Reducing motor evoked potential amplitude variability through normalization.

Background: Transcranial Magnetic Stimulation (TMS) is used for in vivo assessment of human motor cortical excitability, with application of TMS pulses over the motor cortex resulting in muscle responses that can be recorded with electromyography (EMG) as Motor Evoked Potentials (MEPs). These have been widely explored as potential biomarkers for neuropsychiatric disorders but methodological heterogeneity in acquisition, and inherent high variability, have led to constraints in reproducibility. Normalization, consisting in scaling the signal of interest to a known and repeatable measurement, reduces variability and is standard practice for between-subject comparisons of EMG. The effect of normalization on variability of MEP amplitude has not yet been explored and was assessed here using several methods. Methods: Three maximal voluntary isometric contractions (MVICs) and 40 MEPs were collected from the right hand in healthy volunteers, with a retest session conducted 4 to 8 weeks later. MEP amplitude was normalized using either external references (MVICs) or internal references (extreme MEPs). Iterative re-sampling of 30 normalized MEPs per subject was repeated 5,000 times to define, for each normalization method, distributions for between-subject coefficients of variation (CV) of the mean MEP amplitude. Intra-class correlation coefficients (ICC) were used to assess the impact of normalization on test­retest stability of MEP amplitude measurements. Results: In the absence of normalization, MEPs collected from the right hand of 47 healthy volunteers were within reported values regarding between-subject variability (95% confidence intervals for the CV: [1.0567,1.0577]) and showed good temporal stability (ICC = 0.77). Internal reference normalization substantially reduced between-subject variability, by values of up to 64%, while external reference normalization had no impact or increased between-subject variability. Normalization with the smallest references reduced test­retest stability, with use of the largest references resulting in slight reduction or improvement of ICCs. Internal reference normalization using the largest MEPs was found to be robust to several sensitivity analyses. Conclusion: Internal, but not external, reference normalization reduces between-subject variability of MEP amplitude, and has a minimal impact on within-subject variability when conducted with the largest references. Additional research is necessary to further validate these normalization methods toward potential use of MEPs as biomarkers of neuropsychiatric disorders.

Replicability of motor cortex-excitability modulation by intermittent theta burst stimulation.

OBJECTIVE: Transcranial Magnetic Stimulation (TMS) allows for cortical-excitability (CE) assessment and its modulation has been associated with neuroplasticity-like phenomena, thought to be impaired in neuropsychiatric disorders. However, the stability of these measures has been challenged, defying their potential as biomarkers. This study aimed to test the temporal stability of cortical-excitability modulation and study the impact of individual and methodological factors in determining within- and between-subject variability. METHODS: We recruited healthy-subjects to assess motor cortex (MC) excitability modulation, collecting motor evoked potentials (MEP) from both hemispheres, before and after left-sided intermittent theta burst stimulation (iTBS), to obtain a measure of MEPs change (delta-MEPs). To assess stability across-time, the protocol was repeated after 6 weeks. Socio-demographic and psychological variables were collected to test association with delta-MEPs. RESULTS: We found modulatory effects on left MC and not on right hemisphere following iTBS of left MC. Left delta-MEP was stable across-time when performed immediately after iTBS (ICC = 0.69), only when obtained first in left hemisphere. We discovered similar results in a replication cohort testing only left MC (ICC = 0.68). No meaningful associations were found between demographic and psychological factors and delta-MEPs. CONCLUSIONS: Delta-MEP is stable immediately after modulation and not impacted by different individual factors, including expectation about TMS-effect. SIGNIFICANCE: Motor cortex excitability modulation immediately after iTBS should be further explored as a potential biomarker for neuropsychiatric diseases.

Lesion network mapping of mania using different normative connectomes.

Lesion network mapping is a neuroimaging technique that explores the network of regions functionally connected to lesions causing a common syndrome. The technique uses resting state functional connectivity from large databases of healthy individuals, i.e., connectomes, and has allowed for important insight into the potential network mechanisms underlying several neuropsychiatric disorders. However, concerns regarding reproducibility have arisen, that may be due to the use of different connectomes, with variable MRI acquisition parameters and preprocessing methods. Here, we tested the impact of using different connectomes on the results of lesion network mapping for mania. We found results were reliable and consistent independent of the connectome used.

Day-to-day variability in motor threshold during rTMS treatment for depression: Clinical implications.

BACKGROUND: When repetitive transcranial magnetic stimulation (rTMS) is used to treat medication refractory depression, the treatment pulse intensity is individualized according to motor threshold (MT). This measure is often acquired only on the first day of treatment, as per the protocol currently approved by Food and Drug Administration. OBJECTIVE: Here, we aimed to assess daily MT variability across an rTMS treatment course and simulate the effects of different schedules of MT assessment on treatment intensity. METHODS: We conducted a naturalistic retrospective study with 374 patients from a therapeutic rTMS program for depression that measures MT daily. RESULTS: For each patient, in almost half the TMS sessions, MT varied on average more than 5% as compared to the baseline MT acquired in the first treatment day. Such variability was only minimally impacted by having different TMS technicians acquiring MT in different days. In a smaller cohort of healthy individuals, we confirmed that the motor hotspot localization method, a critical step for accurate MT assessment, was stable in different days, arguing that daily MT variability reflects physiological variability, rather than an artifact of measurement error. Finally, in simulations of the effect of one-time MT measurement, we found that half of sessions would have been 5% or more above or below target intensity, with almost 5% of sessions 25% above target intensity. The simulated effects of weekly MT measurements were significantly improved. CONCLUSIONS: In conclusion, MT varies significantly across days, not fully dependent on methods of MT acquisition. This finding may have important implications for therapeutic rTMS practice regarding safety and suggests that regular MT assessments, daily or at least weekly, would ameliorate the effect.