Running Head: Affective Bias Task in Neuromodulation 1
Case Report: Stimulation of the right amygdala induces transient changes in affective bias.
Kelly R. Bijankia, Christopher K. Kovachb, Laurie M. McCormicka, Hiroto Kawasakib, Brian J.
Dlouhyb, Justin Feinsteinc, d, Robert D. Jonesc, Matthew A. Howard IIIb*
a. Department of Psychiatry, University of Iowa Carver College of Medicine
b. Department of Neurosurgery, University of Iowa Carver College of Medicine
c. Department of Neurology, University of Iowa Carver College of Medicine
d. Laureate Institute for Brain Research, Tulsa, OK 74136 USA
* Corresponding Author: Kelly Rowe Bijanki, W290 General Hospital, 200 Hawkins Dr., Iowa
City, IA 52242. Phone: (319)384-9132. E-mail: email@example.com
The current data were presented orally at the World Society for Stereotactic and Functional
Neurosurgery Congress in Tokyo, Japan in 2013.
Keywords: Deep Brain Stimulation, mood, depression, emotion, bioassay
Running Head: Affective Bias Task in Neuromodulation 2
Background: Sensitive outcome measures are needed to quantify the effects of neuromodulation
in mood disorders.
Objective: This study examined the utility of a novel affective bias (AB) task in identifying
transient mood changes induced by amygdala stimulation in a single rare participant.
Methods: Localized, pulsed electrical stimulation was delivered for 8 minutes during measures
of AB and self-reported mood. Responses were compared with those gathered without
stimulation on the same day in the same setting, using paired t-tests.
Results: Stimulation of the basolateral nucleus of the right amygdala at 50Hz, 15V, and 200µs
pulse-width produced a significant positive shift in AB (t=-2.864,df=53,p=.006), despite
equivocal findings on self-reported mood (t=-.184,df=12,p=.857).
Conclusion: Affective bias may be more sensitive to stimulation-induced fluctuations in mood
than subjective report, suggesting utility as an outcome measure in neuromodulation studies.
Running Head: Affective Bias Task in Neuromodulation 3
Neuromodulation has become fertile ground for studies aimed at improving
neuropsychiatric illnesses, especially mood disorders. Such studies have typically quantified
efficacy in terms of self-reported mood using standard illness severity scales (1,2). A major
confound to self-reported mood measures is alexithymia (a lack of insight into one’s own
emotional state) (3), which is frequently comorbid with chronic depression (4). In the pursuit of
more sensitive and reliable outcome measures, affective bias tasks have come to the fore (5).
Affective bias (AB) is the tendency among depressed patients to interpret ambiguous or
positive events as relatively negative (6). This phenomenon is especially pronounced in the
rating of emotional facial expressions (7,8), a process with known amygdala involvement (9).
Previous studies have shown AB in depressed patients, who interpret emotional facial
expressions as either more negative or less positive than matched healthy control participants
(10, 11). This experiment’s first hypothesis was that measures of AB would reflect more stable
aspects of mood tendency than self-report.
The current experiment used an opportunity to stimulate the brain of a chronically
depressed patient who underwent intracranial monitoring prior to surgical treatment for epilepsy.
Surgical epilepsy patients occasionally require depth electrodes targeted to the medial temporal
lobe, including the amygdala, to definitively localize epileptogenic foci. Depth electrodes were
used in the current case to stimulate the amygdala via application of electrical current at a level
below threshold for eliciting epileptiform activity. The amygdala is widely implicated in mood
regulation (12), but it has remained poorly characterized by stimulation studies (13-15). Based
on limited previous studies (16), our second hypothesis was that such stimulation would be
effective in altering mood and AB.
Running Head: Affective Bias Task in Neuromodulation 4
Methods and Materials:
The patient was a 48 year-old right-handed man who underwent intracranial electrode
monitoring to localize the focus of his medically intractable complex partial seizures (Appendix
1). In addition, the patient had a history of stable major depressive disorder beginning at least 1
year prior to the experiment and lasting at least 1 year after (Appendix 1). At the time of the
experiment, the patient exhibited severe depression on the Beck Depression Inventory-II (BDI-II
= 44) (17), and severe alexithymia on the Toronto Alexithymia Scale (TAS-20 = 77) (18). The
timeline of all research-related events is presented in Appendix 2. The research protocol was
approved by the Institutional Review Board of the University of Iowa, and the patient provided
informed consent prior to participation.
The patient underwent surgical implantation of depth electrodes in the basolateral nuclei
of the amygdala bilaterally (Supplemental Figure 1, Appendix 2). The positions of contacts
spanning the basolateral nuclei were confirmed based on post-implantation MRI and they were
projected on the pre-operative MRI.
Amygdala stimulation-mapping was used thirteen days after electrode implantation to
determine the behaviorally active stimulation parameters for the AB and mood-rating tasks.
Continuous stimulations of 30 seconds each were delivered to the amygdala in the following
ranges: 20-130Hz, 3-20V, and 90-200µs pulse-width using a constant-voltage stimulator over the
course of two hours on a single afternoon. The participant was unblinded to stimulation status
during this protocol. During the session, EEG traces were continuously monitored. Stimulation
Running Head: Affective Bias Task in Neuromodulation 5
of the left amygdala induced abnormal after-discharges on EEG with low-intensity stimulation,
(likely due to proximity to the seizure focus). Therefore, the full protocol was only used on the
right amygdala. Stimulation at 50 Hz, 20V, and 200µs pulse-width was found to elicit significant
and reproducible shifts in mood (i.e., rating of sadness changed by 30%, rating of fear changed
Affective bias and mood-rating protocols:
First, to establish baselines and to allow test-retest reliabilities to be calculated for the AB
and mood tasks, they were administered to the participant nine days after electrode implantation
without the use of any electrical stimulation. Later, the tasks were administered a second time
(thirteen days after electrode implantation) to reassess emotional state without stimulation. Then,
the same day, the tasks were administered a third time under electrical stimulation to the
In both tasks, items were presented on a computer screen and ratings were made using a
visual analog scale centered at neutral with no hash marks, with negative and positive anchors on
the left and right respectively. In the AB task, the patient rated the intensity and valence of facial
expressions. Stimuli included three female and three male Caucasian people, whose images were
modified from the MacBrain Face Stimulus Set developed by Nim Tottenham
(www.macbrain.org/resources.htm/). Selected faces were unambiguous exemplars of happy, sad
and neutral emotion categories as evaluated with normative rating data provided by the creators.
Within each identity, photographs of happy, neutral and sad facial expressions were used to
generate more subtle facial expression morphs using image morphing software developed by the
authors, running under Matlab (Nattick, MA). Morphs were created by interpolating pixel value
and location between neutral exemplar faces (0%) and expressive exemplars (100%) using a
Running Head: Affective Bias Task in Neuromodulation 6
piece-wise linear transformation over a Delaunay tessellation of manually selected control
points. The task took approximately five minutes to administer.
The mood-rating task was designed to capture aspects of mood that were possible to
change instantaneously as a result of stimulation (Appendix 3), based on the Symptom Checklist-
90-Revised (19) and the BDI-II (17). Items were rated relative to the participant’s emotional
state at the moment. For example, one prompt asked, “How easy would it be to cry right now”
with response anchors of “very easy” and “very difficult”. The task took approximately two
minutes to administer.
A constant-voltage stimulator delivered pulsed (5sec on, 5sec off), bipolar, biphasic
stimulation to the right amygdala throughout the entire experiment (8 minutes). Pulsed
stimulation was used to minimize the risk of inducing epileptiform discharges, to enable
monitoring of EEG throughout electrical stimulation session and to allow enough time to
complete the affective bias and mood tasks. Lower-voltage stimulation (15V) was used to ensure
that the patient remained blind to stimulation condition and to more clearly distinguish
differential effects of stimulation on mood and AB. With stimulation on, the participant
completed each task at his own pace.
Paired samples t-tests were used to compare ratings between the stimulated and
unstimulated conditions. Post-hoc tests used Pearson’s correlation between the degree
(percentage) of morphing pooled over happy and sad morphs and rating shift between
stimulation and non-stimulation blocks. Test-retest reliability across non-stimulated blocks was
evaluated with Pearson correlations of ratings between sessions for both the mood and AB tasks.
Running Head: Affective Bias Task in Neuromodulation 7
AB and mood-rating paradigms were each repeated three times; first without stimulation
four days prior to the stimulation experiment, then again without stimulation on the same day as
the stimulation experiment, and finally with intermittent (5 sec ON; 5 sec OFF) stimulation to the
right amygdala at 50Hz, 15V, and 200µs pulse-width.
On the AB task, the participant consistently rated the emotional facial expressions as
more positive with stimulation than without (Figure 1). A paired-samples t-test indicated a
significant effect of stimulation (t=-2.864,df=53,p=.006). A relationship was detected between
the intensity of the facial expression (distance from neutral) and the participant’s rating; the
stronger the expression, the larger the positive shift in rating during stimulation. The correlation
between intensity of the facial expression and shift in rating with stimulation was significant
(r=.44,p=.0007). By comparison, a paired-samples t-test across all mood items showed a non-
significant effect of stimulation (t=-.184,df=12,p=.857) (Figure 1).
The AB task showed high test-retest reliability (r=.903). By comparison, the mood-rating
task showed low test-retest reliability (r=.579). Responses on the mood-rating task differed by as
much as 38% across the four days prior to stimulation.
The current study describes substantial changes in AB with amygdala stimulation.
During stimulation, ratings of emotional facial expressions (a measure of AB) showed a
statistically significant positive shift. This stands in contrast to equivocal findings from the
subjective mood-rating task.
Running Head: Affective Bias Task in Neuromodulation 8
Effects of antidepressant treatments on subjective mood typically require several weeks
to become clinically apparent, whether examined in the context of medications (5) or
neuromodulatory treatments such as electroconvulsive therapy (ECT; 20), repeatable transcranial
magnetic stimulation (rTMS; 21), and deep brain stimulation (DBS; 1). Harmer and colleagues
hypothesize that negative bias in information processing could be the element of depressive
symptomatology that responds most rapidly to treatment, suggesting its utility as an outcome
measure. Several studies support this hypothesis. For example, non-depressed people show a
positive shift in AB (on a similar face-rating paradigm) after taking a single dose of
antidepressant medication, even in the absence of subjective change in mood (22). This finding
was later replicated in patients with MDD (5), where a single dose of reboxetine reversed
negative AB in depressed patients, in the absence of any change in subjective ratings of mood or
anxiety. Studies of AB tasks in the most common neuromodulatory treatments for mood
disorders (ECT and rTMS) are wholly lacking, but some studies have recently examined the
utility of other measures of affective bias in transcranial direct current stimulation (tDCS) for
depression using an emotional Stroop task (23), an affective go/no-go task (24), and an
emotional working memory task (25). To our knowledge, the current case is the first to describe
changes in AB under intracranial electrical stimulation.
The current study is limited by the inclusion of a single rare participant who, because
stimulation was carried out in separate experimental blocks, may not have been fully blind to
stimulation status. Due to time constraints, we were unable to repeat the experiment with
modified stimulation parameters (contact location or pulse frequency and level), and therefore
cannot fully dissociate effects across stimulation parameters.
Running Head: Affective Bias Task in Neuromodulation 9
Based on the current study and the literature on the subject to date, we propose that AB
tasks may provide a more sensitive and reliable outcome measure than subjective mood ratings
for neuromodulation studies. The search for better outcome measures is critical because such
improvements could translate to earlier and more consistent identification of treatment
responders, as well as enhanced statistical power for clinical trials. This would elevate the
probative value of each participant in such trials, perhaps meaning that fewer participants would
be necessary or that more elaborate and elegant analyses could be used. AB tasks are also
enticing for their potential use as a screening tool; several studies have shown AB tasks are able
to predict treatment response (26) as well as relapse (27). In the clinical practice of DBS
treatment, AB tasks could additionally be useful in the process of confirming electrode targeting,
contact selection, and stimulation parameter selection. The current study offers preliminary
support for the use of AB tasks for these purposes, though the current findings must be replicated
in a larger sample and extended to patients receiving brain stimulation expressly for the
treatment of mood disorders.
Running Head: Affective Bias Task in Neuromodulation 10
The authors would like to acknowledge the efforts of the research participant in the
current study, whose strength and commitment to the project made these findings possible. The
current study was financially supported by a grant from the NIDCD made to Matthew Howard
III (grant number: 5R01DC004290-14).
Drs. Bijanki, Kovach, McCormick, Kawasaki, Dlouhy, Feinstein, Jones, and Howard report no
biomedical financial interests or potential conflicts of interest.
Running Head: Affective Bias Task in Neuromodulation 11
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Running Head: Affective Bias Task in Neuromodulation 14
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Running Head: Affective Bias Task in Neuromodulation 15
Figure 1: Ratings of emotional facial expressions and mood items during stimulation minus
ratings given without stimulation.
Figure 1 Legend: Column heights indicate difference in rating between stimulation and non-
stimulation blocks of the affective bias (A) and mood-rating (B) tasks. Positive deflection
indicates the item was rated as more positive during stimulation.
Running Head: Affective Bias Task in Neuromodulation 16
The participant was a 48-year-old right-handed male factory worker with 13 years of
education. He suffered complex partial seizures emanating from the medial temporal lobe with
greater than fifteen-year chronicity. MRI and FDG-PET revealed sclerosis and decreased
metabolism in the left mesial temporal lobe. The patient underwent bilateral amygdala depth
electrode recording as it was suspected that there might be bilateral involvement in
epileptogenesis that was not measurable with surface EEG. Following a two-week period of
intracranial EEG monitoring, his seizure focus was confirmed in the left anterior mesial temporal
lobe which was subsequently resected. After the resection surgery, the patient has not had any
Six months prior to the experiment, the participant endorsed items consistent with severe
depression and anxiety on the Beck Depression and Anxiety Inventories (BDI-II = 35, BAI-II =
26). The participant was seen twice more for neuropsychological follow-up after the experiment,
and continued to have symptoms of severe depression and anxiety (6mo: BDI-II = 36, BAI-II =
28; 12mo: BDI-II = 33, BAI-II = 38). He was generally unresponsive to multiple medications
including antidepressants (fluoxetine, mirtazapine), anxiolytics (diazepam, lorazepam), and a
sleep aid (zolpidem).
Running Head: Affective Bias Task in Neuromodulation 17
Timeline of events:
The initial measures of AB and mood occurred nine days after the implantation surgery
(five days prior to the resection surgery). The second administration of non-stimulated AB and
mood measures, as well as the stimulation experiment, took place thirteen days after electrode
implantation (the day before the resection surgery). The figure below describes the precise
intervals between all study-related events.
Supplemental Figure 1: Timeline of experimental events.
Running Head: Affective Bias Task in Neuromodulation 18
Amygdala depth electrode detail:
The amygdala electrodes (AD-Tech Epilepsy/LTM Spencer Probe Depth Electrodes)
were 1.1mm in diameter with 2.4mm platinum low-impedance contacts that delivered targeted
bipolar electrical stimulation. The right amygdala electrode had four contacts with 10mm
spacing. The left amygdala electrode had eight contacts with 12 mm spacing between contact 1
and 2 and 7 mm spacing between remaining contacts.
Supplemental Figure 2: Locations of electrode contacts used to deliver electrical stimulation to
Legend: Electrical stimulation was delivered to the basolateral nucleus of the amygdala by
passing a bipolar, biphasic current between adjacent contacts (A-D=lateral contact, E-H=medial
contact). Panels A-C and E-G show the pre-op amygdala depth electrode target locations. Panels
D and H show the actual location of the lateral amygdala contact (red) on the depth electrode and
locations of all other amygdala contacts (black).
Running Head: Affective Bias Task in Neuromodulation 19
Mood-rating items including overall mood, energy level, focus, ease of crying, worry, guilt,
hopelessness, loneliness, positive self-regard, irritability, anxiety, suicidal ideation, and
restlessness. Omitted areas of mood function (non-transient) were considered to include
vegetative symptoms: sleep patterns, appetite, and interest in sex.
Supplemental Figure 3: Example of mood-rating item:
Legend: The participant moves the red bar along the scale to represent his current mood.
Specific prompts: Anchors:
How is your mood right now?
What is your energy level right now?
How focused you feel right now?
How easy would it be cry right now?
How worried do you feel right now?
How much guilt are you experiencing?
How do you feel about your future?
How lonely do you feel?
How much do you like yourself right now?
How irritable do you feel right now?
How anxious do you feel right now?
Are you having thoughts of ending your life?
How restless do you feel?
Very depressed ------------ Very happy
Exhausted --------------- Very energetic
Very distracted ---------- Very focused
Very easy ---------------- Very difficult
Very worried ------------------ Carefree
Strong guilt --------------------- No guilt
Quite hopeless ---------- Quite hopeful
Very lonely ----------- Not lonely at all
Not at all --------------------- Quite a lot
Very irritable ------- Not at all irritable
Very anxious ------- Not at all anxious
Very much so ----------------- Not at all
Very restless -------- Very comfortable
Running Head: Affective Bias Task in Neuromodulation 21