Bogdan Draganski

The 16p11.2 locus modulates brain structures common to autism, schizophrenia and obesity

Anatomical structures and mechanisms linking genes to neuropsychiatric disorders are not deciphered. Reciprocal copy number variants at the 16p11.2 BP4-BP5 locus offer a unique opportunity to study the intermediate phenotypes in carriers at high risk for autism spectrum disorder (ASD) or schizophrenia (SZ). We investigated the variation in brain anatomy in 16p11.2 deletion and duplication carriers. Beyond gene dosage effects on global brain metrics, we show that the number of genomic copies negatively correlated to the gray matter volume and white matter tissue properties in cortico-subcortical regions implicated in reward, language and social cognition. Despite the near absence of ASD or SZ diagnoses in our 16p11.2 cohort, the pattern of brain anatomy changes in carriers spatially overlaps with the well-established structural abnormalities in ASD and SZ. Using measures of peripheral mRNA levels, we confirm our genomic copy number findings. This combined molecular, neuroimaging and clinical approach, applied to larger datasets, will help interpret the relative contributions of genes to neuropsychiatric conditions by measuring their effect on local brain anatomy.

Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities

IMPORTANCE The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI). OBJECTIVES To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD. DESIGN, SETTING, AND PARTICIPANTS This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives. MAIN OUTCOMES AND MEASURES Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data. RESULTS Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (≤40) and higher than the mean (>100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies. CONCLUSIONS AND RELEVANCE The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits.

The Number of Genomic Copies at the 16p11.2 Locus Modulates Language, Verbal Memory, and Inhibition

BACKGROUND Deletions and duplications of the 16p11.2 BP4-BP5 locus are prevalent copy number variations (CNVs), highly associated with autism spectrum disorder and schizophrenia. Beyond language and global cognition, neuropsychological assessments of these two CNVs have not yet been reported. METHODS This study investigates the relationship between the number of genomic copies at the 16p11.2 locus and cognitive domains assessed in 62 deletion carriers, 44 duplication carriers, and 71 intrafamilial control subjects. RESULTS IQ is decreased in deletion and duplication carriers, but we demonstrate contrasting cognitive profiles in these reciprocal CNVs. Deletion carriers present with severe impairments of phonology and of inhibition skills beyond what is expected for their IQ level. In contrast, for verbal memory and phonology, the data may suggest that duplication carriers outperform intrafamilial control subjects with the same IQ level. This finding is reminiscent of special isolated skills as well as contrasting language performance observed in autism spectrum disorder. Some domains, such as visuospatial and working memory, are unaffected by the 16p11.2 locus beyond the effect of decreased IQ. Neuroimaging analyses reveal that measures of inhibition covary with neuroanatomic structures previously identified as sensitive to 16p11.2 CNVs. CONCLUSIONS The simultaneous study of reciprocal CNVs suggests that the 16p11.2 genomic locus modulates specific cognitive skills according to the number of genomic copies. Further research is warranted to replicate these findings and elucidate the molecular mechanisms modulating these cognitive performances.

Neurobiological origin of spurious brain morphological changes: A quantitative MRI study

The high gray‐white matter contrast and spatial resolution provided by T1‐weighted magnetic resonance imaging (MRI) has made it a widely used imaging protocol for computational anatomy studies of the brain. While the image intensity in T1‐weighted images is predominantly driven by T1, other MRI parameters affect the image contrast, and hence brain morphological measures derived from the data. Because MRI parameters are correlates of different histological properties of brain tissue, this mixed contribution hampers the neurobiological interpretation of morphometry findings, an issue which remains largely ignored in the community. We acquired quantitative maps of the MRI parameters that determine signal intensities in T1‐weighted images (R1 (=1/T1), R2*, and PD) in a large cohort of healthy subjects (n = 120, aged 18–87 years). Synthetic T1‐weighted images were calculated from these quantitative maps and used to extract morphometry features—gray matter volume and cortical thickness. We observed significant variations in morphometry measures obtained from synthetic images derived from different subsets of MRI parameters. We also detected a modulation of these variations by age. Our findings highlight the impact of microstructural properties of brain tissue—myelination, iron, and water content—on automated measures of brain morphology and show that microstructural tissue changes might lead to the detection of spurious morphological changes in computational anatomy studies. They motivate a review of previous morphological results obtained from standard anatomical MRI images and highlight the value of quantitative MRI data for the inference of microscopic tissue changes in the healthy and diseased brain. Hum Brain Mapp 37:1801–1815, 2016.

Differential patterns of functional and structural plasticity within and between inferior frontal gyri support training-induced improvements in inhibitory control proficiency

Ample evidence indicates that inhibitory control (IC), a key executive component referring to the ability to suppress cognitive or motor processes, relies on a right‐lateralized fronto‐basal brain network. However, whether and how IC can be improved with training and the underlying neuroplastic mechanisms remains largely unresolved. We used functional and structural magnetic resonance imaging to measure the effects of 2 weeks of training with a Go/NoGo task specifically designed to improve frontal top‐down IC mechanisms. The training‐induced behavioral improvements were accompanied by a decrease in neural activity to inhibition trials within the right pars opercularis and triangularis, and in the left pars orbitalis of the inferior frontal gyri. Analyses of changes in brain anatomy induced by the IC training revealed increases in grey matter volume in the right pars orbitalis and modulations of white matter microstructure in the right pars triangularis. The task‐specificity of the effects of training was confirmed by an absence of change in neural activity to a control working memory task. Our combined anatomical and functional findings indicate that differential patterns of functional and structural plasticity between and within inferior frontal gyri enhanced the speed of top‐down inhibition processes and in turn IC proficiency. The results suggest that training‐based interventions might help overcoming the anatomic and functional deficits of inferior frontal gyri manifesting in inhibition‐related clinical conditions. More generally, we demonstrate how multimodal neuroimaging investigations of training‐induced neuroplasticity enable revealing novel anatomo‐functional dissociations within frontal executive brain networks. Hum Brain Mapp 36:2527–2543, 2015.

Basal Ganglia-Cortical Structural Connectivity in Huntington's Disease

Huntingtons disease is an incurable neurodegenerative disease caused by inheritance of an expanded cytosine‐adenine‐guanine (CAG) trinucleotide repeat within the Huntingtin gene. Extensive volume loss and altered diffusion metrics in the basal ganglia, cortex and white matter are seen when patients with Huntingtons disease (HD) undergo structural imaging, suggesting that changes in basal ganglia‐cortical structural connectivity occur. The aims of this study were to characterise altered patterns of basal ganglia‐cortical structural connectivity with high anatomical precision in premanifest and early manifest HD, and to identify associations between structural connectivity and genetic or clinical markers of HD. 3‐Tesla diffusion tensor magnetic resonance images were acquired from 14 early manifest HD subjects, 17 premanifest HD subjects and 18 controls. Voxel‐based analyses of probabilistic tractography were used to quantify basal ganglia‐cortical structural connections. Canonical variate analysis was used to demonstrate disease‐associated patterns of altered connectivity and to test for associations between connectivity and genetic and clinical markers of HD; this is the first study in which such analyses have been used. Widespread changes were seen in basal ganglia‐cortical structural connectivity in early manifest HD subjects; this has relevance for development of therapies targeting the striatum. Premanifest HD subjects had a pattern of connectivity more similar to that of controls, suggesting progressive change in connections over time. Associations between structural connectivity patterns and motor and cognitive markers of disease severity were present in early manifest subjects. Our data suggest the clinical phenotype in manifest HD may be at least partly a result of altered connectivity. Hum Brain Mapp 36:1728–1740, 2015.

Deep brain stimulation of the posterior gyrus rectus region for treatment resistant depression

BACKGROUND Deep brain stimulation (DBS) represents an alternative symptomatic treatment for major depressive disorder in case of failure of pharmacotherapy. The sub-genual cingulate-Brodmann area 25 (CG-25), is one of the most widely used targets for electrode implantation. Given the diverging clinical outcome after DBS, there is a pressing need for in-depth study of brain anatomy and function allowing accurate and reliable prognosis before surgery. METHODS We studied five treatment-resistant major depressive disorder patients planned to undergo DBS targeting the CG-25. Before surgery, we acquired high-resolution magnetic resonance (MR) diffusion-weighted images for each patient followed by post-surgery MRI for electrode localization. To estimate individual anatomical connectivity pattern of the active contact location we performed probabilistic diffusion tractography intra-individually. We then correlated connectivity patterns with outcome assessed with standardized clinical tests. Connectivity results were compared between DBS responders and non-responders. RESULTS We observed in one patient an excellent clinical response after DBS of the bilateral posterior gyrus rectus rather than the initially targeted CG-25. The remaining four patients with DBS of the CG-25 were considered as non-responders. In the case patient, we demonstrate a strong connectivity of the stimulated regions to the medial prefrontal cortex (mPFC), which contrasted to the lower mPFC connectivity in non-responders. LIMITATIONS Confirmation in larger cohorts is needed. CONCLUSIONS We propose the posterior gyrus rectus as viable alternative new target for DBS in major depressive disorder. High connectivity between target and mPFC supports the pivotal role of this region in brain networks involved in mood processing.

Embodied neurology: an integrative framework for neurological disorders

From a systems biology perspective, the brain and spinal cord are interwoven with the body: they are ‘embodied’. Freund et al. propose an integrative framework based on biophysical models that aims to characterize neurological disorders and minimize their impact on patients by considering functional interactions between supra-spinal, spinal and peripheral regions simultaneously.

New tissue priors for improved automated classification of subcortical brain structures on MRI.

Despite the constant improvement of algorithms for automated brain tissue classification, the accurate delineation of subcortical structures using magnetic resonance images (MRI) data remains challenging. The main difficulties arise from the low gray-white matter contrast of iron rich areas in T1-weighted (T1w) MRI data and from the lack of adequate priors for basal ganglia and thalamus. The most recent attempts to obtain such priors were based on cohorts with limited size that included subjects in a narrow age range, failing to account for age-related gray-white matter contrast changes. Aiming to improve the anatomical plausibility of automated brain tissue classification from T1w data, we have created new tissue probability maps for subcortical gray matter regions. Supported by atlas-derived spatial information, raters manually labeled subcortical structures in a cohort of healthy subjects using magnetization transfer saturation and R2* MRI maps, which feature optimal gray-white matter contrast in these areas. After assessment of inter-rater variability, the new tissue priors were tested on T1w data within the framework of voxel-based morphometry. The automated detection of gray matter in subcortical areas with our new probability maps was more anatomically plausible compared to the one derived with currently available priors. We provide evidence that the improved delineation compensates age-related bias in the segmentation of iron rich subcortical regions. The new tissue priors, allowing robust detection of basal ganglia and thalamus, have the potential to enhance the sensitivity of voxel-based morphometry in both healthy and diseased brains.

Do we need to revise the tripartite subdivision hypothesis of the human subthalamic nucleus (STN)? Response to Alkemade and Forstmann.

Recently in this journal, Alkemade and Forstmann again challenged the evidence for a tripartite organisation to the subthalamic nucleus (STN) (Alkemade & Forstmann 2014). Additionally, they raised specific issues with the earlier published results using 3T MRI to perform in vivo diffusion weighted imaging (DWI) based segmentation of the STN (Lambert et al. 2012). Their comments reveal a common misconception related to the underlying methodologies used, which we clarify in this reply, in addition to highlighting how their current conclusions are synonymous with our original paper. The ongoing debate, instigated by the controversies surrounding STN parcellation, raises important implications for the assumptions and methodologies employed in mapping functional brain anatomy, both in vivo and ex vivo, and reveals a fundamental emergent problem with the current techniques. These issues are reviewed, and potential strategies that could be developed to manage them in the future are discussed further.