Multimodal MRI reveals structural connectivity differences in 22q11 deletion syndrome related to impaired spatial working memory

Abstract

Introduction: Impaired spatial working memory is a core cognitive deficit observed in people with 22q11 Deletion syndrome (22q11DS) and has been suggested as a candidate endophenotype for schizophrenia. However, to date, the neuroanatomical mechanisms describing its structural and functional underpinnings in 22q11DS remain unclear. We quantitatively investigate the cognitive processes and associated neuroanatomy of spatial working memory in people with 22q11DS compared to matched controls. We examine whether there are significant between-group differences in spatial working memory using task related fMRI, Voxel based morphometry and white matter fiber tractography.

Materials and methods: Multimodal magnetic resonance imaging employing functional, diffusion and volumetric techniques were used to quantitatively assess the cognitive and neuroanatomical features of spatial working memory processes in 22q11DS. Twenty-six participants with genetically confirmed 22q11DS aged between 9 and 52 years and 26 controls aged between 8 and 46 years, matched for age, gender, and handedness were recruited.

Results: People with 22q11DS have significant differences in spatial working memory functioning accompanied by a gray matter volume reduction in the right precuneus. Gray matter volume was significantly correlated with task performance scores in these areas. Tractography revealed extensive differences along fibers between task-related cortical activations with pronounced differences localized to interhemispheric commissural fibers within the parietal section of the corpus callosum.

Conclusions: Abnormal spatial working memory in 22q11DS is associated with aberrant functional activity in conjunction with gray and white matter structural abnormalities. These anomalies in discrete brain regions may increase susceptibility to the development of psychiatric disorders such as schizophrenia. Hum Brain Mapp 37:4689-4705, 2016. © 2016 Wiley Periodicals, Inc.

Keywords: 22q11Deletion syndrome (22q11DS); diffusion weighted imaging (DWI); functional magnetic resonance imaging (fMRI); spatial working memory; tractography; voxel based morphometry (VBM).

Figure 1

Spatial working memory performance scores detailing the three conditions (1DOT, 3DOT, and No Delay) for controls and 22q11DS individuals. Significant between‐group differences are indicated by asterisks.

Figure 2

Functionally defined composite “OR” map determined using a Boolean OR operation to combine the two condition activation maps. Detailed are the ROIs showing significant gray matter volume differences in (a) right middle frontal gyrus (xyz = 26 −6 54), (b) right precuneus (xyz = 27 −50 28), (c) right precuneus (xyz = 19 −55 43), and (e) left superior frontal gyrus (xyz = −16 37 49). * indicates P ≤ 0.05. [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 3

A representation of the fiber tracts connecting regions activated by the SWM task (shown in red). Tracts rendered with increased transparency and subsampled for clarity are displayed on the typical DWI FA background. All diffusion metrics were extracted for the entire fiber tract bundle and represent the mean values for each measure over the tract bundle. [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 4

Macrostructural measures (a) the number of tracts within the SWM bundle (b) mean volume of the bundle, (c) mean tract length and microstructural measures (d) FA, (e) MD, (f) AD, (g) λ2, (h) λ3, (i) RD [(λ2 + λ3)/2), (j) C _L, (k) C _P, (l) C _S for the SWM fiber bundle. Asterisks indicates survives Bonferroni correction at P = 0.004. Charts detail MANCOVA (with age as a covariate) post hoc UNIVARIATE analyses (age corrected).

Figure 5

(a) A typical representation of (i) the commissural posterior parietal fiber tracts of the corpus callosum, (ii) the cerebellar peduncle, and (iii) the genu of the corpus callosum. Boxplots detail between group differences at P = 0.05 and where applicable, the outlier values are shown. UNIVARIATE analyses (age corrected) P values are reported on each boxplot and asterisks. Asterisk indicates that the diffusion measure survives Bonferroni correction applied at P = 0.004. (b) (iv) Left SLF and (v) right SLF respectively and associated extracted diffusion metrics. Boxplots detail between group differences at P = 0.05 and where applicable, the outlier values are shown. UNIVARIATE analyses (age corrected) P values are reported on each boxplot. Asterisks * indicates that the diffusion measure survives Bonferroni correction applied at P = 0.004. [Color figure can be viewed at http://wileyonlinelibrary.com]