Role of the Primate Orbitofrontal Cortex in Mediating
Ned H. Kalin, Steven E. Shelton, and Richard J. Davidson
and affective disorders. Studies in nonhuman primates can provide important information related to the expression of this risk factor, since
threat-induced freezing in rhesus monkeys is a trait-like characteristic analogous to human behavioral inhibition. The orbitofrontal cortex (OFC)
and amygdala are part of a circuit involved in the processing of emotions and associated physiological responses. Earlier work demonstrated
resulted in a leftward shift in frontal brain electrical activity consistent with a reduction in anxiety. The lesions did not significantly decrease
Conclusions: These findings demonstrate a role for the OFC in mediating anxious temperament and fear-related responses in adolescent
primates. Because of the similarities between rhesus monkey threat-induced freezing and childhood behavioral inhibition, these findings are
Key Words: Amygdala, anxiety, monkey, orbitofrontal cortex,
model to study mechanisms relevant to understanding human
behavioral inhibition and anxious temperament (5,6), since these
species share similarities in the expression of anxiety (5,6) and in the
brain structures that mediate emotion (7,8). Using rhesus monkeys,
we have focused our efforts on understanding the physiological
concomitants and neural mechanisms underlying individual differ-
ences in the expression of threat-induced freezing, which has
trait-like characteristics and is analogous to human behavioral
inhibition (5,6). Our earlier studies demonstrated that a propensity
to engage in increased threat-induced freezing is associated with
increased basal hypothalamic-pituitary-adrenal (HPA) activity; in-
creased cerebrospinal fluid (CSF) concentrations of the anxiogenic
peptide, corticotropin releasing factor (CRF); and asymmetrical right
frontal brain electrical activity (9 –11). Many of these physiological
parameters have also been associated with individual differences in
involved in the adaptive processing of emotion and in psychopa-
thology (15,16). More specifically, increased amygdala reactivity
occurs in adults with a childhood history of extreme behavioral
inhibition (17). We demonstrated, in monkeys, that lesions of the
hildren with extreme behavioral inhibition are at risk to
develop social anxiety disorder and depression (1–5). We
demonstrated that rhesus monkeys provide an excellent
central nucleus of the amygdala (CeA) decreased threat-induced
freezing, snake fear, HPA activity, and CSF CRF concentrations (18).
This suggested a mechanistic role for the CeA in mediating acute fear
responses, human behavioral inhibition, and anxious temperament.
The OFC is of interest in relation to behavioral inhibition and
anxious temperament because of its role in mediating longer term
responses associated with emotion-related goal-directed behavior
(19 –23). Furthermore, the OFC is bidirectionally linked to the
amygdala and these connections have been implicated in emotion
regulation processes (5,24,25). The medial regions of the OFC
(areas 13 and 14) receive the densest amygdala projections (7,26),
whereas area 11 and the caudal region of area 12 receive minimal to
moderate amygdala projections (7,27,28). These projections origi-
nate from the lateral, basal, and accessory basal nuclei of the
amygdala (8,27,28). In general, the OFC regions that receive amyg-
dala projections reciprocate with projections back to the amygdala
Therefore, to explore the role of the OFC in mediating behav-
ioral inhibition, anxious temperament, and acute fear, we examined
the effects of lesions of OFC regions that are linked to the amygdala
(areas 11, 12(orbital division), 13, and 14) on threat-induced freezing,
snake fear, and the physiological parameters associated with anx-
humans, anxiety and affective psychopathology commonly emerge
during adolescence and it appears that in monkeys the structural
connections between the amygdala and orbitofrontal cortex are in
place by adolescence (for review, see 29). We hypothesized that the
OFC lesions, similar to the effects of CeA lesions, would reduce the
expression of the behavioral and physiological parameters associ-
ated with acute fear responses and anxious temperament.
Methods and Materials
Twelve experimentally naïve adolescent colony-born rhesus
monkeys (Macaca mulatta) were the subjects. Animal housing and
experimental procedures were in accordance with institutional
guidelines. The animals were housed as pairs; each experimental
animal lived with a control animal. At the beginning of the study,
subjects were, on average, 34.4 months of age. Six randomly
Medical School; and Department of Psychology (NHK, RJD) and Wais-
man Laboratory for Functional Brain Imaging and Behavior (NHK, RJD),
University of Wisconsin, Madison, Wisconsin.
Address reprint requests to Ned H. Kalin, M.D., Wisconsin Psychiatric Insti-
tute and Clinics, University of Wisconsin Medical School, 6001 Research
Park Boulevard, Madison, WI 53719-1176; E-mail: email@example.com.
Received February 8, 2007; revised April 3, 2007; accepted April 5, 2007.
BIOL PSYCHIATRY 2007;62:1134–1139
© 2007 Society of Biological Psychiatry
Six nonoperated male control animals were used for comparison,
since we previously demonstrated that the nonspecific effects of the
surgery do not significantly affect the behavioral and physiological
measures of interest (18).
Prior to surgery, atropine sulfate (.04 mg/kg intramuscular [IM])
was given to depress salivary secretion, and dexamethasone (2
mg/kg) was given to reduce potential brain swelling. Animals were
preanesthetized with ketamine hydrochloride (HCl) (10 mg/kg IM),
fitted with an endotracheal tube, and maintained on isoflurane
anesthesia. An experienced surgeon made an opening in the frontal
bone posterior to the brow ridge to expose the frontal cortex. Both
hemispheres were lesioned in a single procedure by lifting the brain
to expose its ventral surface. Using microscopic guidance, electro-
cautery and suction were applied to the targeted brain area (20,30).
5 mm posterior to front of the brain and the caudal limit was 4 mm
anterior to the junction of the frontal and temporal lobes (regions of
areas 11, 12, 13, and 14) (Figure 1) (31).
Following surgery, dexamethasone 2 mg/kg IM was given twice
daily and tapered by half each day for 3 days. Cefazolin (20 mg/kg
IM) was administered twice daily for 5 days and ketoprofen (2.1
mg/kg IM) was given for analgesia every 8 to 12 hours for 4 days.
Magnetic Resonance Imaging, Development of Lesion Target,
and Lesion Verification
T1-weighted magnetic resonance imaging (MRI) scans were
obtained using either a 1.5 or a 3.0 Tesla GE Signa MRI scanner.
Four of the six animals had presurgical and postsurgical MRIs, and
the remaining two animals had only postsurgical MRIs. For scan-
ning, the monkeys were anesthetized with xylazine (.5 mg/kg IM),
and ketamine was administered as needed (15 mg/kg IM). Postsur-
gical 3.0 Telsa MRIs were acquired an average of 35 days after the
surgery by placing the monkeys in a specially designed plastic head
holder within the scanner.
The intended lesion area was defined using coronal atlas brain
slices beginning at the caudal boundary of area 10 and extending 12
mm posteriorly (Figure 1) (31). The brain atlas was also used to
standardize each animal’s intended lesion to the presurgical mag-
of the animals, the coronal atlas pictures were matched to 12
presurgical MR images, except for one subject that only had nine
images. For the two animals without a presurgical MRI, we used an
MRI from an age- and sex-matched monkey. The postsurgical MRI
was used to define each subject’s actual lesion, which was drawn
onto the presurgical MRI along with the intended lesion. The extent
of the lesion was expressed as a percentage of the intended lesion,
as calculated by counting the pixels within the animal’s actual lesion
and dividing this by the number of pixels in the intended lesion for
each coronal slice.
To assess defensive and anxiety-related behaviors, all animals
were tested before and after the lesions were made using two
different paradigms, each with three different conditions (alone [A],
no eye contact [NEC], and stare [ST]). Control and experimental
subjects were tested at the same time, and the mean time between
the lesioning procedure and the first postsurgical behavioral test
was 4.3 months. The first test was conducted using the classic
human intruder paradigm (HIP), consisting of 9-min periods of A,
NEC, and ST. As part of a separate study, the second test used a
modified HIP paradigm. In the classic HIP, during the A condition,
animals were placed alone in a test cage for 9 min. This condition
predominantly elicits coo vocalizations and locomotion. This was
followed by the NEC condition, in which a human entered the test
room, stood motionless 2.5 m from the cage, and presented her
profile to the monkey while avoiding eye contact. The NEC
condition elicits freezing behavior. After NEC, the intruder left the
test room for 3 min and returned for the ST condition, during which
the intruder stared at the monkey with a neutral face 2.5 m from the
test cage. The ST condition elicits defensive hostility and barking, an
aggressive vocalization. The modified HIP consisted of 20 min of
in Column A: white lines define the intended lesion in the
in the coronal planes by comparing the remaining cortical
gray matter with that of the control animal displayed in
N.H. Kalin et al.
BIOL PSYCHIATRY 2007;62:1134–1139 1135
each of the three conditions (A, NEC, ST) on three different days.
The classic and modified HIP paradigms were repeated for all
behavior was encoded using a microprocessor-based syntactic
behavioral scoring system by one experienced rater unaware of the
treatment conditions (Table 1). For each behavior, the mean dura-
tion or frequency per minute was calculated. These data from both
paradigms were combined for analysis to more accurately represent
each animal’s behavior.
Assessing Snake Fear
Subjects were adapted to the Wisconsin General Testing Appa-
ratus (WGTA) test cage, and their food preference was determined
(32). Subjects were taught to reach for their preferred rewards on
top of the clear plastic stimulus presentation box (57.2 ? 22.1 ? 6.5
cm). Subjects were presented with two of their most preferred foods
randomly placed on the distant left and right corners of the clear
plastic stimulus presentation box, requiring the subjects to reach
over the stimulus for the food rewards. The box contained one of
four stimuli: 1) nothing: empty box; 2) tape: roll of blue masking
tape; 3) rubber snake: curled black rubber snake 120 cm long; and
long. Subjects were tested for 1 day, during which each stimulus
was presented six times in a pseudorandom order. The real snake
was never presented during the first five trials and no item from
either the snake or the nonsnake stimulus categories was presented
for more than three consecutive trials. Each monkey received the
same order of stimuli. Each trial lasted 60 seconds regardless of the
subject’s response, and the intertrial interval was 45 seconds.
Latency for the animal’s first reward retrieval in each trial was used
Hormonal Sampling and Stress Exposure
Basal hormonal status and stress response were evaluated twice
before and twice after surgery, at intervals of at least 1 week, by
obtaining a blood sample within 2 min of capture immediately prior
cage. All samples were collected between 0800 and 0930 hours.
After the second blood sample was obtained following the stress
exposure, ketamine HCl (15 mg/kg IM) was administered and a 3
mL CSF sample was obtained from the cisterna magna. Plasma was
separated from blood by centrifugation at 4oC and frozen at ?70°C.
The CSF samples were immediately frozen on dry ice and main-
tained at ?70°C.
Cortisol, Adrenocorticotropic Hormone, and
kit (Diagnostic Systems Laboratories, Webster, Texas) with an
intra-assay variability of 6.1% and an interassay variability of 6.3%.
The detection limit of the assay was .125 ng. Adrenocorticotropic
hormone (ACTH) was measured using a radioimmunoassay (RIA)
kit from the Nichols Institute Diagnostics (San Clemente,
California). The intra-assay variability was 2.2% and the
interassay variability was 7.2%. The detection limit of the assay
was 1.0 pg. Corticotropin releasing factor assays were per-
formed by RIA using antiserum directed against the N-terminal
portion of the intact peptide (IgG Corporation, Nashville,
Tennessee). The detection limit was .89 pg. The intra-assay
and interassay variability was 6.1% and 10.2%.
Frontal Brain Electrical Asymmetry Assessed
Silver-silver chloride biopotential electrodes were attached with
conditioning cream to awake, manually restrained animals. Elec-
trodes were placed to the central (CZ) area, left and right frontal (F3,
F4) areas, and left and right parietal (P3, P4) areas. Additional
electrodes were placed on the left and right mastoids (A1, A2). All
electroencephalogram (EEG) electrodes and A2 were recorded with
reference to A1, although EEG signals were analyzed after being
rereferenced to a computed averaged mastoid value. The EEG was
acquired using the Vitaport 3 digital recorder from TEMEC Instru-
ments B.V. (Kerkrade, The Netherlands).
2 ?V/msec) to remove artifact. The duration of EEG data used was
similar between groups (mean for control animals ? 452.34 sec and
for lesion subjects ? 476.38 sec). Power spectra were estimated
using Welch’s method (33) applied to 1.0-second linearly detrended
and Hanning-windowed epochs of artifact-free data with .5 seconds
(4–8 Hz), alpha (8–12 Hz), and beta (13–30 Hz) were averaged
from the artifact-free data. The 4 Hz to 8 Hz band was chosen
because robust lateralized changes in this band occur in rhesus
monkeys given diazepam (34). Power density measurements were
normalized by log transformation. The direction and magnitude of
asymmetry were expressed as the log transformed power density of
an electrode position on the right side of the head less the log
transformed power density of the corresponding electrode on the
left side of the head. Positive asymmetry scores reflect greater
Repeated measures analysis of variance (ANOVA) or paired
t tests were used to compare the groups. All post hoc comparisons
used t tests. Nonnormally distributed data were transformed using a
square root transformation for frequency data and a log (X ? 1)
transformation for duration data.
Table 1. Definition of Behaviors
Coo Vocalization made by rounding and pursing the lips with an increase then decrease in
frequency and intensity.
Ambulation of one or more full steps at any speed.
A period of at least 3 seconds characterized by tense body posture without vocalizations
and movement other than slow movements of the head.
Any hostile behavior directed toward the intruder, such as barking, head bobbing, or ear
Vocalization made by rapidly forcing air though the vocal chords from the abdomen,
producing a short, rasping, low-frequency sound.
1136 BIOL PSYCHIATRY 2007;62:1134–1139
N.H. Kalin et al.
Extent of OFC Lesions and Effects on Threat-Induced Anxiety
and Snake Fear
Figure 1 displays the intended lesion target, as well as coronal MRI
slices obtained after the lesioning procedure from representative mon-
of area 12, and the lateral part of the orbital region of area 14. On
average, 70.4% of the targeted area was destroyed, ranging
from 65.7% to 79.1% (Table 2). Areas outside the targeted
region that received minimal damage included the orbital
proisocortex (three animals), the orbital periallocortex (five
animals), and the orbital portion of area 25 (six animals) (31).
During the A condition of the HIP, no significant effects of the
lesions were observed on locomotion or cooing. Likewise, during
ST, neither barking vocalizations nor hostile behaviors were signif-
icantly affected by the lesions. However, during NEC, the lesions
significantly reduced the duration of threat-induced freezing. Anal-
ysis of variance revealed a significant group by test interaction (F ?
5.373; df ? 1,10; p ? .05), such that less freezing occurred in the
levels (p ? .051). After surgery, the lesioned subjects also showed
less freezing compared with the levels of freezing in the control
animals at either of the two testing times (p ? .01) (Figure 2). The
lesions did not significantly affect locomotion during NEC.
In the snake fear test, ANOVA revealed a main effect of object
such that across control and lesioned animals, the greatest latencies
to reach for the treat occurred in the presence of the real snake (F
? 12.881; df ? 3,30; p ? .0001). The latency to reach for the treat in
the presence of the rubber snake was less than that for the real
snake but greater than that occurring in the presence of the roll of
tape or when nothing was presented. In addition, there was a
significant main effect of group and a near significant group by
object interaction. The group effect was characterized by an overall
decrease in the lesioned animals’ latencies to reach (F ? 6.819; df ?
1,10; p ? .03). Figure 3 displays the group by object interaction,
demonstrating that the differences in the lesioned and control
animals’ latencies to reach were greatest in response to the real and
rubber snake (F ? 2.560; df ? 3,30; p ? .074).
Effects of Lesions on Frontal EEG Asymmetry and Stress-
brain electrical activity, as evidenced by a group by test interaction
(F ? 9.503; df ? 1,10; p ? .02). After surgery, the OFC-lesioned
electrical activity. In comparison, the control animals remained
unchanged across the two tests (Figure 4). A similar pattern of
change was observed for parietal brain activity (F ? 4.877; df ?
Table 2. Percent Destruction of the Targeted Orbitofrontal Cortex Region
Subjects Left %Right %Mean %
70.4 Mean %
Figure 2. TheOFClesionsresultedinasignificantreductioninfreezingduration
was observed. The lesions resulted in reduced reach latency in response to all
objects, with the greatest reductions occurring in response to the real and
N.H. Kalin et al.
BIOL PSYCHIATRY 2007;62:1134–1139 1137
1,10; p ? .052). The lesions were without significant effect on
baseline or stress-induced increases in plasma concentrations of
cortisol or ACTH and did not alter CSF CRF concentrations.
These findings from adolescent primates demonstrate involve-
ment of the OFC in mediating threat-induced freezing, a behavior
that is analogous to human behavioral inhibition and is a charac-
teristic of trait-like anxiety. The lesions also affected the monkeys’
overall latencies to reach for a preferred treat in response to the
presentation of fearful and nonfearful objects. The data suggest that
this effect of the lesions was more prominent in relation to the
snake, a fearful stimulus. The OFC lesions also significantly in-
creased left frontal asymmetric brain electrical activity and were
without effect on HPA activity and CSF CRF concentrations. The
behavioral effects of the OFC lesions were similar to those reported
for lesions of the CeA (18). However, unlike the OFC lesions, the
CeA lesions did not affect patterns of frontal brain electrical activity
but did decrease HPA activity and CSF CRF concentrations. Along
with our earlier work, these findings suggest a role for the OFC and
CeA in mediating human behavioral inhibition (1–5). The findings
electrical activity, which is of interest since asymmetric right frontal
electrical activity is associated with anxious temperament (2,3,9,15).
Since rodent and human studies suggest a role for the ventromedial
prefrontal cortex in inhibiting amygdala activity and in mediating
extinction (25,35), it is important to note that our OFC lesions did
not affect this region. Lesions of this area might be expected to have
effects opposite to those of the OFC lesions.
It is of considerable interest that the OFC lesions reduced
threat-induced freezing in adolescent monkeys, since in humans,
anxiety and affective psychopathology emerge during adolescence.
Furthermore, our finding in adolescent monkeys is consistent with
ing that OFC damage decreased the likelihood of developing
anxiety symptoms (36).
In our study, the effects of the OFC lesions on threat-induced
freezing appeared to be selective, since there were no significant
effects of the lesions on locomotion or cooing occurring during the
A or on barking or defensive hostility occurring during ST. A recent
study using four OFC-lesioned monkeys that were tested in a
modification of the HIP failed to find an effect of OFC lesions on
defensive behaviors elicited by the NEC condition (37). The failure
behaviors. Furthermore, our within-subjects design increased the
statistical power to detect effects. In addition, the Izquierdo et al.
(37) study differed from our study in that they did not lesion the
orbital portion of area 12. In contrast to early reports demonstrating
that OFC-lesioned monkeys have altered aggressive behavior
(38,39), we did not find an effect of the lesions on defensive hostility
elicited by ST. More recently, OFC lesions were reported to increase
mild aggression (frown, ears back, and yawn) but not high aggres-
sion (thrusts head or body forward, cage shake, threat face)
occurring during 5 min of ST exposure (37). Since our behavioral
category, defensive hostility, incorporates both mild and high levels
of aggression as defined by Izquierdo et al. (37), the possibility
to detect differences in this more subtle aggressive behavior.
The finding that the OFC lesions decreased snake fear is
consistent with other studies (37,40). While this finding was only
marginally significant, it is likely that the amygdala and OFC work
together to mediate snake fear, as there are a number of primate
studies demonstrating that total amygdala or CeA lesions reduce
snake fear (18,32,38,41). Furthermore, monkeys with combined
unilateral amygdala and OFC lesions demonstrate a reduction in
snake fear (42).
The effects of the OFC lesions on behavior were similar to those
observed for CeA lesions (18); however, the effects of the lesions
differed on the assessed physiological parameters. In contrast to the
CeA lesions, the OFC lesions did not significantly decrease HPA
activity or CSF levels of the anxiogenic neuropeptide, CRF. The
failure to detect a decrease in CSF CRF after the OFC lesions
the CeA lesions may result from lesioning CeA CRF-containing
neurons (18). The relation among the behavioral and physiological
parameters associated with anxious temperament is complex. In-
creased HPA activity has been linked to anxious temperament, as
studies in extremely inhibited children have found increased corti-
sol concentrations (13). We previously demonstrated that individual
differences in monkeys’ freezing behavior positively correlate with
plasma cortisol concentrations (11), and we also found that mon-
keys and children with extreme asymmetric right frontal brain
electrical activity have increased plasma cortisol concentrations
(9,43) and monkeys with right asymmetric frontal brain activity also
have increased CSF CRF levels (10). Furthermore, asymmetric right
frontal brain electrical activity is associated with negative affect in
humans and anxious temperament and increased anxiety-related
behaviors in monkeys (9,10,14,44). Therefore, it is of interest that
the OFC lesions resulted in a shift in frontal brain electrical activity
toward increased left asymmetry but did not affect HPA activity or
CSF CRF concentrations.
In the lesioned monkeys, the association between a decrease in
anxiety and a leftward shift in frontal brain activity is consistent with
an earlier finding demonstrating that the administration of the
antianxiety agent, diazepam, results in a similar effect (34). How-
shift in frontal brain electrical activity, as we previously found that
CeA lesions decreased anxiety responses without affecting patterns
of frontal brain electrical activity (18). It may be that the regions of
OFC lesioned in this study modulate prefrontal cortical connectivity
in a way that is reflected in prefrontal electrical asymmetries. In
contrast, lesions of the amygdala might not directly interfere with
the prefrontal circuitry involved in modulating prefrontal electrical
asymmetries. That CeA and OFC lesions affect threat-induced
freezing along with some but not all of the physiological parameters
associated with anxious temperament again underscores the com-
plex relation among these brain regions with the behavioral and
physiological aspects of this temperament.
In addition to behavioral inhibition, anxious temperament in-
volves avoidant behaviors that are motivated by the habitual
perception that the environment is threatening. A well-established
function of the OFC is to modulate goal-directed behavior based on
the assessment of future positive and negative consequences, and it
has been hypothesized to be involved in emotion regulation
(19 –23). It is therefore logical that the OFC would be involved in
mediating anxious temperament and behavioral inhibition, since
they are enduring dispositions related to emotion regulation. To-
gether with earlier work, these findings suggest that in primates the
OFC and amygdala are components of the circuitry that mediate the
with the anxious temperament. Bidirectional linkages between the
amygdala and OFC provide the pathways to mediate their coordi-
While numerous human functional imaging studies have re-
1138 BIOL PSYCHIATRY 2007;62:1134–1139
N.H. Kalin et al.
ported alterations in OFC and amygdala activity in relation to
human psychopathology (15,16), the conclusions from these stud-
ies are based on associations among behavior, emotion, and brain
activity. By directly disrupting OFC function in primates, the current
study supports the findings from the imaging studies by demon-
strating a mechanistic role of these structures in the processing and
regulation of anxiety. These findings have important implications
for understanding the mechanisms underlying the risk of develop-
ing anxiety and affective disorders.
This work was supported by Grants MH046729, MH052354,
and MH069315; The HealthEmotions Research Institute; and Mer-
iter Hospital. The authors do not have any conflicts to disclose.
We are grateful to H. Van Valkenberg, T. Johnson, E. Zao, K.
Meyer, J. King, S. Mansavage, J. Droster, L. Greischar, and the staff
at the Harlow Center for Biological Psychology and the Wisconsin
National Primate Research Center at the University of Wisconsin
(RR000167) for their technical support and Drs. Elisabeth Murray
and Jocelyne Bachevalier for their neurosurgical advice.
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