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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).