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1.  Personality Disorder and Changes in Affect Consciousness: A 3-Year Follow-Up Study of Patients with Avoidant and Borderline Personality Disorder 
PLoS ONE  2015;10(12):e0145625.
Personality disorders (PDs) are highly prevalent in patients receiving psychiatric services, and are associated with significant personal and social costs. Over the past two decades, an increasing number of treatment studies have documented the effectiveness of treatment for patients with PDs, especially when it comes to reduction of symptom distress, risk taking behavior, self-harm, or suicide attempts. However, less is known about the more complex aims of improving the personality structure itself, such as identity- and interpersonal disturbances. Emotional dysfunction is closely associated with PD pathology. The present study investigated changes in affect consciousness (AC) in patients with avoidant or borderline PD, and how these changes were associated with clinical status after 3 years of follow-up. The study included 52 individuals; 79 percent were females, and mean age was 30 years. The evaluations included the Affect Consciousness Interview, Symptom Checklist-90-R, Circumplex of Interpersonal Problems, the Index of Self-Esteem, and three domains (Identity Integration, Relational Capacities, and Self-Control) of the Severity Indices of Personality Problems (SIPP-118). There was a significant increase in the Global AC and AC scores for most of the specific affects from baseline to follow-up. As the present study did not include a control group, it cannot be concluded that changes in AC are effects of psychotherapy, and the possibility of age-related maturation processes cannot be excluded. The change in Global AC contributed significantly to explained variance in the follow-up levels of Circumplex of Interpersonal Problems, and the two SIPP-118 domains Relational Capacities and Identity Integration. Improved AC was not associated with change in the Self-Control domain or the Global Severity Index of Symptom Checklist-90-R. The results suggest that AC may be altered for patients with borderline and avoidant PDs, and this is the first study to report that improvement in AC contribute significantly to the variance in the self- and interpersonal domains of personality functioning.
PMCID: PMC4689515  PMID: 26699730
2.  Effects of high-intensity aerobic exercise on psychotic symptoms and neurocognition in outpatients with schizophrenia: study protocol for a randomized controlled trial 
Trials  2015;16:557.
The focus in recent years on physical inactivity and metabolic disturbances in individuals with schizophrenia raises the question of potential effects of physical activity. Physical activity has shown beneficial effects on cognition in healthy older individuals as well as on symptom severity in depression. However, opinions diverge regarding whether aerobic high-intensity interval training reduces cognition and key symptoms in schizophrenia. The main objective for the trial is to investigate the potential effects of aerobic high-intensity interval training on neurocognitive function and mental symptoms in outpatients with schizophrenia.
The trial is designed as a randomized controlled, observer-blinded clinical trial. Patients are randomized to 1 of 2 treatment arms with 12-week duration: aerobic high-intensity interval training or computer gaming skills training. All participants also receive treatment as usual. Primary outcome measure is neurocognitive function. Secondary outcome measures will be positive and negative symptoms, wellbeing, tobacco-smoking patterns and physiological/metabolic parameters. Patient recruitment takes place in catchment area-based outpatient clinics.
Trial registration NCT02205684. Registered 29 July 2014.
PMCID: PMC4672547  PMID: 26646670
High-intensity interval training; Schizophrenia; Psychosis; Neurocognition
3.  Transcriptomic Analysis of Induced Pluripotent Stem Cells Derived from Patients with Bipolar Disorder from an Old Order Amish Pedigree 
PLoS ONE  2015;10(11):e0142693.
Fibroblasts from patients with Type I bipolar disorder (BPD) and their unaffected siblings were obtained from an Old Order Amish pedigree with a high incidence of BPD and reprogrammed to induced pluripotent stem cells (iPSCs). Established iPSCs were subsequently differentiated into neuroprogenitors (NPs) and then to neurons. Transcriptomic microarray analysis was conducted on RNA samples from iPSCs, NPs and neurons matured in culture for either 2 weeks (termed early neurons, E) or 4 weeks (termed late neurons, L). Global RNA profiling indicated that BPD and control iPSCs differentiated into NPs and neurons at a similar rate, enabling studies of differentially expressed genes in neurons from controls and BPD cases. Significant disease-associated differences in gene expression were observed only in L neurons. Specifically, 328 genes were differentially expressed between BPD and control L neurons including GAD1, glutamate decarboxylase 1 (2.5 fold) and SCN4B, the voltage gated type IV sodium channel beta subunit (-14.6 fold). Quantitative RT-PCR confirmed the up-regulation of GAD1 in BPD compared to control L neurons. Gene Ontology, GeneGo and Ingenuity Pathway Analysis of differentially regulated genes in L neurons suggest that alterations in RNA biosynthesis and metabolism, protein trafficking as well as receptor signaling pathways may play an important role in the pathophysiology of BPD.
PMCID: PMC4640865  PMID: 26554713
4.  Generation and Characterization of an Immortalized Human Mesenchymal Stromal Cell Line 
Stem Cells and Development  2014;23(19):2377-2389.
Human mesenchymal stromal cells (hMSCs) show great potential for clinical and experimental use due to their capacity to self-renew and differentiate into multiple mesenchymal lineages. However, disadvantages of primary cultures of hMSCs are the limited in vitro lifespan, and the variable properties of cells from different donors and over time in culture. In this article, we describe the generation of a telomerase-immortalized nontumorigenic human bone marrow-derived stromal mesenchymal cell line, and its detailed characterization after long-term culturing (up to 155 population doublings). The resulting cell line, iMSC#3, maintained a fibroblast-like phenotype comparable to early passages of primary hMSCs, and showed no major differences from hMSCs regarding surface marker expression. Furthermore, iMSC#3 had a normal karyotype, and high-resolution array comparative genomic hybridization confirmed normal copy numbers. The gene expression profiles of immortalized and primary hMSCs were also similar, whereas the corresponding DNA methylation profiles were more diverse. The cells also had proliferation characteristics comparable to primary hMSCs and maintained the capacity to differentiate into osteoblasts and adipocytes. A detailed characterization of the mRNA and microRNA transcriptomes during adipocyte differentiation also showed that the iMSC#3 recapitulates this process at the molecular level. In summary, the immortalized mesenchymal cells represent a valuable model system that can be used for studies of candidate genes and their role in differentiation or oncogenic transformation, and basic studies of mesenchymal biology.
PMCID: PMC4172386  PMID: 24857590
5.  The Role of MicroRNAs as Predictors of Response to Tamoxifen Treatment in Breast Cancer Patients 
Endocrine therapy is a key treatment strategy to control or eradicate hormone-responsive breast cancer. However, resistance to endocrine therapy leads to breast cancer relapse. The recent extension of adjuvant tamoxifen treatment up to 10 years actualizes the need for identifying biological markers that may be used to monitor predictors of treatment response. MicroRNAs are promising biomarkers that may fill the gap between preclinical knowledge and clinical observations regarding endocrine resistance. MicroRNAs regulate gene expression by posttranscriptional repression or degradation of mRNA, most often leading to gene silencing. MicroRNAs have been identified directly in the primary tumor, but also in the circulation of breast cancer patients. The few available studies investigating microRNA in patients suggest that seven microRNAs (miR-10a, miR-26, miR-30c, miR-126a, miR-210, miR-342 and miR-519a) play a role in tamoxifen resistance. Ingenuity Pathway Analysis (IPA) reveals that these seven microRNAs interact more readily with estrogen receptor (ER)-independent pathways than ER-related signaling pathways. Some of these pathways are targetable (e.g., PIK3CA), suggesting that microRNAs as biomarkers of endocrine resistance may have clinical value. Validation of the role of these candidate microRNAs in large prospective studies is warranted.
PMCID: PMC4632748  PMID: 26473850
breast cancer; tamoxifen; endocrine resistance; microRNA; biomarker
6.  Infancy Parenting and Externalizing Psychopathology from Childhood through Adulthood: Developmental Trends 
Developmental psychology  2009;45(4):909-912.
Developmental models and previous findings suggest that early parenting is more strongly associated with externalizing problems in early childhood than in adolescence. In this brief report, we addressed the question of whether the association of poor quality infancy parenting and externalizing problems “rebounds” in adulthood. Poor quality infancy parenting was associated with externalizing problems at kindergarten and first grade (mother report), as well as at 23 and 26 years (self-report). Infancy parenting was not significantly associated with either mothers' or youths' reports of externalizing problems at 16 years. These findings are consistent with the notion that poor quality infancy parenting is a risk factor for externalizing problems in developmental periods for which externalizing behavior is most deviant.
PMCID: PMC4532673  PMID: 19586169
Parenting; externalizing; longitudinal; adult follow-up; developmental psychopathology
8.  Parent ratings of executive function in young preschool children with symptoms of attention-deficit/-hyperactivity disorder 
Recent research has demonstrated that deficits in basic, self-regulatory processes, or executive function (EF), may be related to symptoms of attention-deficit/hyperactivity disorder (ADHD) already during the preschool period. As the majority of studies investigating these relations in young children have been based primarily on clinically administered tests, it is not clear how early symptoms of ADHD may be related to observations of EF in an everyday context. The preschool version of the Behavior Rating Inventory of Executive Function (BRIEF-P) was developed to provide information about EF through observable, behavioral manifestations of self-regulation, and is the most commonly used rating scale for EF assessment in children.
Relations between symptoms of ADHD reported in the Preschool Age Psychiatric Assessment interview (PAPA), and EF as measured by the BRIEF-P (parent form), were investigated in a large, nonreferred sample of preschool children (37–47 months, n = 1134) recruited from the Norwegian Mother and Child Cohort Study (MoBa) at the Norwegian Institute of Public Health. The inventory’s discriminative ability was examined in a subsample consisting of children who met the diagnostic criteria for either ADHD, oppositional defiant disorder (ODD) or anxiety disorder, and typically developing controls (n = 308). The four groups were also compared with regard to patterns of EF difficulties reported in the BRIEF-P.
Of the five BRIEF-P subscales, Inhibit and Working Memory were the two most closely related to ADHD symptoms, together explaining 38.5% of the variance in PAPA symptom ratings. Based on their scores on the Inhibit and Working Memory subscales (combined), 86.4% of the children in the ADHD and TD groups were correctly classified. ADHD symptoms were associated with more severe difficulties across EF domains, and a different EF profile in comparison to children with other symptoms (anxiety, ODD) and to typically developing controls.
Early symptoms of ADHD were linked to parent-reported difficulties primarily within inhibition and working memory, suggesting that deficiencies within these two EF domains characterize early forms of ADHD. Our findings support the clinical utility of the BRIEF-P as a measure of EF in young preschool children with symptoms of ADHD.
PMCID: PMC4399220  PMID: 25889243
ADHD; Executive function; Preschool; BRIEF-P; Inhibition; Working memory
9.  Conspicuous carotenoid-based pelvic spine ornament in three-spined stickleback populations—occurrence and inheritance 
PeerJ  2015;3:e872.
Reports on reddish carotenoid-based ornaments in female three-spined sticklebacks (Gasterosteus aculeatus) are few, despite the large interest in the species’ behaviour, ornamentation, morphology and evolution. We sampled sticklebacks from 17 sites in north-western Europe in this first extensive study on the occurrence of carotenoid-based female pelvic spines and throat ornaments. The field results showed that females, and males, with reddish spines were found in all 17 populations. Specimens of both sexes with conspicuous red spines were found in several of the sites. The pelvic spines of males were more intensely red compared to the females’ spines, and large specimens were more red than small ones. Fish infected with the tapeworm (Schistocephalus solidus) had drabber spines than uninfected fish. Both sexes had red spines both during and after the spawning period, but the intensity of the red colour was more exaggerated during the spawning period. As opposed to pelvic spines, no sign of red colour at the throat was observed in any female from any of the 17 populations. A rearing experiment was carried out to estimate a potential genetic component of the pelvic spine ornament by artificial crossing and rearing of 15 family groups during a 12 months period. The results indicated that the genetic component of the red colour at the spines was low or close to zero. Although reddish pelvic spines seem common in populations of stickleback, the potential adaptive function of the reddish pelvic spines remains largely unexplained.
PMCID: PMC4389276  PMID: 25861558
Gasterosteus aculeatus; Stickleback; Ornament; Carotenoid; Pelvic spine; Signal; Female ornament
10.  Avoidant Personality Disorder versus Social Phobia: The Significance of Childhood Neglect 
PLoS ONE  2015;10(3):e0122846.
Avoidant personality disorder (AvPD) and social phobia (SP) are common disorders both in the community and in clinical settings. Whether the two disorders represent different severity levels of social anxiety disorder is currently in dispute. The relationship between AvPD and SP is probably more complex than previously assumed. Several environmental, temperamental, and constitutional factors may play a role in the etiology of AvPD and SP. Better knowledge about childhood experiences may shed light on similarities and differences between the two disorders. The aim of this study was to compare self-reported childhood experiences in AvPD and SP patients.
This is a cross-sectional multi-site study of 91 adult patients with AvPD and/ or SP. We compared patients with AvPD with and without SP (AvPD group) to patients with SP without AvPD (SP group).
The patients were examined using structured diagnostic interviews and self-report measures, including Child Trauma Questionnaire, Parental Bonding Instrument, and Adult Temperament Questionnaire.
Both AvPD and SP were associated with negative childhood experiences. AvPD patients reported more severe childhood neglect than patients with SP, most pronounced for physical neglect. The difference between the disorders in neglect remained significant after controlling for temperamental factors and concurrent abuse.
The study indicates that childhood neglect is a risk factor for AvPD and may be one contributing factor to phenomenological differences between AvPD and SP.
PMCID: PMC4376891  PMID: 25815817
11.  Mother-Infant Attachment and the Intergenerational Transmission of Posttraumatic Stress Disorder 
Evidence for the intergenerational transmission of posttraumatic stress disorder (PTSD) is documented in the literature, though the underlying mechanisms are poorly understood. Attachment theory provides a framework for elucidating the ways in which maternal PTSD may increase offspring PTSD vulnerability. The current study utilized two independent prospective datasets to test the hypotheses that (a) maternal PTSD increases the probability of developing an insecure mother-infant attachment relationship and (b) an insecure mother-infant attachment relationship increases the risk of developing PTSD following trauma exposure in later life. In the first study of urban, primarily low-income ethnic/racial minority mothers and infants (N = 45 dyads), elevated maternal PTSD symptoms at 6 months were associated with increased risk for an insecure, particularly disorganized, mother-infant attachment relationship at 13 months. In the second birth cohort of urban low-income mothers and children (N = 96 dyads), insecure (avoidant or resistant) attachment in infancy was associated in a dose-response manner with increased lifetime risk for a diagnosis of PTSD by adolescence. A history of disorganized attachment in infancy predicted severity of PTSD symptoms, including reexperiencing, avoidance, hyperarousal, and total symptoms, at 17.5 years. In both studies, associations between attachment and PTSD were not attributable to numerous co-occurring risk factors. The findings suggest that promoting positive mother-child relationships in early development, particularly in populations at high risk for trauma exposure, may reduce the incidence of PTSD.
PMCID: PMC4145695  PMID: 24059819
attachment; PTSD; intergenerational; maternal trauma; infant
12.  Gene variations in oestrogen pathways, CYP19A1, daily 17β-estradiol and mammographic density phenotypes in premenopausal women 
High mammographic density is an established breast cancer risk factor, and circulating oestrogen influences oestrogen-regulating gene expression in breast cancer development. However, less is known about the interrelationships of common variants in the CYP19A1 gene, daily levels of oestrogens, mammographic density phenotypes and body mass index (BMI) in premenopausal women.
Based on plausible biological mechanisms related to the oestrogen pathway, we investigated the association of single nucleotide polymorphisms (SNPs) in CYP19A1, 17β-estradiol and mammographic density in 202 premenopausal women. DNA was genotyped using the Illumina Golden Gate platform. Daily salivary 17β-estradiol concentrations were measured throughout an entire menstrual cycle. Mammographic density phenotypes were assessed using a computer-assisted method (Madena). We determined associations using multivariable linear and logistic regression models.
The minor alleles of rs749292 were positively (P = 0.026), and the minor alleles of rs7172156 were inversely (P = 0.002) associated with daily 17β-estradiol. We observed an 87% lower level of daily 17β-estradiol throughout a menstrual cycle in heavier women (BMI >23.6 kg/m2) of rs7172156 with minor genotype aa compared with major genotype AA. Furthermore, the rs749292 minor alleles were inversely associated with absolute mammographic density (P = 0.032). Lean women with rs749292 minor alleles had 70 to 80% lower risk for high absolute mammographic density (>32.4 cm2); Aa: odds ratio (OR) = 0.23 (95% CI 0.07 to 0.75). Lean women with rs7172156 minor homozygous genotype had OR 5.45 for high absolute mammographic density (aa: OR = 5.45 (95% CI 1.13 to 26.3)).
Our findings suggest that two SNPs in CYP19A1, rs749292 and rs7172156, are associated with both daily oestrogen levels and mammographic density phenotypes. BMI may modify these associations, but larger studies are needed.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-014-0499-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4303212  PMID: 25522654
13.  Sociodemographic Risk, Developmental Competence, and PTSD Symptoms in Young Children Exposed to Interpersonal Trauma in Early Life 
Journal of traumatic stress  2013;26(6):686-694.
Children under age six years are disproportionately exposed to interpersonal trauma, including maltreatment and witnessing intimate partner violence (IPV), and may be particularly susceptible to negative sequelae. However, young children have generally been neglected from trauma research; thus, little is known about the factors influencing vulnerability to traumatic stress responses and other negative outcomes in early life. This study examined associations among interpersonal trauma exposure, sociodemographic risk, developmental competence, and posttraumatic stress disorder (PTSD) symptoms in 200 children assessed prospectively from birth to 1st grade via home and laboratory observations, record reviews, and maternal and teacher interviews. Greater trauma exposure and sociodemographic risk and lower developmental competence predicted more severe PTSD symptoms. Developmental competence partially mediated the association between exposures and symptoms. Trauma exposure fully mediated the association between sociodemographic risk and symptoms. Neither sociodemographic risk nor developmental competence moderated trauma exposure effects on symptoms. The findings suggest that (a) exposure to maltreatment and IPV has additive effects on posttraumatic stress risk in early life, (b) associations between sociodemographic adversity and poor mental health may be attributable to increased trauma exposure in disadvantaged populations, and (c) early exposures have a negative cascade effect on developmental competence and child mental health.
PMCID: PMC4157899  PMID: 24490247
14.  Genetic Contributions to Continuity and Change in Attachment Security: A Prospective, Longitudinal Investigation from Infancy to Young Adulthood 
Longitudinal research has demonstrated that individual differences in attachment security show only modest continuity from infancy to adulthood. Recent findings based on retrospective reports suggest that individuals’ genetic variation may moderate the developmental associations between early attachment-relevant relationship experiences and adult attachment security. The purpose of this study was to use a prospective, longitudinal design to investigate genetic contributions to continuity and changes in attachment security from infancy to young adulthood in a higher risk sample.
Infant attachment security was assessed using the Strange Situation Procedure at 12 and 18 months. Adults’ general attachment representations were assessed using the Adult Attachment Interview at age 19 and age 26. Romantic attachment representations were assessed with the Current Relationship Interview at ages 20–21 and ages 26–28. Individuals were genotyped for variants within the oxytocin receptor (OXTR), dopamine D4 receptor (DRD4), and serotonin transporter linked polymorphic region (5-HTTLPR).
The continuity of attachment security from infancy into young adulthood was consistently moderated by OXTR genetic variation. Infant attachment security predicted the security of adults’ general and romantic attachment representations only for individuals with the OXTR G/G genotype. This interaction was significant when predicting adult attachment security as measured by the Adult Attachment Interview at age 19 and 26 and the Current Relationship Interview at ages 26–28. DRD4 and 5-HTTLPR genetic variation did not consistently moderate the longitudinal associations between attachment security during infancy and adulthood.
This study provides initial longitudinal evidence for genetic contributions to continuity and change in attachment security from infancy to young adulthood. Genetic variation related to the oxytocin system may moderate the stability of attachment security across development.
PMCID: PMC3775920  PMID: 23731038
Attachment; continuity; genetics; development
15.  The Developmental Significance of Late Adolescent Substance Use for Early Adult Functioning 
Developmental psychology  2012;49(8):1554-1564.
This study examines the predictive significance of late adolescent substance use groups (i.e., abstainers, experimental users, at-risk users, and abusers) for early adult adaptation. Participants (N = 159) were drawn from a prospective longitudinal study of first-born children of low-income mothers. At 17.5 years of age participants were assigned to substance use groups based on their level of substance use involvement. At 26 years, early adult competence was assessed in the areas of education, work, romantic relationships, and global adaptation. Results indicate that 17.5 year substance use group membership significantly predicted high school completion, regular involvement in a long-term romantic relationship, good or better work ethic, and good or better global adjustment at 26 years when controlling for gender; IQ; 16 year internalizing and externalizing behavior problems, parental monitoring, and peer competence; and current substance use at 26 years. Group comparisons indicate that late adolescent substance use experimenters were significantly more likely in early adulthood to have (a) a high school diploma or higher level of education compared to abstainers (OR = 8.83); (b) regular involvement in long-term romantic relationships (OR = 3.23), and good or better global adaptation (OR = 4.08) compared to at-risk users; and (c) good or better work ethic (OR = 4.04) compared to abusers. This research indicates that patterns of late adolescent substance use has implications for early adult functioning in salient developmental domains.
PMCID: PMC3568218  PMID: 23025264
adolescence; drug use; early adulthood; longitudinal study; competence
16.  Developmental Timing and Continuity of Exposure to Interparental Violence and Externalizing Behavior as Prospective Predictors of Dating Violence 
Development and psychopathology  2013;25(4 0 1):973-990.
This study investigated the prospective pathways of children's exposure to interparental violence (EIPV) in early and middle childhood and externalizing behavior in middle childhood and adolescence as developmental predictors of dating violence perpetration and victimization at ages 23 and 26 years. Participants (N = 168) were drawn from a longitudinal study of low-income families. Path analyses examined whether timing or continuity of EIPV predicted dating violence and whether timing or continuity of externalizing behavior mediated these pathways. Results indicated that EIPV in early childhood directly predicted perpetration and victimization at age 23. There were significant indirect effects from EIPV to dating violence through externalizing behavior in adolescence and life stress at age 23. Independent of EIPV, externalizing behavior in middle childhood also predicted dating violence through externalizing behavior in adolescence and life stress at age 23, but this pathway stemmed from maltreatment. These results highlight that the timing of EIPV and both the timing and continuity of externalizing behavior are critical risks for the intergenerational transmission of dating violence. Findings support a developmental perspective that negative early experiences and children's externalizing behavior are powerful influences for dating violence in early adulthood.
PMCID: PMC4100589  PMID: 24229543
Keywords: exposure to interparental violence; externalizing behavior; dating violence; prospective developmental pathways; life stress
17.  Contributions of maltreatment and serotonin transporter genotype to depression in childhood, adolescence, and early adulthood 
Journal of affective disorders  2012;149(0):30-37.
Past findings on gene-by-environment (G × E) effects on depression have been mixed, leading to a debate of the plausibility of such mechanisms and methodological considerations that warrant attention. A developmental systems perspective postulates that complex, multi-level G × E effects are likely contributors to depression.
Participants from families experiencing low-income status at birth were followed over 28 years. Maltreatment was recorded prospectively using multiple means and sources. Depression was measured repeatedly using well-validated interviews in middle childhood, through adolescence, and into adulthood.
Findings support a G × E effect where the less efficient form of the promoter region of the serotonin transporter gene (5-HTTLPR) contributes to a vulnerability to depressogenic aspects of maltreatment in childhood and adolescence. The presence of less efficient forms of the 5-HTTLPR polymorphism and maltreatment together raised risk for depression. This G × E effect was present generally and also among those who reported clinical levels of depression at only one point in time.
This study used a low-income sample which limits generalizability to other populations. Sample size and rates of different forms of depression and depression at individual developmental stages supported general analyses, but limited the sorts of specific sub-analyses that were possible.
These findings support the plausibility of G × E effects on depression during childhood, adolescence, and early adulthood, key periods for the development of depression. Ongoing debates about the presence of G × E effects would be well served by additional work that was theoretically informed and employed prospective, longitudinal methodologies with well-validated measures of key constructs.
PMCID: PMC3548027  PMID: 22951355
Gene-by-environment interaction; Child maltreatment; 5-HTTLPR; Depression; Childhood; adolescence; and adulthood
18.  Modulation of Adult Hippocampal Neurogenesis by Early-Life Environmental Challenges Triggering Immune Activation 
Neural Plasticity  2014;2014:194396.
The immune system plays an important role in the communication between the human body and the environment, in early development as well as in adulthood. Per se, research has shown that factors such as maternal stress and nutrition as well as maternal infections can activate the immune system in the infant. A rising number of research studies have shown that activation of the immune system in early life can augment the risk of some psychiatric disorders in adulthood, such as schizophrenia and depression. The mechanisms of such a developmental programming effect are unknown; however some preliminary evidence is emerging in the literature, which suggests that adult hippocampal neurogenesis may be involved. A growing number of studies have shown that pre- and postnatal exposure to an inflammatory stimulus can modulate the number of proliferating and differentiating neural progenitors in the adult hippocampus, and this can have an effect on behaviours of relevance to psychiatric disorders. This review provides a summary of these studies and highlights the evidence supporting a neurogenic hypothesis of immune developmental programming.
PMCID: PMC4033517  PMID: 24891958
19.  Does IQ influence Associations between ADHD Symptoms and other Cognitive Functions in young Preschoolers? 
Working memory, inhibition, and expressive language are often impaired in ADHD and many children with ADHD have lower IQ-scores than typically developing children. The aim of this study was to test whether IQ-score influences associations between ADHD symptoms and verbal and nonverbal working memory, inhibition, and expressive language, respectively, in a nonclinical sample of preschool children.
In all, 1181 children recruited from the Norwegian Mother and Child Cohort Study were clinically assessed at the age of 36 to 46 months. IQ-score and working memory were assessed with subtasks from the Stanford Binet test battery, expressive language was reported by preschool teachers (Child Development Inventory), response inhibition was assessed with a subtask from the NEPSY test, and ADHD symptoms were assessed by parent interview (Preschool Age Psychiatric Assessment).
The results showed an interaction between ADHD symptoms and IQ-score on teacher-reported expressive language. In children with below median IQ-score, a larger number of ADHD symptoms were more likely to be accompanied by reports of lower expressive language skills, while the level of ADHD symptoms exerted a smaller effect on reported language skills in children with above median IQ-score. The associations between ADHD symptoms and working memory and response inhibition, respectively, were not influenced by IQ-score.
Level of IQ-score affected the relation between ADHD symptoms and teacher-reported expressive language, whereas associations between ADHD symptoms and working memory and response inhibition, respectively, were significant and of similar sizes regardless of IQ-score. Thus, in preschoolers, working memory and response inhibition should be considered during an ADHD assessment regardless of IQ-score, while language skills of young children are especially important to consider when IQ-scores are average or low.
PMCID: PMC4017812  PMID: 24884579
ADHD; IQ; Intellectual ability; Preschool; Cognition; Working memory; Language skills; Inhibition
20.  Alcohol Use is Not Directly Related to the Perceived Control of Depressive Symptoms in Patients with Depressive Symptoms 
Treatment-seeking patients (N = 233) were recruited as they started a course of relapse prevention and coping with depression. The mean Beck depression inventory (BDI-II) score was 26 points, indicating a moderate degree of depression. The sample was recruited from different outpatient clinics and screened for alcohol-related problems with the alcohol use disorders identification test (AUDIT). Almost half of the total sample had a score on AUDIT >8 indicating an alcohol problem. The participants in this study did not undergo a clinical interview to check out if their symptoms, as assessed with BDI-II and AUDIT, were part of a formal diagnosis in accordance with the criteria in ICD 10 or DSM IV. A specific instrument, perceived uncontrollability of depression (UNCONTROL), was used to measure the persons’ perceived control of depressive symptoms; a set of statements about coping with depressive symptoms where high scores indicate lack of coping with the symptoms. Alcohol problems were not found to be significantly associated with the perceived control of ongoing depressive symptoms and did not moderate the relationship between depressive symptoms and the perceived control of depressive symptoms. The results question the assumption that alcohol use is related to coping with depressive symptoms in patients with alcohol abuse and depressive symptoms.
PMCID: PMC3973897  PMID: 24723895
alcohol; depression; coping; Beck depression inventory; prevention and control
21.  Genomic View of Bipolar Disorder Revealed by Whole Genome Sequencing in a Genetic Isolate 
PLoS Genetics  2014;10(3):e1004229.
Bipolar disorder is a common, heritable mental illness characterized by recurrent episodes of mania and depression. Despite considerable effort to elucidate the genetic underpinnings of bipolar disorder, causative genetic risk factors remain elusive. We conducted a comprehensive genomic analysis of bipolar disorder in a large Old Order Amish pedigree. Microsatellite genotypes and high-density SNP-array genotypes of 388 family members were combined with whole genome sequence data for 50 of these subjects, comprising 18 parent-child trios. This study design permitted evaluation of candidate variants within the context of haplotype structure by resolving the phase in sequenced parent-child trios and by imputation of variants into multiple unsequenced siblings. Non-parametric and parametric linkage analysis of the entire pedigree as well as on smaller clusters of families identified several nominally significant linkage peaks, each of which included dozens of predicted deleterious variants. Close inspection of exonic and regulatory variants in genes under the linkage peaks using family-based association tests revealed additional credible candidate genes for functional studies and further replication in population-based cohorts. However, despite the in-depth genomic characterization of this unique, large and multigenerational pedigree from a genetic isolate, there was no convergence of evidence implicating a particular set of risk loci or common pathways. The striking haplotype and locus heterogeneity we observed has profound implications for the design of studies of bipolar and other related disorders.
Author Summary
Bipolar disorder is a common, heritable mental illness characterized by recurrent episodes of mania and depression. Despite considerable efforts genetic studies have yet to reveal the precise genetic underpinnings of the disorder. In this study we have analyzed a large extended pedigree of Old Order Amish that segregates bipolar disorder. Our study design integrates both dense genotype and whole-genome sequence data. In a combined linkage and association analysis we identify five chromosomal regions with nominally significant or suggestive evidence for linkage, several of which constitute replication of earlier linkage findings for bipolar disorder in non-Amish families. Association analysis of genetic variants in each of the linkage regions yielded a number of plausible candidate genes for bipolar disorder. The striking genetic heterogeneity we observed in this genetic isolate has profound implications for the study of bipolar disorder in the general population.
PMCID: PMC3953017  PMID: 24625924
22.  Depressive Symptoms in People with and without Alcohol Abuse: Factor Structure and Measurement Invariance of the Beck Depression Inventory (BDI-II) Across Groups 
PLoS ONE  2014;9(2):e88321.
This study explored differences in the factor structure of depressive symptoms in patients with and without alcohol abuse, and differences in the severity of depressive symptoms between the two groups. In a sample of 358 patients without alcohol problems and 167 patients with comorbid alcohol problems, confirmatory factor analysis revealed that the same factor structures, Beck et al.'s two-factor Somatic Affective-Cognitive (SA-C) model, and Buckley et al.'s three-factor Cognitive-Affective- Somatic (C-A-S) model, demonstrated the best fit to the data in both groups. The SA-C model was preferred due to its more parsimonious nature. Evidence for strict measurement invariance across the two groups for the SA-C model was found. MIMIC (multiple-indicator-multiple-cause) modeling showed that the level of depressive symptoms was found to be highest on both factors in the group with comorbid alcohol problems. The magnitude of the differences in latent mean scores suggested a moderate difference in the level of depressive symptoms between the two groups. It is argued that patients with comorbid depression and alcohol abuse should be offered parallel and adequate treatment for both conditions.
PMCID: PMC3922762  PMID: 24533075
23.  RCT of Working Memory Training in ADHD: Long-Term Near-Transfer Effects 
PLoS ONE  2013;8(12):e80561.
The aim of the study is to evaluate the long-term near-transfer effects of computerized working memory (WM) training on standard WM tasks in children with Attention-Deficit/Hyperactivity Disorder (ADHD).
Sixty-seven children aged 10–12 years in Vestfold/Telemark counties (Norway) diagnosed with F90.0 Hyperkinetic disorder (ICD-10) were randomly assigned to training or control group. The training group participated in a 25-day training program at school, while the control group received treatment-as-usual. Participants were tested one week before intervention, immediately after and eight months later. Based on a component analysis, six measures of WM were grouped into composites representing Visual, Auditory and Manipulation WM.
The training group had significant long-term differential gains compared to the control group on all outcome measures. Performance gains for the training group were significantly higher in the visual domain than in the auditory domain. The differential gain in Manipulation WM persisted after controlling for an increase in simple storage capacity.
Systematic training resulted in a long-term positive gain in performance on similar tasks, indicating the viability of training interventions for children with ADHD. The results provide evidence for both domain-general and domain-specific models. Far-transfer effects were not investigated in this article.
Trial Registration: ISRCTN19133620
PMCID: PMC3857172  PMID: 24352414
24.  Interpersonal Trauma Exposure and Cognitive Development in Children to Age 8 Years: A Longitudinal Study 
Childhood trauma exposure has been associated with deficits in cognitive functioning. The influence of timing of exposure on the magnitude and persistence of deficits is not well understood. The impact of exposure in early development has been especially under-investigated. This study examined the impact of interpersonal trauma exposure (IPT) in the first years of life on childhood cognitive functioning.
Children (N = 206) participating in a longitudinal birth cohort study were assessed prospectively for exposure to IPT (physical or emotional abuse or neglect, sexual abuse, witnessing maternal partner violence) between birth and 64 months. Child intelligent quotient scores (IQ) were assessed at 24, 64, and 96 months of age. Race/ethnicity, gender, socioeconomic status, maternal IQ, birth complications, birthweight, and cognitive stimulation in the home were also assessed.
IPT was significantly associated with decreased cognitive scores at all time points, even after controlling for sociodemographic factors, maternal IQ, birth complications, birthweight, and cognitive stimulation in the home. IPT in the first two years appeared to be especially detrimental. On average, compared to children not exposed to IPT in the first two years, exposed children scored one-half standard deviation lower across cognitive assessments.
IPT in early life may have adverse effects on cognitive development. IPT during the first two years may have particular impact, with effects persisting at least into later childhood.
PMCID: PMC3731065  PMID: 22493459
cognitive development; IQ; trauma; child abuse; domestic violence
25.  Few Effects of Far Transfer of Working Memory Training in ADHD: A Randomized Controlled Trial 
PLoS ONE  2013;8(10):e75660.
Studies have shown that children with ADHD profit from working memory training, although few studies have investigated transfer effects comprehensively. The current Randomized Controlled Trial analyzes transfer to other neuropsychological (NP) domains, academic performance and everyday functioning at home and school.
Sixty-seven children with ADHD were randomized into a control group or a training group. The training group underwent Cogmed’s RoboMemo program. All participants were assessed pre-training, immediately after and eight months later with a battery of NP tests, measures of mathematical and reading skills, as well as rating scales filled out by parents and teachers.
There was a significant training effect in psychomotor speed, but not to any other NP measures. Reading and mathematics were improved. There were no training induced changes in symptom rating scales either at home or at school. The increased reading scores remained significant eight months later.
The study is the most comprehensive study of transfer effects to date, and with mixed results compared to previous research. More research is needed regarding how to improve the training program and the conditions and thresholds for successful training.
Trial Registration ISRCTN19133620
PMCID: PMC3790857  PMID: 24124503

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