Gray Matter Cortical Thickness Research Articles

Widespread Cortical Thickness Is Associated With Neuroactive Steroid Levels.

BackgroundNeuroactive steroids are endogenous molecules with regenerative and neuroprotective actions. Both cortical thickness and many neuroactive steroid levels decline with age and are decreased in several neuropsychiatric disorders. However, a systematic examination of the relationship between serum neuroactive steroid levels and in vivo measures of cortical thickness in humans is lacking.MethodsPeripheral serum levels of seven neuroactive steroids were assayed in United States military veterans. All (n = 143) subsequently underwent high-resolution structural MRI, followed by parcellelation of the cortical surface into 148 anatomically defined regions. Regression modeling was applied to test the association between neuroactive steroid levels and hemispheric total gray matter volume as well as region-specific cortical thickness. False discovery rate (FDR) correction was used to control for Type 1 error from multiple testing.ResultsNeuroactive steroid levels of allopregnanolone and pregnenolone were positively correlated with gray matter thickness in multiple regions of cingulate, parietal, and occipital association cortices (r = 0.20–0.47; p < 0.05; FDR-corrected).ConclusionPositive associations between serum neuroactive steroid levels and gray matter cortical thickness are found in multiple brain regions. If these results are confirmed, neuroactive steroid levels and cortical thickness may help in monitoring the clinical response in future intervention studies of neuroregenerative therapies.

An overlapping pattern of cerebral cortical thinning is associated with both positive symptoms and aggression in schizophrenia via the ENIGMA consortium.

Positive symptoms are a useful predictor of aggression in schizophrenia. Although a similar pattern of abnormal brain structures related to both positive symptoms and aggression has been reported, this observation has not yet been confirmed in a single sample. To study the association between positive symptoms and aggression in schizophrenia on a neurobiological level, a prospective meta-analytic approach was employed to analyze harmonized structural neuroimaging data from 10 research centers worldwide. We analyzed brain MRI scans from 902 individuals with a primary diagnosis of schizophrenia and 952 healthy controls. The result identified a widespread cortical thickness reduction in schizophrenia compared to their controls. Two separate meta-regression analyses revealed that a common pattern of reduced cortical gray matter thickness within the left lateral temporal lobe and right midcingulate cortex was significantly associated with both positive symptoms and aggression. These findings suggested that positive symptoms such as formal thought disorder and auditory misperception, combined with cognitive impairments reflecting difficulties in deploying an adaptive control toward perceived threats, could escalate the likelihood of aggression in schizophrenia.

Precentral and cerebellar atrophic changes in moyamoya disease using 7-T magnetic resonance imaging.

Background Chronic repeated transient ischemic changes are one of the common symptoms of moyamoya disease that could affect cortical and subcortical atrophy. Purpose We aimed to assess the cortical gray matter volume and thickness, white matter subcortical volume, and clinical characteristics using 7-T magnetic resonance imaging (MRI) and MR angiography (MRA). Material and Methods In this case-control study, whole-brain parcellation of gray matter and subcortical volumes were manually assessed in nine patients with moyamoya disease (18 hemispheres; median age = 34 years; age range = 10–60 years) and nine healthy controls (18 hemispheres; median age = 29 years; age range = 20–62 years) matched for age and sex, who underwent both 7-T MRI and MRA. The volumes were measured using high-resolution image (&lt;1 mm) processing based on the Desikan-Killiany-Tourville (DKT) atlas, via an automated segmentation method (FreeSurfer version 6.0). Results The gray matter volume of the left precentral cortex and the white matter volume of the subcortical cerebellum were lower in both hemispheres in the patients with moyamoya disease compared to the healthy controls. Conclusion Gray matter atrophy in the precentral cortex and cerebellar white matter were detected in this 7-T MRI volumetric analysis study of patients with moyamoya disease who experienced repeated transient ischemic changes. Cortical atrophy in precentral cortex and cerebellum could explain the transient motor weakness in patients with moyamoya disease, as one of the early findings was that patients with moyamoya disease do not have detectable infarction changes on conventional MRI images.

Multimodal data revealed different neurobiological correlates of intelligence between males and females.

Intelligence is a socially and scientifically interesting topic because of its prominence in human behavior, yet there is little clarity on how the neuroimaging and neurobiological correlates of intelligence differ between males and females, with most investigations limited to using either mass-univariate techniques or a single neuroimaging modality. Here we employed connectome-based predictive modeling (CPM) to predict the intelligence quotient (IQ) scores for 166 males and 160 females separately, using resting-state functional connectivity, grey matter cortical thickness or both. The identified multimodal, IQ-predictive imaging features were then compared between genders. CPM showed high out-of-sample prediction accuracy (r > 0.34), and integrating both functional and structural features further improved prediction accuracy by capturing complementary information (r = 0.45). Male IQ demonstrated higher correlations with cortical thickness in the left inferior parietal lobule, and with functional connectivity in left parahippocampus and default mode network, regions previously implicated in spatial cognition and logical thinking. In contrast, female IQ was more correlated with cortical thickness in the right inferior parietal lobule, and with functional connectivity in putamen and cerebellar networks, regions previously implicated in verbal learning and item memory. Results suggest that the intelligence generation of males and females may rely on opposite cerebral lateralized key brain regions and distinct functional networks consistent with their respective superiority in cognitive domains. Promisingly, understanding the neural basis of gender differences underlying intelligence may potentially lead to optimized personal cognitive developmental programs and facilitate advancements in unbiased educational test design.

Structural and Functional Amygdala Abnormalities in Hemifacial Spasm

Background and Purpose: Hemifacial spasm (HFS) is a rare neuromuscular disorder characterized by unilateral, involuntary, and paroxysmal contractions of orofacial muscles. To elucidate the central neural mechanisms of HFS, we investigated brain gray matter and resting-state functional connectivity (rsFC) in HFS patients.Methods: Thirty patients with HFS and 30 age- and sex-matched healthy participants consented to the study. T1-weighted structural magnetic resonance imaging (MRI) and resting-state BOLD images were collected in all participants. Cortical gray matter thickness was assessed, and subcortical volumetric analysis was performed. Seed-based rsFC analysis was performed on structurally abnormal regions in HFS patients. Post hoc correlations with HFS severity and measures of mood (i.e., depression and anxiety) were performed to characterize rsFC alterations.Results: There were no significant differences in cortical thickness in HFS patients compared to healthy controls. Patients with HFS presented smaller right amygdala volume in contrast to healthy controls (q < 0.05, false-discovery rate corrected). We found that the right amygdala had increased rsFC with bilateral medial prefrontal cortex (mPFC), bilateral orbital frontal cortex (OFC), and left posterior insula (L postIns; voxel-wise p < 0.05, family-wise error corrected). Moreover, the connections of amygdala–postIns and amygdala–mPFC were positively related to HFS severity and anxiety, respectively.Conclusions: This is the first study to show structural and functional brain abnormalities in HFS. The volumetric and rsFC amygdala abnormalities were potentially driven by HFS, providing novel insights into HFS pathophysiology.

Whole-exome sequencing identifies variants associated with structural MRI markers in patients with bipolar disorders

Bipolar disorder (BD) is one of the most heritable psychiatric disorders. A growing number of whole-exome sequencing (WES) studies for BD has been performed, however, no research has examined the association between single nucleotide variants (SNVs) from WES and structural magnetic resonance imaging (MRI) data. We sequenced whole-exomes in 53 patients with BD and 82 healthy control participants at an initial discovery stage and investigated the impacts of SNVs in risk genes from WES analysis on the cortical gray-matter thickness and integrity of white matter tracts and in the following stage. Cortical thickness and white matter integrity were investigated using the FreeSurfer and TRACULA (Tracts Constrained by UnderLying Anatomy). We identified 122 BD-related genes including KMT2C, AHNAK, CDH23, DCHS1, FRAS1, MACF1 and RYR3 and observed 27 recurrent copy number alteration regions including gain on 8p23.1 and loss on 15q11.1 - q11.2. Among them, single nucleotide polymorphism (SNP) rs4639425 in KMT2C gene, which regulates histone H3 lysine 4 (H3K4) methylation involved in chromatin remodeling, was associated with widespread alterations of white matter integrity including the cingulum, uncinate fasciculus, cortico-spinal tract, and superior longitudinal fasciculus. The small sample size of patients with BD in the genome data may cause our study to be underpowered when searching for putative rare mutations. This study first combined a WES approach and neuroimaging findings in psychiatric disorders. We postulate the rs4639425 may be associated with BD-related microstructural changes of white matter tracts.

Structural brain differences in emotional processing and regulation areas between male batterers and other criminals: A preliminary study

ABSTRACTPoor emotion processing is thought to influence violent behaviors among male batterers in abusive relationships. Nevertheless, little is known about the neural mechanisms of emotion processing in this population. With the objective of better understanding brain structure and its relation to emotion processing in male batterers, the present study compares the cortical grey matter thickness of male batterers to that of other criminals in brain areas related to emotion. Differences among these brain areas were also compared to an emotional perception task. An MRI study and an emotional perception assessment was conducted with 21 male batterers and 20 men convicted of crimes other than Intimate Partner Violence (IPV). Results demonstrated that batterers’ had significantly thinner cortices in prefrontal (orbitofrontal), midline (anterior and posterior cingulate) and limbic (insula, parahipocampal) brain regions. The thickness of the dorsal posterior cingulate cortex in the batterer group correlated with scores on the emotional perception task. These findings shed light on a neuroscientific approach to analyzing violent behavior perpetrated by male batterers, leading to a better understanding of the underlying mechanisms involved in IPV.

Socioeconomic status moderates age-related differences in the brain’s functional network organization and anatomy across the adult lifespan

An individual's environmental surroundings interact with the development and maturation of their brain. An important aspect of an individual's environment is his or her socioeconomic status (SES), which estimates access to material resources and social prestige. Previous characterizations of the relation between SES and the brain have primarily focused on earlier or later epochs of the lifespan (i.e., childhood, older age). We broaden this work to examine the relationship between SES and the brain across a wide range of human adulthood (20-89 years), including individuals from the less studied middle-age range. SES, defined by education attainment and occupational socioeconomic characteristics, moderates previously reported age-related differences in the brain's functional network organization and whole-brain cortical structure. Across middle age (35-64 years), lower SES is associated with reduced resting-state system segregation (a measure of effective functional network organization). A similar but less robust relationship exists between SES and age with respect to brain anatomy: Lower SES is associated with reduced cortical gray matter thickness in middle age. Conversely, younger and older adulthood do not exhibit consistent SES-related difference in the brain measures. The SES-brain relationships persist after controlling for measures of physical and mental health, cognitive ability, and participant demographics. Critically, an individual's childhood SES cannot account for the relationship between their current SES and functional network organization. These findings provide evidence that SES relates to the brain's functional network organization and anatomy across adult middle age, and that higher SES may be a protective factor against age-related brain decline.

Link between vascular risk factors and grey matter cortical thickness in early MS and the moderating influence of sex (S24.006)

Link between vascular risk factors and grey matter cortical thickness in early MS and the moderating influence of sex (S24.006)

Structural brain abnormalities in the common epilepsies assessed in a worldwide ENIGMA study.

Progressive functional decline in the epilepsies is largely unexplained. We formed the ENIGMA-Epilepsy consortium to understand factors that influence brain measures in epilepsy, pooling data from 24 research centres in 14 countries across Europe, North and South America, Asia, and Australia. Structural brain measures were extracted from MRI brain scans across 2149 individuals with epilepsy, divided into four epilepsy subgroups including idiopathic generalized epilepsies (n =367), mesial temporal lobe epilepsies with hippocampal sclerosis (MTLE; left, n = 415; right, n = 339), and all other epilepsies in aggregate (n = 1026), and compared to 1727 matched healthy controls. We ranked brain structures in order of greatest differences between patients and controls, by meta-analysing effect sizes across 16 subcortical and 68 cortical brain regions. We also tested effects of duration of disease, age at onset, and age-by-diagnosis interactions on structural measures. We observed widespread patterns of altered subcortical volume and reduced cortical grey matter thickness. Compared to controls, all epilepsy groups showed lower volume in the right thalamus (Cohen's d = -0.24 to -0.73; P < 1.49 × 10-4), and lower thickness in the precentral gyri bilaterally (d = -0.34 to -0.52; P < 4.31 × 10-6). Both MTLE subgroups showed profound volume reduction in the ipsilateral hippocampus (d = -1.73 to -1.91, P < 1.4 × 10-19), and lower thickness in extrahippocampal cortical regions, including the precentral and paracentral gyri, compared to controls (d = -0.36 to -0.52; P < 1.49 × 10-4). Thickness differences of the ipsilateral temporopolar, parahippocampal, entorhinal, and fusiform gyri, contralateral pars triangularis, and bilateral precuneus, superior frontal and caudal middle frontal gyri were observed in left, but not right, MTLE (d = -0.29 to -0.54; P < 1.49 × 10-4). Contrastingly, thickness differences of the ipsilateral pars opercularis, and contralateral transverse temporal gyrus, were observed in right, but not left, MTLE (d = -0.27 to -0.51; P < 1.49 × 10-4). Lower subcortical volume and cortical thickness associated with a longer duration of epilepsy in the all-epilepsies, all-other-epilepsies, and right MTLE groups (beta, b < -0.0018; P < 1.49 × 10-4). In the largest neuroimaging study of epilepsy to date, we provide information on the common epilepsies that could not be realistically acquired in any other way. Our study provides a robust ranking of brain measures that can be further targeted for study in genetic and neuropathological studies. This worldwide initiative identifies patterns of shared grey matter reduction across epilepsy syndromes, and distinctive abnormalities between epilepsy syndromes, which inform our understanding of epilepsy as a network disorder, and indicate that certain epilepsy syndromes involve more widespread structural compromise than previously assumed.

Total brain, cortical, and white matter volumes in children previously treated with glucocorticoids.

BackgroundPerinatal exposure to glucocorticoids and elevated endogenous glucocorticoid levels during childhood can have detrimental effects on the developing brain. Here, we examined the impact of glucocorticoid treatment during childhood on brain volumes.MethodsA total of 30 children and adolescents with rheumatic or nephrotic disease previously treated with glucocorticoids and 30 controls matched on age, sex, and parent education underwent magnetic resonance imaging (MRI) of the brain. Total cortical gray and white matter, brain, intracranial volume, and total cortical thickness and surface area were derived from MRI scans.ResultsPatients had significantly smaller gray and white matter and total brain volumes relative to healthy controls. Brain volume differences disappeared when accounting for intracranial volume, as patients had relatively smaller intracranial volumes. Group differences were mainly driven by the children with rheumatic disease. Total cortical thickness and cortical surface area did not significantly differ between groups. We found no significant associations between glucocorticoid-treatment variables and volumetric measures.ConclusionObserved smaller total brain, cortical gray, and white matter volumes in children and adolescents previously treated with glucocorticoids compared with that in healthy controls may reflect both developmental and degenerative processes. Prospective longitudinal studies are warranted to clarify whether findings are related to treatment or disease.

14.3 Patterns of Cortical Gray Matter Changes in Youth With First-Episode Mania: A Surface-Based Magnetic Resonance Imaging Study With Cluster Analysis

Although structural gray matter abnormalities have been identified in youth with bipolar disorder (BD), findings from existing neuroimaging studies are inconsistent. The pathophysiological heterogeneity of the disorder probably contributes to these differences and limits their clinical impact. The aim of this study was to investigate whether different patterns of cortical gray matter thickness are present and predict treatment response in a group of first-episode manic youth.

Reproducibility of quantitative structural and physiological MRImeasurements.

IntroductionQuantitative longitudinal magnetic resonance imaging and spectroscopy (MRI/S) is used to assess progress of brain disorders and treatment effects. Understanding the significance of MRI/S changes requires knowledge of the inherent technical and physiological consistency of these measurements. This longitudinal study examined the variance and reproducibility of commonly used quantitative MRI/S measurements in healthy subjects while controlling physiological and technical parameters.MethodsTwenty‐five subjects were imaged three times over 5 days on a Siemens 3T Verio scanner equipped with a 32‐channel phase array coil. Structural (T1, T2‐weighted, and diffusion‐weighted imaging) and physiological (pseudocontinuous arterial spin labeling, proton magnetic resonance spectroscopy) data were collected. Consistency of repeated images was evaluated with mean relative difference, mean coefficient of variation, and intraclass correlation (ICC). Finally, a “reproducibility rating” was calculated based on the number of subjects needed for a 3% and 10% difference.ResultsStructural measurements generally demonstrated excellent reproducibility (ICCs 0.872–0.998) with a few exceptions. Moderate‐to‐low reproducibility was observed for fractional anisotropy measurements in fornix and corticospinal tracts, for cortical gray matter thickness in the entorhinal, insula, and medial orbitofrontal regions, and for the count of the periependymal hyperintensive white matter regions. The reproducibility of physiological measurements ranged from excellent for most of the magnetic resonance spectroscopy measurements to moderate for permeability‐diffusivity coefficients in cingulate gray matter to low for regional blood flow in gray and white matter.DiscussionThis study demonstrates a high degree of longitudinal consistency across structural and physiological measurements in healthy subjects, defining the inherent variability in these commonly used sequences. Additionally, this study identifies those areas where caution should be exercised in interpretation. Understanding this variability can serve as the basis for interpretation of MRI/S data in the assessment of neurological disorders and treatment effects.

NORMATIVE MODEL OF BRAIN STRUCTURES IN THE KOREAN ELDERLY: A GENERAL LINEAR APPROACH

The study aimed to present the normative information of cortical gray matter thickness and subcortical volumes of the brain in the Korean elderly. We measured cortical gray matter thickness and subcortical volumes from anatomical MRI scans of 681 cognitively normal participants aged 65 to 80 using FreeSurfer. General linear model analyses were performed with age as the independent variable and region of interest measures as the dependent variable. Gender and education level were added into the models as covariates since they are considered as potential confounding variables on evaluating the relationship between brain measures and age. Beta coefficient estimates of age were estimated at each cortical vertex and subcortical structure. Among the four lobes, the temporal lobe, particularly the entorhinal cortex, showed the most rapid decay with age (min(beta) = - 0.02 mm per year). Mean and standard deviation also were calculated. This normative model of the aging brain provides the age-related reference ranges needed to facilitate research and clinical decision making such as diagnosis of neurodegenerative diseases.

LONGITUDINAL EFFECT OF CLUSTERIN LEVELS ON CORTICAL THICKNESS IN THE AUSTRALIAN IMAGING BIOMARKERS LIFESTYLE (AIBL) STUDY OF AGING

Clusterin (Apolipoprotein J) is associated with Alzheimer's disease (AD) pathogenesis, and higher levels of clusterin are associated with increased cognitive decline in AD. We hypothesize that failure of clusterin chaperonic activity contributes to AD and hence could be a valuable therapeutics target for preclinical AD. In this study, we investigated the effect of clusterin levels on cortical grey matter thickness as assessed by Magnetic Resonance Imaging (MRI) data. The data of 87 (35 M) healthy subjects aged 68.8 (SD 5.9) years old from AIBL was used in this study. Neuropsychological classification of the included healthy participants remained unchanged during 36 months. Clusterin levels of each subject was measured at baseline, and at 18 and 36 months follow-ups using Mesoscale Discovery Platform. At each time point, subjects underwent a MRI. Cortical thickness was computed from the T1-weighted MRI data. We used a linear mixed effects model to model temporal reduction of cortical thickness, with respect to age, gender, apolipoprotein E ε4 allele status, baseline clusterin level. Clusterin levels are negatively associated with cortical thickness (p=0.026) at baseline. However, the significant interaction between time-point and clusterin levels (p=0.002) indicates that a higher clusterin level was associated with slower decline in cortical thickness.

Cortical abnormalities in bipolar disorder: an MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group

Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen’s d=−0.293; P=1.71 × 10−21), left fusiform gyrus (d=−0.288; P=8.25 × 10−21) and left rostral middle frontal cortex (d=−0.276; P=2.99 × 10−19). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

Ventricular enlargement and progressive reduction of cortical gray matter are linked in prodromal youth who develop psychosis

In a recent prospective longitudinal neuroimaging study, clinical high-risk (CHR) individuals who later developed full-blown psychosis showed an accelerated rate of gray matter thinning in superior and medial prefrontal cortex (PFC) and expansion of the ventricular system after applying a stringent correction for multiple comparisons. Although cortical and subcortical volume loss and enlarged ventricles are well characterized structural brain abnormalities among patients with schizophrenia, no prior study has evaluated whether these progressive changes of neuroanatomical indicators are linked in time prior to onset of psychosis. Therefore, we investigated the relationship between the changes in cortical gray matter thickness and ventricular volume using the longitudinal neuroimaging data from the North American Prodrome Longitudinal Study at the whole-brain level. The results showed that ventricular expansion is linked in time to progressive reduction of gray matter, rather than to structural changes in proximal subcortical regions, in a broadly distributed set of cortical regions among CHR youth, including superior, medial, lateral, and inferior PFC, superior temporal gyrus, and parietal cortices. In contrast, healthy controls did not show the same pattern of associations. The main findings were further replicated using a third assessment wave of MRI scans in a subset of study participants who were followed for an additional year. These findings suggest that the gray matter regions exhibiting aberrant rates of thinning in relation to psychosis risk are not limited to the PFC regions that survived the statistical threshold in our primary study, but also extend to other cortical regions previously implicated in schizophrenia.

Differential microstructural and morphological abnormalities in mild cognitive impairment and Alzheimer's disease: Evidence from cortical and deep gray matter.

One aim of this study is to use non-Gaussian diffusion kurtosis imaging (DKI) for capturing microstructural abnormalities in gray matter of Alzheimer's disease (AD). The other aim is to compare DKI metrics against thickness of cortical gray matter and volume of deep gray matter, respectively. A cohort of 18 patients with AD, 18 patients with amnestic mild cognitive impairment (MCI), and 18 normal controls underwent morphological and DKI MR imaging. Images were investigated using regions-of-interest-based analyses for deep gray matter and vertex-wise analyses for cortical gray matter. In deep gray matter, more regions showed DKI parametric abnormalities than atrophies at the early MCI stage. Mean kurtosis (MK) exhibited the largest number of significant abnormalities among all DKI metrics. At the later AD stage, diffusional abnormalities were observed in fewer regions than atrophies. In cortical gray matter, abnormalities in thickness were mainly in the medial and lateral temporal lobes, which fit the locations of known early pathological changes. Microstructural abnormalities were predominantly in the parietal and even frontal lobes, which fit the locations of known late pathological changes. In conclusion, MK can complement conventional diffusion metrics for detecting microstructural changes, especially in deep gray matter. This study also provides evidence supporting the notion that microstructural changes predate morphological changes. Hum Brain Mapp 38:2495-2508, 2017. © 2017 Wiley Periodicals, Inc.

Small vessel disease is linked to disrupted structural network covariance in Alzheimer's disease

IntroductionCerebral small vessel disease (SVD) is thought to contribute to Alzheimer's disease (AD) through abnormalities in white matter networks. Gray matter (GM) hub covariance networks share only partial overlap with white matter connectivity, and their relationship with SVD has not been examined in AD. MethodsWe developed a multivariate analytical pipeline to elucidate the cortical GM thickness systems that covary with major network hubs and assessed whether SVD and neurodegenerative pathologic markers were associated with attenuated covariance network integrity in mild AD and normal elderly control subjects. ResultsSVD burden was associated with reduced posterior cingulate corticocortical GM network integrity and subneocorticocortical hub network integrity in AD. DiscussionThese findings provide evidence that SVD is linked to the selective disruption of cortical hub GM networks in AD brains and point to the need to consider GM hub covariance networks when assessing network disruption in mixed disease.

M45 - Exploring The Effects of Muscarinic M1 Receptor Sequence Variation on Executive Functioning In Schizophrenia And Healthy Controls

Background Despite cognitive deficits being recognised as a core feature of schizophrenia (Sz), comprehensive understanding of the underlying aetiology remains elusive. Evidence has implicated a dysfunctional muscarinic system in contributing to the executive functioning (EF) deficits prevalent in Sz. Two independent investigations have investigated a SNP at the M1 receptor gene c.267C (rs2067477) that reportedly spares EF capabilities in Sz. Both studies indicated that patients who were heterozygous at c.267C made less perseverative errors on the Wisconsin Card Sorting Test (WCST) as compared to the homozygous group. This SNP has not been investigated beyond the WCST nor has the influence on cognition been explored in a healthy population. In both a Sz and healthy control sample, the current study sought to determine whether the rs2067477 genotype influences EF outside of that documented using the WCST. To provide a more holistic understanding of the influence M1 receptor sequence variation is having in Sz, the present study explored if differences in the genotype is associated with differential changes in cortical thickness of a number of EF-critical brain regions. Methods Study 1: Genotype and neuropsychological data were obtained from 70 Sz/schizoaffective (SzA) patients and 165 healthy controls. Participants completed the Mazes and Spatial Span Backwards sub-tests of the MATRICS consensus cognitive battery as part of an ongoing investigation. Study 2: Imaging and genotype data were obtained from 176 Sz/SzA patients and 109 healthy controls from the Australian Schizophrenia Research Bank. Image pre-processing and Surfaced-based morphometry was performed using the FreeSurfer analysis suite. Results Study 1: For the Mazes, only a significant main effect of group was returned, with healthy controls outperforming patients. Furthermore, a significant main effect of group and significant group by genotype interaction was returned for Spatial Span Backwards performance. In contrast to previous findings patients who were homozygous outperformed the heterozygous group, whilst homozygous and heterozygous healthy controls both equally outperformed the patient group. Study 2: Group-based statistical analysis across left and right hemispheres for five brain regions (anterior cingulate, rostral middle frontal gyrus, pars opercularis/triangularis/orbitalis) revealed no significant differences in grey matter thickness across genotype. Similarly, no significant group by genotype interactions were returned for any of the five brain regions included in the analysis. An additional exploratory analysis was performed using all 33 bilateral brain regions produced by the FreeSurfer analysis suite, with no significant results being returned. Discussion These preliminary results suggest that our current understanding of the rs2067477 genotype variation is not comprehensive enough, revealing a conflicting pattern of EF-rs20767477 genotype in schizophrenia compared to that previously documented. Furthermore, whilst this is the first study to investigate M1 receptor gene variation effects on EF in healthy controls, it appears that the association is disease specific, however more comprehensive investigations are required and recommended. Additional studies are likewise required to examine if rs2067477 genotype variation is associated with differential changes in brain structure in schizophrenia, as the present study was unable to identify any changes in cortical grey matter thickness.