Background: Synaptic plasticity in forms of long-term potentiation (LTP) and long-term depression
(LTD) are considered to be the neurophysiological correlate of learning and memory.
Impairments of these mechanisms are discussed as a key mechanism in the pathophysiology
of neurodevelopmental disorders. Metaplasticity and homeostatic plasticity are higher
forms of synaptic plasticity leading to a balance of inhibitory and facilitatory neuronal
influences. Quadri-pulse theta burst stimulation (qTBS) is a newly introduced, high-frequent
transcranial magnetic stimulation protocol inducing a long-lasting increase or decrease
in synaptic plasticity—referring to the model of LTP and LTD—in human primary motor
cortex (M1) that enables the evaluation of metaplastic and homeostatic mechanisms.
Aim: The aim of the study was to investigate metaplastic and homeostatic mechanisms in
human M1 using an inhibitory priming qTBS protocol.
Question: To probe homeostatic and metaplastic mechanisms as an important mechanism of successful
learning with therapeutic relevance in human M1 using high-frequent qTBS.
Methods: We investigated the priming effects of an inhibitory qTBS protocol with an interstimulus
interval (ISI) of 50 milliseconds on a following facilitating qTBS protocol (ISI 5
milliseconds; experiment 1) and a following inhibitory qTBS protocol (ISI 50 milliseconds,
experiment 2) in n = 9 healthy volunteers. qTBS consisted of 360 bursts with one burst containing four
pulses (pulse duration 160 μs) given continuously over M1 of the contralateral hand
(i.e., 1,440 pulses in total) with an ISI of 5 or 50 milliseconds and an interburst
interval of 200 milliseconds (qTBS50/200 or qTBS5/200). Resting motor threshold (RMT)
and motor evoked potential (MEP) amplitudes with stimulus intensities to target amplitudes
of 1 mV were measured before priming qTBS50/200 (pre), directly after priming qTBS50/200
(post 1), after 15 minutes (post 2), and after 30 minutes (post 3). Following post
3 measurements of the priming protocol, the second stimulation (qTBS5/200 or qTBS50/200)
was applied, and the RMT and MEP were measured for 60 minutes (post 4–post 7).
Results: In experiment 1 (qTBS50/200–qTBS5/200), priming with qTBS50/200 led to a decrease
of MEP amplitudes (post 1–3), while MEP amplitudes increased following subsequent
qTBS5/200 (post 4–7). Mean changes of post 4 to 7 increased significantly as compared
with mean changes of post 1 to 3. In experiment 2 (qTBS50/200–qTBS50/200), MEP amplitudes
decreased following the priming protocol (post 1–3) and returned to baseline with
a slight increase on post 6 after the subsequent qTBS50/200 protocol. Mean changes
of post 4 to 7 increased significantly as compared with mean changes of post 1 to
3.
Conclusion: Our results point toward homeostatic and metaplastic mechanisms of a priming inhibitory
qTBS protocol and subsequent inhibitory or facilitatory qTBS. These results indicate
that the effects of qTBS, depending on the ISI, reflect LTP- and LTD-like changes
in corticospinal excitability in human M1 and that homeostatic and metaplastic mechanisms
can be probed. This, in turn, may influence the therapeutic application of noninvasive
brain stimulation in the human brain. The very short duration of the protocol of ∼2
minutes may be of particular interest when using this form of stimulation in children.
