Cortical morphology predicts placebo response in multiple sclerosis

Mariya V Cherkasova,Vesna Sossi,A Jon Stoessl,Roger Tam,Shannon Kolind,Francois Emond,David K B Li,Anthony Traboulsee,Lindsay Machan,Jessie F Fu,A Dessa Sadovnick,Reza Vosoughi,Alexander Rauscher,Michael Jarrett,Shawna Abel,Poljanka Johnson,J Marc Girard

doi:10.1038/s41598-021-04462-7

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.

Highlights

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 neuropathological and structural neural correlates of placebo responses of multiple sclerosis (MS) patients undergoing a randomized clinical trial (RCT) of a controversial extracranial venoplasty procedure dubbed the “liberation therapy”
Given our finding of more regular cortical thickness (CT) graphs in placebo non-responders, which could arise from more coordinated tissue loss in anatomically connected regions owing to white matter lesions[25], we explored the associations between CT and lesion load in placebo responders versus non-responders

Summary

Introduction

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. Little is known about the interactions between placebo responses and other brain diseases To address this question, we examined neuropathological and structural neural correlates of placebo responses of multiple sclerosis (MS) patients undergoing a randomized clinical trial (RCT) of a controversial extracranial venoplasty procedure dubbed the “liberation therapy”. Venoplasty subsequently proved ineffective in two double-blind sham-controlled RCTs, one by the pioneers of the procedure[17], and the other by our group[18] In the latter, while venoplasty was not superior to sham venoplasty on any outcome measure, a subset of both venoplasty- and sham-treated patients experienced a significant transient improvement in self-reported health-related quality of life suggesting a placebo response. This presented a unique opportunity to examine brain correlates of placebo responses in an MS clinical trial

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