IntroductionIntermittent theta burst stimulation (iTBS) is a non-invasive brain stimulation technique capable of increasing cortical excitability beyond the stimulation period. Due to the rapid induction of modulatory effects compared to conventional repetitive transcranial magnetic stimulation (rTMS) paradigms, prefrontal application of iTBS is gaining popularity as a therapeutic tool for psychiatric disorders such as depression. In an attempt to increase efficacy, higher than conventional intensities are currently being applied. The assumption that this increases neuromodulatory effect is well established for the standard rTMS paradigms but may be mechanistically false for iTBS. This study examined the influence of intensity on the neurophysiological and behavioural effects of iTBS in the prefrontal cortex.Methods16 healthy participants received iTBS over prefrontal cortex (F1 electrode) at either 50, 75 or 100% resting motor threshold (rMT) in separate sessions. Single-pulse TMS and concurrent electroencephalography (EEG) was used to assess changes in cortical reactivity measured as TMS-evoked potentials (TEPs) and TMS-evoked oscillations. The n-back task (2-back and 3-back) were used to assess changes in working memory (accuracy and reaction time).ResultsThe data can be summarised as an inverse U-shape relationship between intensity and iTBS plastic effects, where 75% iTBS resulted in the largest neurophysiological changes both in TMS-EEG and working memory. Even though 75% iTBS showed significantly decreased reaction time in the 3-back task, between condition comparisons revealed no significant differences.ConclusionsThe assumption that higher intensity results in greater neuromodulatory effects is false, at least in healthy individuals, and should be carefully considered for clinical populations. Neurophysiological changes associated with working memory following iTBS suggest functional relevance. However, the effects of different intensities on behavioural performance remain elusive in the present healthy sample.HighlightsEffects of prefrontal iTBS at 50, 75 and 100% rMT were investigatedInverse U-shape relationship between intensity and neurophysiological effectsEffects on the behavioural performance remain elusive in healthy individualsDisclosures and conflict of interestsSWC was supported by a Monash Graduate Scholarship. NCR is supported by a NHMRC Early Career Fellowship (1072057). KEH is supported by a NHMRC Career Development Fellowship (1082894). PBF is supported by a NHMRC Practitioner Fellowship (1078567). PBF has received equipment for research from MagVenture A/S, Medtronic Ltd, Cervel Neurotech and Brainsway Ltd and funding for research from Neuronetics and Cervel Neurotech. He is on the scientific advisory board for Bionomics Ltd. There are no other conflicts.