Trial Outcomes & Findings for Reward Circuit Targeted iTBS (NCT NCT05468853)

Results Overview

change in self-reported anhedonia from baseline averaged across post-intervention and post-washout measured using the score on the Dimensional Anhedonia Rating Scale (DARS); score range is 0-68 with higher scores meaning better outcomes (less anhedonia)

Recruitment status

COMPLETED

Study phase

NA

Target enrollment

72 participants

Primary outcome timeframe

baseline, one-hour post-intervention, one-week post-intervention

Results posted on

2026-01-27

Participant Flow

After enrollment, participants complete 1) a baseline functional MRI scan to determine targets for transcranial magnetic stimulation (TMS), and 2) motor thresholding to determine intensity of TMS. Participants are not assigned to arms if they cannot perform the task inside the MRI scanner (e.g. due to claustrophobia), if they cannot tolerate TMS (e.g., due to discomfort), and if they have contraindications for MRI or TMS (e.g., pro-epileptic medications, neurological conditions).

Participant milestones

Participant milestones
Measure	rmPFC-iTBS Then Inion-iTBS Transcranial magnetic stimulation: Transcranial magnetic stimulation delivered to the scalp targeting specific brain structures via stereotactic guidance. Each visit consists of 600 pulses delivered in 2 second trains of 50 Hz bursts every 5 Hz with 8 seconds in-between trains at 80% of resting motor threshold to one target. For a given target, stimulation was performed once a day for 5 consecutive days. A 9 day washout period followed prior to stimulating the alternate target. This arm completed transcranial magnetic stimulation to the rostromedial prefrontal cortex (rmPFC) first followed by the inion.	Inion-iTBS Then rmPFC-iTBS Transcranial magnetic stimulation: Transcranial magnetic stimulation delivered to the scalp targeting specific brain structures via stereotactic guidance. Each visit consists of 600 pulses delivered in 2 second trains of 50 Hz bursts every 5 Hz with 8 seconds in-between trains at 80% of resting motor threshold to one target. For a given target, stimulation was performed once a day for 5 consecutive days. A 9 day washout period followed prior to stimulating the alternate target. This arm completed transcranial magnetic stimulation to the inion first followed by the rostromedial prefrontal cortex (rmPFC).
Overall Study STARTED	35	34
Overall Study COMPLETED	28	28
Overall Study NOT COMPLETED	7	6

Reasons for withdrawal

Reasons for withdrawal
Measure	rmPFC-iTBS Then Inion-iTBS Transcranial magnetic stimulation: Transcranial magnetic stimulation delivered to the scalp targeting specific brain structures via stereotactic guidance. Each visit consists of 600 pulses delivered in 2 second trains of 50 Hz bursts every 5 Hz with 8 seconds in-between trains at 80% of resting motor threshold to one target. For a given target, stimulation was performed once a day for 5 consecutive days. A 9 day washout period followed prior to stimulating the alternate target. This arm completed transcranial magnetic stimulation to the rostromedial prefrontal cortex (rmPFC) first followed by the inion.	Inion-iTBS Then rmPFC-iTBS Transcranial magnetic stimulation: Transcranial magnetic stimulation delivered to the scalp targeting specific brain structures via stereotactic guidance. Each visit consists of 600 pulses delivered in 2 second trains of 50 Hz bursts every 5 Hz with 8 seconds in-between trains at 80% of resting motor threshold to one target. For a given target, stimulation was performed once a day for 5 consecutive days. A 9 day washout period followed prior to stimulating the alternate target. This arm completed transcranial magnetic stimulation to the inion first followed by the rostromedial prefrontal cortex (rmPFC).
Overall Study Lost to Follow-up	2	0
Overall Study Withdrawal by Subject	0	1
Overall Study incidental MRI finding	1	2
Overall Study could not tolerate rmPFC-iTBS	3	2
Overall Study illness	1	1

Baseline Characteristics

Reward Circuit Targeted iTBS

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	rmPFC-iTBS Then Inion-iTBS n=35 Participants Transcranial magnetic stimulation: Transcranial magnetic stimulation delivered to the scalp targeting specific brain structures via stereotactic guidance. Each visit consists of 600 pulses delivered in 2 second trains of 50 Hz bursts every 5 Hz with 8 seconds in-between trains at 80% of resting motor threshold to one target. For a given target, stimulation was performed once a day for 5 consecutive days. A 9 day washout period followed prior to stimulating the alternate target. This arm completed transcranial magnetic stimulation to the rostromedial prefrontal cortex (rmPFC) first followed by the inion.	Inion-iTBS Then rmPFC-iTBS n=34 Participants Transcranial magnetic stimulation: Transcranial magnetic stimulation delivered to the scalp targeting specific brain structures via stereotactic guidance. Each visit consists of 600 pulses delivered in 2 second trains of 50 Hz bursts every 5 Hz with 8 seconds in-between trains at 80% of resting motor threshold to one target. For a given target, stimulation was performed once a day for 5 consecutive days. A 9 day washout period followed prior to stimulating the alternate target. This arm completed transcranial magnetic stimulation to the inion first followed by the rostromedial prefrontal cortex (rmPFC).	Total n=69 Participants Total of all reporting groups
Age, Continuous	23.5143 Years STANDARD_DEVIATION 6.38183 • n=25 Participants	24.1176 Years STANDARD_DEVIATION 9.22041 • n=25 Participants	23.8116 Years STANDARD_DEVIATION 7.85582 • n=50 Participants
Sex: Female, Male Female	22 Participants n=25 Participants	26 Participants n=25 Participants	48 Participants n=50 Participants
Sex: Female, Male Male	13 Participants n=25 Participants	8 Participants n=25 Participants	21 Participants n=50 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=25 Participants	0 Participants n=25 Participants	0 Participants n=50 Participants
Race (NIH/OMB) Asian	8 Participants n=25 Participants	3 Participants n=25 Participants	11 Participants n=50 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=25 Participants	0 Participants n=25 Participants	0 Participants n=50 Participants
Race (NIH/OMB) Black or African American	2 Participants n=25 Participants	3 Participants n=25 Participants	5 Participants n=50 Participants
Race (NIH/OMB) White	21 Participants n=25 Participants	25 Participants n=25 Participants	46 Participants n=50 Participants
Race (NIH/OMB) More than one race	2 Participants n=25 Participants	1 Participants n=25 Participants	3 Participants n=50 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=25 Participants	2 Participants n=25 Participants	4 Participants n=50 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	7 Participants n=25 Participants	5 Participants n=25 Participants	12 Participants n=50 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	28 Participants n=25 Participants	29 Participants n=25 Participants	57 Participants n=50 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=25 Participants	0 Participants n=25 Participants	0 Participants n=50 Participants

PRIMARY outcome

Timeframe: baseline, one-hour post-intervention, one-week post-intervention

Population: 4 participants with incomplete data were not analyzed. 16 participants who did not complete the study were not analyzed.

change in self-reported anhedonia from baseline averaged across post-intervention and post-washout measured using the score on the Dimensional Anhedonia Rating Scale (DARS); score range is 0-68 with higher scores meaning better outcomes (less anhedonia)

Outcome measures

Outcome measures
Measure	rmPFC-iTBS n=52 Participants Transcranial magnetic stimulation delivered to the rostral medial prefrontal cortex. 600 pulses delivered in 50 Hz bursts every 5 Hz for 2 seconds followed by 8 seconds of no stimulation repeated 20 times at 80% of resting motor threshold. Repeated daily for 5 consecutive days.	Inion-iTBS n=52 Participants Transcranial magnetic stimulation delivered to the inion. 600 pulses delivered in 50 Hz bursts every 5 Hz for 2 seconds followed by 8 seconds of no stimulation repeated 20 times at 80% of resting motor threshold. Repeated daily for 5 consecutive days.
Change in Anhedonia Post-intervention and Washout	6.4231 Scores on a scale Standard Error 1.4585	5.4327 Scores on a scale Standard Error 1.1042

PRIMARY outcome

Timeframe: baseline, 1 hour post-intervention

Population: 4 participants with incomplete data were not analyzed. 16 participants who did not complete the study were not analyzed.

change in self-reported anhedonia from baseline immediately following the intervention measured using the score on the Dimensional Anhedonia Rating Scale (DARS); score range is 0-68 with higher scores meaning better outcomes (less anhedonia)

Outcome measures

Outcome measures
Measure	rmPFC-iTBS n=52 Participants Transcranial magnetic stimulation delivered to the rostral medial prefrontal cortex. 600 pulses delivered in 50 Hz bursts every 5 Hz for 2 seconds followed by 8 seconds of no stimulation repeated 20 times at 80% of resting motor threshold. Repeated daily for 5 consecutive days.	Inion-iTBS n=52 Participants Transcranial magnetic stimulation delivered to the inion. 600 pulses delivered in 50 Hz bursts every 5 Hz for 2 seconds followed by 8 seconds of no stimulation repeated 20 times at 80% of resting motor threshold. Repeated daily for 5 consecutive days.
Change in Anhedonia Post-intervention	5.8462 Scores on a scale Standard Error 1.4558	4.75 Scores on a scale Standard Error 1.1042

PRIMARY outcome

Timeframe: baseline, 1 week post-intervention

Population: 4 participants with incomplete data were not analyzed. 16 participants who did not complete the study were not analyzed.

change in self-reported anhedonia from baseline following a week of washout post-intervention measured using the score on the Dimensional Anhedonia Rating Scale (DARS); score range is 0-68 with higher scores meaning better outcomes (less anhedonia)

Outcome measures

Outcome measures
Measure	rmPFC-iTBS n=52 Participants Transcranial magnetic stimulation delivered to the rostral medial prefrontal cortex. 600 pulses delivered in 50 Hz bursts every 5 Hz for 2 seconds followed by 8 seconds of no stimulation repeated 20 times at 80% of resting motor threshold. Repeated daily for 5 consecutive days.	Inion-iTBS n=52 Participants Transcranial magnetic stimulation delivered to the inion. 600 pulses delivered in 50 Hz bursts every 5 Hz for 2 seconds followed by 8 seconds of no stimulation repeated 20 times at 80% of resting motor threshold. Repeated daily for 5 consecutive days.
Change in Anhedonia Post-washout	7 Scores on a scale Standard Error 1.5696	6.1154 Scores on a scale Standard Error 1.3255

PRIMARY outcome

Timeframe: baseline, immediately post-intervention, one-week post-intervention

Population: 3 participants who had incomplete data were not analyzed. 16 participants who did not complete the study were not analyzed.

change in reward positivity from baseline averaged across immediately post-intervention and post-washout assessed via the EEG event-related potential (ERP) to feedback over FCz in microvolts

Outcome measures

Outcome measures
Measure	rmPFC-iTBS n=53 Participants Transcranial magnetic stimulation delivered to the rostral medial prefrontal cortex. 600 pulses delivered in 50 Hz bursts every 5 Hz for 2 seconds followed by 8 seconds of no stimulation repeated 20 times at 80% of resting motor threshold. Repeated daily for 5 consecutive days.	Inion-iTBS n=53 Participants Transcranial magnetic stimulation delivered to the inion. 600 pulses delivered in 50 Hz bursts every 5 Hz for 2 seconds followed by 8 seconds of no stimulation repeated 20 times at 80% of resting motor threshold. Repeated daily for 5 consecutive days.
Change in RewP Post-intervention and Washout Measured Via EEG	0.2027 microvolts Standard Error 0.6153	-0.3760 microvolts Standard Error 0.6280

PRIMARY outcome

Timeframe: baseline, immediately post-intervention

Population: 3 participants who had incomplete data were not analyzed. 16 participants who did not complete the study were not analyzed.

change in reward positivity from baseline immediately following the intervention assessed via the EEG event-related potential (ERP) to feedback over FCz in microvolts

Outcome measures

Outcome measures
Measure	rmPFC-iTBS n=53 Participants Transcranial magnetic stimulation delivered to the rostral medial prefrontal cortex. 600 pulses delivered in 50 Hz bursts every 5 Hz for 2 seconds followed by 8 seconds of no stimulation repeated 20 times at 80% of resting motor threshold. Repeated daily for 5 consecutive days.	Inion-iTBS n=53 Participants Transcranial magnetic stimulation delivered to the inion. 600 pulses delivered in 50 Hz bursts every 5 Hz for 2 seconds followed by 8 seconds of no stimulation repeated 20 times at 80% of resting motor threshold. Repeated daily for 5 consecutive days.
Change in RewP Post-intervention Measured Via EEG	0.3579 microvolts Standard Error 0.7129	-0.2191 microvolts Standard Error 0.7721

PRIMARY outcome

Timeframe: baseline, 1 week post-intervention

Population: 3 participants who had incomplete data were not analyzed. 16 participants who did not complete the study were not analyzed.

change in reward positivity from baseline immediately following a week of washout post-intervention assessed via the EEG event-related potential (ERP) to feedback over FCz in microvolts

Outcome measures

Outcome measures
Measure	rmPFC-iTBS n=53 Participants Transcranial magnetic stimulation delivered to the rostral medial prefrontal cortex. 600 pulses delivered in 50 Hz bursts every 5 Hz for 2 seconds followed by 8 seconds of no stimulation repeated 20 times at 80% of resting motor threshold. Repeated daily for 5 consecutive days.	Inion-iTBS n=53 Participants Transcranial magnetic stimulation delivered to the inion. 600 pulses delivered in 50 Hz bursts every 5 Hz for 2 seconds followed by 8 seconds of no stimulation repeated 20 times at 80% of resting motor threshold. Repeated daily for 5 consecutive days.
Change in RewP Post-washout Measured Via EEG	0.0475 microvolts Standard Error 0.8218	-0.5328 microvolts Standard Error 0.7189

SECONDARY outcome

Timeframe: baseline, 15 minutes post-intervention

Population: 8 participants who had excessive head motion (root-mean square of framewise displacement \> 0.3) were not analyzed. 2 participants with missing data were not analyzed. 16 participants who did not complete the study were not analyzed.

Change in reward-related activation in the ventral striatum assessed via the fMRI blood-oxygenation level dependent (BOLD) signal following feedback (arbitrary units). More positive values indicate greater activation relative to baseline (more reward-related signal).

Outcome measures

Outcome measures
Measure	rmPFC-iTBS n=46 Participants Transcranial magnetic stimulation delivered to the rostral medial prefrontal cortex. 600 pulses delivered in 50 Hz bursts every 5 Hz for 2 seconds followed by 8 seconds of no stimulation repeated 20 times at 80% of resting motor threshold. Repeated daily for 5 consecutive days.	Inion-iTBS n=46 Participants Transcranial magnetic stimulation delivered to the inion. 600 pulses delivered in 50 Hz bursts every 5 Hz for 2 seconds followed by 8 seconds of no stimulation repeated 20 times at 80% of resting motor threshold. Repeated daily for 5 consecutive days.
Change in Reward Activation Measured Via fMRI	-0.1067 arbitrary units Standard Error 0.1315	-0.0702 arbitrary units Standard Error 0.1024

SECONDARY outcome

Timeframe: baseline, 15 minutes post-intervention

Population: 10 participants who had excessive head motion (root-mean square of framewise displacement \> 0.3 in any visit) were not analyzed. 2 participants with missing data were not analyzed. 16 participants who did not complete the study were not analyzed.

Change in fMRI connectivity between ventral striatum and medial prefrontal cortex assessed via correlations in the fMRI blood-oxygenation level dependent (BOLD) signal between these areas (z-scored correlation coefficient). More positive values indicate more positive correlations in BOLD signals between the ventral striatum and medial prefrontal cortex relative to baseline.

Outcome measures

Outcome measures
Measure	rmPFC-iTBS n=44 Participants Transcranial magnetic stimulation delivered to the rostral medial prefrontal cortex. 600 pulses delivered in 50 Hz bursts every 5 Hz for 2 seconds followed by 8 seconds of no stimulation repeated 20 times at 80% of resting motor threshold. Repeated daily for 5 consecutive days.	Inion-iTBS n=44 Participants Transcranial magnetic stimulation delivered to the inion. 600 pulses delivered in 50 Hz bursts every 5 Hz for 2 seconds followed by 8 seconds of no stimulation repeated 20 times at 80% of resting motor threshold. Repeated daily for 5 consecutive days.
Change in Reward Connectivity Measured Via fMRI	-0.0463 z-scored correlation coefficient Standard Error 0.0275	0.0049 z-scored correlation coefficient Standard Error 0.0261

Adverse Events

rmPFC-iTBS Then Inion-iTBS

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Inion-iTBS Then rmPFC-iTBS

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Derek Nee

Florida State University

Phone: 8506441963

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place