Chapter 1 - Introduction
1.2 Non-invasive brain stimulation
In recent decades several methods for the assessment of changes in brain activity have been introduced. While functional imaging techniques such as functional magnetic resonance imaging (fMRI) or positron emission tomography (PET) can visualise changes in brain activity with a high spatial resolution or specificity for a certain transmitter system, the neurophysiological techniques such as electroencephalography (EEG) or non-invasive brain stimulation offer a high temporal precision. While functional imaging techniques allow scans of the whole brain neurophysiological approaches are primarily restricted to superficial cortical areas. In addition to observing brain activity stimulation of cortical areas allows interaction with ongoing processes and the induction of neuroplastic changes in itself.
Several methods for non-invasive brain stimulation have been introduced since the 1980s. Transcranial electrical stimulation (TES) (Merton and Morton, 1980) and transcranial magnetic stimulation (TMS) (Barker et al., 1985) were designed to induce action potentials in neuronal tissue using brief high intensity pulses while transcranial direct current stimulation (tDCS) (Nitsche and Paulus, 2000) and the newly introduced forms of transcranial random noise stimulation (tRNS) (Terney et al., 2008) are intended to induce changes in cortical excitability by a sustained polarization or current flow. As all studies included in this dissertation are
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based on different forms of TMS, this technique will be explained in more detail in the following sections.
1.2.1 Transcranial magnetic stimulation
TMS was developed as a means of stimulating the human cerebral cortex in a contactless and painless fashion (Barker et al., 1985). The technique is based on the principle of electromagnetic induction and uses a rapidly changing magnetic field to induce an electrical field and thereby an electrical current in conductive tissue. In order to achieve a very short rise time of the magnetic field a capacitor bank is discharged through a magnetic coil which can be placed over the cortical region of interest.
Additional technical details will be discussed in chapter 2.4 which deals with the effect of pulse duration for TMS.
The focality of stimulation depends on the coil geometry, size and orientation. The figure-of-eight coil with two wings of opposite current flow direction (Ueno et al., 1988) has evolved into a standard for focal application of TMS. It is important to note that the magnetic field decreases exponentially with distance from the coil which limits the use of TMS to superficial cortical areas.
While TES is thought to activate pyramidal neurons directly TMS preferentially activates pyramidal neurons transsynaptically. Within the volume of neural tissue targeted by TMS a mixture of different types of neurons might be activated depending on their orientation in relation to the induced electrical field. Thus TMS might elicit excitatory and inhibitory effects simultaneously. There are only two brain regions where TMS gives rise to a positive response: Suprathreshold stimulation of motor areas leads to excitation of corticospinal projections and measurable muscle twitches. Subjective visual sensations can be induced by stimulation over the visual cortex. In other cortical areas TMS leads to inhibitory processes or disruption of information processing (“virtual lesion”), which are also present in motor and visual system.
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1.2.2 Repetitive transcranial magnetic stimulation
While a single TMS pulse might affect cortical excitability for a few hundred milliseconds a sequence of stimuli can induce bidirectional changes in cortical excitability outlasting the time of stimulation by several minutes up to a few hours. Since the first systematic assessment of rTMS effects using suprathreshold TMS at different intensities and frequencies applied over the motor cortex (Pascual-Leone et al., 1994) an abundance of different stimulation protocols has been introduced. At the starting point of this thesis project the repetition rate of TMS pulses was considered to be the single most important factor determining the direction of the induced after effects (Fitzgerald et al., 2006) with low frequencies of 1 Hz or less leading to inhibition (Chen et al., 1997) and high frequencies of 2 Hz and more leading to facilitation (Peinemann et al., 2004; Quartarone et al., 2005). LTP-/LTD-like plasticity has been proposed to underlie rTMS induced effects based on similar basic properties – associativity of convergent pathways, input specificity, and a similar effect duration of rTMS effects compared to slice experiments (Ziemann et al., 2006). This assumption is supported by pharmacological studies (Thickbroom, 2007).
The aspect of input specificity is even clearer than in rTMS when a peripheral electrical stimulation of a sensory nerve is repeatedly paired with a suprathreshold TMS pulse (Stefan et al., 2000; Wolters et al., 2003). This paired associative stimulation (PAS) protocol is capable of inducing facilitatory and inhibitory after effects depending on the interstimulus interval and thus the order of events at the level of the motor cortex resembling the pattern of spike-timing dependent plasticity (Wolters et al., 2005).
Based on electrophysiological protocols commonly used for the induction of LTP in hippocampal or cortical slices Huang and colleagues developed a special rTMS protocol termed Theta Burst Stimulation (TBS) (Huang et al., 2005). This protocol combines high frequency burst (3 pulses at 50/s) with a repetition rate of these bursts at 5/s (which lies in the theta range of the EEG spectrum). The application of this pattern continuously for 40s leads to inhibition while splitting up the same number of pulses in 2s
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stimulation blocks followed by 8s breaks leads to facilitation. The major advantage of TBS protocols compared to conventional rTMS protocols seemed to be a stronger and more stable effect following conveniently short low intensity stimulation trains.
However, several other parameters of the stimulation itself as well as the properties of the stimulated brain areas might alter the magnitude and even the direction of the after effects (Helmich et al., 2006). In this context the state of excitation at the time of stimulation and the recent history of activation for the targeted cortical area are of particular interest as processes of homeostatic plasticity might enhance or reverse the expected effects (Iyer et al., 2003; Lang et al., 2004; Siebner et al., 2004).
The resulting changes in cortical excitability following rTMS can be assessed by electrophysiological parameters in the motor system, functional imaging techniques or behavioural parameters and have been interpreted as correlates of neuroplastic processes involving alterations of synaptic efficacy.
While TMS can only target superficial cortical areas directly even remote effects of rTMS on functionally connected brain areas can be observed (Strafella et al., 2001; Strafella et al., 2003; Wassermann et al., 1998).
Transcallosal projections between the primary motor cortices can even be demonstrated after single TMS pulses (Ferbert et al., 1992).