.57), Vineland-3 ABC (ρ = 0.60), UBDRS |ρ| range = (0.59;0.77)] measured in the midline PGM. These correlations were accounted for when age was considered. CONCLUSIONS: Based on their correlations to established assessments, NAA and glutamine/glutamate/GABA measured in the midline parietal gray matter may be useful indicators of CLN3 disease state. In a clinical trial, divergence of the MRS measurements and clinical severity markers from age may be useful as surrogate measures for treatment responses.

Use of the Vineland-3, a measure of adaptive functioning, in CLN3.

Progressive vision loss and neurocognitive impairment are early and frequent presentations in CLN3 disease. This highlights neurodevelopmental functioning as critical to the disease, but limits the neuropsychological test repertoire. We evaluated the convergent validity of the Vineland Adaptive Behavior Scales as a potential outcome measure. In a prospective observational study of 22 individuals (female:male 11:11; 6-20 years-old) with a molecular diagnosis of CLN3, we used generalized linear models and Spearman correlations to quantify the relationship of the adaptive behavior composite (ABC) standard score with established outcomes of verbal IQ (VIQ) and disease severity (Unified Batten Disease Rating Scale, UBDRS) scores. We analyzed ABC changes in 1-year follow-up data in a subset of the same cohort (n = 17). The ABC and VIQ, both standard scores, exhibited a strong positive correlation in cross-sectional data (r = 0.81). ABC and UBDRS scores were strongly and positively correlated in cross-sectional data (rrange  = 0.87-0.93). Participants' ABC scores decreased slightly over the 1-year follow-up period (mean change, 95% CI: -5.23, -2.16). The convergent validity of the Vineland-3 for use in CLN3 is supported by its relationships with the established outcomes of VIQ and UBDRS. Future longitudinal research, including replication in other cohorts and evaluation of sensitivity to change, will be important to establish utility of the Vineland-3 for monitoring change in CLN3.

The contribution of platelets to peripheral BDNF elevation in children with autism spectrum disorder.

Brain-derived neurotrophic factor (BDNF), a key peptide in neurocognitive development, has been reported to be elevated in the serum of children with autism spectrum disorder (ASD). In a few studies, however, no differences or the converse have been documented. As a secondary analysis of a natural history study, we examined differences in ELISA serum BDNF between a group of children aged 1 to 9 years (69% white) with ASD (n = 94) and those with typical development (n = 52) or non-ASD developmental delay (n = 21), while accounting for the potential confounding effects of platelet quantity. Platelet counts were measured within 4 h of blood draw using an automated cell counter. Taqman single nucleotide polymorphism (SNP) assays were used to genotype 11 SNPs within the BDNF locus. Unadjusted mean BDNF concentration was higher in children with ASD than in children with typical development (standardized mean difference = 0.23; 95% CI 0.07, 0.38), but not children with non-ASD developmental delay. The magnitude of this difference was reduced after adjusting for platelet count (standardized mean difference = 0.18; 95% CI 0.02, 0.33). Although some BDNF SNPs were related to BDNF concentration, the distributions of these genotypes did not differ across diagnostic groups. This study replicates previous work suggesting that average serum BDNF concentration is higher in ASD compared to typical development, and extends that work by highlighting the potentially confounding role of platelet counts. The etiology of platelet count differences warrants further elucidation. Nonetheless, our results suggest that elevation in BDNF may be partially explained by higher platelet counts in children with ASD, an association that should be considered in future analysis and interpretation.Registration: NCT00298246.

Neurofilament light chain levels correlate with clinical measures in CLN3 disease.

PURPOSE: CLN3 disease is a neurodegenerative disorder with onset in childhood. It affects multiple functions at different developmental stages. Incomplete understanding of the pathophysiology hampers identification of cell and tissue biochemical compounds reflective of the disease process. As treatment approaches are being explored, more sensitive, objective, quantifiable, and clinically relevant biomarkers are needed. METHODS: We collected prospective biosamples from 21 phenotyped individuals with CLN3. We measured neurofilament light chain (NEFL) levels, a marker of neuronal damage, in cross-sectional CSF and serum samples from individuals with CLN3 and in pediatric non-CLN3 controls using two different assays. RESULTS: Cerebrospinal fluid (CSF) and serum NEFL levels are significantly higher in CLN3 (CSF: 2096 ± 1202; serum: 29.0 ± 18.0 pg/mL) versus similarly aged non-CLN3 (CSF: 345 ± 610; serum: 6.7 ± 3.2 pg/mL) samples. NEFL levels correlate with Unified Batten Disease Rating Scale and adaptive behavior composite scores, and magnetic resonance (MR) spectroscopy markers. NEFL levels from CSF and serum are strongly correlated (rp = 0.83; p < 0.0001). CONCLUSION: CSF and serum NEFL levels increase in multiple neurologic conditions. Here, we show that CSF and serum NEFL levels also increase in CLN3 (versus non-CLN3) and correlate with other disease-relevant measures. These findings suggest NEFL as a relevant and feasible biomarker for applications in CLN3 clinical trials and management.

Functional genomics analysis of Phelan-McDermid syndrome 22q13 region during human neurodevelopment.

Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by varying degrees of intellectual disability, severely delayed language development and specific facial features, and is caused by a deletion within chromosome 22q13.3. SHANK3, which is located at the terminal end of this region, has been repeatedly implicated in other neurodevelopmental disorders and deletion of this gene specifically is thought to cause much of the neurologic symptoms characteristic of PMS. However, it is still unclear to what extent SHANK3 deletions contribute to the PMS phenotype, and what other genes nearby are causal to the neurologic disease. In an effort to better understand the functional landscape of the PMS region during normal neurodevelopment, we assessed RNA-sequencing (RNA-seq) expression data collected from post-mortem brain tissue from developmentally normal subjects over the course of prenatal to adolescent age and analyzed expression changes of 65 genes on 22q13. We found that the majority of genes within this region were expressed in the brain, with ATNX10, MLC1, MAPK8IP2, and SULT4A1 having the highest overall expression. Analysis of the temporal profiles of the highest expressed genes revealed a trend towards peak expression during the early post-natal period, followed by a drop in expression later in development. Spatial analysis revealed significant region specific differences in the expression of SHANK3, MAPK8IP2, and SULT4A1. Region specific expression over time revealed a consistently unique gene expression profile within the cerebellum, providing evidence for a distinct developmental program within this region. Exon-specific expression of SHANK3 showed higher expression within exons contributing to known brain specific functional isoforms. Overall, we provide an updated roadmap of the PMS region, implicating several genes and time periods as important during neurodevelopment, with the hope that this information can help us better understand the phenotypic heterogeneity of PMS.

Haploinsufficiency of the brain-derived neurotrophic factor gene is associated with reduced pain sensitivity.

Rare pain-insensitive individuals offer unique insights into how pain circuits function and have led to the development of new strategies for pain control. We investigated pain sensitivity in humans with WAGR (Wilms tumor, aniridia, genitourinary anomaly, and range of intellectual disabilities) syndrome, who have variably sized heterozygous deletion of the 11p13 region. The deletion region can be inclusive or exclusive of the brain-derived neurotrophic factor (BDNF) gene, a crucial trophic factor for nociceptive afferents. Nociceptive responses assessed by quantitative sensory testing demonstrated reduced pain sensitivity only in the WAGR subjects whose deletion boundaries included the BDNF gene. Corresponding behavioral assessments were made in heterozygous Bdnf knockout rats to examine the specific role of Bdnf. These analogous experiments revealed impairment of Aδ- and C-fiber-mediated heat nociception, determined by acute nociceptive thermal stimuli, and in aversive behaviors evoked when the rats were placed on a hot plate. Similar results were obtained for C-fiber-mediated cold responses and cold avoidance on a cold-plate device. Together, these results suggested a blunted responsiveness to aversive stimuli. Our parallel observations in humans and rats show that hemizygous deletion of the BDNF gene reduces pain sensitivity and establishes BDNF as a determinant of nociceptive sensitivity.

Functional brain connectivity in electrical status epilepticus in sleep.

Electrical status epilepticus in sleep (ESES) is an age-related, self-limited epileptic encephalopathy. The syndrome is characterized by cognitive and behavioral abnormalities and a specific EEG pattern of continuous spikes and waves during slow-wave sleep. While spikes and sharp waves are known to result in transient cognitive impairment during learning and memory tasks performed during the waking state, the effect of epileptiform discharges during sleep on cognition and behavior is unclear. There is increasing evidence that abnormalities of coherence, a measure of the consistency of the phase difference between two EEG signals when compared over time, is an important feature of brain oscillations and plays a role in cognition and behavior. The objective of this study was to determine whether coherence of EEG activity is altered during slow-wave sleep in children with ESES when compared to typically developing children. We examined coherence during epochs of ESES versus epochs when ESES was not present. In addition, we compared coherence during slow-wave sleep between typically developing children and children with ESES. ESES was associated with remarkably high coherences at all bandwidths and most electrode pairs. While the high coherence was largely attributed to the spikes and spike-and-wave discharge, activity between spikes and spike-and-wave discharge also demonstrated high coherence. This study indicates that EEG coherence during ESES is relatively high. Whether these increases in coherence correlate with the cognitive and behavioral abnormalities seen in children with this EEG pattern remains to be determined.

Spindle activity in young children with autism, developmental delay, or typical development.

OBJECTIVE: To determine whether spindle activity differs in young children with and without autism. METHODS: We investigated differences in spindle density, duration, and oscillatory features in 135 young children with autism, developmental delay without autism (DD), or typical development (TD) and secondarily assessed the dimensional relationship between spindle density and both cognitive ability and social functioning. RESULTS: Compared to TD, both spindle density (Cohen d 0.93, 95% confidence interval [CI] 0.49-1.37) and duration (Cohen d 0.58, 95% CI 0.15-1.01) were significantly decreased in autism. Spindle density was also significantly reduced in autism compared to DD (Cohen d 0.61, 95% CI 0.13-1.09). Decreased spindle frequency in autism compared to both TD (Cohen d 0.47, 95% CI 0.04-0.90) and DD (Cohen d 0.58, 95% CI 0.10-1.06) did not survive correction. The DD group did not differ significantly from the TD group on any spindle parameter. These results, suggesting a relationship between spindle density and autism but not DD, were further illustrated in exploratory analyses, wherein nonverbal ratio IQ (RIQ) and the Vineland Socialization domain standard score were strongly correlated with spindle density in the full sample (r = 0.33, p ≤ 001 and r = 0.41, p ≤ 001, respectively) but not within group. After nonverbal RIQ was accounted for, the relationship between spindle density and Vineland Socialization remained statistically significant (r = 0.23, p < 0.01). However, Vineland Socialization scores accounted for the relationship between spindle density and nonverbal RIQ (r = 0.04, p = 0.67). CONCLUSION: In a large cohort of young children with autism, spindle density was reduced compared to groups of age-matched children with DD or TD. Alterations in the maturational trajectory of spindles may provide valuable insight into the neurophysiologic differences related to behavior in disorders of neurodevelopment.

Depressive symptoms in young, urban schoolchildren: environmental, social, and cognitive risk.

This study examined relations among stressors, perceived social competence, attributional style, and depressive symptoms in young urban schoolchildren. Data were collected from 85 5- to 11-year-olds, mostly African American, who attended a public elementary school in a low-income urban area. Social competence was examined as a potential mediator, and attributional style was examined as a potential moderator of the relation between stressful life events and depressive symptoms. Separate analyses were conducted by age and gender. For older children and girls, main effects were found for stressful life events as predictors of depressive symptoms. Mediational analyses indicated that perceived peer acceptance served as a mediator of the relation between stressful life events and depressive symptoms for girls. In addition, attributional style moderated the relation between stressors and depressive symptoms in the older children. Together, findings suggest that significant relations exist among stressful life events, social and cognitive processes, and depressive symptoms in young urban children and that these relations are influenced by gender and development.

Treating the whole person with autism: the proceedings of the Autism Speaks National Autism Conference.

The identification of autism spectrum disorders has increased dramatically over the past decade, with the latest estimates indicating prevalence as high as 1 in 54 boys. There is greater awareness of medical conditions that co-occur with autism and expansion of treatment options. Closer scrutiny has led to refinement of the diagnostic criteria, and there have been advances in genetics examining potential causal factors. Transition to adulthood is an area of growing concern, and professionals and families require guidance on this issue. This article summarizes the proceedings of the Autism Speaks conference on Treating the Whole Person with Autism: Care across the Lifespan. The conference was organized with the intent of providing a forum for both families and professionals to learn about the most current research in the field. Dr. Sue Swedo provides important background information regarding the changes in the diagnostic criteria for autism spectrum disorders. She particularly deals with the concerns of individuals and families that their autism diagnosis may change. Recommendations for genetic testing and its interpretation are provided by Dr. David Miller. His discussion helps make sense of the utility of genetic testing for ASD, along with demonstration of the complexity of determining which genetic factors are doing what and through which pathways. Dr. Jeremy Veenstra-VanderWeele provides useful background information on how medicines are initially identified and for what purpose and goes on to describe the present and future treatments in pharmacology. Medical issues are addressed by Dr. Paul Carbone, especially the coordination of comprehensive services through the medical home model of care. Dr. Julie Lounds Taylor concludes with guidance on preparation for adulthood, a topic of great importance to families as their child matures and for the professionals who will help guide this transition.

A magnetization transfer imaging study of corpus callosum myelination in young children with autism.

BACKGROUND: Several lines of evidence suggest that autism may be associated with abnormalities in white matter development. However, inconsistencies remain in the literature regarding the nature and extent of these abnormalities, partly because of the limited types of measurements that have been used. Here, we used magnetization transfer imaging to provide insight into the myelination of the corpus callosum in children with autism. METHODS: Magnetization transfer imaging scans were obtained in 101 children with autism and 35 typically developing children who did not significantly differ with regard to gender or age. The midsagittal area of the corpus callosum was manually traced and the magnetization transfer ratio (MTR) was calculated for each voxel within the corpus callosum. Mean MTR and height and location of the MTR histogram peak were analyzed. RESULTS: Mean MTR and MTR histogram peak height and location were significantly higher in children with autism than in typically developing children, suggesting abnormal myelination of the corpus callosum in autism. CONCLUSIONS: The differences in callosal myelination suggested by these results may reflect an alteration in the normally well-regulated process of myelination of the brain, with broad implications for neuropathology, diagnosis, and treatment of autism.

Observations on intelligence and behavior in 15 patients with Legius syndrome.

Legius syndrome is a RAS-MAPK syndrome characterized by pigmentary findings similar to neurofibromatosis type 1 (NF1), but without tumor complications. Learning difficulties and behavioral problems have been reported to be associated with Legius syndrome, but have not been studied systematically. We investigated intelligence and behavior in 15 patients with Legius syndrome and 7 unaffected family members. We report a mean full-scale IQ of 101.57 in patients with Legius syndrome, which does not differ from the control group. We find a significantly lower Performance IQ in children with Legius syndrome compared to their unaffected family members. Few behavioral problems are present as assessed by the Child Behavior Checklist (CBCL) questionnaire. Our observations suggest that, akin to the milder somatic phenotype, the cognitive phenotype in Legius syndrome is less severe than that of NF1.

Risks of propofol sedation/anesthesia for imaging studies in pediatric research: eight years of experience in a clinical research center.

OBJECTIVES: To quantify the incidence of adverse events associated with anesthesia given for research-driven imaging studies and to identify risk factors for those events in pediatric research subjects. DESIGN: Retrospective cohort study. SETTING: National Institutes of Health Clinical Center. PARTICIPANTS: Children and adolescents enrolled in clinical research protocols who required anesthesia for research-related imaging studies from January 2000 to September 2008. INTERVENTION: Propofol sedation/anesthesia. MAIN OUTCOME MEASURE: The occurrence of respiratory, cardiovascular, and all anesthesia-related adverse events that required intervention while receiving anesthetics for research-driven imaging studies and other noninvasive procedures. RESULTS: We identified 607 children who received 1480 propofol anesthetic procedures for imaging studies. Seventy percent of anesthetics were given to subjects with severe diseases and significant disabilities (American Society of Anesthesiologists Physical Status [ASA] III). Anesthesia had a mean (SD) duration of 115 (55) minutes, and in 12.5% of procedures, an airway device was necessary. There were 98 notable respiratory, cardiovascular, and other events in 79 anesthetic procedures, a rate of 534 per 10 000 anesthetic procedures with 1 or more adverse events. There was no long-lasting morbidity or mortality. The ASA classification (odds ratio [OR], 2.92; 95% confidence interval [CI], 1.24-6.88), anesthetic effect duration (OR, 1.46; 95% CI, 1.25-1.70), and presence of airway abnormalities (OR, 4.41; 95% CI, 1.60-12.12) were independently associated with adverse events during anesthetic use. CONCLUSION: In our clinical research sample of high-risk children who received sedation/anesthesia by an anesthesiologist, we observed a low incidence of adverse events and no long-term complications. Risk factors for adverse events included higher ASA classification, increasing anesthetic duration, and presence of airway abnormalities.

Executive and attention functioning among children in the PANDAS subgroup.

Evidence from past studies indicates that adults and children with Obsessive-Compulsive Disorder (OCD) and Tourette syndrome (TS) experience subtle neuropsychological deficits. Less is known about neuropsychological functioning of children and adolescents with a symptom course consistent with the PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection) subgroup of OCD and tics. To provide such information, we administered three tests of attention control and two of executive function to 67 children and adolescents (ages 5-16) diagnosed with OCD and/or tics and a symptom course consistent with the PANDAS subgroup and 98 healthy volunteers (HV) matched by age, sex, and IQ. In a paired comparison of the two groups, the PANDAS subjects were less accurate than HV in a test of response suppression. Further, in a two-step linear regression analysis of the PANDAS group in which clinical variables were added stepwise into the model and in the second step matching variables (age, sex, and IQ) were added, IQ emerged as a predictor of performance on this task. In the same analysis, ADHD diagnosis and age emerged as predictors of response time in a continuous performance task. Subdividing the PANDAS group by primary psychiatric diagnosis revealed that subjects with TS or OCD with tics exhibited a longer response time compared to controls than subjects with OCD only, replicating previous findings within TS and OCD. This study demonstrates that children with PANDAS exhibit neuropsychological profiles similar to those of their primary psychiatric diagnosis.

Depressive symptoms among reservation-based pregnant American Indian adolescents.

OBJECTIVES: To examine rates and correlates of depressive symptoms among pregnant reservation-based American Indian (AI) adolescents from the Southwestern United States (N = 53). METHODS: Data were derived from a study evaluating a home-visiting program designed to promote positive parenting among young families. Participants included a volunteer, convenience sample of expectant mothers who completed behavioral and mental health self-report questionnaires. Depressive symptoms were assessed using the Center for Epidemiological Studies-Depression scale (CES-D). Three risk domains were analyzed in relation to depressive symptoms: sociodemographics, family relations, and psychosocial functioning. RESULTS: Forty-seven percent of expectant mothers scored at or above the widely accepted clinical cutoff score of 16 on the CES-D; 30% scored at or above 20, a score more likely to reflect elevated depressive symptoms among adolescents; and almost 20% scored at or above 28 (one standard deviation above the mean), a score suggestive of clinical depression. Higher levels of depressive symptoms were associated with less use of public assistance, external locus of control, less social support, and lower self-esteem. CONCLUSIONS: Data suggest that a large proportion of pregnant AI adolescents reported elevated depressive symptoms, though rates are similar to non-pregnant AI adolescent samples.

Gender differences in early risk factors for adolescent depression among low-income urban children.

One component of a model by Nolen-Hoeksema and Girgus, who propose that risk factors for adolescent depression are more common in girls than in boys during childhood, was tested with 85 low-income, urban, African American and Latino kindergarten through fourth grade children who completed inventories of depression, stress, attributional style, gender role, and body image. Endorsing two of three predicted risk factors, girls reported slightly poorer body image and identified more strongly with a feminine gender role. Boys, however, reported a more negative attributional style. Feminine gender role was not associated with body image or negative attributional style. The applicability of the proposed model to a low-income, ethnic minority, urban population is discussed.

Stressors and child and adolescent psychopathology: evidence of moderating and mediating effects.

This paper reviews studies that have tested for moderators or mediators of the relation between stressors and child and adolescent psychopathology. Many studies have tested for moderation, but results of research studying moderators have been inconclusive. There have been few theory-based studies and there have been few consistent findings. Far fewer studies have tested for mediation effects, but these studies have generally been theory-driven, have more often built upon one another in an incremental fashion, and have yielded consistent results. In particular, there is substantial evidence for the mediating role of family relationship in the relation between stressors and child and adolescent psychological symptoms. Future studies should integrate moderator and mediator research by testing for specific mediators in relation to particular moderating contexts, so that we can better understand the complex ways in which stressful life experiences affect the well-being of children and adolescents.

Stressors and child and adolescent psychopathology: measurement issues and prospective effects.

This article reviews existing research on the association between stressors and symptoms of psychopathology in children and adolescents with a focus on measurement issues and prospective effects. The first half of the article focuses on the measurement of stressors, emphasizing checklists and interviews. Available measures of stressful experiences are reviewed and critiqued. Results of this review reveal both substantial progress (i.e., development of valid stressor assessment tools) and remaining problems (i.e., inconsistent measurement across studies). The second half of this article reviews studies that have tested for prospective associations between stressors and symptoms of psychopathology in children and adolescents. Studies that have examined the prospective effects of recent or prior stressors on current psychological symptoms, while controlling for prior psychological symptoms, are reviewed. Results overall suggest that stressors predict changes in rates of symptoms of psychopathology in children and adolescents over time. Results also suggest that symptoms of psychopathology predict changes in rates of stressors over time. Implications of these findings are that conclusive evidence now exists for the importance of stressors in the development of child and adolescent psychopathology.

Stressors and child and adolescent psychopathology: moving from markers to mechanisms of risk.

In the first half of this review, the authors critically evaluate existing research on the association between stressors and symptoms of psychopathology in children and adolescents. This analysis reveals (a) problems with conceptualizations of stress, (b) variability in measurement of stressors, and (c) lack of theory-driven research. To address these problems, the authors propose a general conceptual model of the relation between stressors and child and adolescent psychopathology. The authors examine basic tenets of this general model in the second half of this article by testing a specific model in which negative parenting mediates the relation between economic stressors and psychological symptoms in young people. Results generally provide support for the specific model as well as for the broader model.