Probing Cortical Excitability and Cognitive Function With TMS: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Probing Cortical Excitability and Cognitive Function With TMS (NCT03652012), a non-randomized na study. The primary outcome is Cortical Excitability: Resting Motor Threshold (RMT)..

2. Clinical Question

The broader purpose described in the registry is to develop neurophysiological biomarkers that may be sensitive to preclinical dementia by integrating TMS and fMRI. That is a research aim, not a finding established by the record. The study also lists measures of the stimulus response curve, cortical silent period, baseline functional activation, and change in functional connectivity following TMS. No values for these outcomes are reported in the registry record.

3. Trial Design

This is a completed, non-randomized, parallel study sponsored by the University of Arizona. The registry lists an enrollment of 40 and two groups: participants with mild cognitive impairment (MCI) and healthy controls. Allocation was not randomized, and masking was none. The record identifies transcranial magnetic stimulation (TMS) as the intervention. Because group assignment was non-randomized, the healthy-control group should not be read as a randomized control arm for a causal treatment comparison.

The study’s stated aims cover two related areas. One is cortical excitability and its relation to cognitive function, using a single-pulse TMS paradigm in MCI and healthy older adults. The other is cortical plasticity and its association with cognitive function, using repetitive TMS and resting-state fMRI in those groups. The registry describes the healthy controls as age- and gender-matched, but does not report whether matching was achieved in the enrolled groups or how any remaining differences between groups were handled in analysis.

The primary outcome is resting motor threshold (rMT), measured in % of maximum stimulation output (MSO). Secondary outcomes concern a stimulus response curve and cortical silent period measured with electromyography (EMG), baseline fMRI, and post-TMS change in functional connectivity. The registry lists five outcome measures and five analyses, but does not report the analysis methods or results for them.

The record gives the study start as 2018-04-03, the primary completion as 2020-03-04, and the status as completed. The listed phase is NA. The primary outcome timeframe says up to 10 minutes and describes a single day trial, with a testing session lasting 3 hours. The registry record does not report a rationale for the enrollment target, a sample-size justification, or details of how participants were assigned to the groups.

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 Cortical Excitability: Resting Motor Threshold (RMT)., measured over Up to 10 minutes. This is a single day trial. Testing session will last a total of 3 hours..

The primary endpoint is resting motor threshold (rMT), a measure of the TMS intensity needed to elicit a motor response under a defined protocol. It is expressed as a percentage of maximum stimulator output (%MSO). According to the registry description, rMT was determined with the Parameter Estimation by Sequential Testing (PEST) algorithm during a single-pulse TMS protocol. Surface EMG recorded motor evoked potentials from the target muscle. The stated threshold is the minimum intensity over the motor cortex hotspot that elicits a motor evoked potential of at least 50 μV in peak-to-peak amplitude in 50% of trials.

As a general statistical interpretation, an endpoint should represent a feature relevant to the study question and should be measured consistently across participants. rMT serves the study’s aim of characterizing cortical excitability: it expresses the stimulation intensity associated with the specified motor response, rather than a direct measure of cognition or dementia. Its interpretation therefore depends on the measurement protocol and on how values are distributed across the groups.

The registry identifies the endpoint as a mean of a continuous measure, with standard deviation as the dispersion measure. Those definitions describe how the outcome would be summarized; they are not reported outcome findings. The registry record does not provide group means, standard deviations, a comparison estimate, or an uncertainty interval for rMT. Consequently, the size and precision of any observed group difference are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is continuous: rMT is measured on a scale expressed as a percentage of maximum stimulator output. The registry describes reporting a mean and standard deviation. As a general explanation, a mean gives a measure of the central value of a group, while a standard deviation describes how spread out individual measurements are around that mean. Neither summary alone describes all features of a distribution, and neither can be interpreted without the actual reported values and group sizes used in the analysis.

What would a confidence interval add?

As a general statistical explanation, a confidence interval describes the uncertainty around an estimated quantity, such as a group mean or a difference between group means. It conveys a range of values that are compatible with the data and the method’s assumptions. A narrow interval indicates more precision than a wide interval, but interpretation also depends on the question and the scale of the outcome. The registry record does not report confidence intervals for rMT or for the other listed outcomes, so the precision of the outcome estimates cannot be assessed.

How should group differences be understood?

The study is non-randomized and parallel, with MCI and healthy-control groups. As a general explanation, random allocation can help balance both measured and unmeasured factors between treatment groups. That protection is not present when allocation is non-randomized. In this study, comparisons between groups may reflect differences in participant characteristics, study group, or other factors in addition to variation in the measurements. Matching on age and gender is described for the healthy controls, but the record does not report how matching was implemented or whether the analysis accounted for it.

A statistical adjustment can address some measured differences when the relevant variables and methods are specified. It cannot automatically remove bias from unmeasured factors. The registry record does not report the covariates included in any model, whether an adjusted or unadjusted analysis was used, or how the group comparison was estimated. The analyses therefore cannot be reproduced or evaluated from the information in the record.

Why does over-dispersion matter?

As a general explanation, over-dispersion occurs when observed variability is greater than a statistical model assumes. It is especially relevant for count outcomes and some generalized linear models, where underestimated variability can make uncertainty intervals too narrow and tests appear more conclusive than warranted. The primary endpoint is described as a continuous mean with standard deviation, and the registry record does not say that an over-dispersion model was used. This general concept does not establish that over-dispersion occurred in this study.

For continuous outcomes, distribution shape and influential values can also affect the usefulness of a mean-based summary and the assumptions of a model. A standard deviation can describe spread, but without the underlying data, plots, or diagnostic information, it is not possible to assess whether a particular model’s assumptions are reasonable. The registry record does not report distributional checks or sensitivity analyses.

What do the planning calculations represent?

The registry’s sample-size assumptions describe planning illustrations based on the observed effect, not the trial’s own design. They use a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation; the effect to detect is a stated fraction of the observed effect. These assumptions describe a calculation framework, not an observed finding. The numerical planning results and the observed effect on which they are based are not reported in the registry record. Any sample sizes in such illustrations represent planning quantities, not the number of participants who experienced an outcome, and they should never be described as observed power.

As a general explanation, a sample-size calculation asks what amount of information would be needed to detect a specified effect under stated assumptions. Its answer depends on the target effect, variability, significance level, allocation, and analysis method. If the assumptions differ from the eventual study, the illustration may not represent the study’s actual ability to estimate an effect. It is not a substitute for reporting the observed estimate and its uncertainty.

Five outcome measures and five analyses are listed. The registry record does not explain the analysis plan, the order of testing, or how the analyses relate to one another. The outcome descriptions alone do not identify a model, an estimand, a testing procedure, or a method for handling repeated measurements. Those details are necessary to understand exactly what statistical quantities were estimated.

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("Mild Cognitive Impairment", "Healthy Controls")
n   <- c(20, 20)
m   <- c(51.1, 51.8)
sp  <- c(6.6, 8.3)
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  Mild Cognitive Impairment  20  51.100  6.600  48.011  54.189
CARM  Healthy Controls  20  51.800  8.300  47.915  55.685

11. Multiplicity, Missing Data and Analysis Populations

The registry lists five outcome measures and five analyses, including the primary rMT measure and secondary EMG and fMRI measures. It does not report how many statistical tests were conducted, whether the analyses were prespecified in a statistical analysis plan, or whether any adjustment for multiple comparisons was used. When several outcomes or tests are examined, the chance of at least one apparently notable result can increase. As a general statistical principle, multiplicity methods can address that issue, but the appropriate method depends on the questions and analysis plan. No specific method should be assumed for this study.

The registry record does not report missing-data counts, reasons for missing measurements, or methods for handling missing data. It also does not describe whether all enrolled participants contributed to each outcome analysis. Without those details, the completeness of the outcome data and the potential for bias related to missingness cannot be evaluated. As a general explanation, missingness can affect estimates when the likelihood of a missing measurement is related to participant characteristics or outcome values; the implications depend on the missingness process and the analysis approach.

Analysis populations are not described in the registry record. The record does not state whether analyses included everyone enrolled, only participants who completed a protocol, or another defined group. The registry’s listed enrollment is 40, but that number alone does not establish how many participants contributed data to each endpoint. No assumptions about exclusions or analysis populations can be made from the available record.

The registry also does not report a statistical analysis plan, interim analyses, or a sample-size justification. Their presence or absence in the conduct of the study should not be inferred from the record. These omissions limit assessment of whether the reported analyses, if results were available, followed prespecified procedures.

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.

The registry lists serious adverse events and other adverse events separately for the MCI and healthy-control groups. For each group, 20 participants are listed as at risk, with 0 serious adverse events and 0 other adverse events. The death count is 0 in each group. No serious adverse event terms are listed.

These figures describe what is recorded in the registry for the groups and event categories. They do not establish that no untoward experiences of any kind occurred, because the registry separates serious events from other events and reports only the categories shown. The record does not give further details about event collection, definitions, timing, or whether all participants contributed safety information.

As a general statistical explanation, an observed count of zero is not proof that the underlying event risk is zero. The interpretation of a zero count depends on how many people were observed, for how long, and how events were sought and classified. Here, the registry identifies 20 participants at risk in each group, but the study’s timeframe and reporting details should not be treated as a substitute for a complete safety analysis. The recorded safety counts should be read as registry entries, not as evidence that TMS is free of risk.

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

The registry record documents a completed investigation of TMS-related measures in MCI and healthy older adults. Its stated aims concern cortical excitability, cortical plasticity, cognitive function, and fMRI. The primary endpoint is rMT, defined through a specific single-pulse TMS and EMG procedure. The listed secondary measures include the stimulus response curve, cortical silent period, baseline fMRI, and post-TMS functional connectivity.

What the record does not establish is the result of the primary comparison. It does not report rMT means, standard deviations, group differences, confidence intervals, or p-values. Nor does it report the numerical results for the secondary outcomes. Consequently, the record does not show whether the groups differed on any endpoint, how large a difference might have been, or how precisely any effect was estimated.

The study’s aims should also be distinguished from evidence of biomarker performance. The stated purpose is to develop a technique capable of identifying neurophysiological biomarkers sensitive enough to detect preclinical dementia. The registry does not report measures of diagnostic accuracy, validation in an independent population, or results demonstrating that a biomarker identifies preclinical dementia. The ambition described in the study summary is therefore not itself a finding.

Because allocation was non-randomized, a group difference, if reported, would not by itself demonstrate that a TMS procedure caused the difference. Group membership and other participant characteristics could be associated. The record does not describe an analysis that would resolve that issue.

The recorded safety counts show 0 serious adverse events and 0 other adverse events in each group, with 0 deaths. These are the registry’s reported counts and should not be expanded into a general claim about safety. In short, the record is informative about the research question, design, and measurement definitions, but the posted outcome results are insufficient to judge the magnitude, precision, or interpretation of the study’s findings.

14. Why This Trial Matters Statistically

This study raises a useful statistical distinction between measuring a biological response and establishing what that response means. Resting motor threshold is defined as a TMS intensity linked to a motor evoked potential recorded with EMG. That operational definition supports reproducible measurement, but a measured difference would still need an estimate, uncertainty assessment, and interpretation tied to the research question.

The non-randomized comparison also makes design central to statistical interpretation. An association between group membership and rMT would not, on its own, identify a causal effect. This matters because the study’s aims connect neurophysiological measures with cognitive function, while participant groups may differ in ways beyond the outcome under study. Age and gender matching is described for controls, but the record does not report the matching details or analytic handling of other differences.

The broader goal of identifying biomarkers makes precision and validation especially important. A candidate measure needs more than a plausible rationale: the evidence must characterize its estimates and uncertainty, and the study must explain how the measure relates to the intended use. The registry record does not report the outcome estimates or diagnostic performance needed to evaluate that goal.

The entry also illustrates why registration details and posted results serve different purposes. The record supplies useful definitions of endpoints, design features, and intended aims. Without numerical outcome results and analysis methods, however, readers cannot assess the size or precision of findings, evaluate the handling of multiple outcomes and missing data, or judge whether conclusions are supported by the analyses. The available information is therefore a basis for understanding the planned scientific question, not for drawing a statistical conclusion about the primary endpoint.

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 most consequential limitation of the available record is that it does not report the primary endpoint results. There are no group means or standard deviations for rMT, no estimate comparing the groups, and no uncertainty interval or p-value. The same absence applies to the listed secondary outcomes. Statistical interpretation of the study’s findings is therefore not possible from the registry record.

The design is non-randomized, with no masking. This limits causal interpretation of comparisons between MCI and healthy controls. Although the controls are described as matched for age and gender, the record does not report matching procedures, the extent of matching achieved, or adjustment for other participant characteristics. The available description of MCI eligibility is incomplete, so the enrolled group cannot be fully characterized from the record.

The statistical analysis plan is not reported in the registry record. Model specifications, covariate choices, handling of repeated or correlated measurements, multiplicity procedures, and sensitivity analyses are not described. Missing-data counts, missingness reasons, and analysis populations are likewise not reported. These omissions prevent assessment of how the analyses were conducted and how robust any estimates might be.

The registry describes a broad biomarker-development objective, but does not report diagnostic performance or validation results. It also does not provide a sample-size justification or numerical results for the planning illustrations. The recorded safety counts are limited to the listed event categories and do not describe event ascertainment or timing. Taken together, these gaps mean that the record can characterize the research question and measurement approach, but cannot support a detailed appraisal of efficacy, biomarker validity, precision, or comprehensive safety.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Probing Cortical Excitability and Cognitive Function With TMS — NCT03652012.
• Registry record last updated 2025-06-11; status last verified 2025-05.
• Results first posted 2025-06-11.
• 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

NCT03652012, titled “Probing Cortical Excitability and Cognitive Function With TMS,” is listed as completed and sponsored by the University of Arizona. The study is non-randomized, parallel, and unmasked, with an enrollment of 40. It concerns MCI and healthy-control groups and uses transcranial magnetic stimulation.

The primary outcome is resting motor threshold, measured in % of maximum stimulation output using a TMS and EMG protocol. Listed secondary outcomes include cortical excitability measures and baseline and post-TMS fMRI measures. The registry record does not report numerical outcome results, statistical estimates, uncertainty intervals, analysis methods, missing-data handling, or multiplicity procedures.

For each group, 20 participants are listed at risk, with 0 serious adverse events, 0 other adverse events, and 0 deaths. These are the recorded safety counts and do not constitute a complete risk assessment. The registry describes the study’s biomarker-development aims but does not report results establishing biomarker performance.