Cortical Thickness Measurements Research Articles

Longitudinal ComBat: A method for harmonizing longitudinal multi-scanner imaging data

While aggregation of neuroimaging datasets from multiple sites and scanners can yield increased statistical power, it also presents challenges due to systematic scanner effects. This unwanted technical variability can introduce noise and bias into estimation of biological variability of interest. We propose a method for harmonizing longitudinal multi-scanner imaging data based on ComBat, a method originally developed for genomics and later adapted to cross-sectional neuroimaging data. Using longitudinal cortical thickness measurements from 663 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study, we demonstrate the presence of additive and multiplicative scanner effects in various brain regions. We compare estimates of the association between diagnosis and change in cortical thickness over time using three versions of the ADNI data: unharmonized data, data harmonized using cross-sectional ComBat, and data harmonized using longitudinal ComBat. In simulation studies, we show that longitudinal ComBat is more powerful for detecting longitudinal change than cross-sectional ComBat and controls the type I error rate better than unharmonized data with scanner included as a covariate. The proposed method would be useful for other types of longitudinal data requiring harmonization, such as genomic data, or neuroimaging studies of neurodevelopment, psychiatric disorders, or other neurological diseases.

Valproate Use Is Associated With Posterior Cortical Thinning and Ventricular Enlargement in Epilepsy Patients.

Valproate is a drug widely used to treat epilepsy, bipolar disorder, and occasionally to prevent migraine headache. Despite its clinical efficacy, prenatal exposure to valproate is associated with neurodevelopmental impairments and its use in children and adults was associated with rare cases of reversible brain atrophy and ventricular enlargement. To determine whether valproate use is related with structural brain changes we examined through a cross-sectional study cortical and subcortical structures in a group of 152 people with epilepsy and a normal clinical brain MRI. Patients were grouped into those currently using valproate (n = 54), those taking drugs other than valproate (n = 47), and drug-naïve patients (n = 51) at the time of MRI, irrespectively of their epilepsy syndrome. Cortical thickness and subcortical volumes were analyzed using Freesurfer, version 5.0. Subjects exposed to valproate (either in mono- or polytherapy) showed reduced cortical thickness in the occipital lobe, more precisely in the cuneus bilaterally, in the left lingual gyrus, and in left and right pericalcarine gyri when compared to patients who used other antiepileptic drugs, to drug-naïve epilepsy patients, and to healthy controls. Considering the subgroup of patients using valproate monotherapy (n = 25), both comparisons with healthy controls and drug-naïve groups confirmed occipital lobe cortical thickness reduction. Moreover, patients using valproate showed increased left and right lateral ventricle volume compared to all other groups. Notably, subjects who were non-valproate users at the time of MRI, but who had valproate exposure in the past (n = 27) did not show these cortical or subcortical brain changes. Cortical changes in the posterior cortex, particularly in the visual cortex, and ventricular enlargement, are present in people with epilepsy using valproate, independently from clinical and demographical variables. These findings are relevant both for the efficacy and adverse events profile of valproate use in people with epilepsy.

Extremely preterm children exhibit altered cortical thickness in language areas

Children born extremely preterm (< 28 weeks gestation, EPT) are at increased risk for language and other neurocognitive deficits compared to term controls (TC). Prior studies have reported both increases and decreases in cortical thickness in EPT across the cerebrum. These studies have not formally normalized for intracranial volume (ICV), which is especially important as EPT children often have smaller stature, head size, and ICV. We previously reported increased interhemispheric functional and structural connectivity in a well-controlled group of school-aged EPT children with no known brain injury or neurological deficits. Functional and structural hyperconnectivity between left and right temporoparietal regions was positively related with language scores in EPT, which may be reflected in measures of cortical thickness. To characterize possible language network cortical thickness effects, 15 EPT children and 15 TC underwent standardized assessments of language and structural magnetic resonance imaging at 4 to 6 years of age. Images were subjected to volumetric and cortical thickness analyses using FreeSurfer. Whole-brain analyses of cortical thickness were conducted both with and without normalization by ICV. Non-normalized results showed thinner temporal cortex for EPT, while ICV-normalized results showed thicker cortical regions in the right temporal lobe (FDRq = 0.05). Only ICV-normalized results were significantly related to language scores, with right temporal cortical thickness being positively correlated with performance.

Genome-wide mapping of brain phenotypes in extended pedigrees with strong genetic loading for bipolar disorder.

Bipolar disorder is a highly heritable illness, associated with alterations of brain structure. As such, identification of genes influencing inter-individual differences in brain morphology may help elucidate the underlying pathophysiology of bipolar disorder (BP). To identify quantitative trait loci (QTL) that contribute to phenotypic variance of brain structure, structural neuroimages were acquired from family members (n = 527) of extended pedigrees heavily loaded for bipolar disorder ascertained from genetically isolated populations in Latin America. Genome-wide linkage and association analysis were conducted on the subset of heritable brain traits that showed significant evidence of association with bipolar disorder (n = 24) to map QTL influencing regional measures of brain volume and cortical thickness. Two chromosomal regions showed significant evidence of linkage; a QTL on chromosome 1p influencing corpus callosum volume and a region on chromosome 7p linked to cortical volume. Association analysis within the two QTLs identified three SNPs correlated with the brain measures.

Little evidence for associations between the Big Five personality traits and variability in brain gray or white matter

Attempts to link the Big Five personality traits of Openness-to-Experience, Conscientiousness, Extraversion, Agreeableness, and Neuroticism with variability in trait-like features of brain structure have produced inconsistent results. Small sample sizes and heterogeneous methodology have been suspected in driving these inconsistencies. Here, using data collected from 1,107 university students (636 women, mean age 19.69 ​± ​1.24 years), representing the largest sample to date of unrelated individuals, we tested for associations between the Big Five personality traits and measures of cortical thickness and surface area, subcortical volume, and white matter microstructural integrity. In addition to replication analyses based on a prior study, we conducted exploratory whole-brain analyses. Four supplementary analyses were also conducted to examine 1) possible associations with lower-order facets of personality; 2) modulatory effects of sex; 3) effect of controlling for non-target personality traits; and 4) parcellation scheme effects. Our analyses failed to identify significant associations between the Big Five personality traits and brain morphometry, except for a weak association between greater surface area of the superior temporal gyrus and lower conscientiousness scores. As the latter association is not supported by previous studies, it should be treated with caution. Our supplementary analyses mirrored these predominantly null findings, suggesting they were not substantively biased by our analytic choices. Collectively, these results indicate that if there are associations between the Big Five personality traits and brain structure, they are likely of very small effect size and will require very large samples for reliable detection.

Relationship between ultrasonographically determined renal dimensions and International Renal Interest Society stages in cats with chronic kidney disease.

BackgroundThe correlation between renal dimensions and renal function in cats with chronic kidney disease (CKD) is unclear.Hypothesis/ObjectivesTo investigate the relationship between renal dimensions and CKD severity in cats using ultrasound examination.AnimalsNineteen healthy cats and 30 cats with CKD.MethodsRenal ultrasound images obtained between 2012 and 2016 were reviewed. Severity of CKD was determined using the International Renal Interest Society CKD staging system. Renal length, cortical thickness, medullary thickness, and corticomedullary ratio were measured, and the relationship between these renal dimensions and serum creatinine concentrations as well as differences in dimensions between the control and disease groups was investigated. The sensitivity and specificity of the renal dimensions for differentiation of the CKD also were evaluated.ResultsThe disease group was subdivided into stage I to II (15 cats) and stage III to IV (15 cats) groups. Cortical thickness was significantly decreased in both disease groups and negatively correlated with disease severity. Compared with other renal dimensions, cortical thickness had a stronger linear correlation with the reciprocal of the serum creatinine concentration and superior diagnostic performance (Youden index: left kidney, 90.0% sensitivity and 94.7% specificity for a cutoff of 4.7 mm; right kidney, 83.3% sensitivity and 94.7% specificity for a cutoff of 4.5 mm).Conclusions and Clinical ImportanceDecreased renal cortical thickness is observed in cats with loss of renal function. Measurement of cortical thickness using ultrasonography could be a useful method to evaluate the progression of CKD in cats.

Urate is closely linked to white matter integrity in multiple system atrophy.

ObjectiveWe aimed to investigate the association of the serum urate level with cortical thickness and white matter integrity in multiple system atrophy (MSA).MethodsWe recruited 75 MSA patients and 42 controls who underwent brain MRI and measured serum urate level at baseline. Using cortical thickness and tract‐based spatial statistics analyses, we investigated the correlation between serum urate levels and cortical thickness or diffusion tensor imaging (DTI) measures in controls and MSA patients. Interaction effects were analyzed to find different patterns of correlation according to sex and clinical subtype. We evaluated the relationship between serum urate levels, DTI measures, and total UMSARS score, using path analysis.ResultsSerum urate levels showed a positive correlation with FA values in the corpus callosum and a negative correlation with MD values in widespread regions including cerebellar, brainstem, and cerebral white matter in patients with MSA. Both sexes showed a negative correlation between serum urate levels and MD values without significant interaction effect. In subgroup analysis according to subtype, patients with cerebellar subtype showed a negative correlation. Serum urate levels did not correlated with cortical thickness. Path analysis showed that MD values in middle and inferior cerebellar peduncle mediated the association between serum urate level and total UMSAR score.InterpretationThe present study demonstrated that serum urate levels played a pivotal role in white matter disintegrity and clinical disability in MSA. It would provide an evidence of the role of urate as a potential neuroprotective factor against white matter neurodegeneration in MSA.

Longitudinal Structural MRI in Neurologically Healthy Adults.

BackgroundStructural brain MRI measures are frequently examined in both healthy and clinical groups, so an understanding of how these measures vary over time is desirable.PurposeTo test the stability of structural brain MRI measures over time.PopulationIn all, 112 healthy volunteers across four sites.Study TypeRetrospective analysis of prospectively acquired data.Field Strength/Sequence3 T, magnetization prepared – rapid gradient echo, and single‐shell diffusion sequence.AssessmentDiffusion, cortical thickness, and volume data from the sensorimotor network were assessed for stability over time across 3 years. Two sites used a Siemens MRI scanner, two sites a Philips scanner.Statistical TestsThe stability of structural measures across timepoints was assessed using intraclass correlation coefficients (ICC) for absolute agreement, cutoff ≥0.80, indicating high reliability. Mixed‐factorial analysis of variance (ANOVA) was used to examine between‐site and between‐scanner type differences in individuals over time.ResultsAll cortical thickness and gray matter volume measures in the sensorimotor network, plus all diffusivity measures (fractional anisotropy plus mean, axial and radial diffusivities) for primary and premotor cortices, primary somatosensory thalamic connections, and the cortico‐spinal tract met ICC. The majority of measures differed significantly between scanners, with a trend for sites using Siemens scanners to produce larger values for connectivity, cortical thickness, and volume measures than sites using Philips scanners.Data ConclusionLevels of reliability over time for all tested structural MRI measures were generally high, indicating that any differences between measurements over time likely reflect underlying biological differences rather than inherent methodological variability.Level of Evidence4.Technical Efficacy Stage1.

Association of Dementia and Vascular Risk Scores With Cortical Thickness and Cognition in Low-risk Middle-aged Adults.

Increased risk for the future development of Alzheimer disease begins as early as midlife. Algorithm-based scores, such as the Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) dementia risk score, and the Framingham general cardiovascular disease (CVD) risk score, have been used to determine future risk for the development of cognitive decline and dementia. We evaluated the association between neuroimaging and cognitive measures with the 2 risk scores in middle-aged, cognitively intact adults (49±6 y). In a cohort of 132 participants collected in 2014, magnetic resonance imaging was used to determine measures of cortical thickness in a priori regions of interest and a neuropsychological battery to assess memory and executive function. The CAIDE dementia risk score was significantly and inversely associated with the cortical thickness of the parahippocampal (r=-0.266; P=0.002) and superior frontal gyrus (r=-0.261; P=0.002) despite a considerable percentage of individuals (99.3%) at low risk for CVD. There was a significant negative association between CAIDE and memory (r=-0.251; P=0.003). Framingham general CVD score was not associated with brain structure or cognitive function. These results indicate that the CAIDE dementia risk score is associated with cortical thickness and cognitive function at midlife in a low-risk population. These data provide insight into subclinical structural and functional changes occurring during midlife associated with future risk for the development of dementia.

0873 Obstructive Sleep Apnea Impacts Brain Development in Obese Children and Adolescents: An MRI Study

Abstract Introduction Obstructive sleep apnea (OSA) is a breathing disorder characterized by episodes of nocturnal hypoxia and chronic systemic inflammation, affecting more than 50% of obese youths. Both obesity and OSA independently have a negative impact on brain structure and function, but their combined effect on the developing brain is unknown. The purpose of this study was to assess MRI measurements of cortical thickness (CT) in obese youths with various degrees of OSA severity. We hypothesized that CT is abnormal in obese adolescents with OSA. Methods 55 obese subjects (26 females, 29 males, mean 14.3 ± 2.4 years) were included in the analysis. All subjects were assessed with polysomnography (PSG) to evaluate presence and severity of OSA. T1-weighted MPRAGE images were acquired using a 3T MRI scanner following PSG. CT was extracted using the CIVET 2.1.1 pipeline, and statistical analysis was performed on SurfStat to examine global and regional CT in relation to age using a general linear model. Results Based on PSG outcome, subjects were divided into 3 groups, no OSA (OAHI &amp;lt; 1.5 events/hr., n = 15), mild OSA (OAHI &amp;lt; 5, n = 14), and moderate/severe OSA (OAHI &amp;#8805; 5, n = 26). Cortical thickness analysis revealed a negative-trending correlation between global CT and age in no OSA (T = -0.49, P &amp;gt; 0.6), as seen in typical development. This correlation weakened in the presence of mild OSA (T = -0.20, P &amp;gt; 0.8) and became significantly positive in moderate/severe OSA (T = 3.87, P = 0.001), affecting several cortical areas. Conclusion These results indicate that brain development in obese adolescents with moderate/severe OSA significantly deviates from the typical trajectory of cortical thinning. This thickening could be due to exacerbated inflammation from the combined effect of both diseases, or a neurotrophic effect of leptin. More data is needed to validate these findings. Support None

Linked patterns of biological and environmental covariation with brain structure in adolescence: a population-based longitudinal study

Adolescence is a period of major brain reorganization shaped by biologically timed and by environmental factors. We sought to discover linked patterns of covariation between brain structural development and a wide array of these factors by leveraging data from the IMAGEN study, a longitudinal population-based cohort of adolescents. Brain structural measures and a comprehensive array of non-imaging features (relating to demographic, anthropometric, and psychosocial characteristics) were available on 1476 IMAGEN participants aged 14 years and from a subsample reassessed at age 19 years (n = 714). We applied sparse canonical correlation analyses (sCCA) to the cross-sectional and longitudinal data to extract modes with maximum covariation between neuroimaging and non-imaging measures. Separate sCCAs for cortical thickness, cortical surface area and subcortical volumes confirmed that each imaging phenotype was correlated with non-imaging features (sCCA r range: 0.30–0.65, all PFDR < 0.001). Total intracranial volume and global measures of cortical thickness and surface area had the highest canonical cross-loadings (|ρ| = 0.31−0.61). Age, physical growth and sex had the highest association with adolescent brain structure (|ρ| = 0.24−0.62); at baseline, further significant positive associations were noted for cognitive measures while negative associations were observed at both time points for prenatal parental smoking, life events, and negative affect and substance use in youth (|ρ| = 0.10−0.23). Sex, physical growth and age are the dominant influences on adolescent brain development. We highlight the persistent negative influences of prenatal parental smoking and youth substance use as they are modifiable and of relevance for public health initiatives.

M154. INTRA- AND INTER-SCANNER RELIABILITY OF GRAY MATTER VOLUME AND CORTICAL THICKNESS ESTIMATES: IMPLICATIONS FOR MULTICENTRE IMAGING STUDIES IN PSYCHOSIS

BackgroundHigh-resolution structural MRI has been widely used in clinical research to detect and quantify subtle brain changes in patient populations. Findings from prospective, longitudinal studies show structural brain abnormalities as well as progressive gray matter changes over time in individuals at clinical high risk for psychosis compared to healthy subjects. In recent years, research in this field has seen an increase in multicentre neuroimaging projects, such as EU-GEI, PSYSCAN, PRONIA and NAPLS. Additional sources of variance, alongside known technological and biological factors, may be introduced when MRI images are acquired and combined from different sites. It is imperative for longitudinal multicentre studies to determine the accuracy of quantitative MRI measurements and account for systematic differences both between scanners and across scanning sessions. This is particularly true within psychosis research where morphometric changes as small as 3% or less are expected.MethodsSix healthy participants were scanned on four separate occasions over a two-month period at King’s College London; twice on a GE SIGNA HDx 3T scanner used locally in the EU-GEI High Risk Study and twice on a GE MR750 3T scanner used locally in the PSYSCAN study. Both scanners implemented the ADNI-2 T1 protocol which is used globally across the EU-GEI and PSYSCAN consortia. Structural imaging data was segmented using the FreeSurfer 6.0 longitudinal pipeline. Intraclass correlation coefficients (ICCs) with a two-way mixed effects model of absolute agreement were calculated to assess intra- and inter-scanner reliability of brain morphometry. For volumetric studies, ICC values greater than 0.9 indicate ‘excellent’ reliability. Reliability analyses of key regions implicated in psychosis included gray matter volume estimates of the hippocampus, insula, lateral ventricle, orbitofrontal cortex and anterior cingulate cortex, and average cortical thickness measurements of the whole brain, parahippocampus and superior frontal cortex.ResultsGray matter volume estimates of all structures yielded ‘excellent’ reliability for both intra-scanner (ICCs of 0.979 – 0.998) and inter-scanner analyses (ICCs of 0.976 – 0.999). Intra-scanner reliability for mean cortical thickness measurements was ‘excellent’ for right total cortex, resulting in an ICC of 0.901, but otherwise ‘good’ for left and total cortex, parahippocampus, superior frontal cortex (ICCs of 0.754 – 0.875). Inter-scanner reliability for mean cortical thickness estimates were most variable across the brain structures. Here, results demonstrated ‘excellent’ reliability for the parahippocampus and left total cortex (ICCs of 0.907 – 0.965), ‘good’ for total cortex (ICC of 0.835), ‘moderate’ for right total cortex, right and total superior frontal cortex (ICCs of 0.520 – 0.676), and ‘poor’ for the left superior frontal cortex which produced an ICC of 0.470. Overall, mean cortical thickness estimates of the superior frontal cortex from two different MR scanners showed the least reliability.DiscussionResults confirmed highly reliable estimates for gray matter volumes in all brain structures, both from images acquired within the same scanner and across two different scanners. However, the findings indicated increased variability of mean cortical thickness estimates, particularly between scanners, which should be considered when interpreting study findings. Multicentre structural neuroimaging within the field of psychosis is becoming more common and it must be acknowledged that combining MRI data in multicentre studies will contribute additional sources of variance and potential bias with certain brain regions affected more than others.

M166. THE EFFECT OF INTELLIGENCE AND EDUCATIONAL ATTAINMENT ON THE BRAIN IN THOSE WITH FAMILIAL HIGH RISK FOR SCHIZOPHRENIA OR BIPOLAR DISORDER: AN ENIGMA–RELATIVES STUDY

BackgroundSchizophrenia (SZ) and bipolar disorder (BD) are both associated with generally lower IQ test results and show overlapping structural brain abnormalities, albeit with lower effect sizes in BD. In contrast, our recent ENIGMA-Relatives meta-analysis showed that patients’ first-degree relatives (FDRs) have divergent patterns of global brain measures (De Zwarte et al. Biol. Psychiatry, 2019). FDRs-BD had larger intracranial volumes (ICV) than matched controls, a pattern not found in FDRs-SZ; when we adjusted for ICV, no differences were detected between FDRs-BD and controls. In contrast, FDRs-SZ had significantly smaller brain volumes, mean cortical thickness and larger ventricle volume than controls. Here, we extend this work by adding measures of local cortical thickness and surface area and by investigating the effect of IQ and educational attainment (EA) on global and local brain measures in FDRs.Methods6,134 participants from 36 cohorts worldwide were included: N(FDRs-SZ)=1,103, N(FDRs-BD)=867, N(controls)=2,529 (and N(SZ-patients)=942, N(BD-patients)=693). Most cohorts provided information on IQ and/or EA (years completed education in those aged >25 yr.). (Sub-)cortical reconstruction and volumetric segmentations were performed with FreeSurfer. Linear mixed model analyses were performed on brain measures, IQ, and EA within each cohort comparing FDRs to controls (taking family relatedness into account). Cohen’s d effect sizes (95%CI) were calculated.ResultsFDRs-SZ had a thinner cortex across most cortical regions, compared to controls, with a thinner pars orbitalis surviving correction for multiple testing (left d=– 0.17, right =– 0.16, q<0.05 corrected). FDRs-BD had larger regional surface area in many cortical areas than controls, with a significantly larger cortical surface area in the left transverse temporal, left parahippocampal, right superior temporal, right supramarginal and right transverse temporal regions surviving correction for multiple testing (d’s >+ 0.15, q<0.05, corrected).Mean IQ test scores were lower in both FDRs-SZ (d=–0.42, p<0.001) and FDRs-BD (d=–0.23, p=0.045); while relatives did not differ on EA from controls. The IQ-EA correlation was r=0.39 [0.31–0.47]. When adjusting for IQ or EA, the group differences in brain measures changed, albeit modestly. In FDRs-SZ, controlling for IQ explained part of the effect of familial risk for schizophrenia in total brain, gray and white matter volumes (i.e., reduced effect sizes), while in FDRs-BD IQ correction resulted in a larger average ICV compared to controls.DiscussionThis study showed differential patterns of cortical thickness and surface area abnormalities in FDRs-SZ and FDRs-BD. While present in both relative groups, cognitive deficits (but only IQ not EA) were more pronounced in FDRs-SZ. We found no evidence that larger ICV in FDRs-BD was related to IQ, suggesting that the differential brain developmental trajectories underlying predisposition for schizophrenia or bipolar disorder may be unrelated to IQ. These large-scale studies inform the debate on whether schizophrenia and bipolar disorder represent truly independent diagnostic categories or whether they fall on a continuum of overlapping symptom profiles.

O11.1. MULTIPLE GENOMIC MEASURES OF SCHIZOPHRENIA RISK ARE RELATED TO CORTICAL THICKNESS IN TYPICALLY DEVELOPING YOUTH AND YOUNG ADULTS

BackgroundThe incidence of psychotic disorders increases in adolescence and young adulthood. Transition to a psychotic disorder is associated with atypical development of brain structures, specifically protracted developmental course. It is unknown how polygenic risk for schizophrenia and gene expression profiles of schizophrenia risk genes affect typical brain development. The goal of the current study is to examine relationships multiple genomic measures associated with schizophrenia risk and structural neuroimaging measures thickness in typically developing youth.MethodsWe combined structural neuroimaging and genetic data from three different cohorts of typically developing youth (N=994, 5–30 years old): the Philadelphia Neurodevelopmental Cohort, Pediatric Imaging Neurocognition and Genetics Study, and a locally collected sample at the University of Pittsburgh. All youth were free from psychiatric disorders and not taking psychiatric medications. We used Freesurfer to process the T1-weighted structural scans and calculate subcortical volumes, cortical thickness, and surface area measurements. After regressing out study, sex, ancestry eigenvectors, and grey matter signal-to-noise ratio, we ran principal components analysis on all neuroimaging measures (N=156). We calculated a schizophrenia polygenic risk score using genome-wide summary statistics from the Psychiatric Genome Consortium. Using a generalized linear model, each of the top five principal components was evaluated in relation to the risk score. We then used a computational method, Predixcan, to calculate expected gene expression profiles from the genotype data. We selected 125 genes that were associated with schizophrenia in a previous case-control comparison. Elastic net regression was used to determine significant associations between individual gene expression and the principal components.ResultsSchizophrenia polygenic risk was statistically associated with the 5th principal component (b=-0.10, p=0.001), which consisted of contributions from multiple measures of cortical thickness. Reduced cortical thickness in frontal and temporal regions was associated with increased genetic liability for schizophrenia. Increased cortical thickness in sensory-motor areas was associated with higher schizophrenia polygenic risk scores. This relationship remained when age was included as a predictor of interest and there were no statistically significant interactions between schizophrenia polygenic risk and age. Sixteen unique gene expression profiles were also associated with this principal component, significantly increasing the proportion of variance explained in this measure (from ~1% with the schizophrenia polygenic risk only to ~6% when including the additional gene expression measures). Many of the genes significantly associated with this principal component have important roles during early fetal brain development, including neuronal migration (e.g., SDCCAG8) and DNA repair (e.g., MLH1).DiscussionThese results suggest that that genetic risk for schizophrenia has a consistent influence on subtle, individual differences in a distinct spatial pattern of cortical thickness across typical development. This spatial pattern of cortical thickness is also associated with schizophrenia risk genes that have important functions during early brain development. Taken together, these findings suggest that increased genetic risk for schizophrenia is related to early subtle alterations during early brain development, setting up individuals with higher risk profiles to have a small biological vulnerability for later developing the illness.

M155. RECIPROCAL CHANGES IN WHITE MATTER MICROSTRUCTURE IN 22Q11.2 DELETION AND DUPLICATION SYNDROME

BackgroundThe 22q11.2 deletion syndrome is a neurogenetic disorder that is associated with both physical anomalies and neurocognitive impairments. Deletion carriers have a greatly elevated risk of developing schizophrenia (SCZ); as such, it offers a compelling ‘high-penetrance’ model to explore the neuropathology of SCZ risk. Indeed, widespread structural alterations of both gray and white matter have been reported for 22q11.2 deletion carriers.Interestingly, there are also cases of duplications at the same gene locus. While less is known about the phenotype associated with 22q11.2 duplication, carriers also present physical and neurodevelopmental abnormalities, although they may have reduced risk of developing SCZ compared to the general population. The only study to date which looked at brain structure in duplication carriers found reciprocal effects of 22q11.2 deletion and duplication on cortical thickness and surface measurements.In the present study, we apply diffusion magnetic resonance imaging (MRI) to examine the white matter microstructure in both 22q11.2 deletion and duplication carriers.MethodsMulti-shell diffusion-weighted images were acquired on a 3 Tesla MRI scanner from 13 healthy control individuals (HC), 25 deletion carriers, and 18 22q11.2 duplication carriers. Images were preprocessed utilizing the Human Connectome Project (HCP) Minimal Preprocessing Pipeline v4.0.0.Free Water imaging was applied, which differentiates the diffusion signal into a free-water compartment and a tissue compartment. The output parameters are the free-water fractional volume (FW) and a free-water corrected diffusion tensor from which fractional anisotropy of the tissue (FAT) is calculated.We compared FAT and FW maps between 1) HC and 22q11.2 deletion carriers and 2) HC and 22q11.2 duplication carriers using Tract-Based Spatial Statistics (TBSS) and voxel-wise, non-parametric statistics (5000 permutations, threshold-free cluster enhancement, corrected for age and sex).Lastly, white matter clusters that displayed significant differences between 22q11.2 deletion or duplication and HC were extracted. We averaged FAT and FW values over these significant clusters for each individual and correlated with the scores of the Structured Interview for Prodromal Syndromes (SIPS).Results22q11.2 deletion carriers showed significant (p<0.05) FW reductions (72% of white matter skeleton) and FAT increase (8%) when compared to HC. In contrast, 22q11.2 duplication carriers displayed the opposite effect, with significant (p<0.05) widespread FW increase (51%) and FAT decrease (50%) when compared to HC.Both 22q11.2 deletion and duplication carriers scored higher on the SIPS than HC, with negative symptom score differences being the most pronounced (mean for HC= 1.36, mean for 22q11.2 duplication = 7.0, mean for 22q11.2 deletion =9.96, F=6.68, df=2, p<.003).FAT and FW were not associated with SIPS scores in 22q11.2 deletion syndrome. However, FAT was negatively correlated with the negative symptom score in 22q11.2 duplication carriers (Spearman rho=-.61, p<.009).DiscussionWe observed opposing effects of gene-dosage on FAT and FW. While we did not see an association between WM measurements and psychotic symptoms in 22q11.2 deletion, there was an association of WM structure with negative symptoms in 22q11.2 duplication carriers.These findings highlight the importance of studying the influence of reciprocal chromosomal imbalance on white matter architecture. Ongoing longitudinal studies may help advance understanding of the role of microstructural white matter abnormalities in the emergence of neuropsychiatric symptoms.

Predicting reading ability from brain anatomy and function: From areas to connections

Reading is a complex task involving different brain areas. As a crystallized ability, reading is also known to have effects on brain structure and function development. However, there are still open questions about what are the elements of the reading networks and how structural and functional brain measures shape the reading ability. The present study used a data-driven approach to investigate whether reading-related brain structural measures of cortical thickness, myelination, sulcus depth and structural connectivity and functional connectivity from the whole brain can predict individual differences in reading skills. It used different brain measures and performance scores from the Oral Reading Recognition Test (ORRT) measuring reading ability from 998 participants. We revealed reading-related brain areas and connections, and evaluated how well area and connection measures predict reading performance. Interestingly, the combination of all brain measures obtained the best predictions. We further grouped reading-related areas into positive and negative networks, each with four different levels (Core Regions, Extended-Regions 1, 2, 3), representing different correlation levels with the reading scores, and the non-correlated Region irrelevant to reading ability. The Core Regions are composed of areas that are most strongly correlated with reading performance. Insular and frontal opercular cortex, lateral temporal cortex, and early auditory cortex occupy the positive Core Region, while inferior temporal and motor cortex occupy the negative Core Region. Aside from those areas, the present study also found more reading-related areas including visual and language-related areas. In addition, connections predicting reading scores are denser inside the reading-related networks than outside. Together, the present study reveals extended reading networks of the brain and provides an extended data-driven analytical framework to study interpretable brain-behavior relationships, which are transferable also to studying other abilities.

Characteristics of gray matter alterations in never-treated and treated chronic schizophrenia patients

Though gray matter deficits have been consistently revealed in chronic treated schizophrenia, it is still not clear whether there are different brain alterations between chronic never treated and treated patients. To explore the different patterns of gray matter alterations among chronic never treated patients and those treated with monotherapy, we recruited 35 never-treated chronic schizophrenia patients with illness durations ranging from 5 to 48 years, 20 illness duration-matched risperidone monotherapy and 20 clozapine monotherapy patients, and 55 healthy controls. GM (surface area, cortical thickness, and cortical volume) measures were extracted and compared using ANCOVA across the four groups followed by post hoc tests. Relative to controls, both treated and never-treated chronic schizophrenia patients showed reduced GM mainly involving the bilateral medial and rostral middle frontal, left banks superior temporal sulcus, left fusiform, and left pericalcarine cortex and increased in the left cuneus. Compared with the untreated patient group, the two treated groups showed reductions mainly in the bilateral prefrontal, temporal, and left inferior parietal lobules. The clozapine monotherapy patients demonstrated more severe decreases in the bilateral prefrontal cortex and left cuneus and less severe decreases in the left ventral temporal lobe than risperidone monotherapy patients. These findings provide new insights into the long-term effects of antipsychotic treatment on gray matter alterations in schizophrenia patients. Furthermore, the characteristic findings of reductions in the inferior parietal lobule might be specific for long-term antipsychotic treatment, which could be a possible target for medication development in the future.

Influence of Processing Pipeline on Cortical Thickness Measurement.

In recent years, replicability of neuroscientific findings, specifically those concerning correlates of morphological properties of gray matter (GM), have been subject of major scrutiny. Use of different processing pipelines and differences in their estimates of the macroscale GM may play an important role in this context. To address this issue, here, we investigated the cortical thickness estimates of three widely used pipelines. Based on analyses in two independent large-scale cohorts, we report high levels of within-pipeline reliability of the absolute cortical thickness-estimates and comparable spatial patterns of cortical thickness-estimates across all pipelines. Within each individual, absolute regional thickness differed between pipelines, indicating that in-vivo thickness measurements are only a proxy of actual thickness of the cortex, which shall only be compared within the same software package and thickness estimation technique. However, at group level, cortical thickness-estimates correlated strongly between pipelines, in most brain regions. The smallest between-pipeline correlations were observed in para-limbic areas and insula. These regions also demonstrated the highest interindividual variability and the lowest reliability of cortical thickness-estimates within each pipeline, suggesting that structural variations within these regions should be interpreted with caution.

Genetic and environmental influences on structure of the social brain in childhood

Prosocial behavior and empathy are important aspects of developing social relations in childhood. Prior studies showed protracted structural development of social brain regions associated with prosocial behavior. However, it remains unknown how structure of the social brain is influenced by genetic or environmental factors, and whether overlapping heritability factors explain covariance in structure of the social brain and behavior. The current study examined this hypothesis in a twin sample (aged 7–9-year; N = 512). Bilateral measures of surface area and cortical thickness of the medial prefrontal cortex (mPFC), temporo-parietal junction (TPJ), posterior superior temporal sulcus (pSTS), and precuneus were analyzed. Results showed genetic contributions to surface area and cortical thickness for all brain regions. We found additional shared environmental influences for TPJ, suggesting that this region might be relatively more sensitive to social experiences. Genetic factors also influenced parent-reported prosocial behavior (A = 45%) and empathy (A = 59%). We provided initial evidence that the precuneus shares genetically determined variance with empathy, suggesting a possible small genetic overlap (9%) in brain structure and empathy. These findings show that structure of the social brain and empathy are driven by a combination of genetic and environmental factors, with some factors overlapping for brain structure and behavior.

CACNA1C Risk Variant and Mood Stabilizers Effects in the Prefrontal Cortical Thickness of Mexican Patients with Bipolar Disorder.

PurposeBipolar disorder (BD) is a condition associated with structural alterations in the prefrontal cortex (PFC); some genetic variants and mood stabilizer medications like lithium or valproate are associated with these changes. CACNA1C is a gene involved in BD pathology and brain function; carriers of the A allele of rs1006737 are reported to have increased risk for BD and increased cortical thickness (CT) in the PFC compared to non-carriers. Lithium is also associated with increased CT in the PFC of BD subjects compared to the ones on valproate. The influence of these treatments and gene variants over the PFC structure of Mexican subjects has not been explored. Therefore, we evaluate the effects of mood stabilizers and risk A allele of CACNA1C rs1006737 on the prefrontal cortical thickness of Mexican BD patients treated with lithium or valproate.Patients and MethodsA cross-sectional study of 40 BD type I euthymic adult outpatients (20 treated with lithium and 20 with valproate) who underwent a 3T T1-weighted 3D brain scan and genotyping for CACNA1C risk allele rs1006737 was conducted. We performed a cortical thickness analysis of the dorsolateral and orbitofrontal regions of the prefrontal cortex with BrainVoyager 20.6. The effects of treatment and gene variants were analyzed with a two-way multivariate analysis of covariance.ResultsThere was no association of CACNA1C risk allele rs1006737 with CT measures of both PFCs nor significant interaction between the genetic variant and treatment. Mood stabilizers reported the main effect on the CT measures of the right PFC of our sample. Patients on treatment with lithium showed higher mean CT on the right orbitofrontal cortex.ConclusionWe did not find any association between the prefrontal CT and CACNA1C risk A allele rs1006737 in BD Mexican patients treated with lithium or valproate. Our results suggest that mood stabilizers had the main effect in the CT of the right PFC.