Proefschrift_Holstein

Chapter 2

Box 2.5 | Revealing causal effects One way to alter neuronal excitability in humans is by means of applying non-invasive brain stimulation, or transcranial magnetic stimulation (TMS) ( chapter 7 ). TMS uses electromagnetic induction to generate electrical currents in the brain to alter neuronal excitability. Applying TMS over a cortical region can either increase or decrease neuronal excitability, depending on a number of factors. One important factor is the type of protocol used for stimulation. While single-pulse TMS depolarizes neurons under the coil, causing single action potentials, repetitive TMS (rTMS) can have longer-lasting excitatory (e.g. 5Hz, 10Hz, or intermittent theta burst stimulation; iTBS) or inhibitory (e.g. continuous theta burst stimulation; cTBS) effects (Huang et al., 2005; Wischnewski and Schutter, 2015). Previous work using neurochemical positron emission tomography (PET) imaging has shown that applying rTMS over the frontal cortex can cause changes in dopamine release in the striatum (Strafella et al., 2003; Ko et al., 2008). Subsequent work has shown effects of frontal rTMS in the amygdala, striatum, and cortical regions distant from the stimulation site, using fMRI (e.g. (Volman et al., 2011; van Schouwenburg et al., 2012; Hanlon et al., 2013; Zandbelt et al., 2013). Work in rodents has confirmed that stimulation of the cortex can increase dopamine release in the striatumby directlymeasuring dopamine concentrations using microdialysis (Taber and Fibiger, 1993). Importantly, rodent work has shown that the effects of iTBS crucially depend on midbrain dopamine (Hsieh et al., 2015). This was revealed by showing that the excitatory effects of iTBS (reflected by increased motor evoked potentials) are blocked in animals with dopamine lesions in the substantia nigra. Another way to assess whether a region is necessary for a given function is by studying subjects with brain lesions. Overstimulation of the glutamatergic N-methyl-D-aspartate (NMDA) receptor can induce cell death. NMDA lesions are therefore commonly used to apply excitotoxic lesions ( chapter 6 ) of a given brain region in rodents. Using stereotaxic surgery, we can lower an injection needle into the striatum and infuse the excitotoxic into the brain (Kirby et al., 2012). Next, we can compare animals with lesions to those without any damage (i.e. typically the animals in this group will undergo sham surgery, whereby saline instead of the excitotoxic compound is infused during surgery).

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