Mechanisms of Non-Invasive Neuromodulation Interventions: Influence on Human Neurochemistry and Functional Connectivity: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Mechanisms of Non-Invasive Neuromodulation Interventions: Influence on Human Neurochemistry and Functional Connectivity (NCT02677740), a randomized na study. The primary outcome is Percent Change of GABA Concentration in a Voxel Encompassing the Left Motor Cortex, Measured at 30 Min After rTMS.

2. Clinical Question

The study’s stated aim was to increase understanding of how the two rTMS protocols affect brain functional connectivity and neurochemistry. The primary endpoint addresses the neurochemistry component: it expresses the change in GABA concentration as a percentage of the baseline, or pre-rTMS, concentration. GABA was quantified using MRS at 7 Tesla.

The registry describes a randomized, double-masked, parallel study. It lists 7 participants in the inhibitory arm and 1 in the excitatory arm. The posted group summaries therefore describe a very small study, especially for the excitatory protocol. The record gives no inferential comparison for this endpoint, so the clinical question is represented by descriptive measurements rather than a reported estimate with a confidence interval or a test of the difference between protocols.

3. Trial Design

The registry record describes a randomized, double-masked, parallel study, with enrollment of 8. The interventions were inhibitory rTMS at 1 Hz and excitatory rTMS at 5 Hz. Each arm description specifies a 20-min intervention applied over the primary motor cortex of the presumed dominant hemisphere. The record characterizes the inhibitory protocol as transiently suppressing excitability beneath the stimulation site and the excitatory protocol as transiently increasing net excitability there.

Participants underwent MRI and MRS before and right after the intervention, according to the arm descriptions. The primary outcome timeframe is stated as baseline/pre-rTMS and 30 min after rTMS. Those timing descriptions are not identical, and the registry record does not explain their relationship. The outcome description says that the percent change in GABA concentration was calculated from the baseline concentration.

The posted primary results include 7 participants in the inhibitory arm and 1 in the excitatory arm. Although the study is described as randomized, the sequence-generation method, allocation concealment, and reason for the imbalance in posted group sizes are not reported in the registry record. The identities of the people masked, and how masking was maintained, are also not reported in the registry record.

The registry lists the study as completed, with a start date of 2016-08-29 and primary completion on 2017-03-19. Its phase is listed as NA. Protocol details beyond the brief study aim and arm descriptions, including the intended sample size and a statistical analysis plan, are not reported in the registry record. The design label alone does not establish how the endpoint was analyzed.

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 Percent Change of GABA Concentration in a Voxel Encompassing the Left Motor Cortex, Measured at 30 Min After rTMS, measured over Baseline/Pre-rTMS and 30 min after rTMS.

The primary endpoint is percent change in GABA concentration in a voxel encompassing the left motor cortex, measured at 30 min after rTMS. The registry states that GABA concentration was quantified with MRS at 7 Tesla and that percent change was calculated from the baseline, pre-rTMS concentration. The reported unit is percent change, and the stated summary measure is the mean with standard deviation.

As a general statistical concept, expressing a follow-up measurement relative to baseline can describe the direction and scale of change while accounting for the participant’s starting concentration. It does not, by itself, establish that a change is caused by the intervention. Interpreting the endpoint also depends on how the measurements were collected, how missing observations were handled, and how the two randomized groups were compared; those analysis details are not reported in the registry record.

GABA concentration is a measure of brain neurochemistry, while the study’s broader aim also refers to functional connectivity. The posted primary endpoint concerns GABA, not functional connectivity. The registry lists 4 outcome measures, but the descriptions and results of secondary measures are not posted as secondary results in this record. Thus, the primary endpoint captures one specified neurochemical outcome rather than the full set of mechanisms named in the study title.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the primary outcome as a continuous measure summarized by a mean and standard deviation. A mean describes the center of the observed values, while a standard deviation describes how dispersed those values are around the mean. As a general statistical explanation, these summaries are useful for describing measurements, but they do not alone quantify the precision of a group mean or the uncertainty in a comparison between groups. A confidence interval or another uncertainty estimate would be needed for that purpose; none is posted for this endpoint.

The endpoint is a percentage change from baseline. The baseline measurement is the pre-rTMS GABA concentration, and the outcome description specifies measurement at 30 min after rTMS. The registry reports the resulting arm-level means as 8.0 for inhibitory rTMS and -27.0 for excitatory rTMS. The reported standard deviation of 9.0 applies to the inhibitory arm, which has 7 participants. No standard deviation is reported for the excitatory arm, which has 1 participant. These values should not be read as absolute concentrations or as a direct arm-to-arm estimate.

In a randomized study, an arm comparison can be used to assess whether the groups’ outcomes differ, subject to the design and analysis assumptions. The registry labels allocation as randomized, but it does not post an analysis for this continuous endpoint. No adjusted or unadjusted comparison, confidence interval, test statistic, or p-value is reported. Details of a statistical model, including whether the comparison used change scores or adjusted for baseline concentration, are not reported in the registry record. The posted group summaries therefore support description, not a formal inference about the contrast.

The imbalance in group sizes matters for interpreting precision. The inhibitory arm has observations from 7 participants, while the excitatory arm has an observation from 1 participant. In general, information about variability and the stability of a group estimate depends on the number and spread of observations. A single value does not reveal how much participant-to-participant variation might occur in the excitatory arm. Consequently, its posted mean is a particularly limited estimate of a group-level pattern. The record does not say why the posted group sizes differ or whether all enrolled participants contributed to the primary endpoint.

As a general statistical concept, over-dispersion means that observed variation is greater than a model assumes. It can make model-based uncertainty estimates unreliable if the model does not accommodate that variation. The registry provides a standard deviation for the inhibitory arm but no model or inferential analysis, so there is no reported basis for assessing over-dispersion or its impact on an estimated contrast in this study.

The sample-size assumptions associated with planning illustrations are distinct from the trial’s actual design and results. Those illustrations use the observed effect, a stated fraction of that effect, a two-sided significance level of 0.05, equal allocation, and a normal approximation. They are planning illustrations, not observed power and not evidence of the study’s original sample-size justification. The intended sample-size rationale and protocol planning assumptions are not reported in the registry record.

Randomization and masking are design features, not substitutes for a transparent analysis. The registry does not report how the random sequence was generated, how allocation was concealed, which parties were masked, or whether masking was assessed. It also does not describe quality checks for MRS acquisition, the handling of measurements outside the stated timeframe, or the method used to calculate each participant’s percent change. These omissions prevent a detailed assessment of analysis choices and measurement procedures.

For a continuous endpoint, the interpretation of a group comparison depends on the distribution of observations, the outcome definition, and the estimation method. General methods may use a model for means or a method that does not rely on the same distributional assumptions. The registry record does not identify any such method. Given the small and highly uneven posted arm sizes, assumptions about distributions and uncertainty would be especially consequential, but there is not enough analysis information to evaluate them.

Finally, the registry lists no posted analyses and no posted secondary results. This does not establish that no analyses were conducted outside the registry; it means the registry record does not present them. Readers should distinguish the descriptive endpoint values from an inferential analysis, and should not treat planning calculations as a substitute for one.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 4 outcome measures but reports 0 secondary outcomes with posted results and 0 analyses. It does not describe a hierarchy of outcomes, a multiplicity adjustment, or a rule for interpreting tests across outcomes. Because no inferential results are posted, the record does not show whether or how multiplicity was addressed. As a general statistical concept, testing several outcomes can increase the chance of at least one apparently notable result unless the analysis plan accounts for the family of comparisons. Whether that issue arose in analyses not posted in the registry record is not reported.

Missing-data handling is also not reported in the registry record. The record does not state whether all enrolled participants contributed endpoint measurements, how unavailable or unusable MRI/MRS observations were handled, or whether any imputation or sensitivity analysis was used. The posted primary endpoint includes 7 participants in the inhibitory arm and 1 in the excitatory arm, while total enrollment is 8. Those counts do not, by themselves, explain the group-size imbalance or establish whether measurements were missing.

The analysis populations are not reported in the registry record. It is not stated whether the results use all randomized participants, participants who received the assigned intervention, or a subset with evaluable endpoint measurements. The randomization label does not determine which population was used for the posted summaries. Without a stated population and a description of exclusions or missing measurements, the relationship between enrollment, treatment assignment, and endpoint analysis remains unclear.

These omissions limit interpretation of both the descriptive summaries and any potential comparison. They should not be taken as evidence that missing data or multiplicity problems occurred; they indicate that the registry record does not provide enough information to assess those issues.

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 registry reports serious adverse event counts separately for the two arms. In the inhibitory rTMS arm, 7 participants were at risk and 0 were recorded with a serious adverse event. In the excitatory rTMS arm, 1 participant was at risk and 0 were recorded with a serious adverse event. Deaths are recorded as 0 in each arm. No serious adverse event terms are listed.

The registry also records other adverse events for all participants listed as at risk: 7 at risk and 7 affected in the inhibitory arm, and 1 at risk and 1 affected in the excitatory arm. These counts describe what was recorded; the registry excerpt does not give the event types, severity, timing, or whether an individual experienced more than one event. The counts should not be read as a measure of event burden beyond the information explicitly posted.

As a general statistical point, zero observed serious events in a small study does not establish that the underlying risk is zero. The excitatory arm includes only 1 participant, and the total enrollment is 8, so the serious-event counts provide limited information about uncommon harms. The registry record does not describe the method of adverse-event collection, the observation period for safety, or how events were judged to be related to rTMS. The figures are therefore a record of reported counts, not a complete characterization of safety.

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

The posted result describes GABA percent change after two rTMS protocols in a very small group of healthy subjects. In the inhibitory arm, the mean was 8.0 with a standard deviation of 9.0 among 7 participants. In the excitatory arm, the mean was -27.0 among 1 participant, with no standard deviation reported. The signs of the means point in different directions in these observed summaries, but they do not establish a reproducible difference between protocols.

The registry does not provide a formal comparison or uncertainty interval. As a result, the precision of a between-arm difference cannot be judged from the record. The single-participant excitatory result cannot show how variable responses might be across participants, while the inhibitory summary is also based on a small group. No conclusion about statistical significance, equivalence, or the magnitude of a reliable protocol contrast is supported by the posted summaries alone.

The endpoint is specific: percent change in GABA concentration in a voxel encompassing the left motor cortex, measured at 30 min after rTMS by MRS at 7 Tesla. It is not a direct measure of all neurochemical changes, functional connectivity, or longer-term effects. Although the study’s stated aim mentions both neurochemistry and functional connectivity, the primary result discussed in the registry is the GABA endpoint.

The study record is not a basis for medical advice or treatment decisions. It describes a research measurement in healthy subjects and does not establish clinical benefit or harm. Its result is best understood as a limited descriptive observation that may inform questions for further study, rather than as a definitive estimate of the comparative effects of the two protocols.

13. Why This Trial Matters Statistically

This record illustrates why sample size and balance between arms matter when interpreting clinical research. The primary endpoint has 7 observations in the inhibitory arm and 1 in the excitatory arm. The mean in the one-person arm is an observed individual value as well as the arm’s mean; it cannot reveal participant-to-participant variability. The contrast in group sizes also makes it especially important to have a transparent account of how a comparison was estimated and how uncertainty was quantified.

It also demonstrates the distinction between descriptive summaries and inferential results. Means and a standard deviation can describe observed data, but readers need an estimated contrast and its uncertainty to assess the evidence about a difference between randomized groups. No such analysis is posted in the registry record. This distinction is central to biostatistical interpretation: a direction in two sample means is not, by itself, evidence of a stable difference in the underlying populations.

The endpoint definition highlights the importance of timing and measurement context. The outcome is a baseline-relative change in GABA concentration measured at 30 min after rTMS, while the arm descriptions refer to imaging before and right after the intervention. The registry does not explain this timing distinction. Clear specification of measurement timing, analysis populations, missing-data handling, and planned comparisons is important for assessing whether the reported summaries address the study question as intended.

Finally, the registry record shows how a study’s mechanistic ambition can exceed what its posted primary result establishes. The study aim includes neurochemistry and functional connectivity, but the available primary result concerns GABA concentration. Separating the endpoint actually reported from the broader scientific motivation helps keep interpretation aligned with the evidence in the record.

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.

The primary limitation of the posted evidence is the small, uneven number of participants represented in the two arms: 7 for inhibitory rTMS and 1 for excitatory rTMS. The one-person arm cannot provide an estimate of between-participant variability. The inhibitory arm’s standard deviation describes its observed spread, but neither arm’s summary supplies a confidence interval for a protocol comparison.

The registry record contains no posted analyses, despite listing the continuous primary endpoint. It does not report a between-arm estimate, inferential test, confidence interval, prespecified model, or analysis population. The handling of missing measurements and exclusions is also not reported. Therefore, the posted summaries cannot establish the precision or robustness of a comparative result.

Several design details relevant to appraisal are absent. The record does not report the randomization procedure, allocation concealment, who was masked, the intended sample-size justification, or a statistical analysis plan. It gives MRI/MRS timing in the arm descriptions as before and right after rTMS, while the primary endpoint timeframe specifies 30 min after rTMS, without explaining the relationship. Reasons for the difference between enrollment and the posted arm counts are not reported.

The endpoint is limited to a specific neurochemical measurement in a voxel encompassing the left motor cortex. It does not by itself represent functional connectivity or other outcomes named in the study aim. The registry lists 4 outcome measures but posts no secondary results. The record also provides limited context for safety counts, including no event descriptions or safety observation period. These limitations concern what can be established from the registry record; they do not prove that procedures or analyses were absent outside it.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Mechanisms of Non-Invasive Neuromodulation Interventions: Influence on Human Neurochemistry and Functional Connectivity — NCT02677740.
• Registry record last updated 2019-11-18; status last verified 2019-11.
• Results first posted 2019-08-06.
• 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

The registry record describes NCT02677740, titled “Mechanisms of Non-Invasive Neuromodulation Interventions: Influence on Human Neurochemistry and Functional Connectivity.” The sponsor is the University of Minnesota. The study is listed as randomized, double-masked, and parallel, with phase NA and enrollment of 8. Its status is completed; the recorded start date is 2016-08-29 and primary completion date is 2017-03-19.

The two interventions were inhibitory rTMS at 1 Hz and excitatory rTMS at 5 Hz. The primary endpoint was percent change in GABA concentration in a voxel encompassing the left motor cortex, measured at 30 min after rTMS. The inhibitory arm has a posted mean of 8.0 and standard deviation of 9.0 among 7 participants; the excitatory arm has a posted mean of -27.0 among 1 participant, with no standard deviation reported. No primary analysis or secondary results are posted in the registry record.