Interactions of Fronto-Parietal High Frequency rTMS on Anterior Cingulate Cortex Activation in Schizophrenia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Interactions of Fronto-Parietal High Frequency rTMS on Anterior Cingulate Cortex Activation in Schizophrenia (NCT04309370), a randomized na study. The primary outcome is Change in BOLD Signal in Anterior Cingulate Cortex.

2. Clinical Question

3. Trial Design

The record describes a randomized, quadruple-masked crossover study, classified as completed. In a crossover design, each participant receives more than one study condition, with the sequence assigned at random. The brief summary says participants would receive a session targeting the LDLPFC and a session targeting the LSPC; it also says the order would be randomized and counter-balanced. The two arm descriptions correspond to those alternative orders. This design can support within-participant comparisons, because a participant may contribute measurements under both target conditions, but the posted primary results are presented as separate target-specific means and intervals.

The study is identified as a single-site pilot in its brief summary. It describes baseline functional magnetic resonance imaging during a cognitive-control task and resting-state paradigms, followed by repeat imaging after each stimulation session. A high-resolution structural sequence was included at baseline for neuronavigation. The summary also says investigators would examine cognitive-control performance. The listed primary outcome, however, is change in anterior cingulate cortex BOLD signal during mismatch versus match trials.

The registry lists enrollment as 14. The brief summary describes an intended enrollment of 20 subjects with early phase psychosis. The record does not explain the difference between those entries or identify the number of participants with usable endpoint data. The study dates are 2020-03-12 for start and 2022-04-15 for primary completion. The study phase is recorded as NA. Indiana University is listed as sponsor. Further details about the masking procedures, sequence implementation, or conduct of the crossover are not reported in the registry record.

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.

Overall 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 Change in BOLD Signal in Anterior Cingulate Cortex, measured over 1 day.

The primary endpoint is change in BOLD signal in the anterior cingulate cortex during cognitive-control mismatch trials compared with match trials. BOLD, or blood oxygen level dependent, signal is an fMRI measure that reflects brain activity through changes in blood oxygenation. The task contrast is defined as mismatch minus match, so the measure focuses on the difference between the two trial types rather than either condition alone.

Change is defined as the difference between the baseline mismatch-minus-match signal and the signal measured 30-60 minutes following the intervention. The registry gives the outcome timeframe as 1 day. Higher scores are described as indicating a larger increase in brain activity following the intervention. The reported unit is BOLD signal change (Mismatch vs. Match), and the measure is summarized as a mean with a 95% confidence interval.

A task-contrast endpoint is used to characterize activation associated with cognitive control in the targeted brain region. It is a laboratory imaging measure, not a direct measure of symptoms, daily functioning, or clinical benefit. The registry record does not report a clinically meaningful threshold for interpreting the size of a BOLD change, nor does it report how such a threshold was selected. It also does not provide a separate endpoint result for cognitive-control task performance in the posted results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean summarize?

The primary outcome is continuous, and its reported parameter is the mean. A mean condenses measurements into a central summary, but it does not show the distribution of individual responses. Participants can have values that vary substantially around the mean, and the mean alone cannot show that variation. The record does not give a standard deviation or another measure of participant-level spread for these outcomes.

The posted mean for each target is a change score: the mismatch-minus-match BOLD contrast after stimulation minus the corresponding baseline contrast. A change score can be positive or negative. In this outcome's stated interpretation, higher scores mean a larger increase in brain activity following stimulation. The signs therefore describe the direction of the estimated change under the registry's coding; they should not be read as a clinical benefit or harm without further evidence and a meaningful clinical threshold.

How should the confidence intervals be read?

A confidence interval expresses uncertainty around an estimate under a statistical procedure. It is not a guarantee that the true value lies in the interval, and it does not state the probability that a particular hypothesis is true. A narrower interval generally indicates greater precision, while a wider interval indicates less precision. Precision depends on factors such as measurement variability and the amount of information available.

For the LDLPFC target, the interval runs from -0.176 to 0.187; for the LSPC target, it runs from -0.086 to 0.152. Each interval contains zero, meaning that the summaries do not pin down the direction of the average change. The intervals should be interpreted in the outcome's BOLD signal units. Because no clinically meaningful threshold is reported, statistical uncertainty cannot be translated into a judgment about clinical importance.

Why does the crossover structure matter?

In a crossover trial, observations from the same participant under different conditions are related. A direct comparison should account for that within-participant pairing. Treating the target conditions as if they were independent groups can misrepresent uncertainty, because it ignores the relationship between each participant's measurements. The registry record does not post the within-participant differences, their variability, or a model that accounts for the crossover structure.

The posted target-specific means and confidence intervals describe each condition separately. They cannot reveal the mean paired difference or its uncertainty. A proper target comparison could also require consideration of order or period effects: responses might vary with session sequence or time. The record says order was randomized and counter-balanced, but does not report an analysis of sequence, period, or carryover effects. These are general considerations for crossover designs, not claims that such effects occurred in this study.

What does the missing comparison mean?

The registry indicates that values were missing or not estimable for a two-arm comparison of this continuous endpoint. It posts no analyses. This means that the direct inferential comparison is not available in the registry results; it does not establish why it is absent. The record does not say whether the issue arose from incomplete measurements, an analysis decision, or another reason. It would be inappropriate to infer a p-value or calculate a paired contrast from the target-specific summaries.

In general, uncertainty for a contrast depends on the data contributing to that contrast and, in a crossover, on the covariance between measurements within participants. That covariance is not reported. The separate confidence intervals do not contain enough information to recover it. Consequently, subtracting the target-specific means would not provide the missing crossover analysis, and no such calculation is presented.

What are planning illustrations?

The record describes a sample-size illustration based on the observed effect, using a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. It says that the effect to detect is a stated fraction of the observed effect, and that the non-time-to-event planning figures are participants per arm. The record does not report the resulting planning counts in the registry record for this analysis, so none can be stated.

Such calculations are planning illustrations, not observed power and not evidence about the chance that the trial detected an effect. They depend on assumptions about the effect size and statistical model. Because the record describes a crossover, an equal-allocation two-arm illustration may not capture the pairing or other design features of the study. No sample-size justification for the trial itself is reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The record lists two outcome measures but reports no secondary posted results and no analyses. The primary endpoint is identified as change in anterior cingulate cortex BOLD signal. The registry does not report a statistical plan describing how multiple outcomes, contrasts, or time points were handled, or whether any adjustment for multiple testing was intended. Without that information, the potential effects of multiplicity on interpretation cannot be assessed.

The brief summary describes additional imaging paradigms and says investigators would examine cognitive-control performance. The posted outcome data do not provide results for those assessments. Their absence from the posted results does not establish whether they were collected, analyzed, or excluded; those details are not reported in the registry record.

The registry notes that values were missing or not estimable for a two-arm comparison of the continuous endpoint. It does not report the number or pattern of missing measurements, reasons for missingness, or how missing data were handled. It also does not identify an analysis population, such as all randomized participants or participants with complete measurements. The listed enrollment and per-target outcome counts do not resolve those questions, particularly in a crossover where the same participant may contribute to both conditions.

These omissions limit assessment of the analysis. Missingness can affect an estimate if the availability of measurements is related to participant outcomes, and different analysis populations can lead to different results. Those are general statistical considerations; the record does not establish that either issue altered this study's estimates. The statistical plan, missing-data assumptions, and multiplicity procedures are not reported in the registry record.

11. 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 adverse-event record lists zero serious adverse events and zero deaths for both target groups. It lists one other adverse event for the LDLPFC-target group and two other adverse events for the LSPC-target group. Fourteen are listed at risk in each group for both serious and other events. The record does not provide serious adverse-event terms, and it does not describe the nature, severity, timing, or relatedness of the other events.

These counts are descriptive safety entries, not a statistical comparison between targets. The crossover structure matters: participants may contribute to both target conditions, so the group counts should not be treated as independent sets of people or added to infer a total. The record does not clarify whether entries represent affected participants or event counts, nor does it describe how events were attributed when participants received both targets.

Zero recorded serious events does not establish that serious events are impossible or that a target is safer. In a small pilot, the absence of recorded events provides limited information about uncommon harms. The registry record does not report a formal safety analysis, exposure-adjusted event rates, or detailed event narratives.

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

The posted results provide an estimate of mean BOLD signal change after each stimulation target, along with confidence intervals. They indicate that the target-specific estimates are close to zero on the reported measurement scale and that each interval spans negative and positive values. This is a description of the available summaries, not evidence that the average change is exactly zero or that participants had no response.

The results do not show whether the LDLPFC and LSPC targets differ. A direct comparison is not posted, and the separate means and intervals do not allow the within-participant crossover contrast to be reconstructed. The registry record also provides no p-value, no analysis details, and no posted secondary results. The evidence therefore cannot establish a statistically reliable difference between targets or provide a definitive account of the planned task-performance outcome.

The endpoint is an fMRI measure of task-related activation, not a clinical outcome. The record does not report a threshold for a clinically meaningful BOLD change, nor does it link the observed changes to symptoms or functioning. These results should not be interpreted as showing that either stimulation target improves or worsens schizophrenia or early phase psychosis.

The study is described as a pilot, and the estimates have substantial uncertainty. The registry enrollment is 14, while the brief summary describes an intended enrollment of 20; the record does not reconcile these entries. The posted counts do not establish how many participants contributed complete paired measurements. Together, the absent direct comparison and limited reporting mean that the results are best understood as preliminary descriptive information about the measured imaging endpoint.

13. Why This Trial Matters Statistically

This trial is statistically informative as an example of why study design and result presentation must be considered together. Randomization and counter-balancing of target order are described, and the crossover structure offers a basis for comparing two active stimulation targets within participants. For that design to answer the target question, however, the analysis needs to account for the pairing. The registry posts separate summaries for each target but not the paired contrast that directly addresses whether the targets differ.

The distinction between a condition-specific estimate and a between-condition test is important. Separate means can describe each target's observed average change, and confidence intervals convey uncertainty around those estimates. They do not by themselves establish a difference between conditions. In a crossover, the relation between measurements from the same participant contributes to the uncertainty of the contrast, but that relation is not reported.

The trial also illustrates the limits of imaging endpoints as clinical evidence. BOLD signal change provides a quantitative measure of brain activity during a specified task, but the registry does not report a clinically meaningful threshold or a relationship between this measure and patient-important outcomes. A precise measurement is not automatically a clinically interpretable one.

Finally, the record's lack of a posted analysis, missing-data description, and multiplicity plan restricts reproducibility and evaluation of uncertainty. These are reporting limitations, not proof that the study was conducted improperly. Clear reporting of paired estimates, analysis populations, and missing-data handling would be especially useful for interpreting a pilot crossover study.

14. 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.

Several limitations are specific to the information in this registry record. Although the design is identified as randomized, quadruple-masked, and crossover, the record does not describe who was masked or how masking was maintained. It does not post the randomization procedure beyond stating that target order was randomized and counter-balanced. Details needed to evaluate sequence and period effects are also absent.

The brief summary describes intended enrollment of 20 subjects, whereas registry enrollment is 14. The record does not reconcile the figures or report how many participants completed both sessions, had usable imaging, or contributed to the primary endpoint. It does not provide participant-level data, within-participant differences, or a measure of variability for the endpoint.

The direct comparison between targets is not reported, and no analyses are posted. The registry does not explain why the comparison was not estimable or what analysis would have been used. Missing-data patterns, analysis populations, and procedures for handling missing observations are not reported. Nor does the record state whether period, order, or carryover effects were assessed.

The endpoint is a brain-imaging measure, and the record supplies no clinically meaningful threshold or evidence linking the result to symptoms or functioning. Although the summary mentions cognitive-control performance and other imaging paradigms, no secondary results are posted. Safety reporting gives counts but not event descriptions or attribution details. These gaps restrict conclusions to the posted descriptive summaries and prevent a thorough assessment of the planned analyses.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Interactions of Fronto-Parietal High Frequency rTMS on Anterior Cingulate Cortex Activation in Schizophrenia — NCT04309370.
• Registry record last updated 2023-08-03; status last verified 2023-07.
• Results first posted 2023-08-03.
• 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.

18. Record Summary

NCT04309370 is a completed, randomized, quadruple-masked crossover pilot sponsored by Indiana University. The registry lists schizophrenia as the condition, enrollment of 14, study start on 2020-03-12, and primary completion on 2022-04-15. The brief summary describes a single-site study of early phase psychosis and intended enrollment of 20; the registry record does not reconcile that difference.

The primary outcome is mean change in anterior cingulate cortex BOLD signal for mismatch versus match trials, measured from baseline to 30-60 minutes after intervention. The mean change was -0.019 (95% confidence interval -0.176 to 0.187) for LDLPFC-targeted stimulation and 0.012 (95% confidence interval -0.086 to 0.152) for LSPC-targeted stimulation. No direct target comparison or analysis is posted.

The registry lists zero serious adverse events and zero deaths in both groups, with one and two other adverse events, respectively. Further event details, analysis populations, missing-data methods, and multiplicity procedures are not reported in the registry record.