Mechanisms of Open and Hidden Placebo in Stroke Recovery

ABSTRACT We propose investigating the neural mechanisms of placebo (open and hidden) in stroke subjects. This proposal is built on our recently completed clinical trial NIH R21 (R21HD079048-01A1), which showed that the placebo effect contributing to motor recovery was large and superior to fluoxetine alone. Furthermore, we found a different

neural signature of placebo and M1 rTMS in this trial supported by other prior trials we conducted. Additionally, our laboratory was involved in other large trials with significant large placebo effects on motor learning. This proposal will conduct an experimental trial in which 56 subjects with chronic stroke will be randomized into four

groups (2:2:2:1): open placebo alone (16 subjects), sham rTMS alone (hidden placebo) (16 subjects), no treatment (16 subjects) and M1 rTMS alone (8 subjects). Subjects will be assessed before and after the intervention using neurophysiological markers of connectivity to test specific mechanistic questions based on

our preliminary data. We will use quantitative electroencephalography (EEG) analysis of prefrontal and sensorimotor areas and single and, secondarily, paired-pulse TMS to assess corticospinal and intracortical excitability. Our hypothesis is that placebo (open and hidden) will have a specific EEG/neural signature

characterized by an enhancement in left frontal alpha asymmetry (FAA) EEG and an increased beta band premotor-motor EEG connectivity. Based on this, we will test two aims: Aim 1: Evaluate whether a hidden placebo (placebo as given in a clinical trial indexed by sham rTMS) has a specific placebo EEG signature

compared to no treatment, and Aim 2: Evaluate whether also the open placebo (OP) has a specific EEG signature compared to no treatment (similar to the hidden placebo). Moreover, secondarily, we will also evaluate if active rTMS has a similar signature to sham rTMS and OP compared to no treatment. The significance of this

proposal is understanding the placebo effect in stroke patients. This will help improve the design of future stroke trials. For instance, it could be used to design trials with unmatched placebos such as in a behavioral or surgical trial where the active intervention is given against open placebo (unmatched placebo). If the neural signature of

placebo is known, this could be confirmed in the unmatched placebo arm to validate the results. Furthermore, understanding mechanisms of placebo may also provide insights to develop interventions that would harness these effects to induce motor recovery by targeting reward-motivation systems to enhance motor recovery in

stroke. This proposal is novel as we are developing and testing a new conceptual neural model of the role of expectation and motivation in stroke recovery, and we are quantifying the placebo effects in motor recovery in stroke in a well-controlled trial. Open placebo for motor recovery may open a new avenue for future treatments

in rehabilitation. Our team is a multidisciplinary group with solid research experience and environment, with clinical expertise in different fields, such as neurology, electrophysiology, physical therapy, and psychiatry.