Noninvasive Modulation of Motivational Brain Regions in Healthy Volunteers: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Noninvasive Modulation of Motivational Brain Regions in Healthy Volunteers (NCT04972786), a randomized na study. The primary outcome is dACC BOLD Signal (After Active rTMS Session).

2. Clinical Question

The study’s rationale was to examine whether stimulation of a motivational brain region could modify decision making and dACC activity. Its stated context was a parallel study of apathy in people with traumatic brain injury, with the longer-term aim of informing a patient-centered trial. That context is not itself evidence about outcomes in patients: the participants described for this trial were healthy controls.

The registry lists an enrollment of 21, but the primary outcome summaries are reported for 8 participants in the active-first sequence and 5 in the sham-first sequence. The study therefore addresses a laboratory measure in the reported sequence groups, rather than a clinical outcome in patients with traumatic brain injury. The posted results do not establish whether active stimulation changed the measure relative to sham.

3. Trial Design

The registry describes a randomized, triple-masked, crossover study of active and sham rTMS. In a crossover design, each participant is intended to experience more than one intervention condition, with treatment order represented by the two listed sequences: active rTMS first and sham second, or sham first and active second. This design can allow within-participant comparisons, but a valid comparison depends on an analysis that accounts for repeated measurements and treatment sequence. The registry record does not report such an analysis for the primary outcome.

The study summary describes a baseline visit on Day 1, including reward-guided decision-making tasks, questionnaires, and functional magnetic resonance imaging (fMRI). On Days 2 and 3, participants received active or sham stimulation and repeated a subset of tasks and fMRI sequences. The listed primary outcome is specifically dACC BOLD signal after an active session, measured 30 minutes post-rTMS. The registry gives the stimulation duration as 10-20 minutes for both active and sham sessions.

The record lists the study as completed, with a start date of 2021-08-01 and a primary completion date of 2023-06-21. It reports enrollment of 21. The primary outcome summaries are smaller: 8 participants in the active-first sequence and 5 in the sham-first sequence. The primary outcome description notes that several participants attended a baseline visit but did not return for rTMS visits, and that one participant from Arm 1 elected to discontinue rTMS and did not return for the sham visit.

The registry record does not report the randomization procedure, details of masking implementation, a washout interval, or a rationale for the planned enrollment. It also does not state how the crossover observations were modeled. These details matter for understanding how order, repeated measurements, and incomplete return visits were handled.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Baseline MRI Scan (1 Day)

First Intervention (1 Day)

Reasons for not completing this period:

Washout (7 or More Days)

Second Intervention (1 Day)

Analysis population for the primary outcome, as defined in the registry: Several participants came for baseline visit but did not return for rTMS visits. Once participant from Arm 1 elected to discontinue rTMS and did not return for their sham visit.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: Healthy, non-brain-injured adult participants

6. Primary Endpoint

The registry lists the primary outcome as dACC BOLD Signal (After Active rTMS Session), measured over 30 minutes post-rTMS.

The primary endpoint is dACC BOLD signal after an active rTMS session. It is expressed as percentage of BOLD signal change, with the registry specifying the mean and standard deviation as the summary measures. The measurement is taken 30 minutes post-rTMS.

The endpoint focuses on trial-by-trial encoding of immediate expected value (IEV) in a dACC region of interest targeted with rTMS. In the study’s framework, this captures a brain response associated with processing expected value during reward-guided decision making. fMRI BOLD signal is an indirect measure of brain activity: the endpoint is a signal change, not a direct measure of motivation, behavior in daily life, or clinical improvement.

A brain-region measure can be useful in an early mechanistic study because it can test whether a targeted neural signal is measurable after stimulation. The registry’s rationale connects the dACC to motivational processes, but the endpoint alone cannot establish that a change in the signal causes a change in motivation or decision making. Nor does the endpoint measure treatment benefit in patients with traumatic brain injury; the trial summary describes healthy control participants.

The posted sequence-group means are -1.14 for active rTMS first, then sham rTMS, and -1.27 for sham rTMS first, then active rTMS. The corresponding standard deviations are 0.92 and 0.91. These are descriptive summaries of the endpoint, reported by sequence. The registry does not provide a confidence interval or a direct active-versus-sham estimate for this primary outcome.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The posted primary outcome is a continuous measure. Its descriptive summaries are means and standard deviations for participants grouped by treatment sequence. These statistics communicate different features of the data: the mean gives the group’s average BOLD signal change, while the standard deviation describes how dispersed individual values are around that average. Neither statistic alone quantifies the uncertainty in an active-versus-sham treatment effect.

What a crossover comparison requires

In a crossover study, participants receive the study conditions in an assigned order. The main advantage of a within-participant comparison is that each person can serve as their own reference, reducing the influence of stable differences between people. The corresponding analysis must preserve that pairing. Comparing sequence-group means as though the groups were independent does not reproduce the within-person treatment contrast.

Order can also matter. Measurements may vary by period, and an effect from an earlier condition could potentially influence a later measurement. Crossover analyses commonly distinguish treatment effects from period and sequence effects and consider whether carryover is plausible. These are general statistical considerations, not claims about what happened in this trial. The registry record does not report its crossover model, period effects, carryover assessment, or the timing of any washout between sessions.

Means, variability, and uncertainty

The active-first group’s mean is -1.14 with standard deviation 0.92; the sham-first group’s mean is -1.27 with standard deviation 0.91. The standard deviations describe variability within those reported groups. They do not indicate how accurately a treatment contrast has been estimated. A confidence interval would express a range of values compatible with the data and the analysis assumptions. No confidence interval for a treatment contrast is reported in the registry record.

A hypothesis test, when used, evaluates the data against a specified null hypothesis under a statistical model. A p-value is not the probability that the null hypothesis is true, nor does it measure the size or clinical importance of an effect. The registry record does not post a p-value or an inferential test for the primary outcome. Without a reported treatment contrast and its uncertainty, the descriptive means cannot answer whether active rTMS differed from sham.

Planning assumptions are not trial findings

Planning sample-size illustrations are distinct from observed trial results. The stated planning assumptions use a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation, with the effect to detect defined as a fraction of the observed effect. Such calculations are hypothetical planning exercises; they are not evidence that a study had a particular probability of detecting an effect after the data were collected. They also do not replace the trial’s own design justification, which is not reported in the registry record.

The stated planning approach refers to participants per arm for non-time-to-event outcomes. That format is not a description of the number analyzed in this crossover trial, where the posted outcome groups are sequences and the analysis should account for paired observations. The registry record does not report a sample-size justification or explain how the planned enrollment related to the primary endpoint analysis.

Variation and model choice

General statistical methods must reflect the form of the outcome and the study design. For a continuous endpoint, analysts may estimate a mean contrast and its uncertainty, with an approach suited to repeated measures and the distribution of residuals. If observations show more variability than a simple model expects, over-dispersion can make standard errors too small and confidence intervals too narrow unless the model accounts for it. This is a general consideration; the registry record does not report whether over-dispersion was assessed or whether any alternative variance model was used.

The registry identifies the endpoint as a mean with standard deviation, but does not post model diagnostics, adjusted estimates, covariates, or a prespecified statistical analysis plan. No adjusted or recalculated treatment comparison is available in the posted primary outcome summaries. Consequently, the descriptive summaries can be reported, but a model-based conclusion cannot be reconstructed from the registry record.

Multiplicity and interpretation

When a study tests multiple outcomes or multiple contrasts, repeated testing can increase the chance of a false-positive finding. A prespecified hierarchy or multiplicity adjustment may address that issue, depending on the objectives and analysis plan. The record lists 6 outcome measures, but reports 0 posted secondary outcome results and 0 posted statistical analyses. A multiplicity strategy is not reported in the registry record. This absence does not show which outcomes were analyzed or what decisions were made; it means those details cannot be established from the posted record.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Active rTMS First, Then Sham rTMS", "Sham rTMS First, Then Active rTMS")
n   <- c(8, 5)
m   <- c(-1.14, -1.27)
sp  <- c(0.92, 0.91)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Active rTMS First, Then Sham rTMS  8  -1.140  0.920  -1.909  -0.371
CARM  Sham rTMS First, Then Active rTMS  5  -1.270  0.910  -2.400  -0.140

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 6 outcome measures, but reports 0 posted secondary outcome results and 0 posted statistical analyses. The primary outcome has descriptive mean and standard deviation summaries by sequence, but there is no posted inferential comparison, confidence interval, or p-value. A prespecified analysis plan and multiplicity strategy are not reported in the registry record.

Multiplicity matters when several outcomes, time points, or contrasts are tested. In general, the more statistical tests considered, the more important it is to specify which outcome is primary and how other tests will be interpreted. The record identifies a primary outcome, but does not explain whether or how testing across the listed measures was controlled. No conclusion about such procedures can be drawn from the number of measures alone.

Missing observations are a separate concern. The record says several participants attended baseline but did not return for rTMS visits, and one participant from Arm 1 discontinued rTMS and did not return for the sham visit. The primary outcome sequence summaries include 8 and 5 participants, while overall enrollment is 21. The record does not give a complete participant flow, reasons for all missing measurements, or a missing-data method.

In a crossover study, incomplete return visits can prevent some participants from contributing a paired treatment comparison. General approaches to missing data depend on why measurements are missing and on assumptions about the missingness process. The registry record does not report whether the primary outcome analysis used available cases, imputation, or another approach. It also does not report analysis populations such as intention-to-treat or per-protocol. Therefore the representativeness and potential bias of the analyzed observations cannot be assessed from the posted information.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports serious adverse events for 12 participants at risk in the active rTMS group and 12 at risk in the sham rTMS group. Serious adverse events affected 0 participants in each group. Deaths are reported as 0 in both groups. These are the posted serious-event counts; they do not establish that no serious event could occur outside the recorded observation and reporting framework.

For other adverse events, the record reports 1 affected participant among 12 at risk in the active rTMS group and 0 among 12 at risk in the sham rTMS group. These are counts, not a comparison adjusted for exposure, follow-up, or the crossover sequence. The registry does not state whether the other adverse event was judged related to stimulation, describe its clinical nature, or provide a fuller event narrative. No serious adverse-event terms are listed.

Safety counts should be read in light of the study population and design. The study summary describes healthy control participants, and the groups represent active and sham sessions in a crossover study. The posted group counts do not provide a participant-level account across both periods or clarify how events were attributed when participants experienced both conditions. The registry record also does not report a detailed safety analysis. These figures therefore describe the events recorded, rather than establishing comparative safety or the absence of risk.

13. What the Result Does, and Does Not, Mean

The posted result establishes that the registry contains descriptive primary-outcome summaries for two treatment sequences. The mean dACC BOLD signal change after active rTMS is reported as -1.14 for the active-first sequence and -1.27 for the sham-first sequence. Their standard deviations are 0.92 and 0.91, respectively. The outcome is an fMRI measure of trial-by-trial immediate expected value encoding in a targeted dACC region, measured 30 minutes after active stimulation.

Those sequence-specific summaries are not a direct estimate of the active-versus-sham effect. A crossover comparison should use each participant’s observations under both conditions and account for the study’s order structure. The registry record does not post that comparison, a confidence interval, or a p-value. As a result, the precision and direction of a treatment contrast cannot be established from the reported group summaries alone. They do not demonstrate that active rTMS changes the endpoint, and they do not demonstrate that it has no effect.

The endpoint is also a brain signal rather than a direct measure of everyday motivation or a clinical outcome. The trial summary describes healthy controls, and the proposed relevance to traumatic brain injury is an intended research context, not a result in patients. The posted information cannot establish whether the measured signal is linked to changes in behavior or patient experience.

Enrollment is listed as 21, while the outcome summaries include 8 and 5 participants by sequence. The record notes nonreturn after baseline visits and one participant who discontinued rTMS and did not return for sham. It does not provide a complete missing-data analysis. That limits interpretation of how the reported participants relate to the full enrolled group.

Accordingly, the result is best understood as descriptive evidence about the recorded fMRI endpoint in the posted sequence groups. The registry does not report enough inferential or missing-data detail to support a treatment-effect conclusion or to generalize the endpoint to clinical benefit.

14. Why This Trial Matters Statistically

This trial is statistically notable because its crossover structure affects what the reported numbers can answer. Sequence-group summaries are not interchangeable with a within-participant active-versus-sham contrast. An analysis that respects pairing and treatment order is central to interpreting a crossover study. The registry record reports the sequence groups’ means and standard deviations, but not the paired contrast or its uncertainty.

The primary endpoint is a continuous fMRI measure intended to capture immediate expected value encoding in the targeted dACC region. It illustrates the distinction between a mechanistic measurement and a clinical outcome. A signal in a brain region can be scientifically informative, but interpreting it as evidence about motivation, behavior, or patient benefit would require additional results and a clear link between the measure and those outcomes. Such results are not posted for this trial.

The record also highlights why enrollment and endpoint-specific participant counts need separate attention. The listed enrollment is 21, whereas the primary summaries are reported for 8 and 5 participants by sequence. The explanation notes missed rTMS visits and a discontinuation, but the full flow and missing-data handling are not reported. In a crossover study, missing one session can affect whether a participant contributes a complete within-person comparison.

Finally, descriptive results, statistical inference, and planning exercises serve different purposes. The means and standard deviations describe observed summaries; a confidence interval or model-based contrast would address uncertainty about the treatment comparison; and sample-size illustrations are hypothetical planning aids. The registry record does not post the inferential comparison or the trial’s own sample-size justification. Keeping these roles distinct prevents a descriptive result from being interpreted as a conclusive treatment effect.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The primary limitation for interpreting the endpoint is the absence of a posted active-versus-sham treatment contrast. The registry gives means and standard deviations by sequence, but not a paired estimate, confidence interval, p-value, or crossover model. The sequence summaries therefore cannot establish the size or precision of an active-versus-sham effect.

The primary outcome summaries include fewer participants than the listed enrollment. The record explains that several participants attended baseline but did not return for rTMS visits, and that one participant from Arm 1 elected to discontinue rTMS and did not return for sham. A complete account of missing endpoint measurements, reasons for nonreturn, and the handling of incomplete crossover data is not reported in the registry record.

Other details needed to assess the design and analysis are also not reported: the randomization procedure, the implementation of triple masking, any washout interval, the statistical analysis plan, the sample-size justification, and the analysis population. The record does not state whether the analysis adjusted for sequence or period, assessed carryover, or used a method for missing data.

The outcome is a regional BOLD signal measure in healthy controls, not a direct clinical outcome in people with traumatic brain injury. The record lists traumatic brain injury as a condition and describes a related parallel study, but the current study summary identifies healthy control participants. The registry does not post secondary outcome results that would connect the brain measure to decision-making behavior or patient-centered outcomes.

Safety information is also limited to summary counts. The record does not describe the other adverse event, its relationship to stimulation, or event attribution across crossover periods. These limitations constrain interpretation of both the primary result and the adverse-event summaries.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Noninvasive Modulation of Motivational Brain Regions in Healthy Volunteers — NCT04972786.
• Registry record last updated 2024-07-16; status last verified 2024-06.
• Results first posted 2024-07-16.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

The University of New Mexico-sponsored study, NCT04972786, is titled “Noninvasive Modulation of Motivational Brain Regions in Healthy Volunteers.” It is listed as completed, randomized, triple-masked, and crossover, with enrollment of 21. The registry gives a start date of 2021-08-01 and a primary completion date of 2023-06-21.

The study compared active and sham rTMS in two treatment sequences. Its primary endpoint was mean dACC BOLD signal change, expressed as percentage of BOLD signal change, 30 minutes after active rTMS. The posted sequence-group means are -1.14 and -1.27, with standard deviations of 0.92 and 0.91, based on 8 and 5 participants, respectively.

No direct treatment comparison or inferential analysis is posted for the primary endpoint. The record notes missed rTMS visits and a discontinuation, but does not report a complete missing-data analysis. Serious adverse events and deaths are reported as 0 in each group; other adverse events affected 1 participant in the active group and 0 in the sham group.