Becky Inkster

GABA system dysfunction in autism and related disorders: From synapse to symptoms

Autism spectrum disorders (ASDs) are neurodevelopmental syndromes characterised by repetitive behaviours and restricted interests, impairments in social behaviour and relations, and in language and communication. These symptoms are also observed in a number of developmental disorders of known origin, including Fragile X Syndrome, Rett Syndrome, and Foetal Anticonvulsant Syndrome. While these conditions have diverse etiologies, and poorly understood pathologies, emerging evidence suggests that they may all be linked to dysfunction in particular aspects of GABAergic inhibitory signalling in the brain. We review evidence from genetics, molecular neurobiology and systems neuroscience relating to the role of GABA in these conditions. We conclude by discussing how these deficits may relate to the specific symptoms observed.

Quantitative multi-parameter mapping of R1, PD*, MT, and R2* at 3T: a multi-center validation

Multi-center studies using magnetic resonance imaging facilitate studying small effect sizes, global population variance and rare diseases. The reliability and sensitivity of these multi-center studies crucially depend on the comparability of the data generated at different sites and time points. The level of inter-site comparability is still controversial for conventional anatomical T1-weighted MRI data. Quantitative multi-parameter mapping (MPM) was designed to provide MR parameter measures that are comparable across sites and time points, i.e., 1 mm high-resolution maps of the longitudinal relaxation rate (R1 = 1/T1), effective proton density (PD*), magnetization transfer saturation (MT) and effective transverse relaxation rate (R2* = 1/T2*). MPM was validated at 3T for use in multi-center studies by scanning five volunteers at three different sites. We determined the inter-site bias, inter-site and intra-site coefficient of variation (CoV) for typical morphometric measures [i.e., gray matter (GM) probability maps used in voxel-based morphometry] and the four quantitative parameters. The inter-site bias and CoV were smaller than 3.1 and 8%, respectively, except for the inter-site CoV of R2* (<20%). The GM probability maps based on the MT parameter maps had a 14% higher inter-site reproducibility than maps based on conventional T1-weighted images. The low inter-site bias and variance in the parameters and derived GM probability maps confirm the high comparability of the quantitative maps across sites and time points. The reliability, short acquisition time, high resolution and the detailed insights into the brain microstructure provided by MPM makes it an efficient tool for multi-center imaging studies.

Association of GSK3β Polymorphisms With Brain Structural Changes in Major Depressive Disorder

CONTEXT Indirect evidence suggests that the glycogen synthase kinase-3beta (GSK3beta) gene might be implicated in major depressive disorder (MDD). BACKGROUND We evaluated 15 GSK3beta single-nucleotide polymorphisms (SNPs) to test for associations with regional gray matter (GM) volume differences in patients with recurrent MDD. We then used the defined regions of interest based on significant associations to test for MDD x genotype interactions by including a matched control group without any psychiatric disorder, including MDD. DESIGN General linear model with nonstationary cluster-based inference. SETTING Munich, Germany. PARTICIPANTS Patients with recurrent MDD (n = 134) and age-, sex-, and ethnicity-matched healthy controls (n = 143). MAIN OUTCOME MEASURES Associations between GSK3beta polymorphisms and regional GM volume differences. RESULTS Variation in GM volume was associated with GSK3beta polymorphisms; the most significant associations were found for rs6438552, a putative functional intronic SNP that showed 3 significant GM clusters in the right and left superior temporal gyri and the right hippocampus (P < .001, P = .02, and P = .02, respectively, corrected for multiple comparisons across the whole brain). Similar results were obtained with rs12630592, an SNP in high linkage disequilibrium. A significant SNP x MDD status interaction was observed for the effect on GM volumes in the right hippocampus and superior temporal gyri (P < .001 and P = .01, corrected, respectively). CONCLUSIONS The GSK3beta gene may have a role in determining regional GM volume differences of the right hippocampus and bilateral superior temporal gyri. The association between genotype and brain structure was specific to the patients with MDD, suggesting that GSK3beta genotypes might interact with MDD status. We speculate that this is a consequence of regional neocortical, glial, or neuronal growth or survival. In considering core cognitive features of MDD, the association of GSK3beta polymorphisms with structural variation in the temporal lobe and hippocampus is of particular interest in the context of other evidence for structural and functional abnormalities in the hippocampi of patients with MDD.

Adolescence is associated with genomically patterned consolidation of the hubs of the human brain connectome

Significance Adolescence is a period of human brain growth and high incidence of mental health disorders. Here, we show consistently in two MRI cohorts that human brain changes in adolescence were concentrated on the more densely connected hubs of the connectome (i.e., association cortical regions that mediated efficient connectivity throughout the human brain structural network). Hubs were less myelinated at 14 y but had faster rates of myelination and cortical shrinkage in the 14- to 24-y period. This topologically focused process of cortical consolidation was associated with expression of genes enriched for normal synaptic and myelin-related processes and risk of schizophrenia. Consolidation of anatomical network hubs could be important for normal and clinically disordered adolescent brain development. How does human brain structure mature during adolescence? We used MRI to measure cortical thickness and intracortical myelination in 297 population volunteers aged 14–24 y old. We found and replicated that association cortical areas were thicker and less myelinated than primary cortical areas at 14 y. However, association cortex had faster rates of shrinkage and myelination over the course of adolescence. Age-related increases in cortical myelination were maximized approximately at the internal layer of projection neurons. Adolescent cortical myelination and shrinkage were coupled and specifically associated with a dorsoventrally patterned gene expression profile enriched for synaptic, oligodendroglial- and schizophrenia-related genes. Topologically efficient and biologically expensive hubs of the brain anatomical network had greater rates of shrinkage/myelination and were associated with overexpression of the same transcriptional profile as cortical consolidation. We conclude that normative human brain maturation involves a genetically patterned process of consolidating anatomical network hubs. We argue that developmental variation of this consolidation process may be relevant both to normal cognitive and behavioral changes and the high incidence of schizophrenia during human brain adolescence.

Erythropoietin improves mood and modulates the cognitive and neural processing of emotion 3 days post administration.

Erythropoietin (Epo) has neuroprotective and neurotrophic effects and is a promising candidate for treatment of neurodegenerative and psychiatric disorder. Recently, we demonstrated that Epo modulates memory-relevant hippocampal response and fear processing in human models of antidepressant drug action 1 week post-administration, and improves self-reported mood for 3 days immediately following administration. The present study explored the effects of Epo (40 000 IU) vs saline on self-reported mood and on neural and cognitive function in healthy volunteers 3 days post-administration to test the reliability of the rapid mood improvement and its neuropsychological basis. Neuronal responses during the processing of happy and fearful faces were investigated using functional magnetic resonance imaging (fMRI); facial expression recognition performance was assessed after the fMRI scan. Daily ratings of mood were obtained for 3 days after Epo/saline administration. During faces processing Epo enhanced activation in the left amygdala and right precuneus to happy and fearful expressions. This was paired with improved recognition of all facial expressions, in particular of low intensity happiness and fear. This is similar to behavioral effects observed with acute administration of serotonergic antidepressants. Consistent with our previous finding, Epo improved self-reported mood for all 3 days post-administration. Together, these results suggest that characterization of the effects of Epo in a clinically depressed group is warranted.

Pathway-based approaches to imaging genetics association studies: Wnt signaling, GSK3beta substrates and major depression

Several lines of evidence implicate glycogen synthase kinase 3 beta (GSK3beta) in mood disorders. We recently reported associations between GSK3beta polymorphisms and brain structural changes in patients with recurrent major depressive disorder (MDD). Here we provide supporting observations by showing that polymorphisms in additional genes encoding proteins directly related to GSK3beta biological functions are associated with similar regional grey matter (GM) volume changes in MDD patients. We tested specifically for associations with genetic variation in canonical Wnt signaling pathway genes and in genes that encode substrate proteins of GSK3beta. We applied a general linear model with non-stationary cluster-based inference to examine associations between polymorphisms and regional voxel-based morphometry GM volume differences in recurrent MDD patients (n=134) and in age-, gender-, and ethnicity-matched healthy controls (n=144) to test for genotype-by-MDD interactions. We observed associations for polymorphisms in 8/13 canonical Wnt pathway genes and 5/10 GSK3beta substrate genes, predominantly in the temporolateral and medial prefrontal cortices. Similar associations were not found for 100 unrelated polymorphisms tested. This work suggests that identifying SNPs related to genes that encode functionally-interacting proteins that modulate common anatomical regions offers a useful approach to increasing confidence in outcomes from imaging genetics association studies. This is of particular interest when replication datasets are not available. Our observations lend support to the hypothesis that polymorphisms in GSK3beta play a role in MDD susceptibility or expression, in part, by acting via the canonical Wnt signaling pathway and related substrates.

Affective modulation of anterior cingulate cortex in young people at increased familial risk of depression.

BACKGROUND We previously found that children of parents with depression showed impaired performance on a task of emotional categorisation. AIMS To test the hypothesis that children of parents with depression would show abnormal neural responses in the anterior cingulate cortex, a brain region involved in the integration of emotional and cognitive information. METHOD Eighteen young people (mean age 19.8 years) with no personal history of depression but with a biological parent with a history of major depression (FH+ participants) and 16 controls (mean age 19.9 years) underwent functional magnetic resonance imaging while completing an emotional counting Stroop task. RESULTS Controls showed significant activation in the pregenual anterior cingulate cortex to both positive and negative words during the emotional Stroop task. This activation was absent in FH+ participants. CONCLUSIONS Our findings show that people at increased familial risk of depression demonstrate impaired modulation of the anterior cingulate cortex in response to emotionally valenced stimuli.

A Quantitative Trait Locus Analysis of the Dopamine Transporter Gene in Adults with ADHD

Numerous lines of evidence have shown that attention deficit hyperactivity disorder (ADHD) is a highly heritable disorder, whether it is considered as a category or a dimension. We tested for an association between the dopamine transporter gene (DAT1) and ADHD considering the disorder as categorical as well as a continuous trait. Genotypes for the DAT1 variable number of tandem repeat (VNTR) alleles, along with Brown Attention Deficit Disorder Scale (BADDS) and Wender Utah Rating Scale (WURS) scores were available for 152 adult ADHD patients. In 72 of these patients DNAs from at least one parent were accessible to perform a family-based analysis (FBAT). The mean quantitative trait values of the whole sample of singleton patients were compared among the specific genotype groups using ANOVA. The family-based analysis did not reveal any association between DAT1 alleles and ADHD either when it was considered as a dichotomous trait (Z = 0.16, p = .86) or as a continuous trait (Wender Scale Z = −1.67, p = .09; Brown ADD Scale Z = 0.28, p = .77). No significant differences were detected in the mean symptom scores among the specific genotype groups. The results from our study do not support a major role for the DAT1 VNTR alleles in our sample of adult ADHD. In view of several positive reports in child ADHD, more work is required to elucidate the potential role of the DAT1 VNTR as a risk factor in ADHD.

Structural brain changes in patients with recurrent major depressive disorder presenting with anxiety symptoms.

Major depressive disorder (MDD) presents with extensive clinical heterogeneity. In particular, overlap with anxiety symptoms is common during depressive episodes and as a comorbid disorder. The aim of this study was to test for morphological brain differences between patients having a history of recurrent MDD with, and without, anxiety symptoms (MDD+A and MDD−A).

Histone deacetylase gene variants predict brain volume changes in multiple sclerosis

Neuroimaging measures hold promise for enhancing the detection of disease-related genetic variants. In this study, we use advanced multivariate regression methods to assess the predictive value of single nucleotide polymorphisms (SNPs) on several brain volumetric- and lesion-related neuroimaging measures in a well-characterized cohort of 326 patients with multiple sclerosis (MS). SNP selection was constrained to key epigenetic regulatory genes to further explore the emerging role of epigenetics in MS. Regression models consistently identified rs2522129, rs2675231, and rs2389963 as having among the highest predictive values for explaining differences related to brain volume measures. These SNPs are all contained in genes from the same superfamily, histone deacetylases, which have biological functions that are relevant to MS, neurodegeneration, and aging. Our preliminary findings generate hypotheses for testing in future independent MS data sets as well as other neurodegenerative conditions.