Measuring Plasticity in SFC/dACC Following Theta-Burst-Stimulation Using TMS: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Measuring Plasticity in SFC/dACC Following Theta-Burst-Stimulation Using TMS (NCT03946059), a randomized na study. The primary outcome is Post vs. Pre Change in Mid-frontal Theta Oscillations for iTBS vs. cTBS Stimulation.

2. Clinical Question

The study was designed to evaluate whether the BrainE cognitive task platform could detect neural plasticity and cognitive changes following stimulation. BrainE assessed sustained attention, response inhibition, working memory, interference processing, and emotion processing. The primary outcome combined the evoked EEG response across cognitive tasks, using mid-frontal theta at the FCz electrode as an indicator of superior frontal theta activity.

The comparison is between changes measured after two stimulation protocols, rather than between stimulation and a no-stimulation condition. Both stimulation conditions were administered to participants in different orders, with a washout period between sessions. The registry describes iTBS as a protocol designed to excite brain activity and cTBS as a protocol designed to inhibit it; those descriptions are the study rationale, not a conclusion about the observed results.

The posted outcomes address average changes in neural activity and cognitive performance. They do not establish whether every task, participant, or stimulation sequence showed the same pattern. Details of participant eligibility and other population characteristics are not reported in the registry record.

3. Trial Design

The registry lists this study as randomized, quadruple masked, and using a crossover model. Its status is completed. The listed study start was 2019-04-30, and the primary completion date was 2019-10-30. The sponsor was the University of California, San Diego. The study is listed as phase NA.

Participants received both stimulation conditions in an order that varied by sequence. One sequence began with iTBS in week 1, followed by a one-week washout period and cTBS in week 2. The other began with cTBS in week 1 and then iTBS in week 2. This arrangement allows condition comparisons within a crossover study, while the randomized sequence determines which condition is received first. The registry does not report how the sequence allocation was generated or how concealment was implemented.

For each stimulation session, cognitive-task performance and brain activity were measured immediately before and immediately after stimulation. The primary outcome compared the pre-to-post changes in task-averaged mid-frontal theta oscillations. The secondary outcome concerned pre-to-post change in cognitive performance. The record reports 25 enrolled and states that only 24 completed the study. It does not report the reasons for non-completion or the analysis population rules.

The registry identifies quadruple masking, but does not specify which groups of people were masked or how masking was maintained. The protocol's original sample-size rationale, planned statistical model, handling of the crossover structure, interim analyses, and prespecified analysis details are not reported in the registry record. The posted summary statistics therefore support description of the measured outcomes, but do not reveal all design and analysis decisions that would be needed to reproduce a full trial analysis.

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.

Before assignment: No enrolled participants were excluded.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Although 25 participants enrolled, only 24 completed the study.

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.

6. Primary Endpoint

The registry lists the primary outcome as Post vs. Pre Change in Mid-frontal Theta Oscillations for iTBS vs. cTBS Stimulation, measured over (Post-Pre) iTBS and (Post-Pre) cTBS signals were measured one week apart..

The primary endpoint is the change from immediately before to immediately after stimulation in mid-frontal, stimulus-evoked theta oscillations. The EEG response was measured at the FCz electrode and expressed in microVolts (uV). The study averaged this response across selective attention, response inhibition, working memory, interference processing, and emotion processing tasks to create a task-averaged signal.

The endpoint was selected to represent neural activity associated with the cognitive tasks and the superior frontal region targeted by stimulation. Measuring before and after each stimulation session makes the outcome a change measure: it focuses on how the recorded signal shifted during the session rather than only on the post-stimulation value. Comparing that change between iTBS and cTBS addresses the study's primary contrast.

Averaging across tasks gives a broad summary of the evoked response, but it can conceal variation among individual tasks. A change in the task-averaged signal does not, by itself, specify which task contributed most or whether all task-specific responses moved in the same direction. Task-specific primary results are not reported in the registry record.

The primary outcome is continuous and is summarized using a mean and standard deviation. Those summaries describe the average change and the variability of observed changes; they do not alone determine the precision of the comparison or establish the effect for an individual participant. The registry's reported comparison and its uncertainty are relevant to interpreting the group-level contrast.

7. Results Posted in the Registry

• iTBS: mean 0.02 versus -0.04 on control; difference 0.06 (95% CI -0.02 to 0.14), standardized effect d = 0.41; z-test p = 0.158.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Post vs. Pre Change in Cognitive Performance

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • iTBS: mean 0.01 versus 0.03 on control; difference -0.01 (95% CI -0.03 to 0.00), standardized effect d = -0.51; z-test p = 0.080.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between iTBS and the control. The interval gives the range of effects that remain compatible with the data.

The posted secondary outcome concerns change in cognitive performance averaged across the study's cognitive tasks. Its estimated condition contrast points in the opposite direction from the primary neural outcome contrast: the primary mean difference is positive, whereas the secondary mean difference is negative. Both confidence intervals include zero, so this directional difference between estimates does not establish that the outcomes truly respond differently to the two stimulation conditions.

The cognitive outcome complements the primary endpoint by asking whether the stimulation sessions were associated with a measurable change in task performance as well as a change in evoked theta activity. A neural signal and a behavioral performance measure need not move together, and a group-level association between them is not established by the separate outcome summaries. The registry does not report a joint analysis relating changes in neural activity to changes in cognitive performance.

The secondary result should carry less weight than a prespecified primary result when the analysis plan and multiplicity handling are not documented. Testing multiple outcomes increases the chance that at least one result may appear noteworthy by chance. An adjustment or a clearly stated hierarchy can address that concern, but adjustment procedures are not reported in the registry record. The posted secondary p value is unadjusted.

The overall pattern is therefore mixed rather than confirmatory: the neural and cognitive estimates point in different directions, and neither interval excludes zero. This does not demonstrate that the outcomes contradict each other, because their uncertainty is substantial. It also does not support elevating the secondary finding over the primary comparison. Interpretation is limited by the absence of reported analysis details, including whether the crossover structure and any relationship among outcomes were considered.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Post vs. Pre Change in Cognitive Performance

9. Statistical Interpretation

10. Statistical Methods Explained

Continuous outcomes are measurements that can take values along a scale. The primary outcome, expressed in microVolts (uV), and the secondary outcome, expressed in log(1/sec), are reported as means with standard deviations. A mean describes the central average of observations. A standard deviation describes how spread out observations are around that average. Neither summary conveys the full distribution: unusual values, skew, or subgroups can be hidden by a mean and standard deviation.

What does a pre-to-post change represent?

A change score compares a measurement after a session with its measurement before that session. In this study, each stimulation condition has a pre-to-post change, and the primary comparison contrasts those changes between iTBS and cTBS. This differs from comparing only post-session measurements because baseline values are incorporated into the change. Change scores can be useful for describing within-session shifts, but they can also be affected by measurement variability and by differences in baseline values.

The outcome summaries give the mean change for each stimulation condition. The mean difference is the contrast between those condition means, reported as iTBS versus cTBS. Its sign indicates the direction of the contrast according to that ordering: a positive estimate means the iTBS mean is greater than the cTBS mean, while a negative estimate means it is lower. This is a description of the reported contrast, not a judgment about clinical or practical importance.

Why does the crossover design matter?

In a crossover design, participants receive more than one condition, so observations from the same participant are generally related. A paired analysis can use that within-participant relationship and may differ in precision from an analysis that treats observations as independent. The order of conditions and the time period can also matter. If an effect of the first session persists into the next, the washout period may not remove all carryover. The registry reports a one-week washout but does not report an analysis method for pairing, period, sequence, or carryover. The available condition-level summaries do not allow those methods to be reconstructed.

Randomization concerns the assignment of participants to the order of conditions; masking concerns which people involved in the study were unaware of condition assignment. These design features can reduce some sources of bias, but they do not remove uncertainty or substitute for a clearly described analysis. The registry identifies randomized allocation and quadruple masking but does not report implementation details.

How should the p value be read?

A p value measures the compatibility of the observed data with a specified null model, under the assumptions used in the analysis. A smaller p value indicates that the data would be less compatible with that model; it is not a measure of effect size, clinical importance, or the probability that a finding is true. Here, the primary unadjusted p value is 0.158, and the secondary unadjusted p value is 0.08. These values should be read alongside the effect estimates and confidence intervals, rather than as stand-alone verdicts.

The registry does not report the full statistical model or a multiplicity adjustment. The comparison values and p values should therefore be treated as unadjusted summary evidence. Whether they account for the crossover structure, repeated task measurements, or other design features is not reported in the registry record.

What does a confidence interval add?

A confidence interval gives a range of estimates compatible with the data under a specified method. It expresses uncertainty about the estimated contrast; it does not mean that there is a particular probability that the fixed true effect lies within the interval. The width reflects both the amount of information and variability, as well as the analysis method. An interval that includes zero is compatible with no difference, but it can also include nonzero differences in either direction.

For each posted condition contrast, the reported interval includes zero. This reinforces that the data do not precisely distinguish the estimated contrast from no difference. It does not prove the conditions are equal. The interval's interpretation depends on the model and assumptions used, which are not fully documented in the registry record.

Why does over-dispersion matter?

Over-dispersion is a general issue that arises when observed variability is greater than a model assumes. A model that understates variability can make uncertainty appear too small and can make evidence look stronger than it is. Appropriate variability assumptions are important for standard errors, confidence intervals, and p values. The posted outcomes are continuous means with standard deviations, and the registry does not report an over-dispersion assessment or a model that would allow one to be evaluated. This is a general statistical consideration, not a claim that over-dispersion occurred in this study.

The sample-size figures are planning illustrations based on fractions of the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They describe hypothetical planning under those assumptions, not the original trial design. The registry record does not report the study's original sample-size assumptions or justification.

11. Confidence Intervals and Precision

The primary mean difference is 0.06, with a reported confidence interval extending from -0.023 to 0.143. This interval spans zero. The observed estimate is positive, but the range includes both a negative contrast and a positive contrast. The data therefore leave uncertainty about the direction and size of the underlying condition difference. The unadjusted p value of 0.158 is consistent with that lack of precise separation from zero.

For the secondary outcome, the mean difference is -0.012, with a confidence interval extending from -0.025 to 0.001. This interval also includes zero. The estimated contrast is negative, but the range includes a value very close to zero as well as negative values. The unadjusted p value is 0.08. Neither the point estimate nor the p value should be considered alone; together with the interval, they indicate uncertainty about the size of the condition contrast.

A confidence interval is not a range of individual participant responses. It concerns uncertainty in the estimated group contrast under the method used. It also does not capture every source of uncertainty, such as bias from missing observations or limitations in the analysis model. The registry reports 25 participants enrolled and 24 completing, but does not explain the non-completion or report how missing outcomes were handled.

Precision is distinct from whether an estimate is statistically significant. A wide interval can include effects in more than one direction and leave considerable uncertainty, even when the point estimate appears notable. A narrow interval can be more informative about plausible values. Here, the intervals for both outcomes include zero, and the record does not report additional model-based analyses that could clarify how design features influenced their width.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm, not total event counts. They are illustrations based on the observed primary effect and assume a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The original trial's sample-size justification and design assumptions are not reported in the registry record.

For planning for 100% of the observed primary effect, the figures are 95 participants per arm for 80% power and 127 participants per arm for 90% power. For planning for 75% of the observed effect, they are 168 participants per arm for 80% power and 225 participants per arm for 90% power. For planning for 50% of the observed effect, they are 378 participants per arm for 80% power and 506 participants per arm for 90% power.

Power is the probability, under the assumptions of a particular planning model and a specified effect, that a study would meet its chosen statistical criterion. The 80% and 90% columns describe different target probabilities for detecting the assumed effect under the planning assumptions. A higher target power generally requires more participants, all else being equal. The figures also increase as the effect being planned for becomes smaller: smaller effects are harder to distinguish from random variation and require more information.

These are hypothetical planning estimates, not a measure of the completed study's success or failure at detecting an effect. They are not observed power. The registry record does not report that these assumptions were used to design the trial.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 0.060; pooled standard deviation σ = 0.147.
2. n = 2 × (1.96 + 0.842)² × 0.147² / 0.060² = 94.4, rounded up to 95 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- 0.06                      # observed difference in means
sigma <- 0.147139389695622                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(3946059)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 95 (80% power), 127 (90% power)
 75% of observed effect: n per arm = 168 (80% power), 225 (90% power)
 50% of observed effect: n per arm = 378 (80% power), 506 (90% power)
power.t.test: 95.4 
Simulated power at n = 95 per arm: 0.798 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Multiplicity, Missing Data and Analysis Populations

The registry identifies a primary neural outcome and a secondary cognitive-performance outcome. When more than one outcome is examined, the chance of finding an apparently unusual result by chance can increase. Statistical approaches such as a prespecified outcome hierarchy or an adjustment for multiple comparisons can help control that issue. The registry does not report a multiplicity strategy, so the posted p values should be read as unadjusted rather than as evidence adjusted for the family of outcomes.

The record lists no reported analyses, while outcome summaries and comparisons are posted. It does not describe a prespecified statistical analysis plan, the model used for the condition contrasts, or whether analyses followed an intention-to-treat or another analysis population principle. Those details are not reported in the registry record. This makes it difficult to determine whether the posted comparisons were planned in advance or how they address the randomized crossover sequence.

The study reports 25 participants enrolled and 24 completed. Reasons for non-completion, the number of missing measurements, and the handling of missing outcomes are not reported in the registry record. Missing data can affect precision and can also bias an estimate if the availability of measurements is related to outcomes or treatment condition. The available summary does not establish whether all completers contributed usable measurements for each outcome.

The registry does not report how the crossover pairing was handled, whether period or sequence effects were assessed, or whether carryover was considered. It also does not report interim analyses or a correction for repeated measurement across tasks. These omissions do not prove that the analyses were inappropriate; they mean the relevant decisions cannot be assessed from the record. Transparent reporting of these choices would help readers judge the reliability and scope of the posted comparisons.

15. 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.

The registry reports serious adverse event figures separately for cTBS and iTBS. For each condition, 25 participants were listed as at risk, and zero serious adverse events were reported. The figures for other adverse events are also zero in each group, and deaths are reported as zero in each group. No serious adverse event terms are listed.

These figures describe what was reported in the registry for the listed groups and outcomes. They do not show that adverse events are impossible, nor do zero reported events establish the absence of all symptoms or problems. The record does not provide further detail on event definitions, collection procedures, severity categories beyond serious and other events, or the duration of safety follow-up. The completed study population was limited, and the registry's event counts should be interpreted as a record of reported events rather than a broad estimate of risk.

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

The posted results describe average pre-to-post changes under iTBS and cTBS in a study of mid-frontal theta oscillations and cognitive performance. The primary estimated difference is positive for iTBS versus cTBS, while the secondary estimated difference is negative. The confidence intervals for both comparisons include zero, and the corresponding unadjusted p values do not provide clear evidence separating either contrast from zero.

These findings do not establish that the stimulation conditions are equivalent. Demonstrating equivalence would require a prespecified margin and an analysis designed to test whether the uncertainty is confined within that margin. Such an approach is not reported in the registry record. Nor do the results establish that either stimulation condition causes a reliable change: the study has a small completed sample, and the posted comparisons are uncertain.

The study focused on immediate post-stimulation measures and task-averaged outcomes. It does not establish the duration of any change, whether effects occur for every cognitive task, or whether the findings apply to other populations or settings. The registry does not report detailed participant characteristics, task-specific outcome results, or an analysis linking neural changes to cognitive performance.

The stated aim was to evaluate the sensitivity of the BrainE platform to detect neural plasticity and cognitive enhancements following stimulation. The posted summary offers estimates of measured change in this study, but it does not by itself validate the platform for broader use or show that its measures can reliably detect effects across studies. The results should be understood as limited evidence about the measured outcomes under the study conditions, not as a clinical recommendation or a general claim about treatment benefit.

17. Why This Trial Matters Statistically

This trial illustrates how a study can report several kinds of evidence that answer different questions. The mean difference describes the estimated direction and magnitude of a contrast; the confidence interval conveys uncertainty around that estimate; and the p value assesses compatibility with a null model under analytical assumptions. Reading these together is more informative than treating a p value as a simple yes-or-no conclusion.

The crossover design is statistically important because the same participants experienced both stimulation conditions in different sequences. Accounting for within-participant correlation can influence the estimated uncertainty. Period, sequence, and carryover considerations also matter. The registry gives the order and washout structure but does not describe the analysis of those features, illustrating why reporting the model is essential for evaluating a crossover result.

The trial also compares a neural measure with a cognitive measure. Their estimated directions differ, which highlights the distinction between a biological signal and task performance. A change in an EEG measure does not automatically imply a corresponding change in cognition, and separate summary outcomes do not establish a relationship between the two. Joint analyses and task-level reporting could address different questions from the overall averages.

Finally, the planning illustrations show why sample-size calculations depend on the effect a future study aims to detect. Planning for a smaller effect requires more participants under the stated assumptions. Those figures are not evidence about the completed study's power or its design rationale. Clear separation between observed estimates and hypothetical planning assumptions is important for responsible interpretation.

18. 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 registry's summary does not report detailed participant characteristics, eligibility criteria, or reasons for non-completion. Although 25 participants enrolled and 24 completed, the missing participant's outcomes and the handling of incomplete measurements are not described. This limits assessment of the analysis population and whether missingness could have affected the comparisons.

The reported outcomes average responses across cognitive tasks. That approach supplies an overall summary but may hide task-specific differences. Results for individual tasks, and analyses of whether neural changes track cognitive changes, are not reported in the registry record. The immediate pre-to-post measurement timeframe also does not establish whether any measured change persisted.

The record identifies a randomized, quadruple-masked crossover design and a one-week washout, but does not describe randomization implementation, masking details, or statistical handling of pairing, period, sequence, and carryover. The absence of these details prevents a full assessment of whether the reported uncertainty reflects the crossover design appropriately.

Multiplicity procedures, the original sample-size rationale, interim analyses, and the full statistical plan are not reported in the registry record. The posted p values are unadjusted. The confidence intervals include zero for both posted comparisons, leaving uncertainty about the size and direction of condition differences. These limitations counsel against strong conclusions from the summary estimates, without implying that unreported procedures were necessarily absent from the study conduct.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Measuring Plasticity in SFC/dACC Following Theta-Burst-Stimulation Using TMS — NCT03946059.
• Registry record last updated 2021-03-09; status last verified 2021-02.
• Results first posted 2021-03-09.
• 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.

22. Record Summary

NCT03946059 is a completed randomized, quadruple-masked crossover study sponsored by the University of California, San Diego. It evaluated iTBS and cTBS applied over a midline frontal region, with pre- and post-session measurements of task-averaged mid-frontal theta oscillations and cognitive performance. The record reports 25 enrolled and 24 completing.

The primary comparison reports a mean difference of 0.06 for iTBS versus cTBS, with an unadjusted p value of 0.158 and a confidence interval that includes zero. The secondary cognitive-performance comparison has a negative estimated difference, an unadjusted p value of 0.08, and a confidence interval that also includes zero. The registry reports zero serious adverse events, zero other adverse events, and zero deaths in each stimulation group. Analysis details, missing-data handling, and the original sample-size rationale are not reported in the registry record.