Brain networks disconnection in early multiple sclerosis cognitive deficits: an anatomofunctional study

Abstract

Severe cognitive impairment involving multiple cognitive domains can occur early during the course of multiple sclerosis (MS). We investigated resting state functional connectivity changes in large-scale brain networks and related structural damage underlying cognitive dysfunction in patients with early MS. Patients with relapsing MS (3-5 years disease duration) were prospectively assigned to two groups based on a standardized neuropsychological evaluation: (1) cognitively impaired group (CI group, n = 15), with abnormal performances in at least 3 tests; (2) cognitively preserved group (CP group, n = 20) with normal performances in all tests. Patients and age-matched healthy controls underwent a multimodal 3T magnetic resonance imaging (MRI) including anatomical T1 and T2 images, diffusion imaging and resting state functional MRI. Structural MRI analysis revealed that CI patients had a higher white matter lesion load compared to CP and a more severe atrophy in gray matter regions highly connected to networks involved in cognition. Functional connectivity measured by integration was increased in CP patients versus controls in attentional networks (ATT), while integration was decreased in CI patients compared to CP both in the default mode network (DMN) and ATT. An anatomofunctional study within the DMN revealed that functional connectivity was mostly altered between the medial prefrontal cortex (MPFC) and the posterior cingulate cortex (PCC) in CI patients compared to CP and controls. In a multilinear regression model, functional correlation between MPFC and PCC was best predicted by PCC atrophy. Disconnection in the DMN and ATT networks may deprive the brain of compensatory mechanisms required to face widespread structural damage.

Keywords: MRI; cognition; default mode network; multiple sclerosis; resting state.

Figure 1

Gray matter atrophy in CI MS patients compared to CP MS patients assessed by VBM (P < 0.001, k = 216 mm²). SFG: superior frontal gyrus; MFG: medial frontal gyrus; IFG: inferior frontal gyrus; PCG: posterior cingulate gyrus; SMG: supramarginal gyrus; MTG: medial temporal gyrus; PHG: parahippocampal gyrus; Th: thalamus; C: caudate; BA: Brodmann area.

Figure 2

(Left) Default mode, frontoparietal attentional, dorsal attentional and motor networks identified by independent component analysis. (A) Default mode network (DMN, red); (B) left (ATT‐L, blue) and right (ATT‐R, purple) frontoparietal attentional network; (C) dorsal attentional network (dATT, yellow); (D) motor network (MOT, green); and (right; E) total within‐system integration in the DMN, ATT‐R, ATT‐L, dATT, and MOT; *: P < 0.05; **: P < 5 × 10⁻³; ***: P < 5 × 10⁻⁴; and ns: nonsignificant.

Figure 3

Structural and functional measures within the default mode network. (A) 3D view of the three regions of interest in the DMN together with the bundles identified by tractography in a patient with MS. Red: medial prefrontal cortex (MPFC); blue: posterior cingulate/precuneus (PCC): yellow: parahippocampal gyrus (PHG); pink: anterior cingulum; and green: posterior cingulum. (B) Functional correlation between MPFC and PCC, PCC and left PHG, PCC and right PHG. (C–E) Mean FA, radial diffusivity (RD) and axial diffusivity (AD), respectively, within the anterior cingulum, the left posterior cingulum and the right posterior cingulum; *: P < 0.05; **: P < 5 × 10⁻³; ***: P < 5 × 10⁻⁴; and all other group differences were not statistically significant.

Figure 4

Spearman rank correlation between functional connectivity within the DMN and structural imaging parameters. MPFC: medial prefrontal cortex; PCC: posterior cingulate cortex; MFG: middle frontal gyrus. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]