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Case Report: Stimulation of the Right Amygdala Induces Transient Changes in Affective Bias

  • Holistic Wellness & Psychiatry


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 1
Title Page:
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:
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.
Implantation surgery:
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:
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
by 70%).
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
( 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).
Financial Disclosures:
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 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
Appendix 1:
Medical history:
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
seizure events.
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
Appendix 2:
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.
4 Days
2 Weeks
12 Hours
1 Hour
5 Min.
9 Days
6 Months
Running Head: Affective Bias Task in Neuromodulation 18
Appendix 3:
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
Appendix 4:
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
... We use an affective bias emotional evaluation task (ABT) to examine the relationship between brain activity and behaviour as a function of two constructs: valence and intensity, plus an additional construct known as affective bias, which is the phenomenon whereby external emotional stimuli are interpreted in a manner consistent with one's own emotional state. Negative affective bias (emotional stimuli interpreted as more negative) has been associated with depression, [24][25][26][27][28] reliably dissociates mood groups, predicts depression treatment responses based on behavioural rating of happy and sad faces, 6,7,22,24,27 and when research paradigms permit, allows us to dissociate emotional valence and intensity. ...
... We use an affective bias emotional evaluation task (ABT) to examine the relationship between brain activity and behaviour as a function of two constructs: valence and intensity, plus an additional construct known as affective bias, which is the phenomenon whereby external emotional stimuli are interpreted in a manner consistent with one's own emotional state. Negative affective bias (emotional stimuli interpreted as more negative) has been associated with depression, [24][25][26][27][28] reliably dissociates mood groups, predicts depression treatment responses based on behavioural rating of happy and sad faces, 6,7,22,24,27 and when research paradigms permit, allows us to dissociate emotional valence and intensity. ...
... The dACC extended from a vertical boundary placed orthogonal to the anterior end of the corpus callosum extending to the end boundary between the paracentral lobule and superior frontal gyrus. 24,41 The anterior insula included gyri anterior of the central sulcus of the insula and was split into ventral and dorsal ROIs. All electrodes traversing the orbitofrontal and ventromedial cortex were assigned to the vmPFC ROI. ...
Emotion is represented in limbic and prefrontal brain areas herein termed the Affective Salience Network (ASN). Within the ASN, there are substantial unknowns about how valence and emotional intensity are processed - specifically, which nodes are associated with affective bias (a phenomenon in which participants interpret emotions in a manner consistent with their own mood). A recently developed feature detection approach ("specparam") was used to select dominant spectral features from human intracranial electrophysiological data, revealing affective specialization within specific nodes of the ASN. Spectral analysis of dominant features at the channel level suggests that dorsal anterior cingulate (dACC), anterior insula (aINS) and ventral-medial prefrontal cortex (vmPFC) are sensitive to valence and intensity, while the amygdala is primarily sensitive to intensity. AIC model comparisons corroborated the spectral analysis findings, suggesting all four nodes are more sensitive to intensity compared to valence. The data also revealed that activity in dACC and vmPFC was predictive of the extent of affective bias in the ratings of facial expressions - a proxy measure of instantaneous mood. To examine causality of the dACC in affective experience, 130 Hz continuous stimulation was applied to dACC while patients viewed and rated emotional faces. Faces were rated significantly happier during stimulation, even after accounting for differences in baseline ratings. Together the data suggest a causal role for dACC during the processing of external affective stimuli.
... Despite abundant evidence that electrical stimulation of the human amygdala can induce in some instances internal emotional states, the effect of amygdala stimulation on perception of emotion from external environmental stimuli has not been well investigated. In a single patient case report, Bijanki et al. (2014) studied a patient with intracranial electrodes located in the right amygdala and found that stimulation enhanced positive valence during viewing of faces, i.e., the subject perceived faces more positively when stimulation was applied. This effect of stimulation on perception of valence was measured in the absence of induction of any internal emotional states (Bijanki et al., 2014). ...
... In a single patient case report, Bijanki et al. (2014) studied a patient with intracranial electrodes located in the right amygdala and found that stimulation enhanced positive valence during viewing of faces, i.e., the subject perceived faces more positively when stimulation was applied. This effect of stimulation on perception of valence was measured in the absence of induction of any internal emotional states (Bijanki et al., 2014). ...
... The behavioral effects on valence perception obtained by amygdala stimulation in this study are distinct from several prior human intracranial EEG studies. Bijanki et al. (2014) reported right amygdala stimulation induced augmentation of perceived positive valence from images (Bijanki et al., 2014). This finding is contrary to our results and may be related to lateralized specialization of amygdala function. ...
Full-text available
Background Multiple lines of evidence show that the human amygdala is part of a neural network important for perception of emotion from environmental stimuli, including for processing of intrinsic attractiveness/“goodness” or averseness/“badness,” i.e., affective valence. Objective/Hypothesis With this in mind, we investigated the effect of electrical brain stimulation of the human amygdala on perception of affective valence of images taken from the International Affective Picture Set (IAPS). Methods Using intracranial electrodes in patients with epilepsy, we first obtained event-related potentials (ERPs) in eight patients as they viewed IAPS images of varying affective valence. Next, in a further cohort of 10 patients (five female and five male), we measured the effect of 50 Hz electrical stimulation of the left amygdala on perception of affective valence from IAPS images. Results We recorded distinct ERPs from the left amygdala and found significant differences in the responses between positively and negatively valenced stimuli ( p = 0.002), and between neutral and negatively valenced stimuli ( p = 0.017) 300–500 ms after stimulus onset. Next, we found that amygdala stimulation did not significantly affect how patients perceived valence for neutral images ( p = 0.58), whereas stimulation induced patients to report both positively ( p = 0.05) and negatively (< 0.01) valenced images as more neutral. Conclusion These results render further evidence that the left amygdala participates in a neural network for perception of emotion from environmental stimuli. These findings support the idea that electrical stimulation disrupts this network and leads to partial disruption of perception of emotion. Harnessing this effect may have clinical implications in treatment of certain neuropsychiatric disorders using deep brain stimulation (DBS) and neuromodulation.
... Investigating causal connections related to emotions in the brain at rest, as we did here, is clearly suboptimal, because the different nodes of the network are unlikely to be as interactive during rest as they are during emotion processing. We would thus want to apply the causal discovery methods that we document here to fMRI data that reflects brain states of putative emotions -either induced through sensory stimuli (e.g., watching emotionally laden film clips (Gross and Levenson, 1995)), volitional instruction (e.g., asking people to remember emotional autobiographical events (Damasio et al., 2000)) or through direct electrical stimulation of structures such as the amygdala (Bijanki et al., 2014;Dlouhy et al., 2015;Gloor et al., 1982;Halgren et al., 1978;Willie et al., 2016). The latter is a particularly intriguing aspect: as we demonstrated here it is in fact possible to combine electrical stimulation with concurrent fMRI measures, and it would offer the most direct test of the putative causal roles of brain structures in emotion. ...
... An experiment we plan to do next is to parametrically increase the amplitude and/or duration of the electrical stimulation. As one gradually stimulates the amygdala more and more, measurable components of emotion should be induced: there might be changes in autonomic responses such as skin-conductance response (Willie et al., 2016), changes in cognitive bias such as judgments of facial expressions (Bijanki et al., 2014), or changes in reported conscious experience (Halgren et al., 1978). What changes in the causal graph that describes the brain networks as these emotion components are induced? ...
Emotions involve many cortical and subcortical regions, prominently including the amygdala. It remains unknown how these multiple network components interact, and it remains unknown how they cause the behavioral, autonomic, and experiential effects of emotions. Here we describe a framework for combining a novel technique, concurrent electrical stimulation with fMRI (es-fMRI), together with a novel analysis, inferring causal structure from fMRI data (causal discovery). We outline a research program for investigating human emotion with these new tools, and provide initial findings from two large resting-state datasets as well as case studies in neurosurgical patients with electrical stimulation of the amygdala. The overarching goal is to use causal discovery methods on fMRI data to infer causal graphical models of how brain regions interact, and then to further constrain these models with direct stimulation of specific brain regions and concurrent fMRI. We conclude by discussing limitations and future extensions. The approach could yield anatomical hypotheses about brain connectivity, motivate rational strategies for treating mood disorders with deep brain stimulation, and could be extended to animal studies that use combined optogenetic fMRI.
... A strong relationship between the human amygdala and basic emotions has been revealed in studies of intracranial amygdala stimulation. These studies revealed that amygdala stimulation elicited responses of fear, anxiety, sadness, and joy, with the right hemisphere stimulation producing negative responses but the left hemisphere producing both positive and negative emotions (Bijanki et al., 2014;Inman et al., 2020;Lanteaume et al., 2007;Meletti et al., 2006). Negative emotional responses were induced more frequently than positive emotional experiences, which is consistent with previous research. ...
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Substantial studies of human amygdala function have revealed its importance in processing emotional experience, autonomic regulation, and sensory information; however, the neural substrates and circuitry subserving functions have not been directly mapped at the level of the subnuclei in humans. We provide a useful overview of amygdala functional characterization by using direct electrical stimulation to various amygdala regions in 48 patients with drug-resistant epilepsy undergoing stereoelectroencephalography recordings. This stimulation extends beyond the anticipated emotional, neurovegetative, olfactory, and somatosensory responses to include visual, auditory, and vestibular sensations, which may be explained by the functional connectivity with cortical and subcortical regions due to evoked amygdala-cortical potentials. Among the physiological symptom categories for each subnucleus, the most frequently evoked neurovegetative symptoms were distributed in almost every subnucleus. Laterobasal subnuclei are mainly associated with emotional responses, somatosensory responses, and vestibular sensations. Superficial subnuclei are mainly associated with emotional responses and olfactory and visual hallucinations. Our findings contribute to a better understanding of the functional architecture of the human amygdala at the subnuclei level and as a mechanistic basis for the clinical practice of amygdala stimulation in treating patients with neuropsychiatric disorders.
... The dorsal anterior cingulate was parceled according to 18,47 (which was not certified by peer review) is the author/funder. All rights reserved. ...
Emotion is represented in several limbic and prefrontal cortical brain areas herein referred to as the Affective Salience Network (ASN). Within this network, less is known about how valence and intensity are processed in the dorsal anterior cingulate (dACC), and how affective processes in dACC compare to activity in other nodes within the ASN. Using a novel spectral feature approach to analyze intracranial electrophysiological data, we discover hemispheric specialization in the dACC such that the right hemisphere is sensitive to intensity while the left hemisphere is sensitive to valence and negative affective bias. We further applied 130 Hz continuous stimulation to the anterior cingulum bundle while patients viewed emotional faces. Faces were rated happier in all patients, an effect modulated by baseline affective bias, suggesting a causal role for the dACC during the processing of external affective stimuli.
... Single-cell recordings in neurosurgical patients implicate the amygdala in the processing of faces (Fried et al., 1997). Moreover, stimulation of the amygdala can produce feelings of fear, but is also capable of producing positive emotions (Bijanki et al., 2014). The basolateral amygdala is typically the target of electrophysiological recordings in humans (Rutishauser et al., 2015). ...
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Understanding the interaction between cooperation and conflict in establishing effective social behaviour is a fundamental challenge facing societies. Reflecting the breadth of current research in this area, this volume brings together experts from biology to political science to examine the cooperation–conflict interface at multiple levels, from genes to human societies. Exploring both the exciting new directions and the biggest challenges in their fields, the authors focus on identifying commonalities across species and disciplines to help understand what features are shared broadly and what are limited to specific contexts. Each chapter is written to be accessible to students and researchers from interdisciplinary backgrounds, with text boxes explaining terminology and concepts that may not be familiar across disciplinary boundaries, while being a valuable resource to experts in their fields.
Laboratory threat extinction paradigms and exposure-based therapy both involve repeated, safe confrontation with stimuli previously experienced as threatening. This fundamental procedural overlap supports laboratory threat extinction as a compelling analogue of exposure-based therapy. Threat extinction impairments have been detected in clinical anxiety and may contribute to exposure-based therapy non-response and relapse. However, efforts to improve exposure outcomes using techniques that boost extinction - primarily rodent extinction - have largely failed to date, potentially due to fundamental differences between rodent and human neurobiology. In this review, we articulate a comprehensive pre-clinical human research agenda designed to overcome these failures. We describe how connectivity guided depolarizing brain stimulation methods (i.e., TMS and DBS) can be applied concurrently with threat extinction and dual threat reconsolidation-extinction paradigms to causally map human extinction relevant circuits and inform the optimal integration of these methods with exposure-based therapy. We highlight candidate targets including the amygdala, hippocampus, ventromedial prefrontal cortex, dorsal anterior cingulate cortex, and mesolimbic structures, and propose hypotheses about how stimulation delivered at specific learning phases could strengthen threat extinction.
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Emotional events are often easier to recall, and comprise our most valuable memories. Here, as subjects performed a memory task in which they recalled emotional stimuli more readily than neutral stimuli, we used direct brain recording and stimulation in the hippocampus and amygdala to identify how the brain prioritizes emotional information for memory encoding. High-frequency activity (HFA), a correlate of local neuronal spiking, increased in both hippocampus and amygdala when subjects successfully encoded emotionally arousing stimuli. Direct electrical stimulation applied to these regions during encoding decreased HFA and selectively impaired retrieval for emotional stimuli. Finally, depressed subjects' memory was biased more by valence than arousal, and they exhibited a congruent increase in HFA as a function of valence. Our findings thus provide evidence that emotional stimuli up-regulate activity in the amygdala--hippocampus circuit to enhance memory for emotional information, and suggest that targeted modulation of this circuit alters emotional memory processes.
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Background: Psychotic depression is arguably the most diagnostically stable subtype of major depressive disorder, and an attractive target of study in a famously heterogeneous mental illness. Previous imaging studies have identified abnormal volumes of the hippocampus, amygdala, and subcallosal region of the anterior cingulate cortex (scACC ) in psychotic depression, though studies have not yet examined the role of family history of depression in these relationships. Methods: 20 participants with psychotic depression preparing to undergo electroconvulsive therapy and 20 healthy comparison participants (13 women and 7 men in each group) underwent structural brain imaging in a 1.5T MRI scanner. 15 of the psychotic depression group had a first-degree relative with diagnosed affective disorders, while the healthy control group had no first-degree relatives with affective disorders. Depression severity was assessed with the Hamilton Depression Rating Scale and duration of illness was assessed in all patients. Automated neural nets were used to isolate the hippocampi and amygdalae in each scan, and an established manual method was used to parcellate the anterior cingulate cortex into dorsal, rostral, subcallosal, and subgenual regions. The volumes of these regions were compared between groups. Effects of laterality and family history of affective disorders were examined as well. Results: Patients with psychotic depression had significantly smaller left scACC and bilateral hippocampal volumes, while no group differences in other anterior cingulate cortex subregions or amygdala volumes were present. Hippocampal atrophy was found in all patients with psychotic depression, but reduced left scACC volume was found only in the patients with a family history of depression. Conclusions: Patients with psychotic depression showed significant reduction in hippocampal volume bilaterally, perhaps due to high cortisol states associated with this illness. Reduced left scACC volume may be a vulnerability factor related to family history of depression.
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The amygdala was a popular target during the era of psychosurgery, specifically for the treatment of intractable aggression. This mesiotemporal structure was thought to primarily mediate fear and anger. However, recent evidence suggests that the amygdala is part of a complex network that mediates the formation of a larger repertoire of positive and negative emotions. Dysfunctions within the network or the amygdala itself can lead to various mental illnesses. In those cases, deep brain stimulation (DBS) applied focally may treat the symptoms. This review presents data supporting the potential therapeutic role of DBS of the amygdala in the treatment of anxiety disorders, addiction, and mood disorders. The success of DBS for psychiatric conditions will likely depend on our ability to precisely determine the optimal target for a specific case.
Objective Our aim was to evaluate whether one single section of transcranial direct current stimulation (tDCS), a neuromodulatory technique that noninvasively modifies cortical excitability, could induce acute changes in the negative attentional bias in patients with major depression. Subjects and Methods Randomized, double-blind, sham-controlled, parallel design enrolling 24 age-, gender-matched, drug-free, depressed subjects. Anode and cathode were placed over the left and right dorsolateral prefrontal cortex. We performed a word Emotional Stroop Task collecting the response times (RTs) for positive-, negative-, and neutral-related words. The emotional Stroop effect for negative vs. neutral and vs. positive words was used as the measure of attentional bias. ResultsAt baseline, RTs were significantly slower for negative vs. positive words. We found that active but not sham tDCS significantly modified the negative attentional bias, abolishing slower RT for negative words. Conclusion Active but not sham tDCS significantly modified the negative attentional bias. These findings add evidence that a single tDCS session transiently induces potent changes in affective processing, which might be one of the mechanisms of tDCS underlying mood changes.
Background: Deficient cognitive control over emotional distraction is a central characteristic of major depressive disorder (MDD). Hypoactivation of the dorsolateral prefrontal cortex (dlPFC) has been linked with this deficit. In this study, we aimed to enhance the activity of the dlPFC in MDD patients by anodal transcranial direct current stimulation (tDCS) and thus ameliorate cognitive control. Methods: In a double-blinded, balanced, randomized, sham-controlled crossover trial, we determined the effect of a single-session tDCS to the left dlPFC on the cognitive control in 22 MDD patients and 22 healthy control subjects. To assess the cognitive control, we used a delayed response working memory task with pictures of varying content (emotional vs. neutral) presented during the delay period. Results: Emotional pictures presented during the delay period impaired accuracy and response time of patients with MDD, indicating an attentional bias for emotional stimuli. Anodal tDCS to the dlPFC was associated with an enhanced working memory performance both in patients and control subjects. Specifically in subjects with MDD, the attentional bias was completely abolished by anodal tDCS. Conclusions: The present study demonstrates that anodal tDCS applied to the left dlPFC improves deficient cognitive control in MDD. Based on these data, tDCS might be suitable to support the effects of behavioral training to enhance cognitive control in MDD.
reviewed the theoretical and technical aspects of cognitive therapy with depressed children and adolescents / the cognitive model offers a useful paradigm for the study of depression in this age group (PsycINFO Database Record (c) 2012 APA, all rights reserved)
The preliminary findings reported here suggest that the amygdaloid nuclear complex "may play a role in circulatory regulation as well as in emotional expression." Electrical stimulation of the region in 5 epileptic patients by means of implanted multiple electrodes produced circulatory changes, as well as overt and verbally reported behavior changes. 9 references. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Deep transcranial magnetic stimulation (TMS) is a technique of neuromodulation and neurostimulation based on the principle of electromagnetic induction of an electric field in the brain. The coil (H-coil) used in deep TMS is able to modulate cortical excitability up to a maximum depth of 6cm and is therefore able not only to modulate the activity of the cerebral cortex but also the activity of deeper neural circuits. Deep TMS is largely used for the treatment of drug-resistant major depressive disorder (MDD) and is being tested to treat a very wide range of neurological, psychiatric and medical conditions. The aim of this review is to illustrate the biophysical principles of deep TMS, to explain the pathophysiological basis for its utilization in each psychiatric disorder (major depression, autism, bipolar depression, auditory hallucinations, negative symptoms of schizophrenia), to summarize the results presented thus far in the international scientific literature regarding the use of deep TMS in psychiatry, its side effects and its effects on cognitive functions.