The role of the norepinephrine system in emotion, vigilance and error processing.

In the field of cognitive neuroscience, interest in emotion is rapidly
increasing. A critical distinction in this literature is the one between two
affective dimensions: emotional intensity and emotional valence. Although a lot
is known about the neural basis of valence, the neural basis of emotional
intensity has so far been neglected. A well-known measure for emotional
intensity is the late positive potential (LPP): a specific component of the EEG
signal. The LPP is highly sensitive to emotional intensity of stimuli and is
larger for both pleasant and unpleasant than for neutral stimuli (Cuthbert et
al., 2000; Keil et al., 2002; Lang et al., 1997; Schupp et al., 2000; Schupp et
al., 2003). Because of its functional sensitivity the LPP has often been used
as a tool to study the role of emotion in social behavior (Ito et al., 1998;
Ito et al., 2004). Nonetheless, the neural basis of the LPP is largely unknown.
The amplitude of the LPP was shown to significantly correlate with the brain
activity in the visual cortex (Sabatinelli et al., 2007), whereas the human
amygdala is well-known to be involved in the processing of emotional stimuli
(Zald, 2003). A lesion study showed that increased visual cortex activation by
emotional stimuli depends on an intact amygdala (Vuilleumier et al., 2004).
Thus, it has been suggested that the recruitment of the amygdala in the
processing of emotional stimuli activates the visual cortex, underlying the
sensitivity of the LPP to the emotional intensity of stimuli (Dolcos & Cabeza,
2002; Vuilleumier, 2005).
In order to directly test this hypothesis, we intend to modulate emotional
processing in the amygdala. This is usually done using beta-blockers, which are
known to affect emotional memory by blocking the norepinephrine (NE) receptors
(of the beta type) in the amygdala (Strange & Dolan, 2004). In the proposed
research we will test directly whether modulation of emotional processing in
the amygdala by the beta-blocker propranolol affects the LPP.
Another ongoing debate regarding the role of the NE system in cognition is
about the so-called P3 component of the EEG signal (Nieuwenhuis et al., 2005).
The P3 is typically observed when subjects perform a classic vigilance task:
the oddball task, in which subjects have to detect the rare odd stimulus out of
a series of standard stimuli. Animal research suggested that the P3 reflects
the response of the NE system (Pineda et al., 1989; Pineda & Westerfield, 1993;
Swick et al., 1994). An fMRI study in humans showed that oddball responses
depend on activation of beta-type NE receptors (Strange & Dolan, 2007).
However, it is still unknown whether the P3 in humans depends on activation of
these receptors. In order to test this hypothesis we will investigate whether
beta-blockers affect the P3 in humans during an oddball task.
The Pe component of the EEG signal is elicited when subjects make an error in
typical choice reaction time tasks. It is considered to reflect affective
processing of errors and is closely related to the P3 component (Leuthold &
Sommer, 1999). However, it is still unknown whether the P3 and Pe are similarly
modulated by the NE system. In order to test this hypothesis we will
investigate whether beta-blockers affect the P3 in humans during the Eriksen
Flanker task (Eriksen & Eriksen, 1974).
In behavioral cognitive neuroscience it is well known that emotional stimuli
cause an interference effect (slowing down) in reaction time tasks like the
Aproach-Avoidance task (Roelofs et al., 2005; Heuer et al., 2007; Roelofs et
al., in press). However, it is still unknown whether the emotional intensity or
the emotional valence of these stimuli causes the interference effect. To test
this, we will measure the effect of propranolol on the interference effect as
measured behaviorally in the emotional exogenous cueing task adapted from Fox
and colleagues (Fox et al., 2002) and in the approach-avoidance task (Heuer et
al., 2006, adapted by Roelofs et al., 2008 for the NESDA study). Since
propranolol decreases the effect of emotional intensity we expect that if the
emotional intensity caused the interference effect, the interference effect
should be decreased by propranolol. However, if the emotional valence caused
the interference effect, propranolol should not affect the interference effect.

The primary objective of the current study is to investigate whether
administered beta-blocker (propranolol) affects the following components of the
EEG: the emotion-induced LPP, the vigilance-related P3, and the error-related
Pe. To this end we will measure EEG in healthy subjects twice, once on placebo
and once on propranolol (80 mg, single dose).

While EEG is measured, participants will perform simple computertasks known to
elicit the EEG components of interest (LPP, P3 and Pe) twice, once after taking
80 mg propranolol and once after taking a placebo (double-blind, cross-over
design). The purpose of the study is to investigate the effect of propranolol
on the EEG components of interest (see protocol for details).

80 milligram propranolol in a capsule (once only). Propranolol is a
non-selective beta-blocker mainly used in the treatment of hypertension, but
also often used by musicians and other performers to prevent stage fright and
performance anxiety. The usual maintenance dose ranges for oral propranolol
therapy vary by indication: 120-320 mg daily in divided doses for hypertension
and 10-40 mg 3-4 times daily for anxiety. We intend to administer 80 mg
propranolol since this is a commonly used dose in cognitive research (eg.
Maheu, Joober, Beaulieu, & Lupien, 2004; Maheu, Joober, & Lupien, 2005; van
Stegeren et al., 2005) and we intend to use a single dose only. Metabolism
occurs mainly by means of the kidneys. The biological half-life is 3-6 hours.

Cognitive computer tasks: There are no risks associated with the performance of
cognitive computer tasks except the occasional possibility of some frustration
with poor performance or fatigue. Testing will stop if a subject displays
frustration or appears tired.

EEG: The EEG recording procedure used is standard for electrophysiological
laboratories in hospitals and universities across the country. The only risk is
some very minor skin irritation in a very small number of participants. This
requires no treatment and disappears within several minutes after the
application of the electrode gel is complete. Participants* skin is never
damaged. All the reusable materials that touch the subject*s skin are
thoroughly washed and sterilized between uses, according to standard
electrophysiological lab procedures. There is no risk of electrical shock.

Propranolol: Three earlier psychological studies with healthy subjects using 80
mg propranolol showed that this amount was well endured without side effects
(Maheu, Joober, Beaulieu, & Lupien, 2004; Maheu, Joober, & Lupien, 2005; van
Stegeren et al., 2005). Thus, the risks associated with a single dose of 80 mg
propranolol is considered minimal. However, to reduce the remaining risks,
strict prescreening procedures (chapter 4.3) and safety procedures (chapters
5.1 and 8.2) are in place.