ORIGINAL ARTICLE

Deficient Fear Conditioning in Psychopathy

A Functional Magnetic Resonance Imaging Study
Niels Birbaumer, PhD; Ralf Veit, PhD; Martin Lotze, MD; Michael Erb, PhD; Christiane Hermann, PhD;
Wolfgang Grodd, MD, PhD; Herta Flor, PhD

Context: Psychopaths belong to a larger group of per- trial or were on parole. The healthy controls were re-
sons with antisocial personality disorder and are char- cruited from the community.
acterized by an inability to have emotional involvement
and by the repeated violation of the rights of others. It Main Outcome Measures: Brain activation based on
was hypothesized that this behavior might be the con- functional magnetic resonance imaging, electrodermal re-
sequence of deficient fear conditioning. sponses, emotional valence, arousal, and contingency rat-
ings.
Objective: To study the cerebral, peripheral, and sub-
jective correlates of fear conditioning in criminal psy- Results: The healthy controls showed enhanced differ-
chopaths and healthy control subjects. ential activation in the limbic-prefrontal circuit (amyg-
dala, orbitofrontal cortex, insula, and anterior cingu-
Design: An aversive differential pavlovian delay condi- late) during the acquisition of fear and successful verbal
tioning paradigm with slides of neutral faces serving as and autonomic conditioning. The psychopaths dis-
conditioned and painful pressure as unconditioned played no significant activity in this circuit and failed to
stimuli. show conditioned skin conductance and emotional va-
lence ratings, although contingency and arousal ratings
Setting: The Department of Medical Psychology at the were normal.
University of Tübingen, Tübingen, Germany.
Conclusion: This dissociation of emotional and cogni-
Participants: Ten male psychopaths as defined by the tive processing may be the neural basis of the lack of an-
Hare Psychopathy Checklist–Revised and 10 age- and edu- ticipation of aversive events in criminal psychopaths.
cation-matched healthy male controls. The psycho-
paths were criminal offenders on bail and waiting for their Arch Gen Psychiatry. 2005;62:799-805

P
SYCHOPATHIC BEHAVIOR IS cient fear conditioning where a formerly
characterized by an inabil- neutral stimulus (conditioned stimulus
Author Affiliations: Institute of ity to have emotional in- [CS]) comes to predict a fear-eliciting
Medical Psychology and volvement with others and stimulus (unconditioned stimulus [US])
Behavioral Neurobiology by repeated violation of the after they have been paired several times.4-6
(Drs Birbaumer, Veit, and
rights of others.1 Psychopaths, who are part The brain circuits underlying the acqui-
Lotze) and Section of
Experimental Resonance of a wider group of persons with antiso- sition and maintenance of conditioned fear
Imaging of the CNS, cial personality disorder, seem to lack the in humans have been the focus of major re-
Department of Neuroradiology ability to anticipate punishment and are search efforts. Imaging studies using posi-
(Drs Erb and Grodd), deficient in autonomic responding, eg, skin tron emission tomography or functional
University of Tübingen, conductance responses (SCRs), in antici- magnetic resonance imaging (fMRI) re-
Tübingen, Germany; pation of threatening events.2 High intel- vealed that the amygdala, anterior cingu-
Department of Clinical and ligence and high socioeconomic status may late, insula, and—less consistently—
Cognitive Neuroscience at the protect psychopaths from developing a prefrontal and cerebellar areas are activated
University of Heidelberg, criminal career and turn them into suc- during the acquisition of a conditioned aver-
Central Institute of Mental
cessful psychopaths who display a high in- sive response in a delay paradigm.7-10 Le-
Health, Mannheim, Germany
(Drs Hermann and Flor); and cidence of reckless, risk-taking, and emo- sions of the orbitofrontal cortex (OFC),
Center of Cognitive tionally insensitive behavior patterns.3 which is part of this frontolimbic cir-
Neuroscience, University of Most psychopaths seem to lack the abil- cuitry, lead to behavioral manifestations
Trento, Trento, Italy ity to predict impending harm from sig- designated “acquired sociopathy,”11,12 char-
(Dr Birbaumer). nals of threat and may thus show defi- acterized by socially inadequate choices and

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 irresponsible behavior. This prefrontal-limbic circuit me- with paired presentations of CS⫹ and US and 16 trials of CS−
diates anticipatory planning and emotion regulation and alone), and extinction (like habituation) that occurred succes-
adjustment, particularly in social contexts, whereas the un- sively. The CS was presented for 7.05 seconds; the US (painful
conditioned responses to diverse aversive stimuli and ab- pressure) lasted for 10 milliseconds and was terminated to-
gether with the CS⫹. The US was applied using a plastic cyl-
stract knowledge about correct responses are largely pre-
inder with a 7-mm diameter and a 12-mm length that was placed
served after lesions form in the described circuit. in a small plastic tube and moved by air pressure. A pneu-
Overactivity of the described neuronal structures should matic device (Dokoh-Pneu, Erlangen, Germany) was used to
lead to pathological fear and avoidance of social situa- adjust the pressure applied on the mechanical stimulator with
tions, and underactivity should lead to behaviors compa- pressure velocities ranging from 2 to 20 m/s. The apparatus was
rable to those observed after these structures have been placed outside the scanner, and a flexible tube was connected
lesioned. to the rigid plastic tube. Stimulation intensity was determined
before the conditioning procedure by increasing the pressure
velocity to a point where the subjects estimated the stimulus
METHODS as moderately unpleasant (4 on a scale in which 1 indicates not
at all unpleasant and 5, extremely unpleasant). The pressure
PARTICIPANTS velocities were not significantly different between the groups
(t18 = 0.50; P = .75). Before each CS, a gray square was dis-
We compared 10 emotionally detached psychopaths with crimi- played for 3.5 or 7 seconds to keep the attention constant and
nal records with 10 healthy control subjects matched for age fixed on the CS. Intertrial intervals were random, with a mean
and education (all men). The mean age of the psychopaths was of 24.5 seconds and a range from 21 to 27 seconds. As a pe-
35.30 years (SD, 5.79 years; age range, 23-41 years) and for the ripheral physiological measure of conditioning, SCRs were ob-
healthy controls, 31.50 years (SD, 7.58 years; age range, 21-41 tained. They were measured at the left foot from the skin above
years). This difference was not significant (t18 =−1.49; P=.16). the abductor hallucis muscle about midway between the proxi-
The mean years of education were 12.80 (SD, 1.69 years; range, mal phalanx of the first toe and a point below the ankle medial
10-15 years) for the psychopaths and 12.60 (SD, 2.37 years; to the sole of the left foot. Silver–silver chloride electrodes and
range, 10-18 years) for the healthy controls. This difference was unibase electrolyte were used. The signal was recorded in an
also not significant (t18 =−0.22; P=.83). The psychopaths con- alternating current mode with an ambulatory digital recorder
sisted of offenders out on bail and waiting for their trial or those (Vitaport II; Becker Meditec, Karlsruhe, Germany) using a sam-
out of jail and on parole; both types were screened from a larger pling rate of 16 Hz. The data were bandpass filtered off-line (cut-
sample using the Psychopathy Checklist–Revised (PCL-R).13 off frequencies, 0.05 and 10 Hz) to reduce signal drifts and MRI
We included only psychopaths with (1) a cutoff score of at least artifacts. The SCRs were defined as the maximum of the SCR
10.5 on the emotional detachment scale of the PCL-R because signal from 1 to 5 seconds (first-interval response) after CS on-
we expected more deficient conditioning in this subgroup than set relative to baseline (mean value 1 second before CS onset).
in that with antisocial characteristics and (2) no comorbid dis- For statistical analysis, SCRs were logarithm transformed
order on Axis I of the DSM-IV14 as assessed by the Structured (log[SCR⫹1]). Emotional valence and arousal (values rang-
Clinical Interview for DSM-IV.15 The mean emotional detach- ing from 1-9; Figure 1) related to the CS were rated after the
ment score was 11.63 (SD, 3.60; range, 10.5-14); mean anti- habituation, first and second half of the acquisition, and ex-
social behavior score, 10.87 (SD, 5.23; range, 3-13); and over- tinction phases using the Self-Assessment Manikin.17 The Self-
all PCL-R score, 24.89 (SD, 5.23; range, 15-31). This is much Assessment Manikin is a nonverbal measure of emotional re-
lower than the values reported for American populations of psy- sponses based on pictograms that were displayed on a video
chopaths but in accordance with the lower values for the Ger- screen. Contingency of the CS and US was assessed after the
man norms.16 Six of the psychopaths also met DSM-IV criteria acquisition phase using a 9-point scale (ranging from com-
for antisocial personality disorder as assessed by the Struc- pletely certain [1] that pain will not follow to uncertain [5] to
tured Clinical Interview for DSM-IV. The healthy controls were completely certain [9] that pain will follow subsequent to the
recruited by newspaper advertisements and posters in public presentation of the CS). These 3 measures served as self-
places and had to be free of any mental disorder. They had scores report indices of conditioning.
of less than 2 on both scales of the PCL-R. None of the partici-
pants was taking psychoactive medication or had a previous
head injury. The healthy controls were paid €30 and the psy- FUNCTIONAL MRI
chopaths were paid €100 to ensure participation of this difficult-
to-recruit group. All participants signed informed consent. The One hundred twenty-seven T2*-weighted echoplanar images
study was approved by the local institutional review board and (32 coronary slices; slice thickness, 4-mm⫹1-mm gap; 48⫻64
adhered to the Declaration of Helsinki. German law does not voxels; in-plane resolution, 3⫻3 mm; field of view, 192 mm;
permit the testing of prison inmates. Because of this con- echo time, 36 milliseconds; acquisition time, 2.97 seconds; ef-
straint and the very stringent inclusion criteria, the data ac- fective repetition time, 3.58 seconds) were acquired during each
quisition spanned more than 2 years. measurement block. The short echo time and the coronal ori-
entation were chosen to minimize susceptibility artifacts in the
EXPERIMENTAL DESIGN orbitofrontal and temporal regions. Four blocks were mea-
sured for each subject. In addition, a T1-weighted 3-dimen-
Neuroimaging was performed during classic aversive differen- sional data set consisting of 128 sagittal slices (slice thickness,
tial delay conditioning. Photographs of 4 male neutral faces (2 1.5 mm; matrix, 224⫻256; field of view, 250 mm; repetition
with and 2 without a mustache) served as the CS, with ran- time, 9.7 milliseconds) was acquired.
dom assignment of the mustached and mustacheless faces to During each CS⫹ and CS− presentation, the entire brain was
the CS followed by the US (CS⫹) and to the CS never fol- scanned twice, and 1 scan was performed during the US pre-
lowed by the US (CS−) (Figure 1). The conditioning proce- sentation using a 1.5-T Vision whole-body MRI (Siemens AG,
dure consisted of the following 3 phases: habituation (8 CS⫹ Erlangen) equipped with a head coil. During the scans, the faces
and CS− presentations in random order), acquisition (16 trials were presented on a liquid crystal display video projector. An

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 A B Healthy Controls
9 CS+
Valence CS–
CS +/– Psychopaths
8
CS+
CS–
7

SAM Rating
5

2
US
CS+ 1
Hab AC1 AC2 Ext

9
Arousal

CS–
7

0 3.5 7 10.5 14 17.5 21 24.5 6

SAM Rating
Time, s
5
Onset Gray Square
Onset CS 4
Onset US
3

1
Hab AC1 AC2 Ext

C
9 Contingency Healthy Controls 1.2
SCRs
Psychopaths
8 1.0

7 0.8

6 0.6
log (1 + SCR), µs

0.4
Rating

5
0.2
4
0.0
3
–0.2
2
–0.4
1
–0.6
CS+ CS– Hab AC1 AC2 Ext

Figure 1. A, Schematic illustration of the experimental design showing 2 different trials. Each scan lasted for 3.5 seconds. The onset of each trial (time 0, onset
gray square) was synchronized with the scanner. One presented face (mustached or mustacheless) served as the conditioned stimulus (CS) followed by the
unconditioned stimulus (US) (CS⫹ condition) or as the CS never followed by the US (CS− condition). During the acquisition phase, half of the CSs (CS⫹) were
followed by the US in a pseudorandomized order (100% reinforcement). The US terminated together with the CS⫹ 50 milliseconds after the beginning of the third
scan relative to CS onset. Before the presentation of each face, a gray square was displayed for 3.5 to 7.0 seconds to keep the attention of the subjects focused.
B, Subjective ratings to the CS⫹ and CS− for valence, arousal, and skin conductance responses (SCRs) across all phases (habituation [Hab], early acquisition
[AC1], late acquisition [AC2], and extinction [Ext]) for both groups. The data indicated successful conditioning on the subjective and peripheral level in healthy
control subjects but not in the psychopaths. SAM indicates Self-Assessment Manikin. For the valence rating scale, 1 indicates pleasant; 9, unpleasant. For the
arousal rating scale, 1 indicates arousing; 9, calm. C, Contingency ratings to the CS⫹ minus the CS− for the 2 groups. For the contingency rating scale, 1
indicates completely certain that pain will not follow the presentation of the CS; 9, completely certain that pain will follow the presentation of the CS. Both groups
were able to differentiate between CS⫹ and CS−.

adjustable mirror above the eyes allowed direct view. Data pre- a rigid body spatial transformation (head movements were
processing and statistical evaluation were performed using smaller than 1.5 mm in all subjects). Preprocessing included
SPM99 software (Wellcome Department of Imaging Neurosci- spatial realignment, slice time correction, normalization into
ence, London, England). The first 5 scans were excluded from Montreal Neurological Institute space, and spatial (full-width
the analyses to eliminate T1 saturation effects. The remaining at half-maximum, 15-mm) smoothing. Normalization was per-
122 scans were realigned to the first image of the session using formed in 2 steps (using default values in SPM99). First, the

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 Table 1. Differential Activations (CSⴙ vs CS−) During Conditioning in Healthy Control Subjects and Psychopaths

Region MNI Coordinates T Contrasts P Value

Healthy controls*
Habituation No differential activations
Acquisition
Insula left −36, 3, −12 6.01 .01†
Anterior insula right 36, 12, −15 5.38 .01†
Caudal anterior cingulate −3, 9, 39 6.55 .03†
Rostral anterior cingulate −3, 33, −3 4.97 .03†
Posterior cingulate 3, 18, 39 9.32 .003†
Anteromedial orbitofrontal left −24, 30, −12 5.98 .04†
SII left −60, −27, 33 6.52 .002†
SII right 51, −42, 24 11.23 .001†
SMA 12, 3, 69 6.18 .02†
Amygdala left −27, 3, −18 4.46 .03†
Interaction (CS type ⫻ early/late acquisition) effect
Amygdala right 27, 3, −27 5.79 .004‡
Anterolateral left OFC −36, 57, −3 5.05 .008‡
Ventromedial OFC 0, 57, −9 4.05 .01‡
Extinction No differential activations
Psychopaths
Habituation No differential activations
Acquisition
Amygdala right 21, 6, −18 5.27 .02†
Extinction No differential activations

Abbreviations: AC1, early acquistion; AC2, late acquistion; CS, conditioned stimulus; CS−, CS never followed by the unconditioned stimulus; CS⫹, CS followed
by the unconditioned stimulus; MNI, Montreal Neurological Institute; OFC, orbitofrontal cortex; SII, secondary somatosensory cortex; SMA, supplementary motor
area.
*Early/late interaction corresponds to the contrast [(CS⫹AC1) − (CS−AC1)] − [(CS⫹AC2) − (CS−AC2)].
†Corrected for the expected amount of false-positive findings among suprathreshold voxels of the predefined regions using the atlas of Tzourio-Mazoyer et al.19
‡Corrected for the expected amount of false-positive findings among suprathreshold voxels in a sphere of 10 mm around the maximally activated voxel within
the predefined regions.

values of a 12-parameter affine transformation were deter- analysis using a 1-sample t test. Comparisons between groups
mined followed by an iterative nonlinear parameter estima- were performed using a 2-sample t test.
tion using 7 ⫻ 8 ⫻ 7 basis functions (T1 image to T1 tem- Based on a priori anatomical hypotheses,7,8 the cingulate cor-
plate). The resulting parameters were then used to reslice the tex, insular cortex, supplementary motor area, amygdala, OFC,
functional images. and secondary somatosensory cortex were analyzed. P values
are corrected for the regions of interest using a mask based on
DATA ANALYSIS the anatomical borders of the atlas of Tzourio-Mazoyer et al19
in case of the within-subject analyses for both groups. For the
We chose a linear model approach to estimate hemodynamic between-subject comparison, we used a less conservative cri-
response amplitudes. Boxcar functions convolved with a syn- terion, chosing a spherical region of interest (10 mm) located
thetic hemodynamic response function were used to model he- on the highest activated voxel within these predefined re-
modynamic responses to the visual and pain stimuli. The de- gions. To reduce type I error, a method that corrects for the
rivative of the hemodynamic response and the (first-order) rigid false discovery rate20 was applied to suprathreshold voxels
body transformation parameters (translation and rotation) were (Table 1 and Table 2). Statistical maps were thresholded at
used as additional regressors. The following 3 different event P⬍.05.
types were defined: CS⫹ and CS− as covariates of interest and The self-report and SCR data were analyzed by means of re-
the gray squares as confound. The epoch lengths for CS⫹ and peated-measures analyses of variance (ANOVA) with the groups
CS− were 2 scans. During acquisition, the US presentation was (psychopaths and healthy controls) as between-group factors
used as an additional regressor. We performed t contrasts be- and the phases (habituation, acquisition, and extinction) and
tween CS⫹ and CS− to identify regions with a greater re- CS type (CS⫹ vs CS−) as within-group factors. Because of the
sponse to the CS⫹ as compared with the CS− separately for varying scanner artifact, SCRs were available for 5 psycho-
each phase and group. Based on publications7,8,18 demonstrat- paths and 7 healthy controls.
ing a rapid habituation of the responses in the amygdala dur-
ing conditioning, we investigated the early (first-half ) and late RESULTS
(second-half ) acquisition phases and the interaction between
early and late acquisition for all brain regions separately. Each
subject’s data set was high-pass filtered (cutoff period, 151 sec- SELF-REPORT INDICES OF CONDITIONING
onds) to remove low-frequency drifts. We performed random-
effects analyses by computing a mean subject-specific func-
tional image for the CS⫹/CS− contrast in each conditioning Both groups displayed a conditioned response for arousal
phase (habituation, acquisition, and extinction). These indi- and contingency ratings and clearly differentiated CS⫹
vidual contrast images were then entered into a second-level and CS− (Figure 1B). However, the psychopathic group

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 failed to show a differential response in the emotional
valence ratings. For valence, CS type (F1,18 =4.72; P=.04), Table 2. Differential Activation to CSⴙ vs CS− in the Healthy
CS type⫻phase (F3,16 =5.91; P=.006), and CS type⫻group Control Subjects Minus the Psychopaths*
(F1,18 =5.06; P= .04) were significant, indicating that the
MNI P
CS⫹ was rated as significantly more aversive specifi- Region Coordinates T Contrast Value
cally in the acquisition phase only by the healthy con-
Habituation No differential
trols (P=.01) and not by the psychopaths (P= .53). The activations
arousal ratings yielded a significant CS type (F1,18 =14.76; Acquisition
P⬍.001), phase (F3,16 =5.70; P=.008), and CS type⫻phase SII right −51, −45, 15 5.46 .003†
effect (F3,16 =3.60; P = .04) with arousal ratings being sig- Amygdala left −18, 6, −24 3.76 .04†
nificantly higher in the CS⫹ condition in the early Insula right 33, −6, 15 3.72 .03†
(P=.005) and the late (P = .03) acquisition phase. Con- Rostral anterior cingulate 3, 30, 3 3.29 .045†
Acquisition 2nd half:
tingency yielded a significant CS type effect (F1,18 =250.98;
Ventromedial 15, 24, −12 3.40 .04†
P⬍.001), with the CS⫹ eliciting higher contingency rat- orbitofrontal cortex
ings than the CS− without a significant group differ- Extinction No differential
ence. A marginally significant group ⫻ CS type effect activations
(F1,18 =4.25, P= .05) emerged, which, however, was not
accounted for by significant group differences in per- Abbreviations: CS, conditioned stimulus; CS−, CS never followed by the
unconditioned stimulus; CS⫹, CS followed by the unconditioned stimulus;
ceived contingency for either CS⫹ (P=.3) or CS− (P=.07). MNI, Montreal Neurological Institute; SII, secondary somatosensory cortex.
*Tested by means of the 2-sample t test.
CONDITIONED SCRS †Corrected for the expected amount of false-positive findings among
suprathreshold voxels in a sphere of 10 mm around the maximally activated
voxel within the predefined regions.
The overall ANOVA for SCRs yielded a significant CS type
(F1,10 = 4.49; P = .05) and a trend toward a significant
phase⫻CS type effect (F3,8 =3.35; P=.06) as well as a sig-
(Figure 2 and Table 2), as well as the right ventromedial
nificant CS type⫻group effect (F1,10 =8.00; P=.02), indi-
OFC in the second half of the acquisition phase (early/
cating that SCRs increased to the CS⫹ in the acquisition
late acquisition⫻ CS type; Table 2). An analysis of the
phase only in the healthy controls and not in the psycho-
self-reported, peripheral, and hemodynamic brain re-
paths (Figure 1C). When the healthy controls were en-
sponses to the US indicated no significant group differ-
tered into a separate analysis, a significant CS type effect
ences (all P⬎.20), suggesting that the response to bio-
emerged (F1,6 =13.29; P=.01); the CS⫹ compared with the
logically significant stimuli was equal for both groups.
CS− elicited a significantly higher SCR in the first half of
the acquisition phase (t6 =2.50; P=.05). In addition, the
increase in responding from the habituation to the acqui- COMMENT
sition phases was significant for CS⫹ (t6 =2.83; P=.03).
None of these effects was significant for the psychopaths. The data from the healthy controls confirm that fear con-
ditioning involves the amygdala, OFC, anterior cingu-
fMRI DATA IN THE HEALTHY CONTROLS late, and anterior insula. Activation within the second-
AND PSYCHOPATHS ary somatosensory cortex may be related to the processing
of painful stimulation and interoceptive signals,21-23 and
During acquisition, the healthy controls showed signifi- that of the supplementary motor area to a preparatory
cant activation of the frontolimbic circuit involved in emo- defense response.9,10 The psychopaths were signifi-
tional learning (CS⫹/CS− differentiation; Table 1). The cantly different from the healthy controls in their acti-
brain circuit involves the left amygdala, left anterome- vation in all brain regions. The amygdala and the
dial OFC, anterior and posterior cingulate, right ante- OFC11,24,25 have been implicated in deficits in emotional
rior and left middle insula, supplementary motor area, processing observed in psychopaths. In our study, the
and secondary somatosensory cortex bilaterally. A time- healthy controls showed sustained activation of the left
dependent CS⫹-related response showing more activa- amygdala throughout the acquisition phase, whereas the
tion in the first compared with the second part of the ac- psychopaths displayed only right amygdala activation. In
quisition phase was found in the right amygdala and in the direct comparison, the left amygdala of the psycho-
the medial and lateral OFC (early/late acquisition⫻ CS paths was significantly less active than that of the healthy
type [where early vs late corresponds to the contrast controls when learning occurred. There have been sug-
[(CS⫹AC1)−(CS−AC1)]−[(CS⫹AC2)−(CS−AC2)]. See aster- gestions of differential activations of the right and left
isk footnote to Table 1.]) (Figure 2 and Table 1). The amygdala related to different types of stimulus process-
psychopaths showed no significant changes related to dif- ing26,27; however, methodological problems in most of the
ferential conditioning in these brain regions except for studies do not permit firm conclusions.28 It is conceiv-
a small activation in the right amygdala (Table 1). A di- able that the psychopaths acquired some knowledge about
rect comparison between the CS⫹/CS− differentiation of the association of the CS and US but never processed the
the psychopaths and healthy controls during acquisi- emotional significance of the association, as seen in the
tion showed significantly less activation in the left amyg- lack of a conditioning effect in the emotional valence rat-
dala, left middle and right anterior insula, anterior cin- ings and the deficient anticipatory SCRs. However, they
gulate, and right secondary somatosensory cortex showed intact cognitive stimulus processing as indi-

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 A B C D
Healthy Controls Psychopaths Healthy Controls Minus Psychopaths Healthy Controls, Early/Late

+33 R +33 R +30 R –27 R

6
5
4
3
–12 –15 –12 2
1
0

8 6
5
6
R R R 4 –9 R
4 3
–18 –18 –24 2
2
1
0 0

R R R

–18 –18 –24

R R R

Figure 2. Activation clusters for the contrast conditioned stimulus (CS) followed by the unconditioned stimulus (US) (CS⫹ condition) minus the CS never
followed by the US (CS− condition) during acquisition for the healthy control subjects (A), the psychopaths (B), the comparison of healthy controls minus
psychopaths (C), and the comparison of early minus late acquisition in the healthy controls (D) projected on the normalized mean anatomical image of the
corresponding group. All images were thresholded at P⬍.01 (uncorrected for visualization). A, Controls revealed differential conditioning in the anterior cingulate,
anterior insula, and the left amygdala (as well as the secondary somatosensory cortex and supplementary motor area, not shown here). B, Psychopaths showed a
small differential activation in the right amygdala only. C, The comparison healthy controls minus psychopaths revealed significant differences within the rostral
anterior cingulate, anterior insula (top), and left amygdala (bottom). The ventromedial orbitofrontal cortex (middle) was differentially activated between groups
during the second acquisition phase. D, The right amygdala (middle right) and the ventromedial orbitofrontal cortex (bottom right) were significantly more
activated in the early compared with the late acquisition phase.

cated by the differential contingency ratings. This is in in emotional responses, ie, new decisions are possible by
accordance with previous work supporting the notion of reviving the emotional somatic markers in the orbitofrontal-
“cold” emotional processing devoid of true (emphatic) limbic-postcentral circuit. The lack of amygdalar, orbito-
emotional involvement leading to “myopia for the fu- frontal, and limbic brain responses in the psychopaths is
ture” in psychopaths.4,5,24,25,29-31 in accordance with the results of several positron emis-
Activation of the OFC has been associated with the an- sion tomography and fMRI studies in antisocial person-
ticipation of punishment and reward and the ability of re- ality disorder or psychopathy that reported decreased pre-
versal learning in the face of changing reinforcement con- frontal blood flow, or with those of structural MRI studies
tingencies as well as social cognition in general.24,25,29,30,32-34 that showed reduced prefrontal volume.37,38
The interaction of the amygdala and OFC seems to be cru- Activation in the anterior and middle insula indicates
cial for encoding expected outcomes during learning as emotional processing of anticipated pain and anticipa-
well as producing conditioned SCRs.33,35,36 Our data show tory anxiety and has been implicated especially in aware-
that the psychopaths lack OFC activation, especially in the ness of threat stimuli and associated body states.39-41 These
second half of the acquisition phase when the learned as- processes were absent in the psychopaths. The rostral and
sociation needs to be translated into behavioral respond- caudal anterior cingulate were also differentially active to
ing. Lesions in the ventromedial OFC have been associ- CS⫹ and CS− and showed deficient activation in the psy-
ated with deficient somatic markers.11,12 The “somatic chopaths. Activation in the rostral anterior cingulate cor-
marker” hypothesis stands in the James-Langian tradi- tex, a region that is closely connected with the amygdala,
tion of ascribing feedback from the autonomic, musculo- has been associated with emotional stimulus content, and
skeletal, and endocrine systems to the cortical somato- the dorsal anterior cingulate cortex has been connected
sensory areas, limbic system, and OFC with a critical role to attentional processes and stimulus expectancy.42,43 Thus,

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faces.44 This inability to emotionally relate neutral and bio- individuals? Neuropsychologia. 2002;40:2013-2022.
logically significant events rather than a lack of response 25. Blair RJR. Neurobiological basis of psychopathy. Br J Psychiatry. 2003;182:5-7.
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to biologically relevant stimuli in general may be at the in the human amygdala. Nature. 1998;393:467-470.
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Submitted for Publication: May 28, 2004; final revision 30. Blair RJR, Cipolotti L. Impaired social response reversal: a case of “acquired
received August 22, 2004; accepted October 7, 2004. sociopathy.” Brain. 2000;123:1122-1141.
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Correspondence: Herta Flor, PhD, Department of Clini- ditioning in psychopaths: peripheral and central correlates. Psychophysiology.
cal and Cognitive Neuroscience at the University of Heidel- 2002;39:505-518.
32. Soderstrom H, Hultin L, Tullberg M, Wikkelson C, Ekholm S, Forsman A. Re-
berg, Central Institute of Mental Health, J5, D-68159 Mann- duced frontotemporal perfusion in psychopathic personality. Psychiatry Res. 2002;
heim, Germany ([email protected]). 114:81-94.
Funding/Support: This study was supported by grants 33. Bechara A, Damasio H, Damasio AR, Lee GP. Different contributions of the hu-
man amygdala and ventromedial prefrontal cortex to decision-making. J Neurosci.
FL156/17 and SFB 437 from the Deutsche Forschungsge- 1999;19:5473-5481.
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