AN FMRI STUDY COMPARING PANIC DISORDER PATIENTS, REMITTED
PANIC PATIENTS AND CONTROLS IN RESPONSE TO FEARFUL FACES
April M. Unruh
B.A., California State University, Sacramento, 2009
THESIS
Submitted in partial satisfaction of
the requirements for the degree of
MASTER OF ARTS
in
PSYCHOLOGY
at
CALIFORNIA STATE UNIVERSITY, SACRAMENTO
FALL
2011
AN FMRI STUDY COMPARING PANIC DISORDER PATIENTS, REMITTED
PANIC PATIENTS AND CONTROLS IN RESPONSE TO FEARFUL FACES
A Thesis
by
April M. Unruh
Approved by:
__________________________________, Committee Chair
Dr. Jeffrey Calton
__________________________________, Second Reader
Dr. Richard Maddock
__________________________________, Third Reader
Dr. Kim Roberts
____________________________
Date
ii
Student: April M. Unruh
I certify that this student has met the requirements for format contained in the University
format manual, and that this thesis is suitable for shelving in the Library and credit is to
be awarded for the thesis.
__________________________, Graduate Coordinator
Dr. Jianjian Qin
Department of Psychology
iii
___________________
Date
Abstract
of
AN FMRI STUDY COMPARING PANIC DISORDER PATIENTS, REMITTED
PANIC PATIENTS AND CONTROLS IN RESPONSE TO FEARFUL FACES
by
April M. Unruh
Panic disorder (PD) is characterized by recurrent, unprovoked attacks of somatic and
cognitive symptoms of anxiety. While the causes of PD are not entirely understood, a
hyper-reactive fear circuit involving the amygdala has been implicated in many previous
studies of PD. Using functional magnetic resonance imaging, brain activity was evaluated
in response to fear faces in unmedicated PD patients, remitted PD patients, and controls.
Results revealed that PD patients showed increased amygdala response to fear faces
compared to the other groups. Additionally, greater activity was found in the prefrontal
cortex as well as greater connectivity between the amygdala and the periaqueductal gray
in panic patients compared to the other groups. These results support models of panic
disorder that include increased reactivity of the amygdala to fearful stimuli, however
since this was not found in remitted panic patients this does not appear to be a trait
feature of panic disorder.
_______________________, Committee Chair
Dr. Jeffrey Calton
_______________________
Date
iv
ACKNOWLEDGEMENTS
This thesis would not have been possible without the help and guidance of several
individuals who in one way or another have contributed and extended their valuable
assistance in the preparation and completion of this study. First, I would like to thank Dr.
Richard Maddock, University of California, Davis for allowing me to work with him on
this study. I would also like to thank Dr. Jeffrey Calton and Dr. Kim Roberts for their
help and support on this thesis and throughout my educational years at California State
University, Sacramento.
v
TABLE OF CONTENTS
Page
Acknowledgments......................................................................................................... v
List of Tables ............................................................................................................. vii
List of Figures ........................................................................................................... viii
Chapter
1. AN FMRI STUDY COMPARING PANIC DISORDER PATIENTS,
REMITTED PANIC PATIENTS AND CONTROLS IN RESPONSE TO
FEARFUL FACES …………………………… ............................……………… 1
Panic Disorder ................................................................................................... 1
Initial Studies on the Amygdala ....................................................................... 2
Amygdala Functions ......................................................................................... 4
Stress and Panic Disorder ................................................................................. 5
Serotonin and Panic Disorder .......................................................................... 6
GABA and Panic Disorder................................................................................ 8
Panic Disorder and Classical Conditioning ...................................................... 8
Amygdala and Fear Faces .............................................................................. 10
Overview of Study .......................................................................................... 12
2. METHODS ........................................................................................................... 14
Participants ...................................................................................................... 14
Materials and Procedure ................................................................................. 15
3. RESULTS ............................................................................................................. 19
4. DISCUSSION ....................................................................................................... 27
ROI Amygdala Analysis ...................................................................................... 27
Periaqueductal Gray............................................................................................. 28
Prefrontal Cortex ................................................................................................. 29
State Trait Implications........................................................................................ 31
Limitations ........................................................................................................... 31
References ................................................................................................................... 34
vi
LIST OF TABLES
Page
1. fMRI BOLD Activation in Panic Patients Compared to Control and Remitted
Panic Patients in Fear > Calm Contrast. ................................................................ 22
2. Brain Regions With Greater Connectivity With the Left or Right Amygdala
in Patients > Controls and Patients > Remitted in Fear > Calm Contrast .............. 24
vii
LIST OF FIGURES
Page
1. Mean Z-Scores of Amygdala Activity in Panic Patients, Remitted Panic
Patients and Controls While Viewing Fear Faces ................................................. 20
2. Coronal Plane Showing Significant Clusters of fMRI BOLD Activation
in the Patients > Controls, Fear > Calm Contrast .................................................. 21
3. Coronal Plane Showing Significant Clusters of fMRI BOLD Activation
in the Patients > Remitted, Fear > Calm Contrast ................................................. 21
4. Coronal Plane Showing Significant Activation in the Right Inferior Frontal
Gyrus, Right Middle Temporal Gyrus and Periaqueductal Gray Through
Connectivity Analysis (PPI) With the Right Amygdala in Patients > Remitted,
While Viewing Fear > Calm Faces ........................................................................ 26
5. Coronal Plane Showing Significant Activation in the Right Inferior
Frontal Gyrus Through Connectivity Analysis (PPI) With the Left Amygdala
in Patients > Remitted While Viewing Fear > Calm Faces ................................... 25
6. Coronal Plane Showing Significant Activation in the Periaqueductal
Gray and Superior Temporal Gyrus Through Connectivity Analysis (PPI)
With the Right Amygdala in Patients > Control, Fear > Calm Contrast ............... 23
7. Coronal Plane Showing Significant Activation in the Periaqueductal
Gray Through Connectivity Analysis (PPI) With the Left Amygdala in
Patients > Control, Fear > Calm Contrast .............................................................. 25
viii
1
Chapter 1
AN FMRI STUDY COMPARING PANIC DISORDER PATIENTS, REMITTED
PANIC PATIENTS AND CONTROLS IN RESPONSE TO FEARFUL FACES
Panic Disorder
Panic disorder is characterized by recurrent, unprovoked attacks of somatic and
cognitive symptoms of anxiety (American Psychiatric Association, 2000) that can be
intense enough to be mistaken for a heart attack. Since panic attacks cannot be predicted,
an individual may become stressed or anxious of when the next attack will occur
(American Psychiatric Association, 2000). While it is a common diagnosis that affects
about six million American adults (National Institute of Mental Health [NIMH], 2011),
not everyone who experiences a panic attack will develop panic disorder (National
Institute of Mental Health [NIMH], 2011). Although the prevalence of experiencing a
single panic attack is about 10-25%, the lifetime prevalence of panic disorder with or
without agoraphobia is about 3-4% (Dresler, Hahn, Plichta, Ernst, Tupak, et al., 2010).
Moderate to severe panic disorder is defined as having at least four panic attacks in a
four-week period, and severe panic disorder may be characterized by having at least four
panic attacks a week over a four-week period (Veale & Ashraph, 2011). Although
patients with panic disorder respond well to treatments such as cognitive behavioral
therapy (CBT) or pharmacological manipulation, researchers are still unclear as to which
neurological mechanisms are responsible for recurrent panic attacks (Maddock,
Buonocore, Kile, & Garrett, 2002).
2
Strong autonomic responses associated with a panic attack have led some
preclinical studies to focus attention on the neurological network that mediates endocrine,
autonomic and behavioral reactions during acute fear (Chechko, Wehrle, Erhardt,
Holsboer, Czisch, & Samann, 2009). Fear is defined as an unpleasant, often strong
emotion caused by anticipation or awareness of danger (Miller, Taber, Gabbard, &
Hurley, 2005), and this emotion is the hallmark symptom of panic disorder that has
guided researchers through various brain regions such as the amygdala, thalamic and
brainstem nuclei, medial hypothalamus, hippocampus, and cortical areas such as the
cingulate, medial prefrontal cortex (MFC), and insula (Chechko et al., 2009). Our current
understanding of the neural fear circuit has been based on animal studies, imaging studies
of human subjects with relevant brain lesions, and on human functional neuroimaging
(Miller, Taber, Gabbard, & Hurley, 2005). Previous studies have identified the amygdala
as being central to the generation of the fear response (Miller, Taber, Gabbard, & Hurley,
2005), and this structure will be the central focus of the current study.
Initial Studies on the Amygdala
The classic behavioral syndrome of monkeys with bilateral removal of temporal
lobes, including the amygdala, hippocampus, and surrounding cortical areas was studied
by Kluver and Bucy in 1939, and offered much insight to the study of fear (Davis, 1997).
The lesioned monkeys in this study developed “psychic blindness”, and would approach
animate and inanimate objects without hesitation, when normal monkeys would show
obvious signs of fear in the same situations (Davis, 1997). As described by Kluver and
Bucy,
3
The typical reaction of a “wild” monkey when suddenly turned loose in a
room consists in getting away from the experimenter as rapidly as
possible. It will try to find a secure place near the ceiling or hide in an
inaccessible corner where it cannot be seen. If seen, it will either crouch
and, without uttering a sound, remain in a state of almost complete
immobility or suddenly dash away to an apparently safer place. This
behavior is frequently accompanied by other signs of strong emotional
excitement. In general, all such reactions are absent in the bilateral
temporal monkey. Instead of trying to escape, it will contact and examine
one object after another or other animals…. Expressions of emotions, such
as vocal behavior, “chattering,” and different facial expressions, are
generally lost for several months. In some cases, the loss of fear and anger
is complete (Davis, 1997, p. 387).
The Kluver-Bucy syndrome provided some of the first evidence implicating the
amygdala as being partially responsible in the emotional expression of fear. Although the
Kluver-Bucy syndrome was originally studied in non-human primates, it provided the
groundwork and target areas for future research on humans. For example, further
contributions to the study of fear was provided by Adolphs (2005) during an investigation
of patient S.M, who was diagnosed with a rare condition involving bilateral calcification
confined to the amygdala (Urbach-Wiethe disease) (Davis, 1997). Without a normally
functioning amygdala, patient S.M was unable to identify the emotion of fear in pictures
of human faces, and therefore was unable to draw a fearful face, even though other
4
emotions such as happiness, sadness, anger and disgust were identified and drawn
normally (Davis, 1997). This study provided evidence that the amygdala was not needed
to recognize faces because patient S.M had no difficulty in identifying names of familiar
faces but was required to link visual representation of facial expressions in addition to
linking representations that constitute the concept of fear (Davis, 1997).
Subsequent studies of neurotoxic lesions on the monkey amygdala that destroyed
cells, but not connecting axons, found that monkeys maintained normal trait-like anxiety,
but acute fear and vigilance to threat was diminished (Rosen & Donley, 2006), which
suggested that the purpose of the amygdala was to evaluate information related to threat
and danger. Neuroimaging studies have provided support to this theory by showing that
fearful faces which contain ambiguous information related to threat will produce greater
amygdala activation, when compared to less ambiguous facial expressions such as happy
or angry faces (Rosen & Donley, 2006). Researchers have also suggested that both
positive and negative stimuli could be relayed to the amygdala through various neural
connections to assess the threat potential of the stimuli (Rosen & Donley, 2006). In a
normally functioning amygdala, this neural fear circuit is hypothesized to be important to
maintain vigilance to potentially threatening situations; however, malfunctioning of this
fear circuit could contribute to the pathogenesis of panic disorder.
Amygdala Functions
Through analysis of the volume of different components of the amygdala there is
evidence that different divisions of the amygdala come together to form one structure
(Aggleton & Saunders, 2000). Anatomically, the amygdala includes two groups of nuclei
5
identified as being important in the neurological fear circuit: the corticomedial nuclear
group, including the central nucleus (CeA), and the basolateral nuclear group (BLA)
(Hayano et al., 2009). These nuclei are directly related to amygdala activity through
sensory input and motor output, and are important for learning and memory of fear and
the behavioral responses to fear (Rosen, & Donley, 2006; Hayano et al., 2009). Past
studies have suggested that the BLA evaluates sensory information such as emotional
valence, vigilance and arousal, and then subsequently influences connecting neural
structures to respond to fearful stimuli (Rosen & Donley, 2006; Hayano et al., 2009).
When potentially threatening stimuli are sensed, as indicated by amygdala hyperactivity,
neural networks from the CeA respond to the negative stimuli by activating the
autonomic nervous system to respond to the potential threat or danger (Rosen & Donley,
2006; Hayano et al., 2009). Consequently, the autonomic nervous system turns on the
fight or flight response of the sympathetic nervous system and decreased parasympathetic
activity concurrently.
Stress and Panic Disorder
There are various neurobiological hypotheses of the pathogenesis of panic
disorder (PD), but the true causes still remain unknown. Consideration should also be
given to the premise that no single hypothesis, model, or proposed “panic circuitry” will
explain the development of panic disorder in all patients (Coplan & Lydiard, 1998). A
recent theory, however, implicates chronic stress as being a major contributor to panic
disorder. Studies in support of this theory found negative effects of stress on
neuroanatomical fear regions such as the amygdala (Shekhar et al., 2005), and could
6
explain why many patients experience their initial panic attack within a few months after
experiencing a major stressful event (Farravelli & Pallanti, 1989). Evolutionary
hypotheses of stress suggest that it functions as a catalyst to a variety of hormonal and
behavioral responses that enable an organism to adapt to new environmental pressures
(Shekhar et al., 2005). However, chronic stress might lead to psychiatric disorders, such
as anxiety and panic disorder, by altering the functioning of synapses in the nervous
system (Shekhar et al., 2005). Corticotrophin-releasing factor (CRF), a 41 amino acid
neuropeptide, has been identified as a key neuropeptide that is responsible for initiating
many of the endocrine, autonomic, and behavioral responses to various stressors
(Shekhar et al., 2005). Furthermore, neuroanatomical studies have identified the
amygdala as a major source of CRF-containing neurons (Shekhar et al., 2005). Chronic
activation of CRF-containing neurons in the amygdala has resulted in synaptic plasticity
and contributed to hypersensitive amygdala responses (Shekhar et al., 2005). Shekhar
hypothesizes that the neural fear circuit involved in normal vigilance response can
transition to pathological anxiety leading to panic disorder. While full explanation of
CRF’s role in amygdala response is beyond the scope of this paper, the reader is
encouraged to see Shekhar et al. (2005) for more information.
Serotonin and Panic Disorder
Serotonin, or 5-hydroxytrptamine (5-HT), is an important neural chemical for
mood regulation, and has also become a target for investigating panic disorder. In
particular, dysfunction of serotonin modulation in panic disorder became suspect when
clinical studies found that selective serotonin reuptake inhibitors (SSRIs) were effective
7
treatment for panic disorder (Coplan & Lydiard, 1998). Furthermore, genetic testing on
panic disorder with agoraphobia patients revealed a possible genetic defect that increased
the expression of serotonin autoreceptors, causing a reduction in serotonin transmission
(Rothe et al., 2004). A positron emission tomography (PET) study revealed a significant
reduction in distribution volumes of a selective 5-HT1A radioligand in patients with panic
disorder (Neumeister et al., 2004). Low serotonin levels may contribute to over reaction
to harmful stimuli, due to diminished inhibitory modulation of excitatory sensory
information, in addition to allowing innocuous stimuli to be processed by the amygdala
as emotionally salient (Cools, Calder, Lawrence, Clark, Bullmore, & Robbins, 2005).
Animal research has demonstrated that 5-HT facilitating drugs can calm the aversive
effects of brain stimulation, and can also reduce the acquisition of fear conditioning
(Cools, Calder, Lawrence, Clark, Bullmore, & Robbins, 2005). Another study showed
that tryptophan (the amino acid precursor to 5-HT) could reduce conditioned freezing in a
fear-conditioning model (Inoue, Koyama, & Yamashita, 1993), which implied that
amygdala responsiveness might be modulated by serotonin.
The role of serotonin in panic disorder can be further understood by examining
the functional subdivisions of the brain 5-HT systems, as well as their position in “panic
circuitry.” The amygdala receives many serotonergic inputs from the raphe nucleus in the
pons and midbrain, and several 5-HT receptor subtypes exist within the amygdala (Cools
et al., 2005). The rostral raphe 5-HT system contains two functionally distinct nuclei, the
dorsal raphe nuclei (DRN) and median raphe nuclei (MRN), that provide almost all
serotonin to the forebrain (Coplan & Lydiard, 1998). Studies have suggested that the
8
opposing as well as overlapping functions of these nuclei within the panic circuitry
modulate serotonin, as well as influence the amygdala’s activation to various stimuli.
Dysregulation of the feedback system between the MRN and DRN in the limbic
(amygdalohippocampal), prefrontal cortex and rostral midbrain may manifest as
pathological anxiety (See Coplan & Lydiard, 1998 for a review).
GABA and Panic Disorder
Gamma-aminobutyric acid (GABA) is another important chemical in the brain
that helps regulate neuronal activity and has been theorized to play a role in panic
disorder symptoms. Studies have found that patients with anxiety disorders showed a
deficiency in the GABA system, either in reduced receptor sensitivity or a deficit in the
neurotransmitter (Kasper & Resinger, 2001). Dysfunction of the GABA system is
implicated in the pathogenesis of panic disorder since animal studies have shown that
abnormalities in the regulation of GABA lead to higher fearfulness and decreased
sensitivity to benzodiazepines (Stork et al., 2000). For a review on GABA and anxiety
see File (2000).
Panic Disorder and Classical Conditioning
The classic work of Pavlov combined with recent studies on the amygdala have
provided additional context to understand the suggested neural mechanisms related to
panic disorder. Activation of the amygdala is shown to be involved in learned fear
responses (Miller, Taber, Gabbard, & Hurley, 2005). The central nucleus, in particular, is
thought to be the primary efferent site of the amygdala in eliciting conditioned fear
responses (Shekhar et al., 2005). Additionally, connections between the amygdala and the
9
hippocampus are subsequently thought to be important for the formation of fear
memories (Miller et al., 2005), which may result in an exaggerated amount of long-term
fearful memories in cases where the amygdale is hyperactive. However, studies have
shown that disrupting the function of the BLA can inhibit the acquisition of conditioned
fear/negative affect responses (Shekhar et al., 2005).
Emotion related information received in the hippocampus from the amygdala is
believed to link information about physical contexts with emotional context (Miller et al.,
2005), especially in the case of posttraumatic stress disorder (PTSD). For example, the
basic conception of panic disorder is fear of experiencing a panic attack along with
anticipatory anxiety (Hayano et al., 2009). Through the function of the amygdala, fear
and anxiety are inseparably connected and subsequently, the sense of fear is kept in longterm memory storage (Hayano, et al., 2009). It has also been suggested that fear related
memories might remain salient for long periods of time in panic disorder due to lack of
extinction. Studies of extinction in normally functioning brains show that the prefrontal
cortex (PFC) and hippocampus work together in the process of relearning stimuli that
used to predict threat (Shin & Liberzon, 2010). In other words, extinction retrains the
brain to respond with calm emotion to a previously fearful memory. Patients with anxiety
disorders may continue to have exaggerated fear, anxiety and distress because fear
responses fail to extinguish or extinction learning was not effective even when
conditioned stimulus no longer predicted unconditioned response (Shin & Liberzon,
2010).
10
Amygdala and Fear Faces
Numerous studies on the amygdala’s unique function of evaluating possible
threat-related stimuli found greater activation to fear faces in comparison to other
emotional expressions (Rosen & Donley, 2006). The visual distinction between fear faces
and other emotional expressions could be related to the visibility of fearfully widened
eyes (Gamer & Buchel, 2009). Although patient S.M was unable to discriminate fear
faces from other emotional expressions, further studies by Adolphs (2005) found that
patient S.M’s symptoms were related to her lack of spontaneous gaze fixation on the eye
region of facial stimuli. When patient S.M was given explicit instructions to look at the
eyes, her ability to identify fearful faces was restored (Gamer & Buchel, 2009). Other
studies corroborated Adolphs’ finding, which found that the amygdala was involved in
reflexive gaze initiation toward fearfully widened eyes in healthy participants (Gamer &
Buchel, 2009). However, conflicting studies found that the amygdala was still activated
by fear faces, even when the participants were unaware of the fear face through use of a
masking protocol (Rosen & Donley, 2006).
Facial expressions are important nonverbal displays of emotion that have been
used in neuroimaging studies to evaluate neural processing in healthy participants
(Gamer & Buchel, 2009; Fusar-Poli et al., 2008), or patients with various anxiety
disorders (Stein, Simmons, Feinstein, & Paulus, 2007), but few studies have used panic
disorder patients. Costafreda et al. (2008) used a meta analysis to examine amygdala
activation in healthy participants in response to fearful faces and found that emotional
stimuli were more likely to result in amygdala activation than neutral stimuli. Fusar-Poli
11
et al. (2009) also found that fearful faces significantly increased neural activation in the
bilateral amygdala, fusiform gyrus, right cerebellum, left inferior parietal lobe, left
inferior frontal and right medial frontal gyrus. Another fMRI study tested the reliability
of amygdala activation in response to fearful facial expressions in healthy participants
and found high reliability over extended periods of time (Johnstone, Somerville,
Alexander, Oakes, Davidson, Kalin & Whalen, 2005). One previous study compared
panic disorder patients with controls in response to fearful and neutral facial expressions
and found unusual results with controls producing greater amygdala activation than
patients while viewing fearful faces (Pillay et al., 2006), but the task itself could have
influenced these results. The participants in the study were asked to identify the facial
affect being viewed, which may have affected the way emotions were processed (Pillay et
al., 2006). Previous studies using a similar paradigm in normal subjects also found that
tasks requiring conscious evaluation of the fear face stimuli, as in the study by Pillay and
colleagues (2006), lead to a relative decrease in amygdala activation (Costafreda et al.,
2008). The inhibition of amygdala activity may be mediated by increased recruitment of
the prefrontal cortex (Miller et al., 2005; Costafreda et al., 2008), which may help
individuals stay on task even in the presence of emotional stimuli that could impair task
performance. Studies have also suggested that identification of a fearful facial expression
could be considered a complex task for someone with panic disorder, which could
influence the neural connections between the prefrontal cortex and amygdala during the
task by giving top down processing greater control over the emotional stimuli (Miller et
al., 2005).
12
Overview of Study
As previously mentioned, a common neuroimaging method for examining
neurological responses during emotional perception involves the use of facial images
(Pillay, Gruber, Rogowska, Simpson, & Yurgelun-Todd, 2006). However, relatively few
neuroimaging studies have used a fear face paradigm with panic disorder patients to
examine the fear circuit. The purpose of this study was to collect functional magnetic
resonance imaging (fMRI) data while participants viewed fear faces, calm faces, and
shapes. Two comparisons were used: 1) fear faces compared to calm faces, and 2) calm
faces compared to shapes. The former comparison is the primary focus of the study and is
intended to assess the brain responses specifically to fear expressions while controlling
for the social stimulus of a human face. The latter comparison is intended to assess brain
responses to the social stimulus of a human face while controlling for visual processing
of non-facial information. The design of this study was intended to look for a reliable
amygdala response by asking the participants to identify the gender of the participants to
ensure that their attention was on the facial expressions. The use of a simple task was
intended to prevent hypoactivation of the amygdala as a result of enhanced top down
processing. It was predicted that symptomatic panic disorder patients would show greater
amygdala activation than controls while looking at fear faces compared to calm faces. If
exaggerated reactivity of the amygdala to fear related stimuli is a trait feature of panic
disorder, then it should also be seen in the remitted panic disorder patients during the
task. If exaggerated reactivity of the amygdala to fear-related stimuli only occurs during
symptomatic periods of the disorder, then it should not be observed in remitted panic
13
disorder patients during the task. It was predicted that the three groups would not differ in
amygdala activation while looking at calm faces compared to shapes.
Functional connectivity analysis was also incorporated as the secondary goal of
this study to identify the involvement of different neural regions and networks in the
processing of threat related stimuli (fear faces) in panic disorder patients and controls.
14
Chapter 2
METHODS
Participants
This study included 18 unmedicated, symptomatic patients (14 female, 4 male)
with panic disorder, 14 remitted panic disorder patients (9 female, 5 male), and 26
matched controls (19 female, 7 male). The age of participants ranged from 22 -54 (M =
37.7, SD = 9.43). Participants also had between 12 and 20 years of education (M = 15.7,
SD = 1.74). Patients with panic disorder were recruited through advertisements in the
Sacramento area. All participants were screened by a telephone interview and then
evaluated by Dr. Maddock through a clinical interview as well as the Structural Clinical
Interview for DSM-IV (SCID). The SCID was used to assess anxiety, mood, psychotic
and substance abuse disorders, and to evaluate panic frequency over the previous two
months. Remitted patients included in this study were required to have a primary
diagnosis of panic disorder, but must have been panic free for four months. These
patients may have been currently using an SSRI or could have been medication-free.
Exclusion criteria included the presence of a mood disorder, history of psychotic or
bipolar disorder, history of claustrophobia, history of substance abuse or dependence
within five years, having current medical conditions or medications affecting metabolic,
visual, respiratory, cardiovascular, emotional, or central nervous system function, and age
less than 18 or greater than 55 years. All participants were asked to sign a written consent
form with a description of the study, risks of involvement, and scanning procedures.
Additionally, participants were pre-screened for any contraindications for an MRI, such
15
as any surgical implants or metal fragments. Groups were matched on age, gender,
education, caffeine consumption and time of scanning appointment. Additionally, the
experimenter knew group membership at the time of scanning.
Materials and Procedure
The procedures of this study were reviewed and approved by the human subjects
Institutional Review Board of the University of California, Davis. All participants were
asked to undergo an fMRI scan while viewing blocks of fearful faces, calm faces, and
shapes. Visual stimuli were presented on a screen, which was viewed through a mirror
mounted on top of the head coil. Thirty-six fearful facial images and 36 calm faces were
obtained from the MacBrain Face Stimulus set (MacArthur Research Network on Early
Experience and Brain Development, 2002). Shapes used in the task were created by
rearranging the pixels of the facial stimuli until they were unrecognizable as faces. These
scrambled images were then rendered into either rectangular or oval shapes. Half of the
facial stimuli were female faces, and half of the shapes were oval. All images were
matched for size and luminance. Each stimulus was presented for 2700 ms with a 300 ms
interstimulus interval (ISI), and each stimulus type was in an 18-second block of six
stimuli. There were six blocks of each type of stimulus: six blocks of fear faces, six
blocks of calm faces, and six blocks of shapes. A delay of two seconds occurred between
each block. The stimulus order for shapes (S), fear faces (F), and calm faces (C) for all
participants were: Sx,S,F,C,S,C,F,Sx,S,C,F,S,F,C,S,C,F,Sx,S,F,C. The Sx blocks
represent blocks of shape stimuli that were excluded from the analysis in order to balance
for task-switching effects across stimulus types. For each stimulus, participants pressed a
16
button to appropriately identify the gender of the face, or the type of shape being viewed.
At the end of the fMRI scan, subjects were also asked to rate all facial stimuli for valence
and arousal using the 9-point self-assessment Manikan scale (Lang, 1980). Before
scanning took place, participants were exposed to a mock scanner to attenuate any fears
of being in an fMRI scanner.
Scanned images were obtained using 1.5 Tesla scanner using a T2*-weighted
gradient recalled echo planar imaging (EPI) pulse sequence (TR=2000ms; effective
TE=40 ms; flip angle=90 degrees; matrix = 64 x 64; FOV = 22 cm; thickness = 5 mm
with no gap; 24 axial slices).
Obtained images were reconstructed using a Fourier transform-based algorithm
with removal of N/2 ghost artifacts. Individual subject data were analyzed using
Statistical Parametric Mapping (SPM) and MEDx software (Sensor Systems, Inc.,
Sterling, VA). Data were motion detected and corrected, high pass filtered (period < 180
seconds), and Z-score maps were created for two contrasts (fear versus calm and calm
versus shapes) using a canonical hemodynamic response (lag = 4 seconds). Individual
statistical maps were spatially transformed (by sinc interpolation) into Montreal
Neurological Institute (MNI) atlas space (SPM99 template), resliced into 2 mm isotropic
voxels. An a priori, anatomical region of interest was defined for the left and right
anatomical amygdala using the Talairach daemon (Talairach), with Talairach coordinates
transformed into MNI space using the non-linear algorithm of Lacadie et al. (2008).
Averaged Z-scores for the two contrasts of interest (fear vs. calm, and calm vs. shapes)
were calculated across this ROI using MEDx software analysis package (Sensor Systems,
17
Inc., Sterling, VA). Statistical analysis of amygdala activity in response to visual stimuli
utilized data from the left and right amygdala to represent total amygdala activity. SPSS
software (SPSS 19.0 for Mac, SPSS software) was used to run a one-way analysis of
variance (ANOVA) on total extracted amygdala ROI time series data for each participant.
In addition, a whole brain analysis was conducted to investigate differences
between the three groups. Data was spatially smoothed (8mm FWHM) and SPM group
maps were generated using a random-effects model within SPM with individual contrast
maps (Holmes & Friston, 1998) using a threshold of p  0.0001 and k (number of voxels
in a contiguous cluster) = 25.
A psycho-physiological interaction (PPI) analysis was conducted to identify
significant differences in functional connectivity with the amygdala based on the task
(fearful faces vs. calm faces) (Gitelman, Penny, Ashburner, & Friston, 2003). Since
regions of the brain may show greater connectivity during a task, this analysis examined
regional covariance based on the task. The PPI analysis used a design matrix, which
incorporated the psychological variable (task), the time course of the seed region
(physiological variable) and the interaction between the two variables. Directionality of
the correlation could not be obtained through this analysis (Gitelman et al., 2003).
An eight millimeter (mm) radius sphere around the left amygdala (-24, -2, -22)
and right amygdala (24, -2, -22) was defined to extract activation from these two seed
ROIs (left and right amygdala). A model was created using the general linear model
(GLM) for each seed region individually, which included the psychological condition
(”fear versus calm” contrast), the time course of the seed region (left and right amygdala)
18
and the interaction term. The interaction term was intended to identify region-region
interactions that varied depending on the task (fear vs. calm faces). The interaction effect
was entered into a 2nd level random effects analysis to determine whether task dependent
functional connectivity differed by group (patients vs. controls, patients vs. remitted,
remitted vs. controls). Between-group analyses were performed to observe inter-regional
differences. The SPM group difference maps were generated using a random-effects
model within SPM using a threshold of p  0.001 and k (number of voxels in a
contiguous cluster) = 10.
19
Chapter 3
RESULTS
A one way ANOVA was used to compare amygdala ROI activity between panic
patients, remitted panic patients and controls in the fearful versus calm faces contrast,
F(2, 57) = 4.11, p = .022,  = .10, and calm faces versus shapes contrast, F(2, 57) = .67, p
= .516. In the fearful > calm faces contrast, panic disorder patients (M = 1.08, SD = 1.00)
demonstrated significantly greater amygdala activity than controls (M = .37, SD = .77)
and remitted panic patients (M = .25, SD = 1.12) (Figure 1). No differences were found
between the groups in the calm faces versus shapes contrast.
20
Figure 1. Mean Z-Scores of Amygdala Activity in Panic Patients, Remitted Panic
Patients and Controls While Viewing Fear Faces.
Whole-brain analysis was used to compare differential brain activation between
the three groups (panic patients, remitted panic and controls) on the fearful > calm face
contrast. Significant voxel clusters that met a threshold of p  0.001 and k (number of
contiguous voxels) = 25 were reported in Table 1. FDR correction, which is commonly
used in neuroimaging analysis and has been shown to be effective in controlling for alpha
inflation (Genovese, Lazar, & Nichols, 2001) was used to interpret the results. Compared
to controls, patients with panic disorder demonstrated significantly greater activation of
the medial frontal gyrus, superior frontal gyrus, cingulate gyrus, inferior frontal gyrus,
precuneus and cuneus on exposure to fear faces relative to calm faces (Figure 2). Patients
21
with panic disorder also showed significantly greater activation of the medial frontal
gyrus than remitted panic patients on exposure of fear faces compared to calm faces
(Figure 3). There were no significant differences found between remitted panic patients
and controls on exposure to fear faces compared to calm.
Figure 2. Coronal Plane Showing Significant Clusters of fMRI BOLD Activation in the
Patients > Controls in Fear > Calm Face Contrast.
Figure 3. Coronal Plane Showing Significant Clusters of fMRI BOLD Activation in the
Patients > Remitted, Fear > Calm Face Contrast.
22
Table 1. fMRI BOLD Activation in Panic Patients Compared to Control and Remitted
Panic Patients in Fear > Calm Contrast.
Talairach
Cluster Level
Location
FDR corrected
KE
Coordinates
Z-Score
x
y
z
Medial Frontal Gyrus
3
54
25
5.15
Superior Frontal Gyrus
-28
46
31
4.76
Anterior Cingulate Gyrus
10
17
35
4.72
Inferior Frontal Gyrus
32
17
-10
4.74
45
18
-6
4.72
34
25
5
3.65
8
-61
32
4.11
4
-74
35
3.63
Cuneus
0
-67
30
3.80
Medial Frontal Gyrus
-10
37
27
4.19
0
50
30
3.93
Patient > Control
0.000
0.002
0.038
3227
638
319
Precuneus
Patient > Remitted
0.012
629
The psycho-physiological interaction was used to evaluate differences in brain
connectivity between panic patients, healthy controls, and remitted panic patients. PPI
analyses for patients > controls (results shown in Table 2) showed that activity in the left
and right amygdala was accompanied by greater task-dependent (Fear > Calm) functional
23
interaction with the periaqueductal gray in the patient group (Figures 6 and 7). The PPI
analyses for patients > remitted revealed that the left amygdala had significantly greater
task-dependent covariance with the right inferior frontal gyrus in symptomatic patients
than remitted patients (Figure 5). The right amygdala had significantly more covariance
with the right middle temporal gyrus, right inferior frontal gyrus, and the periaqueductal
gray in the symptomatic than the remitted panic disorder patients (Figure 4). Overall, the
analysis of task-dependent connectivity during the fear vs. calm task revealed that panic
patients had greater connectivity than the other two groups between the amygdala and the
periaqueductal gray, and that panic patients had greater connectivity than remitted
patients in the inferior frontal gyrus and temporal gyrus.
Figure 6. Coronal Plane Showing Significant Activation in the Periaqueductal Gray and
Superior Temporal Gyrus Through Connectivity Analysis (PPI) With the Right
Amygdala in Patients > Control, Fear > Calm Contrast.
24
Table 2. Brain Regions With Greater Connectivity With the Left or Right Amygdala in
Patients > Controls and Patients > Remitted in Fear > Calm Contrast.
Talairach
Cluster Level
Coordinates
FDRSeed
Corr
KE
Location
x
y
z
Z-Score
Patient > Control
L.Amyg
0.729
48
Periaqueductal Gray
-2
-32
-14
4.52
R.Amyg
0.750
16
Periaqueductal Gray
-5
-33
-6
3.69
56
-3
-5
3.65
Patient > Remitted
L.Amyg
0.555
28
Inferior Frontal Gyrus
42
17
-11
3.44
R.Amyg
0.330
77
Middle Temporal Gyrus
46
6
-18
3.95
38
-11
-16
3.26
38
-3
-13
3.23
Inferior Frontal Gyrus
34
7
-13
3.64
Periaqueductal Gray
-3
-35
-6
3.55
-13
-39
-13
3.22
25
Figure 7. Coronal Plane Showing Significant Activation in the Periaqueductal Gray
Through Connectivity Analysis (PPI) With the Left Amygdala in Patients > Control, Fear
> Calm Contrast.
Figure 5. Coronal Plane Showing Significant Activation in the Right Inferior Frontal
Gyrus Through Connectivity Analysis (PPI) With the Left Amygdala in Patients >
Remitted While Viewing Fear > Calm Faces.
26
Figure 4. Coronal Plane Showing Significant Activation in the Right Inferior Frontal
Gyrus, Right Middle Temporal Gyrus and Periaqueductal Gray Through Connectivity
Analysis (PPI) With the Right Amygdala in Patients > Remitted, While Viewing Fear >
Calm Faces.
27
Chapter 4
DISCUSSION
The primary purpose of this study was to use neuroimaging to test the hypothesis
that panic disorder patients exhibit hyper-reactive responses to fear faces in the amygdala
and other brain regions and to examine the functional connectivity of the amygdala
during viewing of facial stimuli in panic patients. The secondary purpose of the study
was to examine whether hyper-reactive brain responses to fear faces is a state or trait
characteristic of patients with a lifetime history of panic disorder. This study examined
the differential neural activation in panic patients relative to controls and remitted panic
patients while viewing fearful faces compared to calm faces. The results confirmed the
hypothesis of increased amygdala activation to fearful faces in panic patients relative to
controls. In response to fear faces, panic patients also demonstrated greater neural
activation in regions of the prefrontal cortex and precuneus in addition to greater
connectivity between the amygdala and spatially distinct regions such as the prefrontal
cortex and periaqueductal gray relative to controls and remitted panic patients.
Amygdala ROI Analysis
As previously mentioned, past studies on healthy participants have found
increased activation in the amygdala in response to fear faces (Fusar-Poli et al., 2008;
Costafreda et al., 2008; Johnston et al., 2005). Our study directly compared activation
differences to fear faces between healthy participants and unmedicated panic patients and
found exaggerated amygdala activity in panic patients relative to controls and remitted.
The amygdala has been implicated in many studies to be the source of conditioned fear
28
(Davidson, 2002; Davis, 1997) and to have an essential role in fear processing in general.
Accordingly, our prediction that patients would demonstrate increased amygdala activity
in response to fearful stimuli relative to controls was confirmed by our findings. One
previous study using a small sample of medicated panic patients and controls in response
to fearful faces found opposite results with greater amygdala activation in controls than
patients (Pillay et al., 2006). Medication, especially SSRI’s, can significantly affect
neural activation, and has been found to reduce recognition and response to fearful faces
in normal volunteers (Harmer, Shelley, Cowen & Goodwin, 2004). This may explain the
negative findings of the Pillay et al. (2006) study.
Periaqueductal Gray
The amygdala is an important region of the brain implicated in the development
of conditioned fear, but this region is only a small portion of the entire fear circuit, which
includes brainstem, midbrain, diencephalic nuclei and the prefrontal cortex (Coplan &
Lydiard, 1998). Through psycho-physiological interaction (PPI) analysis, we evaluated
regions of greater connectivity with the amygdala during our task. Panic patients showed
greater connections between the amygdala and periaqueductal gray (PAG) than remitted
panic patients or controls, which is in agreement with animal models of panic disorder
that posit a primary role for the dorsal PAG (Coplan & Lydiard, 1998; Del-Ben & Graeff,
2008). Many past studies on the PAG focused on animal models and discovered that
through electrical and chemical stimulations of the PAG, urgent defensive reactions such
as freezing, fight or flight were observed (Del-Ben & Graeff, 2008). These results
provided strong evidence to the existence of approach and avoidance defense systems
29
related to anxiety and panic disorder (MacNaughton & Corr, 2004), which may have
encouraged neuroimaging studies to further decode some of the mysteries of the PAG
region. One study examined the spatial imminence of threat through an active avoidance
paradigm, in which healthy volunteers were pursued through a maze by a virtual predator
with the ability to chase and inflict harm when the participant was virtually captured
(Mobbs et al., 2007). Neuroimaging results of the virtual predator study revealed
increased activity in the PAG when the virtual predator loomed close, and when a high
degree of pain was anticipated (Mobbs et al., 2007). Furthermore, the PAG activity was
correlated with increased dread and decreased confidence of escape (Mobbs et al., 2007),
which are similar to symptoms experienced in panic disorder. Our study revealed
important information regarding connectivity between the amygdala and PAG during
exposure to fear faces, which ultimately suggests that PAG may play an important role in
the psychopathology of panic disorder. Future studies should focus exclusively on the
PAG to compare activation between panic patients and controls. Furthermore, it would
also be beneficial in future studies to examine the influence of neural activity from the
PAG with other brain regions during exposure to negative stimuli using dynamic causal
modeling.
Prefrontal Cortex (PFC)
Whole-brain analysis of group differences upon exposure to fearful faces revealed
significantly greater neural activity in several regions of the prefrontal cortex, including
the medial frontal gyrus (MFG), superior frontal gyrus (SFG), anterior cingulate cortex
(ACC), and inferior frontal gyrus (IFG) in panic patients relative to controls.
30
Additionally, the MFG had significantly greater activation in panic patients compared to
remitted panic patients in the fearful versus calm face contrast. These findings, in
addition to the greater connectivity between the PFC and amygdala found in the PPI
analysis suggested strong involvement of the PFC in panic disorder.
Although the amygdala receives direct sensory input from the brainstem
structures, including the PAG, enabling a rapid response to potentially threatening
stimuli, it also receives afferent connections from other regions of the cortex specialized
to process and evaluate sensory information (Gorman et al., 2000). Neurocognitive
malfunctions in these cortical pathways could lead to misinterpretation of sensory
information, a common symptom of panic disorder, resulting in a hyperactive fear
network through misguided excitatory input to the amygdala. Furthermore, panic patients
may have a sensitized brain network that has been conditioned to respond to negative
stimuli. Over time, the regions of the fear network may become stronger or weaker
(Gorman et al., 2000) and may explain the activation differences found in our study.
Panic disorder is associated with malfunctioning emotional processes, with
excessive fears concerning future panic attacks or worries about the implication of the
attack, such as losing control. Increased attention to sensation and stimuli is also a
hallmark symptom of panic disorder, and is associated with increased activation in the
prefrontal cortex (PFC) and anterior cingulate cortex (ACC), as reflected in various
neuroimaging studies using negative stimuli (Seitz, Franz, & Azari, 2009). Furthermore,
other studies have found that unmedicated panic patients demonstrate increased
attentional bias towards negative facial stimuli (Reinecke, Cooper, Favaron, Massey-
31
Chase, & Harmer, 2011). Our study revealed greater dorsal ACC activity in patients
relative to controls in response to fearful faces. This might reflect the tendency for panic
patients to show enhanced attentional focus to the fear-related facial stimuli.
State-Trait Implications
Remitted panic patients who have been panic free for at least four months served
as a way to compare neural activation differences with symptomatic patients and to
evaluate whether specific patterns of brain responses are state or trait characteristics of
panic disorder. Our findings in symptomatic panic disorder patients showed hyperreactivity to fear faces in the amygdala and parts of the prefrontal cortex, and increased
connectivity between the amygdala and the PAG. However, our findings in remitted
panic disorder patients suggest that these abnormalities are state characteristics of
patients with panic disorder. Symptomatic panic patients showed significantly more
amygdala activation and significantly greater connectivity between the amygdala and the
PAG than remitted patients. Furthermore, remitted patients did not differ from control
subjects in any contrasts. Implications of these findings suggest that hyper-reactivity of
the fear circuit observed in symptomatic patients is likely to be found only in patients
who currently experience panic attacks and activation within the fear circuit in response
to negative stimuli could decrease if panic attacks are ceased for a period of at least four
months.
Limitations
A significant limitation of our state-trait conclusions is that this was a crosssectional study rather than a longitudinal study. It is possible that the remitted panic
32
disorder patients represent a less severely ill subset of panic disorder patients than the
symptomatic patients. If so, it may be that the exaggerated amygdala reactivity and
connectivity with the PAG would be found to persist even after the symptomatic panic
disorder patients were in remission. Only a longitudinal study can answer this question
unambiguously.
Our study incorporated the use of statistical parametric mapping to examine brain
activation differences between groups through broad surveying techniques not available
with traditional region of interest techniques (Genovese et al., 2001). This allowed
detection of changes in areas that might not otherwise be found. However, statistical
parametric mapping has limitations related to problems with multiple comparisons related
to the statistical comparison of large numbers of voxels between the groups (Genovese et
al., 2001). Although we used FDR correction (Genovese et al., 2001) to prevent alpha
inflation, our whole-brain group analysis results could still reflect a type I or type II error.
With a small sample size we were unable to test for the effects of gender on
neural activation in panic disorder. One study examined the differences in cortical
activation to negative stimuli between genders and found increased amygdala activation
in women relative to men (Ohrmann et al., 2010). Since most of our subjects were
female, our results may not generalize to males with panic disorder.
In summary, we investigated fMRI BOLD responses to compare the differences
between symptomatic panic patients, remitted panic patients and controls in response to
negative stimuli (fearful faces). Our findings provide evidence of exaggerated brain
responses to fear-related stimuli in symptomatic panic patients compared to control
33
subjects and to remitted panic patients. With greater connectivity between the amygdala
and PAG in symptomatic panic patients, they are more likely to react negatively to
fearful stimuli than healthy controls. Furthermore, greater activation of the prefrontal
cortex with little or no inhibition on the fear network may reflect a disturbance in top
down modulation of emotions contributing to the generation of excessive fears
experienced by panic patients. Exaggerated activation within the fear circuit observed in
symptomatic panic patients might be associated with enhanced fear conditioning to
negative stimuli and could explain the list of phobias experienced by panic patients.
Finally, the exaggerated brain responses to fear faces observed appears to be a statespecific feature of symptomatic panic disorder, as this pattern was not present in remitted
panic disorder patients. However, in light of the limitations of this study, further studies
are needed to confirm these conclusions.
34
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