Ten Years of Theta Burst Stimulation in Humans: Established Knowledge, Unknowns and Prospects
Introduction
Until the late 1980s transcranial magnetic stimulation (TMS) machines could only deliver 1 stimulus every 4 s or so. However a repetitive stimulator was eventually produced that allowed repeated stimulation of the brain at high frequencies. Initially, repetitive TMS (rTMS) was used in “lesion” mode, to interrupt the function of language areas and thereby determine language dominance, or in “activation” mode to locate epileptic foci [1], [2]. However, it was not long before groups began to investigate its potential for inducing after-effects that outlasted the period of stimulation, and which appeared to involve plastic changes in the excitability of cortical synapses. Theta burst stimulation (TBS) is one of many forms of rTMS that were developed after this pioneering work when more advanced stimulators were available [3]. Although it was first thought that TBS produced more powerful and reproducible effects than other rTMS methods, a claim that unfortunately has not stood the test of time, its main attraction is the speed of application. It takes 2–3 min or less to apply TBS protocols, making them more acceptable to participants than longer lasting protocols such as 1 Hz rTMS which can take 20–30 min; the same advantage means that it can even be used in unanaesthetized animals. This has led to a large body of literature, which we have tried to survey below. The review mainly focuses on experimental studies performed on the primary motor cortex (M1) or in other cortical regions known to be functionally connected to M1 in healthy subjects and in patients with various types of movement disorders. We also discuss the experimental evidence coming from TBS studies in animals. Finally, we evaluate the status of TBS as a possible new non-invasive therapy aimed at improving symptoms in various types of neurological disorders.
Section snippets
Neurophysiology of TBS
The original concept of TBS comes from the burst discharge at 4–7 Hz (the theta range in electroencephalography – EEG terminology) recorded from the hippocampus of rats during exploratory behaviour [4]. Theta burst patterns of stimulation are commonly used to induce plasticity in animal brain slices [5], [6], [7], and it seemed reasonable to adapt these to the human brain using TMS. The parameters were adjusted to match the capabilities of rTMS machines available at the time. Each burst had
TBS in animal studies
Animal models supplement human TMS studies by opening the possibility to apply invasive in vivo electrophysiology, post-stimulation in vitro electrophysiology and histology, in addition to behavioural testing. Fortunately, TBS protocols are very suitable for experiments on animals because the short duration allows stimulation of fully awake animals in a stress-free manner after adequate familiarization to the experimental situation including manual restrain [107], [108], [109], [110], [111].
Harnessing TBS for therapy
How to harness metaplasticity in brain disease with disordered network activity is currently most extensively studied after cerebral stroke in order to improve functional outcome. Several studies have been based on a simple concept of a dysbalanced inter-hemispheric equilibrium with (1) decreased excitability in the ipsilesional hemisphere, (2) increased excitability in the contralesional hemisphere, and (3) exaggerated inhibitory control from the contra- to ipsilesional hemisphere [126]. They
Conclusions
In the ten years since its introduction, TBS methods have proved to be a popular and useful addition to the growing number of methods now available to interact with presumed synaptic plasticity in the human brain. The advantages of TBS are its short duration and use of low intensity stimulus pulses, making it more acceptable to participants than some other non invasive brain stimulating protocols. Data from animal studies suggest that the effects observed in the human brain can be replicated in
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