Development of neonatal brain functional centrality and alterations associated with preterm birth.

Formation of the functional connectome in early life underpins future learning and behavior. However, our understanding of how the functional organization of brain regions into interconnected hubs (centrality) matures in the early postnatal period is limited, especially in response to factors associated with adverse neurodevelopmental outcomes such as preterm birth. We characterized voxel-wise functional centrality (weighted degree) in 366 neonates from the Developing Human Connectome Project. We tested the hypothesis that functional centrality matures with age at scan in term-born babies and is disrupted by preterm birth. Finally, we asked whether neonatal functional centrality predicts general neurodevelopmental outcomes at 18 months. We report an age-related increase in functional centrality predominantly within visual regions and a decrease within the motor and auditory regions in term-born infants. Preterm-born infants scanned at term equivalent age had higher functional centrality predominantly within visual regions and lower measures in motor regions. Functional centrality was not related to outcome at 18 months old. Thus, preterm birth appears to affect functional centrality in regions undergoing substantial development during the perinatal period. Our work raises the question of whether these alterations are adaptive or disruptive and whether they predict neurodevelopmental characteristics that are more subtle or emerge later in life.

Familial clustering of psychiatric disorders and low IQ.

BACKGROUND: Although the ICD and DSM differentiate between different psychiatric disorders, these often share symptoms, risk factors, and treatments. This was a population-based, case-control, sibling study examining familial clustering of all psychiatric disorders and low IQ, using data from the Israel Draft-Board Registry on all Jewish adolescents assessed between 1998 and 2014. METHODS: We identified all cases with autism spectrum disorder (ASD, N = 2128), severe intellectual disability (ID, N = 9572), attention-deficit hyperactive disorder (ADHD) (N = 3272), psychotic (N = 7902), mood (N = 9704), anxiety (N = 10 606), personality (N = 24 816), or substance/alcohol abuse (N = 791) disorders, and low IQ (⩾2 SDs below the population mean, N = 31 186). Non-CNS control disorders were adolescents with Type-1 diabetes (N = 2427), hernia (N = 29 558) or hematological malignancies (N = 931). Each case was matched with 10 age-matched controls selected at random from the Draft-Board Registry, with replacement, and for each case and matched controls, we ascertained all full siblings. The main outcome measure was the relative recurrence risk (RRR) of the sibling of a case having the same (within-disorder RRR) or a different (across-disorder RRR) disorder. RESULTS: Within-disorder RRRs were increased for all diagnostic categories, ranging from 11.53 [95% confidence interval (CI): 9.23-14.40] for ASD to 2.93 (95% CI: 2.80-3.07) for personality disorders. The median across-disorder RRR between any pair of psychiatric disorders was 2.16 (95% CI: 1.45-2.43); the median RRR between low IQ and any psychiatric disorder was 1.37 (95% CI: 0.93-1.98). There was no consistent increase in across-disorder RRRs between the non-CNS disorders and psychiatric disorders and/or low IQ. CONCLUSION: These large population-based study findings suggest shared etiologies among most psychiatric disorders, and low IQ.

Neonatal multi-modal cortical profiles predict 18-month developmental outcomes.

Developmental delays in infanthood often persist, turning into life-long difficulties, and coming at great cost for the individual and community. By examining the developing brain and its relation to developmental outcomes we can start to elucidate how the emergence of brain circuits is manifested in variability of infant motor, cognitive and behavioural capacities. In this study, we examined if cortical structural covariance at birth, indexing coordinated development, is related to later infant behaviour. We included 193 healthy term-born infants from the Developing Human Connectome Project (dHCP). An individual cortical connectivity matrix derived from morphological and microstructural features was computed for each subject (morphometric similarity networks, MSNs) and was used as input for the prediction of behavioural scores at 18 months using Connectome-Based Predictive Modeling (CPM). Neonatal MSNs successfully predicted social-emotional performance. Predictive edges were distributed between and within known functional cortical divisions with a specific important role for primary and posterior cortical regions. These results reveal that multi-modal neonatal cortical profiles showing coordinated maturation are related to developmental outcomes and that network organization at birth provides an early infrastructure for future functional skills.

Obstetric, neonatal and child development outcomes following assisted hatching treatment: a retrospective cohort study.

Assisted hatching (AH) involves artificial disruption of the zona pellucida prior to embryo transfer. The purpose of this study is to examine the safety of AH technique and its effect on obstetrical, perinatal and neonatal outcomes and risk of developmental delay. This is a retrospective cohort of ART cycles using laser AH technique. The study group consisted of 120 cases of AH cycles resulting in singleton pregnancies and live births compared with 113 control cases. A current phone questionnaire was conducted to assess child development in the first year of life. AH was not associated with increased risk for all obstetrical and perinatal outcomes examined including PPROM, gestational diabetes, hypertensive diseases of pregnancy, delivery by cesarean section, gestational age at delivery, low birth weight (LBW), preterm birth and neonatal Apgar score (p>.05). No significant differences were observed between AH and control group in rates and risk of congenital malformations (5.8 vs. 4.4%, respectively, OR 1.33, 95% CI 0.41-4.34) and developmental delay (19.2 vs. 12.8%, respectively, OR 1.62, 95% CI 0.74-3.52). AH did not increase the risk of obstetrical and neonatal complications in singleton pregnancies, including congenital malformations and child developmental delay. AH may therefore be considered a safe method of ART.

Cortical morphology at birth reflects spatiotemporal patterns of gene expression in the fetal human brain.

Interruption to gestation through preterm birth can significantly impact cortical development and have long-lasting adverse effects on neurodevelopmental outcome. We compared cortical morphology captured by high-resolution, multimodal magnetic resonance imaging (MRI) in n = 292 healthy newborn infants (mean age at birth = 39.9 weeks) with regional patterns of gene expression in the fetal cortex across gestation (n = 156 samples from 16 brains, aged 12 to 37 postconceptional weeks [pcw]). We tested the hypothesis that noninvasive measures of cortical structure at birth mirror areal differences in cortical gene expression across gestation, and in a cohort of n = 64 preterm infants (mean age at birth = 32.0 weeks), we tested whether cortical alterations observed after preterm birth were associated with altered gene expression in specific developmental cell populations. Neonatal cortical structure was aligned to differential patterns of cell-specific gene expression in the fetal cortex. Principal component analysis (PCA) of 6 measures of cortical morphology and microstructure showed that cortical regions were ordered along a principal axis, with primary cortex clearly separated from heteromodal cortex. This axis was correlated with estimated tissue maturity, indexed by differential expression of genes expressed by progenitor cells and neurons, and engaged in stem cell differentiation, neuron migration, and forebrain development. Preterm birth was associated with altered regional MRI metrics and patterns of differential gene expression in glial cell populations. The spatial patterning of gene expression in the developing cortex was thus mirrored by regional variation in cortical morphology and microstructure at term, and this was disrupted by preterm birth. This work provides a framework to link molecular mechanisms to noninvasive measures of cortical development in early life and highlights novel pathways to injury in neonatal populations at increased risk of neurodevelopmental disorder.

Development of Microstructural and Morphological Cortical Profiles in the Neonatal Brain.

Interruptions to neurodevelopment during the perinatal period may have long-lasting consequences. However, to be able to investigate deviations in the foundation of proper connectivity and functional circuits, we need a measure of how this architecture evolves in the typically developing brain. To this end, in a cohort of 241 term-born infants, we used magnetic resonance imaging to estimate cortical profiles based on morphometry and microstructure over the perinatal period (37-44 weeks postmenstrual age, PMA). Using the covariance of these profiles as a measure of inter-areal network similarity (morphometric similarity networks; MSN), we clustered these networks into distinct modules. The resulting modules were consistent and symmetric, and corresponded to known functional distinctions, including sensory-motor, limbic, and association regions, and were spatially mapped onto known cytoarchitectonic tissue classes. Posterior regions became more morphometrically similar with increasing age, while peri-cingulate and medial temporal regions became more dissimilar. Network strength was associated with age: Within-network similarity increased over age suggesting emerging network distinction. These changes in cortical network architecture over an 8-week period are consistent with, and likely underpin, the highly dynamic processes occurring during this critical period. The resulting cortical profiles might provide normative reference to investigate atypical early brain development.

Understanding the association between advanced paternal age and schizophrenia and bipolar disorder.

BACKGROUND: Previous studies reported an association between advanced paternal age at birth and increased risk for schizophrenia and bipolar disorder. While some hypothesize that this association is caused by de-novo mutations in paternal spermatozoa, others cite factors associated with psycho-social characteristics of fathers who have children at a late age. This study aims to test these hypotheses. METHODS: A historical-prospective, population-based cohort study, performed by linking the Israeli Draft Board Registry and the Israeli National Psychiatric Hospitalization Registry (N = 916 439; 4488 with schizophrenia, 883 with bipolar disorder). Odds ratios (OR) and two-sided 95% confidence intervals (CI) were calculated by logistic regression models, using paternal age as predictor and risk for later hospitalizations for schizophrenia or bipolar disorder as outcome measure. Models were first fitted unadjusted, then adjusted for paternal age at birth of the first child. RESULTS: In the unadjusted model, offspring of fathers aged 45 and above at birth had increased risk of schizophrenia (OR = 1.71, 95% CI 1.49-1.99) and bipolar disorder (OR = 1.63, 95% CI 1.16-2.24). However, taking into account paternal age at birth of first child, advanced paternal age was no longer associated with increased risk of schizophrenia (OR = 0.60, 95% CI 0.48-0.79) or bipolar disorder (OR = 1.03, 95% CI 0.56-1.90). CONCLUSIONS: Controlling for paternal age at birth of the first offspring, advanced paternal age does not predict increased risk for schizophrenia or bipolar disorder. These data indicate that the association between advanced paternal age and having an offspring with schizophrenia and bipolar disorder is likely due to psychos-social factors, or common genetic variation associated with delayed initial fatherhood.

Functioning of Young Adults With ADHD in the Military.

Objective: To assess the functioning of young adults with ADHD in a military setting. Method: In all, 14,655 young adults with ADHD (mean age at first examination 17.8 ± 0.7) attending mandatory service in the Israeli military were compared with matched controls on several functioning domains. Results: Young adults with ADHD had more sessions with mental health care professionals, physician appointments, sick days, and disqualifications of professions than controls (p < .001). Young adults with ADHD were also less medically fit for combat service (odds ratio [OR] = 0.75, 95% confidence interval [CI] = [0.72, 0.79]), more medically unfit for military service in general (OR = 1.26, 95% CI = [1.13, 1.40]), and had higher rates of overweight and obesity (p < .001). In addition, they were more likely to be diagnosed with a personality disorder (OR = 1.29, 95% CI = [1.07, 1.53]) or with minor affective and anxiety disorders (OR = 1.33, 95% CI = [1.06, 1.67]) than matched controls. Conclusion: These results support a negative effect of ADHD on the functioning of young adults in a military setting.

Risk of hospitalization for psychiatric disorders among siblings and parents of probands with psychotic or affective disorders: A population-based study.

Relatives of people diagnosed with psychotic and affective disorders have a higher risk of developing psychiatric disorders compared to the general population. This study examined the risk of hospitalization for psychiatric disorders among siblings and parents of patients affected with major psychiatric disorders. In this large population-based case-control study, 17,895 siblings and parents of 7671 hospitalized subjects with a diagnosis of narrowly defined schizophrenia (SZ), broadly defined SZ, schizoaffective disorder (SAD), bipolar disorder (BD) or unipolar depression (UD) were identified from the Israeli Psychiatric Hospitalization Registry and compared to 71,580 age and gender-matched controls from the Israeli Population Registry. Results indicated that siblings of people diagnosed with broadly defined SZ had a significantly higher risk of hospitalization for broadly (OR=11.06, 95% CI=7.93-15.41) and narrowly defined SZ (OR=10.59, 95% CI=6.8-16.33), SAD (OR=9.69, 95% CI=4.76-19.73), BD (OR=7.46, 95% CI=21.8-25.52), UD (OR=2.84, 95% CI=1.01-8.00), and other psychiatric disorders (OR=1.85, 95% CI=1.16-2.93), compared to controls. Siblings of patients with BD had a significantly higher risk of hospitalization for broadly defined SZ (OR=2.92, 95% CI=1.11-7.71) and for other psychiatric disorders (OR=6.67, 95% CI=2.17-20.50), compared to controls. Parents of probands with SZ were at significantly increased risk for all disorders examined, except for UD and ¨other psychiatric disorders¨, which was not significant in parents of probands with BD. This large, population-based study provides evidence for common genetic risk across different psychiatric disorders.

A Population-Based Longitudinal Study of Symptoms and Signs Before the Onset of Psychosis.

OBJECTIVE: The authors sought to characterize the symptoms of patients later hospitalized for psychotic disorders in primary mental health outpatient settings, and to investigate whether these symptoms can be used to predict later onset of psychotic illness. METHOD: This was a population-based historical prospective cohort study using national registers of clinical psychiatric services. The sample (N=114,983) comprised 18- to 21-year-olds serving in the Israeli military and examined in military mental health outpatient clinics across 72 consecutive months. RESULTS: Overall, 1,092 individuals (0.95%) not diagnosed with a psychotic disorder at the time of examination were hospitalized for nonaffective psychotic disorder up to 9 years after the index examination. A principal components analysis of symptoms presented at index examination found that a symptom cluster of thought disorder, perceptual abnormalities, poor orientation, and suicidality was associated with an increased risk for hospitalization for nonaffective psychotic disorder within 14 days after examination (hazard ratio=45.80, 95% CI=22.87-91.73), 15-111 days after examination, (hazard ratio=19.59, 95% CI=13.08-29.33), 112-365 days after examination (hazard ratio=4.94, 95% CI=2.59-9.40), and 1-3.5 years after examination (hazard ratio=3.42, 95% CI=2.21-5.28), but not for hospitalization 3.5 years or more after examination (hazard ratio=1.57, 95% CI=0.91-2.71). Despite the increased risk, the positive predictive values of this symptom cluster were low, ranging from 0.54% to 1.99%. CONCLUSIONS: In 18- to 21-year-olds, the presence of psychotic symptoms was associated with later hospitalization for a nonaffective psychotic disorder. However, the low positive predictive values of symptoms elicited in primary mental health care settings suggest that symptoms alone are not useful in predicting later hospitalization for nonaffective psychotic disorder.

Health and functioning of adolescents conceived by assisted reproductive technology.

OBJECTIVE: To evaluate the general health, mental health, and cognitive ability of assisted reproductive technology (ART)-conceived adolescents. DESIGN: A nested case-control study within a historic cohort. SETTING: Not applicable. PATIENT(S): A total of 253 ART-conceived adolescents born between 1982 and 1993 and 253 matched references according to birth year, gender, and the high-school they attended. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Medical and psychiatric diagnoses, and cognitive ability recorded at the military preinduction screening (ages 16-17 years) and doctor's appointments throughout the military service. RESULT(S): No differences were detected in general and mental health of ART adolescents or cognitive ability, compared with the reference group. Similar results were obtained after stratification for gender and singleton births. The ART adolescents had fewer cases of discharge from military service due to health reasons (4% vs. 8.3%). Follow-up during the military service revealed that male ART adolescents had significantly more doctor's appointments compared with the reference group (23.80 ± 15.59 vs. 19.95 ± 13.79). CONCLUSION(S): Our preliminary results provide reassurance that in the long-run health and functioning of ART-conceived adolescents is not compromised. Further studies with larger cohorts are needed to confirm these results.

The association between premorbid cognitive ability and social functioning and suicide among young men: A historical-prospective cohort study.

Previous studies have found associations between low cognitive ability and later completed suicide. The aim of this study was to examine the association between cognitive ability and social functioning in adolescence, and later completed suicide in a large population-based longitudinal study. Data from the Israeli Draft Board Register for 634,655 Israeli male adolescents aged 16 and 17 was linked to a causes-of-death data registry, with a mean follow-up of 10.6 years for completed suicide. Our results show that in males without a psychiatric diagnosis, both low (adjusted HR=1.51, 95% CI: 1.19-1.92) and high (adjusted HR=1.36, 95% CI: 1.04-1.77) cognitive ability, and very poor (adjusted HR=2.30, 95% CI: 1.34-3.95) and poor (adjusted HR=1.64, 95% CI: 1.34-2.07) social functioning were associated with increased risk for later completed suicide; however positive predictive values were low (PPVs=0.09% and 0.10%, for low cognitive ability and very poor or poor social functioning, respectively). No association between cognitive ability or social functioning and risk for suicide was found in males with a psychiatric diagnosis. These data do not support the clinical utility of screening for such potential predictors.

[BIPOLAR DISORDER AS A MULTI-SYSTEM ILLNESS].

INTRODUCTION: Bipolar disorder is a chronic condition, characterized by high distress in patients and high suicide rates (30%). Most patients suffer from medical and other psychiatric comorbidities, which worsen the psychiatric symptoms and decrease the likelihood of remission. More than 70% of bipolar patients have cardio-metabolic symptoms, with higher rates compared to other psychiatric disorders. Cardiovascular disease is the major cause of high mortality rates in these patients, with 1.5-2 fold increased risk of mortality, compared to the general population without psychiatric symptoms. The rates of cardiovascular risk factors and their resulting increased mortality rates are similar to those found in schizophrenia. In addition to cardio-metabolic conditions, 50% of patients with bipolar disorder suffer from other medical symptoms, which are also associated with worse outcomes. Therefore, the current perspective is that bipolar disorder is not only a psychiatric disorder, but rather a multi-system illness, affecting the entire body. The optimal treatment for these patients should include diagnosis, monitoring and treatment of both psychiatric and physical symptoms, which would improve their prognosis.

Risk of completed suicide in 89,049 young males assessed by a mental health professional.

In an individual who seeks help or is referred to a mental health professional it is common sense and clinical practice to assume that suicidal thoughts and previous attempts constitute risk factors for imminent suicide. However, this assumption has not been supported by large, population-based longitudinal studies. The current study investigated whether reports of current suicidal ideation and a history of suicide attempts indeed increase risk for later completed suicide in a historical prospective study design. Sequential records on 89,049 young males assessed by mental health professionals were screened for suicidal ideation and a history of suicide attempts. The data were linked with death records from the Israeli Central Bureau of Statistics. Over a follow-up period ranging from 2 months to 9.8 years, 54 individuals died by suicide, constituting an average suicide rate of 6.48 per 100,000 person-years. Overall, neither reporting current suicidal ideation (without a history of suicide attempts; HR=1.29, 95% CI=0.57-2.90) nor reporting a history of suicide attempts (with or without current suicidal ideation; HR=1.67, 95% CI=0.71-3.97) were significantly associated with increased risk for later completed suicide. However, young males with a previously diagnosed psychiatric disorder who reported current suicidal ideation (HR=4.52, 95% CI=1.08-18.91) or a history of suicide attempts (HR=6.43, 95% CI=1.54-26.90) were at increased risk of death by suicide. These findings indicate that in this particular population reports of current suicidal ideation or of a history of suicide attempts are helpful in predicting future suicide only among those with a previous diagnosis of a psychiatric disorder.

A population-based longitudinal study of suicide risk in male schizophrenia patients: Proximity to hospital discharge and the moderating effect of premorbid IQ.

Suicide is a major cause of death in schizophrenia. Identifying factors which increase the risk of suicide among schizophrenia patients might help focus prevention efforts. This study examined risk of suicide in male schizophrenia patients using population-based data, examining the timing of suicide in relation to the last hospital discharge, and the effect of premorbid IQ on risk of suicide. Data on 930,000 male adolescents from the Israeli military draft board were linked with data from the Israeli Psychiatric Hospitalization Case Registry and vital statistics from the Israeli Ministry of Health. The relationship between premorbid IQ and risk for suicide was examined among 2881 males hospitalized with schizophrenia and compared to a control group of 566,726 males from the same cohort, who were not hospitalized for a psychiatric disorder, using survival analysis methods. Over a mean follow-up period of 9.9 years (SD=5.8, range: 0-22 years), 77/3806 males with schizophrenia died by suicide (a suicide rate of 204.4 per 100,000 person-years). Approximately 48% of the suicides occurred within a year of discharge from the last hospital admission for schizophrenia. Risk of suicide was higher in male schizophrenia patients with high premorbid IQ (HR=4.45, 95% CI=1.37-14.43) compared to those with normal premorbid IQ. These data indicate that male schizophrenia patients with high premorbid IQ are at particularly high risk of suicide, and the time of peak risk is during the first year after the last hospitalization discharge.

The impact of Herpes simplex virus type 1 on cognitive impairments in young, healthy individuals - A historical prospective study.

Herpes simplex virus (HSV) is a highly prevalent neurotropic virus. Although on the whole, chronic, latent or persistent infection is considered to be relatively benign, HSV infections can cause cognitive impairment during and after acute encephalitis. Some studies have documented cognitive impairment in exposed persons that is untraceable to encephalitis. Most studies have focused on these impairments in the mentally ill, mostly among individuals with schizophrenia, and only recently have studies begun to examine the impact of HSV infection on the cognition of healthy individuals. Subjects were a representative, random sample of 612 soldiers before active duty in the Israeli military (Israeli defense force - IDF), 62.2% HSV positive (n=381) and 38.8% HSV negative (n=231). Cognitive functioning and language abilities were compared between these groups, controlling for years of education, immigration status, and gender. Compared to soldiers who were sero-negative, soldiers who were sero-positive for HSV had significantly lower IQ scores (IQ=97.96, SD=15.19 vs IQ=103.23, SD=14.23; p≤0.001, effect size (ES)=0.2), and significantly lower Hebrew language scores (ES=0.1, p≤0.01). The results remained significant after removing subjects with mild depression, anxiety or personality disorders. Although we could not control for socio-economic status directly, our findings indicate that infection with HSV-1 is associated with reduced cognitive functioning in healthy individuals. This finding adds to the growing number of studies in the schizophrenia literature and indicates that many research findings seemingly characteristic of schizophrenia are related to the association between HSV exposure and cognitive functioning in general, and are not illness specific.

Beyond the HPA-axis: The role of the gonadal steroid hormone receptors in modulating stress-related responses in an animal model of PTSD.

The hypothalamic-pituitary-adrenal (HPA) axis, which plays a major role in the response to stress, and the hypothalamic-pituitary-gonadal (HPG) axis are closely linked with the ability to inhibit the other. Testosterone, a product of the HPG, has many beneficial effects beyond its functions as a sex hormone including anti-anxiety properties. In this study we examined the effect of stress exposure on gonadal hormones, and their efficacy in modulating anxiety-like response in an animal model of PTSD. Male rats were exposed to predator scent stress, followed by analysis of brain expression of androgen receptor (AR) receptor and estrogen receptor α (ERα). The behavioral effects of immediate treatment with testosterone, testosterone receptor antagonist (flutamide) or vehicle were evaluated using the elevated plus-maze, acoustic startle response and trauma-cue response. Levels of circulating corticosterone and testosterone were also measured after treatment. The behavioral effects of delayed testosterone treatment were explored in the same manner. We report that animals whose behavior was extremely disrupted (EBR) selectively displayed significant down-regulation of AR and ERα in the hippocampus. Immediate treatment with flutamide or delayed treatment with testosterone significantly increased prevalence rates of minimal behavioral response (MBR) and decreased prevalence of EBR with favorable behavioral results. Testosterone levels were higher in control un-exposed animals, while corticosterone was higher in control exposed animals. This study suggests that gonadal steroid hormones are involved in the neurobiological response to predator scent stress and thus warrant further study as a potential therapeutic avenue for the treatment of anxiety-related disorders.

Early post-stressor intervention with minocycline, a second-generation tetracycline, attenuates post-traumatic stress response in an animal model of PTSD.

We assessed the effects of minocycline, a tetracycline with anti-inflammatory, anti-apoptotic and neuroprotective capacities, in an animal model of post-traumatic stress disorder (PTSD). Rats were exposed to psychogenic stress and treated 1h later with minocycline or saline. Behavioral measures included the elevated plus-maze (EPM) and acoustic startle response (ASR) 7 days post stress-exposure. One day after behavioral testing, animals were exposed to a trauma cue and freezing response was assessed. Local levels of cytokines interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in the hippocampus, frontal cortex (FC) and hypothalamus were then examined. Minocycline attenuated anxious-like behaviors in stress-exposed rats. In addition, decreased levels of cytokines were measured in exposed rats treated with minocycline compared to their counterparts treated with saline. This study suggests a potential use of minocycline in preventing physiological and behavioral alternations resulting from acute exposure to psychological stress. As this is the first study to report beneficial outcomes for minocycline treatment in an animal model of PTSD, further investigations of the use of minocycline in stress-related conditions with emphasis on PTSD is needed.