Original Article

Molecular Psychiatry (2009) 14, 946–953; doi:10.1038/mp.2009.40; published online 9 June 2009

Altered connections on the road to psychopathy

M C Craig1,2, M Catani1,2, Q Deeley1, R Latham1, E Daly1, R Kanaan3, M Picchioni3, P K McGuire3, T Fahy4 and D G M Murphy1

  1. 1Section of Brain Maturation, Institute of Psychiatry, De Crespigny Park, London, UK
  2. 2Natbrainlab, Institute of Psychiatry, De Crespigny Park, London, UK
  3. 3Section of Neuroimaging, Institute of Psychiatry, De Crespigny Park, London, UK
  4. 4Department of Forensic Mental Health Science, Institute of Psychiatry, De Crespigny Park, London, UK

Correspondence: Dr MC Craig, Psychological Medicine, Institute of Psychiatry, PO50, 16 De Crespigny Park, Denmark Hill, London SE5 8AF, UK. E-mail: m.craig@iop.kcl.ac.uk

Received 7 August 2008; Revised 25 February 2009; Accepted 13 April 2009; Published online 9 June 2009.

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Abstract

Psychopathy is strongly associated with serious criminal behaviour (for example, rape and murder) and recidivism. However, the biological basis of psychopathy remains poorly understood. Earlier studies suggested that dysfunction of the amygdala and/or orbitofrontal cortex (OFC) may underpin psychopathy. Nobody, however, has ever studied the white matter connections (such as the uncinate fasciculus (UF)) linking these structures in psychopaths. Therefore, we used in vivo diffusion tensor magnetic resonance imaging (DT-MRI) tractography to analyse the microstructural integrity of the UF in psychopaths (defined by a Psychopathy Checklist Revised (PCL-R) score of greater than or equal to25) with convictions that included attempted murder, manslaughter, multiple rape with strangulation and false imprisonment. We report significantly reduced fractional anisotropy (FA) (P<0.003), an indirect measure of microstructural integrity, in the UF of psychopaths compared with age- and IQ-matched controls. We also found, within psychopaths, a correlation between measures of antisocial behaviour and anatomical differences in the UF. To confirm that these findings were specific to the limbic amygdala–OFC network, we also studied two ‘non-limbic’ control tracts connecting the posterior visual and auditory areas to the amygdala and the OFC, and found no significant between-group differences. Lastly, to determine that our findings in UF could not be totally explained by non-specific confounds, we carried out a post hoc comparison with a psychiatric control group with a past history of drug abuse and institutionalization. Our findings remained significant. Taken together, these results suggest that abnormalities in a specific amygdala–OFC limbic network underpin the neurobiological basis of psychopathy.

Keywords:

psychopathy, limbic system, white matter connections, diffusion tensor imaging, tractography

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Introduction

Psychopathic personality disorder (psychopathy) is characterized by features of emotional detachment and antisocial traits,1 and is strongly associated with criminal behaviour and recidivism.2 It has been estimated, for example, that 15% of the prison population are psychopaths and they commit approximately 50% more criminal offences than non-psychopathic criminals.3

The development of reliable and valid methods for diagnosing psychopathy (for example, the Hare Psychopathy Checklist Revised; PCL-R4) in conjunction with brain-imaging techniques is converging towards the identification of neurobiological mechanisms that may underpin psychopathy. Since the report of the case of Phineas Gage,5 who showed ‘acquired sociopathy’ after frontal lobe injury, the orbitofrontal cortex (OFC) and other regions of the prefrontal cortex (PFC) have been considered important for personality and social behaviour.6 For example, OFC is crucial to successful reversal learning (in which previously rewarded stimuli are associated with punishment) and reversal learning is significantly impaired in adult psychopaths7 and in young people with psychopathic traits.8 It has also been reported that violent personality-disordered offenders have reduced PFC grey matter volume9 and glucose metabolism,10 and impaired OFC (and limbic) activation during aversive conditioning.11 In contrast, other researchers have argued that amygdala dysfunction is central to the affective deficits and impaired moral socialization of psychopathy.12 This latter view is supported by evidence that psychopaths show performance deficits in tasks sensitive to amygdala damage,13, 14 and have significantly reduced amygdala volume15 and decreased amygdala activation during verbal learning16 and decreased activity in brain regions modulated by amygdala during facial fear processing.17

More recently, the dichotomy between researchers postulating whether OFC or amygdala dysfunction is central to psychopathy18 has narrowed, and it has been suggested instead that the social and emotional deficits of psychopaths may reflect an interaction between OFC and amygdala dysfunction.19, 20 Analysis of the functional and anatomical links between these structures offers the potential to move beyond theories of regional dysfunction towards a more coherent understanding of the possible brain networks underlying psychopathy. However, to date, nobody has studied the white matter tracts linking these brain regions. The OFC and the amygdala are interconnected by fibres belonging to the uncinate fasciculus (UF), whose volume and integrity can be analysed in vivo using diffusion tensor magnetic resonance imaging (DT-MRI) tractography. This is a non-invasive neuroimaging technique that can be used to reconstruct three-dimensional trajectories of white matter tracts within the living brain,21 and to probe the microstructural integrity of white matter in a wide range of neuropsychiatric conditions.22

We therefore used in vivo DT-MRI to dissect and measure the volume and the microstructural integrity of the UF.21 For each hemisphere, we dissected the fibres of the UF and counted the number of streamlines (SLs) as a surrogate of the tract volume. We also measured the mean fractional anisotropy (FA)—which is an indirect measure of white matter spatial organization and integrity.23 We compared the psychopaths (that is, PCL-R score greater than or equal to2524) with age- and IQ-matched controls. We recruited psychopaths from three specialist forensic inpatient units. All were repeat violent offenders with index offences that included attempted murder, manslaughter, multiple rape with strangulation and false imprisonment.

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Methods

Patients

We studied 18 normal intelligence right-handed adult male volunteers: nine with high PCL-R scores (mean 28.4, range 25–34), aged 34±12 years, with full-scale IQ (FSIQ) 94±7, and nine healthy male controls aged 37±9 years, with FSIQ 91±6. All patients (that is, in both groups) were unmedicated and screened by formal psychiatric semi-structured interview using the ICD-10 research criteria,25 and a review of case notes was carried out to exclude any co-morbid psychiatric illness or neurological/extra-cerebral disorders that might affect brain function.

Most psychopaths had a past history of alcohol and/or substance misuse (polysubstance misuse (n=3), combined polysubstance and alcohol misuse (n=3) and alcohol misuse (n=1)), but none fulfilled the criteria for a substance misuse or dependence disorder within 6 months before scanning, with the exception of one patient who fulfilled the criteria for harmful use of cocaine. Psychopaths were recruited from three specialist forensic inpatient units over a period of 6 years from a group of 34 patients with high PCL-R scores (that is, greater than or equal to25). Sixteen patients initially agreed to participate and nine were suitable for magnetic resonance imaging (MRI). Healthy controls were recruited from the general population through the Institute of Psychiatry, Kings College London, and the absence of psychopathy was confirmed using the Hare Psychopathy Checklist: Screening Version (PCL-SV).26

Ethical approval was obtained from the Ethical Committee of the South London and Maudsley Trust and Institute of Psychiatry, and St Georges Healthcare Trust. After complete description of the study to the patients, written informed consent was obtained.

Neuroimaging and data analysis

Magnetic resonance imaging of the brain was carried out on GE Signa 1.5 Tesla LX MRI system (General Electric, Milwaukee, WI, USA) at the Maudsley Hospital, London.

DT-MRI acquisition
 

Data were acquired with 40mTm−1 gradients, using an acquisition sequence fully optimized for DT-MRI of white matter, providing isotropic resolution (2.5 × 2.5 × 2.5mm) and coverage of the whole head. The acquisition was gated to the cardiac cycle using a peripheral gating device placed on the patients' forefinger. After the correction for image distortions introduced by the application of the diffusion encoding gradients, the diffusion tensor was determined in each voxel following the method of Basser et al.27 The operator (Michael C. Craig) carried out all dissections blind to the diagnosis. Anatomical consistency with classical descriptions of the tracts of interest was confirmed by using neuroanatomy text books and tractography atlases.

Tract reconstructions
 

The trajectories of the UF, inferior longitudinal fasciculus (ILF) and inferior fronto-occipital fasciculus (IFOF) were each reconstructed using an approach that involved dissecting out two regions of interest (ROIs)28 (Figure 1).

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Virtual dissection of the major association pathways connecting to the amygdala and orbitofrontal cortex (OFC). A two-region-of-interest (ROI)-approach was used to carry out virtual dissection of the major association pathways connecting the amygdala and OFC. An anterior ‘frontal’ ROI was defined around the anterior floor of the external capsule in five consecutive axial slices (from MNI −6 to −14). A second ‘temporal’ ROI was defined around the white matter of the anterior temporal lobe in five consecutive axial slices (from MNI −22 to −30). A third ‘occipital’ region was defined in the white matter of the occipital lobe in 10 consecutive axial slices (shown here only from MNI −4 to 4). To dissect the uncinate tract, all fibres passing through the ‘frontal’ and ‘temporal’ regions are shown in yellow. All fibres passing through the frontal and occipital regions are shown in red and correspond to the interior fronto-occipital tract. Finally, all fibres passing through the temporal and occipital regions are shown in green and correspond to the interior longitudinal tract. Dissections were carried out for both hemispheres.

Full figure and legend (328K)

The ILF is a ventral associative bundle with long and short fibres connecting the occipital and temporal lobes.3, 28 The long fibres are medial to the short fibres and connect occipital visual areas to the amygdala and hippocampus. The first (temporal) ROI used to dissect the ILF was defined around the white matter of the anterior temporal lobe, usually on five axial slices. The second (occipital) ROI was defined around the white matter of the occipital lobe, usually on 13–15 slices.

The UF is a ventral anterior associative bundle that connects the anterior temporal lobe (including amygdala and hippocampus) with the medial and lateral OFC. The first (temporal) ROI was defined in the anterior temporal lobe (MNI, −15 to −19), as described for the ILF. The second (external/extreme capsule) ROI was defined around the white matter of the anterior floor of the external/extreme capsule.

The IFOF is a ventral associative bundle that connects the ventral occipital lobe and the OFC. In this occipital course, the IFOF runs parallel to the ILF. On approaching the anterior temporal lobe, the fibres of the IFOF gather together and enter the external capsule dorsally to the fibres of the UF. The first ROI was delineated around the occipital lobe on approximately 13–15 contiguous axial slices in the same manner as the posterior ROI of the ILF. The second region was defined around the external/extreme capsule as described above.

All fibres passing through the temporal and occipital region are shown in light grey and attributed to the ILF. All the SLs passing through the temporal and external/extreme capsule are considered to belong to the UF and are shown in white. Finally, all SLs passing through the occipital and external/extreme capsule are considered to belong to the IFOF.

At the termination of tracking, the FA—a measure that quantifies the directionality of diffusion on a scale from 0 (when diffusion is totally random) to 1 (when water molecules are able to diffuse along one direction only)—were sampled at regular (0.5mm) intervals along the tract (facilitated by the B-spline continuous tensor-field approximation3) and the means computed. We terminated the fibre tracking when the FA fell below an (arbitrary) threshold of 0.15. For each tract, the trajectory obtained was checked to ensure consistency with neuroanatomical atlases by reconstructing in three dimensions.

Analyses of tracts
 

In our initial analysis, we compared the mean number of SL and FA of the UF in psychopaths and controls. We hypothesized that the mean number of SL and FA of the UF in the psychopaths would be significantly less than in the control group.

To test the hypothesis that the FA changes were specific to the UF, we carried out a secondary analysis of the volume and microstructural integrity of connections of two ‘non-limbic’ control tracts connecting the posterior visual areas to the amygdala (through the ILF) and the OFC (through the IFOF). We hypothesized that in these ‘non-limbic’ tracts, there would be no significant between-group differences in the mean number of SL or FA.

We also investigated whether the anatomical differences in the UF of the psychopaths were associated with variation in symptom severity. Early factor analyses of the PCL-R suggested that the two dimensions reflect ‘emotional detachment’ (Factor 1) and ‘antisocial behavior’ (factor 2).29 We therefore correlated anatomical variation with these PCL-R factors within the psychopaths. More recent factor analyses of the PCL-R have also suggested that 18 of the items are underpinned by four factors: Interpersonal (factor 1), Affective (factor 2), Lifestyle (factor 3) and Antisocial (factor 4).30, 31 We therefore correlated anatomical variation with these PCL-R factors within the psychopaths using a ‘two-factor’ and a ‘four-factor’ model.

Finally, as noted above, the psychopaths had a history of substance misuse and institutionalization, and this may have affected the significant difference we found in the UF. Hence, we carried out a post hoc analysis comparing FA in the UF of psychopaths with that in 11 patients who had a past history of alcohol/substance misuse and institutionalized care for psychotic mental illness. These patients did not differ significantly in age (33±6 years), IQ (95±5) or handedness, and were screened to exclude the presence of an Axis II diagnosis (for example, antisocial personality disorder) using the Schedule for Affective Disorders and Schizophrenia, Lifetime version (SADS-L).32

Statistical analysis

Statistical comparisons of the data were carried out using SPSS software (SPSS Inc., Chicago, IL, USA). Student's t-test (two-tailed) for independent samples was used to investigate tract-specific mean group differences in FA and number of SL. Statistical analyses were corrected for multiple comparisons using Bonferroni's correction.

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Results

The psychopath group had a similar number of SLs in the right and left UF compared with age- and IQ-matched controls, but a significantly reduced mean FA in right UF (psychopaths 0.403±0.014, controls 0.435±0.023, P=0.003). There were no differences in the FA of the left UF (psychopaths 0.419±0.027; controls 0.427±0.020, P=0.448) (Table 1, Figure 2).

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Tract-specific measurements of fractional anisotropy (FA) in the psychopathy and control group. Psychopaths had a significantly reduced mean FA in the right UF (P=0.003). There were no differences in the FA of the left UF (P=0.448) or in the FA of two ‘non-limbic’ control tracts: the ILF and IFOF.

Full figure and legend (135K)


There was no significant difference in the number of SLs or FA of the left or right ILF and IFOF (Table 1, Figure 2).

Using a ‘two-factor’ model of psychopathy, we report a significant negative correlation between ‘antisocial behaviour’ (factor 2) scores and total number of SL in the left UF (Pearson's correlation=−0.880, P=0.004) and right UF (Pearson's correlation=−0.884, P=0.004). Using a ‘four-factor’ model, we report a trend towards a negative correlation between antisocial (factor 4) scores and FA and total number of SL in the right UF (Pearson's correlation=−0.797, P=0.058 and Pearson's correlation=−0.794, P=0.059, respectively) and affective (factor 3) scores and total number of SL in the left UF (Pearson's correlation=−0.792, P=0.06) in psychopaths (Table 2).


In our post hoc analysis, comparing psychopaths with patients with an earlier history of substance misuse and institutionalization, the psychopath group had a significantly reduced mean FA in the right UF (psychopaths 0.403±0.014, controls 0.437±0.016, P<0.000). In addition, the mean FA was reduced in the left UF (psychopaths 0.419±0.027, controls 0.460±0.024, P=0.002) and there was no significant difference in the number of SLs or FA of the left or right ILF and IFOF after correction for multiple comparisons.

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Discussion

In summary, we report significantly reduced FA in the right UF of psychopaths compared with age- and IQ-matched controls. Further, within psychopaths, we report associations between measures of antisocial behaviour and anatomical differences in the UF. To confirm that these findings were specific to the limbic amygdala–OFC network, we studied two ‘non-limbic’ control tracts connecting the posterior visual and auditory areas to the amygdala and the OFC, and found no significant between-group differences. In addition, we examined (post hoc) whether our findings could simply be explained by differences in substance misuse and/or institutionalization.

Taken together, our findings suggest that abnormal ‘connectivity’ in the amygdala–OFC limbic network may contribute to the neurobiological mechanisms underpinning the impulsive, antisocial behaviour and emotional detachment associated with psychopathy. This hypothesis is supported by findings of an association between UF dysfunction, impulsivity and reactive aggression. For example, earlier studies have reported (a) UF damage in many cases of Kluver–Bucy syndrome (that is, a disconnection syndrome characterized by aggressive behaviour, loss of normal anger and fear responses, decreased inhibition and other personality changes),33 (b) reduced UF FA in children showing impulsive traits after early severe socio-emotional deprivation34 and (c) reduced functional connectivity between the amygdala and OFC in impulsive aggressive borderline personality-disordered patients.35 It could therefore be argued that our findings are not specific to psychopathy per se; but may underpin antisocial behaviour in general. However, to date, there have been no studies that have specifically analysed the UF in individuals with antisocial personality disorder. Further, post-mortem and DT-MRI studies that have analysed the UF in schizophrenia, that is, another mental illness associated with aggressive and violent behaviour,36 have reported equivocal results.37, 38, 39 However, this is clearly an important issue for future studies to address.

Lesion studies also suggest that executive function and impulse control may be lateralized to the right hemisphere,40 and this might help explain why our main findings were limited to the right UF. Further, the right UF has been reported to play a pivotal role in the recollection of affect-laden autobiographical memory triggered by sensory stimuli (‘ecphory’).41 This relevance of this finding to our study is that psychopaths have been reported to show poorer memory for affect-laden material compared with non-psychopathic offenders42 and healthy controls.43 Therefore, although highly speculative, reduced microstructural integrity of the right UF could contribute to deficits in the processing of emotional autobiographical memory that may underpin psychopathic traits such as shallow affect and lack of empathy.

Finally, it could be argued that a past history of institutionalization, alcohol and/or substance misuse in most psychopaths is responsible for the anatomical differences that we found. Although FA in the white matter of patients with a past history of alcohol misuse has been reported earlier, changes tend to be diffuse and affect multiple tracts rather than being localized to a single tract.44 Further, we carried out a post hoc analysis comparing psychopaths with patients who had a past history of alcohol/substance misuse and institutionalized care. This post hoc analysis confirmed our earlier findings in that the psychopath group still had a significantly reduced mean FA in the right UF.

Thus, in summary, earlier studies support our findings of an association between reduced microstructural integrity of the UF and behavioural traits that characterize psychopathy. However, it remains unclear whether this is because of a primary pathology in the UF white matter, or whether it is secondary to abnormalities in the amygdala and/or the OFC. Further, the biological mechanisms underlying reduced UF microstructural integrity also remain unclear. One possible mechanism may include tract-specific deficits in axonal maturation and/or myelination. This suggestion is based on the fact that FA signal indirectly reflects the degree of myelination and anatomical arrangement of axonal fibres,45 and that the number of SL is an indirect index of tract volume (which may also reduce in proportion with axonal number and/or myelination).

Our study has a number of weaknesses. For example, we only studied a relatively small number of psychopaths, and so our findings need to be replicated in a larger study. However, the difficulties involved with recruiting and scanning our study group cannot be over-emphasized. To control for potential confounds as best as possible, we limited our investigation to a group of psychopaths without co-morbid mental illness, who were off medication and not currently engaging in substance misuse. Nonetheless, the psychopaths we recruited had committed the most serious criminal offences defined by Law (for example, rape, attempted murder, etc.) with minimal guilt or remorse. As predicted, most individuals we identified in this group refused to engage in medical research. In psychopaths who fulfilled the criteria for entering the study, and who agreed to aid our investigation, we then had to negotiate complex security/safety issues. Hence, it is extremely difficult to find/recruit very dangerous psychopaths—especially those who do not have co-morbid mental health problems and/or current drug abuse. These factors contributed to the small sample included in this study and are likely to impede larger studies of this population. Lastly, it is possible that early-onset, longstanding, abnormalities in social interaction may themselves affect brain development. Hence, future studies of neurobiological differences in ‘at-risk’ populations of young individuals that may precede significant violent offending behaviour are also required.

In conclusion, our findings may reconcile the dichotomy suggested by earlier regional-based theories of OFC or amygdala dysfunction18 in psychopathy, and lend support to a network-based model.19, 20 Confirmation of these findings by larger studies may have wider medico-legal implications and may ultimately provide a focus for the development of treatments for psychopathy.

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Conflict of interest

The authors declare no conflict of interest.

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Acknowledgements

We thank Drs Gill Mezey, Dominic Beer, Amory Clarke, Timothea Toulpoulou and John Dowsett for their help in this study.