ABSTRACT
Although significant insights have been gained into the neural mechanisms of acute placebo responses, less is known about the mechanisms of longer-term placebo responses, such as those seen in clinical trials, or the interactions between these mechanisms and brain disease. We examined neuropathological and morphological brain correlates of placebo responses in a randomized clinical trial of a controversial endovascular treatment (“liberation therapy”) for multiple sclerosis. Patients were randomized to receive either balloon or sham extracranial venoplasty and followed for 48 weeks. The trial did not support therapeutic efficacy of venoplasty, but a subset of both venoplasty- and sham-treated patients reported an improvement in health-related quality of life that peaked at 12 weeks following treatment, suggesting a placebo response. Placebo responders had higher lesion activity than placebo non-responders. Although placebo responders did not differ from non-responders in terms of total normalized brain volume, regional grey or white matter volume or cortical thickness, graph theoretical analysis of cortical thickness covariance showed that placebo non-responders had a more homogenous cortical thickness topology with a more small-world-like architecture. In placebo non-responders, lesion load inversely predicted cortical thickness in primary somatosensory and motor areas, association areas, precuneus and insula, primarily in the right hemisphere. In placebo responders, lesion load was unrelated to cortical thickness. The neuropathological process in MS may result in a cortical configuration that is less suited to functional integration and less capable of generating a sustained placebo response.
Competing Interest Statement
Dr. Cherkasova reports no conflict of interest Dr. Fu reports no conflict of interest Mr. Jarrett reports no conflict of interest Ms. Johnson reports no conflict of interest Ms. Abel reports no conflict of interest Dr. Tam reports no conflict of interest Dr. Rauscher reports no conflict of interest Dr. Sossi reports no conflict of interest Dr. Kolind reports grants from Roche, grants from Genzyme, personal fees from Novartis, personal fees from Genzyme, outside the submitted work Dr. Li reports grants from Multiple Sclerosis Society of Canada, during the conduct of the study Dr. Sadovnick reports no conflict of interest Dr. Girard reports no conflict of interest Dr. Vosoughi reports no conflict of interest Dr. Emond reports grants from Canadian Institutes of Health Research (CIHR), grants from MS Society of Canada, grants from Ministere de la Sante et des Services Sociaux du Quebec during the conduct of the study. Dr. Traboulsee reports grants from Canadian Institute for Health Research, grants from Multiple Sclerosis Society of Canada, during the conduct of the study; personal fees from Biogen, grants from Chugai, grants and personal fees from Roche, grants and personal fees from Sanofi Genzyme, personal fees from Teva Neuroscience, outside the submitted work. Dr. Stoessl reports grants from Canada Research Chairs, Canadian Institutes of Health Research, Michael J. Fox Foundation, Pacific Parkinson's Research Institute and Weston Brain Institute during the conduct of the study. He serves as Chair of the DSMB for a trial conducted by Neurocrine/Voyager and is a consultant for Sio Gene Therapies, both outside the submitted work, and is Editor-in-Chief of Movement Disorders.
Footnotes
CONFLICT OF INTEREST STATEMENT: Dr. Cherkasova reports no conflict of interest
Dr. Fu reports no conflict of interest
Mr. Jarrett reports no conflict of interest
Ms. Johnson reports no conflict of interest
Ms. Abel reports no conflict of interest
Dr. Tam reports no conflict of interest
Dr. Rauscher reports no conflict of interest
Dr. Sossi reports no conflict of interest
Dr. Kolind reports grants from Roche, grants from Genzyme, personal fees from Novartis, personal fees from Genzyme, outside the submitted work
Dr. Li reports grants from Multiple Sclerosis Society of Canada, during the conduct of the study
Dr. Sadovnick reports no conflict of interest
Dr. Girard reports no conflict of interest
Dr. Vosoughi reports no conflict of interest
Dr. Dr. Emond reports grants from Canadian Institutes of Health Research (CIHR), grants from MS Society of Canada, grants from Ministère de la Santé et des Services Sociaux du Québec, during the conduct of the study.
Dr. Traboulsee reports grants from Canadian Institute for Health Research, grants from Multiple Sclerosis Society of Canada, during the conduct of the study; personal fees from Biogen, grants from Chugai, grants and personal fees from Roche, grants and personal fees from Sanofi Genzyme, personal fees from Teva Neuroscience, outside the submitted work.
Dr. Stoessl reports grants from Canada Research Chairs, Canadian Institutes of Health Research, Michael J. Fox Foundation, Pacific Parkinson’s Research Institute and Weston Brain Institute during the conduct of the study. He serves as Chair of the DSMB for a trial conducted by Neurocrine/Voyager and is a consultant for Sio Gene Therapies, both outside the submitted work, and is Editor-in-Chief of Movement Disorders.
FUNDING AND ACKNOWLEGMENTS This work was primarily supported by cooperative agreements from the Canadian Institutes of Health Research (CIHR), MS Society of Canada, Michael Smith Foundation for Health Research, Research Manitoba, and Ministère de la Santé et des Services Sociaux du Québec. Healthy control data were provided in part by OASIS-3: Principal Investigators: T. Benzinger, D. Marcus, J. Morris; NIH P50AG00561, P30NS09857781, P01AG026276, P01AG003991, R01AG043434, UL1TR000448, R01EB009352. We thank Andrew Riddehough, and Kevin Atkins and Kevin Lam at the UBC MS/MRI group for computing support and data handling. We thank Dr. Alain Dagher for providing critical feedback on the manuscript.
DATA AVAILABILITY Data and analysis code are available upon request.
ETHICS APPROVAL STATEMENT The clinical research ethics boards at the four participating centers approved the study protocol.
PATIENT CONSENT STATEMENT Patients gave written informed consent.
