[show abstract][hide abstract] ABSTRACT: Offspring of depressed parents are at risk for depression and recent evidence suggests that reduced positive affect (PA) may be a marker of risk. We investigated whether self-reports of PA and fMRI-measured striatal response to reward, a neural correlate of PA, are reduced in adolescent youth at high familial risk for depression (HR) relative to youth at low familial risk for depression (LR). Functional magnetic resonance imaging assessments were conducted with 14 HR and 12 LR youth. All youth completed an ecological momentary assessment protocol to measure PA in natural settings and a self-report measure of depression symptomatology. Analyses found that HR youth demonstrated lower striatal response than LR youth during both reward anticipation and outcome. However, after controlling for youth self-reports of depression, HR youth demonstrated lower striatal response than LR youth only during reward anticipation. No significant differences were found between HR and LR youth on subjective ratings of PA or depressive symptoms. Results are consistent with previous findings that reduced reward response is a marker of risk for depression, particularly during reward anticipation, even in the absence of (or accounting for) disrupted subjective mood. Further examinations of prospective associations between reward response and depression onset are needed.
[show abstract][hide abstract] ABSTRACT: Determining the time of peak of cerebral maturation is vital for our understanding of when cerebral maturation ceases and the cerebral degeneration in healthy aging begins. We carefully mapped changes in fractional anisotropy (FA) of water diffusion for eleven major cerebral white matter tracts in a large group (831) of healthy human subjects aged 11-90. FA is a neuroimaging index of micro-structural white matter integrity, sensitive to age-related changes in cerebral myelin levels, measured using diffusion tensor imaging. The average FA values of cerebral white matter (WM) reached peak at the age 32 ± 6 years. FA measurements for all but one major cortical white matter tract (cortico-spinal) reached peaks between 23 and 39 years of age. The maturation rates, prior to age-of-peak were significantly correlated (r=0.74; p=0.01) with the rates of decline, past age-of-peak. Regional analysis of corpus callosum (CC) showed that thinly-myelinated, densely packed fibers in the genu, that connect pre-frontal areas, maturated later and showed higher decline in aging than the more thickly myelinated motor and sensory areas in the body and splenium of CC. Our findings can be summarized as: associative, cerebral WM tracts that reach their peak FA values later in life also show progressively higher age-related decline than earlier maturing motor and sensory tracts. These findings carry multiple and diverse implications for both theoretical studies of the neurobiology of maturation and aging and for the clinical studies of neuropsychiatric disorders.
Neurobiology of aging 01/2012; 33(1):9-20. · 5.94 Impact Factor
[show abstract][hide abstract] ABSTRACT: Multiple genetic and environmental factors influence the risk for both major depression and alcohol/substance use disorders. In addition, there is evidence that these illnesses share genetic factors. Although, the heritability of these illnesses is well established, relatively few studies have focused on ethnic minority populations. Here, we document the prevalence, heritability, and genetic correlations between major depression and alcohol and drug disorders in a large, community-ascertained sample of Mexican-American families. A total of 1,122 Mexican-American individuals from 71 extended pedigrees participated in the study. All subjects received in-person psychiatric interviews. Heritability, genetic, and environmental correlations were estimated using SOLAR. Thirty-five percent of the sample met criteria for DSM-IV lifetime major depression, 34% met lifetime criteria for alcohol use disorders, and 8% met criteria for lifetime drug use disorders. The heritability for major depression was estimated to be h(2) = 0.393 (P = 3.7 × 10(-6)). Heritability estimates were higher for recurrent depression (h(2) = 0.463, P = 4.0 × 10(-6)) and early onset depression (h(2) = 0.485, P = 8.5 × 10(-5)). While the genetic correlation between major depression and alcohol use disorders was significant (ρ(g) = 0.58, P = 7 × 10(-3)), the environmental correlation between these traits was not significant. Although, there is evidence for increased rates of depression and substance use in US-born individuals of Mexican ancestry, our findings indicate that genetic control over major depression and alcohol/substance use disorders in the Mexican-American population is similar to that reported in other populations.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 07/2011; 156B(5):561-8. · 3.23 Impact Factor
[show abstract][hide abstract] ABSTRACT: We examined age trajectories of fractional anisotropy (FA) of cerebral white matter (WM) and thickness of cortical gray matter (GM) in 1031 healthy human subjects (aged 11-90 years). Whole-brain FA and GM thickness values followed quadratic trajectories with age but the relationship between them was linear, indicating that a putative biological mechanism may explain the non-linearity of their age trajectories. Inclusion of the FA values into the quadratic model of the whole-brain and regional GM thickness changes with age made the effect of the age(2) term no longer significant for the whole-brain GM thickness and greatly reduced its significance for regional GM thickness measurements. The phylogenetic order of cerebral myelination helped to further explain the intersubject variability in GM thickness. FA values for the early maturing WM were significantly better (p=10(-6)) at explaining variability in GM thickness in maturing (aged 11-20) subjects than FA values for the late maturing WM. The opposite trend was observed for aging subjects (aged 40-90) where FA values for the late maturing WM were better (p=10(-16)) at explaining the variability in GM thickness. We concluded that the non-linearity of the age trajectory for GM thickness, measured from T1-weighted MRI, was partially explained by the heterogeneity and the heterochronicity of the age-related changes in the microintegrity of cerebral WM. We consider these findings as the evidence that the measurements of age-related changes in GM thickness and FA are driven, in part, by a common biological mechanism, presumed to be related to changes in cerebral myelination.
[show abstract][hide abstract] ABSTRACT: Consistent sex differences in regulation of the hypothalamic pituitary adrenocortical (HPA) axis have been shown in animal models and emerge over puberty. However, parallel work in humans is lacking despite implications for elucidating the emergence of sex differences in depression over puberty. We investigated sex differences in HPA response to corticotropin releasing hormone (CRH) challenge over puberty in a carefully screened normative sample.
Participants were 68 healthy children (41% girls), ages 6-16, with no personal or family history of psychiatric disorder. Pubertal maturation was determined by Tanner staging. Following 24h of adaptation, 9-10 plasma cortisol samples were collected over 30-40 min pre-infusion baseline, 1 μg/kg CRH infusion, and 90-180 min post-infusion recovery. Thirty-seven participants completed 2+ CRH challenges allowing inclusion of cross-sectional and longitudinal data in all analyses. The influence of gender and pubertal maturation on parameters of cortisol response to CRH challenge was investigated using nonlinear mixed model methodology.
Girls showed increasing total cortisol output following CRH challenge over puberty, while boys showed little change in total cortisol output over puberty. Increased cortisol output in girls was explained by slower reactivity and recovery rates leading to prolonged time to reach peak cortisol and delayed return to baseline over puberty. Girls also showed increasing baseline cortisol over puberty, while boys showed declining baseline over puberty.
Results reveal subtle normative sex differences in the influence of pubertal maturation on HPA regulation at the pituitary level. This normative shift may tip the balance towards stress response dysregulation in girls at high risk for depression, and may represent one potential mechanism underlying elevated rates of depression among pubescent girls.
[show abstract][hide abstract] ABSTRACT: Alterations in white matter integrity of several cortical and subcortical circuits have been reported in relation to unipolar major depressive disorder. It is not clear whether these white matter changes precede the onset of illness. In all, 13 adolescent volunteers with no personal or family history of a psychiatric disorder (controls) and 18 adolescent volunteers with no personal history of a psychiatric illness including depression, but who were at high risk for developing unipolar depression by virtue of parental depression (high-risk youth), underwent diffusion tensor imaging studies. An automated tract-based spatial statistics method, a whole-brain voxel-by-voxel analysis, was used to analyze the scans. Population average diffusion parameter values were also calculated for each tract. Adolescents at high risk for unipolar depression had lower fractional anisotropy (FA) values in the left cingulum, splenium of the corpus callosum, superior longitudinal fasciculi, uncinate, and inferior fronto-occipital fasciculi than did controls. Altered white matter integrity in healthy adolescents at familial risk for unipolar depression suggests that it might serve as a vulnerability marker for the illness.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 11/2010; 36(3):684-91. · 6.99 Impact Factor
[show abstract][hide abstract] ABSTRACT: The risks for depression broadly include biological and environmental factors. Furthermore, having a family member suffering from major depression is also likely to have consequences for the family environment. Further research aimed at understanding the effects of having a child with major depression on family interaction patterns is warranted.
We studied 31 families with an 8- to 17-year-old child (mean age +/- SD = 12.9 +/- 2.7 years) who met the DSM-IV criteria for major depressive disorder (MDD) and 34 families with no mentally ill children (mean age +/- SD = 12.6 +/- 2.9 years) or parents. Children and their parents were assessed with the K-SADS-PL (Kiddie Schedule for Affective Disorders and Schizophrenia--Present and Lifetime Version) interview. Parents completed the Moos Family Environment Scale (FES) to assess their perceptions of current family functioning. Data were analyzed using the nonparametric Wilcoxon-Mann-Whitney test.
Families of MDD children showed significantly different patterns of family functioning on FES subscales representing relationships and personal growth dimensions. The families with MDD children showed higher levels of conflict (p < 0.001) and lower levels of cohesion (p < 0.001), expressiveness (p = 0.003) and active-recreational orientation (p = 0.02) compared to the families without mentally ill children.
Families with MDD children show a lower degree of commitment, provide less support to one another, provide less encouragement to express feelings and have more conflicts compared to families with no mentally ill children or parents. Interventions aimed at improving family dynamics may be beneficial to MDD children and their families.
[show abstract][hide abstract] ABSTRACT: To study the relationship between negative life events and demographic and clinical variables in youth with bipolar I disorder, bipolar II disorder, and bipolar disorder not otherwise specified (NOS), as well as to compare the rates of life events in youth with bipolar disorder, depressive and/or anxiety disorders (DEP-ANX), and healthy controls.
Subjects included 446 youth, aged 7 to 17 years, meeting DSM-IV criteria for bipolar I, bipolar II, or an operationalized definition of bipolar disorder NOS, and were enrolled in the Course and Outcome of Bipolar Illness in Youth study. Subjects completed the Life Events Checklist. Sixty-five DEP-ANX and 65 healthy youth were obtained from previous studies using similar methodology. The study was conducted from October 2000 to July 2006.
Older age, lower socioeconomic status, living with nonintact family, non-Caucasian race, anxiety, and disruptive disorders were associated with greater number of total negative life events. Specifically, increased independent, dependent, and uncertain negative life events were associated with lower socioeconomic status, nonintact family, and comorbid disruptive disorders. Increased independent negative life events were additionally associated with non-Caucasian race and comorbid anxiety disorders. Increased dependent and uncertain negative life events were also associated with older age. DEP-ANX youth reported a similar rate of negative life events as bipolar youth, and both groups had more negative life events than the healthy controls. Bipolar youth reported fewer total and dependent positive life events compared to DEP-ANX and healthy youths.
Similar to DEP-ANX youth, bipolar youth are exposed to excessive negative independent and dependent life events, which may have implications in the long-term outcome and negative consequences associated with this disorder.
The Journal of Clinical Psychiatry 10/2009; 70(10):1452-60. · 5.81 Impact Factor
[show abstract][hide abstract] ABSTRACT: This study examined expressed emotion in the families of children and adolescents who were (a) in a current episode of Major Depressive Disorder (MDD), (b) in remission from a past episode of MDD, (c) at high familial risk for developing MDD, and (d) low-risk controls. Participants were 109 mother-child dyads (children ages 8-19). Expressed emotion was assessed using the Five Minute Speech Sample, and psychiatric follow-ups were conducted annually. Mothers of children with a current or remitted episode of MDD and at high risk for MDD were more likely to be rated high on criticism than mothers of controls. There were no differences in critical expressed emotion among mothers of children in the current, remitted, or high-risk for depression groups. Higher initial critical expressed emotion was associated with a greater likelihood of having a future onset of a depressive episode in high-risk and depressed participants. Diagnostic groups did not differ in Emotional Overinvolvement.
[show abstract][hide abstract] ABSTRACT: To compare mother-child interactions and parenting styles in families of children with major depressive disorder, youths at high risk for depression, and healthy controls.
Currently depressed (n = 43), high-risk (n = 28), and healthy control (n = 41) youths and their mothers engaged in a standardized videotaped problem-solving interaction. Measures of affect and behavior for both mothers and children were obtained, in addition to global measures of parenting.
Depressed children demonstrated more negativity and less positivity in dyadic interactions than did children at high risk and control children. Mothers of depressed children were more disengaged than control mothers. Exploratory repeated-measures analyses in a subgroup of depressed children (n = 16) suggested mother-child interactions do not significantly change when children recover from depression. Children at high risk demonstrated less positivity in dyadic interactions than did controls. Mothers with a history of major depressive disorder and mothers with higher current depressive symptoms demonstrated patterns of disengagement and low control in interactions with children.
Mother-child interactions in depressed youths are marked by maternal disengagement and low child positivity that may not improve when children recover. The bidirectional effects of maternal disengagement and low levels of child positivity may precede onset of major depressive disorder in children and serve as risk factors for recurrent depression in youths.
Journal of the American Academy of Child and Adolescent Psychiatry 06/2008; 47(5):574-82. · 4.98 Impact Factor
[show abstract][hide abstract] ABSTRACT: Discounting future outcomes as a function of their deferred availability underlies much of human decision making. Discounting, or preference for immediate over delayed rewards of larger value, is often associated with impulsivity and is a risk factor for addictive disorders such as pathological gambling, cigarette smoking, and drug and alcohol abuse. The ventral striatum (VS) is involved in mediating behavioral responses and physiological states associated with reward, and dysregulation of the VS contributes to addiction, perhaps by affecting impulsive decision-making. Behavioral tests of delay discounting (DD), which index preference for smaller immediate over larger delayed rewards, covary with impulsive tendencies in humans. In the current study, we examined the relationship between individual differences in DD, measured in a behavioral assessment, and VS activity measured with blood oxygenation level-dependent functional magnetic resonance imaging, in 45 adult volunteers. VS activity was determined using a task involving positive and negative feedback with monetary reward. Analyses revealed that individual differences in DD correlate positively with magnitude of VS activation in response to both positive and negative feedback, compared with a no-feedback control condition. Variability in DD was also associated with differential VS activation in response to positive, compared with negative, feedback. Collectively, our results suggest that increased preference for smaller immediate over larger delayed rewards reflects both a relatively indiscriminate and hyper-reactive VS circuitry. They also highlight a specific neurocognitive mechanism that may contribute to increased risk for addiction.
Journal of Neuroscience 01/2007; 26(51):13213-7. · 6.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: This study investigated whether processing emotionally salient information such as emotional facial expressions influences the performance on a cognitive control task in pediatric anxiety and depression.
The sample included 68 participants between 8 and 16 years of age selected into three diagnostic groups: Anxiety Disorder (ANX, n = 23), Major Depressive Disorder (MDD, n = 19), and Low-Risk Normal Control (LRNC, n = 26). Participants completed an Emotional Go/NoGo task in which participants must either respond to (Go trials) or not respond to (NoGo trials) specific facial expressions (angry, fearful, sad, happy, neutral). In order to manipulate the level of cognitive control needed to perform the task, the probability of occurrence of the Go trials was varied across 3 probability conditions (low, moderate, high).
Analyses showed that the MDD group had significantly faster reaction times to sad face Go trials embedded in neutral face NoGo trials in the moderate probability condition and that the ANX group had significantly slower reaction times to neutral face Go trials embedded in angry face NoGo trials in the low probability condition.
These data demonstrate that processing emotional facial expressions influences the performance on a cognitive control task in children and adolescents diagnosed with an anxiety disorder and major depression.
Journal of Child Psychology and Psychiatry 12/2006; 47(11):1107-15. · 5.42 Impact Factor
[show abstract][hide abstract] ABSTRACT: Advances in molecular biology, neuroimaging, genetic epidemiology, and developmental psychopathology have provided a unique opportunity to explore the interplay of genes, brain, and behavior within a translational research framework. Herein, we begin by outlining an experimental strategy by which genetic effects on brain function can be explored using neuroimaging, namely, imaging genetics. We next describe some major findings in imaging genetics to highlight the effectiveness of this strategy for delineating biological pathways and mechanisms by which individual differences in brain function emerge and potentially bias behavior and risk for psychiatric illness. We then discuss the importance of applying imaging genetics to the study of psychopathology within a developmental framework. By beginning to move toward a systems-level approach to understanding pathways to behavioral outcomes as they are expressed across development, it is anticipated that we will move closer to understanding the complexities of the specific mechanisms involved in the etiology of psychiatric disease. Despite the numerous challenges that lie ahead, we believe that developmental imaging genetics has potential to yield highly informative results that will ultimately translate into public health benefits. We attempt to set out guidelines and provide exemplars that may help in designing fruitful translational research applications that incorporate a developmental imaging genetics strategy.
Development and Psychopathology 02/2006; 18(3):877-92. · 4.40 Impact Factor
[show abstract][hide abstract] ABSTRACT: Changes in the hypothalamic-pituitary-adrenal (HPA) axis, as evidenced by patterns of cortisol secretion, have been of interest in understanding depression and anxiety disorders across the life span. Previous studies of pediatric depression have pointed to the period around sleep onset as a key time point for observing alterations in cortisol secretion associated with affective disorders. Evidence also indicates that pubertal development may influence the expression of HPA dysregulation. We hypothesized that adolescents with depression and youth with anxiety disorders exhibit elevated peri-sleep-onset cortisol.
Plasma cortisol was sampled every 20 min around sleep onset from children and adolescents with major depressive disorder (n = 116), anxiety disorders (n = 32), or no history of psychiatric disorder (control; n = 76). Sleep onset was determined by polysomnography. Classification of participants as children or adolescents was based on Tanner staging of pubertal maturation.
Children with anxiety disorders had higher peri-sleep-onset cortisol than children with depression or control children. Adolescents with depression had marginally higher peri-sleep-onset cortisol than control adolescents and significantly higher peri-sleep-onset cortisol than children with depression.
Depression and anxiety are associated with altered cortisol secretion around sleep onset, and these changes appear to be influenced by pubertal maturation.
[show abstract][hide abstract] ABSTRACT: Children with major depressive disorder (MDD) often complain of sleep disturbances; however, polysomnographic studies have failed to find objective evidence of these disturbances. This article examines subjective sleep reports of children with MDD and healthy controls focusing on comparing subjective and objective sleep measures.
Fifty-one subjects with MDD and 42 healthy subjects, 8-17 years old, participated in a comprehensive psychobiologic study including three nights of EEG sleep recording. Each morning, subjects completed a post-sleep form subjectively rating their sleep, which was then compared with their polysomnographic studies.
Depressed subjects reported significantly worse sleep on four scales: subjective sleep quality, perceived number of awakenings, estimated minutes awake, and perceived ease of waking. In contrast to these subjective complaints, objective EEG measures indicated no evidence of disturbed sleep in the depressed sample compared to controls. Furthermore, exploratory analyses focusing on the subset of depressed subjects with the greatest subjective sleep disturbance showed, paradoxically, significantly better sleep in terms of the number of EEG awakenings and objective disturbances.
Despite clinical evidence of subjective sleep complaints in depressed children, our EEG measures showed little evidence to indicate an objective basis for these perceptions. These findings raise provocative questions regarding the nature of sleep complaints associated with early-onset depression.
Journal of the American Academy of Child & Adolescent Psychiatry 12/2005; 44(11):1158-66. · 6.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: Current research indicates that there is a strong relationship between the depression and anxiety that first appear during childhood. Both depression and anxiety co-segregate in families, indicating that the familial risk for the two disorders is shared. Epidemiologic and clinical evidence has shown that anxiety often precedes the onset of depression and the two disorders share a common genetic pathway that may be expressed differentially across development. From a preventive health perspective, children with depressed or anxious relatives are at increased risk for developing anxiety or depression. In addition, anxious children are at increased risk for developing depression particularly during adolescence.
Child and Adolescent Psychiatric Clinics of North America 11/2005; 14(4):707-26, viii. · 2.60 Impact Factor
[show abstract][hide abstract] ABSTRACT: Recent studies have indicated that a newly identified second isoform of the tryptophan hydroxylase gene (TPH2) is preferentially involved in the rate-limiting synthesis of neuronal serotonin. Genetic variation in the human TPH2 gene (hTPH2) has been associated with altered in vitro enzyme activity as well as increased risk for mood disorders. Here, we provide the first in vivo evidence that a relatively frequent regulatory variant (G(-844)T) of hTPH2 biases the reactivity of the amygdala, a neural structure critical in the generation and regulation of emotional behaviors.
[show abstract][hide abstract] ABSTRACT: The aim of this study was to examine the occurrence of stressful life events in anxious and depressed children.
Children (6-12 years of age) with an anxiety disorder (n = 20), depression (n = 45), and normal controls (n = 11) were assessed using the Life Events Record. Cortisol was assessed from plasma samples collected every 20 minutes from an indwelling catheter in the one and two hour window around sleep onset.
Depressed children had significantly more events and events that were most likely independent of the child's behavior, compared to both the anxious and normal control children. Independent loss events were significantly more prevalent among the depressed children in the preceding year, compared to anxious children, with a trend toward more loss events compared to the normal controls. For both overall events and independent events, depressed females were significantly more likely to be exposed to stressful environments compared to anxious and normal control females. There were no effects of stress on cortisol secretion around sleep onset.
The results of this study suggest that stressful life events are significantly more likely to occur in depressed children, particularly females, compared to anxious children, and that these events are predominantly characterized by independent events outside of the child's control. The results also suggest that loss events may be specific for depression in children. Interestingly, stress does not appear to impact the HPA axis in children, which is true for anxious, depressed, and normal control children. The temporal occurrence and severity, as well as the type of stressful life events as they relate to the onset and maintenance of anxiety and depression in children, need to be more fully explored.
Journal of Child and Adolescent Psychopharmacology 09/2005; 15(4):571-80. · 2.77 Impact Factor