1) The study used PET to measure regional cerebral blood flow while participants performed a reversal learning task with social and nonsocial conditions. 2) Results showed greater activation in the amygdala for social vs nonsocial conditions and in lateral orbitofrontal cortex for reversal vs non-reversal conditions. 3) Functional connectivity analysis revealed that medial orbitofrontal cortex correlated positively with amygdala activity, while lateral orbitofrontal cortex correlated negatively, especially for social stimuli.

1. Functional Connectivity of Amygdala and Orbitofrontal Cortex During
Social and Nonsocial Reversal Measured with PET
Eric King, Daniella Furman, Philip Kohn, Deepak Sarpal,
Andreas Meyer-Lindenberg, Katherine Roe, Karen Faith Berman
Section on Integrative Neuroimaging, Clinical Brain Disorders Branch, Genes Cognition and Psychosis Program, NIMH/IRP/NIH/DHHS
2
Background Image Analysis
Orbitofrontal cortex (OFC) and the amygdala are critically involved in social and •Images were attenuation-corrected and reconstructed (32 planes, 6.5 mm FWHM). After subtraction of •Medial OFC
emotional functioning1. Lesions to either region results in irregular social and emotional background activity and registration, images were normalized to an average template, scaled •Main effect of reversal: A region within lateral orbitofrontal cortex bilaterally
behavior and an abnormal relationship between these regions may be implicated in proportionally to remove global flow variation and smoothed (10mm3 FWHM Gaussian kernel) using showed greater connectivity for reversal conditions as compared with nonsocial
disorders like Williams syndrome and schizophrenia which involve an abnormal social SPM5 software (Wellcome Department of Cognitive Neurology). conditions
and emotional disposition.
•Contrast images for the main effect of the reversal condition (all reversal scans vs. all control scans), •Main effect of social: Anterior cingulate showed greater connectivity for social conditions
Studies on nonhuman primates show a complex relationship among projections of these the main effect of social condition (all social scans vs. all nonsocial scans), the interaction of the as compared with nonsocial conditions
two regions, with both spatially and functionally specific components. One involves the reversal condition with the social condition [(social reversal vs. social control) vs. (nonsocial reversal vs.
lateral network of the OFC which has been characterized by the confluence of sensory nonsocial control)], and post-hoc tests within task type were statistically assessed with a random effects Functional Connectivity with Medial OFC
Figure 6
inputs which give rise to the reward values of stimuli there. The other involves the medial linear model analysis and a statistical threshold of p<0.001, uncorrected. Main effects of cognitive condition
network of the OFC which is thought to relay visceromotor information from the region to Reversal > Control
other areas of the brain. Although the medial and lateral networks of the OFC both have •Connectivity analysis examining functional connectivity 4
Reversal Social > Nonsocial
4 Social
Figure 5 Lateral 3 **Bar represents t-values corresponding to p<.01
Anterior
projections to the amygdala as well as to other subcortical structures, their connections of amygdala and of OFC with the rest of the brain were OFC
M
e 2
M3
e2
Amygdala, Medial, and Lateral OFC Masks 1 Cingulate d1
to these structures appear to preserve the medial versus lateral organization2. performed in SPM5 by creating average rCBF images d
i 0 i 0
a -1 a-1
for each of the four task types. l -2
-3
5 10 15 20 25 l -2
10 15 20 25
-3
R Orbital(44,40,-12) Anterior Cingulat(0,44,16)
Given that OFC is involved in both social cognition and reversal learning, we developed a
reversal task with separable, matched social and nonsocial conditions to probe the •Masks from R and L amygdala were generated Nonreversal
4
anatomically using the SPM99 Pick-Atlas Toolbox. Nonsocial
Connectivity by Social Condition
functional interaction of the OFC and the amygdala under different cognitive demands3. Amygdala M
3 Figure 5 4
M3
Masks for medial and lateral OFC were drawn making e 2 Social > Nonsocial
Based on Petrides and Pandya’s work on the cytoarchitecture of the OFC as well as Medial d 1
L Amygdala
e2
d1
more recent work delineating the regions that comprise the medial and lateral networks, Lateral reference to delineations between the regions outlined i 0
a -1
** i 0
l ** a-1
we developed masks of the regions to selectively investigate their patterns of functional by Ongur et al on a canonical brain image in MRIcro -2 5
-3
10 15 20 l -2
-3
10 15 20
** R Orbital(44,40,-12) Anterior Cingulat(0,44,16)
connectivity and relationship with the amygdala. To map neural activity of OFC without •Mean rCBF values within xtracted as seed values for each task type and were entered as covariates
the susceptibility artifacts that accompany fMRI , we used 15O water PET to measure in a voxelwise connectivity analyses for each condition. The resulting correlation maps were analyzed **Colored t-bars represent t-values corresponding to p<.01 in positive and negative directions
regional cerebral blood flow (rCBF). with a random effects linear model to assess amygdala R Amygdala
and OFC functional connectivity within each task, as well as differences in connectivity between tasks
Subjects , and differences in connectivity between masks (exploratory threshold p<.01, uncorrected). •Lateral OFC
•Main effect of reversal: No significant effects
•Healthy volunteers were chosen with no history of medical, neurological, or Results
psychiatic disorders. •Main effect of social: Nonsocial conditions show greater connectivity with substantia
nigra than with social conditions
•Main Effect of Cognitive Condition
Number of Number of % Right •Functional connectivity comparison
Mean Age Figure 7 Functional Connectivity Comparison
Subjects Females Handed •Main effect of reversal: reversal conditions showed greater activation than non-reversal between Lateral and Medial OFC
Between Lateral and Medial OFC
19 11 26 +/- 5 100 conditions in dorsolateral prefrontal cortex (BA 9) and inferior parietal lobule (BA 40). Non-
reversal conditions showed greater activation than reversal conditions in OFC (BA 11) and
a) Connectivity maps collapsed across conditions •Main effect of seed region: The
Task Design superior frontal gyrus (BA 10). Medial Positive> Negative Lateral Positive> Negative medial network shows greater
correlated activation with pons
•Main effect of the social condition: social conditions showed greater activation than nonsocial
and bilateral hippocampus
Figure 2
Experimental Paradigm conditions in bilateral amygdala and fusiform face area.
whereas the orbital network
Acquisition Trial SOCIAL REVERSAL TASK Reversal Trial Connectivity by shows relative increased
Figure 3 Social Condition
Response Response Reversal Cue** Response Main effect of cognitive condition connectivity with the
3.2
brainstem, VTA, thalamus, and
-3.2
Time Reversal > Control Nonreversal > Reversal Social > Nonsocial lateral prefrontal cortical regions
SOCIAL CONTROL TASK Response
** **
Response Response OFC Amygdala b) Comparison between connectivity maps collapsed across
IPL
conditions Conclusions
Time Medial > Lateral
Acquisition Trial Reversal Trial
OBJECT REVERSAL TASK DLPFC
Hippocampus
We observed differential activation in
Response Respon Reversal Cue** Response
se OFC associated with response reversal,
VTA/ Brainstem but the directionality of the effect was
OBJECT CONTROL TASK Time
Response Respon Response unexpected, with less recruitment of this
se
area during reversal conditions. As
Time **
expected, we observed differential activity
FFA
** ** *** in the amygdala associated with social
**
**Bar represents t-values corresponding to p<.01 in positive and negative direction
**Colored t- bars represent t-values corresponding to stimuli.
**Colored bars represents t-values corresponding to p<.001 in positive and negative directions p<.001 in positive and negative directions
•The task was divided into social and nonsocial components. ***Colored t-bars represent t-values corresponding to
•Stimuli for the social component of the task were made up of pairs of emotional p<.01 in positive and negative directions We also observed anatomically distinct
faces (male and female) where the positive cues were smiles and the negative •Interaction of Reversal Condition with Task type: No significant differences were found in OFC patterns of functional connectivity with
cues were frowns. activation in the interaction analysis. OFC and amygdala. While the medial portion of OFC correlated positively with amygdala
•Stimuli for the nonsocial component of the task were comprised of pairs of •A similar pattern of activation was seen in both social and nonsocial reversal over Figure 7
activity, the orbital region was negatively correlated with the region: The extent of the inverse
socially neurtral objects, either shirts or chairs, where the positive cues were control contrasts as in the main effect of reversal contrast. correlation with the amygdala depended on the cognitive domain of the task showing increased
checkmarks and the negative cues were universal “no” symbols. negative connectivity for social stimuli over nonsocial stimuli.
•Functional Connectivity Analysis
•For each component, there were reversal and control conditions The anatomical distinction between medial and lateral OMPFC also appeared to have functional
•Reversal conditions required participants to change their response to a •Bilateral Amygdala relevance within the OMPFC itself related to the cognitive domains of the task. Reversal 3.2 4.0 4.0
•Connectivity map collapsed across conditions: Medial OFC (BA11) shows a pattern of
-4.0
previously reinforced image (a specific face, chair, or house) by selecting conditions showed an increased connectivity between medial OMPFC and the orbital region
-3.2 -4.0
the alternate image of the pair when presented with a negative cue. The positive connectivity across all conditions than nonreversal conditions.
newly selected image was then reinforced with a positive cue on •Lateral OFC (BA 11) and midbrain show a pattern of negative connectivity across all
subsequent acquisition trials. conditions (p<.001) Overall our findings support the anatomical and functional distinctions between orbital and
•Control conditions required maintenance of the response to an initially medial OMPFC made in nonhuman primates and clarify the relationship between OFC and
positively-cued stimulus. The alternate image remained neutral on •Main effect of social:: Nonsocial conditions showed greater negative connectivity with lateral amygdala for socially relevant stimuli1. The inverse functional relationship between Amyg and
subsequent trials. OFC and the region encompassing the substantia nigra as compared with social conditions lateral OFC may be consistent with inhibitory control of OFC over Amyg 4.
Figure 4 Functional Connectivity with Bilateral Amygdala
Task Methods References
a) Connectivity map collapsed across b) Main effect of social
conditions Social Nonsocial 1Ongur,D
•Subjects underwent sixteen scans with approximately 5 minutes between each scan. Positive> Negative Social > Nonsocial A
3
A
3 et al(2000).Cerebral Cortex 20:206-19
Medial Lateral m
2 m 2 2Amaral,D et al(2003).Neuropsychologia 41:235-40
•Scans alternated between the reversal condition and the control condition. The first OFC Lateral SN OFC y1
g0
y 1
g 0
d d 3Kringelbach,ML et al(2003).Neuroimage 2:1371-83
eight scans involved the social component of the task and the second eight scans OFC a-1 a
-1
l -2 l -2 4Ghashghaei,HT et al(2002).Neuroscience 115:1261-79 conditions
involved the nonsocial component of the task. a
-3 6 11
R OFC (28,48,-12)
16
a -3
6 11
R OFC (28,48,-12)
16
PET Methods
1
0.5
0 **
Effect Size
•rCBF was measured with positron emission tomography (PET) on a GE Advance -0.5
Social
Reversal
Social
Nonreversal
Nonsocial
Reversal
Nonsocial
Nonreversal
Midbrain **
(Milwaukee) three-dimensional PET scanner during task performance. -1
***
•Administration of an intravenous bolus of 10 mCi of oxygen-15 water and the cognitive -3.2 4.0 -1.5
** -2
task was continued throughout the subsequent 60-second scan. -3.2 -4.0
Connectivity with amygdala by social condition
**Colored t-bars represents t-values corresponding to p<.001 in positive and negative directions
***Colored t-bars represents t-values corresponding to p<.01 in positive and negative directions