Cortical morphology predicts placebo response in multiple sclerosis

Abstract

Despite significant insights into the neural mechanisms of acute placebo responses, less is known about longer-term placebo responses, such as those seen in clinical trials, or their interactions with brain disease. We examined brain correlates of placebo responses in a randomized trial of a then controversial and now disproved endovascular treatment for multiple sclerosis. Patients received either balloon or sham extracranial venoplasty and were followed for 48 weeks. Venoplasty had no therapeutic effect, but a subset of both venoplasty- and sham-treated patients reported a transient improvement in health-related quality of life, suggesting a placebo response. Placebo responders did not differ from non-responders in total MRI T2 lesion load, count or location, nor were there differences in normalized brain volume, regional grey or white matter volume or cortical thickness (CT). However, responders had higher lesion activity. Graph theoretical analysis of CT covariance showed that non-responders had a more small-world-like CT architecture. In non-responders, lesion load was inversely associated with CT in somatosensory, motor and association areas, precuneus, and insula, primarily in the right hemisphere. In responders, lesion load was unrelated to CT. The neuropathological process in MS may produce in some a cortical configuration less capable of generating sustained placebo responses.

Figure 1

Method overview.

Figure 2

Cortical thickness covariance patterns in placebo responders and non-responders: graph theoretical analysis. (A) Correlation matrices of cortical thickness values across 78 cortical areas delineated using Automated Anatomical Labeling (AAL) in placebo non-responders (NR), placebo responders (R), and a group of healthy age- and sex-matched controls (HC). (B) A histogram depicting distributions of correlation coefficients in placebo responders and non-responders. (C) Backbone structure for correlation matrices in A at the sparsity threshold of 0.43. (D) Graph theoretical characteristics of these matrices across the range of sparsity thresholds from 0.1 to 0.5. Error ribbons represent standard deviation for parameter estimates from leave-one-out cross-validation. Box plots represent group comparisons at the sparsity threshold of 0.43 based on leave-one-out cross-validations; histograms represent the p-values based on permutation tests at the sparsity threshold of 0.43.

Figure 3

Cortical thickness, white matter lesions and placebo response. (A) Precuneus region whose thickness dimensionally predicts a stronger placebo response as depicted in the scatterplot. (B) Lesion probability maps in placebo responders (red) and non-responders (blue): no significant differences in lesion location between groups. (C) Cortical areas whose thickness was significantly associated with lesion load in the placebo non-responders. (D) Mean cortical thickness of the regions shown in relation to white matter lesion load (FLAIR) in the placebo responders (red) and non-responders (blue). A mask of the regions shown in C was used to extract mean CT values across these regions for all participants.