Methodological considerations of priming repetitive transcranial magnetic stimulation protocols in clinical populations

Priming protocols in clinical populations

Despite the application of rTMS in a wide range of clinical populations,6 priming rTMS protocols have primarily been used in clinical trials of major depressive disorders (MDDs) and motor stroke. rTMS is a well-established non-pharmacological treatment of depression.7 A form of inhibitory priming rTMS protocol, which applied 6 Hz high-frequency rTMS priming followed by a conditioning session of 1 Hz low-frequency rTMS, was tested in a randomised controlled trial (RCT) with patients with MDD. This trial demonstrated a superior effect of priming rTMS to the right dorsolateral prefrontal cortex (DLPFC) compared with low-frequency rTMS alone in improving depressive moods.8 This clinical benefit was attributed to the stronger inhibitory effect of priming rTMS (6 Hz before 1 Hz) on the right DLPFC than that of low-frequency rTMS alone through metaplasticity induction. The fact that the inhibitory rTMS delivered to the right DLPFC is less commonly used in the treatment of MDD compared with the excitatory rTMS delivered to the left DLFPC9 is worth mentioning. Consequently, the effectiveness of priming rTMS protocols to the left DLPFC compared with non-priming (standard) rTMS protocols for antidepressant treatment remains uncertain.

According to a recent review of priming protocols in healthy human subjects,5 the superiority of priming stimulation over non-priming stimulation has frequently been demonstrated in modulating the M1 excitability, measured by MEP. Therefore, priming rTMS may show clinical benefits for motor recovery following neurological disorders, although evidence is currently limited to post-stroke rehabilitation. Cassidy et al applied the same priming inhibitory rTMS protocol (6 Hz before 1 Hz) to the contralesional M1 in patients who had a stroke.10 The study found that single-session priming rTMS significantly decreased the duration of the cortical silent period and short-interval intracortical inhibition over the ipsilesional M1 compared with the non-priming control. However, superiority was not observed in the outcome of paretic hand functions. Another team has recently validated an excitatory form of iTBS priming for stroke rehabilitation.1 The RCT of patients post-stroke compared 10-session priming iTBS (cTBS prior to iTBS), non-priming iTBS (sham cTBS prior to iTBS) and sham stimulation (sham cTBS prior to sham iTBS) that was delivered to the ipsilesional M1, in combination with robot-assisted motor training, on upper extremity motor and neurophysiological outcomes. The primary analysis demonstrated that priming with iTBS was equivalently effective compared with non-priming iTBS in boosting motor outcomes in patients with stroke. Furthermore, priming iTBS demonstrated clinical superiority in improving upper extremity impairment in patients who had a stroke with a higher functioning upper extremity compared with non-priming iTBS and sham stimulation.1

Discussion

In summary, preliminary evidence from RCTs in disease populations supports the utility of priming rTMS for both psychiatric and neurological applications to achieve superior neuromodulatory outcomes. Despite the potential for prolonged treatment sessions, the clinical application of priming rTMS protocols remains highly viable, particularly when employing accelerated protocols such as TBS. The significance of priming rTMS protocols can be summarised as follows. First, experimental studies using priming rTMS have demonstrated the history state dependence of the aftereffect of rTMS in both healthy and pathological brains.4 Second, by using the metaplastic mechanism, priming rTMS offers a clinically feasible solution to induce more robust neuromodulatory effects in the brain. This can lead to improved therapeutic outcomes in psychiatric and neurological rehabilitation.1 8 Therefore, priming rTMS protocols have the potential to overcome the limitations faced by patients who do not adequately respond to standard rTMS protocols.

Although metaplasticity-elicited priming rTMS protocols have shown promise in enhancing therapeutic responses, many unknowns remain. First, the optimal parameters for the priming protocols have not been well studied. Several parameters must be considered (figure 1B). (1) Interstimulation interval: the induction of metaplasia occurs only within a certain time window. A priming transcranial direct current study investigated an interstimulation interval of 3 min, but not of 0 min and 30 min,11 resulting in metaplasticity-induced effects. By contrast, a TBS study established that an interval of 5 min between two iTBS sessions, but not of 15 min, led to a metaplasticity-induced effect.12 No study has systematically investigated the influence of time intervals on the effect of rTMS priming using two non-identical protocols. (2) Intensity: in animal studies, the metaplasticity of hippocampal neurons can be elicited even when priming stimulation does not induce any LTP/LTD effects;13 however, the rationale has yet to be tested in the human cortex. Murakami et al,14 who conducted the only study concerning the intensity, documented that low-intensity TBS priming at 70% active motor threshold (AMT) was not superior to high-intensity TBS priming at 80% AMT, with MEP outcomes; thus, evidence regarding the impact of intensity on the effect of priming rTMS remains inconclusive. (3) Stimulation modes: although priming protocols using conventional rTMS and TBS have demonstrated metaplasticity-induced effects, clinical evidence comparing different modes of stimulation or for developing a hybrid mode of priming stimulation (eg, TBS primed rTMS) is not yet available. Note that experimental evidence concerning parameter selection in priming rTMS is primarily derived from studies conducted on healthy adults. As a result, parameter optimisation for priming rTMS protocols in disease populations remains largely unknown and requires further systematic investigation. A thorough investigation of the parameters that determine the effectiveness of priming rTMS will open up new avenues for optimising therapeutic brain stimulation strategies. By identifying the optimal timing, intensity and stimulation modes for priming rTMS, clinicians and researchers will be able to expand the range of options available for patients who have limited responses to conventional rTMS protocols.

In addition, neural biomarkers that can assess metaplasticity in healthy and pathological brains and predict treatment responses are lacking. Carey et al 15 conducted a single-group pre–post experiment using priming rTMS (6 Hz before 1 Hz) to the contralesional M1 in patients who had a stroke. They reported that the extent of preservation of the ipsilesional posterior limb of the internal capsule (PLIC) predicted an improvement in paretic hand function in patients after receiving priming rTMS. However, the structural reserve in the PLIC is more likely to be a general biomarker reflecting the potential for motor recovery following stroke, but not the brain capacity to induce therapeutically beneficial metaplasticity. Quantified by various measures, such as electroencephalography, functional magnetic resonance imaging (fMRI) or MEP (single-pulse and paired-pulse outcomes), the brain response to priming rTMS appears to be a promising method to evaluate the acute neuroplasticity induced by priming stimulation relative to the non-priming control, and it may be further used to predict the therapeutic response of multiple session priming protocols (figure 1C). The approach using predictive biomarkers also offers a possible solution for identifying patients who may exhibit a more favourable therapeutic response to priming protocols than to conventional non-priming protocols. Longitudinal studies incorporating neural biomarkers are required to substantiate this hypothesis. However, conducting such studies with biomarkers in disease populations presents specific challenges. First, recruiting enough participants and ensuring their repeated measures can be difficult. Collaboration with multiple centres, including acute hospitals, community rehabilitation facilities and patient advocacy groups, would help address this challenge. Second, analysing longitudinal data requires sophisticated statistical techniques. Recent advancements in machine learning and artificial intelligence modelling offer opportunities to develop reliable and efficient prediction models using multimodal neural biomarkers.

Conclusion

Metaplasticity-elicited priming rTMS protocols are likely to achieve superior efficacy in terms of sensorimotor and emotional outcomes in neurological and psychiatric applications compared with conventional rTMS. Further studies are required to investigate parameter optimisation and identify biomarkers that evaluate the brain reserve of therapeutically beneficial metaplasticity.