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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Research Article

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 1

SSRP.

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SSRP. Network analysis of metabolic images obtained for 8 PD patients sc...
Network analysis of metabolic images obtained for 8 PD patients scanned at baseline and again, under the blind, 6 months after SHAM (see text). (A) The resulting SSRP was characterized by increased metabolic activity in the anterior cingulate cortex (BA 32/24), subgenual cingulate gyrus (BA 25), inferior temporal cortex, hippocampus, amygdala, and posterior cerebellar vermis. ACC, anterior cingulate cortex; LOB, lobule; SubCAL, subcallosal gyrus. Pattern is displayed as a bootstrap reliability map thresholded at z =|1.64|, 1-tailed P < 0.05; 1,000 iterations. (B) SSRP also included contributions from the head of the caudate and anterior putamen (top) and from the VA thalamic nucleus. While voxel weights for these clusters significantly contributed to this network (Table 1), these loadings did not meet the prespecified bootstrap reliability criteria (z = 1.575, 1.472, and 1.348 for the 3 regions, respectively; 1,000 iterations). (C) A significant ordinal trend in SSRP expression (left) was seen in the 8 responders to SHAM who were used to identify the pattern. Each subject exhibited an increase in network expression under the blind at 6 months (P < 0.01, binomial test). A similar ordinal trend in SSRP expression under the blind (P < 0.01, binomial test) was evident in the 8 remaining sham responders (middle) who were not used for pattern identification. An ordinal trend was not observed under the blind (P = 1.0) for the 7 sham nonresponders (right). Three violations were evident in this group, whereas no violations were present in either SHAMR group.