Neuromodulatory effects and reproducibility of the most widely used repetitive transcranial magnetic stimulation protocols

Abstract

Background Repetitive transcranial magnetic stimulation (rTMS) is widely used in both research and clinical settings to modulate human brain function and behavior through the engagement of the mechanisms of plasticity. Based upon experiments using single-pulse TMS as a probe, the physiologic mechanism of these effects is often assumed to be via changes in cortical excitability, with 10 Hz rTMS increasing and 1 Hz rTMS decreasing the excitability of the stimulated region. However, the reliability and reproducibility of these rTMS protocols on cortical excitability across and within individual subjects, particularly in comparison to robust sham stimulation, have not been systematically examined. Objectives In a cohort of 28 subjects (39 ± 16 years), we report the first comprehensive study to (1) assess the neuromodulatory effects of traditional 1 Hz and 10 Hz rTMS on corticospinal excitability against both a robust sham control, and two other widely used patterned rTMS protocols (intermittent theta burst stimulation, iTBS; and continuous theta burst stimulation, cTBS), and (2) determine the reproducibility of all rTMS protocols across identical repeat sessions. Results At the group level, neither 1 Hz nor 10 Hz rTMS significantly modulated corticospinal excitability. 1 Hz and 10 Hz rTMS were also not significantly different from sham and both TBS protocols. Reproducibility was poor for all rTMS protocols except for sham. Importantly, none of the real rTMS and TBS protocols demonstrated greater neuromodulatory effects or reproducibility after controlling for potential experimental factors including baseline corticospinal excitability, TMS coil deviation and the number of individual MEP trials. Conclusions These results call into question the effectiveness and reproducibility of widely used rTMS techniques for modulating corticospinal excitability, and suggest the need for a fundamental rethinking regarding the potential mechanisms by which rTMS affects brain function and behavior in humans.

The Use of Transcranial Magnetic Stimulation in Attention Optimization Research: A Review from Basic Theory to Findings in Attention-Deficit/Hyperactivity Disorder and Depression

“…Neuronal plasticity: Repetitive TMS (rTMS) protocols can induce longer-lasting effects on neural circuits. Depending on the stimulation frequency, rTMS can either increase or decrease the excitability of the stimulated brain region [ 48 ]. High-frequency rTMS can enhance synaptic strength and excitability, potentially leading to long-term potentiation (LTP)—a mechanism associated with learning and memory [ 49 ].…”

Variability of pulse width in transcranial magnetic stimulation

“…Stimulation of the human cortex is achieved by an induced electrical current, due to the rapidly changing magnetic field, which passes through the skull and depolarizes the superficial neurons perpendicular to the current [1]. This technique is applied in dedicated laboratories and clinics on a daily basis, but the physiological effect and output parameters such as motor evoked potentials (MEPs) or transcranial evoked potentials (TEPs) are prone to high variability [2][3][4][5][6]. Factors contributing to the variability in the resulting output parameters of TMS are not only due to individual subject factors like different anatomical structures [7] or the intrinsic state of the brain prior to stimulation [8] but could also be the result of different technical, TMS-related factors, e.g.…”

Current perspectives on neuromodulation in ALS patients: A systematic review and meta-analysis

“…Furthermore, accelerated high-frequency rTMS called theta burst stimulation (TBS) is also considered on the rise as it creates similar suppressing and facilitating neuromodulation effects to TMS but consists of shorter sessions and lower modulatory intensities [31]. The impact of continuous, cTBS, in ALS was investigated in four studies conducted by Di Lazzaro et al In an initial randomized trial involving 20 ALS patients, active bilateral cTBS applied to the primary motor cortex (M1) for 5 days per month exhibited an association with a deceleration of disease progression after 6 months of treatment [22].…”