Structural and functional alterations in the brain gray matter among first-degree relatives of schizophrenia patients : A multimodal meta-analysis of fMRI and VBM studies

Objective: We conducted a multimodal coordinate-based meta-analysis (CBMA) to investigate structural and functional brain alterations in first-degree relatives of schizophrenia patients (FRs). Methods: We conducted a systematic literature search from electronic databases to find studies that examined differences between FRs and healthy controls using whole-brain functional magnetic resonance imaging (fMRI) or voxel-based morphometry (VBM). A CBMA of 30 fMRI (754 FRs; 959 controls) and 11 VBM (885 FRs; 775 controls) datasets were conducted using the anisotropic effect-size version of signed differential mapping. Further, we conducted separate meta-analyses about functional alterations in different cognitive tasks: social cognition, executive functioning, working memory, and inhibitory control. Results: FRs showed higher fMRI activation in the right frontal gyrus during cognitive tasks than healthy controls. In VBM studies, there were no differences in gray matter density between FRs and healthy controls. Furthermore, multi-modal meta-analysis obtained no differences between FRs and healthy controls. By utilizing the BrainMap database, we showed that the brain region which showed functional alterations in FRs (i) overlapped only slightly with the brain regions that were affected in the meta-analysis of schizophrenia patients and (ii) correlated positively with the brain regions that exhibited increased activity during cognitive tasks in healthy individuals. Conclusions: Based on this meta-analysis, FRs may exhibit only minor functional alterations in the brain during cognitive tasks, and the alterations are much more restricted and only slightly overlapping with the regions that are affected in schizophrenia patients. The familial risk did not relate to structural alterations in the gray matter. (C) 2019 Elsevier B.V. All rights reserved.Peer reviewe

Prenatal exposure to maternal cigarette smoking and structural properties of the human corpus callosum

Alterations induced by prenatal exposure to nicotine have been observed in experimental (rodent) studies. While numerous developmental outcomes have been associated with prenatal exposure to maternal cigarette smoking (PEMCS) in humans, the possible relation with brain structure is less clear. Here we sought to elucidate the relation between PEMCS and structural properties of human corpus callosum in adolescence and early adulthood in a total of 1,747 youth. We deployed three community-based cohorts of 446 (age 25–27 years, 46% exposed), 934 (age 12–18 years, 47% exposed) and 367 individuals (age 18–21 years, 9% exposed). A mega-analysis revealed lower mean diffusivity in the callosal segments of exposed males. We speculate that prenatal exposure to maternal cigarette smoking disrupts the early programming of callosal structure and increases the relative portion of small-diameter fibres.</p

Functional Consequences of the Human Leptin Receptor ( LEPR ) Q223R Transversion

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93715/1/oby.2008.489.pd

Maternal prepregnancy body mass index and offspring white matter microstructure: results from three birth cohorts

Prepregnancy maternal obesity is a global health problem and has been associated with offspring metabolic and mental ill-health. However, there is a knowledge gap in understanding potential neurobiological factors related to these associations. This study explored the relation between maternal prepregnancy body mass index (BMI) and offspring brain white matter microstructure at the age of 6, 10, and 26 years in three independent cohorts. Maternal BMI was associated with higher FA and lower MD in multiple brain tracts in offspring aged 10 and 26 years, but not at 6 years of age. Future studies should examine whether our observations can be replicated and explore the potential causal nature of the findings.This work was supported by the European Union’s Horizon 2020 research and innovation program [grant agreement no. 633595 DynaHEALTH] and no. 733206 LifeCycle], the Netherlands Organization for Health Research and Development [ZONMW Vici project 016.VICI.170.200]. The PREOBE cohort was funded by Spanish Ministry of Innovation and Science. Junta de Andalucía: Excellence Projects (P06-CTS-02341) and Spanish Ministry of Economy and Competitiveness (BFU2012-40254-C03-01). The first phase of the Generation R Study is made possible by financial support from the Erasmus Medical Centre, the Erasmus University, and the Netherlands Organization for Health Research and Development (ZonMW, grant ZonMW Geestkracht 10.000.1003). The Northern Finland Birth Cohort 1986 is funded by University of Oulu, University Hospital of Oulu, Academy of Finland (EGEA), Sigrid Juselius Foundation, European Commission (EURO-BLCS, Framework 5 award QLG1-CT-2000-01643), NIH/NIMH (5R01MH63706:02

Leptin Receptor Signaling and Action in the Central Nervous System

The increasing incidence of obesity in developed nations represents an ever‐growing challenge to health care by promoting diabetes and other diseases. The discovery of the hormone, leptin, a decade ago has facilitated the acquisition of new knowledge regarding the regulation of energy balance. A great deal remains to be discovered regarding the molecular and anatomic actions of leptin, however. Here, we discuss the mechanisms by which leptin activates intracellular signals, the roles that these signals play in leptin action in vivo, and sites of leptin action in vivo. Using “reporter” mice, in which LRb‐expressing (long form of the leptin receptor) neurons express the histological marker, β‐galactosidase, coupled with the detection of LRb‐mediated signal transducer and activator of transcription 3 signaling events, we identified LRb expression in neuronal populations both within and outside the hypothalamus. Understanding the regulation and physiological function of these myriad sites of central leptin action will be a crucial next step in the quest to understand mechanisms of leptin action and energy balance.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93692/1/oby.2006.310.pd

Early predictors of white matter microstructure in the adult brain

Abstract The foundations for the brain’s structural organisation are laid already during prenatal life. External and internal signals interact to guide brain development in axonal growth, myelination and pruning, but also seem to programme long-term epigenetic effects which may only appear later in life. Altered neurodevelopment has been linked with psychiatric conditions and other states of compromised health. This work focuses on white matter, a brain structure that has received relatively little attention in research on typical and altered neurodevelopment. White matter constitutes about half of the human brain’s volume, and its axonal pathways provide conduction and modulation of signals across brain regions. The variation in the structural features of white matter in association with early-life factors is, however, far from resolved. This work studies associations between prenatal factors and brain white matter structural features from childhood to early adulthood. White matter structural correlates of sex, prenatal maternal BMI and cigarette smoking are studied in five cohort samples from different countries. Statistical models are adjusted for important prenatal and later-life covariates. The structural features of main white matter tracts, including the corpus callosum (CC), are studied using mutually complementary metrics of multimodal brain magnetic resonance imaging (MRI). The findings in the CC showed, first, a correlation between MRI relaxometry measures and small-calibre axons and second, sexual dimorphism in microstructural features in the midsagittal CC. Prenatal maternal BMI and cigarette smoking were observed to be associated with structural alterations of white matter tracts in adolescence and early adulthood, but with inconclusive replication across cohorts at different ages. These findings indicate that early-life factors are associated with alterations of white matter structure in offspring during the first decades of life, and thus pinpoint the importance of health support during pregnancy. The findings also emphasise the importance of considering participant age as well as prenatal and later-life covariates when planning research. Future research would benefit from longitudinal and genetically informed study designs.Tiivistelmä Aivojen rakenteen kehityskulut alkavat hahmottua jo ennen syntymää. Ulkoisten ja sisäisten tekijöiden vuorovaikutus ohjaa hermosyiden kasvua, myelinisaatiota ja hermoyhteyksien karsiutumista, mutta näyttöä on myös pitkäaikaisista vaikutuksista perimän luentaan, jolloin vaikutukset saattavat olla havaittavissa vasta myöhemmin elämässä. Hermoston kehityksellisten poikkeavuuksien on havaittu liittyvän psykiatrisiin sairauksiin ja muihin epäedullisiin terveydentiloihin. Tämän työn kohteena on aivojen valkoinen aine, jonka poikkeavan ja normaalin kehityksen piirteisiin on aiemmin kohdistunut verrattain niukasti tutkimusta. Valkoinen aine kattaa noin puolet ihmisen aivojen tilavuudesta, ja sen aksoniyhteydet välittävät ja muokkaavat aivoalueiden välisiä viestejä. Valkoisen aineen rakenteen yhteydet varhaisiin ennustaviin tekijöihin vaativat kuitenkin lisää tutkimusta. Työssä tutkitaan raskaudenaikaisten tekijöiden yhteyksiä aivojen valkoisen aineen rakenteeseen lapsuudesta nuoreen aikuisuuteen. Valkoisen aineen ominaisuuksia suhteessa sukupuoleen sekä äidin raskaudenaikaiseen painoindeksiin ja tupakointiin tutkitaan hyödyntäen viittä erimaalaista kohorttia. Tilastollisissa malleissa huomioidaan useita raskaudenaikaisia ja myöhempiä sekoittavia muuttujia. Valkoisen aineen ratojen, mukaan lukien aivokurkiaisen (corpus callosum), rakenteellisia piirteitä tutkitaan toisiaan täydentävillä magneettikuvantamisen menetelmillä. Tutkimuksessa havaittiin, että tutkitussa osassa aivokurkiaista magneettikuvantamisen relaksaatioajat ovat yhteydessä ohuiden hermosyiden tiheyteen ja että miesten ja naisten välillä on huomattavia eroja aivokurkiaisen valkoisen aineen mikrorakenteessa. Äidin raskaudenaikaisen painoindeksin ja tupakoinnin osoitettiin olevan yhteydessä lapsen valkoisen aineen ratojen rakenteen poikkeavuuksiin nuoruusiässä ja varhaisessa aikuisuudessa, mutta tulos ei ollut täysin toistettavissa eri-ikäisillä henkilöillä. Tulokset osoittavat, että varhaiset tekijät ovat yhteydessä valkoisen aineen rakenteen ominaisuuksiin elämän ensimmäisten vuosikymmenten aikana, ja tukevat näin raskaudenaikaisen terveystyön merkitystä. Tulokset myös korostavat tutkittavien iän sekä raskaudenaikaisten ja myöhempien tekijöiden huomioinnin tärkeyttä tutkimusta suunniteltaessa. Tulevat tutkimukset hyötyisivät pitkittäisestä sekä yksilöiden sukulaisuusuhteita hyödyntävästä tutkimusasetelmasta

Integrated Liver and Plasma Proteomics in Obese Mice Reveals Complex Metabolic Regulation

Obesity leads to the development of nonalcoholic fatty liver disease (NAFLD) and associated alterations to the plasma proteome. To elucidate the underlying changes associated with obesity, we performed liquid chromatography–tandem mass spectrometry in the liver and plasma of obese leptin-deficient ob/ob mice and integrated these data with publicly available transcriptomic and proteomic datasets of obesity and metabolic diseases in preclinical and clinical cohorts. We quantified 7173 and 555 proteins in the liver and plasma proteomes, respectively. The abundance of proteins related to fatty acid metabolism were increased, alongside peroxisomal proliferation in ob/ob liver. Putatively secreted proteins and the secretory machinery were also dysregulated in the liver, which was mirrored by a substantial alteration of the plasma proteome. Greater than 50% of the plasma proteins were differentially regulated, including NAFLD biomarkers, lipoproteins, the 20S proteasome, and the complement and coagulation cascades of the immune system. Integration of the liver and plasma proteomes identified proteins that were concomitantly regulated in the liver and plasma in obesity, suggesting that the systemic abundance of these plasma proteins is regulated by secretion from the liver. Many of these proteins are systemically regulated during type 2 diabetes and/or NAFLD in humans, indicating the clinical importance of liver–plasma cross talk and the relevance of our investigations in ob/ob mice. Together, these analyses yield a comprehensive insight into obesity and provide an extensive resource for obesity research in a prevailing model organism

Associations between maternal prenatal C-reactive protein and risk factors for psychosis in adolescent offspring:findings from the Northern Finland Birth Cohort 1986

Abstract Prenatal infection is associated with brain structural and functional abnormalities and may increase the risk for psychosis through a direct effect on neurodevelopment. Various infections may exert their effect through a proinflammatory immune response but studies of prenatal maternal inflammatory markers and offspring neurodevelopment are scarce. Using the longitudinal Northern Finland Birth Cohort 1986 study, we examined the associations of maternal prenatal C-reactive protein (CRP) levels with psychosis risk factors in adolescent offspring. CRP was measured in maternal sera collected in pregnancy. In offspring, school performance was measured at age 7 years, while school performance, psychotic experiences, and cannabis use were measured at age 16 years. We tested associations of CRP with offspring measures using regression analysis controlling for offspring sex, maternal education level, and prenatal maternal body mass index, smoking and alcohol use in pregnancy, place of birth, maternal psychiatric admission, paternal psychiatric admission, mothers age at birth, and gestational week of CRP sample. We also tested if adolescent cannabis use mediated the associations between maternal CRP and offspring outcomes. Controlling for covariates, maternal CRP was associated with academic performance at age 16 years (beta = .062, 95% CI = 0.036–0.088), but not with possible psychotic experiences at 16 years (odds ratio [OR] = 1.09, 95% CI = 0.96–1.24). Maternal CRP was also associated with adolescent cannabis use (OR = 1.24, 95% CI = 1.07–1.43). These findings suggest that prenatal inflammation may influence later mental illness risk by affecting neurodevelopment and also indirectly by increasing the risk of exposure to cannabis

Structural properties of the human corpus callosum: Multimodal assessment and sex differences

A number of structural properties of white matter can be assessed in vivo using multimodal magnetic resonance imaging (MRI). We measured profiles of R1 and R2 relaxation rates, myelin water fraction (MWF) and diffusion tensor measures (fractional anisotropy [FA], mean diffusivity [MD]) across the mid-sagittal section of the corpus callosum in two samples of young individuals. In Part 1, we compared histology-derived axon diameter (Aboitiz et al., 1992) to MRI measures obtained in 402 young men (19.55 ± 0.84 years) recruited from the Avon Longitudinal Study on Parents and Children. In Part 2, we examined sex differences in FA, MD and magnetization transfer ratio (MTR) across the corpus callosum in 433 young (26.50 ± 0.51 years) men and women recruited from the Northern Finland Birth Cohort 1986. We found that R1, R2, and MWF follow the anterior-to-posterior profile of small-axon density. Sex differences in mean MTR were similar across the corpus callosum (males > females) while these in FA differed by the callosal segment (Body: M>F; Splenium: F>M). We suggest that the values of R1, R2 and MWF are driven by high surface area of myelin in regions with high density of “small axons”