Subregional hippocampal morphology and psychiatric outcome in adolescents who were born very preterm and at term

Background: The hippocampus has been reported to be structurally and functionally altered as a sequel of very preterm birth ( < 33 weeks gestation), possibly due its vulnerability to hypoxic-ischemic damage in the neonatal period. We examined hippocampal volumes and subregional morphology in very preterm born individuals in mid- and late adolescence and their association with psychiatric outcome. Methods: Structural brain magnetic resonance images were acquired at two time points (baseline and follow-up) from 65 ex-preterm adolescents (mean age = 15.5 and 19.6 years) and 36 termborn controls (mean age=15.0 and 19.0 years). Hippocampal volumes and subregional morphometric differences were measured from manual tracings and with three-dimensional shape analysis. Psychiatric outcome was assessed with the Rutter Parents' Scale at baseline, the General Health Questionnaire at follow-up and the Peters Delusional Inventory at both time points. Results: In contrast to previous studies we did not find significant difference in the cross-sectional or longitudinal hippocampal volumes between individuals born preterm and controls, despite preterm individual having significantly smaller whole brain volumes. Shape analysis at baseline revealed subregional deformations in 28% of total bilateral hippocampal surface, reflecting atrophy, in ex-preterm individuals compared to controls, and in 22% at follow-up. In ex-preterm individuals, longitudinal changes in hippocampal shape accounted for 11% of the total surface, while in controls they reached 20%. In the whole sample (both groups) larger right hippocampal volume and bilateral anterior surface deformations at baseline were associated with delusional ideation scores at follow-up. Conclusions: This study suggests a dynamic association between cross-sectional hippocampal volumes, longitudinal changes and surface deformations and psychosis proneness. Copyright

Newborn brain structural characteristics and their relationships with maternal prenatal distress : Findings from the FinnBrain Birth Cohort MRI Study

Plasticity renders the brain sensitive to its intrauterine environment and susceptible to alterations during early brain development. The amygdala and hippocampus, structures key in socioemotional functions, are susceptible to these alterations. Understanding the normal variation in the newborn brain facilitates the recognition of such aberrant developmental trajectories, which may occur after exposure to maternal prenatal psychological distress (PPD) and result in a predisposition to psychopathology. This study aimed to 1) describe the normal variation of newborn brain volumetric measures in relation to newborn characteristics; 2) assess the prevalence and risk factors of incidental findings in newborn brain magnetic resonance imaging (MRI); 3) investigate how different types and timings of maternal PPD associate with newborn amygdalar and hippocampal volumes, and whether this association is modified by newborn sex. Information on maternal depressive and anxiety symptoms was gathered at gestational weeks (GW) 14, 24 and 34, and pregnancy¬specific anxiety (PSA) symptoms at GW24. Newborns were imaged with MRI at two to five weeks of postnatal age (n=175). The sub studies constituted variant samples sizes from the total population. Newborn brain lobar volumes were similarly asymmetric in both sexes. Modest sex differences were observed in regional brain volumes. Newborn age predicted larger volumes of gray and white matter. The prevalence of incidental findings in brain MRI was 7.4 % and that of hemorrhages 6.9 %. Risk factors for hemorrhages were vaginal and vacuum-assisted deliveries. All the different types of PPD associated with the left newborn amygdalar volume at GW24 in a sex-specific manner. In males, PPD predicted smaller amygdalar volumes, while in females larger amygdalar volumes. Further analyses suggested a negative association between PSA and the right hippocampal volume in females. Newborn sex appears to be a significant factor moderating the relationship between PPD and newborn brain structures, suggesting sex-specific susceptibility to psychopathologies.Vastasyntyneen aivojen rakenteelliset ominaisuudet ja niiden yhteydet äidin raskaudenaikaiseen stressiin – tuloksia FinnBrain syntymäkohortin MRI-tutkimuksesta Aivojen muovautuvuus herkistää aivot kohdunsisäiselle ympäristölle ja lisää alttiutta muutoksille niiden kehityksessä. Muutoksille herkkiä rakenteita ovat mantelitumake ja aivoturso, jotka ovat tärkeitä sosioemotionaalisissa toiminnoissa. Aivorakenteiden normaalivaihtelun ymmärtäminen helpottaa poikkeavien kehityssuuntien havait¬semista, jollaisia voi kehittyä äidin raskaudenaikaiselle psykologiselle stressille (RPS) altistumisen jälkeen ja jotka voivat altistaa psykiatrisille häiriöille. Tutkimuksen tavoitteena oli 1) kuvata vastasyntyneiden aivorakenteiden tilavuuksien normaalivaihtelua suhteessa vastasyntyneen ominaisuuksiin; 2) kartoittaa vastasyntyneiden aivojen magneettikuvantamisen sattumalöydösten esiin¬tyvyys ja riskitekijät; 3) tutkia äidin RPS:n eri tyyppien ja ajoituksen yhteyttä vastasyntyneen mantelitumakkeen ja aivoturson tilavuuksiin, sekä vaikuttaako vastasyntyneen sukupuoli yhteyteen. Raskaana olevien äitien masennus-ja ahdistuneisuusoireita mitattiin raskausviikoilla (RV) 14, 24, 34 ja raskausspesifistä ahdistuneisuutta (RSA) RV:lla 24. Vastasyntyneet (n=175) kuvattiin magneetti¬kameralla kahden-viiden viikon ikäisinä syntymän jälkeen. Osatutkimuksien otoskoot koostuivat vaihtelevista osista koko tutkimuspopulaatiota. Vastasyntyneen aivolohkojen asymmetriassa ei ollut eroa sukupuolten välillä. Maltillisia sukupuolieroja havaittiin aivotilavuuksissa rajatuilla alueilla. Vasta¬syntyneen ikä ennusti suurempia harmaan ja valkean aineen tilavuuksia. Sattuma¬löydösten esiintyvyys aivokuvissa oli 7.4 % ja verenvuotojen 6.9 %. Verenvuotojen riskitekijät olivat alatie-ja imukuppisynnytykset. RPS:n eri tyypit olivat vahvimmin yhteydessä vastasyntyneiden vasemman mantelitumaketilavuuden kanssa RV:lla 24 sukupuoliriippuvaisella tavalla, mikä ilmeni pienempinä tilavuuksina poikavauvoilla ja suurempina tilavuuksina tyttövauvoilla. Lisäanalyysit viittasivat negatiiviseen yhteyteen RPS:n ja tyttöjen oikean aivotursotilavuuden välillä. Sukupuoli vaikuttaisi säätelevän RPS:n vaikutuksia vastasyntyneen aivoihin mahdollisesti lisäten alttiutta tietyllä sukupuolella toista useammin esiintyville psykiatrisille häiriöille.Vastasyntyneen aivojen rakenteelliset ominaisuudet ja niiden yhteydet äidin raskaudenaikaiseen stressiin – tuloksia FinnBrain syntymäkohortin MRI-tutkimuksesta Aivojen muovautuvuus herkistää aivot kohdunsisäiselle ympäristölle ja lisää alttiutta muutoksille niiden kehityksessä. Muutoksille herkkiä rakenteita ovat mantelitumake ja aivoturso, jotka ovat tärkeitä sosioemotionaalisissa toiminnoissa. Aivorakenteiden normaalivaihtelun ymmärtäminen helpottaa poikkeavien kehityssuuntien havait¬semista, jollaisia voi kehittyä äidin raskaudenaikaiselle psykologiselle stressille (RPS) altistumisen jälkeen ja jotka voivat altistaa psykiatrisille häiriöille. Tutkimuksen tavoitteena oli 1) kuvata vastasyntyneiden aivorakenteiden tilavuuksien normaalivaihtelua suhteessa vastasyntyneen ominaisuuksiin; 2) kartoittaa vastasyntyneiden aivojen magneettikuvantamisen sattumalöydösten esiin¬tyvyys ja riskitekijät; 3) tutkia äidin RPS:n eri tyyppien ja ajoituksen yhteyttä vastasyntyneen mantelitumakkeen ja aivoturson tilavuuksiin, sekä vaikuttaako vastasyntyneen sukupuoli yhteyteen. Raskaana olevien äitien masennus-ja ahdistuneisuusoireita mitattiin raskausviikoilla (RV) 14, 24, 34 ja raskausspesifistä ahdistuneisuutta (RSA) RV:lla 24. Vastasyntyneet (n=175) kuvattiin magneetti¬kameralla kahden-viiden viikon ikäisinä syntymän jälkeen. Osatutkimuksien otoskoot koostuivat vaihtelevista osista koko tutkimuspopulaatiota. Vastasyntyneen aivolohkojen asymmetriassa ei ollut eroa sukupuolten välillä. Maltillisia sukupuolieroja havaittiin aivotilavuuksissa rajatuilla alueilla. Vasta¬syntyneen ikä ennusti suurempia harmaan ja valkean aineen tilavuuksia. Sattuma¬löydösten esiintyvyys aivokuvissa oli 7.4 % ja verenvuotojen 6.9 %. Verenvuotojen riskitekijät olivat alatie-ja imukuppisynnytykset. RPS:n eri tyypit olivat vahvimmin yhteydessä vastasyntyneiden vasemman mantelitumaketilavuuden kanssa RV:lla 24 sukupuoliriippuvaisella tavalla, mikä ilmeni pienempinä tilavuuksina poikavauvoilla ja suurempina tilavuuksina tyttövauvoilla. Lisäanalyysit viittasivat negatiiviseen yhteyteen RPS:n ja tyttöjen oikean aivotursotilavuuden välillä. Sukupuoli vaikuttaisi säätelevän RPS:n vaikutuksia vastasyntyneen aivoihin mahdollisesti lisäten alttiutta tietyllä sukupuolella toista useammin esiintyville psykiatrisille häiriöille

Amygdala subnuclei development in adolescents with autism spectrum disorder: Association with social communication and repetitive behaviors

Introduction: The amygdala subnuclei regulate emotional processing and are widely implicated in social cognitive impairments often seen in children with autism spectrum disorder (ASD). Dysregulated amygdala development has been reported in young children with ASD; less is known about amygdala maturation in later adolescence, a sensitive window for social skill development. Methods: The macrostructural development of the amygdala subnuclei was assessed at two time points in a longitudinal magnetic resonance imaging (MRI) study of adolescents with ASD (n = 23) and typically-developing adolescents (n = 15). In adolescents with ASD, amygdala subnuclei growth was assessed in relation to ASD symptomatology based on standardized diagnostic assessments. Participants were scanned with MRI at median age of 12 years and returned for a second scan at a median age of 15 years. The volumes of nine amygdala subnuclei were extracted using an automatic segmentation algorithm. Results: When examining the longitudinal data acquired across two time points, adolescents with ASD had larger basolateral amygdala (BLA) nuclei volumes compared to typically developing adolescents (B = 46.8, p = 0.04). When examining ASD symptomatology in relation to the growth of the amygdala subnuclei, reciprocal social interaction scores on the ADI-R were positively associated with increased growth of the BLA nuclei (B = 8.3, p \u3c 0.001). Growth in the medial nucleus negatively predicted the communication (B = −46.9, p = 0.02) and social (B = −47.7, p \u3c 0.001) domains on the ADOS-G. Growth in the right cortical nucleus (B = 26.14, p = 0.02) positively predicted ADOS-G social scores. Central nucleus maturation (B = 29.9, p = 0.02) was associated with the repetitive behaviors domain on the ADOS-G. Conclusions: Larger BLA volumes in adolescents with ASD may reflect underlying alterations in cellular density previously reported in post-mortem studies. Furthermore, findings demonstrate an association between regional growth in amygdala subnuclei volumes and ASD symptomatology. Improved understanding of the developmental trajectories of the amygdala subnuclei may aid in identifying key windows for interventions, particularly for social communication, in adolescents with ASD

The Reeler Mouse: A Translational Model of Human Neurological Conditions, or Simply a Good Tool for Better Understanding Neurodevelopment?

The first description of the Reeler mutation in mouse dates to more than fifty years ago, and later, its causative gene (reln) was discovered in mouse, and its human orthologue (RELN) was demonstrated to be causative of lissencephaly 2 (LIS2) and about 20% of the cases of autosomal-dominant lateral temporal epilepsy (ADLTE). In both human and mice, the gene encodes for a glycoprotein referred to as reelin (Reln) that plays a primary function in neuronal migration during development and synaptic stabilization in adulthood. Besides LIS2 and ADLTE, RELN and/or other genes coding for the proteins of the Reln intracellular cascade have been associated substantially to other conditions such as spinocerebellar ataxia type 7 and 37, VLDLR-associated cerebellar hypoplasia, PAFAH1B1-associated lissencephaly, autism, and schizophrenia. According to their modalities of inheritances and with significant differences among each other, these neuropsychiatric disorders can be modeled in the homozygous (reln(-/-)) or heterozygous (reln(+/-)) Reeler mouse. The worth of these mice as translational models is discussed, with focus on their construct and face validity. Description of face validity, i.e., the resemblance of phenotypes between the two species, centers onto the histological, neurochemical, and functional observations in the cerebral cortex, hippocampus, and cerebellum of Reeler mice and their human counterparts

Association of Amygdala Development with Different Forms of Anxiety in Autism Spectrum Disorder

Background: The amygdala is widely implicated in both anxiety and autism spectrum disorder. However, no studies have investigated the relationship between co-occurring anxiety and longitudinal amygdala development in autism. Here, the authors characterize amygdala development across childhood in autistic children with and without traditional DSM forms of anxiety and anxieties distinctly related to autism. Methods: Longitudinal MRI scans were acquired at up to four timepoints for 71 autistic and 55 typically developing (TD) children (∼2.5-12 years, 411 timepoints). Traditional DSM anxiety and anxieties distinctly related to autism were assessed at study Time 4 (∼8-12 years) using a diagnostic interview tailored to autism: The Anxiety Disorders Interview Schedule-IV with the Autism Spectrum Addendum. Mixed effects models were used to test group differences at study Time 1 (3.18 years), Time 4 (11.36 years), and developmental differences (age-by-group interactions) in right and left amygdala volume between autistic children with and without DSM or autism distinct anxieties, and TD. Results: Autistic children with DSM anxiety had significantly larger right amygdala volumes compared to TD at both study Time 1 (5.10% increase) and Time 4 (6.11% increase). Autistic children with autism distinct anxieties had significantly slower right amygdala growth compared to TD, autism-no anxiety, and autism-DSM anxiety groups and smaller right amygdala volumes at Time 4 compared to the autism-no anxiety (-8.13% decrease) and autism-DSM anxiety (-12.05% decrease) groups. Conclusions: Disparate amygdala volumes and developmental trajectories between DSM and autism distinct forms of anxiety suggest different biological underpinnings for these common, co-occurring conditions in autism

Maternal Nutrient Restriction with Fetal Growth Restriction in Guinea Pigs Impacts Brain Development and Neuroimaging Correlates in Neonatal Offspring

Aberrant brain development in utero accompanied by fetal growth restriction (FGR) increases the risk of neurodevelopmental disorders in later life. However there are limited non-invasive biomarkers in the brain for the early identification of said neurodevelopmental disorders in an animal model of FGR. Guinea pig sows were fed either ad libitum (Control) or 70% of the control diet pre-pregnancy, increasing to 90% at mid-pregnancy (MNR) creating appropriately grown (AGA) Control and FGR-MNR neonates, respectively. Three to four weeks corrected post-natal age, neonates were imaged using magnetic resonance imaging (MRI) and spectroscopy (MRS) techniques, and were killed 48-72 hours later for histological analysis. FGR-MNR neonates had smaller brain weights, whole brain volume, hippocampal volume and lateral ventricle volume, which correlate to histological findings. While there is a reduction in the hippocampal volume, there are no differences in hippocampus metabolite ratios between the AGA-Control and FGR-MNR neonates. Interestingly, there was a reduction in the width of the stratum oriens and stratum radiatum in the hippocampus proper, as well as the width of the polymorphic layer in the dentate gyrus, with no changes in pyramidal and granule cell number in the FGR-MNR neonates compared to AGA-Control neonates. In conclusion, MNR in guinea pigs produces FGR neonates that display catch up growth and structural differences in the brains while no changes in the metabolite levels in the hippocampal region of the brain. Together these results involve MRI and MRS as reliable imaging tools to detect the presence of brain injury for the future use of biomarkers for neurodevelopmental disorders and potential therapeutic interventions

Prenatal maternal health and child brain structure: Implications for non-verbal ability and optimizing subcortical segmentation

Brain development starts in utero, and the fetal brain can already be affected by the environment, including chemical exposures and maternal health characteristics. These factors range from exposures to large quantities of teratogens (such as alcohol) to variations in the behaviors and characteristics of healthy individuals (such as age, diet, and subclinical levels of depressive and anxiety symptoms), which can nonetheless have long-lasting adverse effects. In this thesis, we reviewed the literature on the effects of prenatal exposures on human neurodevelopment, as well as cognitive, behavioral, and health outcomes. In Study I we found that prenatal exposures are often reported poorly in infant neuroimaging studies and gave recommendations for reporting in future studies. In Study II, we examined which early life factors predicted cortical structure in 5-year-olds. The results from Study II were utilized to make an informed decision regarding confounders in future studies in the 5-year-old neuroimaging sample of the FinnBrain Birth Cohort study. In Study III, we explored the cortical structural correlates of non-verbal ability in 5-year-olds. The findings were generally in line with prior results from adult and adolescent studies, with the important addition of a positive association between gray matter volume and surface area in the right medial occipital region and non-verbal ability as well as visual abstract reasoning ability. Finally, in Study IV, we compared the results from two common segmentation tools, FSL-FIRST and FreeSurfer, against manual segmentation in the hippocampus and subcortical structures. Overall, the agreement with manual segmentation was good, although results were suboptimal for the hippocampus, amygdala, and nucleus accumbens, and careful visual quality control is still recommended. This thesis summarized different perinatal factors affecting the developing brain, and ensured the high quality of our neuroimaging data. This foundational work, together with the multidisciplinary, longitudinal data collection in the FinnBrain Birth Cohort study, can be used to discover how environmental factors affect brain development.Äidin raskausajan terveys ja lapsen aivojen rakenne: yhteydet ei-kielellisiin taitoihin ja subkortikaalisen segmentaation optimointi Aivojen kehitys alkaa kohdussa ja jatkuu läpi elämän. Jo sikiöaikana aivot ovat alttiina ympäristön vaikutuksille, ml. kemialliset altisteet sekä äidin terveyteen liittyvät tekijät. Nämä altisteet vaihtelevat suurista annoksista teratogeeneille (esim. alkoholille) eroihin terveiden yksilöiden ominaisuuksissa ja toiminnassa (esim. ikä, ruokavalio sekä vähäiset masennus- ja ahdistusoireet ilman mielenterveyshäiriön diagnoosia), joilla voi kuitenkin olla kauaskantoisia seuraamuksia. Tässä väitöskirjassa teemme katsauksen raskaudenaikaisten altisteiden vaikutuksista yksilön kehitykseen sekä siihen liittyviin muutoksiin aivoissa. Tutkimuksessa I toteamme, että raskaudenaikaiset altisteet kuvataan usein puutteellisesti vauvojen aivokuvantamista koskevissa tutkimuksissa ja annamme suosituksia raportoinnista. Tutkimuksessa II tutkimme varhaisten altisteiden yhteyksiä 5-vuotiaiden aivojen rakenteeseen. Tämän tutkimuksen tulokset ohjasivat kontrolloitavien muuttujien valintaa. Tutkimuksessa III tutkimme aivokuoren rakenteen yhteyksiä ei-kielelliseen kognitiiviseen kyvykkyyteen 5-vuotiailla. Tulokset olivat pitkälti linjassa aiempien, vanhemmilla osallistujilla tehtyjen tutkimusten kanssa. Uutena tuloksena löysimme yhteyden oikean takaraivolohkon mediaalisen osan tilavuuden ja pinta-alan olevan yhteydessä ei-kielelliseen kyvykkyyteen sekä erityisesti näönvaraiseen päättelyyn. Tutkimuksessa IV vertailimme kahta yleistä segmentointityökalua (FreeSurfer ja FSL-FIRST) käsin tehtyyn segmentaatioon hippokampuksessa ja aivokuoren alaisissa tumakkeissa. Tulokset vaihtelivat paljon rakenteesta riippuen. Huolellista laadunvarmistusta aivoalueiden koon määrityksen yhteydessä suositellaan vahvasti. Tämä väitöskirja antaa kokonaisvaltaisen ymmärryksen aivoihin vaikuttavista varhaisen elämän altisteista. Yhdessä korkealaatuisen aivokuvantamisdatamme sekä muun FinnBrain-syntymäkohortissa kerättävän aineiston kanssa tätä tietoa voidaan hyödyntää useissa tulevissa aivojen kehitystä selvittävissä tutkimuksissa

Dravet syndrome as epileptic encephalopathy: Evidence from long-term course and neuropathology

Dravet syndrome is an epilepsy syndrome of infantile onset, frequently caused by SCN1A mutations or deletions. Its prevalence, long-term evolution in adults and neuropathology are not well known. We identified a series of 22 adult patients, including three adult post-mortem cases with Dravet syndrome. For all patients, we reviewed the clinical history, seizure types and frequency, antiepileptic drugs, cognitive, social and functional outcome and results of investigations. A systematic neuropathology study was performed, with post-mortem material from three adult cases with Dravet syndrome, in comparison with controls and a range of relevant paediatric tissue. Twenty-two adults with Dravet syndrome, 10 female, were included, median age 39 years (range 20–66). SCN1A structural variation was found in 60% of the adult Dravet patients tested, including one post-mortem case with DNA extracted from brain tissue. Novel mutations were described for 11 adult patients; one patient had three SCN1A mutations. Features of Dravet syndrome in adulthood include multiple seizure types despite polytherapy, and age-dependent evolution in seizure semiology and electroencephalographic pattern. Fever sensitivity persisted through adulthood in 11 cases. Neurological decline occurred in adulthood with cognitive and motor deterioration. Dysphagia may develop in or after the fourth decade of life, leading to significant morbidity, or death. The correct diagnosis at an older age made an impact at several levels. Treatment changes improved seizure control even after years of drug resistance in all three cases with sufficient follow-up after drug changes were instituted; better control led to significant improvement in cognitive performance and quality of life in adulthood in two cases. There was no histopathological hallmark feature of Dravet syndrome in this series. Strikingly, there was remarkable preservation of neurons and interneurons in the neocortex and hippocampi of Dravet adult post-mortem cases. Our study provides evidence that Dravet syndrome is at least in part an epileptic encephalopathy

Traumatic Early Life Stress in the Developing Hippocampus: A Meta-Analysis of MRI Studies

Advancements in neuroimaging techniques afford researchers the opportunity to examine the actual brains of living persons, which exponentially contributes to new insights regarding brain and behavior phenomena. However, empirical studies investigating stress and the hippocampus attend primarily to adult populations - less on children and adolescents. Covariates such as the type of trauma, the duration and severity of the abuse, genetic predispositions, gender, poverty, and age often present as confounding factors that muddle the attempts to establish linkages between interpersonal, environmental, and neurobiological correlates. Although researchers primarily agree that traumatic early life stress (TELS) has some impact on early brain development, there is a lack of consensus around specific causes and the strength of influence. Tenets from Charcot\u27s trauma theory and Selye\u27s general adaptation syndrome organized the development of a meta-analysis which carefully examined the relationship between TELS and aberrant hippocampal development. Study selection was based on PRISMA standards which provide a template of a 27-item qualitative checklist for the writing and reviewing of research using secondary data sources. Criteria for inclusion resulted in 22 studies identified for preliminary analysis and 9 for the final report. The analysis revealed a vast range in individual study effect sizes (d = 0.000 to -1.892). The cumulative analysis of p values ranged from p = .005 (random effects) to p \u3c .001 (fixed effects) indicated a relationship between TELS and hippocampal development existed and underscored the necessity for researchers to shift more attention and resources to how covariates influence effect size differences