Network modulation following sham surgery in Parkinson’s disease
Ji Hyun Ko, … , Michael G. Kaplitt, David Eidelberg
Ji Hyun Ko, … , Michael G. Kaplitt, David Eidelberg
Published July 18, 2014
Citation Information: J Clin Invest. 2014;124(8):3656-3666. https://doi.org/10.1172/JCI75073.
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Network modulation following sham surgery in Parkinson’s disease

Abstract

Patient responses to placebo and sham effects are a major obstacle to the development of therapies for brain disorders, including Parkinson’s disease (PD). Here, we used functional brain imaging and network analysis to study the circuitry underlying placebo effects in PD subjects randomized to sham surgery as part of a double-blind gene therapy trial. Metabolic imaging was performed prior to randomization, then again at 6 and 12 months after sham surgery. In this cohort, the sham response was associated with the expression of a distinct cerebello-limbic circuit. The expression of this network increased consistently in patients blinded to treatment and correlated with independent clinical ratings. Once patients were unblinded, network expression declined toward baseline levels. Analogous network alterations were not seen with open-label levodopa treatment or during disease progression. Furthermore, sham outcomes in blinded patients correlated with baseline network expression, suggesting the potential use of this quantitative measure to identify “sham-susceptible” subjects before randomization. Indeed, Monte Carlo simulations revealed that a priori exclusion of such individuals substantially lowers the number of randomized participants needed to demonstrate treatment efficacy. Individualized subject selection based on a predetermined network criterion may therefore limit the need for sham interventions in future clinical trials.

Authors

Ji Hyun Ko, Andrew Feigin, Paul J. Mattis, Chris C. Tang, Yilong Ma, Vijay Dhawan, Matthew J. During, Michael G. Kaplitt, David Eidelberg

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Figure 5

Effects of unblinding on network expression.

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Effects of unblinding on network expression. (A) Eleven sham (SHAMR) and...
(A) Eleven sham (SHAMR) and 6 gene therapy (GADR) responders were rescanned at 12 months after unblinding (see text). The time course of SSRP expression differed for the 2 groups [F(1,15) = 6.900, P = 0.019, group × time interaction, RMANOVA]. Unblinding was associated with a significant decline in network expression in the sham-operated subjects (P = 0.031, LSD test) but not in their gene therapy counterparts (P = 0.152). Outliers (greater than the mean +1.5 × SD) are shown by white circles. (B) After unblinding, the majority of SHAMR subjects (8 of 11 = 72.7%) exhibited a decline in network expression (left), with values falling in the range (dashed line) seen over a comparable time interval in an unblinded disease progression cohort (see text). By contrast, SSRP expression remained above this level (right) in the 4 SHAMR subjects who were still under the blind at 12 months. Dashed line represents 1.5 SD above the mean change in SSRP expression observed in an independent cohort composed of 15 PD subjects scanned twice over a 2-year period (see Supplemental Figure 2B). (C) Six of the 13 gene therapy responders (GADR) who underwent repeat metabolic imaging at 12 months were unblinded prior to the final imaging session. Unblinding had no significant effect on SSRP expression in these subjects. Indeed, in 5 of the unblinded GADR subjects (left), network activity at 12 months was in the open-label progression range (dashed line). Similar network values were observed (right) for the GADR subjects who remained under the blind at the final imaging time point.