Interleaved TMS-fMRI for Hippocampal Stimulation: Modeling Dose-Response Relationship in Amnestic Mild Cognitive Impairment
Phase: PHASE2
Conditions: Mild Cognitive Impairment
Sponsor: University of Arizona

Interleaved TMS-fMRI for Hippocampal Stimulation: Modeling Dose-Response 
Relationship in Amnestic Mild Cognitive Impairment 
  
March 25th, 2025 
 
NCT05515952 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 

Approach ​                                                                                                                         
  
Participants 
 
Thirty-eight right-handed individuals with aMCI (50-80 years old) will be enrolled in this study. 
The following revised Mayo clinic criteria for MCI1 will be used for the inclusion of individuals 
with MCI: (a) self- or informant-reported cognitive complaint; (b) objective cognitive impairment; 
(c) preserved independence in functional abilities; and (d) absence of dementia. The MCI 
diagnosis will be supported by the measures of general cognitive function using Mini-Mental 
State Exam (MMSE) 24-27 (inclusive); (2) Montreal Cognitive Assessment (MoCA) 18-26 
(inclusive); and (3) Clinical Dementia Rating Scale score of 0.5. Only individuals with aMCI (i.e., 
memory is significantly impaired) will be included in the study. The Jak/Bondi actuarial 
neuropsychological test method2 and NACC UDS 3.0 Neuropsychological battery3 will be used 
to identify aMCI (i.e., 1 standard deviation below the mean for their age and education matched 
peers on normative data in at least 2 tasks of the memory domain2). A web-based normative 
calculator will be used to estimate the level of performance (i.e., Z score and percentile) on each 
NACC UDS measure4. We will not include individuals with unstable medical condition, 
contraindications to MRI and TMS, clinical evidence of stroke, psychiatric disorder, and other 
neurological disorders or head injury. 
  
  
Trial design  
 
Thirty-eight individuals with aMCI will be enrolled in the 3-day interleaved TBS-fMRI study. 
Participants will be randomly assigned into one of the two TBS groups: active TBS or sham TBS 
(Figure 1). Participants will receive 3 TBS sessions on day 2 with each TBS session separated 
by 60 minutes to maximize the TBS effect5,6. Participants in the active TBS group will receive 3 
excitatory TBS sessions (the 3 yellow ovals in Figure 1). Participants in the sham TBS group will 
undergo a procedure identical to the 
active TBS except that no TBS will be 
provided (the 3 white ovals in Figure 1). 
Research participants and outcome 
assessors 
will 
be 
blinded 
for 
participants’ allocated group. Outcome 
measures assessing memory function, 
hippocampal 
functional connectivity, 
and hippocampal activation during a 
memory task will be acquired on day 1 
(baseline), day 2 (immediate effect), 
and 
day 
3 
(lasting 
effect). 
We 
hypothesize that active spaced TBS will enhance memory function, strengthen hippocampal 
functional connectivity, and increase hippocampal activation compared to the sham TBS 
immediately and 24 hours after the last TBS session. 
 
  

Outcome measures 
 
Accuracy of the face-name associative memory (FNAME) task, resting-state hippocampal 
functional connectivity, and hippocampal activation pattern will be the primary outcome 
measures. Participants will perform the FNAME task, which was adapted from previous 
paradigm7,8, inside the MRI scanner. The FNAME task consists of both encoding and retrieval 
phases (Figure 4). During the encoding phase, participants will be instructed to remember the 
name that goes with each face and make a subjective decision as to how well each name fits 
the corresponding face (a strategy designed to augment associative encoding)9. Encoding 
phase will be divided across 4 functional runs, each consisting of 16 face-name pairs (display 
duration = 5.5 sec for each pair), interspersed with fixation trials (duration = 0.5-12.5 sec), 
yielding a total of 64 face-name pairs. Following encoding with a 5-min break, participants will 
be presented with 3 types of 
face-name pairs (correct face-name 
pairs, incorrect face-name pairs, or 
new face-name pairs) inside the 
MRI scanner during the retrieval 
phase. There are 4 functional runs, 
each consisting of 10 correct, 6 
incorrect, and 6 new face-name 
pairs 
interspersed 
with 
fixation 
trials, 
yielding 
a 
total 
of 
88 
face-name pairs. Accuracy will be measured as the number of right responses (e.g., Figure 4 
face-name pairs B-D) relative to the total number of face-name pairs shown during the retrieval 
phase. We created 8 versions of the face-name tasks. Our pilot data from 20 healthy adults 
indicated excellent parallel-forms reliability across the 8 test versions (ICC = 0.93, 95%CI = 
[0.88, 0.97]). The administration order of different versions will be randomized across the 
participants. The score of the FNAME task has been found to be correlated with beta amyloid 
burden7, reduced hippocampal volume, and APOΕ4 carrier status in cognitively normal older 
adults10. The FNAME task is sensitive to longitudinal clinical decline in MCI11 and in those at 
genetic risk for AD12-14. 
 
 
  
Statistical design and analysis  
 
This study employs a parallel group design with 2 groups (active TBS and sham TBS) and 3 
primary data collection time points (day1, day 2, and day 3). Participants will be randomized to 
one of the 2 groups using a randomization scheme stratified on age (50-65 vs. 66-80) and sex. 
For the accuracy of the FNAME task, a linear mixed effects model will be fit to the accuracy 
scores from the FNAME task to look at the change in accuracy over time for both the active and 
sham TBS groups. The model will include fixed predictors for time (3 levels: day 1, day 2, and 
day 3), group (2 levels: active TBS and sham TBS), their interaction, age, sex, and education. A 

random intercept per participant will be included to account for the potential correlation among 
data from the same participant. 
 
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275, 214-228 (2014). https://doi.org/10.1111/joim.12190 
2 .     ​ Jak, A. J. et al. Neuropsychological Criteria for Mild Cognitive Impairment and Dementia 
Risk in the Framingham Heart Study. J Int Neuropsychol Soc 22, 937-943 (2016). 
https://doi.org/10.1017/S1355617716000199 
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Test Battery in the Uniform Data Set (UDS). Alzheimer Dis Assoc Disord (2017). 
https://doi.org/10.1097/WAD.0000000000000223 
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Shirk, S. D. et al. A web-based normative calculator for the uniform data set (UDS) 
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