Abstract
Transcranial Magnetic Stimulation (TMS) is a form of non-invasive brain stimulation, used to alter cortical excitability both in research and clinical applications. The intermittent and continuous Theta Burst Stimulation (iTBS and cTBS) protocols have been shown to induce opposite after-effects on human cortex excitability. Animal studies have implicated synaptic plasticity mechanisms long-term potentiation (LTP, for iTBS) and depression (LTD, for cTBS). However, the neural basis of TMS effects has not yet been studied in human neuronal cells, in particular at the level of gene expression and synaptogenesis. To investigate responses to TBS in living human neurons, we differentiated human SH-SY5Y cells toward a mature neural phenotype, and stimulated them with iTBS, cTBS, or sham (placebo) TBS. Changes in (a) mRNA expression of a set of target genes (previously associated with synaptic plasticity), and (b) morphological parameters of neurite outgrowth following TBS were quantified. We found no general effects of stimulation condition or time on gene expression, though we did observe a significantly enhanced expression of plasticity genes NTRK2 and MAPK9 24 h after iTBS as compared to sham TBS. This specific effect provides unique support for the widely assumed plasticity mechanisms underlying iTBS effects on human cortex excitability. In addition to this protocol-specific increase in plasticity gene expression 24 h after iTBS stimulation, we establish the feasibility of stimulating living human neuron with TBS, and the importance of moving to more complex human in vitro models to understand the underlying plasticity mechanisms of TBS stimulation.
Highlights
Transcranial Magnetic Stimulation (TMS) is a widely used neuromodulation technique, where electromagnetic pulses can non-invasively stimulate cortical structures (Barker et al, 1985; Hallett, 2007)
Differentiation status of SH-SY5Y cells was verified through visual inspection of increased neurite length, and confirmed by a significant increase in tyrosine kinase receptor B (TrkB) expression (NTRK2) at day 10 of differentiation [t(7) = 8.657, p < 0.0001], as reported previously (Ehrhard et al, 1993; Jahn et al, 2017; see Figure 2)
We were interested in gene expression changes in the BDNFTrkB signaling cascade, in downstream targets related to plasticity
Summary
Transcranial Magnetic Stimulation (TMS) is a widely used neuromodulation technique, where electromagnetic pulses can non-invasively stimulate cortical structures (Barker et al, 1985; Hallett, 2007). Multiple pulses administered in a certain frequency (repetitive TMS: rTMS), can have effects on cortical excitability lasting beyond the period of stimulation (PascualLeone et al, 1994; Huang et al, 2005). In humans, such effects are often revealed with physiological outcome measures, such as Motor-Evoked Potentials (MEPs; Rothwell et al, 1999). The commonly used Theta Burst Stimulation (TBS) protocols intermittent and continuous TBS (iTBS and cTBS) have been shown to increase or decrease MEPs for up to 1 h following stimulation, respectively, (Huang et al, 2005). A method to reliably verify rTMS effects, for example in an in vivo model, is urgently needed
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