See	discussions,	stats,	and	author	profiles	for	this	publication	at:	https://www.researchgate.net/publication/271515642 Punishment	and	psychopathy:	A	case-control functional	MRI	investigation	of	reinforcement learning	in	violent	antisocial	personality disordered	men ARTICLE in THE	LANCET	PSYCHIATRY	*	FEBRUARY	2015 DOI:	10.1016/S2215-0366(14)00071-6 CITATIONS 2 READS 929 7	AUTHORS,	INCLUDING: Andy	Simmons King's	College	London 500	PUBLICATIONS 20,250	CITATIONS SEE	PROFILE Veena	Kumari King's	College	London 290	PUBLICATIONS 8,478	CITATIONS SEE	PROFILE Hodgins	Sheilagh King's	College	London 279	PUBLICATIONS 5,966	CITATIONS SEE	PROFILE Nigel	Blackwood King's	College	London 27	PUBLICATIONS 1,382	CITATIONS SEE	PROFILE Available	from:	Nigel	Blackwood Retrieved	on:	13	February	2016 www.thelancet.com/psychiatry Vol 2 February 2015 153 Articles Lancet Psychiatry 2015; 2: 153–60 See Comment page 115 Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, King's College London, London, UK (S Gregory PhD, N Blackwood MD); Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA (Prof R J Blair PhD); Department of Old Age Psychiatry, Institute of Psychiatry, King's College London, London, UK (D ff ytche MD); NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, King's College London, London, UK (A Simmons PhD, Prof V Kumari PhD); and Département de Psychiatrie, Université de Montréal, Montréal, QC, Canada (Prof S Hodgins PhD) Correspondence to: Dr Nigel Blackwood, Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Kings College London, PO Box 23, De Crespigny Park, London SE5 8AF, UK nigel.blackwood@kcl.ac.uk Punishment and psychopathy: a case-control functional MRI investigation of reinforcement learning in violent antisocial personality disordered men Sarah Gregory, R James Blair, Dominic ff ytche, Andrew Simmons, Veena Kumari, Sheilagh Hodgins, Nigel Blackwood Summary Background Men with antisocial personality disorder show lifelong abnormalities in adaptive decision making guided by the weighing up of reward and punishment information. Among men with antisocial personality disorder, modifi cation of the behaviour of those with additional diagnoses of psychopathy seems particularly resistant to punishment. Methods We did a case-control functional MRI (fMRI) study in 50 men, of whom 12 were violent off enders with antisocial personality disorder and psychopathy, 20 were violent off enders with antisocial personality disorder but not psychopathy, and 18 were healthy non-off enders. We used fMRI to measure brain activation associated with the representation of punishment or reward information during an event-related probabilistic response-reversal task, assessed with standard general linear-model-based analysis. Findings Off enders with antisocial personality disorder and psychopathy displayed discrete regions of increased activation in the posterior cingulate cortex and anterior insula in response to punished errors during the task reversal phase, and decreased activation to all correct rewarded responses in the superior temporal cortex. This fi nding was in contrast to results for off enders without psychopathy and healthy non-off enders. Interpretation Punishment prediction error signalling in off enders with antisocial personality disorder and psychopathy was highly atypical. This fi nding challenges the widely held view that such men are simply characterised by diminished neural sensitivity to punishment. Instead, this fi nding indicates altered organisation of the informationprocessing system responsible for reinforcement learning and appropriate decision making. This diff erence between violent off enders with antisocial personality disorder with and without psychopathy has implications for the causes of these disorders and for treatment approaches. Funding National Forensic Mental Health Research and Development Programme, UK Ministry of Justice, Psychiatry Research Trust, NIHR Biomedical Research Centre. Introduction Most violent crimes are committed by a small number of men.1 They display a pattern of antisocial and aggressive behaviour that begins in childhood and remains stable throughout the lifespan. They meet diagnostic criteria for conduct disorder in childhood and for antisocial personality disorder in adulthood. Lifelong patterns of poor decision making, impulsivity, and risk-taking behaviours characterise such men, and persist despite repeated punishments enacted by parents, teachers, and the criminal justice system. Within this population, a subgroup presents with antisocial personality disorder and psychopathy, defi ned by the psychopathy checklist-revised (PCL-R)2 as including callousness, lack of empathy, an interpersonal style involving grandiosity and manipulation of others, and persistent reactive and instrumental aggression. Such individuals show reduced tonic skin conductance and cortisol concentrations, and have diffi culty recognising fear and sadness in the faces of others.3 By contrast, men who have antisocial personality disorder without psychopathy are characterised by emotional lability, mood and anxiety disorders, and reactive aggression.4 Although the two phenotypes emerge early in life, those who develop antisocial personality disorder with psychopathy begin off ending at an earlier age, engage in a broader range and higher frequency of off ending behaviours,4 and respond less well to treatment in childhood5 and adulthood6 than those without psychopathy. The two groups show distinct diff erences in brain structure7 and functional responses to empathy-eliciting scenarios8 and emotional stimuli when engaged in goal-directed behaviour.9 Diagnostic classifi cation systems, however, do not distinguish between antisocial personality disorder with and without psychopathy. Rehabilitation programmes typically exclude off enders with psychopathy. Many decisions, including whether or not to engage in an antisocial act, involve the ability to assess consequences. Selecting an action is dependent on reinforcement learning, whereby possible rewards are weighed against possible punishments on the basis of past experience.10 Men with antisocial personality disorder show impairments in adaptive decision making, characterised by abnormal processing of reinforcement information.11,12 Their Articles 154 www.thelancet.com/psychiatry Vol 2 February 2015 behaviour seems to be driven more by potential rewards than potential punishments (reward dominance). Impaired learning about the consequences of actions might result in overly optimistic and inaccurate predictions of favourable outcomes, resulting in frustration, which could predispose to reactive aggression. Impaired self-control lowers the threshold for aggression in response to such frustration.13 In behavioural studies off enders with antisocial personality disorder and psychopathy have shown notable impairment in using reinforcement information when choosing between punished and rewarded objects in passive avoidance,14 extinction,15 and reversal learning tasks.11,16,17 The failure to use punishment information to signal inappropriate behaviour is thought to be the primary defi cit in psychopathy, and emerges early in childhood.18 Reversal learning tasks examine the ability to adjust behaviour to changes in reinforcement contingency. Studies of healthy adults and adults with brain lesions have identifi ed a neural network recruited during reversal learning.19 The dorsomedial prefrontal cortex, ventrolateral prefrontal cortex, and dorsolateral prefrontal cortex serve, respectively, to allocate attentional resources, assess confl icting responses, and initiate response modulation. The ventromedial prefrontal cortex, posterior cingulate cortex, and dorsal caudate track changes in reinforcement information, reducing activation in response to punishment, thus signalling behavioural error, change in reinforcement contingency (when reward is expected but punishment received), and the need to adapt behaviour.20,21 Little is known about the neural systems serving reinforcement learning anomalies in off enders with antisocial personality disorder with and without psychopathy. Offl ine versions of probabilistic response reversal tasks are self-paced, which means that intervals between the stimulus presentation, response, and feedback vary across trials.11 A variant of this task has been developed for the functional MRI (fMRI) scanning environment that is designed specifi cally to minimise behavioural diff erences between antisocial individuals and normal controls. Importantly, the scanner version of the task provides reinforcement more often and more consistently than the offl ine task. This change lessens task diffi culty and the likelihood of confounding introduced by large diff erences in performance, such as diff erential contamination by error events.22 The scanner version of the task has been used to assess adolescents with conduct disorder and callous unemotional traits,21 which are the childhood antecedents of antisocial personality disorder with psychopathy.5 Compared with healthy teenagers, adolescents who have conduct disorder with callous unemotional traits showed intact recruitment of the dorsomedial prefrontal cortex, dorsolateral prefrontal cortex, and inferior frontal cortices when changing their behaviour in response to punishment signals, but did not appropriately reduce activation of the ventromedial prefrontal cortex. This fi nding was interpreted as intact recruitment of regions involved in response change immediately after punishment, but impairment in regions that alter longterm value associated with responses, thereby increasing the likelihood of future incorrect responding. We used the scanning environment probabilistic response reversal task to do an fMRI study of reinforcement processing and decision making in violent adult off enders with antisocial personality disorder with and without psychopathy. Focusing on responses to punished reversal errors relative to rewarded correct responses, we tested the hypothesis that violent off enders with antisocial personality disorder and psychopathy would show increased activation within the ventromedial prefrontal cortex, caudate, and posterior cingulate cortex to punished reversal errors, as identifi cation of anomalous responding to reinforcement information within such individuals could be useful as a diagnostic biomarker. Materials and methods Participants and study design Between January, 2007, and January, 2011, we enrolled 50 men, aged 20–50 years, with reading age higher than 10 years as defi ned by the Schonell instrument. Eligible participants had no history of major mental disorders (bipolar 1, bipolar 2, major depression, or psychotic disorders), as defi ned by the structured clinical interview for Diagnostic and Statistical Manual of Mental Disorder, fourth edition (DSM-IV), axis I disorders (SCID I), or selfreported neurological disorders, head injury resulting in loss of consciousness for 1 h or longer, severe visual or hearing impairments, or contraindications to MRI. Off enders with convictions for violent crimes (murder, rape, attempted murder, and grievous bodily harm) who met DSM-IV criteria for antisocial personality disorder were recruited via the National Probation Service of England and Wales. Healthy non-off enders were recruited via community websites and from unemployment offi ces. All participants completed diagnostic and PCL-R inter views and authorised access to their criminal records. A cross-cultural validation study23 of the PCL-R demon strated that cutoff scores for psychopathy in men vary between North America (30 of a possible 40 points) and Europe (25 of a possible 40 points). We used a score of 25 as the threshold for psychopathy. We calculated total PCL-R, factor 1 (interpersonal and aff ective traits) and factor 2 (impulsivity and antisocial lifestyle) scores for all participants.7 This study was approved by the Joint South London and Maudsley and the Institute of Psychiatry NHS Research and Ethics Committee. Participants were paid the UK minimum hourly wage for their time and were encouraged to desist from using substances, including alcohol and illicit drugs (appendix), from 2 weeks before and during the study, and use was assessed in urine and saliva samples collected at each session. Measures Forensic psychiatrists did diagnostic interviews in which they assessed participants with SCID I and SCID for axis See Online for appendix Articles www.thelancet.com/psychiatry Vol 2 February 2015 155 II disorders (SCID II) in video-taped interviews. Trained forensic psychiatrists and psychologists administered the PCL-R in interviews, whichwere also video-taped. A random sample of 25% of participants was rerated by a second psychologist to test the intraclass correlation for total scores. All participants completed the Wechsler adult intelligence scale, third edition, and the reactiveproactive aggression questionnaire. Probabilistic response reversal task The scanning environment event-related probabilistic response reversal task assesses the ability to learn (acquisition phase) and alter (reversal phase) stimulusresponse associations as a function of contingency change. Participants were presented with pairs of images (line drawings of animals or furniture) on a screen while in the fMRI scanner and asked to select one. Each choice received positive or negative feedback (gain or loss of points; fi gure 1). To increase task diffi culty, stimulus pairs had reinforcement probabilities of 100:0 (positive or negative feedback was given for 100% of right or wrong selections, respectively) or 80:20 (positive or negative feedback was given for 80% of right or wrong selections, respectively, but swapped for 20% of trials). In the acquisition phase, pairs of images were presented 20 times for the 100:0 condition or 25 times for the 80:20 condition, with each individual image assigned rewarding reinforcement. In the reversal phase, the reinforcement contingency associated with the pair of images then reversed and they were presented a further 20 or 25 times. Running point totals were displayed for each acquisition or reversal trial (appendix). Image acquisition and processing Participants were scanned in a 1*5 T Excite MRI scanner (GE Medical Systems, Hatfi eld, UK), with use of an eightchannel head coil. Four dummy acquisition scans were Figure 1: Schematic of the probabilistic response-reversal task (A) The acquisition phase. (B) The reversal phase. 80:20 reinforcement probability is illustrated, where positive or negative feedback was given for 80% of right or wrong selections, respectively, but was swapped for 20% of trials. Participants selected one of the pair of images and received rewarding or punishing feedback for 25 acquisition trials, after which the contingency was reversed for 25 trials so that previously rewarded images resulted in punishment. A Punished error acquisition Rewarded correct acquisition Rewarded correct acquisition You lose 100 points Total –100 →×01 of 50 → You win 100 points Total 0 →✔02 of 50 → You win 100 points Total 100 →✔03 of 50 → Rewarded correct acquisition Rewarded correct acquisition Rewarded correct acquisition You win 100 points Total 200 →✔04 of 50 → You win 100 points Total 300 →✔05 of 50 → You win 100 points Total 400 →✔06 of 50 → B Punished reversal error Punished correct reversal Rewarded correct reversal You lose 100 points Total 1000 →×26 of 50 → You win 100 points Total 900 →×27 of 50 → You win 100 points Total 1000 →✔28 of 50 → Rewarded correct reversal Rewarded correct reversal Rewarded correct reversal You win 100 points Total 1100 →✔29 of 50 → You win 100 points Total 1200 →✔30 of 50 → You win 100 points Total 1300 →✔31 of 50 → Articles 156 www.thelancet.com/psychiatry Vol 2 February 2015 used to establish steady-state longitudinal magnetisation. For each participant, 192 T2*-weighted images were acquired with a gradient-echo, planar, imaging sequence with repetition time 2500 ms, echo time 40 ms, fl ip angle 90°, and in-plane resolution 3*75 mm2. 25 axial slices of 5 mm thickness with 0*5 mm gaps between were collected. A high-resolution T1-weighted spoiled gradient re-echo image was also acquired, which was used for coregistration and normalisation of the data. 124 slices of 1*6 mm thickness were collected with repetition time 34 ms, echo time 9 ms, fl ip angle 30°, fi eld of view 20 cm, and an acquisition matrix of 256 × 192. Statistical analysis Demographic and clinical variables were compared with two-sample t tests, ANOVA, or χ2 and Fisher's exact tests. To test for diff erences in performance between groups, the percentage of errors and response latency were each assessed with 3 × 2 (group × phase) repeated-measures ANOVA. In the general linear model, we applied seven conditions modelled at the fi rst level for each partici pant: baseline; rewarded correct acquisition; rewarded cor rect reversal; punished correct acquisition; punished correct reversal; punished errors acquisition; punished errors reversal. The numbers of trials within each of these conditions (excluding the motor baseline which was consistent for each block) for each group were also assessed with one-way ANOVA. All analyses were done with SPSS (version 15). Image preprocessing and analyses were done with SPM5 software (running under Matlab 7.0.1 on a UNIX platform). All fMRI time series were realigned, coregistered to the spoiled gradient re-echo image, spatially normalised to the International Consortium for Brain Mapping template image and smoothed with an 8 mm full width at half maximum Gaussian kernel. Movement parameters were included as regressors. At the group level we assessed the contrast in bloodoxygenation-level-dependent (BOLD) responses for punished reversal errors versus rewarded correct responses (rewarded correct acquisition + rewarded correct reversal). One-sample t tests were done to identify punished reversal error and rewarded correct response task systems for each group, with an initial signifi cance threshold of p=0*001 and a familywise error cluster corrected signifi cance threshold of 0*05. The t test values, which were modelled within the SPM factorial design, were calculated to investigate potential diff erences between groups to the punished reversal error and rewarded correct response trials, with an initial signifi cance threshold of p=0*005 and familywise error cluster corrected. We extracted β values from regions of diff erential activation from men with antisocial personality disorder with and without psychopathy by use of the SPM toolbox for illustrative purposes. Finally, a secondary analysis was done to explore whether the observed group diff erences in BOLD contrast between off enders with antisocial personality disorder with and without psychopathy for punished reversal errors versus rewarded correct responses were specifi cally related to the syndrome of psychopathy or could alternatively be explained by antisocial personality disorder symptom severity. Thus, independent correlations between activity during punished reversal errors compared Group Group comparison Post-hoc test NO (n=18) ASPD−P (n=20) ASPD+P (n=12) Statistic p value NO vs ASPD−P NO vs ASPD+P ASPD−P vs ASPD+P Age (years) 34*8 (8*8) 36*8 (7*6) 40*1 (8*9) F2,47=1*39 0*26 1 0*31 0*88 FSIQ score 97*2 (11*0) 91*7 (12*2) 89*8 (11*2) F2,47=1*71 0*19 0*46 0*3 1 Duration of education (years) 12*2 (1*5) 10*5 (0*8) 10*4 (1*2) F2,47=11*43 0*001 0*001 0*001 1 Personality disorder other than ASPD (%) Cluster A 0 10 8*3 1*92 0*45 ** ** ** Cluster B 0 10 8*3 1*92 0*45 ** ** ** Cluster C 0 5 8*3 1*65 0*71 ** ** ** PCL-R score (mean [range]) Total (0–40) 3*4 (0–8) 15*9 (10–24) 28*2 (26–30) F2,45=246*79 0*001 0*001 0*001 0*001 Factor 1 (0–20) 0*6 (0–4) 4*5 (0–11) 9*6 (6–13) F2,45=55*36 0*001 0*001 0*001 0*001 Factor 2 (0–20) 2*3 (0–6) 10*3 (5–15) 15*8 (12–19) F2,45=110*70 0*001 0*001 0*001 0*001 Age at fi rst violent conviction (years) N/A 22*3 (9*9) 17*1 (3*8) t=2*08, df=27 0*05 ** ** ** Number of violent convictions N/A 4*5 (3*2) 7*6 (5*9) t=–1*68, df=15 0*11 ** ** ** Aggression score Total 7*1 (3*6) 15*7 (7*3) 22*9 (12*0) F2,42=13*44 0*001 0*001 0*002 0*22 Proactive 2*0 (2*3) 7*4 (3*9) 13*8 (6*6) F2,42=24*03 0*012 0*001 0*001 0*02 Reactive 5*1 (3*4) 8*3 (5*7) 11*7 (7*0) F2,42=4*91 0*001 0*151 0*027 0*44 Group data are mean (SD) unless stated otherwise. NO=non-off enders. ASPD−P=violent off enders with antisocial personality disorder but not psychopathy. ASPD+P=violent off enders with antisocial personality disorder and psychopathy. FSIQ=full-scale intelligence quotient. PCL-R=psychopathy checklist-revised. N/A=not applicable. Table 1: Sociodemographic, clinical, and behavioural characteristics of participants For the SPM toolbox see http:// marsbar.sourceforge.net// Articles www.thelancet.com/psychiatry Vol 2 February 2015 157 with rewarded correct responses for PCL-R scores and total number of SCID II antisocial personality disorder symptoms in the entire group of off enders with antisocial personality disorder were modelled. Role of the funding source The funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had fi nal responsibility for the decision to submit for publication. Results The three groups did not diff er signifi cantly except for education and PCL-R score (table 1). The off enders with antisocial personality disorder and psychopathy were signifi cantly younger at fi rst conviction than those without psychopathy. They also had higher numbers of convictions for violent crime, but this diff erence was not signifi cant. Signifi cantly more off enders had lifetime diagnoses of alcohol and cocaine dependence than nonoff enders (appendix). Of note, though, the pro portions of off enders with and without psychopathy and with lifetime substance use disorders did not diff er. Intraclass correlation for PCL-R total scores was 0*83. Groups did not diff er signifi cantly for percentage errors (F2,47=1*22, p=0*31) or response latencies (F2,47=0*87, p=0*43) in the acquisition and reversal phases of the task (appendix). For percentage errors, there was an eff ect of phase (F1,47=107*4, p=0*001), with more errors being committed during the reversal phase, but no signifi cant phase-group interaction (F2,47=0*511, p=0*60). For response latencies, an eff ect of phase was seen but was not quite signifi cant (F1,47=3*51, p=0*07), with responses being slower during the reversal phase, but no signifi cant interaction was seen for phase and group (F2,47=0*15, p=0*86). The number of trials for each condition (appendix) and the proportion of trials completed were similar in all groups (p=0*25). Off enders with antisocial personality disorder and psychopathy, compared with those without psychopathy and non-off enders, displayed increased BOLD responses to punished reversal error trials within the bilateral posterior cingulate cortex and precuneus (Brodmann areas 23 and 31). Increased activation was also seen in off enders with psychopathy during punished reversal errors trials in the right anterior insula when compared with off enders without psychopathy, but not non-off enders. A diff erence between off enders with antisocial personality disorder and psychopathy and non-off enders, however, did become evident when a lower cluster-defi ning threshold of p=0*01 was used. Conversely, the antisocial off enders without psychopathy and the non-off enders showed signifi cantly increased BOLD responses during rewarded correct response trials in the right superior temporal gyrus (Brodmann area 22), extending to the anterior middle temporal gyrus (Brodmann area 21) compared with off enders with antisocial personality disorder and psychopathy. No signifi cant diff erences in BOLD activity in either direction were seen between the off enders with antisocial personality disorder but not psychopathy and non-off enders (table 2, fi gures 2, 3). All three groups showed signifi cantly greater activation during punished reversal error trials than during rewarded correct response trials within the ventrolateral prefrontal cortex, dorsolateral prefrontal cortex, and dorsomedial prefrontal cortex. Off enders with antisocial personality disorder with psychopathy and non-off enders also showed signifi cantly greater activity within the inferior parietal lobe during punished reversal error trials than during rewarded correct response trials. Only off enders with antisocial personality disorder and psychopathy showed signifi cantly Brodmann area MNI coordinates Cluster size Z score p value* x y z ASPD+P>ASPD–P, punished reversal errors>rewarded correct responses Left posterior cingulate cortex Posterior cingulate cortex 23 –3 –24 30 818 3*84 0*001 Posterior cingulate cortex 31 0 –39 27 ** ** Precuneus 7 –3 –69 42 ** ** Right posterior cingulate cortex Posterior cingulate cortex 31 6 –45 36 ** ** Precuneus 7 0 –63 36 ** ** Posterior cingulate cortex 23 9 –57 12 ** ** Right anterior insula Inferior frontal gyrus 44 51 3 18 204 3*16 0*044 Insula ** 36 3 0 ** ** Insula ** 33 9 –3 ** ** ASPD+P>non-off enders, punished reversal errors>rewarded correct responses Left posterior cingulate cortex Posterior cingulate cortex 23 –3 –39 27 281 3*47 0*011 Posterior cingulate cortex 31 –3 –63 15 ** ** Posterior cingulate cortex 23 –6 –54 9 ** ** Right posterior cingulate cortex Posterior cingulate cortex 23 3 –54 9 ** ** Precuneus 7 3 –66 33 ** ** Precuneus 7 3 –54 39 ** ** ASPD–P>ASPD+P, rewarded correct responses>punished reversal errors Right superior temporal gyrus Middle temporal gyrus 21 54 –36 –6 211 3*68 0*039 Superior temporal gyrus 21 60 –18 –3 ** ** Superior temporal gyrus 22 45 –21 3 ** ** Non-off enders>ASPD+P, rewarded correct responses>punished reversal errors Right superior temporal gyrus Superior temporal gyrus 22 45 –18 3 251 3*76 0*019 Superior temporal gyrus ** 48 –6 0 ** ** Superior temporal gyrus ** 39 –15 18 ** ** BOLD=blood-oxygenation-level-dependent. ASPD−P=violent off enders with antisocial personality disorder but not psychopathy. ASPD+P=violent off enders with antisocial personality disorder and psychopathy.*Corrected for familywise error. Table 2: Areas with signifi cantly diff erent BOLD responses for the contrast punished reversal error trials versus rewarded correct response trials Articles 158 www.thelancet.com/psychiatry Vol 2 February 2015 greater BOLD responses in the posterior cingulate cortex during punished reversal error trials than during rewarded correct response trials. By contrast, those without psychopathy and non-off enders showed signifi cantly greater activity to rewarded correct response trials than to punished reversal error trials within this region and in the superior temporal gyrus. In off enders with antisocial personality disorder and psychopathy, no regions showed signifi cantly greater activity to rewarded correct response trials than to punished reversal error trials. The results remained unchanged when group comparisons were repeated excluding off enders who had positive urinary drug screens on the day of scanning (appendix). The secondary correlation analyses in off enders showed a positive relation between PCL-R scores and activity within the posterior cingulate cortex region (MNI coordinates x=– 3, y=–66, and z=42, cluster size 323, Z=3*52, p=0*005 corrected) during punished reversal error trials versus rewarded correct response trials. However, no signifi cant relation was seen between the number of SCID II antisocial personality disorder symptoms and activation in this area. Discussion We investigated the neural basis of reversal learning in violent off enders with antisocial personality disorder with and without psychopathy. Off enders with antisocial personality disorder and psychopathy displayed abnormal responding to punishment signals within the posterior cingulate and insula, illustrated by signifi cantly greater BOLD activation to punished reversal errors than to rewarded correct responses in both regions. These diff erences were not related to the number of antisocial per sonality disorder symptoms. Off enders with antisocial personality disorder but not psychopathy and nonoff enders showed signifi cant reductions in activation in the posterior cingulate cortex, and the off enders without psychopathy had signifi cantly reduced activation in the anterior insula. Reversal learning impairments have been robustly identifi ed in children with conduct disorder and callous unemotional traits and in adult men with psychopathy.12,24 In this study, however, we noted no behavioural defi cits, which is consistent with results of the fMRI investigation with the same task in adolescents with conduct disorder and callous unemotional traits.21 In these two fMRI studies, abnormal activations were seen in brain regions signalling prediction errors. Adolescents with conduct disorder and callous unemotional traits showed greater activity within the ventromedial prefrontal cortex to punished reversal errors than did healthy adolescent controls.21 Off enders with antisocial personality disorder and psychopathy, unlike those without psychopathy and non-off enders, showed signifi cantly greater activation within the posterior cingulate cortex to punished reversal errors. Consistent with previous fi ndings in healthy adults, reduced BOLD responses within the posterior cingulate to punished reversal errors compared with those for rewarded correct responses were seen in the off enders with antisocial personality disorder but not psycho pathy and in the non-off enders.19,20 The posterior cingulate cortex plays an important part in altering behaviour in response to an unexpected change.25 Animal and human studies have shown the relevance of this cortex in representing subjective value, particularly in relation to rewards,26 and in error signalling after the omission of an expected reward.27 The posterior cingulate Figure 2: Mean values for the contrast punished reversal errors>rewarded correct responses (A) Bilateral posterior cingulate cortex. (B) Right anterior insula. In these two regions the ASPD+P group showed signifi cantly increased activation to punished reversal errors relative to the two comparison groups. Areas of signfi cantly increased activation in ASPD+P group compared with the ASPD−P group are overlaid on the MNI T1 template. Error bars represent SE. Rew=rewarded correct responses. Pun=punished reversal errors. ASPD−P=antisocial personality disorder without psychopathy. ASPD+P=antisocial personality disorder with psychopathy. Figure 3: Mean values for the contrast rewarded correct responses>punished reversal errors in the right superior temporal gyrus In this region the ASPD−P and the non-off ender groups showed signifi cantly increased activation to rewarded correct responses relative to the ASPD+P group. Error bars represent SE. Rew=rewarded correct responses. Pun=punished reversal errors. ASPD−P=antisocial personality disorder without psychopathy. ASPD+P=antisocial personality disorder with psychopathy. –6*0 –5*0 –4*0 –3*0 –2*0 –1*0 0 2*0 3*0 1*0 Pa ra m et er e st im at es (β ) A Rew Pun –3*0 –2*0 –1*0 0 2*0 3*0 1*0 Pa ra m et er e st im at es (β ) Non-offenders Rew Pun ASPD–P Rew Pun ASPD+P B –3*0 –2*0 –1*0 0 2*0 3*0 1*0 Pa ra m et er e st im at es (β ) Rew Pun Non-offenders Rew Pun ASPD–P Rew Pun ASPD+P Articles www.thelancet.com/psychiatry Vol 2 February 2015 159 typically responds to prediction error in conjunction with the ventromedial prefrontal cortex.27 In previous studies, structural posterior cingulate cortex abnormalities were seen in children with callous unemotional traits28 and some adults with psychopathy,29 but these were not seen in the sample in this study.7 Reduced posterior cingulate cortex responsivity to emotional stimuli,30 including personal moral dilemmas,31 has also been seen in investigations of adults with psychopathy. A white-matter diff usion tensor imaging study of the off enders with antisocial personality disorder and psychopathy from this study revealed reduced fractional anisotropy suggestive of reduced axonal integrity and organisation in the dorsal cingulum, which links the posterior cingulate cortex to the medial prefrontal cortex.32 The fi ndings from this study support the proposition that the representation of reinforcement value is profoundly disturbed in adult men with psychopathy (panel).33 Thus, in adolescents21 and adults, rather than psychpathic traits being associated with decreases in activity within reinforcement-sensitive regions after unexpected punish ment, signifi cantly greater activation within these regions was seen in response to punished trials. This result challenges the notion that individuals with psychopathy are simply insensitive to subjective value, prediction errors, or both.33 Men with psychopathy were sensitive to this infor mation and used it to inform appropriate behavioural change, but processed it in a highly atypical way. This atypical processing was associated with psychopathy but not with the number of antisocial personality disorder symptoms. Replications and further elucidation of this anomalous responding are urgently needed, not least because treatments for psychopathy that increase sensitivity to reinforcement information might be misdirected. Instead, interventions aimed at modifying the subjective value accorded to punishment information, perhaps by focusing attention appropriately, might need to be developed.15 Among the off enders with antisocial personality disorder and psychopathy, a similar abnormality was seen within the anterior insula. The anterior insula is connected to limbic regions, such as the ventromedial prefrontal cortex and amygdala, and is innervated by dopaminergic neurons. This area is involved in motivation and represents context-dependent aversive value and reward and tracks the salience of outcomes, including recognition of errors.34 Insular damage in human beings promotes risky decision-making because of impaired signalling of the probability of aversive outcomes.35 Reductions in grey-matter volume in the insula have been reported in adults with psychopathy,7,29 as have reductions in insula activity during aversive conditioning30 and atypically increased activation in response to empathy-eliciting scenarios.8 Regions involved in representing subjective value, such as the ventromedial prefrontal cortex and posterior cingulate cortex, have been proposed to integrate input from the superior temporal gyrus.36 In this study, off enders with antisocial personality disorder without psychopathy and non-off enders showed signifi cantly greater activity within this region to rewarded correct responses than to punished reversal errors, whereas off enders with antisocial personality disorder and psychopathy showed signifi cantly less activity. These results augment those from previous studies that have suggested structural29 and functional37 abnormalities within the superior temporal gyrus in individuals with psychopathy. More over, they suggest that this dysfunction contributes to defi cits in decision making.36 This study has several limitations. The violent off enders with antisocial personality disorder who participated in the study, like most men with this disorder, had additional personality disorders and current or previous substance use disorders. The proportions of such disorders that could aff ect reversal learning, however, were similar in our two off ender groups. The observed functional diff erences, therefore, cannot simply be attributed to these factors. The use of the contrast of punished reversal errors versus rewarded correct responses cannot distinguish between value representations (contingency tracking) and prediction errors (the amount and valence of surprise associated with feedback on a given trial). The strengths of the study included diagnoses and PCL-R ratings made by trained clinicians, the use of offi cial criminal records to classify participants, and measurement of substance use before the scan. We identifi ed neural dysfunctions in violent off enders with antisocial personality disorder and psychopathy that Panel: Research in context Systematic review We searched PubMed for reports published in English up to Aug 8, 2014, with the search terms ''punishment AND psychopathy", "fMRI AND psychopathy", "response reversal AND psychopathy", "reinforcement learning AND psychopathy'', and "fMRI AND antisocial". We also checked the reference lists of identifi ed reports for relevant publications. We found no studies that had assessed the neural underpinnings of reversal learning in men with antis ocial personality disorder with and without psychopathy. Interpretation We found distinctive neural mechanisms related to the severe impairment in learning from punishment that characterises violent off enders with antisocial personality disorder and psychopathy. Important neurobiological distinctions between men with antisocial personality disorder with and without psychopathy have been theorised. The lack of evidence for such diff erences, however, has led to diagnostic classifi cation schemes that favour a single diagnosis of antisocial personality disorder, which has greatly hindered progress in understanding the causes of subtypes and their optimum treatment. Child diagnostic classifi cation systems specify the developmental precursor of psychopathy, limited prosocial emotions, as an important subgroup within those with conduct disorder. Our fi ndings add to the weight of evidence encouraging similar specifi cations in adult diagnostic schemes to distinguish the syndrome of psychopathy from antisocial personality disorder and to take the subgroups into account when planning rehabilitation programmes. As most violent crimes are committed by men with this early-onset stable pattern of antisocial and aggressive behaviour, interventions that target the specifi c underlying brain mechanisms and eff ect change in the behaviour have the potential to signifi cantly reduce the rate of violent crime. Articles 160 www.thelancet.com/psychiatry Vol 2 February 2015 did not characterise antisocial personality disorder in violent off enders without psychopathy or non-off enders. The important areas of diff erential activity in off enders with antisocial personality disorder and psychopathy were the posterior cingulate cortex and anterior insula, where activity was increased in response to punished reversal errors, which is indicative of dysfunctional prediction error signalling. Additionally, off enders in this group were hyporesponsive to reward information in the superior temporal gyrus, which suggests a failure to consolidate reward information. We have provided further evidence of distinctive neural anomalies that distinguish between individuals with antisocial personality disorder with and without psychopathy. Diagnostic classifi cation schemes, off ender rehabilitation programmes,38 and childhood prevention programmes would benefi t from taking account of this mounting evidence. Contributors RJB, Dff , VK, SH, and NB conceived and designed the study and Dff , VK, SH, and NB obtained funding. SG and NB were responsible for acquisition of data. 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