Participants will take part in five experimental sessions. These will involve neuropsychological testing, a decision making battery, functional and structural MRI, and two sessions of transcranial magnetic stimulation applied to either a target or control region. The clinical trial component concerns only the last two sessions where subjects will be randomly assigned to different groups to receive different TMS interventions. For completeness, all sessions are described below:
240 participants (110 younger, 130 older, 50% female) will be recruited from the local Tucson population. Neuropsychological testing in the first session will be used to exclude participants who exhibit symptoms of mild cognitive impairment or early stage Alzheimer's.
Decision making battery: All participants will perform the Horizon Task (Wilson et al. 2014) to measure explore-exploit behavior in addition to a Decision Making battery to measure risk taking, ambiguity attitude, temporal discounting, and behavioral variability.
Neuroimaging: 92 younger and 92 older adults will return to take part in the MRI experiment. All participants will be screened during the telephone interview and the behavioral session to rule out contraindications for MRI and TMS and screened once more at the start of the MRI session. MRI experiments will take place in the 3T Skyra scanner at the neuroimaging facility at Banner University Medical Center. All neuroimaging experiments will be run according to standard safety guidelines (Rossi et al. 2009) and participants will be screened and give informed consent before the procedure beings.
Each scan session will last about 90 minutes and will include a short localizer scan (approximately 1 minute), a T1-weighted structural scan (6 minutes), diffusion tensor imaging to assess structural connectivity (DTI, 10 minutes), FLAIR to quantify white matter hyperintensities (2 minutes), a field map to correct for magnetic field inhomogeneities, especially in frontal pole (2 minutes), resting-state fMRI to measure functional connectivity (8 minutes), and event-based fMRI using the task described below (50-60 minutes). All functional scans will be acquired with parameters that are optimized prevent signal dropout in frontal pole and other frontal regions (Deichmann et al. 2003).
Sessions 4 and 5 (TMS): The TMS sessions fit the definition of a clinical trial because subjects will be prospectively assigned to different groups who will receive different interventions in different orders. Participants in each age group will be pseudo-randomly assigned to groups according to whether the target region for TMS is frontal pole of IFG. Thus, there will be four distinct groups of subjects: older frontal pole, younger frontal pole, older IFG, younger IFG, with 42 participants (21 males, 21 females) in each group. Each participant will take part in two TMS sessions, one target and one control session. The order of sessions will be counterbalanced across subjects.
TMS sessions will take place in new TMS facility at Banner University Medical Center. All TMS will be delivered in line with established safety guidelines (Rossi et al, 2009) under the supervision of co-I Chou who is the director of the TMS facility and has extensive experience with TMS in young, old and cognitively impaired subjects. When followed correctly, these guidelines ensure that TMS is a very safe procedure with only a handful of adverse events occurring in approximately 20 years of research.
After completing consent and screening procedures, each TMS session will begin with the measurement of the action motor threshold (AMT). The AMT is defined as the minimum stimulus intensity that produces a liminal motor-evoked potential (about 200 μV in 50% of 10 trials) during isometric contraction of the tested muscle. After the AMT has been measured, participants will receive cTBS (50Hz stimulation at 80% AMT for 40 seconds; Huang et al 2005). Stimulation will be applied to either the target area (frontal pole or IFG) or control area (vertex) with the order of sessions counterbalanced across participants. Proper targeting of each region will be achieved using a frameless neuronavigation system (Localite TMS Navigator) with a Polaris Spectra infrared camera (Northern Digital, Waterloo, Ontario, Canada). This system enables stimulation to be centered on specific coordinates in Montreal Neurological Institute (MNI) space. Coordinates \[x,y,z\] = \[35,50,15\] will be used for frontal pole (based previous fMRI work and our original TMS study, Daw et al., 2006; Zajkowski et al. 2017) and \[x,y,z\] = \[56,16,22\] for right IFG based on the location of our activations in the young pilot group. The vertex control site is defined as the Cz position of a 10-20 EEG system. After receiving TMS, participants will stare at a white wall for 1 minute before performing the Horizon Task for 45 minutes.
