The causal role of the right ventrolateral prefrontal cortex in suppressing emotional
interference
Introduction
The mammalian brain can quickly allocate attentional resources to threatening
stimuli in a bottom-up manner, an adaptation crucial for survival. However, in psychiatric
conditions such as post-traumatic stress (PTS) and generalized anxiety disorder (GAD),
preferential processing of non-threatening negative emotional stimuli can interfere with
goal directed behavior (Monk et al., 2008; Morey et al., 2009; Zhang et al., 2013). These
disorders may result from a failure to engage cognitive control mechanisms to suppress
stimulus driven processes.
Previous work has shown that blood oxygen level dependant (BOLD) activity in the
right ventrolateral prefrontal cortex (vlPFC) is associated with successful suppression of
negative interfering stimuli in a working memory task, indicating that this region may be
involved in cognitive control over emotion (Anticevic, Repovs, & Barch, 2010; Dolcos et al.,
2013). The purpose of this proposed research is to establish the causal role of the right
vlPFC in suppressing task-irrelevant emotional interference. I will achieve this in three
aims, 1.) by characterizing the functional connectivity of the right vlPFC using functional
magnetic resonance imaging (fMRI), 2.) by investigating the temporal dynamics of right
vlPFC connectivity using electroencephalography (EEG) with source localization, and 3.) by
exciting or inhibiting right vlPFC activity with transcranial magnetic stimulation (TMS). If
successful, this project may identify the right vlPFC as a target for cognitive and/or
pharmacological therapeutics in the treatment of emotional disorders.
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Background
Evidence from prior neuroimaging studies suggests that the right vlPFC plays an
important role in suppressing task-irrelevant negative emotional distractors. In 2006,
Dolcos and McCarthy found that in addition to impairing working memory, emotional
distractors were associated with BOLD activation in the amygdala and the bilateral vlPFC.
Furthermore, they found that increased activity in the right vlPFC was associated with
lower subjective ratings of both emotional content and distractibility of negative images
(Dolcos & McCarthy, 2006). Using similar paradigms, Anticevic et al. and Dolcos et al. both
found that the right vlPFC was more active in trials where participants correctly performed
a working memory task in the presence of an emotional distractor than in incorrect trials
(Anticevic et al., 2010; Dolcos et al., 2013).
While the aforementioned studies looked at healthy adults, other work has found
that the right vlPFC shows reduced activity in anxiety disorders. Monk et al. found that
adolescents with GAD showed weaker negative connectivity between the right vlPFC and
the amygdala while viewing angry faces (Monk et al., 2008). Zhang et al. found that
patients with PTS showed decreased activation of the bilateral frontal triangle (a subregion of the vlPFC) when presented with emotional distractors relative to controls, and
that this correlated with decreased working memory performance (Zhang et al., 2013).
Taken together, these studies indicate that patients with emotion disorders show
decreased activity in the right vlPFC.
One limitation of these previous studies is that they measured BOLD fMRI signal,
which has a relatively low temporal resolution. Studies of emotional distraction using
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higher temporal resolution recording techniques such as EEG have been limited. Aftanas et
al. found that negative emotional stimuli produced synchronization of low-frequency
frontal theta (4-7 Hz) activity, and that this synchronization was deficient in participants
with high anxiety (Aftanas, 2003). In an EEG study of cognitive reappraisal of negative
emotional stimuli, Ertl et al. found that frontal theta synchronization correlated with
successful emotion regulation (Ertl, Hildebrandt, Ourina, Leicht, & Mulert, 2013). While
these two studies demonstrate the importance of frontal theta in emotion regulation, it
remains to be seen if BOLD activation of the vlPFC is mediated by theta oscillations.
Specific Aims
Aim 1.) Characterize the functional connectivity between the right vlPFC using fMRI
In this aim I will investigate how activity in the right vlPFC correlates with activity in
other brain regions in the context of a working memory task. I will use a modified version
of the paradigms presented by Dolcos and McCarthy and Clapp et al. (Clapp, Rubens, &
Gazzaley, 2010; Dolcos & McCarthy, 2006).
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Briefly, the experiment will contain 3 block types, distracting stimulus (DS), no
interference (NI), and passive view (PV). During DS blocks, participants will be instructed
to hold a male or female face in working memory while ignoring any non-facial stimuli. The
face will remain on screen for 800 ms, followed by a delay period. The participant will then
be presented with a distractor of either neutral or negative emotional valence, followed by
a second delay period. Neutral and negative distractors will each be presented in 50% of
trials in a random order. Finally, the participant will be presented with a face that is either
identical or gender matched, and instructed to report whether the face is old or new.
NI blocks will be identical to DS blocks, except they will not include a distractor. The
purpose of NI blocks is to record baseline working memory performance to compare to DS
blocks. PV blocks will also be identical to NI blocks except they will not include a probe. The
purpose of PV blocks is to provide a baseline neural response to neutral and emotional
images without the context of a working memory task.
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To identify the emotion specific region of the right vlPFC, I will contrast BOLD signal
for neutral trials vs. negative trials during the presentation of the interference, negative PV
trails vs. negative DS trials, and correct negative DS trials vs. incorrect negative DS trials.
Once I have identified the emotional area of the right vlPFC, I will use it as a seed
region to explore connectivity across the whole brain. Consistent with Monk et al., I expect
the right vlPFC to be negatively correlated with the amygdala (Monk et al., 2008). In
addition, I expect the right vlPFC to be positively correlated with the dorsolateral
prefrontal cortex (dlPFC), a region associated with cognitive control and working memory.
Once I’ve established regions whose activity correlates with the right vlPFC, I can
investigate the causal role the vlPFC plays in these connections using dynamic causal
modeling (Friston, Harrison, & Penny, 2003).
Aim 2: Characterize the temporal dynamics of the right vlPFC using EEG source localization
During a second visit, the same participants will perform a similar paradigm while
recording EEG. In order to overcome the limited spatial resolution of EEG, I will employ a
high density (>100 electrods) EEG cap. Using each participant’s previously obtained
structural MRI, I will project EEG data from individual sensors into the three dimensional
brain volume using forward modeling. I will generate a mask of the right vlPFC and
investigate evoked potentials for neutral and emotional images presented during DS and
PV blocks. Furthermore, I will investigate the frequency components of right vlPFC activity.
I hypothesize that right vlPFC evoked potentials will display greater amplitudes and
lower latency for negative DS trials compared to other trial types. Consistent with previous
EEG studies, I predict that right vlPFC activity will be most prominent in the theta band.
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Therefore, I will investigate theta connectivity between the right vlPFC, the dlPFC and the
amygdala.
It is possible that even with a high density EEG cap, the spatial resolution will be
insufficient to overcome smearing of the electromagnetic signal through the head. One way
to test the accuracy is to pass simulated data with known spatial sources through the
forward model and check the accuracy of the inverse solution. If the spatial resolution is
too limited in three dimensional volume space, an intermediate solution may be to restrict
source localization to the cortical surface.
Aim 3.) Excite or inhibit right vlPFC activity with electromagnetic stimulation in the context of
a working memory task
In my second aim, I will use high frequency TMS to stimulate or low frequency TMS
to inhibit activity in the right vlPFC and investigate its impact on suppressing emotional
distractors. Participants will return for three more visits, where they will perform the same
working memory paradigm after receiving either high frequency TMS, low frequency TMS,
or sham TMS to the right vlPFC. Participants will not be aware of the stimulation type they
receive on each visit, and the order of stimulation types will be randomized across visits.
By using the same participants, I will be able to use previous data to target specific regions
of the vlPFC that are associated with inhibiting emotion distraction. In addition, I will
record EEG data during the working memory paradigm and perform source localization,
focusing on the dlPFC and the amygdala.
I hypothesize that high frequency TMS to the right vlPFC will improve participants’
performance in the working memory task in the presence of emotional distractors, and that
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low frequency TMS will worsen participants’ performance in the working memory task. In
addition, I predict that stimulating the right vlPFC will also enhance activity in the dlPFC
and reduce activity in the amygdala, and inhibiting the right vlPFC will suppress activity in
the dlPFC and enhance activity in the amygdala.
If repeated TMS pulses are insufficient to modulate vlPFC activity, an alternative
method would be to apply transcranial direct current stimulation (tDCS), although the
spatial resolution of tDCS is more limited than TMS.
Conclusion
In a series of EEG, fMRI, and TMS experiments, I hope to establish the causal role of
the right vlPFC in suppressing negative emotional interference in a working memory task.
If activity in the right vlPFC proves to cause successful suppression of emotional
interference, this may drive novel therapies for emotional disorders. For instance,
electromagnetic stimulation of the right vlPFC could be used in conjunction with exposure
therapy in treating PTS. Alternatively, cognitive training that is shown to enhance vlPFC
activity over time may also have benefits for emotion regulation.
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Anticevic, A., Repovs, G., & Barch, D. M. (2010). Resisting emotional interference: brain
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and episodic memory: an event-related FMRI investigation. Frontiers in Psychology, 4,
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Ertl, M., Hildebrandt, M., Ourina, K., Leicht, G., & Mulert, C. (2013). Emotion regulation by
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Monk, C. S., Telzer, E. H., Mogg, K., Bradley, B. P., Mai, X., Louro, H. M. C., … Pine, D. S.
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