title: 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.forename: Ji Hyun
authors.initials: JH
authors.lastname: Ko
authors.forename: Andrew
authors.initials: A
authors.lastname: Feigin
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Mattis
authors.forename: Chris C
authors.initials: CC
authors.lastname: Tang
authors.forename: Yilong
authors.initials: Y
authors.lastname: Ma
authors.forename: Vijay
authors.initials: V
authors.lastname: Dhawan
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: During
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kaplitt
authors.forename: David
authors.initials: D
authors.lastname: Eidelberg
mesh_terms: D000978:Antiparkinson Agents / Q000627:therapeutic use; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000601:surgery*; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000378:metabolism; D003198:Computer Simulation; D004311:Double-Blind Method; D005260:Female; D059907:Functional Neuroimaging; D015316:Genetic Therapy; D005968:Glutamate Decarboxylase / Q000235:genetics; D006801:Humans; D007980:Levodopa / Q000627:therapeutic use; D008032:Limbic System / Q000000981:diagnostic imaging / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways; D008875:Middle Aged; D008959:Models, Neurological; D009010:Monte Carlo Method; D010300:Parkinson Disease / Q000378:metabolism* / Q000601:surgery* / Q000628:therapy; D015990:Placebo Effect; D010919:Placebos; D049268:Positron-Emission Tomography
chemical_list: D000978:Antiparkinson Agents; D010919:Placebos; D007980:Levodopa; D005968:Glutamate Decarboxylase