Ana Maria Iosif

Activation of the maternal immune system during pregnancy alters behavioral development of rhesus monkey offspring.

BACKGROUND Maternal infection during pregnancy is associated with an increased risk of schizophrenia and autism in the offspring. Supporting this correlation, experimentally activating the maternal immune system during pregnancy in rodents produces offspring with abnormal brain and behavioral development. We have developed a nonhuman primate model to bridge the gap between clinical populations and rodent models of maternal immune activation (MIA). METHODS A modified form of the viral mimic, synthetic double-stranded RNA (polyinosinic:polycytidylic acid stabilized with poly-L-lysine) was delivered to two separate groups of pregnant rhesus monkeys to induce MIA: 1) late first trimester MIA (n = 6), and 2) late second trimester MIA (n = 7). Control animals (n = 11) received saline injections at the same first or second trimester time points or were untreated. Sickness behavior, temperature, and cytokine profiles of the pregnant monkeys confirmed a strong inflammatory response to MIA. RESULTS Behavioral development of the offspring was studied for 24 months. Following weaning at 6 months of age, MIA offspring exhibited abnormal responses to separation from their mothers. As the animals matured, MIA offspring displayed increased repetitive behaviors and decreased affiliative vocalizations. When evaluated with unfamiliar conspecifics, first trimester MIA offspring deviated from species-typical macaque social behavior by inappropriately approaching and remaining in immediate proximity of an unfamiliar animal. CONCLUSIONS In this rhesus monkey model, MIA yields offspring with abnormal repetitive behaviors, communication, and social interactions. These results extended the findings in rodent MIA models to more human-like behaviors resembling those in both autism and schizophrenia.

Diagnostic stability in young children at risk for autism spectrum disorder: a baby siblings research consortium study.

BACKGROUND The diagnosis of autism spectrum disorder (ASD) made before age 3 has been found to be remarkably stable in clinic- and community-ascertained samples. The stability of an ASD diagnosis in prospectively ascertained samples of infants at risk for ASD due to familial factors has not yet been studied, however. The American Academy of Pediatrics recommends intensive surveillance and screening for this high-risk group, which may afford earlier identification. Therefore, it is critical to understand the stability of an ASD diagnosis made before age 3 in young children at familial risk. METHODS Data were pooled across seven sites of the Baby Siblings Research Consortium. Evaluations of 418 later-born siblings of children with ASD were conducted at 18, 24, and 36 months of age and a clinical diagnosis of ASD or Not ASD was made at each age. RESULTS The stability of an ASD diagnosis at 18 months was 93% and at 24 months was 82%. There were relatively few children diagnosed with ASD at 18 or 24 months whose diagnosis was not confirmed at 36 months. There were, however, many children with ASD outcomes at 36 months who had not yet been diagnosed at 18 months (63%) or 24 months (41%). CONCLUSIONS The stability of an ASD diagnosis in this familial-risk sample was high at both 18 and 24 months of age and comparable with previous data from clinic- and community-ascertained samples. However, almost half of the children with ASD outcomes were not identified as being on the spectrum at 24 months and did not receive an ASD diagnosis until 36 months. Thus, longitudinal follow-up is critical for children with early signs of social-communication difficulties, even if they do not meet diagnostic criteria at initial assessment. A public health implication of these data is that screening for ASD may need to be repeated multiple times in the first years of life. These data also suggest that there is a period of early development in which ASD features unfold and emerge but have not yet reached levels supportive of a diagnosis.

Maternal antibodies from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey

Antibodies directed against fetal brain proteins of 37 and 73 kDa molecular weight are found in approximately 12% of mothers who have children with autism spectrum disorder (ASD), but not in mothers of typically developing children. This finding has raised the possibility that these immunoglobulin G (IgG) class antibodies cross the placenta during pregnancy and impact brain development, leading to one form of ASD. We evaluated the pathogenic potential of these antibodies by using a nonhuman primate model. IgG was isolated from mothers of children with ASD (IgG-ASD) and of typically developing children (IgG-CON). The purified IgG was administered to two groups of female rhesus monkeys (IgG-ASD; n=8 and IgG-CON; n=8) during the first and second trimesters of pregnancy. Another control group of pregnant monkeys (n=8) was untreated. Brain and behavioral development of the offspring were assessed for 2 years. Behavioral differences were first detected when the macaque mothers responded to their IgG-ASD offspring with heightened protectiveness during early development. As they matured, IgG-ASD offspring consistently deviated from species-typical social norms by more frequently approaching familiar peers. The increased approach was not reciprocated and did not lead to sustained social interactions. Even more striking, IgG-ASD offspring displayed inappropriate approach behavior to unfamiliar peers, clearly deviating from normal macaque social behavior. Longitudinal magnetic resonance imaging analyses revealed that male IgG-ASD offspring had enlarged brain volume compared with controls. White matter volume increases appeared to be driving the brain differences in the IgG-ASD offspring and these differences were most pronounced in the frontal lobes.

Maternal autoantibodies are associated with abnormal brain enlargement in a subgroup of children with autism spectrum disorder

Autism spectrum disorder (ASD) is very heterogeneous and multiple subtypes and etiologies likely exist. The maternal immune system has been implicated in the pathogenesis of some forms of ASD. Previous studies have identified the presence of specific maternal IgG autoantibodies with reactivity to fetal brain proteins at 37 and 73kDa in up to 12% of mothers of children with ASD. The current study evaluates the presence of these autoantibodies in an independent cohort of mothers of 181 preschool-aged male children (131 ASD, 50 typically developing (TD) controls). We also investigated whether ASD children born to mothers with these autism-specific maternal IgG autoantibodies exhibit a distinct neural phenotype by evaluating total brain volume using structural magnetic resonance imaging (MRI). Of the 131 ASD children, 10 (7.6%) were born to mothers with the 37/73kDa IgG autoantibodies (ASD-IgG). The mothers of the remaining ASD children and all TD controls were negative for these paired autoantibodies. While both ASD groups exhibited abnormal brain enlargement that is commonly observed in this age range, the ASD-IgG group exhibited a more extreme 12.1% abnormal brain enlargement relative to the TD controls. In contrast, the remaining ASD children exhibited a smaller 4.4% abnormal brain enlargement relative to TD controls. Lobar and tissue type analyses revealed that the frontal lobe is selectively enlarged in the ASD-IgG group and that both gray and white matter are similarly affected. These results suggest that maternal autoantibodies associated with autism spectrum disorder may impact brain development leading to abnormal enlargement.

A Feasibility Study of the Use of Asynchronous Telepsychiatry for Psychiatric Consultations

OBJECTIVE This study examined the feasibility of conducting psychiatric consultations using asynchronous, or store-and-forward, video-based telepsychiatry. METHODS Video-recorded 20- to 30-minute assessments of 60 nonemergency, English-speaking adult patients in a medically underserved county in California were uploaded along with other patient data to a Web-based record. Two psychiatrists then used the record to provide psychiatric consultations to the referring primary care providers. RESULTS Eighty-five percent of patients received diagnoses of mood disorders, 32% diagnoses of substance use disorders, 53% diagnoses of anxiety disorders, and 5% other axis I diagnoses. Psychiatrists recommended short-term medication changes for 95% of the patients and provided guidelines for possible future changes. CONCLUSIONS This study-the first study of asynchronous telepsychiatry to be published-demonstrated the feasibility of this approach. This type of assessment should not replace the face-to-face psychiatric interview, but it may be a very helpful additional process that improves access to care and expertise.

Month of Conception and Risk of Autism

Background: Studies of season of birth or season of conception can provide clues about etiology. We investigated whether certain months or seasons of conception are associated with increased risk of autism spectrum disorders, for which etiology is particularly obscure. Methods: The study population comprises 6,604,975 children born from 1990 to 2002 in California. Autism cases (n = 19,238) were identified from 1990 through 2008 in databases of the California Department of Developmental Services, which coordinates services for people with developmental disorders. The outcome in this analysis was autism diagnosed before the childs sixth birth date. The main independent variables were month of conception and season of conception (winter, spring, summer, and fall). Multivariate logistic regression models were used to estimate odds ratios (ORs) with their 95% confidence intervals (CIs) for autism by month of conception. Results: Children conceived in December (OR = 1.09 [95% CI = 1.02–1.17]), January (1.08 [1.00–1.17]), February (1.12 [1.04–1.20]), or March (1.16 [1.08–1.24]) had higher risk of developing autism compared with those conceived in July. Conception in the winter season (December, January, and February) was associated with a 6% (OR = 1.06, 95% CI = 1.02–1.10) increased risk compared with summer. Conclusions: Higher risks for autism among those conceived in winter months suggest the presence of environmental causes of autism that vary by season.

Transcultural Psychiatry Made Simple—Asynchronous Telepsychiatry as an Approach to Providing Culturally Relevant Care

OBJECTIVE To examine the feasibility and diagnostic reliability of asynchronous telepsychiatry (ATP) consultations in Spanish and ATP consultation with Spanish-to-English translation. SUBJECTS AND METHODS Twenty-four interviews of Spanish-speaking patients were videorecorded by a bilingual clinician who also collected patient history data and gave the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) to each patient. The ATP data (video of the interview and patient history) were forwarded for psychiatric consultation and a diagnostic assessment by the investigators. The ATP data were then examined separately by two Spanish-speaking psychiatrists, before being translated into English and then re-examined by two English-speaking psychiatrists. Agreement between the expert diagnoses of the investigators and the diagnoses from the Spanish consultations, the Spanish-to-English translated consultations, and the SCID-I results was assessed using kappa statistics. RESULTS We found acceptable levels of agreement for major diagnostic groupings among the Spanish- and English-speaking psychiatrists. Kappa values for diagnostic agreement between the expert and the translated consultations, the original language consultations, and the SCID-I were at least 0.52 (percentage agreement, 79%) and higher. CONCLUSIONS ATP consultations in Spanish, and those translated from Spanish to English, are feasible, and broad diagnostic reliability was achieved. The ATP process allows for rapid language translation. This approach could be useful across national boundaries and in numerous ethnic groups. Cross-language ATP may also offer significant benefits over the use of real-time interpreting services and has the potential to improve the quality of care by allowing for the addition of culturally relevant information.

Influence of functional connectivity and structural MRI measures on episodic memory

Age-related memory decline is the consequence of multiple biological factors that lead to brain structural and functional change, including gray matter atrophy, white matter injury, and loss of functional coordination between regions. However, the independent roles that each of these brain changes play in mediating memory decline is not clear. Therefore, we used magnetic resonance imaging (MRI) to measure gray matter (GM) volume, white matter hyperintensity (WMH) volumes, and blood oxygen level-dependent (BOLD) functional magnetic resonance imaging-based functional connectivity among default mode network nodes in 76 cognitive normal older adults. We found that GM, WMH, and connectivity between left inferior parietal and medial prefrontal cortex (MPF_LIP) were independently associated with episodic memory performance. Within the group with GM volumes below the median, greater MPF_LIP connectivity was associated with better memory performance, whereas this association was not present for individuals with GM volume above the median. These findings confirm the heterogeneous nature of brain-behavior relationships in cognitive aging. In addition, the relationship between resting state functional connectivity and memory performance, particularly amongst those individuals with more brain atrophy, strongly suggests compensation against the effects of neuronal injury.

Sex differences in the corpus callosum in preschool-aged children with autism spectrum disorder

BackgroundAbnormalities in the corpus callosum have been reported in individuals with autism spectrum disorder (ASD), but few studies have evaluated young children. Sex differences in callosal organization and diffusion characteristics have also not been evaluated fully in ASD.MethodsStructural and diffusion-weighted images were acquired in 139 preschool-aged children with ASD (112 males/27 females) and 82 typically developing (TD) controls (53 males/29 females). Longitudinal scanning at two additional annual time points was carried out in a subset of these participants. Callosal organization was evaluated using two approaches: 1) diffusion tensor imaging (DTI) tractography to define subregions based on cortical projection zones and 2) as a comparison to previous studies, midsagittal area analysis using Witelson subdivisions. Diffusion measures of callosal fibers were also evaluated.ResultsAnalyses of cortical projection zone subregions revealed sex differences in the patterns of altered callosal organization. Relative to their sex-specific TD counterparts, both males and females with ASD had smaller regions dedicated to fibers projecting to superior frontal cortex, but patterns differed in callosal subregions projecting to other parts of frontal cortex. While males with ASD had a smaller callosal region dedicated to the orbitofrontal cortex, females with ASD had a smaller callosal region dedicated to the anterior frontal cortex. There were also sex differences in diffusion properties of callosal fibers. While no alterations were observed in males with ASD relative to TD males, mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were all increased in females with ASD relative to TD females. Analyses of Witelson subdivisions revealed a decrease in midsagittal area of the corpus callosum in both males and females with ASD but no regional differences in specific subdivisions. Longitudinal analyses revealed no diagnostic or sex differences in the growth rate or change in diffusion measures of the corpus callosum from 3 to 5 years of age.ConclusionsThere are sex differences in the pattern of altered corpus callosum neuroanatomy in preschool-aged children with ASD.

Self-reported anxiety, depressive, and vasomotor symptoms: a study of perimenopausal women presenting to a specialized midlife assessment center.

Objective: The aim of this study was to examine the association of vasomotor symptoms (VMS) with anxiety and/or depressive symptoms in perimenopausal women. Methods: A retrospective chart review of 487 women 40 to 64 years old seen during October 2004 to December 2006 in the Womens Midlife Assessment Program at the University of California, Davis, was performed. Of these, 395 women were included in the analysis: 58 (15%) were premenopausal, 199 (50%) were perimenopausal, and 138 (35%) were postmenopausal. VMS bothersomeness was represented by converting Likert-scale ratings for hot flashes and night sweats to scores and adding them into an overall score. Multiple logistic regression models were used to quantify the association of self-reported anxiety and/or depressive symptoms with VMS bothersomeness. Results: Thirty-one (53%) premenopausal, 131 (66%) perimenopausal, and 69 (50%) postmenopausal women reported anxiety and/or depressive symptoms. Perimenopausal and postmenopausal women reporting anxiety and/or depressive symptoms had significantly higher VMS bothersomeness scores (2.2 ± 1.7 and 2.2 ± 1.9, respectively) than did women who did not report these symptoms (1.7 ± 1.7 and 1.6 ± 1.7, respectively; both P values < 0.05). Women experiencing more bothersome VMS were significantly more likely to report anxiety and/or depressive symptoms (odds ratio, 1.5; P < 0.01). Perimenopausal women were significantly more likely to report anxiety and/or depressive symptoms than were postmenopausal women (odds ratio, 1.9; P < 0.01). Both associations remained significant after restricting the analyses to women not taking hormone therapy or psychotropics. Conclusions: VMS bothersomeness was associated with self-reported anxiety and/or depressive symptoms, showing the importance of screening for anxiety and mood changes during perimenopause.