Temporal Interference Methods for Non-invasive Deep Brain Stimulation, Study 1.2: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Temporal Interference Methods for Non-invasive Deep Brain Stimulation, Study 1.2 (NCT07339072), a randomized na study. The primary outcome is Change From Baseline (no Stimulation) in Brain Activity in the Nucleus Accumbens During 5 Hz Versus 10 Hz Temporal Interference Stimulation.

2. Clinical Question

The clinical question is primarily a question about measurement and stimulation conditions in healthy volunteers, not a comparison of clinical outcomes in people with a disorder. The study description places this work within a broader research program intended to characterize temporal interference effects on brain activity and to investigate stimulation of deep brain regions. The primary endpoint compares two active stimulation frequencies. Separate secondary outcomes address active versus sham stimulation at each frequency and connectivity between the nucleus accumbens and other brain regions.

The registry describes the primary outcome as change from a no-stimulation baseline, quantified using nucleus accumbens region-of-interest beta estimates from BOLD signal during fMRI. It also states that whole-brain voxelwise analyses did not identify statistically significant activation differences after correction for multiple comparisons; descriptive ROI-level estimates are reported. These analyses address different spatial summaries, so the ROI measure should be read as a focused descriptive result rather than as evidence of a whole-brain activation finding.

The participant-level crossover structure means the stimulation conditions were experienced within the study rather than assigned as separate parallel groups. That structure is relevant to how results should be interpreted: the reported observations describe activity associated with the tested sessions and conditions in participants with analyzable data. They do not, by themselves, establish a clinical effect or answer questions about use in patient populations.

3. Trial Design

The registry record describes a randomized, single-masked crossover study of temporal interference electrical stimulation in healthy volunteers. The study is marked completed, with enrollment of 30 participants. The phase is listed as not applicable. The sponsor is Indiana University. The record gives no further description of what was masked, so the identity of the masked party and the masking procedures are not reported in the registry record.

Participants were assigned to one of four listed orders of stimulation conditions. Each order included active and sham stimulation at 5 Hz and 10 Hz, with the sequence varying across orders. Stimulation targeted the nucleus accumbens using two pairs of carbon fiber electrodes. The registry’s primary comparison concerns active 5 Hz versus active 10 Hz stimulation; secondary comparisons concern active versus sham at each frequency. The crossover model indicates that observations were contributed across conditions by the same participants, rather than representing independent groups of participants for each condition.

The reported primary outcome analysis included 28 participants for each active-frequency condition. The registry explains that two participants were excluded from outcome analysis because the study was not completed and/or complete usable imaging and behavioral data were unavailable. The record does not describe how the four orders were allocated, whether sequence balance was achieved, or whether the statistical analysis accounted for order or period effects. These details are not reported in the registry record.

The outcome time frame was during fMRI scanning for each study session, approximately 60 minutes. The study also listed a connectivity outcome and outcomes of active versus sham stimulation at both frequencies. The registry contains no reported analyses for the listed secondary outcomes. The original design assumptions, including any target sample-size rationale, are not reported in the registry record. The planning illustrations based on observed effects are separate from the study’s original design and should not be read as documentation of how enrollment was chosen.

Although the study is marked completed, that status does not mean every enrolled participant contributed usable data to every outcome. For the primary endpoint, 28 participants are reported in each condition. The registry does not provide a detailed account of participant flow, missing-data handling, or analysis-population definitions beyond the explanation for the two exclusions.

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: Participants completed eligibility and MRI safety screening before assignment. This within-subject crossover study assigned all participants to receive 10 Hz Active TI, 10 Hz Sham TI, 5 Hz Active TI, and 5 Hz Sham TI once each, with the order counterbalanced across the 24 possible randomized block sequences. There was no separate run-in or washout period before assignment. This record reports results for Study 1.2 only; additional studies described in the protocol are reported separately.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants contributed data to the stimulation conditions as part of the within-subject crossover design. Two participants were excluded from the outcome analysis because the study was not completed and/or complete usable imaging and behavioral data were not available for analysis.

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 From Baseline (no Stimulation) in Brain Activity in the Nucleus Accumbens During 5 Hz Versus 10 Hz Temporal Interference Stimulation, measured over During fMRI scanning for each study session (5 Hz and 10 Hz stimulation conditions), approximately 60 minutes.

The primary endpoint is change from a no-stimulation baseline in nucleus accumbens brain activity during 5 Hz versus 10 Hz temporal interference stimulation. Activity was measured with fMRI, and the regional summary was an ROI beta estimate derived from BOLD signal changes. In the registry’s description, beta estimates reflect the magnitude of task-related neural activation in the ROI; higher values indicate greater task-related activation.

An ROI measure focuses the analysis on a prespecified brain region of interest, here the nucleus accumbens, rather than summarizing every voxel across the brain. This can make a regional question more directly interpretable, while not establishing that any observed difference is specific to that region or that a whole-brain effect exists. The record reports that whole-brain voxelwise analyses did not identify statistically significant activation differences after correction for multiple comparisons, and therefore gives descriptive ROI-level beta estimates.

The endpoint is useful for describing how the measured regional signal varied between the tested stimulation-frequency conditions during fMRI. It is not a direct measure of clinical benefit, symptoms, or functioning. Nor does the outcome description establish that the signal reflects only the stimulation effect; interpretation also depends on the design and analysis details, including handling of within-person correlation and session order. Those details are not reported in the registry record.

The reported primary comparison includes 28 participants in each active-frequency condition. The registry gives the mean beta estimate and its standard error for each condition, along with a mean difference, an interval estimate, and an unadjusted p value. These are descriptive and inferential summaries of the measured ROI signal, not evidence about treatment effects in people with a medical condition.

7. Results Posted in the Registry

• 10 Hz Active TI Stimulation: mean -0.03 versus -0.01 on control; difference -0.02 (95% CI -0.09 to 0.04), standardized effect d = -0.18; z-test p = 0.492.

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.

Change From Baseline (no Stimulation) in Brain Activity in the Nucleus Accumbens During Active Versus Sham Stimulation at 5 Hz

• 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 errors.
• Result:
  • 5 Hz Active TI Stimulation: mean -0.01 versus 0.01 on control; difference -0.01 (95% CI -0.08 to 0.06), standardized effect d = -0.08; z-test p = 0.756.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 5 Hz Active TI Stimulation and the control. The interval gives the range of effects that remain compatible with the data.

Change From Baseline (no Stimulation) in Brain Activity in the Nucleus Accumbens During Active Versus Sham Stimulation at 10 Hz

• 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 errors.
• Result:
  • 10 Hz Active TI Stimulation: mean -0.03 versus 0.09 on control; difference -0.12 (95% CI -0.23 to -0.02), standardized effect d = -0.60; z-test p = 0.025.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for 10 Hz Active TI Stimulation than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes extend the primary frequency comparison by examining active stimulation against sham at 5 Hz and 10 Hz, and by listing connectivity between the nucleus accumbens and other brain regions. Across the posted numerical activity outcomes, the active-versus-sham pattern is not uniform: the unadjusted comparison at 5 Hz does not indicate a clear difference, while the 10 Hz contrast has an interval estimate below zero and an unadjusted p value of 0.025. The connectivity outcome has no numerical results in the registry record.

These secondary results add context to the primary comparison, but they do not directly answer the same question. The primary comparison is active 5 Hz versus active 10 Hz, whereas the secondary activity comparisons assess active versus sham within each frequency. A result for one contrast cannot be substituted for another. In particular, a nominal active-versus-sham result at one frequency does not demonstrate a difference between the two active frequencies.

Unadjusted secondary results carry less weight because multiple outcomes and comparisons create more opportunities for a seemingly unusual result to arise by chance. The registry does not report a multiplicity adjustment or a prespecified hierarchy among the outcomes. The 10 Hz secondary result should therefore be considered exploratory or nominal in interpretation, rather than treated as definitive evidence. The record does not state that the analysis was exploratory; the caution follows from the absence of reported multiplicity handling and the number of listed outcomes.

The secondary endpoint descriptions also indicate that activity was measured during fMRI sessions of approximately 60 minutes, and the activity summaries include 28 participants per condition. The registry does not report the analysis details needed to establish how the crossover dependence was handled. These limitations apply when comparing the secondary findings with the primary result. Overall, the secondary outcomes provide a broader set of observations but do not replace the primary frequency contrast, and the unreported connectivity result leaves that part of the planned outcome set unevaluable from the posted numerical results.

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

• Change From Baseline (no Stimulation) in Brain Activity in the Nucleus Accumbens During Active Versus Sham Stimulation at 5 Hz
• Change From Baseline (no Stimulation) in Brain Activity in the Nucleus Accumbens During Active Versus Sham Stimulation at 10 Hz
• Change in Brain Connectivity Between the Nucleus Accumbens and Other Brain Regions During Temporal Interference Stimulation

9. Statistical Interpretation

10. Statistical Methods Explained

For a continuous outcome such as an ROI beta estimate, a mean describes the average measured value among participants contributing data to a condition. The registry reports means and standard errors for the primary and two secondary activity outcomes. The standard error describes the statistical uncertainty in an estimated mean, rather than the spread of individual participant measurements. A standard error can be used in estimating the precision of a mean, but it does not by itself describe the full range of participant-level values.

The primary comparison is a mean difference between active 10 Hz and active 5 Hz stimulation. The secondary comparisons are active versus sham at each frequency. A mean difference expresses the contrast between the two condition means in the order used for that comparison; the sign depends on which condition is subtracted from which. The estimates are most interpretable alongside the condition labels, interval estimates, and the outcome’s direction: the registry states that higher beta values indicate greater task-related activation.

In general, a confidence interval combines an estimate with an indication of its statistical precision under an analysis model. An interval that includes zero is compatible with no mean difference under that model, as well as with differences in either direction that fall within the interval. An interval that does not include zero indicates that zero is outside the range represented by that interval, but this alone does not settle the importance, robustness, or clinical meaning of a finding. The confidence level for the posted interval estimates is not reported in the registry record, so it should not be assumed from the record alone.

The registry reports unadjusted p values. In general, a p value describes how unusual data at least as incompatible with a null hypothesis would be if that hypothesis and the statistical model were correct. It is not the probability that the null hypothesis is true, and it does not measure the size or importance of an effect. An unadjusted p value also does not account for the possibility of false-positive findings across a set of multiple outcomes or comparisons. The registry record does not report a multiplicity adjustment for the posted secondary comparisons.

The crossover design is important because each participant contributed data to more than one condition. In general, measurements from the same person are correlated, so an analysis that treats all condition observations as independent can misstate uncertainty. A suitable crossover analysis may account for within-person correlation and may consider period or sequence effects, depending on the design and analysis plan. The registry record does not report the model used for the posted comparisons, whether within-person pairing was accounted for, or whether period, sequence, or carryover effects were assessed. The reported summaries therefore cannot be attributed to a specific statistical model beyond what the record states.

The study lists four stimulation orders, each containing active and sham conditions at 5 Hz and 10 Hz. Varying the order can be relevant to separating condition differences from changes associated with session sequence. However, the record does not describe allocation across these orders or report an analysis of order effects. It would be inappropriate to assume that the sequences were perfectly balanced or that carryover was absent. Those design and analysis details are not reported in the registry record.

The primary outcome description distinguishes the ROI summaries from whole-brain voxelwise analyses. In general, voxelwise analyses assess signal across brain locations and can involve many simultaneous tests. Correction for multiple comparisons is used to address the increased chance of false-positive findings when many locations are tested. The registry states that whole-brain analyses did not identify statistically significant activation differences after correction. It then reports descriptive ROI-level beta estimates. The record does not give the correction method, the voxelwise test details, or a multiplicity procedure for the ROI and secondary comparisons.

Standard errors and interval estimates provide information about precision, but the sample size and analysis design both matter. Here, 28 participants contributed to each reported activity condition, out of enrollment of 30. Because this is a crossover study, the observations are not simply two independent sets of 28 people. The registry provides condition-level counts but does not provide a detailed participant-level analysis or a model-based explanation of the uncertainty calculations. No new inference about the crossover correlation should be made from the condition counts alone.

The planning illustrations use observed effects and state assumptions of a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The figures are participants per arm for each stated fraction of the observed effect. In general, a planning calculation asks how many participants would be needed under its assumptions to detect a specified effect with a specified probability. These planning figures do not describe the actual sample-size rationale for this trial, and the original design assumptions are not reported in the registry record.

There is no posted analysis for the connectivity outcome, and the registry lists no reported analyses for the secondary outcomes. For the reported activity outcomes, the record supplies descriptive means, standard errors, comparison estimates, interval limits, and unadjusted p values. It does not report whether there were prespecified hypotheses for each comparison, how missing observations were handled beyond the exclusion note, or how the reported comparisons were selected. These omissions limit how fully the statistical analysis can be reconstructed from the registry record.

11. Confidence Intervals and Precision

The primary mean difference has an interval estimate that extends below and above zero, and the unadjusted p value is 0.492. This combination indicates substantial uncertainty about the direction and size of the difference between active 5 Hz and active 10 Hz stimulation in the analyzed sample. It does not provide evidence that the conditions are the same; it indicates that the posted estimate is not precise enough to distinguish a difference from zero using the reported summaries.

The interval estimates for the secondary comparisons also illustrate differing levels of precision. The 5 Hz active-versus-sham interval spans zero, alongside an unadjusted p value of 0.756. The 10 Hz active-versus-sham interval lies below zero, with an unadjusted p value of 0.025. Precision is not the same as importance: even when an interval excludes zero, the estimate’s meaning depends on the size and context of the measured outcome, the analysis, and the multiplicity of comparisons. The registry does not report a confidence level for these intervals.

Each reported activity condition includes data from 28 participants, while enrollment was 30. The standard errors express uncertainty in condition means, but the registry does not give enough methodological detail to verify how the crossover structure was reflected in the comparison uncertainty. The listed interval limits should therefore be read as posted rather than as a complete account of the analysis model.

The primary result is an ROI-level measure, and the record says that whole-brain voxelwise activation differences were not statistically significant after correction for multiple comparisons. The absence of a corrected whole-brain finding does not make the ROI estimate more precise; these are distinct summaries. The connectivity outcome has no numerical result in the registry record, so its precision cannot be assessed from the posted results.

In general, wider intervals indicate less precise estimates, while narrower intervals indicate greater precision under the analysis assumptions. Precision also differs from certainty about a biological or clinical interpretation. Here the measured endpoint is a fMRI beta estimate in healthy volunteers, and the registry does not report a clinical outcome or a threshold for a meaningful change.

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 events. They are illustrations based on the observed effect, not the original trial design. The stated planning assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The calculation considers the full observed effect and smaller fractions of that effect. The original sample-size assumptions and justification for enrollment are not reported in the registry record.

The 80% power column describes a planning target under which the calculation would have an 80% chance of detecting the specified effect if the assumptions and effect were correct. The 90% power column uses a higher target chance of detection under the same general planning framework. These are prospective planning interpretations, not statements about what the completed study achieved. This is not observed power.

Each planning row uses a different fraction of the observed effect. Smaller effects are harder to distinguish from random variation under otherwise similar assumptions, so detecting them requires more participants. This explains why the participant requirements increase as the assumed effect gets smaller. The observed effects are estimated from this study and may be uncertain; using them as planning inputs does not guarantee that a future study would have the same effect.

The registry describes the trial as a crossover study, whereas the planning assumptions specify equal allocation between two arms. The planning illustrations therefore should not automatically be treated as a design recommendation for a future crossover study. They do not incorporate details such as within-person correlation or session order, which are not reported in the registry record. Their proper use is as a simple illustration of how sample-size requirements change with a chosen effect fraction and a power target, rather than as a reconstruction of the study’s own design calculation.

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 = -0.023; pooled standard deviation σ = 0.126.
2. n = 2 × (1.96 + 0.842)² × 0.126² / -0.023² = 465.5, rounded up to 466 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 <- -0.0231680872                      # observed difference in means
sigma <- 0.126159762659141                     # 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(7339072)
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 = 466 (80% power), 624 (90% power)
 75% of observed effect: n per arm = 828 (80% power), 1,108 (90% power)
 50% of observed effect: n per arm = 1,862 (80% power), 2,493 (90% power)
power.t.test: 466.4 
Simulated power at n = 466 per arm: 0.796 (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 lists multiple outcome questions: the primary comparison of active 5 Hz with active 10 Hz, secondary active-versus-sham comparisons at each frequency, and connectivity between the nucleus accumbens and other brain regions. The record also notes whole-brain voxelwise analyses. Testing multiple outcomes or locations increases the opportunity to observe a nominally unusual result even when no underlying difference exists. Statistical procedures can account for this multiplicity, but the registry record does not report an adjustment method for the posted secondary comparisons or the ROI summaries.

The record does state that whole-brain voxelwise analyses did not identify statistically significant activation differences after correction for multiple comparisons. It does not specify the correction procedure or provide the detailed voxelwise results. That statement applies to those whole-brain analyses; it should not be taken to mean that the reported ROI and secondary results were corrected in the same way. The 10 Hz active-versus-sham comparison has an unadjusted p value of 0.025, so it should be interpreted with the multiple-outcome context in mind.

Two participants were excluded from outcome analysis because the study was not completed and/or complete usable imaging and behavioral data were not available. The registry does not report a detailed missing-data analysis, whether any values were imputed, or whether the excluded participants differed from those analyzed. It also does not report the amount or pattern of missing data for individual outcomes. The reason given combines noncompletion and lack of complete usable data, without separating those circumstances.

The record reports 28 participants for each condition in the primary and activity secondary summaries, but does not define analysis populations such as intention-to-treat or per-protocol. It does not report whether all randomized participants were included in any analysis or whether outcome-specific populations were used. The precise handling of incomplete crossover observations is also not reported.

The registry gives no detailed statistical analysis plan, including hypotheses, model specification, handling of within-person correlation, period or sequence effects, or criteria for selecting reported analyses. It lists no reported analyses for the secondary outcomes. These gaps make it difficult to determine which inferential comparisons were planned in advance and how missing observations and multiplicity were handled. The reported numerical results can be described, but their analytic context remains limited.

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.

Most frequent non-serious adverse event terms

The registry lists serious adverse events, other adverse events, and deaths for active and sham stimulation at both 5 Hz and 10 Hz. For each of the four condition entries, 30 participants are listed as at risk for serious adverse events and 30 as at risk for other adverse events. The registry lists 0 affected participants for serious events and 0 for other events in each condition, and 0 deaths.

These figures describe what the registry record reports for the listed conditions. Because participants took part in a crossover design, the same people may contribute to more than one condition; the condition counts should not be added together to produce a unique-participant total. The record does not describe event definitions, ascertainment procedures, duration of safety follow-up, or whether events were attributed to stimulation. No serious adverse event terms are listed.

A zero count in the registry is not proof that an event is impossible or that no unrecorded event occurred. It means that no affected participants are reported in these entries. The safety figures should be read as registry reporting for this study, in the healthy-volunteer population and under the listed study conditions, rather than as a general statement about safety in other populations or settings.

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

The primary result describes an uncertain difference in a fMRI-derived nucleus accumbens measure between active 5 Hz and active 10 Hz stimulation. The unadjusted p value is 0.492, and the interval estimate spans zero. These findings do not establish a clear difference between the active frequencies in the analyzed participants. They also do not establish equivalence, because the record does not report an equivalence margin or an analysis designed to test equivalence.

The endpoint is a regional beta estimate of task-related activation, not a symptom measure or clinical outcome. A difference in this signal would not by itself establish a meaningful effect on cognition, functioning, or a disorder. The participants were healthy volunteers, and the registry describes the work as part of a broader research program that aims to characterize temporal interference and inform future research. The posted results do not answer whether stimulation benefits people with addiction, obsessive-compulsive disorder, Parkinson’s disease, or another condition.

The secondary activity results should also be read in context. The 10 Hz active-versus-sham comparison has an unadjusted p value of 0.025, but it is one of multiple listed outcomes and the registry does not report multiplicity adjustment for the secondary comparisons. This result therefore does not, on its own, establish a robust or clinically meaningful effect. Numerical connectivity results are not reported in the registry record.

The registry notes that whole-brain voxelwise analyses did not identify statistically significant activation differences after correction for multiple comparisons, while descriptive ROI estimates are reported. These statements are not contradictory: they refer to analyses at different spatial scales. The ROI estimates can describe a focused signal, but they should not be presented as a corrected whole-brain finding.

In general, statistical evidence, measurement, and clinical meaning are distinct. The reported comparisons describe condition differences in a measured fMRI outcome, with uncertainty. The record does not report an outcome threshold for meaningful change, detailed analysis methods, or evidence that the signal changes translate into clinical outcomes. The results are best understood as limited observations about brain activity during the tested sessions, not as conclusions about clinical effectiveness.

17. Why This Trial Matters Statistically

This trial is statistically informative because it combines a crossover design with a regional fMRI outcome. In a crossover study, each participant contributes observations under multiple conditions, which can make within-person contrasts relevant to the question. At the same time, analysis must account for the dependence among observations from the same participant. The registry reports condition-level summaries but does not state how that dependence was handled, making the distinction between design and analysis important when interpreting precision.

The study also illustrates why a focused ROI summary and a whole-brain analysis should not be conflated. The nucleus accumbens beta estimates provide a descriptive regional view, while the registry reports no statistically significant whole-brain voxelwise activation differences after correction for multiple comparisons. Different analysis scopes can yield different forms of evidence, and the conclusions should match the scope of the analysis.

Multiplicity is another central statistical issue. Several outcomes and condition contrasts are listed, but the registry does not report an adjustment strategy for the secondary comparisons. A nominal secondary result may look more compelling when viewed alone than when considered as one finding among multiple analyses. The record’s reporting makes it especially important to distinguish the primary frequency question from the secondary active-versus-sham questions.

Finally, the study makes clear that outcome-specific sample size and trial enrollment are not interchangeable. The record reports enrollment of 30 and 28 participants contributing to the activity analyses. Separate planning illustrations use observed effects and stated assumptions, but those calculations do not reveal the original design rationale. The registry record does not report that rationale, the detailed analysis plan, or the full handling of incomplete data. Those omissions limit reconstruction of the study’s inferential framework, even though the posted summaries allow a careful description of the observed contrasts.

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.

Several limitations specific to this study constrain interpretation. The analyzed activity outcomes include 28 participants, while enrollment was 30. The registry attributes the exclusions to noncompletion and/or unavailable complete usable imaging and behavioral data, but does not separate those reasons or describe whether missingness could have influenced the results. It does not report imputation or other missing-data procedures.

The study is a crossover design with four listed condition sequences, but the registry does not explain allocation across the sequences or report analyses of sequence, period, or carryover effects. It also does not identify what was masked under the single-masked designation. These details matter for understanding potential sources of bias and the analysis of repeated observations, but are not reported in the registry record.

The posted outcome summaries include condition means, standard errors, comparison estimates, interval limits, and unadjusted p values. The statistical model used for the comparisons and the confidence level for interval estimates are not reported. The registry does not describe whether the within-person structure was reflected in the uncertainty estimates. This limits independent interpretation of the inferential summaries.

The primary outcome is a fMRI ROI beta estimate in healthy volunteers, not a clinical endpoint. The registry reports that whole-brain voxelwise analyses were not statistically significant after correction for multiple comparisons, while providing descriptive ROI-level estimates. The secondary 10 Hz active-versus-sham finding is unadjusted among multiple outcomes, and numerical results for the listed connectivity outcome are not reported. The record also does not report a multiplicity strategy for the secondary comparisons.

Finally, the registry does not report the original sample-size justification, a detailed prespecified analysis plan, or an outcome threshold that would define a meaningful change in beta estimate. The planning illustrations are based on observed effects rather than the trial’s original design. Together, these limitations mean the findings should be treated as limited statistical descriptions of the measured sessions, rather than broad conclusions about stimulation or clinical outcomes.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Temporal Interference Methods for Non-invasive Deep Brain Stimulation, Study 1.2 — NCT07339072.
• Registry record last updated 2026-10-15; status last verified 2026-08.
• Results first posted 2026-10-15.
• 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

The registry record describes a completed randomized, single-masked crossover study of temporal interference electrical stimulation in healthy volunteers, with enrollment of 30. Four listed condition orders included active and sham stimulation targeting the nucleus accumbens at 5 Hz and 10 Hz. The primary outcome was a fMRI-derived nucleus accumbens ROI beta estimate during active 5 Hz versus active 10 Hz stimulation.

For the primary outcome, 28 participants contributed data in each condition. The unadjusted comparison has a p value of 0.492 and an interval estimate spanning zero. The record reports descriptive ROI estimates and states that whole-brain voxelwise analyses did not identify statistically significant activation differences after correction for multiple comparisons. One secondary active-versus-sham comparison has an unadjusted p value of 0.025; the other has a p value of 0.756. Numerical connectivity results are not reported in the registry record.

The registry lists 0 serious adverse events, 0 other adverse events, and 0 deaths in each condition entry. Detailed analysis methods, missing-data handling, multiplicity procedures for secondary results, and original sample-size assumptions are not reported in the registry record.