Multiple sclerosis lesions that impair memory map to a connected memory circuit

Abstract

Background: Nearly 1 million Americans are living with multiple sclerosis (MS) and 30-50% will experience memory dysfunction. It remains unclear whether this memory dysfunction is due to overall white matter lesion burden or damage to specific neuroanatomical structures. Here we test if MS memory dysfunction is associated with white matter lesions to a specific brain circuit.

Methods: We performed a cross-sectional analysis of standard structural images and verbal memory scores as assessed by immediate recall trials from 431 patients with MS (mean age 49.2 years, 71.9% female) enrolled at a large, academic referral center. White matter lesion locations from each patient were mapped using a validated algorithm. First, we tested for associations between memory dysfunction and total MS lesion volume. Second, we tested for associations between memory dysfunction and lesion intersection with an a priori memory circuit derived from stroke lesions. Third, we performed mediation analyses to determine which variable was most associated with memory dysfunction. Finally, we performed a data-driven analysis to derive de-novo brain circuits for MS memory dysfunction using both functional (n = 1000) and structural (n = 178) connectomes.

Results: Both total lesion volume (r = 0.31, p < 0.001) and lesion damage to our a priori memory circuit (r = 0.34, p < 0.001) were associated with memory dysfunction. However, lesion damage to the memory circuit fully mediated the association of lesion volume with memory performance. Our data-driven analysis identified multiple connections associated with memory dysfunction, including peaks in the hippocampus (T = 6.05, family-wise error p = 0.000008), parahippocampus, fornix and cingulate. Finally, the overall topography of our data-driven MS memory circuit matched our a priori stroke-derived memory circuit.

Conclusions: Lesion locations associated with memory dysfunction in MS map onto a specific brain circuit centered on the hippocampus. Lesion damage to this circuit fully mediated associations between lesion volume and memory. A circuit-based approach to mapping MS symptoms based on lesions visible on standard structural imaging may prove useful for localization and prognosis of higher order deficits in MS.

Keywords: Lesion network mapping; Memory; Multiple sclerosis; White matter lesion; fMRI.

Figure 1:. Methodology to test if MS memory dysfunction is associated with disruption of memory circuits.

A) Structural imaging, lesion segmentation and memory assessment collected on patients with MS showing two representative lesion maps from a patient with normal and a patient with low memory score. Lesion maps and memory testing are used in subsequent analyses. B) Determine if MS lesion damage to the a priori stroke-derived memory circuit associates with memory dysfunction. B1. Assess lesion overlap with stroke derived memory circuit and then B2. analyze association of MS lesion overlap with stroke derived memory circuit to memory scores C) Derive a unique MS memory circuit based on lesion location employing a functional connectome. C1. Compute lesion connectivity using normative database of resting-state functional connectivity and then C2. perform voxelwise permutation testing to determine functional connections significantly associated with verbal memory scores. D) Derive a unique MS memory circuit based on lesion location employing a structural connectome. D1. Compute lesion connectivity using normative database of structural connectivity and then D2. perform voxelwise permutation testing to determine functional connections significantly associated with verbal memory scores.

Figure 2:. MS lesion locations associated with memory dysfunction overlap an a priori memory circuit.

In purple is the a priori stroke derived memory circuit (Ferguson et. al. 2019) and in red are MS lesions grouped by A) lower memory performance and B) normal range memory performance. Intersection between MS lesion locations and our a priori memory circuit was correlated with memory performance (p<0.001). Inset) Box plot of MS lesion damage to the a priori stroke-derived memory circuit comparing patients with lower memory scores (1 standard deviation below mean of the group) versus patients with higher memory scores (1 standard deviation above mean of the group) (t=4.7, p<0.001).

Figure 3:

Lesion network mapping of memory dysfunction in multiple sclerosis using a functional connectome. A) Functional connections with MS lesion locations significantly associated with verbal memory. Voxels displayed are p<0.05 on voxelwise family-wise error correction. B) Comparison of the topography of the MS lesion derived functional memory circuit from 4A (warm colors) to the stroke derived memory circuit from Ferguson et. al. 2019 (purple). The high threshold for the stroke-based memory circuit in 4B was chosen to facilitate comparison to the MS-based circuit topography.

Figure 4:

Lesion network mapping of memory dysfunction in multiple sclerosis using a structural connectome. A) Structural connections with MS lesion locations significantly associated with verbal memory. Voxels are displayed after voxelwise family-wise error p<0.0005 B) Comparison of the topography of the MS lesion derived structural memory circuit from 4A (warm colors) to the stroke derived memory circuit from Ferguson et. al. 2019 (purple).