Trial Outcomes & Findings for Functional Connectivity as a Biomarker of rTMS (NCT NCT03050801)

Last Updated: 2021-04-12

Results Overview

Transcranial Magnetic Stimulation (TMS) is a non-invasive technique which applies magnetic pulses to the brain via a coil inducing an electrical current in the brain. Stimulation is typically applied at sufficient intensity to trigger action potentials in nearby neurons.The motor threshold is defined as the minimum percentage of the stimulator output to elicit a motor evoked potential. Repetitive TMS (rTMS) was delivered at 100% of the motor evoked potential threshold with repeated magnetic pulses at a frequency of 20 Hz. Functional MRI (fMRI) measures the change in oxygenated blood in the brain; at rest these levels fluctuate over time. These fluctuations can be similar between different parts of the brain. FC is the similarity in fluctuations of these fMRI signals and suggest how strongly two regions communicate with each other. We measured how TMS can change FC between specific areas of the brain. A positive score suggests a stronger communication between regions of the brain.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

68 participants

Primary outcome timeframe

Changes are calculated before and the day after rTMS

Results posted on

2021-04-12

Participant Flow

Healthy Volunteers with an age range of 18-50 years were recruited for participation in Experiment 1 and 2. HV participants self-referred either directly or via the NIH Clinical Research Volunteer Program. Interested participants were pre-screened over the telephone. Participants with Traumatic Brain Injury were not recruited for this study, as Experiment 3 was not performed.

Participants were pre-screened by telephone and scheduled for consent and formal screening. Participants meeting eligibility were enrolled in the experiment. Study participants were either enrolled in Experiment 1 or 2. Experiment 1 was designed to determine the optimal number of rTMS sessions to produce a meaningful change in brain connectivity. Experiment 2 used the optimal number of rTMS sessions identified in Experiment 1, to stimulate different brain regions to study the effect on memory.

Participant milestones

Participant milestones
Measure	Experiment 1: Parietal Cortex rTMS Stimulation - 1 Day Experiment 1 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Parietal Cortex over 1 day	Experiment 1: Parietal Cortex rTMS Stimulation - 3 Days Experiment 1 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Parietal Cortex over 3 days	Experiment 1: Parietal Cortex rTMS Stimulation - 4 Days Experiment 1 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Parietal Cortex over 4 days	Experiment 2: Parietal Cortex rTMS Stimulation - 3 Days Experiment 2 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Parietal Cortex over 3 days	Experiment 2: Vertex rTMS Stimulation - 3 Days Experiment 2 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Vertex, over 3 days	Experiment 2: Prefrontal Cortex Stimulation Experiment 2 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Prefrontal Cortex, over 3 days
Experiment 1 STARTED	3	13	8	0	0	0
Experiment 1 COMPLETED	3	6	6	0	0	0
Experiment 1 NOT COMPLETED	0	7	2	0	0	0
Experiment 2 STARTED	0	0	0	21	19	4
Experiment 2 COMPLETED	0	0	0	15	15	2
Experiment 2 NOT COMPLETED	0	0	0	6	4	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Experiment 1: Parietal Cortex rTMS Stimulation - 3 Days Experiment 1 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Parietal Cortex over 3 days	Experiment 1: Parietal Cortex rTMS Stimulation - 4 Days Experiment 1 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Parietal Cortex over 4 days	Experiment 2: Parietal Cortex rTMS Stimulation - 3 Days Experiment 2 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Parietal Cortex over 3 days	Experiment 2: Vertex rTMS Stimulation - 3 Days Experiment 2 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Vertex, over 3 days	Experiment 2: Prefrontal Cortex Stimulation Experiment 2 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Prefrontal Cortex, over 3 days
Experiment 1 Lost to Follow-up	1	0	0	0	0
Experiment 1 Physician Decision	3	0	0	0	0
Experiment 1 Change of experimental design	3	0	0	0	0
Experiment 1 Unable to obtain critical rTMS measure	0	2	0	0	0
Experiment 2 Lost to Follow-up	0	0	1	1	0
Experiment 2 Physician Decision	0	0	0	1	0
Experiment 2 Pregnancy	0	0	0	1	0
Experiment 2 Withdrawal by Subject	0	0	1	0	0
Experiment 2 Poor data quality	0	0	4	1	0
Experiment 2 Discomfort during stimulation	0	0	0	0	2

Baseline Characteristics

Functional Connectivity as a Biomarker of rTMS

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Experiment 1: Parietal Cortex rTMS Stimulation - 1 Day n=3 Participants Experiment 1 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Parietal Cortex over 1 day	Experiment 1: Parietal Cortex rTMS Stimulation - 3 Days n=6 Participants Experiment 1 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Parietal Cortex over 3 days	Experiment 1: Parietal Cortex rTMS Stimulation - 4 Days n=6 Participants Experiment 1 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Parietal Cortex over 4 days	Experiment 2: Parietal Cortex rTMS Stimulation - 3 Days n=15 Participants Experiment 2 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Parietal Cortex over 3 days	Experiment 2: Vertex rTMS Stimulation - 3 Days n=15 Participants Experiment 2 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Vertex, over 3 days	Experiment 2: Prefrontal rTMS Stimulation - 3 Days n=2 Participants Experiment 2 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Prefrontal Cortex over 3 days	Total n=47 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants
Age, Categorical Between 18 and 65 years	3 Participants n=5 Participants	6 Participants n=7 Participants	6 Participants n=5 Participants	15 Participants n=4 Participants	15 Participants n=21 Participants	2 Participants n=8 Participants	47 Participants n=8 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants
Age, Continuous	28.33 Years STANDARD_DEVIATION 9.24 • n=5 Participants	23.83 Years STANDARD_DEVIATION 2.64 • n=7 Participants	26.67 Years STANDARD_DEVIATION 3.14 • n=5 Participants	25.60 Years STANDARD_DEVIATION 5.46 • n=4 Participants	24.93 Years STANDARD_DEVIATION 4.40 • n=21 Participants	21.00 Years STANDARD_DEVIATION 2.82 • n=8 Participants	25.27 Years STANDARD_DEVIATION 4.88 • n=8 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants	6 Participants n=4 Participants	6 Participants n=21 Participants	1 Participants n=8 Participants	19 Participants n=8 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants	9 Participants n=4 Participants	9 Participants n=21 Participants	1 Participants n=8 Participants	28 Participants n=8 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	6 Participants n=4 Participants	2 Participants n=21 Participants	0 Participants n=8 Participants	9 Participants n=8 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants n=5 Participants	5 Participants n=7 Participants	6 Participants n=5 Participants	9 Participants n=4 Participants	13 Participants n=21 Participants	2 Participants n=8 Participants	38 Participants n=8 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	5 Participants n=4 Participants	2 Participants n=21 Participants	1 Participants n=8 Participants	10 Participants n=8 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	1 Participants n=21 Participants	0 Participants n=8 Participants	5 Participants n=8 Participants
Race (NIH/OMB) White	2 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants	5 Participants n=4 Participants	10 Participants n=21 Participants	1 Participants n=8 Participants	24 Participants n=8 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	2 Participants n=21 Participants	0 Participants n=8 Participants	4 Participants n=8 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	3 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	4 Participants n=8 Participants

PRIMARY outcome

Timeframe: Changes are calculated before and the day after rTMS

Population: Healthy volunteers participants

Outcome measures

Outcome measures
Measure	Experiment 1: Parietal Cortex rTMS Stimulation - 1 Day n=3 Participants Experiment 1 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Parietal Cortex over 1 day	Experiment 1: Parietal Cortex rTMS Stimulation - 3 Days n=6 Participants Experiment 1 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Parietal Cortex over 3 days	Experiment 1: Parietal Cortex rTMS Stimulation - 4 Days n=6 Participants Experiment 1 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Parietal Cortex over 4 days	Experiment 2: Parietal Cortex rTMS Stimulation - 3 Days n=15 Participants Experiment 2 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Parietal Cortex over 3 days	Experiment 2: Vertex rTMS Stimulation - 3 Days n=15 Participants Experiment 2 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Vertex, over 3 days	Experiment 2: Prefrontal Cortex rTMS Stimulation - 3 Days n=2 Participants Experiment 2 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Prefrontal Cortex, over 3 days
Functional Connectivity (FC) Changes Between the Left Hippocampus and Left Parietal Cortex	-0.03 Change in z-transformed R-value Standard Deviation 0.089	0.13 Change in z-transformed R-value Standard Deviation 0.202	0.02 Change in z-transformed R-value Standard Deviation 0.123	-0.01 Change in z-transformed R-value Standard Deviation 0.109	-0.05 Change in z-transformed R-value Standard Deviation 0.141	0.03 Change in z-transformed R-value Standard Deviation 0.088

PRIMARY outcome

Timeframe: Changes are calculated before and the day after rTMS and before and 7-14 days after rTMS

Population: Experiment 1 identified the optimal number of rTMS sessions to be applied in Experiment 2. The optimal number of rTMS sessions, i.e., 3 days, was applied to different regions of the brain in Experiment 2. Therefore, only the Experiment 2 data is reported for this outcome measure.

Participants studied 20 face-word pairs, and after a short delay, were required to recall the word associated with each pair. The number of correctly remembered pairs was recorded. rTMS was administered over different regions of the brain over 3 days. The Associative Memory test was administered at baseline (within a week before the first rTMS session), 1 day after the last rTMS session, and again 7-14 days after the last rTMS session. We calculated improvements on this task by subtracting the number of successfully remembered pairs 1 day after stimulation from the number remembered at baseline ("Changes one day after rTMS"). We also calculated whether these improvements lasted longer by subtracting the number of successfully remembered pairs 7-14 days after stimulation from the number remembered at baseline ("Changes 7-14 days after rTMS"). Positive scores represent increases in associative memory.

Outcome measures

Outcome measures
Measure	Experiment 1: Parietal Cortex rTMS Stimulation - 1 Day n=15 Participants Experiment 1 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Parietal Cortex over 1 day	Experiment 1: Parietal Cortex rTMS Stimulation - 3 Days n=15 Participants Experiment 1 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Parietal Cortex over 3 days	Experiment 1: Parietal Cortex rTMS Stimulation - 4 Days n=2 Participants Experiment 1 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Parietal Cortex over 4 days	Experiment 2: Parietal Cortex rTMS Stimulation - 3 Days Experiment 2 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Parietal Cortex over 3 days	Experiment 2: Vertex rTMS Stimulation - 3 Days Experiment 2 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Vertex, over 3 days	Experiment 2: Prefrontal Cortex rTMS Stimulation - 3 Days Experiment 2 rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Prefrontal Cortex, over 3 days
Associative Memory Test Score Changes Changes one day after rTMS	0.08 Change in proportion of remembered pairs Standard Deviation 0.133	0.01 Change in proportion of remembered pairs Standard Deviation 0.166	0.03 Change in proportion of remembered pairs Standard Deviation 0.035	—	—	—
Associative Memory Test Score Changes Changes 7-14 days after rTMS	0.08 Change in proportion of remembered pairs Standard Deviation 0.173	0.02 Change in proportion of remembered pairs Standard Deviation 0.149	0.13 Change in proportion of remembered pairs Standard Deviation 0.071	—	—	—

SECONDARY outcome

Timeframe: Changes are calculated before and the day after rTMS, and before and 7-14 days after rTMS

Participants learn implicit, probabilistic relationships between stimuli and responses through feedback. 1, 2 and 3 card combinations of 4 possible cards are presented on a computer; the subject is asked to predict whether it will be rainy or fine. After each prediction, the subject receives corrective feedback. Each card is independently associated with one outcome with a fixed probability.The WPT was administered at baseline and 1 day after and 7-14 days after the last rTMS session. Scores at each time point represent the proportion of responses associated with a reward (optimal responses). We calculated improvement by subtracting the number of optimal responses 1 day after stimulation from the number at baseline (Changes one day after rTMS). We also calculated if these improvements lasted longer by subtracting the number of optimal responses 7-14 days after stimulation from the number at baseline (Changes 7-14 days after rTMS).Positive scores represent increases in implicit memory.