Activation of anterior paralimbic structures during guilt-related script-driven imagery.
ABSTRACT Several recent neuroimaging studies have examined the neuroanatomical correlates of normal emotional states, such as happiness, sadness, fear, anger, anxiety, and disgust; however, no previous study has examined the emotional state of guilt.
In the current study, we used positron emission tomography and the script-driven imagery paradigm to study regional cerebral blood flow (rCBF) during the transient emotional experience of guilt in eight healthy male participants. In the Guilt condition, participants recalled and imagined participating in a personal event involving the most guilt they had ever experienced. In the Neutral condition, participants recalled and imagined participating in an emotionally neutral personal event.
In the Guilt versus Neutral comparison, rCBF increases occurred in anterior paralimbic regions of the brain: bilateral anterior temporal poles, anterior cingulate gyrus, and left anterior insular cortex/inferior frontal gyrus.
These results, along with those of previous studies, are consistent with the notion that anterior paralimbic regions of the brain mediate negative emotional states in healthy individuals.
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ABSTRACT: Neuroimaging studies of language have typically focused on either production or comprehension of single speech utterances such as syllables, words, or sentences. In this study we used a new approach to functional MRI acquisition and analysis to characterize the neural responses during production and comprehension of complex real-life speech. First, using a time-warp based intrasubject correlation method, we identified all areas that are reliably activated in the brains of speakers telling a 15-min-long narrative. Next, we identified areas that are reliably activated in the brains of listeners as they comprehended that same narrative. This allowed us to identify networks of brain regions specific to production and comprehension, as well as those that are shared between the two processes. The results indicate that production of a real-life narrative is not localized to the left hemisphere but recruits an extensive bilateral network, which overlaps extensively with the comprehension system. Moreover, by directly comparing the neural activity time courses during production and comprehension of the same narrative we were able to identify not only the spatial overlap of activity but also areas in which the neural activity is coupled across the speaker's and listener's brains during production and comprehension of the same narrative. We demonstrate widespread bilateral coupling between production- and comprehension-related processing within both linguistic and nonlinguistic areas, exposing the surprising extent of shared processes across the two systems.Proceedings of the National Academy of Sciences 09/2014; · 9.81 Impact Factor
- Psychological Inquiry 08/2014; 25(3-4):394-413. · 4.73 Impact Factor
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ABSTRACT: Background Voxel-based morphometry (VBM) has demonstrated structural brain changes between patients with Major Depressive Disorder (MDD) and healthy individuals. The initial response to antidepressants is crucial to predict prognosis in the treatment of MDD. The aim of the present study was to investigate gray matter abnormalities predicting antidepressant responsiveness and the relationships between volumetric differences and clinical/cognitive traits in MDD patients. Methods Fifty MDD patients who received 8 week period antidepressant treatment and 29 healthy controls participated in this study. VBM was applied to assess structural changes between MDD groups and control group. Neuropsychological tests were conducted on all participants. Results Both treatment responsive and non-responsive patients showed a significant volume reduction of the left insular, but only non-responsive patients had decreased volume in the right superior frontal gyrus compared to healthy controls. The comparison between treatment responsive and non-responsive patient groups demonstrated a significant difference in gray matter volume in the lingual gyrus. The larger volume of lingual gryus predicted early antidepressant response, which was attributable to better performance in neuropsychological tests. Limitation This study included a small sample size and the patients received various antidepressants and benzodiazepines. Conclusion Our findings suggest that the patients who responded poorly to antidepressants were morphologically and cognitively impaired, whereas the treatment responsive patients showed less structural changes and relatively preserved cognitive functions. The lingual gyrus may be a possible candidate region to predict antidepressant responsiveness and maintained cognition in MDD.Journal of Affective Disorders 12/2014; 169:179–187. · 3.71 Impact Factor
Activation of Anterior Paralimbic Structures during
Guilt-Related Script-Driven Imagery
Lisa M. Shin, Darin D. Dougherty, Scott P. Orr, Roger K. Pitman, Mark Lasko,
Michael L. Macklin, Nathaniel M. Alpert, Alan J. Fischman, and Scott L. Rauch
Background: Several recent neuroimaging studies have
examined the neuroanatomical correlates of normal emo-
tional states, such as happiness, sadness, fear, anger,
anxiety, and disgust; however, no previous study has
examined the emotional state of guilt.
Methods: In the current study, we used positron emission
tomography and the script-driven imagery paradigm to
study regional cerebral blood flow (rCBF) during the
transient emotional experience of guilt in eight healthy
male participants. In the Guilt condition, participants
recalled and imagined participating in a personal event
involving the most guilt they had ever experienced. In the
Neutral condition, participants recalled and imagined
participating in an emotionally neutral personal event.
Results: In the Guilt versus Neutral comparison, rCBF
increases occurred in anterior paralimbic regions of the
brain: bilateral anterior temporal poles, anterior cingu-
late gyrus, and left anterior insular cortex/inferior frontal
Conclusions: These results, along with those of previous
studies, are consistent with the notion that anterior para-
limbic regions of the brain mediate negative emotional
states in healthy individuals. Biol Psychiatry 2000;48:
43–50 © 2000 Society of Biological Psychiatry
Key Words: PET, emotion, anterior cingulate, insula,
and negative emotional states in healthy participants (e.g.,
Chua et al 1999; Fischer et al 1996; George et al 1995,
1996; Kimbrell et al 1999; Lane et al 1997a, 1997b;
everal recent studies have examined the regions of the
brain that are activated during the induction of positive
Paradiso et al 1997; Pardo et al 1993; Reiman et al 1997;
Schneider et al 1995, 1997). These studies, which have
included conditions of happiness, sadness, fear, anger,
anxiety, and disgust, typically report increased activation
in limbic and paralimbic regions of the brain, especially
during negative emotional states. These findings are con-
sistent with the notion that limbic and paralimbic regions
of the brain mediate emotional states and the processing of
information with affective significance (e.g., LeDoux
1992; Mesulam 1985). For example, George et al (1996)
used positron emission tomography (PET) to study re-
gional cerebral blood flow (rCBF) during transient sadness
and happiness in healthy males and females. In separate
scanning conditions, participants recalled neutral, sad, and
happy events while they viewed affect-appropriate faces
and attempted to experience the emotion corresponding to
each facial expression. In the Sad versus Neutral compar-
ison, participants exhibited blood flow increases in left
insular cortex, and female participants showed additional
blood flow increases in anterior cingulate gyrus.
Lane et al (1997b) used PET to examine rCBF during
happiness, sadness, and disgust versus neutral states in
healthy females. In separate scans, each of these states was
induced via a film clip (Film Condition) and script-driven
recall (Recall Condition). Within the Recall Condition
only, rCBF increases during sadness occurred in insular
cortex. Within the Film Condition only, rCBF increases
during sadness occurred in bilateral amygdala. In both
conditions combined, all three emotional states were
associated with rCBF increases in anterior temporal poles.
Guilt is a negative emotion that has not been studied
with neuroimaging techniques. Usually associated with the
belief that one has harmed another person (Frijda 1994),
guilt is a complex emotion, and situations that provoke
guilt may also provoke other negative emotions. Further-
more, whether guilt is associated with a particular pattern
of psychophysiological changes is not known (Levenson
1994). Despite these difficulties, the emotional state of
guilt merits investigation because of its prevalence in
healthy individuals and in patients with psychiatric disor-
ders, such as depression and posttraumatic stress disorder
(e.g., Berrios et al 1992; Henning and Frueh 1997).
From the Department of Psychology, Tufts University, Medford, Massachusetts
(LMS); the Departments of Psychiatry (LMS, DDD, SPO, RKP, SLR) and
Radiology (DDD, NMA, AJF, SLR), Massachusetts General Hospital and
Harvard Medical School, Boston, Massachusetts; and the VA Research
Service, Manchester, New Hampshire (SPO, RKP, ML, MLM).
Address reprint requests to Lisa M. Shin, Ph.D., Tufts University, Department of
Psychology, 490 Boston Avenue, Medford MA 02155.
Received October 7, 1999; revised December 28, 1999; accepted December 31,
© 2000 Society of Biological Psychiatry0006-3223/00/$20.00
In the current study, we used PET and the script-driven
imagery paradigm (Lang 1985; Lang et al 1983; Pitman et
al 1987; Rauch et al 1996; Shin et al 1999) to study the
neural correlates of transient emotional experiences of
guilt in eight healthy male volunteers. In the script-driven
imagery paradigm, participants are presented with audio-
taped descriptions of personal events and are asked to
recall and imagine those events and their related emotions
as vividly as possible. During script-driven imagery, we
measured participants’ peripheral psychophysiologic re-
sponses (heart rate, skin conductance, and lateral frontalis
electromyogram [EMG]), as well as rCBF. We sought to
examine rCBF changes in the Guilt condition, relative to
the Neutral condition. Given the results of previous studies
of negative emotional states in both healthy individuals
and patients with psychiatric disorders (e.g., George et al
1996; Lane et al 1997a, 1997b; Rauch et al 1994, 1995,
1996; Shin et al 1999), we predicted that rCBF increases
in the Guilt versus Neutral comparison would occur in
anterior paralimbic regions of the brain (i.e., orbitofrontal
cortex, anterior cingulate gyrus, anterior insular cortex,
anterior temporal poles) and amygdala. We had no specific
predictions about rCBF decreases in the Guilt condition.
Methods and Materials
Participants were eight healthy, right-handed (Oldfield 1971)
men with a mean age of 25.0 years (SD ? 4.4) and mean
education of 15.9 years (SD ? 3.6). Participants had no history
of psychiatric disorders (as determined by the Structured Clinical
Interview for DSM-IIIR; Spitzer et al 1990), neurological disor-
ders, head injury, or other major medical conditions. In addition,
no participant was taking psychotropic or cardiovascular medi-
cation. The study was approved by the Subcommittee on Human
Studies of the Massachusetts General Hospital, Boston, MA, and
the Veterans Affairs Medical Center, Manchester, NH. Written
informed consent was obtained from each participant.
Prior to the PET scanning session, participants provided written
descriptions of personal events: one involving the most guilt the
participant had ever experienced, and two additional events
involving no prominent emotion. These descriptions were then
modified according to established procedures (Lang et al 1983;
Pitman et al 1987, 1990; Rauch et al 1996; Shin et al 1999) and
were written in the second person, present tense. Scripts were
read and tape-recorded in a neutral male voice for playback in the
PET scanner. All scripts were between 30 and 40 sec in duration.
ductance, and left lateral frontalis electromyograms (EMG) were
Participants’ heart rate, skin con-
measured via a Coulbourn Instruments (Allentown, PA) Modular
Instrument System in the PET laboratory according to estab-
lished procedures (Orr et al 1998; Pitman et al 1987, 1990).
Psychophysiologic measurements were recorded for 30 sec
before each PET scan (baseline), and for 60 sec during each PET
scan (imagery). Within the baseline and imagery periods (for
each scan), readings were averaged. For each scan, the mean
value of the baseline period was subtracted from the mean value
of the imagery period, yielding “response” (i.e., change) scores.
the intensity of several emotions using separate visual analog
scales (Pitman et al 1987, 1990; Rauch et al 1996; Shin et al
1999; 0 ? absent; 10 ? maximal). The rated emotions included
guilt, shame, sadness, disgust, anger, fear, surprise, happiness,
general arousal, competitive arousal, and sexual arousal. Partic-
ipants also rated the overall valence (?5 to ?5) of their
emotional state during each scan.
After each scan, participants rated
State Induction/Imagery Procedure
Participants underwent PET scanning in two conditions: Guilt
(one scan) and Neutral (two scans, with two different scripts).
(Participants also underwent scanning in three other conditions
[anger, competitive arousal, and sexual arousal] as part of a
larger study; however, those other conditions are not relevant to
the current results and are presented elsewhere; see Dougherty et
al 1999; Rauch et al 1999.) During each scan, participants
recalled and imagined the contents of a single script. The neutral
scans always occurred first and last; the order of the remaining
scans (one Guilt and three other scans not reported here) were
completely counterbalanced in a Latin Square design.
Immediately before each scan, participants were instructed to
close their eyes, listen carefully to the audiotaped script, and
imagine the described event as vividly as possible, as if they were
actually participating in the event again. The script started
playing and the PET camera was turned on when there were 30
sec left in the script. At the end of the script,
administration began. During the next 60 sec, participants con-
tinued to recall and imagine the event while PET and peripheral
psychophysiologic data were acquired. Then15O-CO2adminis-
tration and PET data acquisition were terminated, and partici-
pants were instructed to stop imagining the event and to relax.
Thirty sec later, participants gave ratings of their emotional
experiences during the preceding scan. PET scans were separated
by at least 10 min in order to allow for radiation decay and a
return to a baseline emotional state.
been described previously (Rauch et al 1996; Shin et al 1997,
1999). Briefly, PET data were gathered by a 15-slice, whole-
body tomograph (Scanditronix PC 4096, General Electric, Mil-
waukee). The camera produced contiguous slices 6.5 mm apart,
with axial resolution at 6.0 mm full-width half maximum
(FWHM; axial field, 97.5 mm). Images were reconstructed using
a measured attenuation correction and a Hanning-weighted
The PET equipment and procedures have
44L.M. Shin et al
reconstruction filter set to allow for 8-mm in-plane spatial
After entering the scanner, each participant was fitted with a
thermoplastic custom-molded face mask, an overlying face mask
attached to a vacuum, and nasal cannulae which delivered the
15O-CO2. The concentration of the15O-CO2was 2960 MBq/L;
the flow rate was 2 L/min. Each participant’s head was aligned
in the scanner relative to the canthomeatal line, and transmission
measurements were made using an orbiting pin source.
A total of 15 measurements were made within each data
acquisition run: the first three (10 sec each) occurred immedi-
ately prior to15O-CO2administration, and the final 12 (5 sec
each) occurred during15O-CO2administration. After reconstruc-
tion, measurements 4–15 were summed to form images of
cerebral blood flow. Terminal count rates were between 100,000
and 200,000 events/sec.
The PET images were corrected for interscan head movement
and were transformed to the standard coordinate system of
Talairach and Tournoux (1988). The images were smoothed and
scaled using a two-dimensional Gaussian filter of 20-mm width
conducted using the SPM95 software package (Wellcome De-
partment of Cognitive Neurology, London) which follows the
theory of statistical parametric mapping (Friston et al 1991,
1995). At each voxel the PET data were normalized by the global
mean and fit to a linear statistical model by the method of least
squares. The analysis of variance considered Scan Condition as
the main effect and Participants as a block effect. Planned
contrasts at each voxel were conducted; this method fits a linear
statistical model, voxel-by-voxel, to the data. Hypotheses were
tested as contrasts in which linear compounds of the model
parameters were evaluated using t statistics. Data from both
conditions (Guilt and Neutral) were used to compute the contrast
Regions containing foci of activation with Z scores greater
than 3.09 are reported. For our a priori regions of interest, a Z
score threshold of 3.09 (p ? .001, one-tailed, uncorrected for
multiple comparisons) was selected, because we had strong and
directional a priori predictions about rCBF increases in limbic
and paralimbic regions of the brain in the Guilt versus Neutral
comparison. These predictions were based on the results of
previous neuroimaging studies of other normal emotional states
(e.g., George et al 1995, 1996; Lane et al 1997a, 1997b; Pardo et
al 1993; Reiman et al 1997). For the sake of completeness and in
order to obviate bias, we also report other (nonpredicted) regions
that exhibited rCBF increases with Z scores greater than 3.09,
although we advise the reader to use caution in interpreting them
given their post-hoc nature.
Statistical analysis of the PET data was
Psychophysiology and Ratings
Psychophysiologic responses were not significantly differ-
ent in the Guilt condition than in the Neutral condition.
Mean heart rate response scores for the Guilt and Neutral
conditions were ?0.17 (SD ? 3.15) and ?1.57 (SD ?
3.28), respectively [F(1,7) ? 1.42, p ? .27]. Mean skin
conductance response scores for the Guilt and Neutral
conditions were ?0.19 (SD ? 0.43) and ?0.11 (SD ?
0.25), respectively [F(1,7) ? .44, p ? .53]. Mean EMG
response scores for the Guilt and Neutral conditions were
0.41 (SD ? 0.89) and 0.09 (SD ? 0.60), respectively
[F(1,7) ? .72, p ? .43].
Subjective ratings of emotional state during the Guilt
and Neutral conditions are presented in Table 1. Ratings of
guilt were significantly higher in the Guilt condition than
in the Neutral condition [F(1,7) ? 317.59, p ? .0001].
Ratings of valence were significantly more negative in the
Guilt condition than in the Neutral condition [F(1,7) ?
61.83, p ? .0001], but ratings of arousal did not signifi-
cantly differ between the two conditions [F(1,7) ? 0.93,
p ? .37]. Ratings of shame, sadness, disgust, anger, and
fear were also higher in the Guilt condition than in the
Neutral condition; however, within the Guilt condition,
ratings of guilt were the highest of all ratings, and they
were significantly higher than ratings of all other emo-
tions, except for sadness and shame (guilt vs. sadness
[F(1,7) ? 3.21, p ? .12]; guilt vs. shame [F(1,7) ? 3.32,
p ? .11]).
Table 1. Subjective Ratings of Emotional State during the
Guilt and Neutral Conditions
Rating scale Guilt conditionNeutral condition
Competitive arousal .35
Means of subjective ratings are reported. The rating scale was ?5 to ?5 for
valence and 0 to ?10 for all other measures. Standard deviations are given in
PET Study of Guilt 45
In the Guilt versus Neutral comparison, rCBF increases
occurred in three of our paralimbic regions of interest:
bilateral anterior temporal poles, anterior cingulate gyrus,
and left anterior insular cortex/inferior frontal cortex (see
Table 2 and Figure 1). No rCBF increases (or decreases)
were observed in amygdala. rCBF increases occurred in
the following other areas: mid-cingulate gyrus, cerebel-
lum, and left precentral gyrus. rCBF decreases occurred in
left posterior insular cortex, visual association cortex, right
precuneus, left fusiform gyrus, and right precentral gyrus.
Relative to the Neutral condition, the Guilt condition was
associated with rCBF increases in three of our paralimbic
regions of interest: bilateral anterior temporal poles, ante-
rior cingulate gyrus, and left anterior insular cortex/
inferior frontal cortex. rCBF decreases occurred in more
posterior portions of left insular cortex. These findings are
generally consistent with those of previous studies of
normal emotional states.
Studies of nonhuman primates have revealed direct
connections from anterior temporal poles to the amygdala
(Aggleton et al 1980). In addition, electrical stimulation of
anterior temporal poles can elicit autonomic responses in
monkeys and cats (Anand and Dua 1956; Kaada et al
1949) and reports of fear and nervousness in humans
(Mullan and Penfield 1959). Activation in anterior tempo-
ral poles has been reported in other studies of normal
emotion (e.g., Lane et al 1997a, 1997b; Kimbrell et al
1999; Reiman et al 1997), as well as in studies of patients
with anxiety disorders (Rauch et al 1995, 1996; Shin et al
1999). In two previous studies of anxiety, rCBF increases
in temporal poles were attributed to extracranial artifacts
of jaw muscle contraction (Drevets et al 1992; Benkelfat et
al 1995); however, the temporopolar activations reported
in the current study were clearly within brain. Although
activation in anterior temporal poles has largely been
associated with negative emotional states, at least one
study has reported these types of activations during film-
and recall-generated happiness (Lane et al 1997b). Thus,
the anterior temporal poles may be involved in informa-
tion processing of emotional material, possibly regardless
The cingulate gyrus is a large structure that appears to
have different functional subdivisions (Devinsky et al
1995; Vogt et al 1992, 1995). The activation reported in
the present study is located in a region of the anterior
cingulate gyrus (approximately Brodmann area 32) that
lies just superior to the genu of the corpus callosum,
approximately 24 mm above the anterior commissure–
posterior commissure (AC–PC) plane. This region may
correspond to superior portions of the affective division of
the anterior cingulate gyrus (ACad), which lies inferior to
the dorsal region of the anterior cingulate that is thought to
principally mediate cognitive processes (e.g., Bush et al
1998; Pardo et al 1990; see Vogt et al 1992, 1995), and
superior to the portion of the anterior cingulate that is
thought to mediate visceral functions (Vogt et al 1992,
1995). Activations in this vicinity (roughly 10–24 mm
above the AC–PC plane) have also been reported in
studies involving procaine-induced fear (Ketter et al 1996;
Servan-Schreiber et al 1998), the recollection of traumatic
events in trauma-exposed healthy individuals (Shin et al
1999), the performance of the emotional Stroop task
(Whalen et al 1998a), the prediction of treatment response
in depression (Mayberg et al 1997), and symptom provo-
cation in patients with obsessive-compulsive disorder
(Rauch et al 1994).
In the current study, the Guilt condition was associated
with rCBF increases in anterior insular cortex/inferior
frontal gyrus and rCBF decreases in more posterior re-
gions of insular cortex. Anterior and posterior portions of
insular cortex appear to differ considerably in terms of
cellular organization, connections with other brain re-
gions, and function (Mesulam and Mufson 1982a, 1982b;
Mufson and Mesulam 1982). Anterior insular cortex
contains agranular and dysgranular cells, shares extensive
connections with other anterior paralimbic regions and the
amygdala (Aggleton et al 1980), and is involved in
olfactory, gustatory, and autonomic function (Mesulam
Table 2. Regions with Blood Flow Changes in the Guilt vs.
Paralimbic regions of interest
Temporal poles 4.82
?44, ?4, ?24
?46, ?12, ?28
?44, ?20, ?20
?12, ?34, ?24
?44, ?16, ?4
Anterior cingulate gyrus (32)
Anterior insular cortex/
inferior frontal gyrus
Posterior insular cortex
Visual association cortex (19)
?14, ?10, ?44
?20, ?50, ?24
?32, ?14, ?44
?38, ?12, ?12
?6, ?80, ?40
?10, ?72, ?48
?38, ?44, ?12
?52, ?8, ?12
For each focus of activation, Z scores and coordinates are given. Coordinates
are expressed in millimeters: x ? 0 is right of the midsagittal plane, y ? 0 is anterior
to the anterior commissure, and z ? 0 is superior to the anterior commissure–
posterior commissure plane. Numbers in parentheses immediately following region
names refer to approximate Brodmann areas. rCBF, regional cerebral blood flow.
46 L.M. Shin et al
and Mufson 1982b; Small et al 1999). Electrical stimula-
tion of anterior insular cortex is associated with reports of
fear in humans (Mullan and Penfield 1959), and activation
of anterior insular cortex has occurred during symptom
provocation in patients with phobias (Rauch et al 1995),
the recollection of negative events in healthy individuals
(George et al 1996; Shin et al 1999), procaine-induced fear
(Ketter et al 1996; Servan-Schreiber et al 1998), the
perception of facial expressions of disgust (Phillips et al
1997), imagery of aversive stimuli (Kosslyn et al 1996),
and aversive gustatory stimulation (Zald et al 1998). In
contrast, posterior insular cortex contains granular cells,
shares connections with superior temporal, parietal, pre-
motor, and somatosensory cortex, and is involved in the
processing of auditory and somatosensory information
(Coghill et al 1994; Francis et al 1999; Mesulam and
Mufson 1982a, 1982b; Mufson and Mesulam 1982;
Schneider et al 1993). Activation in anterior insular cortex
during the emotional state of guilt is consistent with theory
and data regarding the role that this region may play in the
processing of emotional information. Deactivation in more
posterior regions of insular cortex during the Guilt condi-
tion was unexpected, but could reflect a reallocation of
blood flow toward more anterior regions of insular cortex
during a negative emotional state.
No activation occurred in the amygdala or orbitofrontal
cortex during the Guilt condition in this study. Indeed, the
amygdala may be more involved in fear and the processing
of fear-related stimuli (e.g., LaBar et al 1998; Morris et al
1996; Rauch et al 1996; Whalen et al 1998b). In addition,
in healthy individuals, the amygdala may be more respon-
sive during conditions involving the perception of emo-
tional stimuli than the recollection and imagery of those
stimuli (Reiman et al 1997; Whalen 1998). Furthermore,
the limited spatial and temporal resolution of PET may
have hindered our ability to detect activation in the
amygdala. The absence of activation in orbitofrontal
cortex in this study was somewhat surprising, given
previous reports of orbitofrontal activation during negative
emotional states in healthy humans (e.g., Fischer et al
1996; Paradiso et al 1997; Pardo et al 1993; Zald et al
Possible limitations of this study include the modest
sample size, the lack of behavioral measures, and the
dependence on self-report data. In addition, one might
argue that the absence of significant peripheral psycho-
Figure 1. Regional cerebral blood flow increases in the Guilt versus Neutral comparison were observed in (A) anterior temporal poles
(horizontal view), (B) anterior cingulate gyrus (sagittal view), and (C) left anterior insular cortex/inferior frontal gyrus (sagittal view).
PET Study of Guilt47
physiologic changes between the Guilt and Neutral con-
ditions was a limitation. To our knowledge, however, there
is no evidence that the emotional state of guilt is accom-
panied by such changes. Furthermore, although great care
was taken to match the conditions as closely as possible on
a number of different variables (such as script length,
tense, voice), the conditions may have differed in more
subtle ways. For example, although the Guilt condition
was indeed marked by high subjective ratings of guilt, it
was also accompanied by moderate ratings of related
emotions, especially shame and sadness. Anxiety, which
has been associated with paralimbic activation (e.g., Chua
et al 1999; Cottraux et al 1996; Kimbrell et al 1999; Rauch
et al 1994, 1995, 1996; Shin et al 1997, 1999), also may
have occurred in the Guilt condition, although the lack of
peripheral psychophysiologic changes during the Guilt
condition may not be consistent with this possibility. In
short, activations in the Guilt versus Neutral comparison
may have reflected changes in other related emotions as
well. Finally, PET studies in general are limited by errors
in precise neuroanatomical localization that can arise from
constraints set by the spatial resolution of PET, unavoid-
able head movement, or stereotaxic transformation. In
addition, normalizing whole-brain blood flow prevented
us from detecting any absolute blood flow changes be-
In conclusion, the Guilt condition was associated with
rCBF increases in bilateral anterior temporal poles, ante-
rior cingulate gyrus, and left anterior insular cortex/
inferior frontal cortex and rCBF decreases in more poste-
rior portions of left insular cortex. The results of this and
other similar studies are consistent with the notion that
anterior paralimbic regions of the brain mediate negative
emotional states in healthy individuals and are involved in
the processing of information with affective significance.
This study was supported in part by NIMH Grant MH01215 (Dr. Rauch).
Dr. Dougherty received support as a fellow in the Clinical Investigator
Training Program: Harvard/MIT Health Sciences and Technology-Beth
Israel Deaconess Medical Center, in collaboration with Pfizer, Inc.
We thank Patrick Shin and Paul Whalen for their comments on this
manuscript, and Sandra Barrow, Avis Loring, and Steve Weise for their
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